Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
  • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
  • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
  • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
  • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
  • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
  • C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
  • C07C211/03—Monoamines
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
  • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
  • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
  • C07C215/10—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with one amino group and at least two hydroxy groups bound to the carbon skeleton
• • 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 present invention is directed to 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8- yl)ethyl]amino]benzoic acid (“Compound A”), pharmaceutically acceptable salts thereof, and use thereof for the treatment of disease.
• the PIK3CA gene encoding the PI3K catalytic isoform pl 10a is the most frequently mutated gene in solid tumors and is also the most frequent site of genetic alteration within the PI3K pathway.
• PIK3CA mutations are most frequently found in endometrial, breast, and head and neck cancers. Approximately 40% of patients with HR+/HER2- breast cancer harbor activating mutations in PIK3CA, which activates pl 10a and the PI3K7AKT/mTOR signaling network. H1047R is the most common missense mutation in PIK3CA.
• PI3K ⁇ inhibitors with improved therapeutic indices for the treatment of diseases associated with mutant PI3K, including PIK3CA-mutant cancers.
• solid forms of PI3K ⁇ inhibitors having advantageous physical stability, chemical stability, solubility, or pharmacokinetic properties.
• compositions of Compound A include a tromethamine salt of 2-[[(1R)-1 -(3,6-dimethyl-4-oxo-2-phenyl-chromen-8- yl)ethyl] amino] benzoic acid and an erbumine salt of 2-[[(1R)-1 -(3,6-dimethyl-4-oxo-2- phenyl-chromen-8-yl)ethyl]amino]benzoic acid.
• therapies including Compound A. or a pharmaceutically acceptable salt thereof, for the treatment of disease, such as PIK3CA-mutated cancer.
• FIG. 1 is an XRPD patern of crystalline Compound A Form A.
• FIG. 2 is an XRPD patern of crystalline Compound A Form B.
• FIG. 3 is an XRPD patern of crystalline Compound A Form C.
• FIG. 4 is an XRPD patern of crystalline Compound A Tromethamine Salt Form A.
• FIG. 5 is an XRPD pattern of crystalline Compound A Tromethamine Salt Form C.
• FIG. 6 is an XRPD patern of crystalline Compound A Tromethamine Salt Form D.
• FIG. 7 is an XRPD patern of a crystalline Compound A Erbumine Salt.
• Compound A The compound 2-[[(1R)-1 -(3,6-dimethyl-4-oxo-2-phenyl-chromen-8- yl)ethyl]amino]benzoic acid (“Compound A”) is a potent and mutant-selective inhibitor of PI3K ⁇ H1047R.
• crystalline 2-[[(1R)-1 -(3,6-dimethyl-4-oxo-2-phenyl-chromen- 8-yl)ethyl]amino]benzoic acid Form A also referred to as Compound A Form A.
• Compound A Form A is characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having at least one peak at diffraction angle 2-theta selected from 7.8° ⁇ 0.2°, 12.1° ⁇ 0.2°, 13.7° ⁇ 0.2°, 14.1° ⁇ 0.2°, 16.8° ⁇ 0.2°, 17.5° ⁇ 0.2°, 18.2° ⁇ 0.2°, 18.9° ⁇ 0.2°, 19.5° ⁇ 0.2°, 20.7° ⁇ 0.2°, 21.2° ⁇ 0.2°, and 24.1° ⁇ 0.2°.
• Compound A Form A is characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 12.1° ⁇ 0.2° in combination with at least one peak selected from 14.1° ⁇ 0.2°, 16.8° ⁇ 0.2°, 18.9° ⁇ 0.2°, and 20.7° ⁇ 0.2°.
• Compound A Form A is characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 12.
• Compound A Form A is characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 12.1° ⁇ 0.2° in combination with at least three peaks selected from 14.1° ⁇ 0.2°, 16.8° ⁇ 0.2°, 18.9° ⁇ 0.2°, and 20.7° ⁇ 0.2°.
• Compound A Form A is characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 12. 1° ⁇ 0.2° in combination with the peaks 14.1° ⁇ 0.2°, 16.8° ⁇ 0.2°, 18.9° ⁇ 0.2°, and 20.7° ⁇ 0.2°.
• Compound A Form A is characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having peaks at diffraction angle 2-theta of 7.8° ⁇ 0.2°, 12.1° ⁇ 0.2°, 13.7° ⁇ 0.2°, 14.1° ⁇ 0.2°. 16.8° ⁇ 0.2°.
• Compound A Form B is characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having at least one peak at diffraction angle 2-theta selected from 7.0° ⁇ 0.2°. 9.7° ⁇ 0.2°, 11.9° ⁇ 0.2°, 14.9° ⁇ 0.2°. and 17.4° ⁇ 0.2°.
• Compound A Form B is characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 9.7° ⁇ 0.2° in combination with at least one peak selected from 14.9° ⁇ 0.2°, 11.9° ⁇ 0.2°, 17.4° ⁇ 0.2°, and 7.0° ⁇ 0.2°.
• Compound A Form B is characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 9.7° ⁇ 0.2° in combination with at least two peaks selected from 14.9° ⁇ 0.2°, 11.9° ⁇ 0.2°, 17.4° ⁇ 0.2°, and 7.0° ⁇ 0.2°.
• Compound A Form B is characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2- theta of 9.7° ⁇ 0.2° in combination with at least three peaks selected from 14.9° ⁇ 0.2°.
• Compound A Form B is characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having peaks at diffraction angle 2-theta of 7.0° ⁇ 0.2°, 9.7° ⁇ 0.2°, 11.9° ⁇ 0.2°, 14.9° ⁇ 0.2°, and 17.4° ⁇ 0.2°.
• Compound A Form C is characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having at least one peak at diffraction angle 2-theta selected from 7.4° ⁇ 0.2°, 8.5° ⁇ 0.2°, 10.6° ⁇ 0.2°, 13.4° ⁇ 0.2°, and 15.7° ⁇ 0.2°.
• Compound A Form C is characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 13.4° ⁇ 0.2° in combination with at least one peak selected from 8.5° ⁇ 0.2°, 15.7° ⁇ 0.2°, 10.6° ⁇ 0.2°, and 7.4° ⁇ 0.2°.
• Compound A Form C is characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 13.4° ⁇ 0.2° in combination with at least two peaks selected from 8.5° ⁇ 0.2°, 15.7° ⁇ 0.2°, 10.6° ⁇ 0.2°, and 7.4° ⁇ 0.2°.
• Compound A Form C is characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 13.4° ⁇ 0.2° in combination with at least three peaks selected from 8.5° ⁇ 0.2°, 15.7° ⁇ 0.2°, 10.6° ⁇ 0.2°, and 7.4° ⁇ 0.2°.
• Compound A Form C is characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having peaks at diffraction angle 2-theta of 7.4° ⁇ 0.2°, 8.5° ⁇ 0.2°, 10.6° ⁇ 0.2°, 13.4° ⁇ 0.2°, and 15.7° ⁇ 0.2°.
• a tromethamine salt of 2-[[(1R)-1 -(3,6-dimethyl-4- oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid may have advantageous physical stability, chemical stability, solubility, or pharmacokinetic properties. Certain tromethamine salts of Compound A may have processability or other manufacturing advantages. Certain tromethamine salts of Compound A may provide a chiral enhancement of Compound A upon crystallization of the tromethamine salt.
• a crystalline tromethamine salt of 2-[[(1R)-1 -(3,6- dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid referred to as Compound A Tromethamine Salt Form A.
• Compound A Tromethamine Salt Form A is characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having at least one peak at diffraction angle 2-theta selected from 6.4° ⁇ 0.2°, 8.4° ⁇ 0.2°, 10.9° ⁇ 0.2°, 11.8° ⁇ 0.2°, 13.0° ⁇ 0.2°, 16.5° ⁇ 0.2°, 16.9° ⁇ 0.2°, 22.1° ⁇ 0.2°, 23.0° ⁇ 0.2°, and 24.9° ⁇ 0.2°.
• Compound A Tromethamine Salt Form A is characterized by an X- ray powder diffraction patern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 6.4° ⁇ 0.2° in combination with at least one peak selected from 8.4° ⁇ 0.2°, 10.9° ⁇ 0.2°, 16.9° ⁇ 0.2°, and 22.1° ⁇ 0.2°.
• Compound A Tromethamine Salt Form A is characterized by an X-ray powder diffraction patern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 6.4° ⁇ 0.2° in combination with at least two peaks selected from 8.4° ⁇ 0.2°, 10.9° ⁇ 0.2°, 16.9° ⁇ 0.2°, and 22.1° ⁇ 0.2°.
• Compound A Tromethamine Salt Form A is characterized by an X-ray powder diffraction patern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 6.4° ⁇ 0.2° in combination with at least three peaks selected from 8.4° ⁇ 0.2°, 10.9° ⁇ 0.2°, 16.9° ⁇ 0.2°, and 22. 1° ⁇ 0.2°. In another embodiment.
• Compound A Tromethamine Salt Form A is characterized by an X-ray powder diffraction patern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 6.4° ⁇ 0.2° in combination with the peaks 8.4° ⁇ 0.2°, 10.9° ⁇ 0.2°, 16.9° ⁇ 0.2°, and 22. 1° ⁇ 0.2°.
• Compound A Tromethamine Salt Form A is characterized by an X-ray powder diffraction patern using CuK ⁇ radiation having peaks at diffraction angle 2-theta of 6.4° ⁇ 0.2°, 8.4° ⁇ 0.2°, 10.9° ⁇ 0.2°, 11.8° ⁇ 0.2°, 13.0° ⁇ 0.2°, 16.5° ⁇ 0.2°, 16.9° ⁇ 0.2°, 22.1° ⁇ 0.2°, 23.0° ⁇ 0.2°, and 24.9° ⁇ 0.2°.
• Compound A Tromethamine Salt Form A is characterized by a 13 C solid state NMR (100.6 MHz) spectrum which comprises at least one peak referenced to glycine (external reference at 176.5 ppm) selected from: 179.0, 158.7, 151.7, 149.7, 136.3, 134.7, 132.9, 129.3, 127.4, 125.2, 121.7, 117.0, 115.5, 115.2, 110.4, 64.1, 63.2, 45.3, 22.6, 20.3, and 11.6 ppm ( ⁇ 0.2 ppm, respectively).
• Compound A Tromethamine Salt Form A is characterized by a 13 C solid state NMR (100.6 MHz) spectrum which comprises at least one peak referenced to glycine (external reference at 176.5 ppm) selected from: 179.0, 129.3, 63.2, 20.3, and 11.6 ppm ( ⁇ 0.2 ppm, respectively).
• Compound A Tromethamine Salt Form A is characterized by a 13 C solid state NMR (100.6 MHz) spectrum which comprises peaks referenced to glycine (external reference at 176.5 ppm) at: 179.0, 158.7, 151.7, 149.7, 136.3, 134.7, 132.9. 129.3, 127.4.
• Compound A Tromethamine Salt Form C is a crystalline tromethamine salt of 2-[[(1R)-1-(3.6- dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid, referred to as Compound A Tromethamine Salt Form C.
• Compound A Tromethamine Salt Form C is characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having at least one peak at diffraction angle 2-theta selected from 10.6° ⁇ 0.2°, 13.2° ⁇ 0.2°, 14.5° ⁇ 0.2°, 15.9° ⁇ 0.2°, and 17.4° ⁇ 0.2°.
• Compound A Tromethamine Salt Form C is characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 15.9° ⁇ 0.2° in combination with at least one peak selected from 10.6° ⁇ 0.2°, 17.4° ⁇ 0.2°, 13.2° ⁇ 0.2°, and 14.5° ⁇ 0.2°.
• Compound A Tromethamine Salt Form C is characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 15.9° ⁇ 0.2° in combination with at least two peaks selected from 10.6° ⁇ 0.2°, 17.4° ⁇ 0.2°, 13.2° ⁇ 0.2°, and 14.5° ⁇ 0.2°.
• Compound A Tromethamine Salt Form C is characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 15.9° ⁇ 0.2° in combination with at least three peaks selected from 10.6° ⁇ 0.2°, 17.4° ⁇ 0.2°, 13.2° ⁇ 0.2°, and 14.5° ⁇ 0.2°.
• Compound A Tromethamine Salt Form C is characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having peaks at diffraction angle 2-theta of 10.6° ⁇ 0.2°, 13.2° ⁇ 0.2°, 14.5° ⁇ 0.2°, 15.9° ⁇ 0.2°, and 17.4° ⁇ 0.2°.
• Compound A Tromethamine Salt Form D is characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having at least one peak at diffraction angle 2-theta selected from 6.3° ⁇ 0.2°, 11.1° ⁇ 0.2°, 12.6° ⁇ 0.2°, 17.1° ⁇ 0.2°, and 18.9° ⁇ 0.2°.
• Compound A Tromethamine Salt Form D is characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 11. 1° ⁇ 0.2° in combination with at least one peak selected from 12.6° ⁇ 0.2°, 17.1° ⁇ 0.2°, 6.3° ⁇ 0.2°, and 18.9° ⁇ 0.2°.
• Compound A Tromethamine Salt Form D is characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 11. 1° ⁇ 0.2° in combination with at least two peaks selected from 12.6° ⁇ 0.2°, 17.
• Compound A Tromethamine Salt Form D is characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 11.1° ⁇ 0.2° in combination with at least three peaks selected from 12.6° ⁇ 0.2°, 17.1° ⁇ 0.2°, 6.3° ⁇ 0.2°, and 18.9° ⁇ 0.2°.
• Compound A Tromethamine Salt Form D is characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having peaks at diffraction angle 2-theta of 6.3° ⁇ 0.2°, 1 1. 1° ⁇ 0.2°, 12.6° ⁇ 0.2°, 17.1° ⁇ 0.2°, and 18.9° ⁇ 0.2°.
• an erbumine salt of 2-[[(1R)-1 -(3,6-dimethyl-4- oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid may have advantageous physical stability, chemical stability, solubility, or pharmacokinetic properties. Certain erbumine salts of Compound A may have processability or other manufacturing advantages.
• a crystalline erbumine salt of 2-[[(1R)-1-(3,6-dimethyl-4- oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid referred to as Compound A Erbumine Salt Form A.
• Compound A Erbumine Salt Form A is characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having at least one peak at diffraction angle 2-theta selected from 6.5° ⁇ 0.2°, 10.5° ⁇ 0.2°, 11.1° ⁇ 0.2°, 15.2° ⁇ 0.2°, 15.9° ⁇ 0.2°, 17.6° ⁇ 0.2°, 18.0° ⁇ 0.2°, 19.3° ⁇ 0.2°, 21.5° ⁇ 0.2°, 22.2° ⁇ 0.2°, 22.7° ⁇ 0.2°, and 26.3° ⁇ 0.2°.
• Compound A Erbumine Salt Form A is characterized by an X- ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 11 . 1° ⁇ 0.2° in combination with at least one peak selected from 10.5° ⁇ 0.2°, 15.2° ⁇ 0.2°, 18.0° ⁇ 0.2°, and 19.3° ⁇ 0.2°.
• Compound A Erbumine Salt Form A is characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 11.
• Compound A Erbumine Salt Form A is characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 11. 1° ⁇ 0.2° in combination with at least three peaks selected from 10.5° ⁇ 0.2°, 15.2° ⁇ 0.2°, 18.0° ⁇ 0.2°, and 19.3° ⁇ 0.2°.
• Compound A Erbumine Salt Form A is characterized by an X-ray powder diffraction patern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 11.1° ⁇ 0.2° in combination with the peaks 10.5° ⁇ 0.2°, 15.2° ⁇ 0.2°, 18.0° ⁇ 0.2°, and 19.3° ⁇ 0.2°.
• Compound A Erbumine Salt Form A is characterized by an X-ray powder diffraction patern using CuK ⁇ radiation having peaks at diffraction angle 2-theta of 66.5° ⁇ 0.2°, 10.5° ⁇ 0.2°, 11.1° ⁇ 0.2°, 15.2° ⁇ 0.2°, 15.9° ⁇ 0.2°, 17.6° ⁇ 0.2°, 18.0° ⁇ 0.2°, 19.3° ⁇ 0.2°, 21.5° ⁇ 0.2°, 22.2° ⁇ 0.2°, 22.7° ⁇ 0.2°, and 26.3° ⁇ 0.2°.
• Compound A Erbumine Salt Form A is characterized by a 13 C solid state NMR (100.6 MHz) spectrum which comprises at least one peak referenced to glycine (external reference at 176.5 ppm) selected from: 177.4, 174.8, 159.8, 151.7, 149.5, 134.0, 132.6. 130.7, 130.3. 129.0, 128.1, 123.1, 122.4, 119.4. 116.8, 115.9. 112.3, 53.0, 47.5, 27.4, 23.3, 21.3, and 11.3 ppm ( ⁇ 0.2 ppm, respectively).
• Compound A Erbumine Salt Form A is characterized by a 13 C solid state NMR (100.6 MHz) spectrum which comprises at least one peak referenced to glycine (external reference at 176.5 ppm) selected from: 177.4. 132.6, 27.4, 21.3, and 11.3 ppm ( ⁇ 0.2 ppm, respectively).
• Compound A Erbumine Salt Form A is characterized by a 13 C solid state NMR (100.6 MHz) spectrum which comprises peaks referenced to glycine (external reference at 176.5 ppm) at: 177.4, 174.8, 159.8, 151.7, 149.5, 134.0, 132.6, 130.7, 130.3, 129.0, 128.1, 123.1, 122.4. 119.4, 116.8. 115.9, 112.3, 53.0. 47.5. 27.4, 23.3, 21.3, and 11.3 ppm ( ⁇ 0.2 ppm, respectively).
• therapies including Compound A, or a pharmaceutically acceptable salt thereof, for the treatment of patients with a disease, including PIK3CA- mutated cancer, such as PIK3CA-mutated advanced or metastatic breast cancer, or other solid tumors with a PIK3CA mutation.
• Compound A, or a pharmaceutically acceptable salt thereof may be used in monotherapy or in combination with one or more additional therapeutic agents.
• the therapies may provide new treatment options for patients, and may provide an enhanced and/or unexpected beneficial therapeutic effect in some patients over known therapies.
• the efficacy of a cancer treatment can be measured by various endpoints commonly used in evaluating cancer treatments, including but not limited to. tumor regression, tumor weight or size shrinkage, time to progression, overall survival, progression free survival. overall response rate, duration of response, best overall response, disease control rate, clinical benefit rate, time to response, and quality of life.
• Therapeutic agents may cause inhibition of metastatic spread without shrinkage of the primary tumor, may induce shrinkage of the primary tumor, or may simply exert a tumoristatic effect.
• Novel approaches to determining efficacy of any particular mono- or combination therapy of the present invention can be optionally employed, including, for example, measurement of plasma or urinary markers of angiogenesis and/or cell cycle activity, tissue-based biomarkers for angiogenesis and/or cell cycle activity, and measurement of response through radiological imaging.
• PI3K mutant phosphoinositide 3-kinase
• PIK3C A-mutated cancer comprising administering to the patient an effective amount of Compound A, or a pharmaceutically acceptable salt thereof.
• a method of treating a patient with a PIK3CA-mutated solid tumor comprising administering to the patient an effective amount of Compound A, or a pharmaceutically acceptable salt thereof.
• a method of treating a patient with PIK3CA-mutated breast cancer comprising administering to the patient an effective amount of Compound A, or a pharmaceutically acceptable salt thereof.
• PIK3C A-mutated, advanced or metastatic breast cancer comprising administering to the patient an effective amount of Compound A, or a pharmaceutically acceptable salt thereof.
• a method of treating a patient with CLOVES syndrome congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal, and spinal syndrome), or PIK3CA-related overgrowth syndrome (PROS) comprising administering to the patient an effective amount of Compound A, or a pharmaceutically acceptable salt thereof.
• CLOVES syndrome congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal, and spinal syndrome
• PROS PIK3CA-related overgrowth syndrome
• Compound A or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease associated with mutant phosphoinositide 3- kinase (PI3K).
• PI3K mutant phosphoinositide 3- kinase
• Compound A or a pharmaceutically acceptable salt thereof, for use in the treatment of PIK3CA-mutated cancer.
• Compound A or a pharmaceutically acceptable salt thereof, for use in the treatment of a PIK3C A-mutated solid tumor.
• Compound A or a pharmaceutically acceptable salt thereof, for use in the treatment of PIK3C A-mutated breast cancer.
• Compound A or a pharmaceutically acceptable salt thereof, for use in the treatment of PIK3C A-mutated, advanced or metastatic breast cancer.
• Compound A for use in the treatment of CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal. and spinal syndrome), or PIK3CA-related overgrowth syndrome (PROS).
• CLOVES syndrome congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal. and spinal syndrome
• PROS PIK3CA-related overgrowth syndrome
• Compound A or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease associated with mutant phosphoinositide 3-kinase (PI3K).
• PI3K mutant phosphoinositide 3-kinase
• Compound A or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of PIK3C A-mutated breast cancer.
• Compound A or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of PIK3C A-mutated, advanced or metastatic breast cancer.
• Compound A or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal, and spinal syndrome), or PIK3CA-related overgrowth syndrome (PROS).
• CLOVES syndrome congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal, and spinal syndrome
• PROS PIK3CA-related overgrowth syndrome
• the PIK3C A-mutated cancer is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, aids-related cancers, aids-related lymphoma, anal cancer, astrocytoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, osteosarcoma, malignant fibrous histiocytoma, brain tumors, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor, cancer of unknown primary, cardiac (heart) tumors, atypical teratoid/rhabdoid tumor, primary CNS lymphoma, cervical cancer, cholangiocarcinoma, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), colorectal cancer, craniopharyngioma, cutaneous t-cell lymphoma, mycosis fun
• ALL acute lympho
• the PIK3CA-mutated cancer is endometrial cancer, breast cancer, oesophageal squamous-cell cancer, cervical squamous-cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small-cell lung cancer, esophagogastric cancer, nerve-sheath tumor, head and neck squamous-cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft-tissue sarcoma, prostate cancer, fibrolamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, cholangiocarcinoma, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, renal non-clear-cell carcinoma, renal clear-cell carcinoma,
• the PIK3CA-mutated cancer is breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer.
• the PIK3CA-mutated cancer is breast cancer, prostate cancer, or brain cancer. In an embodiment, the PIK3CA-mutated cancer is breast cancer. In an embodiment, the PIK3CA-mutated cancer is prostate cancer. In an embodiment, the PIK3CA-mutated cancer is brain cancer.
• the PIK3CA-mutated cancer is a breast neoplasm, a thyroid neoplasm, an ovarian neoplasm, non-small-cell lung carcinoma, an endometrial neoplasm, or a pancreatic neoplasm.
• the PIK3CA-mutated cancer is a breast neoplasm.
• the PIK3CA-mutated cancer is a thyroid neoplasm.
• the PIK3CA-mutated cancer is an ovarian neoplasm.
• the PIK3CA-mutated cancer is non-small-cell lung carcinoma.
• the PIK3CA-mutated cancer is an endometrial neoplasm.
• the PIK3CA-mutated cancer is a pancreatic neoplasm.
• the PIK3CA-mutated. advanced or metastatic breast cancer is PIK3CA H1047R-mutant advanced or metastatic breast cancer.
• the PIK3CA-mutated, advanced or metastatic breast cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated, advanced or metastatic breast cancer.
• the PIK3CA-mutated, advanced or metastatic breast cancer is estrogen receptor-positive (ER+). human epidermal growth factor receptor 2- negative (HER2-), PIK3CA-mutated, advanced or metastatic breast cancer.
• the PIK3CA-mutated, advanced or metastatic breast cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R-mutant, advanced or metastatic breast cancer.
• the PIK3CA-mutated, advanced or metastatic breast cancer is estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R-mutant, advanced or metastatic breast cancer.
• the PIK3CA-mutated solid tumor is a PIK3CA-mutated advanced solid tumor.
• the PIK3CA-mutated advanced solid tumor is selected from gynecological cancer, head and neck cancer, and triple negative breast cancer.
• the PIK3CA-mutated advanced solid tumor is gynecological cancer.
• the PIK3CA-mutated advanced solid tumor is head and neck cancer.
• the PIK3CA-mutated advanced solid tumor is triple negative breast cancer.
• Compound A, or a pharmaceutically salt thereof can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions.
• Compound A, or a pharmaceutically salt thereof can also be formulated for intravenous (bolus or in-fusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.
• Compound A. or a pharmaceutically salt thereof, or a pharmaceutical composition thereof may be administered to a subject by any convenient route of administration, whether systemically/ peripherally or topically (i.e., at the site of desired action).
• Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary ); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular. subcapsular, intraorbital, intraperitoneal, intratracheal, subcut
• Compound A can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below. Compound A can be synthesized by following the steps outlined in General Schemes 1 and 2. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated below.
• Scheme 1 depicts an exemplary preparation of Compund A.
• Acylation of substituted phenol (1) can provide ester (2).
• Ester (2) can undergo rearrangement under Lewis acid (e.g., AICI 3 ) or Bronsted acid (e.g., triflic acid) conditions to the hydroxy aryl ketone (3).
• Lewis acid e.g., AICI 3
• Bronsted acid e.g., triflic acid
• alkylation of hydroxy aryl ketone (3) with an aryl halide in the presence of a base e.g., pyridine or lithium bis(trimethylsilyl)amide
• acidic conditions e.g., HC1
• Phenyl bromide (5) can be acylated via palladium catalysis to produce acyl chromen-4- one (6).
• Exemplary palladium catalysis conditions include phenyl bromide (5), about 5-10 mol% PdCl 2 (Ph 3 ) 2 and about 1.2 mol% tributyl(l -ethoxy vinyl)stannane in about 30-35 equivalents dioxane at 95°C for about 16 hours; or phenyl bromide (5), about 1 mol% Pd(OAc)2, about 2 mol% l,3-bis(diphenylphosphino)propane, about 5 equivalents butyl vinyl ether, about 3 equivalents tri ethylamine, and about 10 volumes of ethylene glycol at about 100°C for about 16 hours.
• ketimine (7) Condensation of ketone (6) with tert-butanesulfmamide using a Lewis acidic dehydrating agent such as a titanium(IV) alkoxide can afford ketimine (7).
• Asymmetric reduction of sulfinimine (7) can be affected with a borohydride reagent in the presence of a transition metal catalyst such as cerium (III) chloride to yield chirally enriched sulfmamide (8).
• a transition metal catalyst such as cerium (III) chloride
• Removal of the sulfinyl group under acidic conditions may be used to transform sulfmamide (8) to benzylamine (9) which can be alkylated with aryl halide (10) under Finkelstein or Ullmann-type conditions to give Compound A.
• Scheme 2 depicts another exemplary preparation of Compound A.
• Ketone (6) can be reduced to hydroxy compound (11) with a chiral catalyst such as the Noyori catalyst.
• the hydroxyl group can be converted into a leaving group with methanesulfonic anhydride or methanesulfonyl chloride to give mesylate (12).
• Mesylate (12) can be used to alkylate arylamine (13) to give Compound A.
• ketone (6) can be reduced to hydroxy compound (14) with a chiral catalyst such as the Noyori catalyst.
• the hydroxyl group can be converted to chloride (15) with a chlorinating agent such as 2,4,6-trichloro-l,3,5-triazine. Chloride (15) can then be used to alky late arylamine (13) to give Compound A.
• treating refers to restraining, slowing, stopping, reducing, shrinking, maintaining stable disease, or reversing the progression or severity of an existing symptom, disorder, condition, or disease.
• the term “patient” refers to a mammal, preferably, a human.
• cancer and “cancerous” refer to or describe the physiological condition in patients that is typically characterized by unregulated cell proliferation. Included in this definition are benign and malignant cancers.
• the term "advanced” or “metastatic” means cancers that have spread to one or more parts of the body that were not the site of the original cancerous tissue.
• the term ‘’effective amount’ refers to the amount or dose of a therapeutic agent, or a pharmaceutically acceptable salt thereof, for example Compound A or a pharmaceutically acceptable salt thereof, optionally in combination with one or more additional agents, or a pharmaceutically acceptable salt thereof, which provides an effective response in the patient under diagnosis or treatment.
• the term ‘’effective response” of a patient or a patient’s ‘’responsiveness” to treatment with a therapeutic agent, or a pharmaceutically acceptable salt thereof refers to the clinical or therapeutic benefit imparted to a patient upon administration of the therapeutic agent, or pharmaceutically acceptable salt thereof optionally in combination with one or more additional agents, or a pharmaceutically acceptable salt thereof.
• the term “in combination with” refers to the administration of a therapeutic agent, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, or a pharmaceutically acceptable salt thereof, either separately, simultaneously or sequentially in any order, such as for example, at repeated intervals as during a standard course of treatment for a single cycle or more than one cycle, such that one agent can be administered prior to, at the same time, or subsequent to the administration of the other agent, or any combination thereof.
• tromethamine may otherwise be referred to as tris(hydroxymethyl)aminomethane or tris.
• erbumine may otherwise be referred to as tert-butylamine.
• Clause 4 The compound of any one of clauses 1-3, characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having at least one peak at diffraction angle 2-theta selected from 7.8° ⁇ 0.2°, 12.1° ⁇ 0.2°, 13.7° ⁇ 0.2°, 14.1° ⁇ 0.2°, 16.8° ⁇ 0.2°. 17.5° ⁇ 0.2°. 18.2° ⁇ 0.2°, 18.9° ⁇ 0.2°, 19.5° ⁇ 0.2°, 20.7° ⁇ 0.2°, 21.2° ⁇ 0.2°, and 24.1° ⁇ 0.2°.
• Clause 5 The compound of any one of clauses 1-3, characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 12. 1° ⁇ 0.2° in combination with at least one peak selected from 14.1° ⁇ 0.2°, 16.8° ⁇ 0.2°. 18.9° ⁇ 0.2°, and 20.7° ⁇ 0.2°.
• Clause 6 The compound of any one of clauses 1-3, characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 12. 1° ⁇ 0.2° in combination with at least two peaks selected from 14. 1° ⁇ 0.2°, 16.8° ⁇ 0.2°, 18.9° ⁇ 0.2°, and 20.7° ⁇ 0.2°.
• Clause 7 The compound of any one of clauses 1-3, characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 12. 1° ⁇ 0.2° in combination with at least three peaks selected from 14.1° ⁇ 0.2°, 16.8° ⁇ 0.2°, 18.9° ⁇ 0.2°, and 20.7° ⁇ 0.2°.
• Clause 8 The compound of any one of clauses 1-3, characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 12. 1° ⁇ 0.2° in combination with the peaks 14. l° ⁇ 0.2°, 16.8° ⁇ 0.2°, 18.9° ⁇ 0.2°, and 20.7° ⁇ 0.2°.
• Clause 9 The compound of any one of clauses 1-3, characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having peaks at diffraction angle 2-theta of 7.8° ⁇ 0.2°, 12.1° ⁇ 0.2°, 13.7° ⁇ 0.2°, 14.1° ⁇ 0.2°, 16.8° ⁇ 0.2°, 17.5° ⁇ 0.2°, 18.2° ⁇ 0.2°, 18.9° ⁇ 0.2°, 19.5° ⁇ 0.2°, 20.7° ⁇ 0.2°, 21.2° ⁇ 0.2°, and 24.1° ⁇ 0.2°.
• Clause 10 The compound of any one of clauses 1-3, having an X-ray powder diffraction pattern substantially as shown in FIG. 1.
• Clause 11 The compound of any one of clauses 1-3, characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having at least one peak at diffraction angle 2-theta selected from 7.0° ⁇ 0.2°, 9.7° ⁇ 0.2°, 11.9° ⁇ 0.2°, 14.9° ⁇ 0.2°, and 17.4° ⁇ 0.2°.
• Clause 12 The compound of any one of clauses 1-3, characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 9.7° ⁇ 0.2° in combination with at least one peak selected from 14.9° ⁇ 0.2°, 11.9° ⁇ 0.2°, 17.4° ⁇ 0.2°, and 7.0° ⁇ 0.2°.
• Clause 13 The compound of any one of clauses 1-3, characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 9.7° ⁇ 0.2° in combination with at least two peaks selected from 14.9° ⁇ 0.2°, 11.9° ⁇ 0.2°, 17.4° ⁇ 0.2°, and 7.0° ⁇ 0.2°.
• Clause 14 The compound of any one of clauses 1-3, characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 9.7° ⁇ 0.2° in combination with at least three peaks selected from 14.9° ⁇ 0.2°, 11.9° ⁇ 0.2°, 17.4° ⁇ 0.2°, and 7.0° ⁇ 0.2°.
• Clause 15 The compound of any one of clauses 1-3, characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having peaks at diffraction angle 2-theta of 7.0° ⁇ 0.2°, 9.7° ⁇ 0.2°, 11.9° ⁇ 0.2°, 14.9° ⁇ 0.2°, and 17.4° ⁇ 0.2°.
• Clause 16 The compound of any one of clauses 1-3. having an X-ray powder diffraction pattern substantially as shown in FIG. 2.
• Clause 17 The compound of any one of clauses 1-3, characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having at least one peak at diffraction angle 2-theta selected from 7.4° ⁇ 0.2°, 8.5° ⁇ 0.2°, 10.6° ⁇ 0.2°, 13.4° ⁇ 0.2°, and 15.7° ⁇ 0.2°.
• Clause 18 The compound of any one of clauses 1-3, characterized by an X-ray pow der diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 13.4° ⁇ 0.2° in combination with at least one peak selected from 8.5° ⁇ 0.2°, 15.7° ⁇ 0.2°, 10.6° ⁇ 0.2°, and 7.4° ⁇ 0.2°.
• Clause 19 The compound of any one of clauses 1-3, characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 13.4° ⁇ 0.2° in combination with at least two peaks selected from 8.5° ⁇ 0.2°, 15.7° ⁇ 0.2°, 10.6° ⁇ 0.2°, and 7.4° ⁇ 0.2°.
• Clause 20 The compound of any one of clauses 1-3. characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 13.4° ⁇ 0.2° in combination with at least three peaks selected from 8.5° ⁇ 0.2°, 15.7° ⁇ 0.2°, 10.6° ⁇ 0.2°, and 7.4° ⁇ 0.2°.
• Clause 21 The compound of any one of clauses 1-3, characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having peaks at diffraction angle 2-theta of 7.4° ⁇ 0.2°, 8.5° ⁇ 0.2°, 10.6° ⁇ 0.2°, 13.4° ⁇ 0.2°, and 15.7° ⁇ 0.2°.
• Clause 22 The compound of any one of clauses 1-3, having an X-ray powder diffraction pattern substantially as shown in FIG. 3.
• Clause 25 The tromethamine salt of clause 23 or clause 24, characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having at least one peak at diffraction angle 2-theta selected from 6.4° ⁇ 0.2°, 8.4° ⁇ 0.2°, 10.9° ⁇ 0.2°, 11.8° ⁇ 0.2°, 13.0° ⁇ 0.2°, 16.5° ⁇ 0.2°, 16.9° ⁇ 0.2°, 22.1° ⁇ 0.2°, 23.0° ⁇ 0.2°, and 24.9° ⁇ 0.2°.
• Clause 26 The tromethamine salt of clause 23 or clause 24, characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 6.4° ⁇ 0.2° in combination with at least one peak selected from 8.4° ⁇ 0.2°, 10.9° ⁇ 0.2°, 16.9° ⁇ 0.2°, and 22.1° ⁇ 0.2°.
• Clause 27 The tromethamine salt of clause 23 or clause 24, characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 6.4° ⁇ 0.2° in combination with at least two peaks selected from 8.4° ⁇ 0.2°, 10.9° ⁇ 0.2°, 16.9° ⁇ 0.2°, and 22.1° ⁇ 0.2°.
• Clause 28 The tromethamine salt of clause 23 or clause 24, characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 6.4° ⁇ 0.2° in combination with at least three peaks selected from 8.4° ⁇ 0.2°, 10.9° ⁇ 0.2°, 16.9° ⁇ 0.2°, and 22.1° ⁇ 0.2°.
• Clause 29 The tromethamine salt of clause 23 or clause 24, characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 6.4° ⁇ 0.2° in combination with the peaks 8.4° ⁇ 0.2°, 10.9° ⁇ 0.2°, 16.9° ⁇ 0.2°, and 22.1° ⁇ 0.2°.
• Clause 30 The tromethamine salt of clause 23 or clause 24, characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having peaks at diffraction angle 2-theta of 6.4° ⁇ 0.2°, 8.4° ⁇ 0.2°, 10.9° ⁇ 0.2°, 11.8° ⁇ 0.2°, 13.0° ⁇ 0.2°, 16.5° ⁇ 0.2°, 16.9° ⁇ 0.2°, 22.1° ⁇ 0.2°, 23.0° ⁇ 0.2°, and 24.9° ⁇ 0.2°.
• Clause 32 The tromethamine salt of any one of clauses 23-31, characterized by a 13 C solid state NMR (100.6 MHz) spectrum which comprises at least one peak referenced to glycine (external reference at 176.5 ppm) selected from: 179.0, 158.7, 151.7, 149.7, 136.3, 134.7, 132.9. 129.3, 127.4. 125.2, 121.7, 117.0, 115.5, 115.2. 110.4, 64.1, 63.2, 45.3. 22.6. 20.3, and 11.6 ppm ( ⁇ 0.2 ppm, respectively).
• Clause 33 The tromethamine salt of any one of clauses 23-31, characterized by a 13 C solid state NMR (100.6 MHz) spectrum which comprises at least one peak referenced to glycine (external reference at 176.5 ppm) selected from: 179.0, 129.3, 63.2, 20.3, and 11.6 ppm ( ⁇ 0.2 ppm, respectively).
• Clause 34 The tromethamine salt of any one of clauses 23-31, characterized by a 13 C solid state NMR (100.6 MHz) spectrum which comprises peaks referenced to glycine (external reference at 176.5 ppm) at: 179.0, 129.3, 63.2, 20.3, and 11.6 ppm ( ⁇ 0.2 ppm, respectively).
• Clause 36 The tromethamine salt of clause 23 or clause 24, characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having at least one peak at diffraction angle 2-theta selected from 10.6° ⁇ 0.2°, 13.2° ⁇ 0.2°, 14.5° ⁇ 0.2°, 15.9° ⁇ 0.2°, and 17.4° ⁇ 0.2°.
• Clause 37 The tromethamine salt of clause 23 or clause 24, characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 15.9° ⁇ 0.2° in combination with at least one peak selected from 10.6° ⁇ 0.2°, 17.4° ⁇ 0.2°, 13.2° ⁇ 0.2°, and 14.5° ⁇ 0.2°.
• Clause 50 The erbumine salt of clause 48 or clause 49, characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having at least one peak at diffraction angle 2-theta selected from 6.5° ⁇ 0.2°, 10.5° ⁇ 0.2°, 11.1° ⁇ 0.2°, 15.2° ⁇ 0.2°, 15.9° ⁇ 0.2°, 17.6° ⁇ 0.2°, 18.0° ⁇ 0.2°, 19.3° ⁇ 0.2°, 21.5° ⁇ 0.2°, 22.2° ⁇ 0.2°, 22.7° ⁇ 0.2°, and 26.3° ⁇ 0.2°.
• Clause 51 The erbumine salt of clause 48 or clause 49, characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of 11.1 ° ⁇ 0.2° in combination with at least one peak selected from 10.5° ⁇ 0.2°, 15.2° ⁇ 0.2°, 18.0° ⁇ 0.2°, and 19.3° ⁇ 0.2°.
• Clause 52 The erbumine salt of clause 48 or clause 49, characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of
• Clause 54 The erbumine salt of clause 48 or clause 49, characterized by an X-ray powder diffraction pattern using CuK ⁇ radiation having a peak at diffraction angle 2-theta of
• Clause 58 The erbumine salt of any one of clauses 48-56, characterized by a 13 C solid state NMR (100.6 MHz) spectrum which comprises at least one peak referenced to glycine (external reference at 176.5 ppm) selected from: 177.4, 132.6, 27.4, 21.3, and 11.3 ppm ( ⁇ 0.2 ppm, respectively).
• Clause 61 A pharmaceutical composition comprising a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, or an erbumine salt of any one of clauses 48-60, and a pharmaceutically acceptable carrier.
• Clause 62 A method of inhibiting phosphoinositide 3-kinase (PI3K). comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumine salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61.
• PI3K phosphoinositide 3-kinase
• Clause 63 A method of treating a patient with a disease associated with mutant phosphoinositide 3-kinase (PI3K), comprising administering to the patient a therapeutically effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumine salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61.
• PI3K mutant phosphoinositide 3-kinase
• Clause 64 The method of clause 62 or clause 63, wherein the P13K is P13Ka.
• Clause 66 The method of any one of clauses 63-65, wherein the disease is a cancer.
• Clause 70 The method of any one of clauses 63-65, wherein the disease is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal, and spinal syndrome), or PIK3CA-related overgrowth syndrome (PROS).
• CLOVES syndrome congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal, and spinal syndrome
• PROS PIK3CA-related overgrowth syndrome
• Clause 71 A method of treating a patient with PIK3CA-mutated cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumine salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61.
• Clause 72 A method of treating a patient with a PIK3CA-mutated solid tumor, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumine salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61.
• Clause 73 A method of treating a patient with PIK3CA-mutated breast cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumine salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61.
• Clause 74 A method of treating a patient with PIK3CA-mutated. advanced or metastatic breast cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumine salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61.
• Clause 80 The method of clause 77, wherein the PIK3CA-mutated solid tumor is triple negative breast cancer.
• Clause 85 A compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumine salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for use in therapy.
• Clause 86 A compound of any one of clauses 1-22. a tromethamine salt of any one of clauses 23-47, an erbumine salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for use in treating a disease associated with mutant phosphoinositide 3-kinase (PI3K).
• PI3K mutant phosphoinositide 3-kinase
• Clause 88 The compound, tromethamine salt, erbumine salt, or pharmaceutical composition, for use according to clause 86 or 87, wherein the PI3K has a H1047R mutation.
• Clause 90 The compound, tromethamine salt, erbumine salt, or pharmaceutical composition, for use according to clause 89, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.
• Clause 93 The compound, tromethamine salt, erbumine salt, or pharmaceutical composition, for use according to any one of clauses 86-88, wherein the disease is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal, and spinal syndrome), or PIK3CA-related overgrowth syndrome (PROS).
• CLOVES syndrome congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal, and spinal syndrome
• PROS PIK3CA-related overgrowth syndrome
• Clause 94 A compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumine salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for use in the treatment of PIK3CA-mutated cancer.
• Clause 95 A compound of any one of clauses 1-22. a tromethamine salt of any one of clauses 23-47, an erbumine salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for use in the treatment of a PIK3CA-mutated solid tumor.
• Clause 96 A compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumine salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for use in the treatment of PIK3CA-mutated breast cancer.
• Clause 97 A compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumine salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for use in the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.
• Clause 101 The compound, tromethamine salt, erbumine salt, or pharmaceutical composition for use according to clause 100, wherein the PIK3CA-mutated solid tumor is gynecological cancer.
• Clause 108 The use of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumine salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in the manufacture of a medicament for the treatment of PIK3CA- mutated cancer.
• Clause 110 The use of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumine salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, in the manufacture of a medicament for the treatment of PIK3CA- mutated breast cancer.
• Clause 111 The use of a compound of any one of clauses 1-22, a tromethamine salt of any one of clauses 23-47, an erbumine salt of any one of clauses 48-60. or a pharmaceutical composition of clause 61, in the manufacture of a medicament for the treatment of PIK3CA- mutated, advanced or metastatic breast cancer.
• Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz or 300 MHz as stated and at 300.3 K unless otherwise stated; the chemical shifts (3) are reported in parts per million (ppm). Spectra were recorded using a Bruker or Varian instrument with 8, 16 or 32 scans.
• LC-MS chromatograms and spectra were recorded using an Agilent 1200 or Shimadzu LC-20 AD&MS 2020 instrument using a C-18 column such as a Luna-C18 2.0x30 mm or Xbridge Shield RPC 18 2.1x50 mm. Injection volumes were 0.7 - 8.0 pl and the flow rates were typically 0.8 or 1.2 ml/min. Detection methods were diode array (DAD) or evaporative light scattering (ELSD) as well as positive ion electrospray ionization. MS range was 100 - 1000 Da. Solvents were gradients of water and acetonitrile both containing a modifier (typically 0.01 - 0.04 %) such as trifluoroacetic acid or ammonium carbonate.
• DAD diode array
• ELSD evaporative light scattering
• MS range was 100 - 1000 Da.
• Solvents were gradients of water and acetonitrile both containing a modifier (typically 0.01
• the XRPD patterns of cry stalline solids were obtained on a Bruker D8 Endeavor X-ray powder diffractometer, equipped with a CuK ⁇ (1.5418 ) source and a Linxeye detector, operating at 40 kV and 40 mA.
• the samples were scanned between 4 and 42 20°, with a step size of 0.009 20° and a scan rate of 0.5 seconds/step, and using 0.3° primary slit opening, and 3.9° PSD opening; or were scanned between 4 and 30 20°, with a step size of 0.009 20° and a scan rate of 0.25 seconds/step, and using 0.3° primary slit opening, and 3.9° PSD opening.
• the dry’ powder was packed on a quartz sample holder and a smooth surface was obtained using a glass slide.
• the crystal form diffraction patterns were collected at ambient temperature and relative humidity. Crystal peak positions were determined in MDI-Jade after whole pattern shifting based on an internal NIST 675 standard with peaks at 8.853 and 26.774 20°. It is well known in the crystallographic art that, for any given crystal form, the relative intensities of the diffraction peaks may vary due to preferred orientation resulting from factors such as crystal morphology and habit. Where the effects of preferred orientation are present, peak intensities are altered, but the characteristic peak positions of the polymorph are unchanged. See, e.g. The United States Pharmacopeia #23, National Formulary #18, pages 1843-1844, 1995.
• the angular peak positions may vary slightly.
• peak positions can shift due to a variation in the temperature at which a sample is analyzed, sample displacement, or the presence or absence of an internal standard.
• a peak position variability of ⁇ 0.2 20° is presumed to take into account these potential variations without hindering the unequivocal identification of the indicated crystal form. Confirmation of a crystal form may be made based on any unique combination of distinguishing peaks.
• DSC Differential scanning calorimetry
• Thermogravimetric analysis was collected using a TA Instruments Q5000 TGA (run by TA Thermal Advantage Software v5.2.6 and data analyzed by Universal Analysis 2000 v4.5a. Samples (3-10 mg) were heated from ambient temperature (approximately 25 °C) to 200 °C at a rate of 10 °C/min. N2 was the earner (10 mL/min) and purge (50 mL/min) gas. Temperature was calibrated by Curie temperature determination with nickel and alumel standards. The weight calibration was performed with manufacturer-supplied standards.
• the reaction was removed from the cooling bath and treated with RuCl(p- cymene)[(S,S)-Ts-DPEN] (CAS 192139-90-5, 0.66 g. 1.12 mmol). The reaction was stirred at 45 °C for 16 h. The reaction was transferred to a separatory funnel and washed with 2M aqueous HC1 (2 x 50 mL). The organic layer was concentrated under vacuum at 45 - 50 °C to 50 to 100 mL. Diluted with ACN (150 mL) and concentrated under vacuum at 45 - 50 °C to 50 mL. The solvent swap was done again until the amount of solvent was 50 mL.
• the material was cooled to rt over 1-2 h and the slurry aged for 4 h.
• the product (10. 10 g, 92%) was collected by filtration, washed with ACN (25 mL), washed with heptane (50 mL), and dried under vacuum at 45 °C.
• the slurry was then warmed to 45 °C and stirred at that temperature for 2 h and allowed to cool to rt.
• the material was treated with 80 mL of water via syringe pump over 4 h and the reaction aged overnight.
• the product (18.4 g, 87%) was collected by filtration, washed with 40 mL of 1 : 1 IPA/water and dried at 45 °C.
• Aqueous 3M NaOH (5 L/kg, 480 L) was slowly added, the mixture warmed to 25 °C, and the mixture stirred for 45 min. After standing for 30 min, the aqueous layer was removed. Charged the reactor with water (5 L/kg, 480 L) and stirred for 15 min. After standing for 30 min, the aqueous layer was removed and the resulting organic layer filtered. The filtrate was allowed to stand for 30 min and the aqueous layer removed again. The resulting organic solution was solvent exchanged into isopropanol (5 L/kg, 480 L) and used in the next step without further purification.
• Route 4 Charged a solution of 8-[(lS)-l-chloroethyl]-3,6-dimethyl-2-phenyl-chromen- 4-one in isopropanol prepared according to the Alternate Synthesis of Intermediate 12 to a reactor and added anthranilic acid (1 11.9 kg, 816.3 mol, 2.5 eq) and sodium bicarbonate (41.1 kg, 489.4 mol, 1.5 eq). Isopropanol (2 L/kg, 192 L) w as added and the reaction stirred at 65 °C for 24 h. Upon completion, the reaction was solvent exchanged into 2-MeTHF (15 L/kg, 1400 L).
• the slurry was stirred at 65 °C for 2 h before being cooled to 20 °C over 12 h. After stirring at 20 °C for 4 h, the slurry was filtered and the wet cake washed with 1 : 1 2- MeTHF/n-heptane (3 L/kg, 288 L) and n-heptane (3 L/kg, 288 L) and then dried under vacuum at 45 °C for 16 h to afford the title compound in 77% yield over 3 steps.
• Example 2 2-[[(1R)-1 -(3,6-DimethyI-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid Form A (“Compound A Form A”)
• a prepared sample of Form A was characterized by an XRD pattern using CuK ⁇ radiation as having diffraction peaks (2-theta values) as described in Table 1 below, and in particular having a peak at 12. 1° in combination with one or more of the peaks selected from the group consisting of 14.1°, 16.8°, 18.9°, and 20.7°; with a tolerance for the diffraction angles of 0.2 degrees. Table 1. XRPD peaks
• Form A was confirmed to be anhydrous based on the lack of mass loss detected on heating from 25 °C to 200 °C.
• the sharp endothermic peak at 185 °C was attributed to Form A melting.
• An exothermic transition was observ ed at 192 °C followed by an endothermic event at 211 °C, consistent with Form C crystallization and melting, respectively.
• a THF solvate was produced by slow evaporation of a saturated solution of 2-[[(1R)-1 - (3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid in THF at ambient temperature.
• the XRPD pattern of the THF solvate filtrate shown in FIG. 2 was successfully indexed confirming that the material is a single crystalline phase, designated as Form B.
• the unit cell volume is consistent with a mono-THF solvate.
• a prepared sample of Form B was characterized by an XRD pattern using CuK ⁇ radiation as having diffraction peaks (2 -theta values) as described in Table 2 below, and in particular having a peak at 9.7° in combination with one or more of the peaks selected from the group consisting of 14.9°, 11.9°, 17.4°, and 7.0°; with a tolerance for the diffraction angles of 0.2 degrees. Table 2. XRPD peaks
• Form C was produced by annealing Compound A Form A at 194 °C for 30 min. From XRPD indexing (FIG. 3), the phase purity of Form C was confirmed, and the unit cell volume is consistent with an anhydrous material.
• a prepared sample of Form C was characterized by an XRD pattern using CuK ⁇ radiation as having diffraction peaks (2 -theta values) as described in Table 3 below, and in particular having a peak at 13.4° in combination with one or more of the peaks selected from the group consisting of 8.5°, 15.7°, 10.6°, and 7.4°; with a tolerance for the diffraction angles of 0.2 degrees.
• a prepared sample of the crystalline tromethamine salt was characterized by an XRD pattern (FIG. 4) using CuK ⁇ radiation as having diffraction peaks (2-theta values) as described in Table 4 below, and in particular having a peak at 6.4° in combination with one or more of the peaks selected from the group consisting of 8.4°, 10.9°, 16.9°, and 22. 1°; with a tolerance for the diffraction angles of 0.2 degrees.
• a suitable single crystal was selected and analyzed by single-crystal X-ray diffractometry.
• the single crystal structure of Compound A Tromethamine Salt Form A was determined to confirm the molecular structure and absolute configuration.
• the structure was determined to be an anhydrous cry stal form, composed of one Compound A anion and one tromethamine cation in the asymmetric unit.
• the absolute structure was determined from the crystal structure and the molecule was found to bond in the R configuration.
• a prepared sample of Compound A Tromethamine Salt Form A was characterized by solid state NMR. 13 C Solid state NMR (100.6 MHz) ⁇ 179.0, 158.7, 151.7, 149.7, 136.3, 134.7, 132.9, 129.3, 127.4, 125.2, 121.7, 117.0, 115.5, 115.2, 110.4, 64.1, 63.2, 45.3, 22.6, 20.3, 11.6 ppm.
• the resulting slurry was cooled to 10 °C over 5 h and stirred at 10 °C for 4 h.
• the slurry was filtered and the wet cake washed with 1 :2 (1 : 1 THF/MeOH):n-heptane (3.8 L/kg) and then n- heptane (3.8 L/kg).
• the wet cake was dried under vacuum at 50 °C to afford the title compound in 87% yield.
• the solid was pin milled in a Hosokawa Alpine 160 UPZ pin mill to obtain material with a particle size below 20 micrometers.
• Preparation of seed material was performed by dissolving tris(hydroxymethyl)aminomethane (>1 eq) in either water (0.5 - 1.7 mL) and acetone (0.1 - 0.2 mL) or ⁇ 3: 1 water: acetone (0.6 mL), followed by addition of Compound A Form A (30 - 100 mg). Additional acetone was added if the resulting slurry was difficult to stir. Samples were stirred at rt for a couple hours or overnight. Suspensions were centrifuged at rt for 5 min and dried overnight at rt to give solids consistent with Compound A Tromethamine Salt Form C as a monohydrate.
• a prepared sample of Compound A Tromethamine Salt Form C was characterized by an XRD pattern (FIG. 5) using CuK ⁇ radiation as having diffraction peaks (2-theta values) as described in Table 5 below, and in particular having a peak at 15.9° in combination with one or more of the peaks selected from the group consisting of 10.6°, 17.4°, 13.2°, and 14.5°; with a tolerance for the diffraction angles of 0.2 degrees.
• Form D has only been observed in situ (VT-XRPD). Atempts to produce Form D via high temperature annealing have resulted in Form A via XRPD, suggesting conversion to Form A occurs within minutes at RT.
• Peak Angle °2-Theta +/- 0.2° Relative Intensity (% of most intense peak)
• the MDA-MB-453 (ATCC-HTB-131) cell line was obtained from the American Type Culture Collection (Manassas. VA). Cells were maintained in Dulbecco’s Modified Eagle Media (DMEM, Gibco 1 1965-092) supplemented with 10% Fetal Bovine Serum, heat inactivated (FBS HI, Gibco 10082-147), IX non-essential amino acids (NEAA, Gibco 11140- 050). and 1 mM sodium pyruvate (Gibco 11360-070). Cultures were maintained in a humidified incubator at 37°C under 5% CO2/95% air.
• DMEM Modified Eagle Media
• FBS HI Fetal Bovine Serum
• FBS HI heat inactivated
• NEAA IX non-essential amino acids
• NEAA Gibco 11140- 050
• 1 mM sodium pyruvate Gibco 11360-070
• MDA-MB-453 cells were seeded at a density of 1.5x 10 4 cells per well in white 384-well plates in 20 pl of Minimum Essential Media (MEM) assay media with IX NEAA, 1 mM sodium pyruvate, and 1 pg/mL human insulin (Sigma 19278).
• MEM Minimum Essential Media
• Compounds dissolved in 10 mM stock solutions in DMSO were serially diluted 1 :3 in DMSO to generate a 10-point dilution series and plated using an acoustic liquid handler system (Echo 550 Series Liquid Handler, Labcyte).
• a 5X intermediate compound dilution plate in MEM with IX NEAA and 1 mM sodium pyruvate (150 pM starting compound concentration in 1.5% DMSO) was then prepared.
• Five pl of the intermediate serially diluted compounds were added to the cell plate to final concentrations ranging from 30 mM to 0.0015 mM in 0.3% DMSO.
• 0.3% DMSO alone was used to establish the maximum (MAX) signal and GDC-0032 at a final concentration of 1 pM was used as a reference compound for the minimum (MIN) signal.
• MAX maximum
• GDC-0032 a final concentration of 1 pM was used as a reference compound for the minimum (MIN) signal.
• the medium was removed, and the cells lysed in 10 pL of IX SureFire Lysis buffer with shaking for 10 minutes at room temperature.
• the Acceptor Mix (Reaction Buffer 1 + Reaction Buffer 2 + Activation Buffer + SureFire Ultra Acceptor Beads) was prepared by diluting Activation buffer 25-fold in combined Reaction Buffer 1 and Reaction Buffer 2. The Acceptor beads were diluted 50-fold in the combined Reaction Buffers. Five pL of Acceptor Mix was added to each well, the plate was sealed and covered with foil and incubated for 1 hour at room temperature. The Donor Mix (dilution buffer + SureFire Ultra Donor Beads) was prepared by diluting Donor Beads 50- fold in dilution buffer. Five pL of the Donor Mix was added to each well and the plate sealed and covered with foil and incubated for 1 hour at room temperature in the dark. The plates were read on aNeo2 plate reader instrument from Biotek using standard AlphaLisa settings.
• %Inhibition [(signal at X - median Min)/ (median Max - median Min)] x 100
• IC 50 concentration of compound that reduces a given response (ligand binding, enzyme response) by 50%.
• Relative IC 50 concentration giving half the compound's maximum response.
• Compound A was determined to have an IC 50 value of 6.83 nanomolar.

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