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WO2025096666A1 - Formes solides d'antagonistes de hpk1 - Google Patents

Formes solides d'antagonistes de hpk1 Download PDF

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Publication number
WO2025096666A1
WO2025096666A1 PCT/US2024/053733 US2024053733W WO2025096666A1 WO 2025096666 A1 WO2025096666 A1 WO 2025096666A1 US 2024053733 W US2024053733 W US 2024053733W WO 2025096666 A1 WO2025096666 A1 WO 2025096666A1
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compound
diffraction pattern
ray powder
powder diffraction
peaks
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Jon P. Lawson
Stuart Levy
Avinash S. Phadke
Osama SULEIMAN
Emma GREEN
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Nimbus Saturn Inc
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Nimbus Saturn Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/10—Succinic acid
    • 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
    • C07C57/15—Fumaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/255—Tartaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/04—Monocyclic monocarboxylic acids
    • C07C63/06—Benzoic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the MAP4Ks family includes MAP4Kl/HPK1, MAP4K2/GCK, MAP4K3/GLK, MAP4K4/HGK, MAP4K5/KHS, and MAP4K6/MINK.
  • HPK1 is a tissue ⁇ specific upstream activator of the MEKK/JNK/SAPK signaling pathway.
  • HPK1 is of particular interest because it is predominantly expressed in hematopoietic cells such as T cells, B cells, macrophages, dendritic cells, neutrophils, and mast cells (Hu, M.C., et al., Genes Dev, 1996.10(18): p.2251-64; Kiefer, F., et al., EMBO J, 1996.15(24): p.7013-25). HPK1 kinase activity has been shown to be induced upon activation of T cell receptors (TCR) (Liou, J., et al., Immunity, 2000.12(4): p.
  • TCR T cell receptors
  • BCR B cell receptors
  • TGF-PR transforming growth factor receptor
  • EP2 and EP4 Gs-coupled PGE2 receptors
  • HPK1 is also an example of a negative regulator of dendritic cell activation, and T and B cell responses that can be targeted to enhance anti-tumor immunity.
  • HPK1 is expressed predominantly by hematopoietic cells, including early progenitors. In T cells, it is believed that HPK1 negatively regulates T cell activation by reducing the persistence of signaling microclusters by phosphorylating SLP76 at Ser376 (Di Bartolo et al.
  • HPK1 can also become 3 2197122.1 Page 1 of 214 398110-82HPWO (213249) activated in response to prostaglandin E2, which is often secreted by tumors, contributing to the escape of tumor cells from the immune system.
  • HPK1 is important in regulating the functions of various immune cells and it has been implicated in autoimmune diseases and anti-tumor immunity (Shui, J.W., et al., Nat Immunol, 2007.8(1): p.84-91; Wang, X., et al., J Biol Chem, 2012.287(14): p.11037-48).
  • FIG.1 depicts an XRPD diffractogram of Form 1 of Compound 1.
  • FIG.2 depicts an HNMR and LCMS spectrums of Form 1 of Compound 1.
  • FIG.3 depicts an XRPD diffractogram of Form 2 of Compound 1.
  • FIG.4 depicts an XRPD diffractogram of Form 3 of Compound 1.
  • FIG.5 depicts an XRPD diffractogram of Form 4 of Compound 1.
  • FIG.6 depicts an XRPD diffractogram of Form 1 of Compound 2.
  • FIG.7 depicts an XRPD diffractogram of Form 1 of Compound 3.
  • FIG.8 depicts an XRPD diffractogram of Form 2 of Compound 3.
  • FIG.9 depicts an XRPD diffractogram of Form 1 of Compound 4.
  • FIG.10 depicts an XRPD diffractogram of Form 2 of Compound 4.
  • FIG.11 depicts an XRPD diffractogram of Form 1 of Compound 5.
  • FIG.12 depicts an XRPD diffractogram of Form 2 of Compound 5.
  • FIG.13 depicts an XRPD diffractogram of Form 1 of Compound 6.
  • FIG.14 depicts an XRPD diffractogram of Form 2 of Compound 6.
  • FIG.15 depicts an XRPD diffractogram of Form 1 of Compound 7.
  • FIG.16 depicts an XRPD diffractogram of Form 2 of Compound 7.
  • FIG.17 depicts an XRPD diffractogram of Form 3 of Compound 7.
  • FIG.18 depicts an XRPD diffractogram of Form 4 of Compound 7.
  • FIG.19 depicts an XRPD diffractogram of Form 1 of Compound 8. 3 2197122.1 Page 2 of 214 398110-82HPWO (213249)
  • FIG.20 depicts an XRPD diffractogram of Form 2 of Compound 8.
  • FIG.21 depicts an XRPD diffractogram of Form 3 of Compound 8.
  • FIG.22 depicts an XRPD diffractogram of Form 1 of Compound 9.
  • FIG.23 depicts an XRPD diffractogram of Form 2 of Compound 9.
  • FIG.24 depicts an XRPD diffractogram of Form 3 of Compound 9.
  • FIG.25 depicts an XRPD diffractogram of Form 1 of Compound 10.
  • FIG.26 depicts an XRPD diffractogram of Form 2 of Compound 10.
  • FIG.27 depicts an XRPD diffractogram of Form 3 of Compound 10.
  • FIG.28 depicts an XRPD diffractogram of Form 4 of Compound 10.
  • FIG.29 depicts an XRPD diffractogram of Form 1 of Compound 11.
  • FIG.30 depicts an XRPD diffractogram of Form 1 of Compound 12.
  • FIG.31 depicts a DSC-TGA overlay of Form 1 of Compound 5.
  • FIG.32 depicts a DSC-TGA overlay of Form 1 of Compound 6.
  • FIG.33 depicts a DSC-TGA overlay of Form 2 of Compound 6.
  • FIG.34 depicts a DSC-TGA overlay of Form 1 of Compound 7.
  • FIG.35 depicts a DSC spectrum of Form 1 of Compound 7.
  • FIG.36 depicts a DSC-TGA overlay of Form 1 of Compound 9.
  • FIG.37 depicts a DSC spectrum of Form 1 of Compound 9.
  • FIG.38 depicts a DSC-TGA overlay of Form 1 of Compound 10.
  • FIG.39 depicts a DSC-TGA overlay of Form 2 of Compound 10.
  • FIG.40 depicts a DSC-TGA overlay of Form 1 of Compound 11.
  • FIG.41 depicts a DSC-TGA overlay of Form 1 of Compound 12.
  • FIG.42 depicts a DSC-TGA overlay of Form 1 of Compound 7.
  • FIG.43 depicts a DSC-TGA overlay of Form 2 of Compound 9.
  • FIG.44 depicts a DSC-TGA overlay of Form 3 of Compound 10.
  • FIG. 45 depicts a view of Form 1 of Compound 7 monohydrate from the crystal structure showing the atom numbering scheme. Anisotropic atomic displacement ellipsoids for the non-hydrogen atoms are shown at the 50% probability level.
  • FIG.46 depicts a simulated XRPD diffractogram of Form 1 of Compound 7 monohydrate.
  • FIG.47 depicts a simulated XRPD diffractogram of Form 1 of Compound 1-1. DETAILED DESCRIPTION OF THE INVENTION 1.
  • Compound 1 is designated I-479 and its synthesis is described in Example 21 of WO 2021/050964, the entirety of which is herein incorporated by reference. [0056] It would be desirable to provide a solid form of Compound 1 (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 and salt forms of Compound 1. Free Base Forms of Compound 1 [0057] 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.
  • the present disclosure provides a form of Compound 1 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 1, 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 a form of Compound 1 is present.
  • at least about 99% by weight of a form of Compound 1 is present.
  • a form of Compound 1 is present in an amount of at least about 3 2197122.1 Page 4 of 214 398110-82HPWO (213249) 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • a form of 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.
  • a form of 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.
  • a form of Compound 1 is present with an enantiomeric excess (i.e., ee) of at least 95%, preferably more than 96%, 97%, 98%, 99%, or 99.5% ee. In some embodiments, a form of Compound 1 is present in more than 95% ee.
  • a form of Compound 1 is present in more than 96% ee. In some embodiments, a form of Compound 1 is present in more than 97% ee. In some embodiments, a form of Compound 1 is present in more than 98% ee. In some embodiments, a form of Compound 1 is present in more than 99% ee. In some embodiments, a form of Compound 1 is present in more than 99.5% ee. [0061] The structure depicted for a form of 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.
  • Compound 1 can exist in a variety of solid forms. Exemplary such forms include polymorphs such as those described herein.
  • polymorph refers to the different crystal structures into which a compound, or a salt or solvate thereof, can crystallize.
  • Compound 1 is a crystalline solid. In other embodiments, Compound 1 is a crystalline solid substantially free of amorphous Compound 1.
  • 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. [0065] It has been found that the Compound 1 can exist in at least four distinct polymorphic forms. In certain embodiments, the present disclosure provides a polymorphic form of Compound 1 referred to herein as Form 1. In certain embodiments, the present disclosure provides a polymorphic form of Compound 1 3 2197122.1 Page 5 of 214 398110-82HPWO (213249) referred to herein as Form 2.
  • the present disclosure provides a polymorphic form of Compound 1 referred to herein as Form 3. In certain embodiments, the present disclosure provides a polymorphic form of Compound 1 referred to herein as Form 4. [0066] In some embodiments, Form 1 of Compound 1 contains Form 1 and 20% or less, 19% or less, 18% or less, 17% or less, 16% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, or 0.2% or less weight percent of all other solid forms of Compound 1 in total disclosed herein, or of a specified solid form of Compound 1 disclosed herein, such as Form 2, Form 3, Form 4, or a combination of these.
  • Form 2 of Compound 1 contains Form 2 and 20% or less, 19% or less, 18% or less, 17% or less, 16% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, or 0.2% or less weight percent of all other solid forms of Compound 1 in total disclosed herein, or of a specified solid form of Compound 1 disclosed herein, such as Form 1, Form 3, Form 4, or a combination of these.
  • Form 3 of Compound 1 contains free base Form 3 and 20% or less, 19% or less, 18% or less, 17% or less, 16% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, or 0.2% or less weight percent of all other solid forms of Compound 1 in total disclosed herein, or of a specified solid form of Compound 1 disclosed herein, such as Form 1, Form 2, Form 4, or a combination of these.
  • Form 4 of Compound 1 contains free base Form 4 and 20% or less, 19% or less, 18% or less, 17% or less, 16% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, or 0.2% or less weight percent of all other solid forms of Compound 1 in total disclosed herein, or of a specified solid form of Compound 1 disclosed herein, such as Form 1, Form 2, Form 3, or a combination of these.
  • Compound 1 is amorphous. In some embodiments, Compound 1 is amorphous, and is substantially free of crystalline Compound 1.
  • Form 1 of Compound 1 [0071] In some embodiments, Form 1 of Compound 1 is a form having at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 1 below. 3 2197122.1 Page 6 of 214 398110-82HPWO (213249) Table 1 - XRPD Peak Positions for Form 1 of Compound 1 Position (°2 ⁇ ) Intensity % Position (°2 ⁇ ) Intensity % 4.7 28.5 18.2 9.9 .
  • Form 1 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 4.7, about 8.8, about 18.8, about 21.3, and about 28.8 degrees 2-theta. In some embodiments, Form 1 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 4.7, about 8.8, about 18.8, about 21.3, and about 28.8 degrees 2-theta.
  • Form 1 of Compound 1 is characterized in that it has three or more peaks in its X-ray powder diffraction pattern selected from those at about 4.7, about 8.8, about 18.8, about 21.3, and about 28.8 degrees 2-theta. In some embodiments, Form 1 of Compound 1 is characterized in that it has four or more peaks in its X-ray powder diffraction pattern selected from those at about 4.7, about 8.8, about 18.8, about 21.3, and about 28.8 degrees 2-theta. In some embodiments, Form 1 of Compound 1 is characterized in that it has five peaks in its X-ray powder diffraction pattern selected from those at about 4.7, about 8.8, about 18.8, about 21.3, and about 28.8 degrees 2-theta.
  • Form 1 of Compound 1 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 1 having a relative intensity greater than 10%, 3 2197122.1 Page 7 of 214 398110-82HPWO (213249) 20%, 30% or 40%.
  • the X-ray powder diffraction pattern is substantially similar (e.g., having peaks ⁇ 0.2 degree 2-theta) to the XRPD provided in FIG.1.
  • Methods for preparing Form 1 of Compound 1 are described infra.
  • Form 2 of Compound 1 is a form having at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 2 below.
  • Form 2 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 6.4, about 12.9, about 16.8, about 21.2, and about 23.5 degrees 2-theta.
  • Form 2 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 6.4, about 12.9, about 16.8, about 21.2, and about 23.5 degrees 2-theta. In some embodiments, Form 2 of Compound 1 is characterized in that it has three or more peaks in its X-ray powder diffraction pattern selected from those at about 6.4, about 12.9, about 16.8, about 21.2, and about 23.5 degrees 2-theta.
  • Form 2 of Compound 1 is characterized in that it has four or more peaks in its X-ray powder diffraction pattern selected from those at about 6.4, about 12.9, about 16.8, about 21.2, and about 23.58 degrees 2- theta. In some embodiments, Form 2 of Compound 1 is characterized in that it has five peaks in its X-ray 3 2197122.1 Page 8 of 214 398110-82HPWO (213249) powder diffraction pattern selected from those at about 6.4, about 12.9, about 16.8, about 21.2, and about 23.5 degrees 2-theta. As used herein, the term "about”, when used in reference to a degree 2-theta value refers to the stated value ⁇ 0.2 degree 2-theta.
  • Form 2 of Compound 1 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 2 having a relative intensity greater than 10%, 20%, 30% or 40%.
  • the X-ray powder diffraction pattern is substantially similar (e.g., having peaks ⁇ 0.2 degree 2-theta) to the XRPD provided in FIG. 3.
  • Methods for preparing Form 2 of Compound 1 are described infra.
  • Form 3 of Compound 1 is a form having at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 3 below.
  • Form 3 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 7.1, about 10.5, about 14.1, about 15.4, and about 21.6 degrees 2-theta. In some embodiments, Form 3 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 7.1, about 10.5, about 14.1, about 15.4, and about 21.6 degrees 2-theta.
  • Form 3 of Compound 1 is characterized in that it has three or more peaks in its X-ray powder diffraction pattern selected from those at about 7.1, about 10.5, about 14.1, about 15.4, and about 21.6 degrees 2-theta. In some embodiments, Form 3 of Compound 1 is characterized in that it has four or more peaks in its X-ray powder diffraction 3 2197122.1 Page 9 of 214 398110-82HPWO (213249) pattern selected from those at about 7.1, about 10.5, about 14.1, about 15.4, and about 21.6 degrees 2-theta.
  • Form 3 of Compound 1 is characterized in that it has five peaks in its X-ray powder diffraction pattern selected from those at about 7.1, about 10.5, about 14.1, about 15.4, and about 21.6 degrees 2-theta.
  • the term "about”, when used in reference to a degree 2-theta value refers to the stated value ⁇ 0.2 degree 2-theta.
  • Form 3 of Compound 1 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 3 having a relative intensity greater than 10%, 20%, 30% or 40%.
  • the X-ray powder diffraction pattern is substantially similar (e.g., having peaks ⁇ 0.2 degree 2-theta) to the XRPD provided in FIG. 4.
  • Methods for preparing Form 3 of Compound 1 are described infra.
  • Form 4 of Compound 1 is a form having at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 4 below.
  • Form 4 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 8.5, about 9.2, about 13.7, about 16.2, and about 20.9 degrees 2-theta. In some embodiments, Form 4 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 8.5, about 9.2, 3 2197122.1 Page 10 of 214 398110-82HPWO (213249) about 13.7, about 16.2, and about 20.9 degrees 2-theta.
  • Form 4 of Compound 1 is characterized in that it has three or more peaks in its X-ray powder diffraction pattern selected from those at about 8.5, about 9.2, about 13.7, about 16.2, and about 20.9 degrees 2-theta. In some embodiments, Form 4 of Compound 1 is characterized in that it has four or more peaks in its X-ray powder diffraction pattern selected from those at about 8.5, about 9.2, about 13.7, about 16.2, and about 20.9 degrees 2-theta. In some embodiments, Form 4 of Compound 1 is characterized in that it has five peaks in its X-ray powder diffraction pattern selected from those at about 8.5, about 9.2, about 13.7, about 16.2, and about 20.9 degrees 2-theta.
  • Form 4 of Compound 1 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 4 having a relative intensity greater than 10%, 20%, 30% or 40%.
  • the X-ray powder diffraction pattern is substantially similar (e.g., having peaks ⁇ 0.2 degree 2-theta) to the XRPD provided in FIG. 5.
  • Methods for preparing Form 4 of Compound 1 are described infra.
  • a solvent and Compound 1 are associated (e.g., electrostatic interactions, ⁇ -interactions, van der Waals forces, hydrophobic effects, etc.) to form a solvated form of Compound 1, as described below.
  • the solvated form of Compound 1 can exist in a variety of physical forms.
  • a solvated form of Compound 1 can be in solution, suspension, or in solid form.
  • a solvated form of Compound 1 is in solid form.
  • said compound may be amorphous, crystalline, or a mixture thereof.
  • a solvated solid form of Compound 1 is crystalline.
  • the crystalline solvate forms of Compound 1 described herein can be referred to as a co-crystal. Exemplary such solvated forms of Compound 1 are described in more detail below.
  • the present disclosure provides a solvate form of Compound 1 substantially free of impurities. Such extraneous matter may include different forms of Compound 1 or any other impurities that may result from the preparation of, and/or isolation of, Compound 1.
  • at least about 85% by weight of a solvate form of Compound 1 is present.
  • at least about 90% by weight of a solvate form of Compound 1 is present.
  • a solvate form of Compound 1 is present in an amount of at least about 80, 85, 90, 95, 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are 3 2197122.1 Page 11 of 214 398110-82HPWO (213249) based on the total weight of the composition.
  • a solvate form of Compound 1 contains no more than about 20.0 area percent HPLC of total organic impurities, no more than about 15.0 area percent HPLC of total organic impurities, no more than about 10.0 area percent HPLC of total organic impurities, no more than about 5.0 area percent HPLC of total organic impurities, no more than about 20.0 area percent HPLC of total organic impurities, no more than about 20.0 area percent HPLC of total organic impurities, or no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram.
  • a solvate form of Compound 1 contains no more than about 10% area percent HPLC of any single impurity, no more than about 5% area percent HPLC of any single impurity, or no more than about 1% area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
  • a solvate form of Compound 1 is present with an enantiomeric excess (i.e., ee) of at least 95%, preferably more than 96%, 97%, 98%, 99%, or 99.5% ee.
  • a solvate form of Compound 1 is present in more than 95% ee.
  • a solvate form of Compound 1 is present in more than 96% ee. In some embodiments, a solvate form of Compound 10 is present in more than 97% ee. In some embodiments, a solvate form of Compound 1 is present in more than 98% ee. In some embodiments, a solvate form of Compound 1 is present in more than 99% ee. In some embodiments, a solvate form of Compound 1 is present in more than 99.5% ee. [0091] The structure depicted for a solvate form of Compound 1 is also meant to include all tautomeric solvate forms of Compound 1.
  • Compound 1 is a solvated crystalline solid.
  • Compound 1 is a solvated crystalline solid substantially free of amorphous Compound 1.
  • at least about 95% by weight of solvated crystalline Compound 1 is present.
  • at least about 99% by weight of solvated crystalline Compound 1 is present.
  • the solvent is a protic solvent, aprotic solvent, polar aprotic solvent, or mixtures thereof; and 0 ⁇ x ⁇ 10.
  • the present invention provides a compound of formula I-a, wherein said compound is crystalline.
  • the present invention provides a compound of formula I-a, wherein said compound is a crystalline solid substantially free of a compound of formula I-a that is amorphous.
  • the present invention provides Compound I-a, wherein said compound is substantially free of impurities.
  • the solvent includes water, alcohols, ethers, esters, ketones, halocarbons, aromatic hydrocarbons, or a mixture thereof.
  • the solvent is one or more alcohols.
  • the solvent is an aromatic hydrocarbon.
  • the solvent is water, methanol, ethanol, 1-propanol, isopropanol, 2- methyl-1-propane, 1-butanol, ethylene glycol, tert-butanol, or toluene.
  • the solvent is water.
  • the solvent is methanol.
  • the solvent is ethanol.
  • the solvent is 1-propanol.
  • the solvent is isopropanol. In some embodiments, the solvent is 2-methyl-1-propanol. In some embodiments, the solvent is 1-butanol. In some embodiments, the solvent is ethylene glycol. In some embodiments, the solvent is tert-butanol. In some embodiments, the solvent is toluene.
  • x is 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0.
  • the present invention provides a composition comprising Compound 1- 3 2197122.1 Page 13 of 214 398110-82HPWO (213249) a and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a method of modulating HPK1 activity in a patient comprising administering to said patient a compound of formula I-a or composition thereof.
  • the present invention provides a method of selectively modulating HPK1 activity in a patient comprising administering to said patient a compound of formula I-a or composition thereof.
  • the present invention provides a method of activating HPK1 in a patient comprising administering to said patient a compound of formula I-a or composition thereof.
  • the present invention provides a method of treating an HPK1-mediated disease, disorder, or condition in a patient in need thereof, comprising administering to a patient a compound of formula I-a or composition thereof.
  • the HPK1-mediated disease, disorder, or condition is a proliferative disorder.
  • the proliferative disorder is a tumor.
  • the proliferative disorder is a cancer.
  • the proliferative disorder is associated with one or more activating mutations in HPK1.
  • the cancer is a solid tumor or hematological cancer.
  • the tumor is selected from a leukemia, lymphoma, prostate cancer, colon cancer, esophageal cancer, endometrial cancer, cervical cancer, ovarian cancer, uterine cancer, urothelial cancer, renal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, skin cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, and bladder cancer.
  • Compound 1 described herein is a compound of formula I-a.
  • the present invention provides Compound 1 as a solvate.
  • the present invention provides Compound 1 as a hydrate.
  • the present invention provides Compound 1 as a monohydrate. In some embodiments, the present invention provides a solid crystalline solvated form of Compound 1. In some embodiments, the present invention provides a solid crystalline hydrated form of Compound 1. In some embodiments, the present invention provides a crystalline solid monohydrate form of Compound 1. [0104] As described herein, it has been found that the solvate forms of Compound 1 can exist in at least one polymorphic forms. In certain embodiments, the present disclosure provides a polymorphic form of a compound of formula I-a referred to herein as Form 1.
  • Compound 1-1 (Isopropanol Solvate of Compound 1) [0105] According to one embodiment, the present invention provides an isopropanol solvate of Compound 1, represented by Compound 1-1: 3 2197122.1 Page 14 of 214 398110-82HPWO (213249)
  • Compound 1-1 can exist in a variety of physical forms.
  • Compound 1-1 can be in solution, suspension, or in solid form.
  • Compound 1-1 is in solid form.
  • said compound may be amorphous, crystalline, or a mixture thereof.
  • Compound 1-1 is crystalline. Exemplary solid forms are described in more detail below.
  • the present invention provides Compound 1-1 substantially free of impurities.
  • Such extraneous matter may include excess Compound 1, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, Compound 1-1.
  • at least about 85% by weight of Compound 1-1 is present.
  • at least about 90% by weight of Compound 1-1 is present.
  • Compound 1-1 is present in an amount of at least about 80, 85, 90, 9597, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • Compound 1-1 contains no more than about 15.0 area percent HPLC of total organic impurities and, in certain embodiments, no more than about 10 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram. In other embodiments, Compound 1-1 contains no more than about 10% area percent HPLC of any single impurity, no more than about 5% area percent HPLC of any single impurity, and in certain embodiments, no more than about 1% area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
  • Compound 1-1 is present with an enantiomeric excess (i.e., ee) of at least 95%, preferably more than 96%, 97%, 98%, 99%, or 99.5% ee. In some embodiments, Compound 1-1 is present in more than 95% ee. In some embodiments, Compound 1-1 is present in more 3 2197122.1 Page 15 of 214 398110-82HPWO (213249) than 96% ee. In some embodiments, Compound 1-1 is present in more than 97% ee. In some embodiments, Compound 1-1 is present in more than 98% ee. In some embodiments, Compound 1-1 is present in more than 99% ee.
  • ee an enantiomeric excess
  • Compound 1-1 is present in more than 99.5% ee.
  • the structure depicted for Compound 1-1 is also meant to include all tautomeric forms of Compound 1-1. 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 invention.
  • Compound 1-1 can exist in a variety of solid forms. Exemplary such forms include polymorphs such as those described herein.
  • Compound 1 and isopropanol are in a ratio of from about 1:2 to about 2:1. In some embodiments, Compound 1 and isopropanol are in about a 1:2 ratio. In some embodiments, Compound 1 and isopropanol are in about a 1:1 ratio (e.g., mono isopropanol solvate). In some embodiments, Compound 1 and isopropanol are in about a 2:1 ratio (e.g., hemi isopropanol solvate). [0112] In some embodiments, x is about 1 ⁇ 2 for Compound 1 (e.g., hemi isopropanol solvate). In some embodiments, x is about 2/3 for Compound 1-1.
  • x is about 3 ⁇ 4 for Compound 1-1. In some embodiments, x is about 1 for Compound 1-1 (e.g., mono isopropanol solvate). In some embodiments, x is about 2 for Compound 1-1. [0113] In certain embodiments, Compound 1-1 is a crystalline solid. In other embodiments, Compound 1-1 is a crystalline solid substantially free of amorphous Compound 1-1. In certain embodiments, at least about 90% by weight of crystalline Compound 1-1 is present. In certain embodiments, at least about 95% by weight of crystalline Compound 1-1 is present. In still other embodiments of the invention, at least about 99% by weight of crystalline Compound 1-1 is present.
  • Form 1 of Compound 1-1 contains Form 1 and 20% or less, 19% or less, 18% or less, 17% or less, 16% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, or 0.2% or less weight percent of all other solvate forms of Compound 1-1 in total or of a specified solid form of Compound 1 disclosed herein, or a combination of these.
  • Compound 1-1 is amorphous.
  • Compound 1-1 is amorphous, and is substantially free of crystalline Compound 1-1.
  • Form 1 of Compound 1-1 [0116] In some embodiments, Form 1 of Compound 1-1 is characterized in that it has one or more 3 2197122.1 Page 16 of 214 398110-82HPWO (213249) peaks in its X-ray powder diffraction pattern selected from those at about 7.2, about 11.0, about 22.2, about 22.6, and about 25.9 degrees 2-theta.
  • Form 1 of Compound 1-1 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 7.2, about 11.0, about 22.2, about 22.6, and about 25.9 degrees 2-theta. In some embodiments, Form 1 of Compound 1-1 is characterized in that it has three or more peaks in its X-ray powder diffraction pattern selected from those at about 7.2, about 11.0, about 22.2, about 22.6, and about 25.9 degrees 2-theta.
  • Form 1 of Compound 1-1 is characterized in that it has four or more peaks in its X-ray powder diffraction pattern selected from those at about 7.2, about 11.0, about 22.2, about 22.6, and about 25.9 degrees 2-theta. In some embodiments, Form 1 of Compound 1-1 is characterized in that it has five peaks in its X-ray powder diffraction pattern selected from those at about 7.2, about 11.0, about 22.2, about 22.6, and about 25.9 degrees 2-theta. As used herein, the term "about”, when used in reference to a degree 2-theta value refers to the stated value ⁇ 0.2 degree 2-theta.
  • the X-ray powder diffraction pattern is substantially similar (e.g., having peaks ⁇ 0.2 degree 2-theta) to the simulated XRPD provided in FIG.47.
  • Form 1 of Compound 1-1 can be obtained from IPA:H2O (10%) with cooling.
  • the present invention provides a process of preparing Form 1 of Compound 1-1 from IPA:H2O (10%) with cooling.
  • Salt Forms of Compound 1 [0119]
  • an acid and Compound 1 are ionically bonded to form one of Compounds 2 to 12, described below. It is contemplated that Compounds 2 to 12 can exist in a variety of physical forms.
  • Compounds 2 to 12 can be in solution, suspension, or in solid form. In certain embodiments, Compounds 2 to 12 are in solid form. When Compounds 2 to 12 are in solid form, said compounds may be amorphous, crystalline, or a mixture thereof. Exemplary such solid forms of Compounds 2 to 12 are described in more detail below.
  • the present disclosure provides a salt form of Compound 1 substantially free of impurities. Such extraneous matter may include different forms of Compound 1 or any other impurities that may result from the preparation of, and/or isolation of, Compound 1. In certain embodiments, at least about 85% by weight of a salt form of Compound 1 is present.
  • a salt form of Compound 1 is present in an amount of at least about 80, 85, 90, 95, 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on 3 2197122.1 Page 17 of 214 398110-82HPWO (213249) the total weight of the composition.
  • a salt form of Compound 1 contains no more than about 20.0 area percent HPLC of total organic impurities, no more than about 15.0 area percent HPLC of total organic impurities, no more than about 10.0 area percent HPLC of total organic impurities, no more than about 5.0 area percent HPLC of total organic impurities, no more than about 20.0 area percent HPLC of total organic impurities, no more than about 20.0 area percent HPLC of total organic impurities, or no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram.
  • a salt form of Compound 1 contains no more than about 10% area percent HPLC of any single impurity, no more than about 5% area percent HPLC of any single impurity, or no more than about 1% area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
  • a salt form of Compound 1 is present with an enantiomeric excess (i.e., ee) of at least 95%, preferably more than 96%, 97%, 98%, 99%, or 99.5% ee.
  • salt form of Compound 1 is present in more than 95% ee.
  • a salt form of Compound 1 is present in more than 96% ee.
  • a salt form of Compound 1 is present in more than 97% ee. In some embodiments, a salt form of Compound 1 is present in more than 98% ee. In some embodiments, a salt form of Compound 1 is present in more than 99% ee. In some embodiments, a salt form of Compound 1 is present in more than 99.5% ee. [0123]
  • the structure depicted for a salt form of Compound 1 is also meant to include all tautomeric salt 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.
  • Compound 1 is a solid crystalline salt.
  • Compound 1 is a solid crystalline salt substantially free of amorphous Compound 1.
  • at least about 95% by weight of a solid crystalline salt form of Compound 1 is present.
  • at least about 99% by weight of a solid crystalline salt form of Compound 1 is present.
  • the acid is a mineral acid, organic acid, or mixtures thereof; and 0 ⁇ y ⁇ 5.
  • the present invention provides a compound of formula I-b, wherein said compound is crystalline.
  • the present invention provides a compound of formula I-b, wherein said compound is a crystalline solid substantially free of a compound of formula I-b that is amorphous.
  • the present invention provides a compound of formula I-b, wherein said compound is substantially free of impurities.
  • the mineral acid is hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid.
  • the organic acid is acetic acid, glycolic acid, oxalic acid, maleic acid, malic acid, hippuric acid, lactic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, citric acid, succinic acid, malonic acid, benzoic acid, or mixtures thereof.
  • y is 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0. [0131] In some embodiments, y is 1 comprising one or more acids.
  • the present invention provides a composition comprising a compound of formula I-b and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a method of modulating HPK1 activity in a patient comprising administering to said patient a compound of formula I-b or composition thereof.
  • the present invention provides a method of selectively modulating HPK1 activity in a patient comprising administering to said patient a compound of formula I-b or composition thereof.
  • the present invention provides a method of activating HPK1 in a patient comprising administering to said patient a compound of formula I-b or composition thereof.
  • the present invention provides a method of treating an HPK1-mediated disease, disorder, or condition in a patient in need thereof, comprising administering to a patient a compound of formula I-b or composition thereof.
  • the HPK1-mediated disease, disorder, or condition is a proliferative disorder.
  • the proliferative disorder is a tumor.
  • the proliferative disorder is a cancer.
  • the proliferative disorder is associated with one or more activating mutations in HPK1.
  • the cancer is a solid tumor or hematological cancer.
  • the tumor is selected from a leukemia, lymphoma, prostate cancer, colon cancer, esophageal cancer, endometrial cancer, cervical cancer, ovarian cancer, uterine cancer, urothelial cancer, renal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, skin cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, and bladder cancer.
  • the salt forms of Compound 1 can exist in at least eleven polymorphic forms.
  • Compound 2 (Hydrobromide Salts of Compound 1) [0136] According to one embodiment, the present disclosure provides a hydrobromide salt of Compound 1, represented by Compound 2: [0137] It will be that the hydrobromic acid and Compound 1 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 3 2197122.1 Page 20 of 214 398110-82HPWO (213249) certain embodiments, Compound 2 is in solid form. When Compound 2 is in solid form, said 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 2 substantially free of impurities.
  • impurities or extraneous matter may include different forms of Compound 2, 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 a form of Compound 2 is present.
  • at least about 99% by weight of a form of Compound 2 is present.
  • a form of Compound 2 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • a form of 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, a form of 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.
  • a form of Compound 2 is present with an enantiomeric excess (i.e., ee) of at least 95%, preferably more than 96%, 97%, 98%, 99%, or 99.5% ee. In some embodiments, a form of Compound 2 is present in more than 95% ee. In some embodiments, a form of Compound 2 is present in more than 96% ee. In some embodiments, a form of Compound 2 is present in more than 97% ee. In some embodiments, a form of Compound 2 is present in more than 98% ee. In some embodiments, a form of Compound 2 is present in more than 99% ee.
  • ee an enantiomeric excess
  • a form of Compound 2 is present in more than 99.5% ee.
  • the structure depicted for a form of 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 a variety of solid forms. Exemplary such forms include polymorphs such as those described herein.
  • Form 1 of Compound 2 contains Form 1 and 20% or less, 19% or less, 18% or less, 17% or less, 16% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% 3 2197122.1 Page 21 of 214 398110-82HPWO (213249) or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, or 0.2% or less weight percent of all other solid forms of Compound 2 in total or of a specified salt form of Compound 1 disclosed herein, or a combination of these.
  • 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. [0145] It has been found that Compound 2 can exist in at least one distinct polymorphic form. In certain embodiments, 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 1 of Compound 2 [0147] In some embodiments, Form 1 of Compound 2 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 5 below.
  • Form 1 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 19.2, about 19.5, about 24.7, about 25.6, and about 25.9 degrees 2-theta.
  • Form 1 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 19.2, about 19.5, about 24.7, about 25.6, and about 25.9 degrees 2-theta. In some embodiments, Form 1 of Compound 2 is characterized in that it has three or more peaks in its X-ray powder diffraction pattern selected from those at about 19.2, about 19.5, about 24.7, about 25.6, and about 25.9 degrees 2-theta. In some embodiments, Form 1 of Compound 2 is characterized in that it has four or more peaks in its X-ray powder diffraction pattern selected from those at about 19.2, about 19.5, about 24.7, about 25.6, and about 25.9 degrees 2- theta.
  • Form 1 of Compound 2 is characterized in that it has five peaks in its X-ray powder diffraction pattern selected from those at about 19.2, about 19.5, about 24.7, about 25.6, and about 25.9 degrees 2-theta.
  • the present disclosure provides Form 1 of Compound 2, wherein said compound has thermal DSC events (e.g., endothermic and exothermic) or TGA events (e.g., weight loss and decomposition) substantially similar to those provided in Table 37 or Table 38.
  • Form 1 of Compound 2 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 5 having a relative intensity greater than 10%, 20%, 30% or 40%.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.6.
  • Methods for preparing Form 1 of Compound 2 are described infra.
  • the present invention provides Compound 2: 3 2197122.1 Page 23 of 214 398110-82HPWO (213249) 2 wherein said compound is crystalline.
  • the present disclosure provides Compound 2, wherein said compound is substantially free of amorphous Compound 2.
  • the present disclosure provides Compound 2, wherein said compound is substantially free of impurities.
  • the present disclosure provides Compound 2, wherein said compound has at least two peaks in its XRPD selected from those at about 19.2, about 19.5, about 24.7, about 25.6, and about 25.9 degrees 2-theta.
  • the present disclosure provides compound 2, wherein said compound has at least three peaks in its XRPD selected from those at about 19.2, about 19.5, about 24.7, about 25.6, and about 25.9 degrees 2-theta.
  • the present disclosure provides Compound 2, wherein said compound is of Form 1.
  • the present disclosure provides Compound 2, wherein said compound has an XRPD substantially similar to that depicted in FIG.6.
  • the present disclosure provides a composition comprising Compound 2 and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a method of modulating HPK1 activity in a patient comprising administering to said patient Compound 2 or composition thereof.
  • the present invention provides a method of selectively modulating HPK1 activity in a patient comprising administering to said patient Compound 2 or composition thereof.
  • the present invention provides a method of activating HPK1 in a patient comprising administering to said patient Compound 2 or composition thereof.
  • the present invention provides a method of treating an HPK1-mediated disease, disorder, or condition in a patient in need thereof, comprising administering to a patient Compound 2 or composition thereof.
  • the HPK1-mediated disease, disorder, or condition is a proliferative disorder.
  • the proliferative disorder is a cancer.
  • the proliferative disorder is a tumor.
  • the proliferative disorder is associated with one or more activating mutations in HPK1.
  • the cancer is a solid tumor or hematological cancer.
  • the tumor is selected from a leukemia, lymphoma, prostate cancer, colon cancer, esophageal cancer, endometrial cancer, cervical cancer, ovarian cancer, uterine cancer, urothelial cancer, renal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, skin cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, and bladder cancer.
  • the present disclosure provides a hydrochloride salt of Compound 1, represented by Compound 3: [0160] It will be that the hydrochloric acid and Compound 1 are ionically bonded to form Compound 3. It is contemplated that Compound 2 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, said compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.
  • the present disclosure provides a form Compound 3 substantially free of impurities.
  • impurities or extraneous matter may include different forms of Compound 3, 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 a form of Compound 3 is present.
  • at least about 99% by weight of a form of Compound 3 is present.
  • a form of Compound 3 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • a form of 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, a form of 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.
  • a form of Compound 3 is present with an enantiomeric excess (i.e., ee) of at least 95%, preferably more than 96%, 97%, 98%, 99%, or 99.5% ee. In some embodiments, a form of Compound 3 is present in more than 95% ee. In some embodiments, a form of Compound 3 is present in more than 96% ee. In some embodiments, a form of Compound 3 is present in more than 97% ee. In some embodiments, a form of Compound 3 is present in more than 98% ee.
  • a form of Compound 3 is present in more than 99% ee. In some embodiments, a form of Compound 3 is present in more than 99.5% ee.
  • the structure depicted for a form of 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. [0165] It has been found that Compound 3 can exist in a variety of solid forms.
  • 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. [0167] It has been found that Compound 3 can exist in at least two distinct polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of Compound 3 referred to herein as Form 1.
  • Form 1 of Compound 3 contains Form 1 and 20% or less, 19% or less, 18% or less, 17% or less, 16% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, or 0.2% or less weight percent of all other solid forms of Compound 3 in total disclosed herein, or of a specified solid form of Compound 3 disclosed herein, such as Form 2.
  • Form 2 of Compound 3 contains Form 2 and 20% or less, 19% or less, 18% or less, 17% or less, 16% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, or 0.2% or less weight percent of all other solid forms of Compound 3 in total disclosed 3 2197122.1 Page 26 of 214 398110-82HPWO (213249) herein, or of a specified solid form of Compound 3 disclosed herein, such as Form 1.
  • Compound 3 is amorphous. In some embodiments, Compound 3 is amorphous, and is substantially free of crystalline Compound 3.
  • Form 1 of Compound 3 [0171] In some embodiments, Form 1 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 1 of Compound 3 Position (°2 ⁇ ) Intensity % Position (°2 ⁇ ) Intensity % 61 766 188 188 .
  • Form 1 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 6.1, about 6.7, about 12.3, about 14.3, and about 26.2 degrees 2-theta. In some embodiments, Form 1 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 6.1, about 6.7, about 12.3, about 14.3, and about 26.2 degrees 2-theta.
  • Form 1 of Compound 3 is characterized in that it has three or more peaks in its X-ray powder diffraction pattern selected from those at about 6.1, about 6.7, about 12.3, about 14.3, and about 26.2 degrees 2-theta. In some embodiments, Form 1 of Compound 3 is characterized in that it has four or more peaks in its X-ray powder diffraction pattern 3 2197122.1 Page 27 of 214 398110-82HPWO (213249) selected from those at about 6.1, about 6.7, about 12.3, about 14.3, and about 26.2 degrees 2-theta.
  • Form 1 of Compound 3 is characterized in that it has five peaks in its X-ray powder diffraction pattern selected from those at about 6.1, about 6.7, about 12.3, about 14.3, and about 26.2 degrees 2-theta.
  • the present disclosure provides Form 1 of Compound 3, wherein said compound has thermal DSC events (e.g., endothermic and exothermic) or TGA events (e.g., weight loss and decomposition) substantially similar to those provided in Table 37 or Table 38.
  • Form 1 of Compound 3 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 6 having a relative intensity greater than 10%, 20%, 30% or 40%. In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.7. [0175] Methods for preparing Form 1 of Compound 3 are described infra.
  • Form 2 of Compound 3 [0176] In some embodiments, Form 2 of Compound 3 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 7 below.
  • Form 2 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 6.1, about 7.9, about 14.6, about 22.4, and about 25.8 degrees 2-theta.
  • Form 2 of Compound 3 is characterized in that it 3 2197122.1 Page 28 of 214 398110-82HPWO (213249) has two or more peaks in its X-ray powder diffraction pattern selected from those at about 6.1, about 7.9, about 14.6, about 22.4, and about 25.8 degrees 2-theta. In some embodiments, Form 2 of Compound 3 is characterized in that it has three or more peaks in its X-ray powder diffraction pattern selected from those at about 6.1, about 7.9, about 14.6, about 22.4, and about 25.8 degrees 2-theta.
  • Form 2 of Compound 3 is characterized in that it has four or more peaks in its X-ray powder diffraction pattern selected from those at about 6.1, about 7.9, about 14.6, about 22.4, and about 25.8 degrees 2-theta. In some embodiments, Form 2 of Compound 3 is characterized in that it has five peaks in its X-ray powder diffraction pattern selected from those at about 6.1, about 7.9, about 14.6, about 22.4, and about 25.8 degrees 2-theta.
  • the present disclosure provides Form 2 of Compound 3, wherein said compound has thermal DSC events (e.g., endothermic and exothermic) or TGA events (e.g., weight loss and decomposition) substantially similar to those provided in Table 37 or Table 38.
  • Form 2 of Compound 3 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 7 having a relative intensity greater than 10%, 20%, 30% or 40%.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.8.
  • Methods for preparing Form 2 of Compound 3 are described infra.
  • the disclosure provides Compound 3: wherein said compound is disclosure provides Compound 3, wherein said compound is substantially free of amorphous Compound 1. [0182] In some embodiments, the present disclosure provides Compound 3, wherein said compound is substantially free of impurities. [0183] In some embodiments, the present disclosure provides Compound 3, wherein said compound 3 2197122.1 Page 29 of 214 398110-82HPWO (213249) has two or more peaks in its XRPD selected from those at about 6.1, about 6.7, about 12.3, about 14.3, and about 26.2 degrees 2-theta.
  • the present disclosure provides Compound 3, wherein said compound has three or more peaks in its XRPD selected from those at about 6.1, about 6.7, about 12.3, about 14.3, and about 26.2 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 3, wherein said compound is Form 1. [0184] In some embodiments, the present disclosure provides Compound 3, wherein said compound has an XRPD substantially similar to that depicted in FIG.7. [0185] In some embodiments, the present disclosure provides Compound 3, wherein said compound has two or more peaks in its XRPD selected from those at about 6.1, about 7.9, about 14.6, about 22.4, and about 25.8 degrees 2-theta.
  • the present disclosure provides Compound 3, wherein said compound has three or more peaks in its XRPD selected from those at about 6.1, about 7.9, about 14.6, about 22.4, and about 25.8 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 3, wherein said compound is Form 2. [0186] In some embodiments, the present disclosure provides Compound 3, wherein said compound has an XRPD substantially similar to that depicted in FIG.8. [0187] In some embodiments, the present disclosure provides a composition comprising Compound 3 and a pharmaceutically acceptable carrier or excipient. [0188] In some embodiments, the present invention provides a method of modulating HPK1 activity in a patient comprising administering to said patient Compound 3 or composition thereof.
  • the present invention provides a method of selectively modulating HPK1 activity in a patient comprising administering to said patient Compound 3 or composition thereof. In some embodiments, the present invention provides a method of activating HPK1 in a patient comprising administering to said patient Compound 3 or composition thereof. [0189] In some embodiments, the present invention provides a method of treating an HPK1-mediated disease, disorder, or condition in a patient in need thereof, comprising administering to a patient Compound 3 or composition thereof. In some embodiments, the HPK1-mediated disease, disorder, or condition is a proliferative disorder. In some embodiments, the proliferative disorder is a cancer. In some embodiments, the proliferative disorder is a tumor.
  • the proliferative disorder is associated with one or more activating mutations in HPK1.
  • the cancer is a solid tumor or hematological cancer.
  • the tumor is selected from a leukemia, lymphoma, prostate cancer, colon cancer, esophageal cancer, endometrial cancer, cervical cancer, ovarian cancer, uterine cancer, urothelial cancer, renal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, skin cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, and bladder 3 2197122.1 Page 30 of 214 398110-82HPWO (213249) cancer.
  • Compound 4 (Sulfate Salts of Compound 1) [0190]
  • the present disclosure provides a sulfate salt of Compound 1, represented by Compound 4: [0191] It will be the sulfuric acid and Compound 1 are ionically bonded to form Compound 4.
  • Compound 4 can be a sulfate salt, a hydrogen sulfate salt, or mixtures thereof. 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, said compound may be amorphous, crystalline, or a mixture thereof.
  • the present disclosure provides a form Compound 4 substantially free of impurities.
  • impurities or extraneous matter may include different forms of Compound 4, 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 a form of Compound 4 is present.
  • at least about 99% by weight of a form of Compound 4 is present.
  • a form of Compound 4 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • a form of 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.
  • a form of 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 3 2197122.1 Page 31 of 214 398110-82HPWO (213249) chromatogram.
  • a form of Compound 4 is present with an enantiomeric excess (i.e., ee) of at least 95%, preferably more than 96%, 97%, 98%, 99%, or 99.5% ee.
  • a form of Compound 4 is present in more than 95% ee. In some embodiments, a form of Compound 4 is present in more than 96% ee. In some embodiments, a form of Compound 4 is present in more than 97% ee. In some embodiments, a form of Compound 4 is present in more than 98% ee. In some embodiments, a form of Compound 4 is present in more than 99% ee. In some embodiments, a form of Compound 4 is present in more than 99.5% ee. [0195] The structure depicted for a form of Compound 4 is also meant to include all tautomeric forms of Compound 4.
  • structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • 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 a variety of solid forms. Exemplary such forms include polymorphs such as those described herein.
  • Compound 4 is a crystalline solid. In other embodiments, Compound 4 is a crystalline solid substantially free of amorphous Compound 4.
  • 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. [0198] It has been found that Compound 4 can exist in at least two distinct polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of Compound 4 referred to herein as Form 1. In certain embodiments, the present disclosure provides a polymorphic form of Compound 4 referred to herein as Form 2.
  • Form 1 of Compound 4 contains Form 1 and 20% or less, 19% or less, 18% or less, 17% or less, 16% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, or 0.2% or less weight percent of all other solid forms of Compound 4 in total disclosed herein, or of a specified solid form of Compound 4 disclosed herein, such as Form 2.
  • Form 2 of Compound 4 contains Form 2 and 20% or less, 19% or less, 18% or less, 17% or less, 16% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or 3 2197122.1 Page 32 of 214 398110-82HPWO (213249) less, 0.5% or less, or 0.2% or less weight percent of all other solid forms of Compound 4 in total disclosed herein, or of a specified solid form of Compound 4 disclosed herein, such as Form 1.
  • Compound 4 is amorphous. In some embodiments, Compound 4 is amorphous, and is substantially free of crystalline Compound 4.
  • Form 1 of Compound 4 [0202] In some embodiments, Form 1 of Compound 4 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 1 of Compound 4 Position (°2 ⁇ ) Intensity % Position (°2 ⁇ ) Intensity % 62 190 206 135 .
  • Form 1 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 12.0, about 23.0, about 24.1, about 25.4, and about 25.7 degrees 2-theta. In some embodiments, Form 1 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 12.0, about 23.0, 3 2197122.1 Page 33 of 214 398110-82HPWO (213249) about 24.1, about 25.4, and about 25.7 degrees 2-theta.
  • Form 1 of Compound 4 is characterized in that it has three or more peaks in its X-ray powder diffraction pattern selected from those at about 12.0, about 23.0, about 24.1, about 25.4, and about 25.7 degrees 2-theta. In some embodiments, Form 1 of Compound 4 is characterized in that it has four or more peaks in its X-ray powder diffraction pattern selected from those at about 12.0, about 23.0, about 24.1, about 25.4, and about 25.7 degrees 2- theta.
  • Form 1 of Compound 4 is characterized in that it has five peaks in its X-ray powder diffraction pattern selected from those at about 12.0, about 23.0, about 24.1, about 25.4, and about 25.7 degrees 2-theta.
  • the present disclosure provides Form 1 of Compound 4, wherein said compound has thermal DSC events (e.g., endothermic and exothermic) or TGA events (e.g., weight loss and decomposition) substantially similar to those provided in Table 37 or Table 38.
  • Form 1 of Compound 4 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 8 having a relative intensity greater than 10%, 20%, 30% or 40%. In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.9. [0206] Methods for preparing Form 1 of Compound 4 are described infra.
  • Form 2 of Compound 4 [0207] In some embodiments, Form 2 of Compound 4 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 9 below.
  • Form 2 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 6.1, about 17.7, about 19.3, about 20.1, and about 22.4 degrees 2-theta.
  • Form 2 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 6.1, about 17.7, about 19.3, about 20.1, and about 22.4 degrees 2-theta. In some embodiments, Form 2 of Compound 4 is characterized in that it has three or more peaks in its X-ray powder diffraction pattern selected from those at about 6.1, about 17.7, about 19.3, about 20.1, and about 22.4 degrees 2-theta. In some embodiments, Form 2 of Compound 4 is characterized in that it has four or more peaks in its X-ray powder diffraction pattern selected from those at about 6.1, about 17.7, about 19.3, about 20.1, and about 22.4 degrees 2-theta.
  • Form 2 of Compound 4 is characterized in that it has five peaks in its X-ray powder diffraction pattern selected from those at about 6.1, about 17.7, about 19.3, about 20.1, and about 22.4 degrees 2-theta.
  • the present disclosure provides Form 2 of Compound 4, wherein said compound has thermal DSC events (e.g., endothermic and exothermic) or TGA events (e.g., weight loss and decomposition) substantially similar to those provided in Table 37 or Table 38.
  • Form 2 of Compound 4 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 9 having a relative intensity greater than 10%, 20%, 30% or 40%.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.10.
  • Methods for preparing Form 2 of Compound 4 are described infra.
  • the disclosure provides Compound 4: wherein said compound is disclosure provides Compound 4, wherein said compound is substantially free of amorphous Compound 4.
  • the present disclosure provides Compound 4, wherein said compound is substantially free of impurities.
  • the present disclosure provides Compound 4, wherein said compound has two or more peaks in its XRPD selected from those at about 12.0, about 23.0, about 24.1, about 25.4, and about 25.7 degrees 2-theta.
  • the present disclosure provides Compound 4, wherein said compound has three or more peaks in its XRPD selected from those at about 12.0, about 23.0, about 24.1, about 25.4, and about 25.7 degrees 2-theta.
  • the present disclosure provides Compound 4, wherein said compound is Form 1.
  • the present disclosure provides Compound 4, wherein said compound has an XRPD substantially similar to that depicted in FIG.9. [0216] In some embodiments, the present disclosure provides Compound 4, wherein said compound has two or more peaks in its XRPD selected from those at about 6.1, about 17.7, about 19.3, about 20.1, and about 22.4 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 4, wherein said compound has three or more peaks in its XRPD selected from those at about 6.1, about 17.7, about 19.3, about 20.1, and about 22.4 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 4, wherein said compound is Form 2.
  • the present disclosure provides Compound 4, wherein said compound has an XRPD substantially similar to that depicted in FIG.10.
  • the present disclosure provides a composition comprising Compound 4 and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a method of modulating HPK1 activity in a patient comprising administering to said patient Compound 4 or composition thereof.
  • the present invention provides a method of selectively modulating HPK1 activity in a patient comprising administering to said patient Compound 4 or composition thereof.
  • the present invention provides a method of activating HPK1 in a patient comprising administering to said patient Compound 4 or composition thereof.
  • the present invention provides a method of treating an HPK1-mediated disease, disorder, or condition in a patient in need thereof, comprising administering to a patient Compound 4 or composition thereof.
  • the HPK1-mediated disease, disorder, or condition is a proliferative disorder.
  • the proliferative disorder is a cancer.
  • the proliferative disorder is a tumor.
  • the proliferative disorder is associated with one or more activating mutations in HPK1.
  • the cancer is a solid tumor or hematological cancer.
  • the tumor is selected from a leukemia, lymphoma, prostate 3 2197122.1 Page 36 of 214 398110-82HPWO (213249) cancer, colon cancer, esophageal cancer, endometrial cancer, cervical cancer, ovarian cancer, uterine cancer, urothelial cancer, renal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, skin cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, and bladder cancer.
  • Compound 5 (p-Tolulenesulfonate Salts of Compound 1) [0221] According to one embodiment, the present disclosure provides a p-toluenesulfonic acid salt of Compound 1, represented by Compound 5: [0222] It will be the p-toluenesulfonic acid and Compound 1 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, said compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.
  • the present disclosure provides a form Compound 5 substantially free of impurities.
  • impurities or extraneous matter may include different forms of Compound 5, 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 a form of Compound 5 is present.
  • at least about 99% by weight of a form of Compound 5 is present.
  • a form of Compound 5 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • a form of 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.
  • a form of 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.
  • a form of Compound 5 is present with an enantiomeric excess (i.e., ee) of at least 95%, preferably more than 96%, 97%, 98%, 99%, or 99.5% ee. In some embodiments, a form of Compound 5 is present in more than 95% ee. In some embodiments, a form of Compound 5 is present in more than 96% ee. In some embodiments, a form of Compound 5 is present in more than 97% ee. In some embodiments, a form of Compound 5 is present in more than 98% ee. In some embodiments, a form of Compound 5 is present in more than 99% ee.
  • ee an enantiomeric excess
  • a form of Compound 5 is present in more than 99.5% ee.
  • the structure depicted for a form of 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. [0227] It has been found that Compound 5 can exist in a variety of solid forms. Exemplary such forms include polymorphs such as those described herein.
  • 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. [0229] It has been found that Compound 5 can exist in at least two distinct polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of Compound 5 referred to herein as Form 1.
  • Form 1 of Compound 5 contains Form 1 and 20% or less, 19% or less, 18% or less, 17% or less, 16% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, or 0.2% or less weight percent of all other solid forms of Compound 5 in total disclosed herein, or of a specified solid form of Compound 5 disclosed herein, such as Form 2.
  • Form 2 of Compound 5 contains Form 2 and 20% or less, 19% or less, 18% or less, 17% or less, 16% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, or 0.2% or less weight percent of all other solid forms of Compound 5 in total disclosed herein, or of a specified solid form of Compound 5 disclosed herein, such as Form 1.
  • Compound 5 is amorphous. In some embodiments, Compound 5 is amorphous, and is substantially free of crystalline Compound 5.
  • Form 1 of Compound 5 [0233] In some embodiments, Form 1 of Compound 5 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 10 below. Table 10 - XRPD Peak Positions for Form 1 of Compound 5 Position (°2 ⁇ ) Intensity % Position (°2 ⁇ ) Intensity % 55 455 187 733 .
  • Form 1 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 10.5, about 13.0, about 14.8, about 24.1, and about 26.0 degrees 2-theta. In some embodiments, Form 1 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 10.5, about 13.0, about 14.8, about 24.1, and about 26.0 degrees 2-theta.
  • Form 1 of Compound 5 is characterized in that it has three or more peaks in its X-ray powder diffraction pattern selected from those at about 10.5, about 13.0, about 14.8, about 24.1, and about 26.0 degrees 2-theta. In some embodiments, Form 1 of Compound 5 is characterized in that it has four or more peaks in its X-ray powder diffraction pattern selected from those at about 10.5, about 13.0, about 14.8, about 24.1, and about 26.0 degrees 2- theta. In some embodiments, Form 1 of Compound 5 is characterized in that it has five peaks in its X-ray powder diffraction pattern selected from those at about 10.5, about 13.0, about 14.8, about 24.1, and about 26.0 degrees 2-theta.
  • the present disclosure provides Form 1 of Compound 5, wherein said compound has thermal DSC events (e.g., endothermic and exothermic) or TGA events (e.g., weight loss and decomposition) substantially similar to those provided in Table 37 or Table 38.
  • the thermal DSC and TGA events are substantially similar to those depicted in the DSC-TGA overlay of FIG.31.
  • Form 1 of Compound 5 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 10 having a relative intensity greater than 10%, 20%, 30% or 40%.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.11.
  • Methods for preparing Form 1 of Compound 5 are described infra.
  • Form 2 of Compound 5 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 11 below.
  • Form 2 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 5.8, about 14.8, about 17.4, about 22.4, and about 25.6 degrees 2-theta. In some embodiments, Form 2 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 5.8, about 14.8, about 17.4, about 22.4, and about 25.6 degrees 2-theta. In some embodiments, Form 2 of Compound 5 is characterized in that it has three or more peaks in its X-ray powder diffraction pattern selected from those at about 5.8, about 14.8, about 17.4, about 22.4, and about 25.6 degrees 2-theta.
  • Form 2 of Compound 5 is characterized in that it has four or more peaks in its X-ray powder diffraction pattern selected from those at about 5.8, about 14.8, about 17.4, about 22.4, and about 25.6 degrees 2-theta. In some embodiments, Form 2 of Compound 5 is characterized in that it has five peaks in its X-ray powder diffraction pattern selected from those at about 5.8, about 14.8, about 17.4, about 22.4, and about 25.6 degrees 2-theta.
  • the present disclosure provides Form 2 of Compound 5, wherein said compound has thermal DSC events (e.g., endothermic and exothermic) or TGA events (e.g., weight loss and decomposition) substantially similar to those provided in Table 37 or Table 38.
  • Form 2 of Compound 5 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 11 having a relative intensity greater than 10%, 20%, 30% or 40%.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.12.
  • the disclosure provides Compound 5: wherein said compound is disclosure provides Compound 5, wherein said compound is 5. [0244] In some embodiments, the present disclosure provides Compound 5, wherein said compound is substantially free of impurities. [0245] In some embodiments, the present disclosure provides Compound 5, wherein said compound has two or more peaks in its XRPD selected from those at about 10.5, about 13.0, about 14.8, about 24.1, and about 26.0 degrees 2-theta.
  • the present disclosure provides Compound 5, wherein said compound has three or more peaks in its XRPD selected from those at about 10.5, about 13.0, about 14.8, about 24.1, and about 26.0 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 5, wherein said compound is Form 1. [0246] In some embodiments, the present disclosure provides Compound 5, wherein said compound has an XRPD substantially similar to that depicted in FIG.11. [0247] In some embodiments, the present disclosure provides Compound 5, wherein said compound has two or more peaks in its XRPD selected from those at about 5.8, about 14.8, about 17.4, about 22.4, and about 25.6 degrees 2-theta.
  • the present disclosure provides Compound 5, wherein said compound has three or more peaks in its XRPD selected from those at about 5.8, about 14.8, about 17.4, about 22.4, and about 25.6 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 5, wherein said compound is Form 2. [0248] In some embodiments, the present disclosure provides Compound 5, wherein said compound has an XRPD substantially similar to that depicted in FIG.12. [0249] In some embodiments, the present disclosure provides a composition comprising Compound 5 and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a method of modulating HPK1 activity in a patient comprising administering to said patient Compound 5 or composition thereof. In some embodiments, the present invention provides a method of selectively modulating HPK1 activity in a patient comprising administering to said patient Compound 5 or composition thereof. In some embodiments, the present invention provides a method of activating HPK1 in a patient comprising administering to said patient Compound 5 or composition thereof. [0251] In some embodiments, the present invention provides a method of treating an HPK1-mediated disease, disorder, or condition in a patient in need thereof, comprising administering to a patient Compound 5 or composition thereof.
  • the HPK1-mediated disease, disorder, or condition is a proliferative disorder.
  • the proliferative disorder is a cancer.
  • the proliferative disorder is a tumor.
  • the proliferative disorder is associated with one or more activating mutations in HPK1.
  • the cancer is a solid tumor or hematological cancer.
  • the tumor is selected from a leukemia, lymphoma, prostate cancer, colon cancer, esophageal cancer, endometrial cancer, cervical cancer, ovarian cancer, uterine cancer, urothelial cancer, renal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, skin cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, and bladder cancer.
  • Compound 6 (Methanesulfonate Salts of Compound 1) [0252]
  • the present disclosure provides a methanesulfonic acid salt of Compound 1, represented by Compound 6: [0253] It will be the methanesulfonic acid and Compound 1 are ionically bonded to form Compound 6.
  • 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.
  • said compound may be amorphous, crystalline, or a mixture thereof.
  • the present disclosure provides a form Compound 6 substantially free of impurities.
  • impurities or extraneous matter may include different forms of Compound 6, 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 a form of Compound 6 is present.
  • at least about 99% by weight of a form of Compound 6 is present.
  • a form of Compound 6 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • a form of 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.
  • a form of 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.
  • a form of Compound 6 is present with an enantiomeric excess (i.e., ee) of at least 95%, preferably more than 96%, 97%, 98%, 99%, or 99.5% ee. In some embodiments, a form of Compound 6 is present in more than 95% ee.
  • a form of Compound 6 is present in more than 96% ee. In some embodiments, a form of Compound 6 is present in more than 97% ee. In some embodiments, a form of Compound 6 is present in more than 98% ee. In some embodiments, a form of Compound 6 is present in more than 99% ee. In some embodiments, a form of Compound 6 is present in more than 99.5% ee. [0257]
  • the structure depicted for a form of Compound 6 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.
  • Compound 6 can exist in a variety of solid forms. Exemplary such forms include polymorphs such as those described herein.
  • Compound 6 is a crystalline solid. In other embodiments, Compound 6 is a crystalline solid substantially free of amorphous Compound 6.
  • substantially 3 2197122.1 Page 44 of 214 398110-82HPWO (213249) free of amorphous Compound 6 means that the compound contains no significant amount of amorphous Compound 6.
  • 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. [0260] It has been found that Compound 6 can exist in at least two distinct polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of Compound 6 referred to herein as Form 1. In certain embodiments, the present disclosure provides a polymorphic form of Compound 6 referred to herein as Form 2.
  • Form 1 of Compound 6 contains Form 1 and 20% or less, 19% or less, 18% or less, 17% or less, 16% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, or 0.2% or less weight percent of all other solid forms of Compound 6 in total disclosed herein, or of a specified solid form of Compound 6 disclosed herein, such as Form 2.
  • Form 2 of Compound 6 contains Form 2 and 20% or less, 19% or less, 18% or less, 17% or less, 16% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, or 0.2% or less weight percent of all other solid forms of Compound 6 in total disclosed herein, or of a specified solid form of Compound 6 disclosed herein, such as Form 1.
  • Compound 6 is amorphous.
  • Compound 6 is amorphous, and is substantially free of crystalline Compound 6.
  • Form 1 of Compound 6 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 12 below.
  • Form 1 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 6.3, about 14.5, about 17.2, about 17.9, and about 26.9 degrees 2-theta. In some embodiments, Form 1 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 6.3, about 14.5, about 17.2, about 17.9, and about 26.9 degrees 2-theta.
  • Form 1 of Compound 6 is characterized in that it has three or more peaks in its X-ray powder diffraction pattern selected from those at about 6.3, about 14.5, about 17.2, about 17.9, and about 26.9 degrees 2-theta. In some embodiments, Form 1 of Compound 6 is characterized in that it has four or more peaks in its X-ray powder diffraction pattern selected from those at about 6.3, about 14.5, about 17.2, about 17.9, and about 26.9 degrees 2-theta. In some embodiments, Form 1 of Compound 6 is characterized in that it has five peaks in its X-ray powder diffraction pattern selected from those at about 6.3, about 14.5, about 17.2, about 17.9, and about 26.9 degrees 2-theta.
  • the present disclosure provides Form 1 of Compound 6, wherein said compound has thermal DSC events (e.g., endothermic and exothermic) or TGA events (e.g., weight loss and decomposition) substantially similar to those provided in Table 37 or Table 38.
  • the thermal DSC and TGA events are substantially similar to those depicted in the DSC-TGA overlay of FIG.32.
  • Form 1 of Compound 6 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 12 having a relative intensity greater than 10%, 20%, 30% or 40%.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.13.
  • Methods for preparing Form 1 of Compound 6 are described infra.
  • Form 2 of Compound 6 3 2197122.1 Page 46 of 214 398110-82HPWO (213249)
  • Form 2 of Compound 6 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 13 below.
  • Form 2 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 14.8, about 17.6, about 17.9, about 22.4, and about 24.0 degrees 2-theta. In some embodiments, Form 2 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 14.8, about 17.6, about 17.9, about 22.4, and about 24.0 degrees 2-theta.
  • Form 2 of Compound 6 is characterized in that it has three or more peaks in its X-ray powder diffraction pattern selected from those at about 14.8, about 17.6, about 17.9, about 22.4, and about 24.0 degrees 2-theta. In some embodiments, Form 2 of Compound 6 is characterized in that it has four or more peaks in its X-ray powder diffraction pattern selected from those at about 14.8, about 17.6, about 17.9, about 22.4, and about 24.0 degrees 2- theta. In some embodiments, Form 2 of Compound 6 is characterized in that it has five peaks in its X-ray powder diffraction pattern selected from those at about 14.8, about 17.6, about 17.9, about 22.4, and about 24.0 degrees 2-theta.
  • the present disclosure provides Form 2 of Compound 6, wherein said compound has thermal DSC events (e.g., endothermic and exothermic) or TGA events (e.g., weight loss and decomposition) substantially similar to those provided in Table 37 or Table 38.
  • the thermal DSC and TGA events are substantially similar to those depicted in the DSC-TGA overlay of FIG.33.
  • Form 2 of Compound 6 is characterized in that it has each of the spectral 3 2197122.1 Page 47 of 214 398110-82HPWO (213249) peaks in its X-ray powder diffraction pattern listed in Table 13 having a relative intensity greater than 10%, 20%, 30% or 40%.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.14.
  • Methods for preparing Form 2 of Compound 6 are described infra.
  • the disclosure provides Compound 6: wherein said compound is disclosure provides Compound 6, wherein said compound is substantially free of amorphous Compound 6.
  • the present disclosure provides Compound 6, wherein said compound is substantially free of impurities.
  • the present disclosure provides Compound 6, wherein said compound has two or more peaks in its XRPD selected from those at about 6.3, about 14.5, about 17.2, about 17.9, and about 26.9 degrees 2-theta.
  • the present disclosure provides Compound 6, wherein said compound has three or more peaks in its XRPD selected from those at about 6.3, about 14.5, about 17.2, about 17.9, and about 26.9 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 6, wherein said compound is Form 1. [0277] In some embodiments, the present disclosure provides Compound 6, wherein said compound has an XRPD substantially similar to that depicted in FIG.13. [0278] In some embodiments, the present disclosure provides Compound 6, wherein said compound has two or more peaks in its XRPD selected from those at about 14.8, about 17.6, about 17.9, about 22.4, and about 24.0 degrees 2-theta.
  • the present disclosure provides Compound 6, wherein said compound has three or more peaks in its XRPD selected from those at about 14.8, about 17.6, about 17.9, about 22.4, and about 24.0 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 6, wherein said compound is Form 2. 3 2197122.1 Page 48 of 214 398110-82HPWO (213249) [0279] In some embodiments, the present disclosure provides Compound 6, wherein said compound has an XRPD substantially similar to that depicted in FIG.14. [0280] In some embodiments, the present disclosure provides a composition comprising Compound 6 and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a method of modulating HPK1 activity in a patient comprising administering to said patient Compound 6 or composition thereof. In some embodiments, the present invention provides a method of selectively modulating HPK1 activity in a patient comprising administering to said patient Compound 6 or composition thereof. In some embodiments, the present invention provides a method of activating HPK1 in a patient comprising administering to said patient Compound 6 or composition thereof. [0282] In some embodiments, the present invention provides a method of treating an HPK1-mediated disease, disorder, or condition in a patient in need thereof, comprising administering to a patient Compound 6 or composition thereof.
  • the HPK1-mediated disease, disorder, or condition is a proliferative disorder.
  • the proliferative disorder is a cancer.
  • the proliferative disorder is a tumor.
  • the proliferative disorder is associated with one or more activating mutations in HPK1.
  • the cancer is a solid tumor or hematological cancer.
  • the tumor is selected from a leukemia, lymphoma, prostate cancer, colon cancer, esophageal cancer, endometrial cancer, cervical cancer, ovarian cancer, uterine cancer, urothelial cancer, renal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, skin cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, and bladder cancer.
  • Compound 7 (L-Malate Salts of Compound 1) [0283] According to one embodiment, the present disclosure provides a L-malic acid salt of Compound 1, represented by Compound 7: 3 2197122.1 Page 49 of 214 398110-82HPWO (213249) 7 [0284] It will be appreciated by one of ordinary skill in the art that the L-malic acid and Compound 1 are ionically bonded to form Compound 7.
  • Compound 7 can be a L-malate salt, a hydrogen L-malate salt, or mixtures thereof. It is contemplated that Compound 6 can exist in a variety of physical forms. For example, Compound 7 can be in solution, suspension, or in solid form. In certain embodiments, Compound 7 is in solid form.
  • the present disclosure provides a form Compound 7 substantially free of impurities.
  • impurities or extraneous matter may include different forms of Compound 7, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, Compound 7.
  • at least about 95% by weight of a form of Compound 7 is present.
  • at least about 99% by weight of a form of Compound 7 is present.
  • a form of Compound 7 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • a form of Compound 7 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 7 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.
  • a form of Compound 7 is present with an enantiomeric excess (i.e., ee) of at least 95%, preferably more than 96%, 97%, 98%, 99%, or 99.5% ee. In some embodiments, a form of Compound 7 is present in more than 95% ee.
  • a form of Compound 7 is present in more than 96% ee. In some embodiments, a form of Compound 7 is present in more than 97% ee. In some embodiments, a form of Compound 7 is present in more than 98% ee. In some embodiments, a form of Compound 7 is present in more than 99% ee. In some embodiments, a form of Compound 7 is present in more than 99.5% ee. [0288] The structure depicted for a form of Compound 7 is also meant to include all tautomeric forms of Compound 7. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • Compound 7 can exist in a variety of solid forms. Exemplary such forms include polymorphs such as those described herein. [0290] In certain embodiments, Compound 7 is a crystalline solid. In other embodiments, Compound 7 is a crystalline solid substantially free of amorphous Compound 7. As used herein, the term “substantially free of amorphous Compound 7” means that the compound contains no significant amount of amorphous Compound 7.
  • At least about 95% by weight of crystalline Compound 7 is present. In still other embodiments of the disclosure, at least about 99% by weight of crystalline Compound 7 is present. [0291] It has been found that Compound 7 can exist in at least two distinct polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of Compound 7 referred to herein as Form 1. In certain embodiments, the present disclosure provides a polymorphic form of Compound 7 referred to herein as Form 2.
  • Form 1 of Compound 7 contains Form 1 and 20% or less, 19% or less, 18% or less, 17% or less, 16% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, or 0.2% or less weight percent of all other solid forms of Compound 7 in total disclosed herein, or of a specified solid form of Compound 7 disclosed herein, such as Form 2.
  • Form 2 of Compound 7 contains Form 2 and 20% or less, 19% or less, 18% or less, 17% or less, 16% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, or 0.2% or less weight percent of all other solid forms of Compound 7 in total disclosed herein, or of a specified solid form of Compound 7 disclosed herein, such as Form 1.
  • Compound 7 is amorphous.
  • Compound 7 is amorphous, and is substantially free of crystalline Compound 7.
  • Form 1 of Compound 7 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 14 below.
  • Form 1 of Compound 7 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 6.3, about 17.1, about 19.9, about 20.9, and about 24.7 degrees 2-theta. In some embodiments, Form 1 of Compound 7 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 6.3, about 17.1, about 19.9, about 20.9, and about 24.7 degrees 2-theta.
  • Form 1 of Compound 7 is characterized in that it has three or more peaks in its X-ray powder diffraction pattern selected from those at about 6.3, about 17.1, about 19.9, about 20.9, and about 24.7 degrees 2-theta. In some embodiments, Form 1 of Compound 7 is characterized in that it has four or more peaks in its X-ray powder diffraction pattern selected from those at about 6.3, about 17.1, about 19.9, about 20.9, and about 24.7 degrees 2-theta. In some embodiments, Form 1 of Compound 7 is characterized in that it has five peaks in its X-ray powder diffraction pattern selected from those at about 6.3, about 17.1, about 19.9, about 20.9, and about 24.7 degrees 2-theta.
  • the present disclosure provides Form 1 of Compound 7, wherein said compound has thermal DSC events (e.g., endothermic and exothermic) or TGA events (e.g., weight loss and decomposition) substantially similar to those provided in Table 37, Table 38, or Table 39.
  • thermal DSC events e.g., endothermic and exothermic
  • TGA events e.g., weight loss and decomposition
  • the thermal DSC and TGA events are substantially similar to those depicted in the DSC-TGA overlays of FIGs.34 and 42 and DSC spectrum of FIG.35.
  • Form 1 of Compound 7 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 14 having a relative intensity greater than 10%, 20%, 30% or 40%. In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.15. [0299] Methods for preparing Form 1 of Compound 7 are described infra.
  • Form 2 of Compound 7 [0300] In some embodiments, Form 2 of Compound 7 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 15 below.
  • Form 2 of Compound 7 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 4.4, about 12.5, about 15.3, about 17.2, and about 19.2 degrees 2-theta. In some embodiments, Form 2 of Compound 7 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 4.4, about 12.5, about 15.3, about 17.2, and about 19.2 degrees 2-theta.
  • Form 2 of Compound 7 is characterized in that it has three or more peaks in its X-ray powder diffraction pattern selected from those 3 2197122.1 Page 53 of 214 398110-82HPWO (213249) at about 4.4, about 12.5, about 15.3, about 17.2, and about 19.2 degrees 2-theta. In some embodiments, Form 2 of Compound 7 is characterized in that it has four or more peaks in its X-ray powder diffraction pattern selected from those at about 4.4, about 12.5, about 15.3, about 17.2, and about 19.2 degrees 2-theta.
  • Form 2 of Compound 7 is characterized in that it has five peaks in its X-ray powder diffraction pattern selected from those at about 4.4, about 12.5, about 15.3, about 17.2, and about 19.2 degrees 2-theta.
  • the present disclosure provides Form 2 of Compound 7, wherein said compound has thermal DSC events (e.g., endothermic and exothermic) or TGA events (e.g., weight loss and decomposition) substantially similar to those provided in Table 37 or Table 38.
  • Form 2 of Compound 7 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 15 having a relative intensity greater than 10%, 20%, 30% or 40%.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.16.
  • Methods for preparing Form 2 of Compound 7 are described infra.
  • Form 3 of Compound 7 [0305] In some embodiments, Form 3 of Compound 7 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 16 below. Table 16 - XRPD Peak Positions for Form 3 of Compound 7 Position (°2 ⁇ ) Intensity % Position (°2 ⁇ ) Intensity % .
  • Form 3 of Compound 7 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 7.1, about 10.5, about 15.4, about 19.7, 3 2197122.1 Page 54 of 214 398110-82HPWO (213249) and about 21.6 degrees 2-theta.
  • Form 3 of Compound 7 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 7.1, about 10.5, about 15.4, about 19.7, and about 21.6 degrees 2-theta.
  • Form 3 of Compound 7 is characterized in that it has three or more peaks in its X-ray powder diffraction pattern selected from those at about 7.1, about 10.5, about 15.4, about 19.7, and about 21.6 degrees 2-theta. In some embodiments, Form 3 of Compound 7 is characterized in that it has four or more peaks in its X-ray powder diffraction pattern selected from those at about 7.1, about 10.5, about 15.4, about 19.7, and about 21.6 degrees 2-theta. In some embodiments, Form 3 of Compound 7 is characterized in that it has five peaks in its X-ray powder diffraction pattern selected from those at about 7.1, about 10.5, about 15.4, about 19.7, and about 21.6 degrees 2-theta.
  • Form 3 of Compound 7 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 16 having a relative intensity greater than 10%, 20%, 30% or 40%. In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.17. [0308] Methods for preparing Form 3 of Compound 7 are described infra.
  • Form 4 of Compound 7 [0309] In some embodiments, Form 4 of Compound 7 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 17 below.
  • Form 4 of Compound 7 is characterized in that it has one or more peaks 3 2197122.1 Page 55 of 214 398110-82HPWO (213249) in its X-ray powder diffraction pattern selected from those at about 8.5, about 9.2, about 13.7, about 16.2, and about 20.9 degrees 2-theta.
  • Form 4 of Compound 7 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 8.5, about 9.2, about 13.7, about 16.2, and about 20.9 degrees 2-theta. In some embodiments, Form 4 of Compound 7 is characterized in that it has three or more peaks in its X-ray powder diffraction pattern selected from those at about 8.5, about 9.2, about 13.7, about 16.2, and about 20.9 degrees 2-theta. In some embodiments, Form 4 of Compound 7 is characterized in that it has four or more peaks in its X-ray powder diffraction pattern selected from those at about 8.5, about 9.2, about 13.7, about 16.2, and about 20.9 degrees 2-theta.
  • Form 4 of Compound 7 is characterized in that it has five peaks in its X-ray powder diffraction pattern selected from those at about 8.5, about 9.2, about 13.7, about 16.2, and about 20.9 degrees 2-theta. [0311] In some embodiments, Form 4 of Compound 7 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 17 having a relative intensity greater than 10%, 20%, 30% or 40%. In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.18. [0312] Methods for preparing Form 4 of Compound 7 are described infra.
  • the disclosure provides Compound 7: wherein said compound is crystalline. In some embodiments, the present disclosure provides Compound 7, wherein said compound is substantially free of amorphous Compound 7. [0314] In some embodiments, the present disclosure provides Compound 7, wherein said compound is substantially free of impurities. [0315] In some embodiments, the present disclosure provides Compound 7, wherein said compound has two or more peaks in its XRPD selected from those at about 6.3, about 17.1, about 19.9, about 20.9, 3 2197122.1 Page 56 of 214 398110-82HPWO (213249) and about 24.7 degrees 2-theta.
  • the present disclosure provides Compound 7, wherein said compound has three or more peaks in its XRPD selected from those at about 6.3, about 17.1, about 19.9, about 20.9, and about 24.7 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 7, wherein said compound is Form 1. [0316] In some embodiments, the present disclosure provides Compound 7, wherein said compound has an XRPD substantially similar to that depicted in FIG.15. [0317] In some embodiments, the present disclosure provides Compound 7, wherein said compound has two or more peaks in its XRPD selected from those at about 4.4, about 12.5, about 15.3, about 17.2, and about 19.2 degrees 2-theta.
  • the present disclosure provides Compound 7, wherein said compound has three or more peaks in its XRPD selected from those at about 4.4, about 12.5, about 15.3, about 17.2, and about 19.2 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 7, wherein said compound is Form 2. [0318] In some embodiments, the present disclosure provides Compound 7, wherein said compound has an XRPD substantially similar to that depicted in FIG.16. [0319] In some embodiments, the present disclosure provides Compound 7, wherein said compound has two or more peaks in its XRPD selected from those at about 7.1, about 10.5, about 15.4, about 19.7, and about 21.6 degrees 2-theta.
  • the present disclosure provides Compound 7, wherein said compound has three or more peaks in its XRPD selected from those at about 7.1, about 10.5, about 15.4, about 19.7, and about 21.6 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 7, wherein said compound is Form 2. [0320] In some embodiments, the present disclosure provides Compound 7, wherein said compound has an XRPD substantially similar to that depicted in FIG.17. [0321] In some embodiments, the present disclosure provides Compound 7, wherein said compound has two or more peaks in its XRPD selected from those at about 8.5, about 9.2, about 13.7, about 16.2, and about 20.9 degrees 2-theta.
  • the present disclosure provides Compound 7, wherein said compound has three or more peaks in its XRPD selected from those at about 8.5, about 9.2, about 13.7, about 16.2, and about 20.9 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 7, wherein said compound is Form 2. [0322] In some embodiments, the present disclosure provides Compound 7, wherein said compound has an XRPD substantially similar to that depicted in FIG.18. [0323] In some embodiments, the present disclosure provides a composition comprising Compound 7 and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a method of modulating HPK1 activity 3 2197122.1 Page 57 of 214 398110-82HPWO (213249) in a patient comprising administering to said patient Compound 7 or composition thereof. In some embodiments, the present invention provides a method of selectively modulating HPK1 activity in a patient comprising administering to said patient Compound 7 or composition thereof. In some embodiments, the present invention provides a method of activating HPK1 in a patient comprising administering to said patient Compound 7 or composition thereof. [0325] In some embodiments, the present invention provides a method of treating an HPK1-mediated disease, disorder, or condition in a patient in need thereof, comprising administering to a patient Compound 7 or composition thereof.
  • the HPK1-mediated disease, disorder, or condition is a proliferative disorder.
  • the proliferative disorder is a cancer.
  • the proliferative disorder is a tumor.
  • the proliferative disorder is associated with one or more activating mutations in HPK1.
  • the cancer is a solid tumor or hematological cancer.
  • the tumor is selected from a leukemia, lymphoma, prostate cancer, colon cancer, esophageal cancer, endometrial cancer, cervical cancer, ovarian cancer, uterine cancer, urothelial cancer, renal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, skin cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, and bladder cancer.
  • Compound 8 Phosphate Salts of Compound 1 [0326]
  • the present disclosure provides a phosphoric acid salt of Compound 1, represented by Compound 8: [0327] It will be phosphoric acid and Compound 1 are ionically bonded to form Compound 8.
  • Compound 8 can be a phosphate salt, a hydrogen phosphate salt, or mixtures thereof. It is contemplated that Compound 6 can exist in a variety of physical forms. For example, Compound 8 can be in solution, suspension, or in solid form. In certain 3 2197122.1 Page 58 of 214 398110-82HPWO (213249) embodiments, Compound 8 is in solid form. When Compound 8 is in solid form, said compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below. [0328] In some embodiments, the present disclosure provides a form Compound 8 substantially free of impurities.
  • Such impurities or extraneous matter may include different forms of Compound 8, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, Compound 8.
  • at least about 95% by weight of a form of Compound 8 is present.
  • at least about 99% by weight of a form of Compound 8 is present.
  • a form of Compound 8 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • a form of Compound 8 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 8 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.
  • a form of Compound 8 is present with an enantiomeric excess (i.e., ee) of at least 95%, preferably more than 96%, 97%, 98%, 99%, or 99.5% ee. In some embodiments, a form of Compound 8 is present in more than 95% ee. In some embodiments, a form of Compound 8 is present in more than 96% ee. In some embodiments, a form of Compound 8 is present in more than 97% ee. In some embodiments, a form of Compound 8 is present in more than 98% ee. In some embodiments, a form of Compound 8 is present in more than 99% ee.
  • ee an enantiomeric excess
  • a form of Compound 8 is present in more than 99.5% ee.
  • the structure depicted for a form of Compound 8 is also meant to include all tautomeric forms of Compound 8. 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 8 can exist in a variety of solid forms. Exemplary such forms include polymorphs such as those described herein.
  • Compound 8 is a crystalline solid. In other embodiments, Compound 8 is a crystalline solid substantially free of amorphous Compound 8. As used herein, the term “substantially free of amorphous Compound 8” means that the compound contains no significant amount of amorphous 3 2197122.1 Page 59 of 214 398110-82HPWO (213249) Compound 8. In certain embodiments, at least about 95% by weight of crystalline Compound 8 is present. In still other embodiments of the disclosure, at least about 99% by weight of crystalline Compound 8 is present. [0334] It has been found that Compound 8 can exist in at least three distinct polymorphic form.
  • the present disclosure provides a polymorphic form of Compound 8 referred to herein as Form 1. In certain embodiments, the present disclosure provides a polymorphic form of Compound 8 referred to herein as Form 2. In certain embodiments, the present disclosure provides a polymorphic form of Compound 8 referred to herein as Form 3.
  • Form 1 of Compound 8 contains Form 1 and 20% or less, 19% or less, 18% or less, 17% or less, 16% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, or 0.2% or less weight percent of all other solid forms of Compound 8 in total disclosed herein, or of a specified solid form of Compound 8 disclosed herein, such as Form 2 or Form 3.
  • Form 2 of Compound 8 contains Form 2 and 20% or less, 19% or less, 18% or less, 17% or less, 16% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, or 0.2% or less weight percent of all other solid forms of Compound 8 in total disclosed herein, or of a specified solid form of Compound 8 disclosed herein, such as Form 1 or Form 3.
  • Form 3 of Compound 8 contains Form 3 and 20% or less, 19% or less, 18% or less, 17% or less, 16% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, or 0.2% or less weight percent of all other solid forms of Compound 8 in total disclosed herein, or of a specified solid form of Compound 8 disclosed herein, such as Form 1 or Form 2.
  • Compound 8 is amorphous.
  • Compound 8 is amorphous, and is substantially free of crystalline Compound 8.
  • Form 1 of Compound 8 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 18 below.
  • Form 1 of Compound 8 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 5.0, about 7.6, about 18.2, about 24.1, and about 26.4 degrees 2-theta. In some embodiments, Form 1 of Compound 8 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 5.0, about 7.6, about 18.2, about 24.1, and about 26.4 degrees 2-theta.
  • Form 1 of Compound 8 is characterized in that it has three or more peaks in its X-ray powder diffraction pattern selected from those at about 5.0, about 7.6, about 18.2, about 24.1, and about 26.4 degrees 2-theta. In some embodiments, Form 1 of Compound 8 is characterized in that it has four or more peaks in its X-ray powder diffraction pattern selected from those at about 5.0, about 7.6, about 18.2, about 24.1, and about 26.4 degrees 2-theta. In some embodiments, Form 1 of Compound 8 is characterized in that it has five peaks in its X-ray powder diffraction pattern selected from those at about 5.0, about 7.6, about 18.2, about 24.1, and about 26.4 degrees 2-theta.
  • the present disclosure provides Form 1 of Compound 8, wherein said compound has thermal DSC events (e.g., endothermic and exothermic) or TGA events (e.g., weight loss and decomposition) substantially similar to those provided in Table 37 or Table 38.
  • Form 1 of Compound 8 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 18 having a relative intensity greater than 10%, 20%, 30% or 40%.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.19.
  • Form 2 of Compound 8 3 2197122.1 Page 61 of 214 398110-82HPWO (213249) [0001]
  • Form 2 of Compound 8 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 19 below.
  • Form 2 of Compound 8 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 5.4, about 15.3, about 17.1, about 23.4, and about 24.3 degrees 2-theta.
  • Form 2 of Compound 8 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 5.4, about 15.3, about 17.1, about 23.4, and about 24.3 degrees 2-theta. In some embodiments, Form 2 of Compound 8 is characterized in that it has three or more peaks in its X-ray powder diffraction pattern selected from those at about 5.4, about 15.3, about 17.1, about 23.4, and about 24.3 degrees 2-theta. In some embodiments, Form 2 of Compound 8 is characterized in that it has four or more peaks in its X-ray powder diffraction pattern selected from those at about 5.4, about 15.3, about 17.1, about 23.4, and about 24.3 degrees 2-theta.
  • Form 2 of Compound 8 is characterized in that it has five peaks in its X-ray powder diffraction pattern selected from those at about 5.4, about 15.3, about 17.1, about 23.4, and about 24.3 degrees 2-theta.
  • the present disclosure provides Form 2 of Compound 8, wherein said compound has thermal DSC events (e.g., endothermic and exothermic) or TGA events (e.g., weight loss and decomposition) substantially similar to those provided in Table 37 or Table 38.
  • Form 2 of Compound 8 is characterized in that it has each of the spectral 3 2197122.1 Page 62 of 214 398110-82HPWO (213249) peaks in its X-ray powder diffraction pattern listed in Table 19 having a relative intensity greater than 10%, 20%, 30% or 40%.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.20.
  • Methods for preparing Form 2 of Compound 8 are described infra.
  • Form 3 of Compound 8 [0348] In some embodiments, Form 3 of Compound 8 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 20 below.
  • Form 3 of Compound 8 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 6.9, about 16.7, about 18.5, about 22.4, and about 22.9 degrees 2-theta. In some embodiments, Form 3 of Compound 8 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 6.9, about 16.7, about 18.5, about 22.4, and about 22.9 degrees 2-theta.
  • Form 3 of Compound 8 is characterized in that it has three or more peaks in its X-ray powder diffraction pattern selected from those at about 6.9, about 16.7, about 18.5, about 22.4, and about 22.9 degrees 2-theta. In some embodiments, Form 3 of Compound 8 is characterized in that it has four or more peaks in its X-ray powder diffraction pattern selected from those at about 6.9, about 16.7, about 18.5, about 22.4, and about 22.9 degrees 2-theta. In some embodiments, Form 3 of Compound 8 is characterized in that it has five peaks in its X-ray powder diffraction pattern selected from those at about 6.9, about 16.7, about 18.5, about 22.4, and about 22.9 degrees 2-theta.
  • Form 3 of Compound 8 wherein said compound has thermal DSC events (e.g., endothermic and exothermic) or TGA events (e.g., weight loss and decomposition) substantially similar to those provided in Table 37 or Table 38.
  • Form 3 of Compound 8 is characterized in that it has each of the spectral 3 2197122.1 Page 63 of 214 398110-82HPWO (213249) peaks in its X-ray powder diffraction pattern listed in Table 20 having a relative intensity greater than 10%, 20%, 30% or 40%.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.21.
  • the disclosure provides Compound 8: wherein said compound is disclosure provides Compound 8, wherein said compound is substantially free of amorphous Compound 8.
  • the present disclosure provides Compound 8, wherein said compound is substantially free of impurities.
  • the present disclosure provides Compound 8, wherein said compound has two or more peaks in its XRPD selected from those at about 5.0, about 7.6, about 18.2, about 24.1, and about 26.4 degrees 2-theta.
  • the present disclosure provides Compound 8, wherein said compound has three or more peaks in its XRPD selected from those at about 5.0, about 7.6, about 18.2, about 24.1, and about 26.4 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 8, wherein said compound is Form 1. [0356] In some embodiments, the present disclosure provides Compound 8, wherein said compound has an XRPD substantially similar to that depicted in FIG.19. [0357] In some embodiments, the present disclosure provides Compound 8, wherein said compound has two or more peaks in its XRPD selected from those at about 5.4, about 15.3, about 17.1, about 23.4, and about 24.3 degrees 2-theta.
  • the present disclosure provides Compound 8, wherein said compound has three or more peaks in its XRPD selected from those at about 5.4, about 15.3, about 17.1, about 23.4, and about 24.3 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 8, wherein said compound is Form 2. 3 2197122.1 Page 64 of 214 398110-82HPWO (213249) [0358] In some embodiments, the present disclosure provides Compound 8, wherein said compound has an XRPD substantially similar to that depicted in FIG.20.
  • the present disclosure provides Compound 8, wherein said compound has two or more peaks in its XRPD selected from those at about 6.9, about 16.7, about 18.5, about 22.4, and about 22.9 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 8, wherein said compound has three or more peaks in its XRPD selected from those at about 6.9, about 16.7, about 18.5, about 22.4, and about 22.9 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 8, wherein said compound is Form 3. [0360] In some embodiments, the present disclosure provides Compound 8, wherein said compound has an XRPD substantially similar to that depicted in FIG.21.
  • the present disclosure provides a composition comprising Compound 8 and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a method of modulating HPK1 activity in a patient comprising administering to said patient Compound 8 or composition thereof.
  • the present invention provides a method of selectively modulating HPK1 activity in a patient comprising administering to said patient Compound 8 or composition thereof.
  • the present invention provides a method of activating HPK1 in a patient comprising administering to said patient Compound 8 or composition thereof.
  • the present invention provides a method of treating an HPK1-mediated disease, disorder, or condition in a patient in need thereof, comprising administering to a patient Compound 8 or composition thereof.
  • the HPK1-mediated disease, disorder, or condition is a proliferative disorder.
  • the proliferative disorder is a cancer.
  • the proliferative disorder is a tumor.
  • the proliferative disorder is associated with one or more activating mutations in HPK1.
  • the cancer is a solid tumor or hematological cancer.
  • the tumor is selected from a leukemia, lymphoma, prostate cancer, colon cancer, esophageal cancer, endometrial cancer, cervical cancer, ovarian cancer, uterine cancer, urothelial cancer, renal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, skin cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, and bladder cancer.
  • Compound 9 (L-Tartarate Salts of Compound 1) [0364]
  • the present disclosure provides a L-tartaric acid salt of Compound 1, represented by Compound 9: 3 2197122.1 Page 65 of 214 398110-82HPWO (213249)
  • Compound 9 can be a L-tartarate salt, a hydrogen L-tartarate salt, or mixtures thereof. It is contemplated that Compound 9 can exist in a variety of physical forms. For example, Compound 9 can be in solution, suspension, or in solid form. In certain embodiments, Compound 9 is in solid form. When Compound 9 is in solid form, said compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below. [0366] In some embodiments, the present disclosure provides a form Compound 9 substantially free of impurities.
  • Such impurities or extraneous matter may include different forms of Compound 9, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, Compound 9.
  • at least about 95% by weight of a form of Compound 9 is present.
  • at least about 99% by weight of a form of Compound 9 is present.
  • a form of Compound 9 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • a form of Compound 9 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 9 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.
  • a form of Compound 9 is present with an enantiomeric excess (i.e., ee) of at least 95%, preferably more than 96%, 97%, 98%, 99%, or 99.5% ee. In some embodiments, a form of Compound 9 is present in more than 95% ee. In some embodiments, a form of Compound 9 is 3 2197122.1 Page 66 of 214 398110-82HPWO (213249) present in more than 96% ee. In some embodiments, a form of Compound 9 is present in more than 97% ee. In some embodiments, a form of Compound 9 is present in more than 98% ee.
  • a form of Compound 9 is present in more than 99% ee. In some embodiments, a form of Compound 9 is present in more than 99.5% ee.
  • the structure depicted for a form of Compound 9 is also meant to include all tautomeric forms of Compound 9. 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. [0370] It has been found that Compound 9 can exist in a variety of solid forms.
  • Compound 9 is a crystalline solid. In other embodiments, Compound 9 is a crystalline solid substantially free of amorphous Compound 9. As used herein, the term “substantially free of amorphous Compound 9” means that the compound contains no significant amount of amorphous Compound 9. In certain embodiments, at least about 95% by weight of crystalline Compound 9 is present. In still other embodiments of the disclosure, at least about 99% by weight of crystalline Compound 9 is present. [0372] It has been found that Compound 9 can exist in at least three distinct polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of Compound 9 referred to herein as Form 1.
  • Form 1 of Compound 9 contains Form 1 and 20% or less, 19% or less, 18% or less, 17% or less, 16% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, or 0.2% or less weight percent of all other solid forms of Compound 9 in total disclosed herein, or of a specified solid form of Compound 9 disclosed herein, such as Form 2 or Form 3.
  • Form 2 of Compound 9 contains Form 2 and 20% or less, 19% or less, 18% or less, 17% or less, 16% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, or 0.2% or less weight percent of all other solid forms of Compound 9 in total disclosed herein, or of a specified solid form of Compound 9 disclosed herein, such as Form 1 or Form 3.
  • Form 3 of Compound 9 contains Form 3 and 20% or less, 19% or less, 3 2197122.1 Page 67 of 214 398110-82HPWO (213249) 18% or less, 17% or less, 16% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, or 0.2% or less weight percent of all other solid forms of Compound 9 in total disclosed herein, or of a specified solid form of Compound 9 disclosed herein, such as Form 1 or Form 2.
  • Compound 9 is amorphous. In some embodiments, Compound 9 is amorphous, and is substantially free of crystalline Compound 9.
  • Form 1 of Compound 9 [0377] In some embodiments, Form 1 of Compound 9 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 21 below. Table 21 - XRPD Peak Positions for Form 1 of Compound 9 Position (°2 ⁇ ) Intensity % Position (°2 ⁇ ) Intensity % 63 763 214 100 .
  • Form 1 of Compound 9 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 6.3, about 17.1, about 19.8, about 24.2, and about 25.8 degrees 2-theta. In some embodiments, Form 1 of Compound 9 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 6.3, about 17.1, about 19.8, about 24.2, and about 25.8 degrees 2-theta.
  • Form 1 of Compound 9 is 3 2197122.1 Page 68 of 214 398110-82HPWO (213249) characterized in that it has three or more peaks in its X-ray powder diffraction pattern selected from those at about 6.3, about 17.1, about 19.8, about 24.2, and about 25.8 degrees 2-theta. In some embodiments, Form 1 of Compound 9 is characterized in that it has four or more peaks in its X-ray powder diffraction pattern selected from those at about 6.3, about 17.1, about 19.8, about 24.2, and about 25.8 degrees 2-theta.
  • Form 1 of Compound 9 is characterized in that it has five peaks in its X-ray powder diffraction pattern selected from those at about 6.3, about 17.1, about 19.8, about 24.2, and about 25.8 degrees 2-theta.
  • the present disclosure provides Form 1 of Compound 8, wherein said compound has thermal DSC events (e.g., endothermic and exothermic) or TGA events (e.g., weight loss and decomposition) substantially similar to those provided in Table 37, Table 38, or Table 40.
  • the thermal DSC and TGA events are substantially similar to those depicted in the DSC-TGA overlay and DSC spectrum of FIGs.36-37.
  • Form 1 of Compound 9 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 21 having a relative intensity greater than 10%, 20%, 30% or 40%. In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.22. [0381] Methods for preparing Form 1 of Compound 9 are described infra. Form 2 of Compound 9 [0382] In some embodiments, Form 2 of Compound 9 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 22 below.
  • Form 2 of Compound 9 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 6.2, about 12.5, about 15.3, about 24.7, and about 26.3 degrees 2-theta.
  • Form 2 of Compound 9 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 6.2, about 12.5, about 15.3, about 24.7, and about 26.3 degrees 2-theta. In some embodiments, Form 2 of Compound 9 is characterized in that it has three or more peaks in its X-ray powder diffraction pattern selected from those at about 6.2, about 12.5, about 15.3, about 24.7, and about 26.3 degrees 2-theta. In some embodiments, Form 2 of Compound 9 is characterized in that it has four or more peaks in its X-ray powder diffraction pattern selected from those at about 6.2, about 12.5, about 15.3, about 24.7, and about 26.3 degrees 2-theta.
  • Form 2 of Compound 9 is characterized in that it has five peaks in its X-ray powder diffraction pattern selected from those at about 6.2, about 12.5, about 15.3, about 24.7, and about 26.3 degrees 2-theta.
  • the present disclosure provides Form 2 of Compound 9, wherein said compound has thermal DSC events (e.g., endothermic and exothermic) or TGA events (e.g., weight loss and decomposition) substantially similar to those provided in Table 37 or Table 38.
  • the thermal DSC and TGA events are substantially similar to those depicted in the DSC-TGA overlay of FIG.41.
  • Form 2 of Compound 9 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 22 having a relative intensity greater than 10%, 20%, 30% or 40%. In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.23. [0386] Methods for preparing Form 2 of Compound 9 are described infra.
  • Form 3 of Compound 9 [0387] In some embodiments, Form 3 of Compound 9 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 23 below.
  • Form 3 of Compound 9 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 6.1, about 6.5, about 15.4, about 24.2, and about 24.7 degrees 2-theta.
  • Form 3 of Compound 9 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 6.1, about 6.5, about 15.4, about 24.2, and about 24.7 degrees 2-theta. In some embodiments, Form 3 of Compound 9 is characterized in that it has three or more peaks in its X-ray powder diffraction pattern selected from those at about 6.1, about 6.5, about 15.4, about 24.2, and about 24.7 degrees 2-theta. In some embodiments, Form 3 of Compound 9 is characterized in that it has four or more peaks in its X-ray powder diffraction pattern selected from those at about 6.1, about 6.5, about 15.4, about 24.2, and about 24.7 degrees 2-theta.
  • Form 3 of Compound 9 is characterized in that it has five peaks in its X-ray powder diffraction pattern selected from those at about 6.1, about 6.5, about 15.4, about 24.2, and about 24.7 degrees 2-theta.
  • the present disclosure provides Form 3 of Compound 9, wherein said compound has thermal DSC events (e.g., endothermic and exothermic) or TGA events (e.g., weight loss and decomposition) substantially similar to those provided in Table 38 or Table 39.
  • Form 3 of Compound 9 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 23 having a relative intensity greater than 10%, 20%, 30% or 40%.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.24.
  • Methods for preparing Form 3 of Compound 9 are described infra.
  • the disclosure provides Compound 9: 3 2197122.1 Page 71 of 214 398110-82HPWO (213249)
  • the present disclosure provides Compound 9, wherein said compound is substantially free of amorphous Compound 9.
  • the present disclosure provides Compound 9, wherein said compound is substantially free of impurities.
  • the present disclosure provides Compound 9, wherein said compound has two or more peaks in its XRPD selected from those at about 6.3, about 17.1, about 19.8, about 24.2, and about 25.8 degrees 2-theta.
  • the present disclosure provides Compound 9, wherein said compound has three or more peaks in its XRPD selected from those at about 6.3, about 17.1, about 19.8, about 24.2, and about 25.8 degrees 2-theta.
  • the present disclosure provides Compound 9, wherein said compound is Form 1.
  • the present disclosure provides Compound 9, wherein said compound has an XRPD substantially similar to that depicted in FIG.22. [0396] In some embodiments, the present disclosure provides Compound 9, wherein said compound has two or more peaks in its XRPD selected from those at about 6.2, about 12.5, about 15.3, about 24.7, and about 26.3 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 9, wherein said compound has three or more peaks in its XRPD selected from those at about 6.2, about 12.5, about 15.3, about 24.7, and about 26.3 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 9, wherein said compound is Form 2.
  • the present disclosure provides Compound 9, wherein said compound has an XRPD substantially similar to that depicted in FIG.23. [0398] In some embodiments, the present disclosure provides Compound 9, wherein said compound has two or more peaks in its XRPD selected from those at about 6.1, about 6.5, about 15.4, about 24.2, and about 24.7 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 3 2197122.1 Page 72 of 214 398110-82HPWO (213249) 9, wherein said compound has three or more peaks in its XRPD selected from those at about 6.1, about 6.5, about 15.4, about 24.2, and about 24.7 degrees 2-theta.
  • the present disclosure provides Compound 9, wherein said compound is Form 3. [0399] In some embodiments, the present disclosure provides Compound 9, wherein said compound has an XRPD substantially similar to that depicted in FIG.24. [0400] In some embodiments, the present disclosure provides a composition comprising Compound 9 and a pharmaceutically acceptable carrier or excipient. [0401] In some embodiments, the present invention provides a method of modulating HPK1 activity in a patient comprising administering to said patient Compound 9 or composition thereof. In some embodiments, the present invention provides a method of selectively modulating HPK1 activity in a patient comprising administering to said patient Compound 9 or composition thereof.
  • the present invention provides a method of activating HPK1 in a patient comprising administering to said patient Compound 9 or composition thereof.
  • the present invention provides a method of treating an HPK1-mediated disease, disorder, or condition in a patient in need thereof, comprising administering to a patient Compound 9 or composition thereof.
  • the HPK1-mediated disease, disorder, or condition is a proliferative disorder.
  • the proliferative disorder is a cancer.
  • the proliferative disorder is a tumor.
  • the proliferative disorder is associated with one or more activating mutations in HPK1.
  • the cancer is a solid tumor or hematological cancer.
  • the tumor is selected from a leukemia, lymphoma, prostate cancer, colon cancer, esophageal cancer, endometrial cancer, cervical cancer, ovarian cancer, uterine cancer, urothelial cancer, renal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, skin cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, and bladder cancer.
  • Compound 10 (Fumarate Salts of Compound 1) [0403]
  • the present disclosure provides a fumaric acid salt of Compound 1, represented by Compound 10: 3 2197122.1 Page 73 of 214 398110-82HPWO (213249)
  • Compound 10 can be a fumarate salt, a hydrogen fumarate salt, or mixtures thereof. It is contemplated that Compound 10 can exist in a variety of physical forms. For example, Compound 10 can be in solution, suspension, or in solid form. In certain embodiments, Compound 10 is in solid form. When Compound 10 is in solid form, said compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below. [0405] In some embodiments, the present disclosure provides a form Compound 10 substantially free of impurities.
  • Such impurities or extraneous matter may include different forms of Compound 10, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, Compound 10.
  • at least about 95% by weight of a form of Compound 10 is present.
  • at least about 99% by weight of a form of Compound 10 is present.
  • a form of Compound 10 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • a form of Compound 10 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 10 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.
  • a form of Compound 10 is present with an enantiomeric excess (i.e., ee) of at least 95%, preferably more than 96%, 97%, 98%, 99%, or 99.5% ee. In some embodiments, a form of Compound 10 is present in more than 95% ee. In some embodiments, a form of Compound 10 3 2197122.1 Page 74 of 214 398110-82HPWO (213249) is present in more than 96% ee. In some embodiments, a form of Compound 10 is present in more than 97% ee. In some embodiments, a form of Compound 10 is present in more than 98% ee.
  • a form of Compound 10 is present in more than 99% ee. In some embodiments, a form of Compound 10 is present in more than 99.5% ee.
  • the structure depicted for a form of Compound 10 is also meant to include all tautomeric forms of Compound 10. 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. [0409] It has been found that Compound 10 can exist in a variety of solid forms.
  • Compound 10 is a crystalline solid. In other embodiments, Compound 10 is a crystalline solid substantially free of amorphous Compound 10. As used herein, the term “substantially free of amorphous Compound 10” means that the compound contains no significant amount of amorphous Compound 10. In certain embodiments, at least about 95% by weight of crystalline Compound 10 is present. In still other embodiments of the disclosure, at least about 99% by weight of crystalline Compound 10 is present. [0411] It has been found that Compound 10 can exist in at least three distinct polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of Compound 10 referred to herein as Form 1.
  • Form 1 of Compound 10 contains Form 1 and 20% or less, 19% or less, 18% or less, 17% or less, 16% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, or 0.2% or less weight percent of all other solid forms of Compound 10 in total disclosed herein, or of a specified solid form of Compound 10 disclosed herein, such as Form 2, Form 3, or Form 4.
  • Form 2 of Compound 10 contains Form 2 and 20% or less, 19% or less, 18% or less, 17% or less, 16% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, or 0.2% or less weight percent of all other solid forms of Compound 10 in total disclosed herein, or of a specified solid form of Compound 10 disclosed herein, such as Form 1, Form 3, or Form 4.
  • Form 3 of Compound 10 contains Form 3 and 20% or less, 19% or less, 3 2197122.1 Page 75 of 214 398110-82HPWO (213249) 18% or less, 17% or less, 16% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, or 0.2% or less weight percent of all other solid forms of Compound 10 in total disclosed herein, or of a specified solid form of Compound 10 disclosed herein, such as Form 1, Form 2, or Form 4.
  • Form 4 of Compound 10 contains Form 4 and 20% or less, 19% or less, 18% or less, 17% or less, 16% or less, 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, or 0.2% or less weight percent of all other solid forms of Compound 10 in total disclosed herein, or of a specified solid form of Compound 10 disclosed herein, such as Form 1, Form 2, or Form 3.
  • Compound 10 is amorphous.
  • Compound 10 is amorphous, and is substantially free of crystalline Compound 10.
  • Form 1 of Compound 10 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 24 below. Table 24 - XRPD Peak Positions for Form 1 of Compound 10 Position (°2 ⁇ ) Intensity % Position (°2 ⁇ ) Intensity % .
  • Form 1 of Compound 10 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 4.8, about 15.2, about 19.7, about 24.4, and about 25.3 degrees 2-theta.
  • Form 1 of Compound 10 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 4.8, about 15.2, about 19.7, about 24.4, and about 25.3 degrees 2-theta. In some embodiments, Form 1 of Compound 10 is characterized in that it has three or more peaks in its X-ray powder diffraction pattern selected from those at about 4.8, about 15.2, about 19.7, about 24.4, and about 25.3 degrees 2-theta. In some embodiments, Form 1 of Compound 10 is characterized in that it has four or more peaks in its X-ray powder diffraction pattern selected from those at about 4.8, about 15.2, about 19.7, about 24.4, and about 25.3 degrees 2-theta.
  • Form 1 of Compound 10 is characterized in that it has five peaks in its X-ray powder diffraction pattern selected from those at about 4.8, about 15.2, about 19.7, about 24.4, and about 25.3 degrees 2-theta.
  • the present disclosure provides Form 1 of Compound 10, wherein said compound has thermal DSC events (e.g., endothermic and exothermic) or TGA events (e.g., weight loss and decomposition) substantially similar to those provided in Table 37 or Table 38.
  • the thermal DSC and TGA events are substantially similar to those depicted in the DSC-TGA overlay of FIG.36.
  • Form 1 of Compound 10 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 24 having a relative intensity greater than 10%, 20%, 30% or 40%. In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.25. [0421] Methods for preparing Form 1 of Compound 10 are described infra.
  • Form 2 of Compound 10 [0422] In some embodiments, Form 2 of Compound 10 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 25 below.
  • Form 2 of Compound 10 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 6.2, about 14.7, about 15.4, about 19.2, and about 24.7 degrees 2-theta.
  • Form 2 of Compound 10 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 6.2, about 14.7, about 15.4, about 19.2, and about 24.7 degrees 2-theta. In some embodiments, Form 2 of Compound 10 is characterized in that it has three or more peaks in its X-ray powder diffraction pattern selected from those at about 6.2, about 14.7, about 15.4, about 19.2, and about 24.7 degrees 2-theta. In some embodiments, Form 2 of Compound 10 is characterized in that it has four or more peaks in its X-ray powder diffraction pattern selected from those at about 6.2, about 14.7, about 15.4, about 19.2, and about 24.7 degrees 2-theta.
  • Form 2 of Compound 10 is characterized in that it has five peaks in its X-ray powder diffraction pattern selected from those at about 6.2, about 14.7, about 15.4, about 19.2, and about 24.7 degrees 2-theta.
  • the present disclosure provides Form 2 of Compound 10, wherein said compound has thermal DSC events (e.g., endothermic and exothermic) or TGA events (e.g., weight loss and decomposition) substantially similar to those provided in Table 37 or Table 38.
  • the thermal DSC and TGA events are substantially similar to those depicted in the DSC-TGA overlay of FIG.39.
  • Form 2 of Compound 10 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 25 having a relative intensity greater than 10%, 20%, 30% or 40%. In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.26. [0426] Methods for preparing Form 2 of Compound 10 are described infra.
  • Form 3 of Compound 10 [0002] In some embodiments, Form 3 of Compound 10 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 26 below.
  • Form 3 of Compound 10 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 15.2, about 18.9, about 23.2, and about 25.3 degrees 2-theta.
  • Form 3 of Compound 10 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 15.2, about 18.9, about 23.2, and about 25.3 degrees 2-theta. In some embodiments, Form 3 of Compound 10 is characterized in that it has three or more peaks in its X-ray powder diffraction pattern selected from those at about 7.8, about 15.2, about 18.9, about 23.2, and about 25.3 degrees 2-theta. In some embodiments, Form 3 of Compound 10 is characterized in that it has four or more peaks in its X-ray powder diffraction pattern selected from those at about 7.8, about 15.2, about 18.9, about 23.2, and about 25.3 degrees 2-theta.
  • Form 3 of Compound 10 is characterized in that it has five peaks in its X-ray powder diffraction pattern selected from those at about 7.8, about 15.2, about 18.9, about 23.2, and about 25.3 degrees 2-theta.
  • the present disclosure provides Form 3 of Compound 10, wherein said compound has thermal DSC events (e.g., endothermic and exothermic) or TGA events (e.g., weight loss and decomposition) substantially similar to those provided in Table 38, Table 39, or Table 42.
  • the thermal DSC and TGA events are substantially similar to those depicted in the DSC-TGA overlay of FIG.44.
  • Form 3 of Compound 10 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 26 having a relative intensity greater than 10%, 20%, 30% or 40%.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.27. 3 2197122.1 Page 79 of 214 398110-82HPWO (213249) [0430] Methods for preparing Form 3 of Compound 10 are described infra.
  • Form 4 of Compound 10 [0003] In some embodiments, Form 4 of Compound 10 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 27 below.
  • Form 4 of Compound 10 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 2.0, about 4.6, about 9.0, about 24.0, and about 26.6 degrees 2-theta. In some embodiments, Form 4 of Compound 10 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 2.0, about 4.6, about 9.0, about 24.0, and about 26.6 degrees 2-theta.
  • Form 4 of Compound 10 is characterized in that it has three or more peaks in its X-ray powder diffraction pattern selected from those at about 2.0, about 4.6, about 9.0, about 24.0, and about 26.6 degrees 2-theta. In some embodiments, Form 4 of Compound 10 is characterized in that it has four or more peaks in its X-ray powder diffraction pattern selected from those at about 2.0, about 4.6, about 9.0, about 24.0, and about 26.6 degrees 2-theta. In some embodiments, Form 4 of Compound 10 is characterized in that it has five peaks in its X-ray powder diffraction pattern selected from those at about 2.0, about 4.6, about 9.0, about 24.0, and about 26.6 degrees 2-theta.
  • the present disclosure provides Form 4 of Compound 10, wherein said compound has thermal DSC events (e.g., endothermic and exothermic) or TGA events (e.g., weight loss and decomposition) substantially similar to those provided in Table 37 or Table 38.
  • Form 4 of Compound 10 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 27 having a relative intensity greater than 10%, 20%, 30% or 40%.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.28.
  • the disclosure provides Compound 10: wherein said compound is some disclosure provides Compound 10, wherein said compound is substantially free of amorphous Compound 10. [0436] In some embodiments, the present disclosure provides Compound 10, wherein said compound is substantially free of impurities. [0437] In some embodiments, the present disclosure provides Compound 10, wherein said compound has two or more peaks in its XRPD selected from those at about 4.8, about 15.2, about 19.7, about 24.4, and about 25.3degrees 2-theta.
  • the present disclosure provides Compound 10, wherein said compound has three or more peaks in its XRPD selected from those at about 4.8, about 15.2, about 19.7, about 24.4, and about 25.3 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 10, wherein said compound is Form 1. [0438] In some embodiments, the present disclosure provides Compound 10, wherein said compound has an XRPD substantially similar to that depicted in FIG.25. [0439] In some embodiments, the present disclosure provides Compound 10, wherein said compound has two or more peaks in its XRPD selected from those at about 6.2, about 14.7, about 15.4, about 19.2, and about 24.7 degrees 2-theta.
  • the present disclosure provides Compound 10, wherein said compound has three or more peaks in its XRPD selected from those at about 6.2, about 14.7, about 15.4, about 19.2, and about 24.7 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 10, wherein said compound is Form 2. [0440] In some embodiments, the present disclosure provides Compound 10, wherein said compound has an XRPD substantially similar to that depicted in FIG.26.
  • the present disclosure provides Compound 10, wherein said compound has two or more peaks in its XRPD selected from those at about 7.8, about 15.2, about 18.9, about 23.2, 3 2197122.1 Page 81 of 214 398110-82HPWO (213249) and about 25.3 degrees 2-theta.
  • the present disclosure provides Compound 10, wherein said compound has three or more peaks in its XRPD selected from those at about 7.8, about 15.2, about 18.9, about 23.2, and about 25.3 degrees 2-theta.
  • the present disclosure provides Compound 10, wherein said compound is Form 3.
  • the present disclosure provides Compound 10, wherein said compound has an XRPD substantially similar to that depicted in FIG.27.
  • the present disclosure provides Compound 10, wherein said compound has two or more peaks in its XRPD selected from those at about 2.0, about 4.6, about 9.0, about 24.0, and about 26.6 degrees 2-theta.
  • the present disclosure provides Compound 10, wherein said compound has three or more peaks in its XRPD selected from those at about 2.0, about 4.6, about 9.0, about 24.0, and about 26.6 degrees 2-theta.
  • the present disclosure provides Compound 10, wherein said compound is Form 4.
  • the present disclosure provides Compound 10, wherein said compound has an XRPD substantially similar to that depicted in FIG.28.
  • the present disclosure provides a composition comprising Compound 10 and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a method of modulating HPK1 activity in a patient comprising administering to said patient Compound 10 or composition thereof.
  • the present invention provides a method of selectively modulating HPK1 activity in a patient comprising administering to said patient Compound 10 or composition thereof.
  • the present invention provides a method of activating HPK1 in a patient comprising administering to said patient Compound 10 or composition thereof.
  • the present invention provides a method of treating an HPK1-mediated disease, disorder, or condition in a patient in need thereof, comprising administering to a patient Compound 9 or composition thereof.
  • the HPK1-mediated disease, disorder, or condition is a proliferative disorder.
  • the proliferative disorder is a cancer.
  • the proliferative disorder is a tumor.
  • the proliferative disorder is associated with one or more activating mutations in HPK1.
  • the cancer is a solid tumor or hematological cancer.
  • the tumor is selected from a leukemia, lymphoma, prostate cancer, colon cancer, esophageal cancer, endometrial cancer, cervical cancer, ovarian cancer, uterine cancer, urothelial cancer, renal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, skin cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, and bladder cancer.
  • Compound 11 (Citrate Salts of Compound 1) [0448] According to one embodiment, the present disclosure provides a citrate salt of Compound 1, represented by Compound 11: O 2 H [0449] It will be one acid and Compound 1 are ionically bonded to form Compound 11.
  • Compound 11 can be a citrate salt, a hydrogen citrate salt, a dihydrogen citrate salt, or mixtures thereof. It is contemplated that Compound 11 can exist in a variety of physical forms. For example, Compound 11 can be in solution, suspension, or in solid form. In certain embodiments, Compound 11 is in solid form.
  • the present disclosure provides a form of Compound 11 substantially free of impurities.
  • impurities or extraneous matter may include different forms of Compound 11, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, Compound 11.
  • at least about 95% by weight of a form of Compound 11 is present.
  • at least about 99% by weight of a form of Compound 11 is present.
  • a form of Compound 11 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • a form of Compound 11 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 11 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, 3 2197122.1 Page 83 of 214 398110-82HPWO (213249) no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
  • a form of Compound 11 is present with an enantiomeric excess (i.e., ee) of at least 95%, preferably more than 96%, 97%, 98%, 99%, or 99.5% ee.
  • a form of Compound 11 is present in more than 95% ee. In some embodiments, a form of Compound 11 is present in more than 96% ee. In some embodiments, a form of Compound 11 is present in more than 97% ee. In some embodiments, a form of Compound 11 is present in more than 98% ee. In some embodiments, a form of Compound 11 is present in more than 99% ee. In some embodiments, a form of Compound 11 is present in more than 99.5% ee. [0453] The structure depicted for a form of Compound 11 is also meant to include all tautomeric forms of Compound 11.
  • structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • 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 11 can exist in a variety of solid forms. Exemplary such forms include polymorphs such as those described herein.
  • Compound 11 is a crystalline solid. In other embodiments, Compound 11 is a crystalline solid substantially free of amorphous Compound 11.
  • the term “substantially free of amorphous Compound 11” means that the compound contains no significant amount of amorphous Compound 11. In certain embodiments, at least about 95% by weight of crystalline Compound 11 is present. In still other embodiments of the disclosure, at least about 99% by weight of crystalline Compound 11 is present. [0456] It has been found that Compound 11 can exist in at least one distinct polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of Compound 11 referred to herein as Form A. [0457] In some embodiments, Compound 11 is amorphous. In some embodiments, Compound 11 is amorphous, and is substantially free of crystalline Compound 11.
  • Form 1 of Compound 11 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 28 below.
  • Form 1 of Compound 11 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 15.0, about 16.8, about 18.0, and about 26.3 degrees 2-theta. In some embodiments, Form 1 of Compound 11 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 15.0, about 16.8, about 18.0, and about 26.3 degrees 2-theta.
  • Form 1 of Compound 11 is characterized in that it has three or more peaks in its X-ray powder diffraction pattern selected from those at about 4.6, about 15.0, about 16.8, about 18.0, and about 26.3 degrees 2-theta. In some embodiments, Form 1 of Compound 11 is characterized in that it has four or more peaks in its X-ray powder diffraction pattern selected from those at about 4.6, about 15.0, about 16.8, about 18.0, and about 26.3 degrees 2-theta. In some embodiments, Form 1 of Compound 11 is characterized in that it has five peaks in its X-ray powder diffraction pattern selected from those at about 4.6, about 15.0, about 16.8, about 18.0, and about 26.3 degrees 2-theta.
  • the present disclosure provides Form 1 of Compound 11, wherein said compound has thermal DSC events (e.g., endothermic and exothermic) or TGA events (e.g., weight loss and decomposition) substantially similar to those provided in Table 37 or Table 38.
  • the thermal DSC and TGA events are substantially similar to those depicted in the DSC-TGA overlay of FIG.40.
  • Form 1 of Compound 11 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 28 having a relative intensity greater than 10%, 20%, 30% or 40%.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.29.
  • Methods for preparing Form 1 of Compound 11 are described infra. 3 2197122.1 Page 85 of 214 398110-82HPWO (213249)
  • the present invention provides Compound 11: O 2H wherein said compound provides Compound 11, wherein said [0464]
  • the present disclosure provides Compound 11, wherein said compound is substantially free of impurities.
  • the present disclosure provides Compound 11, wherein said compound has at least two peaks in its XRPD selected from those at about 4.6, about 15.0, about 16.8, about 18.0, and about 26.3 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 11, wherein said compound has at least three peaks in its XRPD selected from those at about 4.6, about 15.0, about 16.8, about 18.0, and about 26.3 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 11, wherein said compound is of Form 1. [0466] In some embodiments, the present disclosure provides Compound 11, wherein said compound has an XRPD substantially similar to that depicted in FIG.29.
  • the present disclosure provides a composition comprising Compound 11 and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a method of modulating HPK1 activity in a patient comprising administering to said patient Compound 11 or composition thereof.
  • the present invention provides a method of selectively modulating HPK1 activity in a patient comprising administering to said patient Compound 11 or composition thereof.
  • the present invention provides a method of activating HPK1 in a patient comprising administering to said patient Compound 11 or composition thereof.
  • the present invention provides a method of treating an HPK1-mediated disease, disorder, or condition in a patient in need thereof, comprising administering to a patient Compound 3 2197122.1 Page 86 of 214 398110-82HPWO (213249) 11 or composition thereof.
  • the HPK1-mediated disease, disorder, or condition is a proliferative disorder.
  • the proliferative disorder is a cancer.
  • the proliferative disorder is a tumor.
  • the proliferative disorder is associated with one or more activating mutations in HPK1.
  • the cancer is a solid tumor or hematological cancer.
  • the tumor is selected from a leukemia, lymphoma, prostate cancer, colon cancer, esophageal cancer, endometrial cancer, cervical cancer, ovarian cancer, uterine cancer, urothelial cancer, renal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, skin cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, and bladder cancer.
  • Compound 12 (Benzoate Salts of Compound 1)
  • the present disclosure provides a benzoate salt of Compound 1, represented by Compound 12: O [0471] It will be acid and Compound 1 are ionically bonded to form Compound 12.
  • Compound 12 can exist in a variety of physical forms.
  • Compound 12 can be in solution, suspension, or in solid form.
  • Compound 12 is in solid form.
  • said 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 12 substantially free of impurities.
  • impurities or extraneous matter may include different forms of Compound 12, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, Compound 12.
  • at least about 95% by weight of a form of Compound 12 is present.
  • a form of Compound 12 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • a form of Compound 12 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 12 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.
  • a form of Compound 12 is present with an enantiomeric excess (i.e., ee) of at least 95%, preferably more than 96%, 97%, 98%, 99%, or 99.5% ee. In some embodiments, a form of Compound 12 is present in more than 95% ee.
  • a form of Compound 12 is present in more than 96% ee. In some embodiments, a form of Compound 12 is present in more than 97% ee. In some embodiments, a form of Compound 12 is present in more than 98% ee. In some embodiments, a form of Compound 12 is present in more than 99% ee. In some embodiments, a form of Compound 12 is present in more than 99.5% ee. [0475]
  • the structure depicted for a form of Compound 12 is also meant to include all tautomeric forms of Compound 12. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • Compound 12 can exist in a variety of solid forms. Exemplary such forms include polymorphs such as those described herein.
  • Compound 12 is a crystalline solid. In other embodiments, Compound 12 is a crystalline solid substantially free of amorphous Compound 12. As used herein, the term “substantially free of amorphous Compound 12” means that the compound contains no significant amount of amorphous Compound 12. In certain embodiments, at least about 95% by weight of crystalline Compound 12 is present.
  • At least about 99% by weight of crystalline Compound 12 is present.
  • Compound 12 can exist in at least one distinct polymorphic form.
  • the present disclosure provides a polymorphic form of Compound 12 referred to herein as Form A.
  • Compound 12 is amorphous.
  • Compound 12 is 3 2197122.1 Page 88 of 214 398110-82HPWO (213249) amorphous, and is substantially free of crystalline Compound 12.
  • Form 1 of Compound 12 [0480] In some embodiments, Form 1 of Compound 12 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 29 below.
  • Form 1 of Compound 12 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 16.9, about 22.0, about 23.8, about 24.5, and about 25.1 degrees 2-theta. In some embodiments, Form 1 of Compound 12 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 16.9, about 22.0, about 23.8, about 24.5, and about 25.1 degrees 2-theta.
  • Form 1 of Compound 12 is characterized in that it has three or more peaks in its X-ray powder diffraction pattern selected from those at about 16.9, about 22.0, about 23.8, about 24.5, and about 25.1 degrees 2-theta. In some embodiments, Form 1 of Compound 12 is characterized in that it has four or more peaks in its X-ray powder diffraction pattern selected from those at about 16.9, about 22.0, about 23.8, about 24.5, and about 25.1 degrees 2-theta.
  • Form 1 of Compound 12 is characterized in that it has five 3 2197122.1 Page 89 of 214 398110-82HPWO (213249) peaks in its X-ray powder diffraction pattern selected from those at about 16.9, about 22.0, about 23.8, about 24.5, and about 25.1 degrees 2-theta.
  • the present disclosure provides Form 1 of Compound 12, wherein said compound has thermal DSC events (e.g., endothermic and exothermic) or TGA events (e.g., weight loss and decomposition) substantially similar to those provided in Table 37 or Table 38.
  • the thermal DSC and TGA events are substantially similar to those depicted in the DSC-TGA overlay of FIG.41.
  • Form 1 of Compound 12 is characterized in that it has each of the spectral peaks in its X-ray powder diffraction pattern listed in Table 29 having a relative intensity greater than 10%, 20%, 30% or 40%. In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.30. [0484] Methods for preparing Form 1 of Compound 12 are described infra. [0485] In some embodiments, the present invention provides Compound 12: O wherein said compound is disclosure provides Compound 12, wherein said compound is substantially free of amorphous Compound 12. [0486] In some embodiments, the present disclosure provides Compound 12, wherein said compound is substantially free of impurities.
  • the present disclosure provides Compound 12, wherein said compound has at least two peaks in its XRPD selected from those at about 16.9, about 22.0, about 23.8, about 24.5, and about 25.1 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 12, wherein said compound has at least three peaks in its XRPD selected from those at about 16.9, about 22.0, about 23.8, about 24.5, and about 25.1 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 12, wherein said compound is of Form 1.
  • the present disclosure provides Compound 12, wherein said compound has an XRPD substantially similar to that depicted in FIG.30.
  • the present disclosure provides a composition comprising Compound 12 and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a method of modulating HPK1 activity in a patient comprising administering to said patient Compound 12 or composition thereof.
  • the present invention provides a method of selectively modulating HPK1 activity in a patient comprising administering to said patient Compound 12 or composition thereof.
  • the present invention provides a method of activating HPK1 in a patient comprising administering to said patient Compound 12 or composition thereof.
  • the present invention provides a method of treating an HPK1-mediated disease, disorder, or condition in a patient in need thereof, comprising administering to a patient Compound 12 or composition thereof.
  • the HPK1-mediated disease, disorder, or condition is a proliferative disorder.
  • the proliferative disorder is a cancer.
  • the proliferative disorder is a tumor.
  • the proliferative disorder is associated with one or more activating mutations in HPK1.
  • the cancer is a solid tumor or hematological cancer.
  • the tumor is selected from a leukemia, lymphoma, prostate cancer, colon cancer, esophageal cancer, endometrial cancer, cervical cancer, ovarian cancer, uterine cancer, urothelial cancer, renal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, skin cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, and bladder cancer.
  • an acid and Compound 1 are ionically bonded to form one of Compounds 2 to 12 described herein, and are associated with a solvent (e.g., electrostatic interactions, ⁇ - interactions, van der Waals forces, hydrophobic effects, etc.) to form a solvated salt form of Compound 1.
  • a solvent e.g., electrostatic interactions, ⁇ - interactions, van der Waals forces, hydrophobic effects, etc.
  • solvates of Compounds 2 to 12 can exist in a variety of physical forms.
  • Solvates of Compounds 2 to 12 can be in solution, suspension, or in solid form.
  • Solvates of Compounds 2 to 12 are in solid form.
  • solvates of Compounds 2 to 12 When solvates of Compounds 2 to 12 are in solid form, said compounds may be amorphous, crystalline, or a mixture thereof. Exemplary such solid forms of solvates of Compounds 2 to 12 are described in more detail below.
  • the present disclosure provides a solvated salt form of Compound 1 substantially free of impurities. Such extraneous matter may include different forms of Compound 1 or any 3 2197122.1 Page 91 of 214 398110-82HPWO (213249) other impurities that may result from the preparation of, and/or isolation of, Compound 1. In certain embodiments, at least about 85% by weight of a solvated salt form of Compound 1 is present.
  • a solvated salt form of Compound 1 is present in an amount of at least about 80, 85, 90, 95, 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • a solvated salt form of Compound 1 contains no more than about 20.0 area percent HPLC of total organic impurities, no more than about 15.0 area percent HPLC of total organic impurities, no more than about 10.0 area percent HPLC of total organic impurities, no more than about 5.0 area percent HPLC of total organic impurities, no more than about 20.0 area percent HPLC of total organic impurities, no more than about 20.0 area percent HPLC of total organic impurities, or no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram.
  • a solvated salt form of Compound 1 contains no more than about 10% area percent HPLC of any single impurity, no more than about 5% area percent HPLC of any single impurity, or no more than about 1% area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
  • a solvated salt form of Compound 1 is present with an enantiomeric excess (i.e., ee) of at least 95%, preferably more than 96%, 97%, 98%, 99%, or 99.5% ee.
  • a solvated salt form of Compound 1 is present in more than 95% ee.
  • a solvated salt form of Compound 1 is present in more than 96% ee. In some embodiments, a solvated salt form of Compound 1 is present in more than 97% ee. In some embodiments, a solvated salt form of Compound 1 is present in more than 98% ee. In some embodiments, a solvated salt form of Compound 1 is present in more than 99% ee. In some embodiments, a solvated salt form of Compound 1 is present in more than 99.5% ee. [0496] The structure depicted for a solvated salt form of Compound 1 is also meant to include all tautomeric solvate forms of Compound 1.
  • Compound 1 is a solid crystalline solvated salt.
  • Compound 1 is a solid crystalline solvated salt substantially free of amorphous Compound 1.
  • at least about 95% by weight of a solid crystalline solvated salt form of Compound 1 is 3 2197122.1 Page 92 of 214 398110-82HPWO (213249) present.
  • the present invention provides a solvated salt form of Compound 1, represented by a compound of formula I-c: wherein: the solvent is a protic solvent, aprotic solvent, polar aprotic solvent, or mixtures thereof; 0 ⁇ x ⁇ 10; the acid is a mineral acid, organic acid, or mixtures thereof; and 0 ⁇ y ⁇ 5.
  • the present invention provides a compound of formula I-c, wherein said compound is crystalline.
  • the present invention provides a compound of formula I-c, wherein said compound is a crystalline solid substantially free of a compound of formula I-c that is amorphous. [0501] In some embodiments, the present invention provides a compound of formula I-c, wherein said compound is substantially free of impurities. [0502] In certain embodiments, the solvent includes water, alcohols, ethers, esters, ketones, halocarbons, aromatic hydrocarbons, or a mixture thereof. In some embodiments, the solvent is one or more alcohols. In some embodiments, the solvent is an aromatic hydrocarbon.
  • the solvent is water, methanol, ethanol, 1-propanol, isopropanol, 2- methyl-1-propane, 1-butanol, ethylene glycol, tert-butanol, or toluene.
  • the solvent is water.
  • the solvent is methanol.
  • the solvent is ethanol.
  • the solvent is 1-propanol.
  • the solvent is isopropanol.
  • the solvent is 2-methyl-1-propanol.
  • the solvent is 1-butanol.
  • the solvent is ethylene glycol. In some embodiments, the solvent is tert-butanol. In some embodiments, the solvent is toluene.
  • x is 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0.
  • the mineral acid is hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid.
  • the organic acid is acetic acid, glycolic acid, oxalic acid, maleic acid, malic acid, hippuric acid, lactic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, citric acid, succinic acid, malonic acid, or benzoic acid.
  • y is 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0.
  • y is 1 comprising one or more acids.
  • the present invention provides a composition comprising a compound of formula I-c and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a method of modulating HPK1 activity in a patient comprising administering to said patient a compound of formula I-c or composition thereof.
  • the present invention provides a method of selectively modulating HPK1 activity in a patient comprising administering to said patient a compound of formula I-c or composition thereof.
  • the present invention provides a method of activating HPK1 in a patient comprising administering to said patient a compound of formula I-c or composition thereof.
  • the present invention provides a method of treating an HPK1-mediated disease, disorder, or condition in a patient in need thereof, comprising administering to a patient a compound of formula I-c or composition thereof.
  • the HPK1-mediated disease, disorder, or condition is a proliferative disorder.
  • the proliferative disorder is a tumor.
  • the proliferative disorder is a cancer.
  • the proliferative disorder is associated with one or more activating mutations in HPK1.
  • the cancer is a solid tumor or hematological cancer.
  • the tumor is selected from a leukemia, lymphoma, prostate cancer, colon cancer, esophageal cancer, endometrial cancer, cervical cancer, ovarian cancer, uterine cancer, urothelial cancer, renal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, skin cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, 3 2197122.1 Page 94 of 214 398110-82HPWO (213249) and bladder cancer.
  • Compounds 2 to 12 described herein are a compound of formula I-c.
  • the present invention provides any one of Compounds 2 to 12 as a solvate.
  • the present invention provides any one of Compounds 2 to 12 as a hydrate. In some embodiments, the present invention provides any one of Compounds 2 to 12 as a monohydrate. In some embodiments, the present invention provides a solid crystalline form of any one of Compounds 2 to 12 as a solvate. In some embodiments, the present invention provides a solid crystalline form of any one of Compounds 2 to 12 as a hydrate. In some embodiments, the present invention provides a solid crystalline form of any one of Compounds 2 to 12 as a monohydrate. [0512] In some embodiments, the present invention provides Compound 7 as a hydrate. In some embodiments, the present invention provides Compound 7 as a monohydrate.
  • the present invention provides a solid crystalline form of Compound 7 as a hydrate. In some embodiments, the present invention provides a solid crystalline form of Compound 7 as a monohydrate. In some embodiments, the present invention provides Form 1 of Compound 7 as a hydrate. In some embodiments, the present invention provides Form 1 of Compound 7 as a monohydrate. In some embodiments, the present invention provides (S)-7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(7- fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one L-malate hydrate.
  • the present invention provides (S)-7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(7- fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one L-malate monohydrate.
  • the present invention provides a solid crystalline form of (S)-7-((6-((dimethylamino)methyl)-5- (tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one L- malate hydrate.
  • the present invention provides a solid crystalline form of (S)-7-((6- ((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin- 3-yl)isoindolin-1-one L-malate monohydrate.
  • the X-ray powder diffraction pattern of (S)-7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-4-(7- fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one L-malate monohydrate is substantially similar to the XRPD provided in FIG.15 or FIG.46. 2.
  • General Methods of Providing a Salt Compound [0513] Salt compounds of formula I-b, which formula encompasses, inter alia, salt compounds 2 through 12, and/or particular forms thereof, are prepared from Compound 1, according to the general Scheme below. 3 2197122.1 Page 95 of 214 398110-82HPWO (213249)
  • each of salt compounds 2 through 12, and forms thereof are prepared from Compound 1 by combining Compound 1 with an appropriate acid to form a salt of that acid.
  • another aspect of the present disclosure provides a method for preparing salt compounds 2 through 12, and forms thereof.
  • the present disclosure provides a method for preparing a salt compound of formula I-b: wherein: the acid is a mineral acid, organic acid, or mixtures thereof; and 0 ⁇ y ⁇ 5; comprising step of combining Compound 1: 3 2197122.1 Page 96 of 214 398110-82HPWO (213249)
  • an acid is hydrobromic acid.
  • the present disclosure provides a method of making a hydrobromide salt of Compound 1.
  • the hydrobromide salt of Compound 1 is Compound 2.
  • the hydrobromide salt of Compound 1 is Form 1 of Compound 2.
  • the present invention provides a process of preparing Form 1 of Compound 2 as described in Example 3, below.
  • an acid is hydrochloric acid.
  • the present disclosure provides a method of making a hydrochloride salt of Compound 1.
  • the hydrochloride salt of Compound 1 is Compound 3. In certain embodiments, the hydrochloride salt of Compound 1 is Form 1 of Compound 3. In some embodiments, the present invention provides a process of preparing Form 1 of Compound 2 as described in Example 3, below. In certain embodiments, the hydrochloride salt of Compound 1 is Form 2 of Compound 3. In some embodiments, the present invention provides a process of preparing Form 2 of Compound 3 as described in Example 3, below. [0518] In some embodiments, an acid is succinic acid. In some embodiments, the present disclosure provides a method of making a succinate salt of Compound 1. In certain embodiments, the succinate salt of Compound 1 is Compound 4.
  • the succinate salt of Compound 1 is Form 1 of Compound 4. In some embodiments, the present invention provides a process of preparing Form 1 of Compound 4 as described in Example 3, below. In certain embodiments, the succinate salt of Compound 1 is Form 2 of Compound 4. In some embodiments, the present invention provides a process of preparing Form 2 of Compound 4 as described in Example 3, below. [0519] In some embodiments, an acid is p-toluenesulfonic acid. In some embodiments, the present disclosure provides a method of making a p-toluenesulfonate salt of Compound 1.
  • the p-toluenesulfonate salt of Compound 1 is Compound 5.
  • the p-toluenesulfonate salt of Compound 1 is Form 1 of Compound 5.
  • the present invention provides a process of preparing Form 1 of Compound 5 as described in Example 3, below.
  • the p-toluenesulfonate salt of Compound 1 is Form 2 of Compound 5.
  • the present invention provides a process of preparing Form 2 of Compound 5 as described in Example 3, below.
  • an acid is methanesulfonic acid.
  • the present disclosure provides a method of making a methanesulfonate salt of Compound 1.
  • the methanesulfonate salt of Compound 1 is Compound 6.
  • the methanesulfonate salt of Compound 1 is Form 1 of Compound 6.
  • the present invention provides a process of preparing Form 1 of Compound 6 as described in Example 3, below.
  • the methanesulfonate salt of Compound 1 is Form 2 of Compound 6.
  • the present invention provides a process of preparing Form 2 of Compound 6 as described in Example 3, below.
  • an acid is L-malic acid.
  • the present disclosure provides a method of making a L-malate salt of Compound 1.
  • the L-malate salt of Compound 1 is Compound 7.
  • the L-malate salt of Compound 1 is Form 1 of Compound 7.
  • the present invention provides a process of preparing Form 1 of Compound 7 as described in Example 3 or Example 5, below.
  • the L-malate salt of Compound 1 is Form 2 of Compound 7.
  • the present invention provides a process of preparing Form 2 of Compound 7 as described in Example 3 or Example 5, below.
  • the L-malate salt of Compound 1 is Form 3 of Compound 7.
  • the present invention provides a process of preparing Form 3 of Compound 7 as described in Example 7 or Example 8, below.
  • the L-malate salt of Compound 1 is Form 4 of Compound 7.
  • the present invention provides a process of preparing Form 4 of Compound 7 as described in Example 7 or Example 8, below.
  • an acid is phosphoric acid.
  • the present disclosure provides a method of making a phosphate salt of Compound 1.
  • the phosphate salt of Compound 1 is Compound 8.
  • the phosphate salt of Compound 1 is Form 1 of Compound 8.
  • the present invention provides a process of preparing Form 1 of Compound 8 as described in Example 3, below.
  • the phosphate salt of Compound 1 is Form 2 of Compound 8. In some embodiments, the present invention provides a process of preparing Form 3 of Compound 8 as described in Example 3, below. In certain embodiments, the phosphate salt of Compound 1 is Form 3 of Compound 8. In some embodiments, the present invention provides a process of preparing Form 3 of Compound 8 as described in Example 3, below. 3 2197122.1 Page 98 of 214 398110-82HPWO (213249) [0523] In some embodiments, an acid is L-tartaric acid. In some embodiments, the present disclosure provides a method of making a L-tartrate salt of Compound 1. In certain embodiments, the L-tartrate salt of Compound 1 is Compound 9.
  • the L-tartrate salt of Compound 1 is Form 1 of Compound 9. In some embodiments, the present invention provides a process of preparing Form 1 of Compound 9 as described in Example 3 or Example 5, below. In certain embodiments, the L-tartrate salt of Compound 1 is Form 2 of Compound 9. In some embodiments, the present invention provides a process of preparing Form 3 of Compound 9 as described in Example 3 or Example 5, below. In certain embodiments, the L-tartrate salt of Compound 1 is Form 3 of Compound 9. In some embodiments, the present invention provides a process of preparing Form 3 of Compound 9 as described in Example 3 or Example 5, below. [0524] In some embodiments, an acid is fumaric acid.
  • the present disclosure provides a method of making a fumarate salt of Compound 1.
  • the fumarate salt of Compound 1 is Compound 10.
  • the fumarate salt of Compound 1 is Form 1 of Compound 10.
  • the present invention provides a process of preparing Form 1 of Compound 10 as described in Example 3 or Example 5, below.
  • the fumarate salt of Compound 1 is Form 2 of Compound 10.
  • the present invention provides a process of preparing Form 3 of Compound 10 as described in Example 3 or Example 5, below.
  • the fumarate salt of Compound 1 is Form 3 of Compound 10.
  • the present invention provides a process of preparing Form 3 of Compound 10 as described in Example 3 or Example 5, below.
  • the fumarate salt of Compound 1 is Form 4 of Compound 10.
  • the present invention provides a process of preparing Form 4 of Compound 10 as described in Example 3 or Example 5, below.
  • an acid is citric acid.
  • the present disclosure provides a method of making a citrate salt of Compound 1.
  • the hydrobromide salt of Compound 1 is Compound 11.
  • the citrate salt of Compound 1 is Form 1 of Compound 11.
  • the present invention provides a process of preparing Form 1 of Compound 11 as described in Example 3, below.
  • an acid is benzoic acid.
  • the present disclosure provides a method of making a benzoate salt of Compound 1.
  • the benzoate salt of Compound 1 is Compound 12.
  • the benzoate salt of Compound 1 is Form 1 of Compound 12.
  • the present invention provides a process of preparing Form 1 of Compound 12 as described in Example 3, below.
  • a suitable solvent may be any solvent system (e.g., one solvent or a mixture of 3 2197122.1 Page 99 of 214 398110-82HPWO (213249) solvents) in which Compound 1 and/or an acid are soluble or are at least partially soluble.
  • suitable solvents useful in the presently disclosed methods 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 said solvent is anhydrous or in combination with water or heptane.
  • suitable solvents include tetrahydrofuran, dimethyl formamide, dimethylsulfoxide, glyme, diglyme, methyl t-butyl ether, t-butanol, n-butanol, and acetonitrile.
  • a suitable solvent is tetrahydrofuran.
  • a suitable solvent is water and isopropanol.
  • a suitable solvent is 5-10% water in an alcohol.
  • a suitable solvent is 10% water in isopropanol.
  • a suitable solvent is 10% water in methanol.
  • a suitable solvent is 5-10% water in an ether.
  • a suitable solvent is 10% water in tetrahydrofuran.
  • the present disclosure provides a method for preparing a salt compound of formula I-b, 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 Examples.
  • a method for preparing a salt compound of formula I-b comprises one or more steps of heating or cooling a preparation.
  • a method for preparing a salt compound of formula I-b comprises one or more steps of agitating or stirring a preparation. [0533] In some embodiments, a method for preparing a salt compound of formula I-b comprises slow evaporation of the solvent. In some embodiments, a method for preparing a salt compound of formula I-b comprises slow evaporation of the solvent through exposure to ambient atmosphere at room temperature. In some embodiments, a method for preparing a salt compound of formula I-b comprises evaporation of the solvent under a flow of an inert gas, e.g., nitrogen gas.
  • an inert gas e.g., nitrogen gas.
  • a method for preparing a salt compound of formula I-b comprises a step of adding an acid to a solution or slurry of Compound 1.
  • a method for preparing a salt compound of formula I-b comprises a step of heating. 3 2197122.1 Page 100 of 214 398110-82HPWO (213249)
  • a salt compound of formula I-b precipitates from the mixture.
  • a salt compound of formula I-b crystallizes from the mixture.
  • a salt compound of formula I-b crystallizes from solution following seeding of the solution (i.e., adding crystals of a salt compound of formula I-b to the solution).
  • a salt compound of formula I-b 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, filtration (ex. nanofiltration, ultrafiltration), 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 I-b is optionally isolated. It will be appreciated that a salt compound of formula I-b 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 A is separated from the supernatant by filtration.
  • precipitated solid salt compound of formula I-b is separated from the supernatant by decanting the supernatant.
  • a salt compound of formula I-b is separated from the supernatant by filtration.
  • an isolated salt compound of formula I-b is dried in air.
  • an isolated salt compound of formula I-b is dried under reduced pressure, optionally at elevated temperature.
  • a method for preparing a salt compound of formula I-b as described herein also includes preparing a solvated salt form of a compound of formula I-c. 3.
  • the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the amount of compound in compositions of this invention is such that is effective to measurably inhibit HPK1, or a mutant thereof, in a biological sample or in a patient.
  • the amount of compound in compositions of this invention is such that is effective to measurably inhibit HPK1, or a mutant thereof, in a biological sample or in a patient.
  • a composition of this invention is formulated for administration to a patient in need of such composition.
  • a composition of this invention is formulated for oral administration to a patient.
  • patient means an animal, preferably a mammal, and most preferably 3 2197122.1 Page 101 of 214 398110-82HPWO (213249) a human.
  • pharmaceutically acceptable carrier, adjuvant, or vehicle refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • compositions of this invention 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.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial
  • a “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.
  • the term "inhibitorily active metabolite or residue thereof” means that a metabolite or residue thereof is also an inhibitor of HPK1, or a mutant thereof.
  • the subject matter disclosed herein includes prodrugs, metabolites, derivatives, and pharmaceutically acceptable salts of compounds of the invention.
  • Metabolites include compounds produced by a process comprising contacting a compound of the invention with a mammal for a period of time sufficient to yield a metabolic product thereof.
  • the compound of the invention is a base
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, 3 2197122.1 Page 102 of 214 398110-82HPWO (213249) and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • a compound of the invention can be in the form of a "prodrug," which includes compounds with moieties which can be metabolized in vivo.
  • the prodrugs are metabolized in vivo by esterases or by other mechanisms to active drugs.
  • Examples of prodrugs and their uses are well known in the art (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19).
  • the prodrugs can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form or hydroxyl with a suitable esterifying agent. Hydroxyl groups can be converted into esters via treatment with a carboxylic acid.
  • prodrug moieties include substituted and unsubstituted, branch or unbranched lower alkyl ester moieties, (e.g., propionic acid esters), lower alkenyl esters, di-lower alkyl-amino lower-alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g., acetyloxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-lower alkyl esters (e.g., benzyl ester), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl esters, amides, lower-alkyl amides, di-lower alkyl amides, and hydroxy amides.
  • compositions of the present invention may 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, intrasternal, 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 invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may 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.
  • the acceptable vehicles and solvents that may 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 may be employed including synthetic mono- or di- glycerides.
  • 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.
  • oils such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the 3 2197122.1 Page 103 of 214 398110-82HPWO (213249) formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • compositions of this invention may 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 corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • compositions of this invention may 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.
  • compositions of this invention may 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 may also be used.
  • provided pharmaceutically acceptable compositions may 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 invention 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 may be formulated as 3 2197122.1 Page 104 of 214 398110-82HPWO (213249) 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 may be formulated in an ointment such as petrolatum.
  • Pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation.
  • compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may 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.
  • pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.
  • the amount of compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration.
  • 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 will depend 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 invention in the composition will also depend upon the particular compound in the composition. 4.
  • HPK1 is a member of the germinal center kinase subfamily of Ste20-related serine/threonine kinases. HPK1 functions as a MAP4K by phosphorylating and activating MAP3K proteins, including MEKK1, MLK3 and TAK1, leading to the activation of the MAPK Jnk.
  • the invention relates to a method of inhibiting HPK1, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.
  • the invention relates to a method of irreversibly inhibiting HPK1, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.
  • biological sample includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • Inhibition of HPK1 (or a mutant thereof) activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays.
  • the invention relates to a method of inhibiting activity of HPK1, or a mutant thereof, in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound.
  • the invention relates to a method of reversibly or irreversibly inhibiting one or more of HPK1, or a mutant thereof, activity in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound.
  • the present invention provides a method for treating a disorder mediated by HPK1, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a Compound 1ccording to the present invention or pharmaceutically acceptable composition thereof.
  • a disorder mediated by HPK1, or a mutant thereof in a patient in need thereof, comprising the step of administering to said patient a Compound 1ccording to the present invention or pharmaceutically acceptable composition thereof.
  • Such disorders are described in detail herein.
  • the subject matter disclosed herein is directed to a method for enhancing an immune response in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of a compound of the invention or a pharmaceutical composition described herein.
  • the T cells in the subject have at least one of enhanced priming, enhanced activation, enhanced migration, enhanced proliferation, enhanced survival, and enhanced cytolytic activity relative to prior to the administration of the compound or pharmaceutical composition.
  • the T cell activation is characterized by an elevated frequency of ⁇ -IFN+ CD8 T cells or enhanced levels of IL-2 or granzyme B production by T cells relative to prior to administration of the compound or pharmaceutical composition.
  • the number of T cells is elevated relative to prior to administration of the compound or pharmaceutical composition.
  • the T cell is an antigen-specific CD8 T cell.
  • the antigen presenting cells in the subject have enhanced 3 2197122.1 Page 106 of 214 398110-82HPWO (213249) maturation and activation relative prior to the administration of the compound or pharmaceutical composition.
  • the antigen presenting cells are dendritic cells.
  • the maturation of the antigen presenting cells is characterized by increased frequency of CD83+ dendritic cells.
  • the activation of the antigen presenting cells is characterized by elevated expression of CD80 and CD86 on dendritic cells.
  • the presently disclosed compounds reduce, inhibit, or otherwise diminish the HPK1- mediated phosphorylation of SLP76 and/or Gads.
  • the presently disclosed compounds may or may not be a specific HPK1 antagonist.
  • a specific HPK1 antagonist reduces the biological activity of HPK1 by an amount that is statistically greater than the inhibitory effect of the antagonist on any other protein (e.g., other serine/threonine kinases).
  • the presently disclosed compounds specifically inhibit the serine/threonine kinase activity of HPK1.
  • the IC50 of the HPK1 antagonist for HPK1 is about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, 0.001%, or less of the IC50 of the HPK1 antagonist for another serine/threonine kinase or other type of kinase (e.g., tyrosine kinase).
  • the presently disclosed compounds can be used in a method for inhibiting HPK1. Such methods comprise contacting HPK1 with an effective amount of a presently disclosed compound.
  • contact is intended bringing the compound within close enough proximity to an isolated HPK1 enzyme or a cell expressing HPK1 (e.g., T cell, B cell, dendritic cell) such that the compound is able to bind to and inhibit the activity of HPK1.
  • the compound can be contacted with HPK1 in vitro or in vivo via administration of the compound to a subject.
  • any method known in the art to measure the kinase activity of HPK1 may be used to determine if HPK1 has been inhibited, including in vitro kinase assays, immunoblots with antibodies specific for phosphorylated targets of HPK1, such as SLP76 and Gads, or the measurement of a downstream biological effect of HPK1 kinase activity, such as the recruitment of 14-3-3 proteins to phosphorylated SLP7 and Gads, release of the SLP76-Gads-14-3-3 complex from LAT-containing microclusters, or T or B cell activation.
  • the presently disclosed compounds can be used to treat a HPK1-dependent disorder.
  • a "HPK1-dependent disorder” is a pathological condition in which HPK1 activity is necessary for the genesis or maintenance of the pathological condition.
  • the HPK1-dependent disorder is cancer.
  • the presently disclosed compounds also find use in enhancing an immune response in a subject in need thereof. Such methods comprise administering an effective amount of a compound of the 3 2197122.1 Page 107 of 214 398110-82HPWO (213249) invention.
  • enhancing an immune response refers to an improvement in any immunogenic response to an antigen.
  • Non-limiting examples of improvements in an immunogenic response to an antigen include enhanced maturation or migration of dendritic cells, enhanced activation of T cells (e.g., CD4 T cells, CD8 T cells), enhanced T cell (e.g., CD4 T cell, CD8 T cell) proliferation, enhanced B cell proliferation, increased survival of T cells and/or B cells, improved antigen presentation by antigen presenting cells (e.g., dendritic cells), improved antigen clearance, increase in production of cytokines by T cells (e.g., interleukin-2), increased resistance to prostaglandin E2-induced immune suppression, and enhanced priming and/or cytolytic activity of CD8 T cells.
  • the CD8 T cells in the subject have enhanced priming, activation, proliferation and/or cytolytic activity relative to prior to the administration of the compound of the invention or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof.
  • the CD8 T cell priming is characterized by elevated CD44 expression and/or enhanced cytolytic activity in CD8 T cells.
  • the CD8 T cell activation is characterized by an elevated frequency of ⁇ -IFN + CD8 T cells.
  • the CD8 T cell is an antigen-specific T-cell.
  • the antigen presenting cells in the subject have enhanced maturation and activation relative to prior to the administration of the compound of the invention or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof.
  • the antigen presenting cells are dendritic cells.
  • the maturation of the antigen presenting cells is characterized by an increased frequency of CD83 + dendritic cells.
  • the activation of the antigen presenting cells is characterized by elevated expression of CD80 and CD86 on dendritic cells.
  • the serum levels of cytokine IL-10 and/or chemokine IL-8, a human homolog of murine KC, in the subject are reduced relative to prior to the administration of the compound of Formula I or Ia or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof.
  • Engagement of the TCR leads to HPK1 activation, which functions as a negative regulator of TCR-induced AP-1 response pathway. It is believed that HPK1 negatively regulates T cell activation by reducing the persistence of signaling microclusters by phosphorylating SLP76 at Ser376 (Di Bartolo et al.
  • a compound of the invention or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof results in an enhancement of T cell 3 2197122.1 Page 108 of 214 398110-82HPWO (213249) function.
  • T cell dysfunctional disorder is a disorder or condition of T cells characterized by decreased responsiveness to antigenic stimulation.
  • a T cell dysfunctional disorder is a disorder that is specifically associated with increased kinase activity of HPK1.
  • a T cell dysfunctional disorder is one in which T cells are anergic or have decreased ability to secrete cytokines, proliferate, or execute cytolytic activity.
  • the decreased responsiveness results in ineffective control of a pathogen or tumor expressing an immunogen.
  • T cell dysfunctional disorders characterized by T-cell dysfunction include unresolved acute infection, chronic infection and tumor immunity.
  • the presently disclosed compounds can be used in treating conditions where enhanced immunogenicity is desired, such as increasing tumor immunogenicity for the treatment of cancer.
  • the term "dysfunction" in the context of immune dysfunction refers to a state of reduced immune responsiveness to antigenic stimulation. The term includes the common elements of both exhaustion and/or anergy in which antigen recognition may occur, but the ensuing immune response is ineffective to control infection or tumor growth.
  • the term "dysfunctional”, as used herein, also includes refractory or unresponsive to antigen recognition, specifically, impaired capacity to translate antigen recognition into downstream T-cell effector functions, such as proliferation, cytokine production (e.g., IL-2, ⁇ -IFN) and/or target cell killing.
  • T-cell effector functions such as proliferation, cytokine production (e.g., IL-2, ⁇ -IFN) and/or target cell killing.
  • Anergy refers to the state of unresponsiveness to antigen stimulation resulting from incomplete or insufficient signals delivered through the T-cell receptor (e.g. increase in intracellular Ca +2 in the absence of ras-activation).
  • T cell anergy can also result upon stimulation with antigen in the absence of co-stimulation, resulting in the cell becoming refractory to subsequent activation by the antigen even in the context of costimulation.
  • the unresponsive state can often be overridden by the presence of Interleukin- 2.
  • Anergic T-cells do not undergo clonal expansion and/or acquire effector functions.
  • exhaust refers to T cell exhaustion as a state of T cell dysfunction that arises from sustained TCR signaling that occurs during many chronic infections and cancer. It is distinguished from anergy in that it arises not through incomplete or deficient signaling, but from sustained signaling.
  • Exhaustion prevents optimal control of infection and tumors. Exhaustion can result from both extrinsic negative regulatory pathways (e.g., immunoregulatory cytokines) as well as cell intrinsic negative regulatory (costimulatory) pathways (PD-1, 3 2197122.1 Page 109 of 214 398110-82HPWO (213249) B7-H3, B7-H4, etc.).
  • extrinsic negative regulatory pathways e.g., immunoregulatory cytokines
  • costimulatory costimulatory pathways
  • “Enhancing T cell function” means to induce, cause or stimulate a T cell to have a sustained or amplified biological function, or renew or reactivate exhausted or inactive T cells.
  • enhancing T cell function include: increased secretion of cytokines (e.g., ⁇ -interferon, IL-2, IL-12, and TNF ⁇ ), increased proliferation, increased antigen responsiveness (e.g., viral, pathogen, or tumor clearance) relative to such levels before the intervention, and increased effector granule production by CD8 T cells, such as granzyme B.
  • the level of enhancement is as least 50%, alternatively 60%, 70%, 80%, 90%, 100%, 120%, 150%, 200%.
  • Tumor immunity refers to the process in which tumors evade immune recognition and clearance. Thus, as a therapeutic concept, tumor immunity is "treated” when such evasion is attenuated, and the tumors are recognized and attacked by the immune system. Examples of tumor recognition include tumor binding, tumor shrinkage and tumor clearance.
  • the present disclosure provides methods of modulating (e.g., inhibiting) HPKl activity, said method comprising administering to a patient a compound provided herein, or a pharmaceutically acceptable salt thereof.
  • a solid or salt form of this invention is for use in medicine.
  • a method for treating of cancer in a subject in need thereof comprising administering to the subject an effective amount of a compound of the invention or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof.
  • a compound of the invention or a pharmaceutical composition thereof is administered to a subject that has cancer.
  • a patient has a relapsed and/or refractory cancer.
  • a patient has a relapsed and/or refractory tumor.
  • a patient has a relapsed and/or refractory solid tumor.
  • a patient has a relapsed and/or refractory liquid tumor. In some embodiments, the patient has received at least one prior therapy. In some embodiments, the patient has received at least two prior therapies. In some embodiments, the patient has received at least three prior therapies. In some embodiments, the patient has received at least four prior therapies. In some embodiments, the patient has received at least five prior therapies. In some embodiments, the patient has received at least six prior therapies.
  • the subject matter disclosed herein is directed to a method for treating 3 2197122.1 Page 110 of 214 398110-82HPWO (213249) a HPK1-dependent disorder, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention or a pharmaceutical composition described herein.
  • the HPK1-dependent disorder is a cancer.
  • the cancer comprises at least one cancer selected from the group consisting of colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, breast cancer, pancreatic cancer, a hematological malignancy, and a renal cell carcinoma.
  • the cancer has elevated levels of T-cell infiltration.
  • the cancer cells in the subject selectively have elevated expression of MHC class I antigen expression relative to prior to the administration of the compound or composition.
  • the subject matter disclosed herein is directed to a method for treatment of chronic viral infections.
  • the subject matter disclosed herein is directed to the use of an HPK1 inhibitor as an adjuvant treatment for increasing the efficacy of vaccination.
  • the invention provides a pharmaceutical composition comprising an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier.
  • the invention provides a method of treating cell proliferation disorders, including cancers, benign papillomatosis, gestational trophoblastic diseases, and benign neoplastic diseases, such as skin papilloma (warts) and genital papilloma.
  • the invention provides a method of treating a cell proliferation disorder in a subject, comprising administering a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, to the subject.
  • the cell proliferation disorder is cancer.
  • cancers that are treatable using the compounds of the present disclosure include, but are not limited to, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, endometrial cancer, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, 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, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lympho
  • cancers that are treatable using the compounds of the present disclosure include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, cervical cancer, ovarian cancer, uterine cancer, urothelial cancer, renal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, skin cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, and bladder cancer, etc.), liquid tumors such as hematological cancers (e.g., lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrent
  • the present invention provides a method of treating a lymphoma in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating prostate cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating colon cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating esophageal cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating endometrial cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating cervical cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating ovarian cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating uterine cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating urothelial cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating renal cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating kidney cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating liver cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating pancreatic cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating gastric cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating breast cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating lung cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating skin cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating cancers of the head and neck in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating thyroid cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating glioblastoma in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating sarcoma in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating bladder cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.
  • the cancer is brain cancer, leukemia, skin cancer, prostate cancer, thyroid cancer, colon cancer, lung cancer or sarcoma.
  • the cancer is selected from the group consisting of glioma, glioblastoma multiforme, paraganglioma, supratentorial primordial neuroectodermal tumors, acute myeloid leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, melanoma, breast, prostate, thyroid, colon, lung, central chondrosarcoma, central and periosteal chondroma tumors, fibrosarcoma, and cholangiocarcinoma.
  • the cancer is selected from brain and spinal cancers, cancers of the head and neck, leukemia and cancers of the blood, skin cancers, cancers of the reproductive system, cancers of the gastrointestinal system, liver and bile duct cancers, kidney and bladder cancers, bone cancers, lung cancers, malignant mesothelioma, sarcomas, lymphomas, glandular cancers, thyroid cancers, heart tumors, germ cell tumors, malignant neuroendocrine (carcinoid) tumors, midline tract cancers, and cancers of unknown primary (cancers in which a metastasized cancer is found but the original cancer site is not known).
  • the cancer is present in an adult patient; in additional embodiments, the cancer is present in a pediatric patient. In particular embodiments, the cancer is AIDS-related. [0625] In a further embodiment, the cancer is selected from brain and spinal cancers. In particular embodiments, the cancer is selected from the group consisting of anaplastic astrocytomas, glioblastomas, astrocytomas, and estheosioneuroblastomas (olfactory blastomas).
  • the brain cancer is selected from the group consisting of astrocytic tumor (e.g., pilocytic astrocytoma, subependymal giant-cell astrocytoma, diffuse astrocytoma, pleomorphic xanthoastrocytoma, anaplastic astrocytoma, astrocytoma, giant cell glioblastoma, glioblastoma, secondary glioblastoma, primary adult glioblastoma, and primary pediatric glioblastoma), oligodendroglial tumor (e.g., oligodendroglioma, and anaplastic 3 2197122.1 Page 114 of 214 398110-82HPWO (213249) oligodendroglioma), oligoastrocytic tumor (e.g., oligoastrocytoma, and anaplastic oligoastrocytoma), ependymoma (e.g., pilocy
  • the brain cancer is selected from the group consisting of glioma, glioblastoma multiforme, paraganglioma, and supratentorial primordial neuroectodermal tumors (sPNET).
  • the cancer is selected from cancers of the head and neck, including nasopharyngeal cancers, nasal cavity and paranasal sinus cancers, hypopharyngeal cancers, oral cavity cancers (e.g., squamous cell carcinomas, lymphomas, and sarcomas), lip cancers, oropharyngeal cancers, salivary gland tumors, cancers of the larynx (e.g., laryngeal squamous cell carcinomas, rhabdomyosarcomas), and cancers of the eye or ocular cancers.
  • larynx e.g., laryngeal squamous cell carcinomas, rhabdomyosarcomas
  • the ocular cancer is selected from the group consisting of intraocular melanoma and retinoblastoma.
  • the cancer is selected from leukemia and cancers of the blood.
  • the cancer is selected from the group consisting of myeloproliferative neoplasms, myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasms, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), myeloproliferative neoplasm (MPN), post-MPN AML, post-MDS AML, del(5q)-associated high risk MDS or AML, blast- phase chronic myelogenous leukemia, angioimmunoblastic lymphoma, acute lymphoblastic leukemia, Langerans cell histiocytosis, hairy cell leukemia, and
  • Leukemias referenced herein may be acute or chronic.
  • the cancer is selected from skin cancers.
  • the skin cancer is selected from the group consisting of melanoma, squamous cell cancers, and basal cell cancers.
  • the cancer is selected from cancers of the reproductive system.
  • the cancer is selected from the group consisting of breast cancers, cervical cancers, vaginal cancers, ovarian cancers, prostate cancers, penile cancers, and testicular cancers.
  • the cancer is a breast cancer selected from the group consisting of ductal carcinomas and phyllodes tumors.
  • the breast cancer may be male breast cancer or female breast cancer.
  • the cancer is a cervical cancer selected from the group consisting of squamous cell carcinomas and adenocarcinomas.
  • the cancer is an ovarian cancer selected from the group consisting 3 2197122.1 Page 115 of 214 398110-82HPWO (213249) of epithelial cancers.
  • the cancer is selected from cancers of the gastrointestinal system.
  • the cancer is selected from the group consisting of esophageal cancers, gastric cancers (also known as stomach cancers), gastrointestinal carcinoid tumors, pancreatic cancers, gallbladder cancers, colorectal cancers, and anal cancer.
  • the cancer is selected from the group consisting of esophageal squamous cell carcinomas, esophageal adenocarcinomas, gastric adenocarcinomas, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gastric lymphomas, gastrointestinal lymphomas, solid pseudopapillary tumors of the pancreas, pancreatoblastoma, islet cell tumors, pancreatic carcinomas including acinar cell carcinomas and ductal adenocarcinomas, gallbladder adenocarcinomas, colorectal adenocarcinomas, and anal squamous cell carcinomas.
  • the cancer is selected from liver and bile duct cancers.
  • the cancer is liver cancer (hepatocellular carcinoma).
  • the cancer is bile duct cancer (cholangiocarcinoma); in instances of these embodiments, the bile duct cancer is selected from the group consisting of intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma.
  • the cancer is selected from kidney and bladder cancers.
  • the cancer is a kidney cancer selected from the group consisting of renal cell cancer, Wilms tumors, and transitional cell cancers.
  • the cancer is a bladder cancer selected from the group consisting of urethelial carcinoma (a transitional cell carcinoma), squamous cell carcinomas, and adenocarcinomas.
  • the cancer is selected from bone cancers.
  • the bone cancer is selected from the group consisting of osteosarcoma, malignant fibrous histiocytoma of bone, Ewing sarcoma, and chordoma.
  • the cancer is selected from lung cancers.
  • the lung cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancers, bronchial tumors, and pleuropulmonary blastomas.
  • the cancer is selected from malignant mesothelioma.
  • the cancer is selected from the group consisting of epithelial mesothelioma and sarcomatoids.
  • the cancer is selected from sarcomas.
  • the sarcoma is selected from the group consisting of central chondrosarcoma, central and periosteal chondroma, fibrosarcoma, clear cell sarcoma of tendon sheaths, and Kaposi's sarcoma.
  • the cancer is selected from lymphomas.
  • the cancer is selected from the group consisting of Hodgkin lymphoma (e.g., Reed-Sternberg cells), non- 3 2197122.1 Page 116 of 214 398110-82HPWO (213249) Hodgkin lymphoma (e.g., diffuse large B-cell lymphoma, follicular lymphoma, mycosis fungoides, Sezary syndrome, primary central nervous system lymphoma), cutaneous T-cell lymphomas, and primary central nervous system lymphomas.
  • the cancer is selected from glandular cancers.
  • the cancer is selected from the group consisting of adrenocortical cancer, pheochromocytomas, paragangliomas, pituitary tumors, thymoma, and thymic carcinomas.
  • the cancer is selected from thyroid cancers.
  • the thyroid cancer is selected from the group consisting of medullary thyroid carcinomas, papillary thyroid carcinomas, and follicular thyroid carcinomas.
  • the cancer is selected from germ cell tumors.
  • the cancer is selected from the group consisting of malignant extracranial germ cell tumors and malignant extragonadal germ cell tumors.
  • the malignant extragonadal germ cell tumors are selected from the group consisting of nonseminomas and seminomas.
  • the cancer is selected from heart tumors.
  • the heart tumor is selected from the group consisting of malignant teratoma, lymphoma, rhabdomyosarcoma, angiosarcoma, chondrosarcoma, infantile fibrosarcoma, and synovial sarcoma.
  • the cell-proliferation disorder is selected from benign papillomatosis, benign neoplastic diseases and gestational trophoblastic diseases.
  • the benign neoplastic disease is selected from skin papilloma (warts) and genital papilloma.
  • the gestational trophoblastic disease is selected from the group consisting of hydatidiform moles, and gestational trophoblastic neoplasia (e.g., invasive moles, choriocarcinomas, placental-site trophoblastic tumors, and epithelioid trophoblastic tumors).
  • the subject has melanoma.
  • the melanoma may be at early stage or at late stage.
  • the subject has colorectal cancer.
  • the colorectal cancer may be at early stage or at late stage.
  • the subject has non-small cell lung cancer.
  • the non-small cell lung cancer may be at early stage or at late stage.
  • the subject has pancreatic cancer.
  • the pancreatic cancer may be at early stage or late state.
  • the subject has a hematological malignancy.
  • the hematological malignancy may be at early stage or late stage.
  • the subject has ovarian cancer.
  • the ovarian cancer may be at early stage or at late stage.
  • the subject has breast cancer.
  • the breast cancer may be at early stage or at late stage.
  • the subject has renal cell carcinoma.
  • the renal cell carcinoma may be at early stage or at late stage.
  • cancers treatable with compounds of the present disclosure include 3 2197122.1 Page 117 of 214 398110-82HPWO (213249) melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g. clear cell carcinoma), prostate cancer (e.g. hormone refractory prostate adenocarcinoma), breast cancer, triple-negative breast cancer, colon cancer and lung cancer (e.g. non-small cell lung cancer and small cell lung cancer). Additionally, the disclosure includes refractory or recurrent malignancies whose growth may be inhibited using the compounds of the disclosure.
  • melanoma e.g., metastatic malignant melanoma
  • renal cancer e.g. clear cell carcinoma
  • prostate cancer e.g. hormone refractory prostate adenocarcinoma
  • breast cancer triple-negative breast cancer
  • colon cancer e.g. non-small cell lung cancer and small cell lung cancer
  • lung cancer e.g. non-small cell lung cancer and small cell lung
  • diseases and indications that are treatable using the compounds of the present disclosure include, but are not limited to hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.
  • Exemplary hematological cancers include lymphomas and leukemias such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma, myeloproliferative diseases (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplasia syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, Waldenstrom's Macroglubul
  • ALL
  • Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma, and teratoma.
  • Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer, bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, and mesothelioma.
  • NSCLC non-small cell lung cancer
  • small cell lung cancer bronchogenic carcinoma
  • squamous cell undifferentiated small cell, undifferentiated large cell
  • adenocarcinoma adenocarcinoma
  • alveolar (bronchiolar) carcinoma bronchial adenoma
  • chondromatous hamartoma chondromatous hamartoma
  • mesothelioma mesothelioma
  • Exemplary gastrointestinal cancers include cancers of the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer.
  • esophagus squamous cell carcinoma, adenocarcinoma, leiomy
  • Exemplary genitourinary tract cancers include cancers of the kidney (adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, 3 2197122.1 Page 118 of 214 398110-82HPWO (213249) adenocarcinoma), prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma).
  • kidney adenocarcinoma, Wilm's tumor [nephroblastoma]
  • bladder and urethra squamous cell carcinoma, transitional cell carcinoma, 3 2197122.1 Page 118 of 214 398110-82HPWO (213249
  • liver cancers include hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.
  • Exemplary bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma ( osteocartilaginous exostoses ), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumors
  • Exemplary nervous system cancers include cancers of the skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, meduoblastoma, glio
  • Exemplary gynecological cancers include cancers of the uterus (endometrial carcinoma), cervix (cervical carcinoma, pre -tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), and fallopian tubes (carcinoma).
  • endometrial carcinoma endometrial carcinoma
  • cervix cervical carcinoma, pre -tumor cervical dysplasia
  • Exemplary skin cancers include melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, moles dysplastic nevi, lipoma, angioma, dermatofibroma, and keloids.
  • diseases and indications that are treatable using the compounds of the present disclosure include, but are not limited to, sickle cell disease (e.g., sickle cell anemia), triple-negative breast cancer (TNBC), myelodysplastic syndromes, testicular cancer, bile duct cancer, esophageal cancer, and urothelial carcinoma.
  • Exemplary head and neck cancers include glioblastoma, melanoma, rhabdosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinomas, adenocarcinomas, oral cancer, laryngeal cancer, nasopharyngeal cancer, nasal and paranasal cancers, thyroid and parathyroid cancers.
  • HPKl inhibitors may be used to treat tumors producing PGE2 (e.g. Cox- 2 overexpressing tumors) and/or adenosine (CD73 and CD39 over-expressing tumors).
  • Overexpression 3 2197122.1 Page 119 of 214 398110-82HPWO (213249) ofCox-2 has been detected in a number of tumors, such as colorectal, breast, pancreatic and lung cancers, where it correlates with a poor prognosis.
  • Overexpression of COX-2 has been reported in hematological cancer models such as RAJI (Burkitt's lymphoma) and U937 (acute promonocytic leukemia) as well as in patient's blast cells.
  • CD73 is up-regulated in various human carcinomas including those of colon, lung, pancreas and ovary.
  • the compounds of the invention are useful in preventing or reducing the risk of developing any of the diseases referred to herein; e.g., preventing or reducing the risk of developing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.
  • the presently disclosed compounds may be administered in any suitable manner known in the art.
  • the compound of the invention or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, intratumorally, or intranasally.
  • the HPK1 antagonist is administered continuously. In other embodiments, the HPK1 antagonist is administered intermittently.
  • treatment of a subject with an effective amount of a HPK1 antagonist can include a single treatment or can include a series of treatments.
  • the active compound depends upon a number of factors within the knowledge of the ordinarily skilled physician or veterinarian.
  • the dose(s) of the active compound will vary, for example, depending upon the age, body weight, general health, gender, and diet of the subject, the time of administration, the route of administration, the rate of excretion, and any drug combination.
  • the effective dosage of a compound of the invention or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof used for treatment may increase or decrease over the course of a particular treatment. Changes in dosage may result and become apparent from the results of diagnostic assays.
  • the HPK1 antagonist is administered to the subject at a dose of between about 0.001 ⁇ g/kg and about 1000 mg/kg, including but not limited to about 0.001 ⁇ g/kg, 0.01 ⁇ g/kg, 0.05 ⁇ g/kg, 0.1 ⁇ g/kg, 0.5 ⁇ g/kg, 1 ⁇ g/kg, 10 ⁇ g/kg, 25 ⁇ g/kg, 50 ⁇ g/kg, 100 ⁇ g/kg, 250 ⁇ g/kg, 500 ⁇ g/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 25 mg/kg, 50 mg/kg, 100 mg/kg, and 200 mg/kg.
  • the method can further comprise administering a 3 2197122.1 Page 120 of 214 398110-82HPWO (213249) chemotherapeutic agent to the subject.
  • the chemotherapeutic agent is administered to the subject simultaneously with the compound or the composition.
  • the chemotherapeutic agent is administered to the subject prior to administration of the compound or the composition.
  • the chemotherapeutic agent is administered to the subject after administration of the compound or the composition.
  • 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 may be administered after one or more symptoms have developed.
  • treatment may be administered in the absence of symptoms.
  • treatment may 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 may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • administration includes routes of introducing the compound(s) to a subject to perform their intended function.
  • routes of administration include injection (subcutaneous, intravenous, parenterally, intraperitoneally, intrathecal), topical, oral, inhalation, rectal and transdermal.
  • effective amount includes an amount effective, at dosages and for periods of time necessary, to achieve the desired result.
  • An effective amount of compound may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response.
  • systemic administration means the administration of a compound(s), drug or other material, such that it enters the patient's system and, thus, is subject to metabolism and other like processes.
  • therapeutically effective amount means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
  • the therapeutically effective amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the cancer.
  • the drug may prevent growth and/or kill existing cancer cells, it may be cytostatic 3 2197122.1 Page 121 of 214 398110-82HPWO (213249) and/or cytotoxic.
  • efficacy can be measured, for example, by assessing the time to disease progression (TTP) and/or determining the response rate (RR).
  • subject refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In certain embodiments, the subject is a human.
  • additional therapeutic agents which are normally administered to treat that condition, may be administered in combination with compounds and compositions of this invention. 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.”
  • a provided combination, or composition thereof is administered in combination with another therapeutic agent.
  • MS Multiple
  • combination therapies of the present invention or a pharmaceutically 3 2197122.1 Page 122 of 214 398110-82HPWO (213249) acceptable composition thereof, are administered in combination with a monoclonal antibody or an siRNA therapeutic.
  • Those additional agents may be administered separately from a provided combination therapy, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.
  • the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention.
  • a combination of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • the present invention provides a single unit dosage form comprising a compound of the current invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the amount of additional therapeutic agent present in the compositions of this invention will 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 additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • the present invention provides a composition comprising a solid or salt form described herein and one or more additional therapeutic agents.
  • the therapeutic agent and solid or salt form may be administered together, or may be administered prior to or following administration of a solid or salt form. Suitable therapeutic agents are described in further detail below.
  • a solid or salt form described herein may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent.
  • a solid or salt form described herein may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours following the therapeutic agent.
  • the present invention provides a method of treating an inflammatory disease, disorder or condition by administering to a patient in need thereof a solid or salt form described herein and one or more additional therapeutic agents.
  • additional therapeutic agents may be small molecules or recombinant biologic agents and include, for example, acetaminophen, non-steroidal anti- 3 2197122.1 Page 123 of 214 398110-82HPWO (213249) inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, probenecid, allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®), antimalarials such as hydroxychlor
  • NSAIDS non
  • the present invention provides a method of treating rheumatoid arthritis comprising administering to a patient in need thereof a solid or salt form described herein and one or more additional therapeutic agents selected from non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin (Ridaura®), D
  • NSAIDS non-
  • the present invention provides a method of treating osteoarthritis comprising administering to a patient in need thereof a solid or salt form described herein and one or more additional therapeutic agents selected from acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®) and monoclonal antibodies such as tanezumab.
  • NSAIDS non-steroidal anti-inflammatory drugs
  • the present invention provides a method of treating cutaneous lupus erythematosus or systemic lupus erythematosus comprising administering to a patient in need thereof a solid or salt form described herein and one or more additional therapeutic agents selected from acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®) and anticoagulants such as heparin (NSAIDS) such as aspirin
  • the present invention provides a method of treating Crohn’s disesase, ulcerative colitis, or inflammatory bowel disease comprising administering to a patient in need thereof a solid or salt form described herein and one or more additional therapeutic agents selected from mesalamine 3 2197122.1 Page 125 of 214 398110-82HPWO (213249) (Asacol®) sulfasalazine (Azulfidine®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binding agents such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk of Magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot® and anticholinergics or antispasmodics such as dicyclomine (Bentyl®
  • the present invention provides a method of treating asthma comprising administering to a patient in need thereof a solid or salt form described herein and one or more additional therapeutic agents selected from Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone aceton
  • Singulair® beta
  • the present invention provides a method of treating COPD comprising administering to a patient in need thereof a solid or salt form described herein and one or more additional therapeutic agents selected from beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), methylxanthines such as theophylline (Theo- Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, inhaled corticosteroids such as prednisone
  • beta-2 agonists such
  • the present invention provides a method of treating a solid tumor 3 2197122.1 Page 126 of 214 398110-82HPWO (213249) comprising administering to a patient in need thereof a solid or salt form described herein and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.
  • the present invention provides a method of treating a hematological malignancy comprising administering to a patient in need thereof a solid or salt form described herein and a Hedgehog (Hh) signaling pathway inhibitor.
  • the hematological malignancy is DLBCL (Ramirez et al “Defining causative factors contributing in the activation of hedgehog signaling in diffuse large B-cell lymphoma” Leuk. Res. (2012), published online July 17).
  • the present invention provides a method of treating diffuse large B- cell lymphoma (DLBCL) comprising administering to a patient in need thereof a solid or salt form described herein and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, and combinations thereof.
  • rituximab Renuxan®
  • Cytoxan® cyclophosphamide
  • doxorubicin Hadrodaunorubicin®
  • vincristine Oncovin®
  • prednisone a hedgehog signaling inhibitor
  • the present invention provides a method of treating multiple myeloma comprising administering to a patient in need thereof a solid or salt form described herein and one or more additional therapeutic agents selected from bortezomib (Velcade®), and dexamethasone (Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor in combination with lenalidomide (Revlimid®).
  • additional therapeutic agents selected from bortezomib (Velcade®), and dexamethasone (Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor in combination with lenalidomide (Revlimid®).
  • the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a solid or salt form described herein and a BTK inhibitor, wherein the disease is selected from inflammatory bowel disease, arthritis, cutaneous lupus erythematosus, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still’s disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto’s thyroiditis, Ord’s thyroiditis, Graves’ disease, autoimmune thyroiditis, Sjogren’s syndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison’s disease, opsoclonus
  • the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a solid or salt form described herein and a PI3K inhibitor, wherein the disease is selected from a cancer, a neurodegenative disorder, an angiogenic disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hormone-related disease, conditions associated with organ transplantation, immunodeficiency disorders, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin- induced platelet aggregation, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, and a CNS disorder.
  • the disease is selected from a cancer, a neurodegenative disorder, an angiogenic disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hormone-related disease, conditions associated with organ
  • the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a solid or salt form described herein and a PI3K inhibitor, wherein the disease is selected from benign or malignant tumor, carcinoma or solid tumor of the brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma or gastrointestinal cancer, especially colon carcinoma or colorectal adenoma or a tumor of the neck and head, an epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia,
  • hemolytic anemia aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia
  • cutaneous lupus erythematosus systemic lupus erythematosus
  • rheumatoid arthritis polychondritis
  • sclerodoma a progressive granulamatosis
  • dermatomyositis chronic active hepatitis
  • myasthenia gravis Steven-Johnson syndrome
  • idiopathic sprue autoimmune inflammatory bowel disease (e.g.
  • ulcerative colitis and Crohn's disease endocrine opthalmopathy
  • Grave's disease sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g.
  • idiopathic nephrotic syndrome or minal change nephropathy, restenosis, cardiomegaly, atherosclerosis, myocardial infarction, ischemic stroke and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity and hypoxia.
  • the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a solid or salt form described 3 2197122.1 Page 130 of 214 398110-82HPWO (213249) herein and a Bcl-2 inhibitor, wherein the disease is an inflammatory disorder, an autoimmune disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation.
  • the disorder is a proliferative disorder, lupus, or lupus nephritis.
  • the proliferative disorder is chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Hodgkin’s disease, small-cell lung cancer, non-small-cell lung cancer, myelodysplastic syndrome, lymphoma, a hematological neoplasm, or solid tumor.
  • the disease is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation.
  • the JH2 binding compound is a solid or salt form described herein .
  • Other suitable JH2 domain binding compounds include those described in WO2014074660A1, WO2014074661A1, WO2015089143A1.
  • Suitable JH1 domain binding compounds include those described in WO2015131080A1.
  • a compound of the current invention may also be used to advantage in combination with other therapeutic compounds.
  • the other therapeutic compounds are antiproliferative compounds.
  • 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 metalloprotein
  • 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 3 2197122.1 Page 131 of 214 398110-82HPWO (213249) 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 ArimidexTM.
  • Letrozole is marketed under the trade names FemaraTM or FemarTM.
  • Aminoglutethimide is marketed under the trade name OrimetenTM.
  • a combination of the invention 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.
  • 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 invention 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).
  • 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 Acriblastin TM 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.
  • 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).
  • antiproliferative activity This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • antiproliferative activity This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • antiproliferative activity includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • antiproliferative activity includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • antiproliferative activity This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • antiproliferative activity This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • 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 factor-receptors (FGFR); c) compounds targeting, decreasing or inhibiting the activity of the insulin-like growth factor receptor I (IGF-
  • 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, BTK and TEC family, and/or members of the cyclin-dependent kinase family (CDK) including staurosporine derivatives, such as midostaurin; examples of further
  • 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 PI3K ⁇ , PI3K ⁇ , PI3K ⁇ , PI3K ⁇ , PI3K-C2 ⁇ , PI3K-C2 ⁇ , PI3K-C2 ⁇ , Vps34, p110- ⁇ , p110- ⁇ , p110- ⁇ , p110- ⁇ , p110- ⁇ , p85- ⁇ , p85- ⁇ , p55- ⁇ , p150, p101, and p87.
  • PI3K inhibitors useful in this invention 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.
  • BK 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.
  • 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 WO2008118802), navitoclax (and analogs thereof, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ.
  • PI3K inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2004019973, WO2004089925, 3 2197122.1 Page 135 of 214 398110-82HPWO (213249) WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554, and WO2007044729.
  • JAK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246, and WO2007070514.
  • 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.
  • proteasome inhibitors useful for use in combination with compounds of the invention 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, ⁇ - ⁇ - or ⁇ - tocopherol or ⁇ - ⁇ - or ⁇ -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.
  • Cox-2 inhibitors 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.
  • 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 as used herein refers to a lymphokine or interferons.
  • 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 “farnesyl transferase inhibitor” such as L-744832, DK8G557 or R115777 (ZarnestraTM).
  • telomerase inhibitor refers to compounds which target, decrease or inhibit the activity of telomerase.
  • telomere inhibitor refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase.
  • methionine aminopeptidase inhibitor refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase.
  • 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.
  • 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- ⁇ -D- arabinofuransylcytosine (ara-c) and bisulfan; ALK inhibitors, which are compounds which target, decrease or inhibit anaplastic lymphoma kinase, and Bcl-2 inhibitors.
  • 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 HDAC inhibitors.
  • antiproliferative antibodies includes, but is not limited to, trastuzumab (HerceptinTM), Trastuzumab-DM1, erbitux, bevacizumab (AvastinTM), rituximab (Rituxan ® ), PRO64553 (anti-CD40) and 2C4 Antibody.
  • antibodies is meant intact monoclonal antibodies, polyclonal 3 2197122.1 Page 137 of 214 398110-82HPWO (213249) 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 invention can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML.
  • compounds of the current invention 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.
  • the present invention provides a method of treating AML associated with an ITD and/or D835Y mutation, comprising administering a compound of the present invention together with a one or more FLT3 inhibitors.
  • the FLT3 inhibitors are selected from quizartinib (AC220), a staurosporine derivative (e.g.
  • the FLT3 inhibitors are selected from quizartinib, midostaurin, lestaurtinib, sorafenib, and sunitinib.
  • HDAC 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-1H-indol-3-yl)- ethyl]- amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof and N- hydroxy-3-[4-[(2-hydroxyethyl) ⁇ 2-(1H-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.248-275 (1993).
  • EDG binders and ribonucleotide reductase inhibitors.
  • EDG binders refers to a class of immunosuppressants that modulates lymphocyte recirculation, 3 2197122.1 Page 138 of 214 398110-82HPWO (213249) 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-1H-isoindole-1 ,3-dione derivatives.
  • VEGF vascular endothelial growth factor
  • compounds, proteins or monoclonal antibodies of VEGF such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; AngiostatinTM; EndostatinTM; 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 (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 as used herein refers to compounds which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 11- ⁇ -epihydrocotisol, cortexolone, 17 ⁇ - hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.
  • Implants containing corticosteroids refers to compounds, such as fluocinolone and dexamethasone.
  • 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.
  • the compounds of the invention are also useful as co-therapeutic compounds for use in combination with other drug substances such as anti-inflammatory, bronchodilatory or antihistamine drug substances, particularly in the treatment of obstructive or inflammatory airways diseases such as those mentioned hereinbefore, for example as potentiators of therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such drugs.
  • a compound of the invention may be mixed with the other drug substance in a fixed pharmaceutical composition or it may be administered separately, before, simultaneously with or after the other drug substance.
  • the invention includes a combination of a compound of the invention as hereinbefore described with an anti-inflammatory, bronchodilatory, antihistamine or anti-tussive drug substance, said compound of the invention and said drug substance being in the same or different pharmaceutical composition.
  • Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate; non- steroidal glucocorticoid receptor agonists; LTB4 antagonists such LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4 antagonists such as montelukast and zafirlukast; PDE4 inhibitors such cilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden),V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering- Plough), Arofylline (Almirall
  • Suitable bronchodilatory drugs include anticholinergic or antimuscarinic compounds, in particular ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate.
  • Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine.
  • chemokine receptors e.g. CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR- 7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonists such as Schering-Plough antagonists SC-351125, SCH- 55700 and SCH-D, and Takeda antagonists such as N-[[4-[[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8- yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4- aminium chloride (TAK-770).
  • TAK-770 antagonists such as N-[[4-[[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8- yl
  • 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 invention 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, 3 2197122.1 Page 140 of 214 398110-82HPWO (213249) 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/Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LT ⁇ R, LIGHT, DcR3, HVEM, VEGI/TL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, Lymphotoxin ⁇ /TNF ⁇ , TNFR2, TNF ⁇ , LT ⁇ R, Lymphotoxin ⁇ 1 ⁇ 2, FA
  • an immuno-oncology agent is a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF- ⁇ , VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation, for stimulating an immune response.
  • a combination of a compound of the invention and an immuno-oncology agent can stimulate T cell responses.
  • 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, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD28H.
  • T cell activation e.g., immune checkpoint inhibitors
  • an antagonist of a protein that inhibits T cell activation e.g., immune
  • 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), LIBTAYO (cemiplimab), TYVYT (sintilimab), TEVIMBRA (tislelizumab), 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 IgG1, 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 (WO2007/005874), 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 (WO10/19570, 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 (WO006/105021, WO009/009116), or MK-4166 (WO11/028683).
  • an immuno-oncology agent is an indoleamine (2,3)-dioxygenase (IDO) antagonist.
  • 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 (WO09/73620, WO009/1156652, WO11/56652, WO12/142237).
  • an immuno-oncology agent is an OX40 agonist.
  • an OX40 agonist is an agonistic OX40 antibody.
  • an OX40 antibody is MEDI-6383 or MEDI-6469.
  • an immuno-oncology agent is an OX40L antagonist.
  • an OX40L antagonist is an antagonistic OX40 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. In some embodiments, a CD40 antagonist is an antagonistic CD40 antibody. In some embodiments, a CD40 antibody is lucatumumab or dacetuzumab. [0762] 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. [0763] In some embodiments, an immuno-oncology agent is MGA271 (to B7H3) (WO11/109400).
  • 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 et al. (2016) Sci. Transl. Med. 8.
  • the anti-PD-1 antibody nivolumab (OPDIVO ® , Bristol-Myers Squibb, also 3 2197122.1 Page 143 of 214 398110-82HPWO (213249) 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.
  • 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
  • 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 (NCT01166542); 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- 3 2197122.1 Page 144 of 214 398110-82HPWO (213249) 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-hTNF ⁇ -IRES-hIL20; and VSV-GP (ViraTherapeutics) a vesicular stomatitis virus (VSV) engineered to express the glycoprotein (GP) of
  • 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.
  • 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
  • the CAR-T cell is one of those described in U.S. Patent 8,906,682 (June et al.), which discloses CAR-T cells engineered to comprise an extracellular domain having an antigen binding domain (such as a domain that binds to CD19), 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 CD19
  • CD3 zeta intracellular signaling domain of the T cell antigen receptor complex
  • an immunostimulatory agent is an activator of retinoic acid receptor- related orphan receptor ⁇ (ROR ⁇ t).
  • ROR ⁇ t is a transcription factor with key roles in the differentiation and maintenance of Type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) T cells, as well as the differentiation of IL-17 expressing innate immune cell subpopulations such as NK cells.
  • an activator of ROR ⁇ t 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 toll-like receptor (TLR).
  • TLR toll-like 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 invention 3 2197122.1 Page 145 of 214 398110-82HPWO (213249) 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 invention 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 (IPH2102/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.
  • urelumab BMS-663513, Bristol-
  • an immunostimulatory agent is selected from elotuzumab, mifamurtide, an agonist or activator of a toll-like receptor, and an activator of ROR ⁇ t.
  • 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 et 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 3 2197122.1 Page 146 of 214 398110-82HPWO (213249) agent targeting the pathways as described in Peter L. Toogood.
  • an immune-oncology agent is a T Cell Engager (TCE).
  • the TCE is a bi-specific antibody, tri-specific antibody, or a BITE small molecule, such as teclistamab or talquetamab.
  • 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.
  • 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 comprises tumor-associated antigen (TAA) negatgive cancer cells.
  • 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-infiltrating 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 a checkpoint regulators.
  • CTL-4 cytotoxic T-lymphocyte antigen 4
  • BTLA B and T Lymphocyte Attenuator
  • Tim-3 T cell Immunoglobulin and Mucin domain-3
  • Lymphocyte Activation Gene-3 Lag-3; CD223
  • an immune checkpoint inhibitor is an antibody to PD-1.
  • the checkpoint inhibitor 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, PDLl, PDL2, PDl, 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.
  • a checkpoint protein selected from CTLA-4, PDLl, PDL2, PDl, 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, PDLl, PDL2, PDl, 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, ⁇ , and memory CD8 + ( ⁇ ) 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, ⁇ , and memory CD8 + ( ⁇ ) 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-Ll 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 3 2197122.1 Page 148 of 214 398110-82HPWO (213249) antibody), MPLDL3280A (anti-PDLl antibody), MSB0010718C (anti-PDLl antibody), and ipilimumab (anti-CTLA-4 checkpoint inhibitor).
  • CTLA-4 blocking antibody PD-Ll monoclonal Antibody
  • Anti-B7-Hl MEDI4736
  • MK-3475 PD-1 blocker
  • Nivolumab anti-PDl antibody
  • Checkpoint protein ligands include, but are not limited to PD-Ll, PD- L2, B7-H3, B7-H4, CD28, CD86 and TIM-3.
  • the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 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-L1 antibody, IMFINZI®, AstraZeneca); and atezolizumab (anti-PD-L1 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-L1 antibody, IMFINZI®,
  • 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 IgG1 anti-PD-L1 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 PDR
  • 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 3 2197122.1 Page 149 of 214 398110-82HPWO (213249) containing protein-3 (TIM-3).
  • TIM-3 inhibitors that may be used in the present invention 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).
  • 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 invention include BMS-986207 (Bristol-Myers Squibb), an anti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); and anti-TIGIT monoclonal antibody (NCT03119428).
  • a checkpoint inhibitor is an inhibitor of Lymphocyte Activation Gene- 3 (LAG-3).
  • LAG-3 inhibitors that may be used in the present invention 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 invention include OX40 agonists.
  • OX40 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); MEDI0562 (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-My
  • Checkpoint inhibitors that can be used in the present invention 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- 3 2197122.1 Page 150 of 214 398110-82HPWO (213249) CD137 antibody in metastatic or locally advanced malignancies (NCT03881488).
  • Checkpoint inhibitors that can be used in the present invention 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 invention 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 IgG1 Fc domain, in advanced solid tumors (NCT02583165).
  • TRX518 Leap Therapeutics
  • Checkpoint inhibitors that can be used in the present invention 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 invention include killer IgG-like receptor (KIR) inhibitors.
  • KIR killer IgG-like receptor
  • 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).
  • Checkpoint inhibitors that can be used in the present invention 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 IgG1, acts by binding human CD47, and 3 2197122.1 Page 151 of 214 398110-82HPWO (213249) 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
  • Checkpoint inhibitors that can be used in the present invention 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 invention 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 invention 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-1R antibody, in pancreatic cancer (NCT03153410), melanoma (NCT03101254), and solid tumors (NCT02718911); and BLZ945 (4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6- yloxyl]-pyridine-2-carboxylic acid methylamide, Novartis), an orally available inhibitor of CSF1R, in advanced solid
  • Checkpoint inhibitors that can be used in the present invention include NKG2A receptor inhibitors.
  • NKG2A receptor inhibitors that are being studied in clinical trials include monalizumab (IPH2201, 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, pidilizumab, cemiplimab, sintilimab, or tislelizumab.
  • a compound of the current invention may 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 invention 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 invention 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 invention 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.
  • Those additional agents may be administered separately from an inventive compound- containing composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.
  • compositions of this invention should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of an inventive compound can be administered.
  • that additional therapeutic agent and the compound of this invention may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent.
  • compositions of this invention a dosage of between 0.01 – 1,000 ⁇ g/kg body weight/day of the additional therapeutic agent can be administered.
  • the amount of additional therapeutic agent present in the compositions of this invention will 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 additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • the compounds of this invention, or pharmaceutical compositions thereof may 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 3 2197122.1 Page 153 of 214 398110-82HPWO (213249) restenosis (re-narrowing of the vessel wall after injury).
  • patients using stents or other implantable devices risk clot formation or platelet activation.
  • Implantable devices coated with a compound of this invention are another embodiment of the present invention.
  • XRPD diffractograms were collected on a Bruker AXS C2 GADDS diffractometer using Cu K ⁇ radiation (40 kV, 40 mA), an automated XYZ stage, a laser video microscope for auto-sample positioning and a V ⁇ ntec-5002-dimensional area detector.
  • X-ray optics consists of a single Göbel multilayer mirror coupled with a pinhole collimator of 0.3 mm.
  • the beam divergence i.e., the effective size of the X-ray beam on the sample, was approximately 4 mm.
  • a ⁇ - ⁇ continuous scan mode was employed with a sample – detector distance of 20 cm which gives an effective 2 ⁇ range of 1.5° – 32.5°.
  • XRPD diffractograms were collected on a Bruker D8 diffractometer using Cu K ⁇ radiation (40 kV, 40 mA) and a ⁇ -2 ⁇ goniometer fitted with a Ge monochromator.
  • the incident beam passes through a 2.0 mm divergence slit followed by a 0.2 mm anti-scatter slit and knife edge.
  • the diffracted beam passes through an 8.0 mm receiving slit with 2.5° Soller slits followed by the Lynxeye Detector.
  • the software used for data collection and analysis was Diffrac Plus XRD Commander and Diffrac Plus EVA respectively. Samples were run under ambient conditions as flat plate specimens using powder as received.
  • the sample was prepared on a polished, zero-background (510) silicon wafer by gently pressing onto the flat surface or packed into a cut cavity. The sample was rotated in its own plane.
  • the details of the standard Pharmorphix data collection method are: ⁇ Angular range: 2 to 42° 2 ⁇ ⁇ Step size: 0.05° 2 ⁇ ⁇ Collection time: 0.5 s/step (total collection time: 6.40 min)
  • PANalytical Empyrean PANalytical Empyrean. XRPD diffractograms were collected on a PANalytical Empyrean 3 2197122.1 Page 155 of 214 398110-82HPWO (213249) diffractometer using Cu K ⁇ radiation (45 kV, 40 mA) in transmission geometry.
  • a 0.5° slit, 4 mm mask and 0.04 rad Soller slits with a focusing mirror were used on the incident beam.
  • the software used for data collection was X’Pert Data Collector using X’Pert Operator Interface. The data were analyzed and presented using Diffrac Plus EVA or HighScore Plus. Samples were prepared and analyzed in either a metal or Millipore 96 well-plate in transmission mode. X-ray transparent film was used between the metal sheets on the metal well-plate and powders (approximately 1 – 2 mg) were used as received.
  • the Millipore plate was used to isolate and analyze solids from suspensions by adding a small amount of suspension directly to the plate before filtration under a light vacuum.
  • the scan mode for the metal plate used the gonio scan axis, whereas a 2 ⁇ scan was utilized for the Millipore plate.
  • the details of the standard screening data collection method are: ⁇ Angular range: 2.5 to 32.0° 2 ⁇ ⁇ Step size: 0.0130° 2 ⁇ ⁇ Collection time: 12.75 s/step (total collection time of 2.07 min) Nuclear Magnetic Resonance (NMR) [0818] Solution State NMR.
  • 0.5 - 3 mg of each sample, in a pin-holed aluminum pan was heated at 10 °C/min from 25 °C to 300 °C. A purge of dry nitrogen at 50 ml/min was maintained over the sample.
  • the instrument control software was Advantage for Q Series and Thermal Advantage and the data were analyzed using Universal Analysis or TRIOS.
  • TA Instruments Discovery DSC DSC data were collected on a TA Instruments Discovery DSC equipped with a 50 position auto-sampler.
  • 0.5 - 3 mg of each sample, in a pin-holed aluminum pan was heated at 10 °C/min from 25 °C to 300 °C. A purge of dry nitrogen at 50 ml/min was maintained over the sample.
  • the instrument control software was TRIOS and the data were analyzed using TRIOS or Universal Analysis. 3 2197122.1 Page 156 of 214 398110-82HPWO (213249) Thermo-Gravimetric Analysis (TGA) [0821] TA Instruments Q500. TGA data were collected on a TA Instruments Q500 TGA, equipped with a 16 position auto-sampler. Typically, 5 - 10 mg of each sample was loaded onto a pre-tared aluminum DSC pan and heated at 10 °C/min from ambient temperature to 350 °C. A nitrogen purge at 60 ml/min was maintained over the sample. The instrument control software was Advantage for Q Series and Thermal Advantage and the data were analyzed using Universal Analysis or TRIOS.
  • TA Instruments Discovery TGA TGA data were collected on a TA Instruments Discovery TGA, equipped with a 25 position auto-sampler. Typically, 5 - 10 mg of each sample was loaded onto a pre- tared aluminum DSC pan and heated at 10 °C/min from ambient temperature to 350 °C. A nitrogen purge at 25 ml/min was maintained over the sample. The instrument control software was TRIOS and the data were analyzed using TRIOS or Universal Analysis.
  • Polarized Light Microscopy (PLM) PLM
  • Leica LM/DM Polarized Light Microscope Samples were analyzed on a Leica LM/DM polarized light microscope with a digital video camera for image capture.
  • the relative humidity was measured by a calibrated Rotronic probe (dynamic range of 1.0 – 100 %RH), located near the sample.
  • the weight change, (mass relaxation) of the sample as a function of %RH was constantly monitored by a microbalance (accuracy ⁇ 0.005 mg).
  • 5 - 30 mg of sample was placed in a tared mesh stainless steel basket under ambient conditions.
  • the sample was loaded and unloaded at 40 %RH and 25 °C (typical room conditions).
  • a moisture sorption isotherm was performed as outlined below (2 scans per complete cycle).
  • the standard isotherm was performed at 25 °C at 10 %RH intervals over a 0 – 90 %RH range.
  • a double cycle (4 scans) was carried out.
  • Aqueous solubility was determined by suspending sufficient compound in relevant media to give a maximum final concentration of ⁇ 10 mg/ml of the parent free-form of the compound. The suspension was equilibrated at 25 °C, on a Heidolph plate shaker set to 750 rpm for 24 hours. The pH of the saturated solution was then measured, and the suspension filtered through a glass fiber C filter (particle retention 1.2 ⁇ m) and diluted appropriately. Quantitation was by HPLC with reference to a standard solution of approximately 0.15 mg/ml in DMSO. Different volumes of the standard, diluted and undiluted sample solutions were injected.
  • solubility was calculated using the peak areas determined by integration of the peak found at the same retention time as the principal peak in the standard injection.
  • Table 32 HPLC method for solubility measurements Parameter Value T f th R h ith i t l ti Ana de array detector and using OpenLAB software. 3 2197122.1 Page 159 of 214 398110-82HPWO (213249) Ion Chromatography (IC) [0828] Data were collected on a Metrohm 930 Compact IC Flex with 858 Professional autosampler and 800 Dosino dosage unit monitor, using IC MagicNet software. Accurately weighed samples were prepared as stock solutions in a suitable solvent. Quantification was achieved by comparison with standard solutions of known concentration of the ion being analyzed.
  • reaction was cooled to RT, then treated portion wise with further di-tert-butyl dicarbonate (2.27 g, 10.4 mmol) and heated at 60 °C for 5 h. After cooling to RT, the solvent was removed in vacuo and the residue partitioned between EtOAc (3 x 30 mL) and saturated aqueous sodium bicarbonate (20 mL). The combined organic phase was washed with brine (20 mL), passed through a hydrophobic filter and concentrated in vacuo.
  • Step 2 tert-Butyl (5-bromo-6-(hydroxymethyl)pyridin-2-yl)(tert-butoxycarbonyl)carbamate (Intermediate AB50-3) and tert-butyl (5-bromo-6-(hydroxymethyl)pyridin-2-yl)carbamate (Intermediate AB50-3’)
  • Intermediate AB50-2 3.37 g, 7.8 mmol
  • ethanol 40 mL
  • sodium borohydride (0.89 g, 23.4 mmol
  • Step 4 tert-Butyl (5-(2,5-dihydrofuran-3-yl)-6-((dimethylamino)methyl)pyridin-2-yl)carbamate AB50-5)
  • Step 2 Synthesis of Methyl 2-(bromomethyl)-3-chlorobenzoate (3.0) [0838] To a solution of methyl 3-chloro-2-methylbenzoate (3.0a) (320 g, 1.72 mol) in carbon tetrachloride (3000 mL) were added N-bromosuccinimide (336.2 g, 1.88 mol) and benzoyl peroxide (0.798 g, 0.0032 mol) at RT. After stirring at 90 °C for 4h, the reaction was poured into ice/ water ( ⁇ 5000 mL) water and extracted with ethyl acetate.
  • Step 4 Synthesis of 4-Chloro-7-nitroisoindolin-1-one (3.2) [0840] To a solution of 4-chloro-isoindolin-1-one (3.1) (200 g, 1.19 mol) in c.H 2 SO 4 (1200 mL) at - 10 °C was added dropwise with HNO3 (69-72% aq. 120 mL). After stirring cold for 2h then warming to ambient temperature for 2h, the reaction was poured onto ice water ( ⁇ 4000 mL).
  • Step 5 Synthesis of 7-Amino-4-chloroisoindolin-1-one (3.3) [0841] To a solution of 4-chloro-7-nitroisoindolin-1-one 2 (3.2) (245 g, 1.15 mol) in EtOH (2500 mL) and water (500 mL) were added iron powder (322 g, 5.75 mol) and ammonium chloride (372.67 g, 6.90 mol). After mechanically stirring at reflux for 2 h, the mixture was filtered through Celite washing the filter cake with EtOAc and DCM ( ⁇ 5 L). The filtrate was concentrated under vacuum to low volume whereby a solid precipitated from solution.
  • Step 6 Synthesis of 4-Chloro-7-bromoisoindolin-1-one (3.4) [0842] To a suspension of 7-amino-4-chloroisoindolin-1-one (3.3) (100 g, 0.547 mol) in HBr (47%, 500 mL) at -10 °C was added a solution of sodium nitrite (75.5 g,1.09 mol) in water (500 mL). After stirring cold for 60 min, copper (I) bromide (86.04 g, 0.60 mol) was added. After stirring at 80 °C for 40 min, the reaction mixture was poured onto ice water.
  • Step 7 Synthesis of tert-Butyl 7-bromo-4-chloro-1-oxoisoindoline-2-carboxylate (3.5) [0843] To a of 4-chloro-7-bromoisoindolin-1-one (3.4) (12 o 0 g, 0.487 mol) in THF at 0 C (1500 mL) were added di-tert-butyl dicarbonate (159 g, 0.731 mol) and DMAP (74 g, 0.60 mol). After stirring at RT for 4 h, the mixture was diluted with EtOAc, washed with water and brine dried over Na2SO4, and concentrated in vacuum.
  • Step 2 Synthesis of compound tert-butyl 7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3- yl)pyridin-2-yl)amino)-1-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2- carboxylate (21.2) [0845] To a solution of the 21.1 (58 g, 119.0 mmol) suspended in 1-4 dioxane (580 mL) was added bis(pinacolato)diboron (60.50 g, 238.0 mmol, 2.0 eq) and potassium acetate (35.01 g, 357.0 mmol, 3.0 eq).
  • Step 3 Synthesis of compound tert-butyl 7-((6-((dimethylamino)methyl)-5-( tetrahydrofuran-3- yl)pyridin-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-1-oxoisoindoline-2-carboxylate 21.3 [0846] To a solution of the 21.2 (45 g, 77.0 mmol) and 7-fluoro-3-iodoimidazo[1,2-a]pyridine Intermediate BB63 (24.47 g, 93.0 mmol, 1.2 eq) in 1-4 dioxane (360 mL) and water (90 mL) was added potassium phosphate tribasic (49.51 g, 233.0 mmol, 3.0 eq).
  • Step 4 Chiral Separation [0847] 21.3 (30g racemic) were separated on Shimadzu LC-20AP and UV detector using Chiralpak IC (250*21.0) mm, 5 micron, at 20.0 mL/min. Mobile phases were (A) 0.1% Diethylamine in n-Hexane (B) 0.1% Diethylamine in Propane-2-ol: Acetonitrile (70:30) to afford compounds 21.4 (10 g) and 21.5 (9 g).
  • Step 5b Synthesis of (S)-7-((6-((dimethylamino)methyl)-5-(tetrahydrofuran-3-yl)pyridin-2- yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one (I-479; Compound 1) 3 2197122.1 Page 167 of 214 398110-82HPWO (213249) [0848] To a solution of 21.5 (1 g, 17.15 mmol) in DCM (10 mL) was added 4M hydrochloric acid in 1-4 dioxane (4 mL) at RT.
  • Example 2 Identification of Compound 1 Form 1 [0849] The preparation of Compound 1 in Example 1 above resulted in the formation of Compound 1 Form 1. Compound 1 Form 1 was characterized by XRPD, NMR, and HPLC (see FIGs.1-2) and used in the following salt screen.
  • Example 3 Salt Screen [0850] Salt screening experiments were performed on Compound 1 Form 1 in THF and IPA:H2O (10%) solvent systems. Multiple approaches were employed in efforts to isolate crystalline salts including, cooling, evaporation, antisolvent addition and reactive crystallization.
  • a number of crystalline salts were identified: hydrobromide, hydrochloride (two forms), sulfate (two forms), p-toluenesulfonate, methanesulfonate (two forms), L-malate, L-tartrate, citrate, fumarate (two forms) and benzoate. All of the isolated crystalline salt forms were characterized by NMR, IC, TGA, DSC and static storage experiments at 40 °C/75% relative humidity to determine the most suitable salts for scale-up. Based on the results, the Compound 7 Form 1, Compound 9 Form 1, and Compound 10 Form 1 and 2 were scaled up to generate sufficient material for further characterization. Form the scale up, Compound 7 was successfully obtained as the same form with much improved chemical purity.
  • Compound 9 and Compound 10 were obtained as either as Compound 9 Form 2 or Compound 10 Form 2.
  • Compound 7 Form 1 Based on further solid state characterization, as well as ease of scale up and handleability of the recovered solid, Compound 7 Form 1, a mono hydrated form, was recommended for further development.
  • Methods [0852] Salt Screen in THF. Compound 1 Form 1 (50 mg ⁇ 1 mg) was weighed into 12 x 4 mL vials and heated in 50 vol THF (2.5 mL) at 50 °C. To each vial, 1 eq.
  • Compound 1 Form 1 (50 mg ⁇ 1 mg) was weighed into 12 x 4 mL vials and dissolved in 30 vol IPA/H 2 O (10%) (1.5 mL) at 50 °C. To each vial, 1 eq. (102.8 ⁇ l of each counterion except fumaric acid where 205.6 ⁇ l was added) of the selected counterion was added as a stock solution and all samples were cooled to 25 °C at 0.1 °C/min. All suspensions formed were filtered via positive pressure. All solutions were further cooled to 5 °C at 0.1 °C/min to produce solids. All isolated solids were analyzed by XRPD.
  • New salt forms were identified in the experiments run in IPA:H2O (10%) using hydrochloric acid, sulfuric acid, methanesulfonic acid, and fumaric acid. These new salt forms were denoted as Compound 3 Form 2, Compound 4 Form 2, Compound 6 Form 2 and Compound 10 Form 2.
  • Amorphous material was observed in the experiment run in IPA:H2O (10%) using phosphoric acid.
  • a general trend was noticed on isolation and characterization of the materials from the two different solvent systems. In general the materials isolated from THF tended to be easier to filter, whereas the a number of the IPA:H2O (10%) samples required centrifugation as they passed through the frit and/or appeared to have low yields.
  • Compound 1 Form 1 was obtained using succinic acid and an amorphous phase was observed with phosphoric acid in THF. Two salts forms were observed, one from each solvent system for the samples containing chloride, sulfate, mesylate and fumarate. [0858] All new salts were further characterized by 1 H-NMR/IC, TGA, DSC and static storage experiments at 40 °C/75% relative humidity. It was determined that the most suitable salts for scale-up work were Compound 7 Form 1, Compound 9 Form 1, and Compound 10 Form 1 or 2. These salts were selected to progress to the next stage as they all showed good stability at elevated temperature and humidity in combination with desirable thermal properties. Example 4.
  • Compound 1 Form 1 (20 mg ⁇ 1 mg) was weighed into 2 x HPLC vials and both samples were dissolved in THF (50 vol, 1 ml) at 50 °C, 500 rpm on a Polar Bear. To one vial, 1 eq. (41 ⁇ l) of L-malic acid was added and to the other 1 eq. (41 ⁇ l) of L-tartaric acid was added. A heat/cool cycle was set between 50 °C and 5 °C and was left to cycle for 24 hours before cooling to 5 °C and isolating the samples by filtering via positive pressure. All isolated solids were analyzed by XRPD. [0861] Crystallization in THF:H2O (5%).
  • Compound 1 Form 1 (20 mg ⁇ 1 mg) was weighed into 2 x HPLC vials and both samples were dissolved in THF:H2O (5%) (50 vol, 1 ml) at 50 °C, 500 rpm on a Polar Bear. To one vial, 1 eq. (41 ⁇ l) of L-malic acid was added and to the other 1 eq. (41 ⁇ l) of L-tartaric acid was added. A heat/cool cycle was set between 50 °C and 5 °C and was left to cycle for 24 hours before cooling to 5 °C and isolating the samples by filtering via positive pressure. All isolated solids were analyzed by XRPD.
  • Compound 1 Form 1 (200 mg ⁇ 1 mg) was weighed into a 20 ml vial and dissolved in 50 vol THF (10 ml) at 50 °C, 700 rpm on a Polar Bear to achieve a clear yellow solution. To the vial, 1 eq. (822.2 ⁇ l) of fumaric acid was added as stock solution and a heat/cool cycle was set between 50 °C and 5 °C to cycle for 72 hours. The sample was then isolated at 5°C, filtered via positive pressure and analyzed by XRPD. Results and Discussion [0867] The scale-up of Compound 7 Form 1 was successful in THF:H2O (5%) on a 200 mg scale which was confirmed by the characterization summarized in Table 39.
  • a large sharp endotherm at 207.4 °C (onset) of 108 J/g indicates the melt of the sample with degradation (onset) at 200 °C.
  • GVS analysis showed the sample to be hygroscopic with a maximum uptake of 4.3% w/w water 3 2197122.1 Page 176 of 214 398110-82HPWO (213249) at 90% RH, also relating to the water content observed in TGA and KF analysis.
  • the mass change between 10% RH and 80% RH was only 1.0%, showing much lower hydroscopic behavior at more moderate humidities. No change was observed in the XRPD pattern of Compound 7 Form 1 following GVS analysis showing the samples stability in elevated humidity conditions.
  • VT-XRPD shows that upon heating to 100 °C, Compound 7 Form 1 converts to a new form denoted as Compound 7 Form 2, likely a dehydrated form. This new pattern is shown to persists up to 175 °C but converts back to Compound 7 Form 1 upon cooling to RT. Therefore, it is recommended not to store Compound 7 Form 1 in conditions above 100 °C to avoid conversion to Compound 7 Form 2.
  • Compound 3 2197122.1 Page 180 of 214 398110-82HPWO (213249) 7 Form 1 also exhibits good stability over the range 10% RH to 80% RH with only a small change in mass. The solubility was shown to be higher in FaSSGF and water when compared to the free form. Compound 7 Form 1 also exhibits less polymorphic behavior than the other salts with Compound 7 Form 1 being the only form isolated at ambient temperature and humidity.
  • Example 6 Compound 7 Form 1 Monohydrate [0879] Crystals of the L-malate salt of Compound 1 monohydrate were obtained by evaporative crystallization from a MeOH:Water (10:1 v/v) solution. The crystal structure of Compound 7 Form 1 monohydrate was determined at 99.8(5) K.
  • the structure was identified as depicted in FIG.45 and the asymmetric unit found to contain one fully ordered cation of Compound 1, one fully ordered L-malate anion, and one water molecule.
  • the simulated XRPD pattern of Compound 7 Form 1 monohydrate is shown in FIG. 46.
  • the simulated diffractogram from the single crystal structure is consistent with the experimental diffractogram of Compound 7 Form 1 monohydrate.
  • Example 7 Further Forms of Compound 7 [0880] Compound 1 Form 1 (30 mg ⁇ 1 mg) was weighed into 12 x 4 ml vials and suspended in selected solvent system (30 vol, 900 ⁇ l) at 50 °C, 500 rpm on a Polar Bear. To each vial, 1 eq. of L-malic acid (61.7 ⁇ l) was added at 50 °C. All samples were then cooled from 50 °C to 5 °C @ 0.1 °C/min and held at 5 °C for 24 hours.
  • Compound 7 Form 2 formed when heating Compound 7 Form 1 to above 100 o C.
  • Compound 7 Form 3 was found to be a partially crystalline isostructural solvate forming from MEK.
  • Compound 7 Form 4 was found to be a methanol solvate form. 3 2197122.1 Page 184 of 214 398110-82HPWO (213249)

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Abstract

La présente divulgation concerne, de manière générale, diverses formes solides et salines de composés utiles pour antagoniser la kinase progénitrice hématopoïétique 1 (HPK1) et leurs utilisations dans le traitement de diverses maladies.
PCT/US2024/053733 2023-10-30 2024-10-30 Formes solides d'antagonistes de hpk1 Pending WO2025096666A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190256500A1 (en) * 2018-02-20 2019-08-22 Incyte Corporation Indazole compounds and uses thereof
US20210078997A1 (en) * 2019-09-13 2021-03-18 Nimbus Saturn, Inc. SUBSTITUTED ISOINDOLIN-1-ONES AND 2,3-DIHYDRO-1H-PYRROL[3,4-c]PYRIDIN-1-ONES AS HPK1 ANTAGONISTS
WO2023015199A1 (fr) * 2021-08-03 2023-02-09 Nimbus Saturn, Inc. Antagonistes de hpk1 et leurs utilisations

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190256500A1 (en) * 2018-02-20 2019-08-22 Incyte Corporation Indazole compounds and uses thereof
US20210078997A1 (en) * 2019-09-13 2021-03-18 Nimbus Saturn, Inc. SUBSTITUTED ISOINDOLIN-1-ONES AND 2,3-DIHYDRO-1H-PYRROL[3,4-c]PYRIDIN-1-ONES AS HPK1 ANTAGONISTS
WO2023015199A1 (fr) * 2021-08-03 2023-02-09 Nimbus Saturn, Inc. Antagonistes de hpk1 et leurs utilisations

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