Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • 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
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • 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
  • 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

• ErbB inhibitors are a known treatment for a number of cancers. However, not every' patient is responsive satisfactorily to this treatment. Thus, there is a long-felt need in the art for new therapies that are able to address the variable responsiveness of cancer patients to known therapies.
• the present disclosure provides compositions and methods for preventing or treating cancer in patients with these oncogenic mutations.
• the present disclosure provides a morphic form of Compound No. 1 : a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof
• the present disclosure provides a pharmaceutical composition
• a pharmaceutical composition comprising a therapeutically effective amount of a morphic form of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
• the present disclosure provides a method of inhibiting an oncogenic variant of an ErbB receptor, comprising administering to the subject in need thereof a therapeutically effective amount of a morphic form of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
• the present disclosure provides a method of preventing or treating cancer, comprising administering to the subject in need thereof a therapeutically effective amount of a morphic form of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof
• the present disclosure provides a morphic form of Compound No. 1 , a solvate thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof, for use in the inhibition of an oncogenic variant of an ErbB receptor.
• the present disclosure provides a morphic form of Compound No. 1, a solvate thereof a hydrate thereof, or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of cancer.
• the present disclosure provides use of a morphic form of Compound No.
• the present disclosure provides use of a morphic form of Compound No.
• FIG. 1 is a graph depicting the XRPD spectrum for Form A of Compound No. 1.
• FIG. 2 is a graph depicting the XRPD spectrum for Form B of Compound No. 1.
• FIG. 3 is a graph depicting the XRPD spectrum for Form C of Compound No. 1.
• FIG. 4 is a graph depicting the XRPD spectrum for Form D of Compound No. 1.
• FIG. 5 is a graph depicting the XRPD spectrum for Form E of Compound No. 1,
• FIG 6 is a graph depicting the XRPD spectrum for Form F of Compound No, 1.
• FIG. 7 is a graph depicting the XRPD spectrum for Form G of Compound No. 1.
• FIG 8 is a graph depicting the XRPD spectrum for Form H of Compound No. 1.
• FIG. 9 is a graph depicting the XRPD spectrum for Form I of Compound No. 1.
• FIG 10 is a graph depicting the XRPD spectrum for Form J of Compound No. 1.
• FIG. 1 1 is a graph depicting the XRPD spectrum for Form K of Compound No. 1
• FIG 12 is a graph depicting the XRPD spectrum for Form L. of Compound No. 1
• Compound No, 1 may be identified by the TUPAC name of (E)-N-(4-((3-chloro ⁇ 2- fluorophenyl)amino)-7-(((lR,5S)-3-methyl-3-azabicyclo[3.1,0]hexan-l-yl)ethynyl)quinazolin-6- yl)-4-morpholmobut-2-enamide.
• the present disclosure provides a morphic form of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
• the morphic form is a crystalline form.
• the morphic form is a morphic form (e.g., crystalline form) of Compound No. 1, the solvate thereof, or the hydrate thereof. [030] In some embodiments, the morphic form is a morphic form (e.g., crystalline form) of Compound No. 1.
• the morphic form is a morphic form (e.g., crystalline form) of a solvate (e.g., heterosolvate) of Compound No. 1.
• the morphic form is a morphic form (e.g., crystalline form) of a hydrate of Compound No. 1 ,
• the morphic form is Form A of Compound No. 1, the solvate thereof) the hydrate thereof, or the pharmaceutically acceptable salt thereof,
• the morphic form is Form B of Compound No, 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof.
• the morphic form is Form C of Compound No, 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof.
• the morphic form is Form D of Compound No. 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof.
• the morphic form is Form E of Compound No. 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof.
• the morphic form is Form F of Compound No. 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof.
• the morphic form is Form G of Compound No. 1 , the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof.
• the morphic form is Form H of Compound No. 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof.
• the morphic form is Form I of Compound No. 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof.
• the morphic form is Form J of Compound No. 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof.
• the morphic form is Form K of Compound No. 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof.
• the morphic form is Form L of Compound No. 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof.
• the present disclosure provides a method of preparing a morphic form of Compound No. 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof.
• the morphic form is Form A of Compound No. 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof.
• the morphic form is Form A of Compound No. 1.
• Form A is characterized by an X-ray diffraction (“XRPD”) pattern comprising peaks at 4.8 ⁇ 0.2, 5.6 ⁇ 0.2, and 17.6 ⁇ 0.2 °20 (e.g., 4.8 ⁇ 0. 1, 5.6 ⁇ 0. 1, and 17.6 ⁇ 0.1 °20 (e.g., 4.8, 5.6, and 17.6 °20)) using Cu Ka radiation.
• XRPD X-ray diffraction
• the XRPD pattern of Form A further comprises at least one peak selected from 9.6 ⁇ 0.2, 20.0 ⁇ 0.2, and 24.6 ⁇ 0.2 °20 (e.g., 9.6 ⁇ 0.1, 20.0 ⁇ 0.1, and 24.6 ⁇ 0.1 °20 (e.g.,
• the XRPD pattern of Form A further comprises at least two peaks selected from 9.6 ⁇ 0.2, 20.0 ⁇ 0.2, and 24.6 ⁇ 0.2 °20 (e.g., 9.6 ⁇ 0.1 , 20.0 ⁇ 0. 1 , and 24.6 ⁇ 0.1 °20 (e.g.,
• the XRPD pattern of Form A further comprises peaks at 9.6 ⁇ 0.2, 20.0.0.2. and 24.6 : 0.2 °20 (e.g., 9.6 ⁇ 0.1, 20.0 ⁇ 0.1, and 24.6. 0.1 °20 (e.g., 9.6, 20.0, and 24.6 : '20 ) ) using Cu Ka radiation.
• Form A is characterized by an X-ray diffraction (“XRPD”) pattern comprising at least three peaks selected from 4.8 ⁇ 0.2, 5.6 ⁇ 0.2, 9.6 ⁇ 0.2, 17.6 ⁇ 0.2, 20.0 ⁇ 0.2, and 24.6. 0.2 °26 (e.g., 4.8 : 0.1. 5.6 : 0. 1. 9.6.0.1, 17.6 : 0.1. 20.0 : 04. and 24.6. 04 ⁇ 20 (e.g., 4.8, 5.6,
• the XRPD pattern of Form A comprises at least four peaks selected from 4.8+0.2, 5.6+0.2, 9.6 ⁇ 0.2, 17.6 : 0.2. 20.0 ⁇ 0.2, and 2.4.6 ⁇ 0.2 °20 (e.g., 4.8+0.1, 5.6+0.1, 9.6+0.1, 17.6+0.1, 20.0+0.1, and 24.6 : 04 °29 (e.g., 4.8, 5.6, 9.6, 17.6, 20.0, and 24.6 °20)) using Cu Ka radiation.
• the XRPD pattern of Form A comprises at least five peaks selected from 4.8+0.2, 5.6+0.2, 9.6+0.2, 17.6 : 0.2. 20.0+0.2, and 2.4.6 ⁇ 0.2 °20 (e.g., 4.8+0.1, 5.6+0.1, 9.6 ⁇ 0.1, 17.6 ⁇ 0.1, 20.0X0.1, and 24.6 ⁇ 0.1 c 20 (e.g., 4.8, 5.6, 9.6, 17.6, 20.0, and 24.6 : .20)) using
• the XRPD pattern of Form A comprises peaks at 4.8 ⁇ 0.2, 5.6 ⁇ 0.2,
• Form A is characterized by an XRPD patern substantially similar to that shown in FIG. 1.
• Form A is characterized by an XRPD patern comprising peaks at approximately the positions shown in the table below. It is understood that the values in the table are approximate and subject to instrumental and experimental variations.
• Form A is characterized by a DSC curve having at least one endothermic peak selected from 76 ⁇ 20, 141 ⁇ 20, 156 ⁇ 20, and 170 ⁇ 20 °C (e.g., 76 ⁇ 10, 141 ⁇ 10, 156 ⁇ 10, and 170 ⁇ 10 °C (e.g., 76 ⁇ 5, 141 ⁇ 5, 156 ⁇ 5, and 170 ⁇ 5 °C (e.g., 76 ⁇ 4, 141 ⁇ 4, 156 ⁇ 4, and 170 ⁇ 4 °C (e.g., 76 ⁇ 3, 141 ⁇ 3, 156 ⁇ 3, and 170 ⁇ 3 °C (e.g., 76 ⁇ 2, 141 ⁇ 2, 156 ⁇ 2, and 170 ⁇ 2 °C (e.g., 76 ⁇ 1, 141 ⁇ 1, 156 ⁇ 1, and 170 ⁇ 1 °C (e.g., 76 ⁇ 0.5, 141 ⁇ 0.5, 141 ⁇ 0.5, 76
• Form A is characterized by a DSC curve having at least two endothermic peaks selected from 76 ⁇ 20, 141 ⁇ 20, 156 ⁇ 20, and 170 ⁇ 20 °C (e.g., 76 ⁇ 10, 141 ⁇ 10, 156 ⁇ 10, and 170 ⁇ 10 °C (e.g., 76 ⁇ 5, 141 ⁇ 5, 156 ⁇ 5, and 170 ⁇ 5 °C (e.g., 76 ⁇ 4, 141 ⁇ 4, 156 ⁇ 4, and 170 ⁇ 4 °C (e.g., 76 ⁇ 3, 141 ⁇ 3, 156 ⁇ 3, and 170 ⁇ 3 °C (e.g., 76 ⁇ 2, 141 ⁇ 2,156 ⁇ 2, and 170 ⁇ 2 °C (e.g., 76 + 1, 141 ⁇ 1 , 156 ⁇ 1, and 170 ⁇ 1 °C (e.g., 76 ⁇ 0.5, 141 ⁇ 0.5,
• Form A is characterized by a DSC curve having at least three endothermic peaks selected from 76 ⁇ 20, 141 ⁇ 20, 156 ⁇ 20, and 170 ⁇ 20 °C (e.g., 76 ⁇ 10, 141 ⁇ 10, 156 ⁇ 10, and 170 ⁇ 10 °C (e.g., 76 ⁇ 5, 141 ⁇ 5, 156 ⁇ 5, and 170 ⁇ 5 °C (e.g., 76 ⁇ 4, 141 ⁇ 4. 156 ⁇ 4, and 170 ⁇ 4 °C (e.g., 76 ⁇ 3, 141 ⁇ 3, 156 ⁇ 3, and 170 ⁇ 3 °C (e.g., 76 ⁇ 2.
• a DSC curve having at least three endothermic peaks selected from 76 ⁇ 20, 141 ⁇ 20, 156 ⁇ 20, and 170 ⁇ 20 °C (e.g., 76 ⁇ 10, 141 ⁇ 10, 156 ⁇ 10, and 170 ⁇ 10 °C (e.g.
• Form A is characterized by a DSC curve having endothermic peaks at 76 ⁇ 20, 141 ⁇ 20, 156 ⁇ 20, and 170 ⁇ 20 °C (e.g., 76 ⁇ 10, 141 ⁇ 10, 156 ⁇ 10, and 170 ⁇ 10 °C (e.g., 76 ⁇ 5, 141 ⁇ 5, 156 ⁇ 5, and 170 ⁇ 5 °C (e.g., 76 ⁇ 4, 141 ⁇ 4, 156 ⁇ 4, and 170 ⁇ 4 °C (e.g., 76 ⁇ 3, 141 ⁇ 3, 156 ⁇ 3, and 170 ⁇ 3 °C (e.g., 76 ⁇ 2, 141 ⁇ 2, 156 ⁇ 2, and 170 ⁇ 2 °C (e.g., 76 ⁇ 1, 141 ⁇ 1, 156 ⁇ 1, and 170 ⁇ 1 °C (e.g., 76 ⁇ 0.5, 141 ⁇ 0.5, 156 ⁇ 20, and 170 ⁇ 20
• Form A is characterized by a DSC curve having an endothermic peak at 76 °C. In some embodiments, Form A of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 141 °C. In some embodiments, Form A of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 156 °C. In some embodiments, Form A of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 170 °C.
• Form A shows a weight loss of approximately 1-3% between about 28 ⁇ 20 °C (e.g., 28 ⁇ 10 °C (e.g., 28 ⁇ 5 °C (e.g., 28 ⁇ 4 °C (e.g., 28 ⁇ 3 °C (e.g., 28 ⁇ 2 °C (e.g., 28 ⁇ 1 C C (e.g., 28 ⁇ 0.5 °C)))))))))))))))) and about 130 ⁇ 20 °C (e.g., 130 ⁇ 10 °C (e.g., 130 + 5 C C (e.g., 130 ⁇ 4 °C (e.g., 130 ⁇ 3 °C (e.g., 130 ⁇ 2 °C (e.g., 130 ⁇ 1 °C (e.g., 150 ⁇ 0.5 °C)))))), as measured by TGA.
• 28 ⁇ 10 °C e.g., 28
• Form A shows a weight loss of approximately 2.2% between about 28 °C and about 130 °C, as measured by TGA.
• the morphic form is Form B of Compound No, 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof,
• the morphic form is Form B of Compound No. I .
• the present disclosure provides a form of Compound No. 1 (“Form B”) characterized by an X-ray diffraction (“XRPD”) patern comprising peaks at 6.5+0.2, 16.7+0.2, and 18.6+0.2 °20 (e.g., 6.5+0.1 , 16.7+0.1, and 18.6+0.1 °29 (e.g., 6.5, 16.7, and 18.6 °20)) using Cu Ka radiation.
• XRPD X-ray diffraction
• the XRPD pattern of Form B further comprises at least one peak selected from 3.2+0.2, 13.4+0.2, and 17.7+0.2 °20 (e.g., 3.2+0.1, 13.4+0.1, and 17.7+0.1 °20 (e.g., 3.2, 13.4, and 17.7 °20)) using Cu Ka radiation.
• the XRPD pattern of Form B further comprises at least two peaks selected from 3.2+0.2, 13.4+0.2, and 17.7+0.2 °20 (e.g., 3.2+0.1, 13.4+0.1, and 17.7+0.1 °20 (e.g., 3.2, 13.4, and 17.7 °20)) using Cu Ka radiation.
• the XRPD pattern of Form B further comprises peaks at 3.2+0.2, 13.4+0.2, and 17.7+0.2 °20 (e.g., 3.2+0.1, 13.4+0.1, and 17.7+0.1 °20 (e.g., 3.2, 13.4, and 17.7 O 29)) using Cu Ka radiation.
• the present disclosure provides a form of Compound No. 1 (“Form B”) characterized by an X-ray diffraction (“XRPD”) patern comprising at least three peaks selected from 3.2 - 0.2. 6.5+0.2, 13.4 : 9.2. 16.7 : 0.2. 17.7 : 0.2. and 18.6 : 0.2 °20 (e.g., 3.2 : 0.1. 6.5 - 0. L 13.4 : 0.1. 16.7 : 0.1. 17.7+0.1, and 18.6+0.1 °20 (e.g., 3.2, 6.5, 13.4, 16.7, 17.7, and 18.6 20)) using Cu Ka radiation.
• XRPD X-ray diffraction
• the XRPD pattern of Form B comprises at least four peaks selected from 3.2+0.2, 6.5+0.2, 13.4+0.2, 16.7+0.2, 17.7+0.2, and 18.6+0.2. °29 (e.g., 3.2+0.1, 6.5+0.1, 1 3.4 : 04. 16.7+0.1, 17.7+0.1, and 18.6+0.1 °20 (e.g., 3.2, 6.5, 13.4, 16.7, 17.7, and 18.6 20)) using Cu Kot radiation.
• the XRPD pattern of Form B comprises at least five peaks selected from 3, 2+0.2, 6.5+0.2, 13.4+0.2, 16.7+0.2, 17.7+0.2, and 18.6+0.2 °20 (e.g., 3.2+0.1, 6.5+0.1, 13.4+0.1, 16.7+0.1, 17.7+0.1, and 18.6+0.1 °20 (e.g., 3.2, 6.5, 13.4, 16.7, 17.7, and 18.6 20)) using Cu Ka radiation.
• the XRPD pattern of Form B comprises peaks at 3.2+0, 2, 6.5+0.2, 13.4+0.2, 16.7+0.2, 17.7+0.2, and 18.6+0.2 °26 (e.g., 3.2+0.1 , 6.5+0. 1, 13.4+0.1 , 16.7+0.1, 17.7+0.1 , and 18,6+0, 1 °20 (e.g., 3.2, 6.5, 13.4, 16.7, 17.7, and 18.6 °20)) using Cu Ka radiation.
• Form B is characterized by an XRPD pattern substantially similar to that shown in FIG. 2.
• Form B is characterized by an XRPD patern comprising peaks at approximately the positions shown in the table below. It is understood that the values in the table are approximate and subject to instrumental and experimental variations.
• Form B of Compound No. 1 is characterized by a DSC curve having at least one endothermic peak selected from 155 ⁇ 20 and 176 ⁇ 20 °C (e.g., 155 ⁇ 10 and 176 ⁇ 10 °C (e.g., 155 ⁇ 5 and 176 ⁇ 5 C C (e.g., 155 ⁇ 4 and 176 ⁇ 4 °C (e.g., 155 ⁇ 3 and 176 ⁇ 3 °C (e.g., 155 ⁇ 2 and 176 ⁇ 2 °C (e.g., 155 ⁇ 1 and 176 ⁇ 1 °C (e.g., 155 ⁇ 0.5 and 176 ⁇ 0.5
• Form B of Compound No. 1 is characterized by a DSC curve having endothermic peaks at 155 ⁇ 20 and 176 ⁇ 20 °C (e.g., 155 ⁇ 10 and 176 ⁇ 10 °C (e.g., 155 ⁇ 5 and 176 ⁇ 5 °C (e.g., 155 ⁇ 4 and 176 ⁇ 4 °C (e.g., 155 ⁇ 3 and 176 ⁇ 3 °C (e.g., 155 ⁇ 2 and 176 ⁇ 2 °C (e.g., 155 ⁇ 1 and 176 ⁇ 1 °C (e.g., 155 ⁇ 0.5 and 176 ⁇ 0.5 °C)))))))))).
• 155 ⁇ 20 and 176 ⁇ 20 °C e.g., 155 ⁇ 10 and 176 ⁇ 10 °C (e.g., 155 ⁇ 5 and 176 ⁇ 5 °C (e.g., 155
• Form B of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 155 °C. In some embodiments. Form B of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 176 °C.
• Form B of Compound No. 1 shows a weight loss of approximately 1-3% between about 35 ⁇ 20 °C (e.g., 35 ⁇ 10 °C (e.g., 35 ⁇ 5 °C (e.g., 35 ⁇ 4 °C (e.g., 35 ⁇ 3 °C (e.g., 35 ⁇ 2 °C (e.g., 35 ⁇ 1 °C (e.g., 35 ⁇ 0.5 °C))))))))))))))))))) and about 150 ⁇ 20 °C (e.g., 150 ⁇ 10 °C (e.g., 150 ⁇ 5 °C (e.g., 150 ⁇ 4 °C (e.g., 150 ⁇ 3 °C (e.g., 150 ⁇ 2 °C (e.g., 150 ⁇ 1 °C (e.g., 150 ⁇ 0.5 °C))))))))))))))) and
• Form B of Compound No. 1 shows a weight loss of approximately 1.5% between about 35 °C and about 150 °C, as measured by TGA.
• the morphic form is Form C of Compound No. 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof.
• the morphic form is Form C of Compound No. 1.
• the present disclosure provides a form of Compound No. 1 (“Form C”) characterized by an X-ray diffraction (“XRPD”) pattern comprising peaks at 16. l ⁇ 0.2, 16.7 ⁇ 0.2, and 19.1 ⁇ 0.2 °20 (e.g., 16.H-0.1, 16.7 ⁇ 0.1, and 19.1 ⁇ 0.1 °20 (e.g., 16.1, 16.7, and 19.1 °20)) using Cu Ka radiation.
• XRPD X-ray diffraction
• the XRPD pattern of Form C further comprises at least one peak selected from 4.0 ⁇ 0.2, 12.6 ⁇ 0.2, and 14.H0.2 °20 (e.g., 4.0 ⁇ 0.1, 12.6 ⁇ 0.1, and 14.H0.1 °20 (e.g.,
• the XRPD pattern of Form C further comprises at least two peaks selected from 4.0 ⁇ 0.2, 12.6 ⁇ 0.2, and 14.1 ⁇ 0.2 °2 ⁇ (e.g., 4.0 ⁇ 0.1, 12.6 ⁇ 0.1, and 14.1 ⁇ 0.1 °2 ⁇ (e.g., 4.0, 12.6, and 14.1 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form C further comprises peaks at 4.0 ⁇ 0.2, 12.6 ⁇ 0.2, and 14.1 ⁇ 0.2 °2 ⁇ (e.g., 4.0 ⁇ 0.1, 12.6 ⁇ 0.1, and 14.1 ⁇ 0.1 °2 ⁇ (e.g., 4.0, 12.6, and 14.1 °2 ⁇ )) using Cu K ⁇ radiation.
• the present disclosure provides a form of Compound No.
• Form C characterized by an X-ray diffraction (“XRPD”) pattern comprising at least three peaks selected from 4.0 ⁇ 0.2, 12.6 ⁇ 0.2, 14.1 ⁇ 0.2, 16.1 ⁇ 0.2, 16.7 ⁇ 0.2, and 19.1 ⁇ 0.2 °2 ⁇ (e.g., 4.0 ⁇ 0.1, 12.6 ⁇ 0.1, 14.1 ⁇ 0.1, 16.1 ⁇ 0.1, 16.7 ⁇ 0.1, and 19.1 ⁇ 0.1 °2 ⁇ (e.g., 4.0, 12.6, 14.1, 16.1, 16.7, and 19.1 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• the XRPD pattern of Form C comprises at least four peaks selected from 4.0 ⁇ 0.2, 12.6 ⁇ 0.2, 14.1 ⁇ 0.2, 16.1 ⁇ 0.2, 16.7 ⁇ 0.2, and 19.1 ⁇ 0.2 °2 ⁇ (e.g., 4.0 ⁇ 0.1, 12.6 ⁇ 0.1, 14.1 ⁇ 0.1, 16.1 ⁇ 0.1, 16.7 ⁇ 0.1, and 19.1 ⁇ 0.1 °2 ⁇ (e.g., 4.0, 12.6, 14.1, 16.1, 16.7, and 19.1 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form C comprises at least five peaks selected from 4.0 ⁇ 0.2, 12.6 ⁇ 0.2, 14.1 ⁇ 0.2, 16.1 ⁇ 0.2, 16.7 ⁇ 0.2, and 19.1 ⁇ 0.2 °2 ⁇ (e.g., 4.0 ⁇ 0.1, 12.6 ⁇ 0.1, 14.1 ⁇ 0.1, 16.1 ⁇ 0.1, 16.7 ⁇ 0.1, and 19.1 ⁇ 0.1 °2 ⁇ (e.g., 4.0, 12.6, 14.1, 16.1, 16.7, and 19.1 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form C comprises peaks at 4.0 ⁇ 0.2, 12.6 ⁇ 0.2, 14.1 ⁇ 0.2, 16.1 ⁇ 0.2, 16.7 ⁇ 0.2, and 19.1 ⁇ 0.2 °2 ⁇ (e.g., 4.0 ⁇ 0.1, 12.6 ⁇ 0.1, 14.1 ⁇ 0.1, 16.1 ⁇ 0.1, 16.7 ⁇ 0.1, and 19.1 ⁇ 0.1 °2 ⁇ (e.g., 4.0, 12.6, 14.1, 16.1, 16.7, and 19.1 °2 ⁇ )) using Cu K ⁇ radiation.
• Form C is characterized by an XRPD pattern substantially similar to that shown in FIG.3.
• Form C is characterized by an XRPD pattern comprising peaks at approximately the positions shown in the table below. It is understood that the values in the table are approximate and subject to instrumental and experimental variations.
• Table 3 XRPD peak list for Form C Differential Scanning Calorimeter (DSC) Characterizations
• DSC Differential Scanning Calorimeter
• Form C of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 181 ⁇ 20 °C (e.g., 181 ⁇ 10 °C (e.g., 181 ⁇ 5 °C (e.g., 181 ⁇ 4 °C (e.g., 181 ⁇ 3 °C (e.g., 181 ⁇ 2 °C (e.g., 181 ⁇ 1 °C (e.g., 181 ⁇ 0.5 °C)))))))))))))))))))).
• Form C of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 181 °C.
• Form C of Compound No. 1 shows a weight loss of approximately 1-3% between about 28 ⁇ 20 °C (e.g., 28 ⁇ 10 °C (e.g., 28 ⁇ 5 °C (e.g., 28 ⁇ 4 °C (e.g., 28 ⁇ 3 °C (e.g., 28 ⁇ 2 °C (e.g., 28 ⁇ 1 °C (e.g., 28 ⁇ 0.5
• Form C of Compound No. 1 shows a weight loss of approximately 1.3% between about 28 °C and about 170 °C, as measured by TGA.
• Form D X-Ray Powder Diffraction (XRPD) Characterization [098]
• the morphic form is Form D of Compound No. 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof.
• the morphic form is Form D of the dioxane solvate of Compound No.1.
• the morphic form is Form D of Compound No.1.
• the present disclosure provides a form of Compound No.
• Form D characterized by an X-ray diffraction (“XRPD”) pattern comprising peaks at 15.3 ⁇ 0.2, 19.3 ⁇ 0.2, and 23.5 ⁇ 0.2 °2 ⁇ (e.g., 5.3 ⁇ 0.1, 19.3 ⁇ 0.1, and 23.5 ⁇ 0.1 °2 ⁇ (e.g., 5.3, 19.3, and 23.5 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• the XRPD pattern of Form D further comprises at least one peak selected from 5.4 ⁇ 0.2, 9.7 ⁇ 0.2, and 18.8 ⁇ 0.2 °2 ⁇ (e.g., 5.4 ⁇ 0.1, 9.7 ⁇ 0.1, and 18.8 ⁇ 0.1 °2 ⁇ (e.g., 5.4, 9.7, and 18.8 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form D further comprises at least two peaks selected from 5.4 ⁇ 0.2, 9.7 ⁇ 0.2, and 18.8 ⁇ 0.2 °2 ⁇ (e.g., 5.4 ⁇ 0.1, 9.7 ⁇ 0.1, and 18.8 ⁇ 0.1 °2 ⁇ (e.g., 5.4, 9.7, and 18.8 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form D further comprises peaks at 5.4 ⁇ 0.2, 9.7 ⁇ 0.2, and 18.8 ⁇ 0.2 °2 ⁇ (e.g., 5.4 ⁇ 0.1, 9.7 ⁇ 0.1, and 18.8 ⁇ 0.1 °2 ⁇ (e.g., 5.4, 9.7, and 18.8 °2 ⁇ )) using Cu K ⁇ radiation.
• the present disclosure provides a form of Compound No. 1 (“Form D”) characterized by an X-ray diffraction (“XRPD”) pattern comprising at least three peaks selected from 5.4 ⁇ 0.2, 9.7 ⁇ 0.2, 15.3 ⁇ 0.2, 18.8 ⁇ 0.2, 19.3 ⁇ 0.2, and 23.5 ⁇ 0.2 °2 ⁇ (e.g., 5.4 ⁇ 0.1, 9.7 ⁇ 0.1, 15.3 ⁇ 0.1, 18.8 ⁇ 0.1, 19.3 ⁇ 0.1, and 23.5 ⁇ 0.1 °2 ⁇ (e.g., 5.4, 9.7, 15.3, 18.8, 19.3, and 23.5 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• the XRPD pattern of Form D comprises at least four peaks selected from 5.4 ⁇ 0.2, 9.7 ⁇ 0.2, 15.3 ⁇ 0.2, 18.8 ⁇ 0.2, 19.3 ⁇ 0.2, and 23.5 ⁇ 0.2 °2 ⁇ (e.g., 5.4 ⁇ 0.1, 9.7 ⁇ 0.1, 15.3 ⁇ 0.1, 18.8 ⁇ 0.1, 19.3 ⁇ 0.1, and 23.5 ⁇ 0.1 °2 ⁇ (e.g., 5.4, 9.7, 15.3, 18.8, 19.3, and 23.5 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form D comprises at least five peaks selected from 5.4 ⁇ 0.2, 9.7 ⁇ 0.2, 15.3 ⁇ 0.2, 18.8 ⁇ 0.2, 19.3 ⁇ 0.2, and 23.5 ⁇ 0.2 °2 ⁇ (e.g., 5.4 ⁇ 0.1, 9.7 ⁇ 0.1, 15.3 ⁇ 0.1, 18.8 ⁇ 0.1, 19.3 ⁇ 0.1, and 23.5 ⁇ 0.1 °2 ⁇ (e.g., 5.4, 9.7, 15.3, 18.8, 19.3, and 23.5 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form D comprises peaks at 5.4 ⁇ 0.2, 9.7 ⁇ 0.2, 15.3 ⁇ 0.2, 18.8 ⁇ 0.2, 19.3 ⁇ 0.2, and 23.5 ⁇ 0.2 °2 ⁇ (e.g., 5.4 ⁇ 0.1, 9.7 ⁇ 0.1, 15.3 ⁇ 0.1, 18.8 ⁇ 0.1, 19.3 ⁇ 0.1, and 23.5 ⁇ 0.1 °2 ⁇ (e.g., 5.4, 9.7, 15.3, 18.8, 19.3, and 23.5 °2 ⁇ )) using Cu K ⁇ radiation.
• Form D is characterized by an XRPD pattern substantially similar to that shown in FIG.4.
• Form D is characterized by an XRPD pattern comprising peaks at approximately the positions shown in the table below. It is understood that the values in the table are approximate and subject to instrumental and experimental variations.
• Table 4 XRPD peak list for Form D Differential Scanning Calorimeter (DSC) Characterizations [0111] In some embodiments, Form D of Compound No.
• 1 is characterized by a DSC curve having at least one endothermic peak selected from 128 ⁇ 20, 149 ⁇ 20, and 175 ⁇ 20 °C (e.g., 128 ⁇ 10, 149 ⁇ 10, and 175 ⁇ 10 °C (e.g., 128 ⁇ 5, 149 ⁇ 5, and 175 ⁇ 5 °C (e.g., 128 ⁇ 4, 149 ⁇ 4, and 175 ⁇ 4 °C (e.g., 128 ⁇ 3, 149 ⁇ 3, and 175 ⁇ 3 °C (e.g., 128 ⁇ 2, 149 ⁇ 2, and 175 ⁇ 2 °C (e.g., 128 ⁇ 1, 149 ⁇ 1, and 175 ⁇ 1 °C (e.g., 128 ⁇ 0.5, 149 ⁇ 0.5, and 175 ⁇ 0.5 °C))))))))))))))))))))))).
• Form D of Compound No. 1 is characterized by a DSC curve having at least two endothermic peaks selected from 128 ⁇ 20, 149 ⁇ 20, and 175 ⁇ 20 °C (e.g., 128 ⁇ 10, 149 ⁇ 10, and 175 ⁇ 10 °C (e.g., 128 ⁇ 5, 149 ⁇ 5, and 175 ⁇ 5 °C (e.g., 128 ⁇ 4, 149 ⁇ 4, and 175 ⁇ 4 °C (e.g., 128 ⁇ 3, 149 ⁇ 3, and 175 ⁇ 3 °C (e.g., 128 ⁇ 2, 149 ⁇ 2, and 175 ⁇ 2 °C (e.g., 128 ⁇ 1, 149 ⁇ 1, and 175 ⁇ 1 °C (e.g., 128 ⁇ 0.5, 149 ⁇ 0.5, and 175 ⁇ 0.5 °C))))))))))))))))))))).
• Form D of Compound No. 1 is characterized by a DSC curve having endothermic peaks at 128 ⁇ 20, 149 ⁇ 20, and 175 ⁇ 20 °C (e.g., 128 ⁇ 10, 149 ⁇ 10, and 175 ⁇ 10 °C (e.g., 128 ⁇ 5, 149 ⁇ 5, and 175 ⁇ 5 °C (e.g., 128 ⁇ 4, 149 ⁇ 4, and 175 ⁇ 4 °C (e.g., 128 ⁇ 3, 149 ⁇ 3, and 175 ⁇ 3 °C (e.g., 128 ⁇ 2, 149 ⁇ 2, and 175 ⁇ 2 °C (e.g., 128 ⁇ 1, 149 ⁇ 1, and 175 ⁇ 1 °C (e.g., 128 ⁇ 0.5, 149 ⁇ 0.5, and 175 ⁇ 0.5 °C)))))))))))))).
• a DSC curve having endothermic peaks at 128
• Form D of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 128 °C. In some embodiments, Form D of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 149 °C. In some embodiments, Form D of Compound No.1 is characterized by a DSC curve having an endothermic peak at 175 °C. Thermogravimetric Analysis (TGA) Characterizations [0115] In some embodiments, Form D of Compound No.
• Form D of Compound No.1 shows a weight loss of approximately 13.8% between about 33 °C and about 185 °C, as measured by TGA.
• Form E X-Ray Powder Diffraction (XRPD) Characterization [0117] In some embodiments, the morphic form is Form E of Compound No. 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof. [0118] In some embodiments, the morphic form is Form E of Compound No.1. [0119] In some embodiments, the present disclosure provides a form of Compound No.
• Form E characterized by an X-ray diffraction (“XRPD”) pattern comprising peaks at 7.4 ⁇ 0.2, 15.8 ⁇ 0.2, and 16.3 ⁇ 0.2 °2 ⁇ (e.g., 7.4 ⁇ 0.1, 15.8 ⁇ 0.1, and 16.3 ⁇ 0.1 °2 ⁇ (e.g., 7.4, 15.8, and 16.3 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• the XRPD pattern of Form E further comprises at least one peak selected from 13.3 ⁇ 0.2, 19.2 ⁇ 0.2, and 22.4 ⁇ 0.2 °2 ⁇ (e.g., 13.3 ⁇ 0.1, 19.2 ⁇ 0.1, and 22.4 ⁇ 0.1 °2 ⁇ (e.g., 13.3, 19.2, and 22.4 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form E further comprises at least two peaks selected from 13.3 ⁇ 0.2, 19.2 ⁇ 0.2, and 22.4 ⁇ 0.2 °2 ⁇ (e.g., 13.3 ⁇ 0.1, 19.2 ⁇ 0.1, and 22.4 ⁇ 0.1 °2 ⁇ (e.g., 13.3, 19.2, and 22.4 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form E further comprises peaks at 13.3 ⁇ 0.2, 19.2 ⁇ 0.2, and 22.4 ⁇ 0.2 °2 ⁇ (e.g., 13.3 ⁇ 0.1, 19.2 ⁇ 0.1, and 22.4 ⁇ 0.1 °2 ⁇ (e.g., 13.3, 19.2, and 22.4 °2 ⁇ )) using Cu K ⁇ radiation.
• the present disclosure provides a form of Compound No.
• Form E characterized by an X-ray diffraction (“XRPD”) pattern comprising at least three peaks selected from 7.4 ⁇ 0.2, 13.3 ⁇ 0.2, 15.8 ⁇ 0.2, 16.3 ⁇ 0.2, 19.2 ⁇ 0.2, and 22.4 ⁇ 0.2 °2 ⁇ (e.g., 7.4 ⁇ 0.1, 13.3 ⁇ 0.1, 15.8 ⁇ 0.1, 16.3 ⁇ 0.1, 19.2 ⁇ 0.1, and 22.4 ⁇ 0.1 °2 ⁇ (e.g., 7.4, 13.3, 15.8, 16.3, 19.2, and 22.4 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• the XRPD pattern of Form E comprises at least four peaks selected from 7.4 ⁇ 0.2, 13.3 ⁇ 0.2, 15.8 ⁇ 0.2, 16.3 ⁇ 0.2, 19.2 ⁇ 0.2, and 22.4 ⁇ 0.2 °2 ⁇ (e.g., 7.4 ⁇ 0.1, 13.3 ⁇ 0.1, 15.8 ⁇ 0.1, 16.3 ⁇ 0.1, 19.2 ⁇ 0.1, and 22.4 ⁇ 0.1 °2 ⁇ (e.g., 7.4, 13.3, 15.8, 16.3, 19.2, and 22.4 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form E comprises at least five peaks selected from 7.4 ⁇ 0.2, 13.3 ⁇ 0.2, 15.8 ⁇ 0.2, 16.3 ⁇ 0.2, 19.2 ⁇ 0.2, and 22.4 ⁇ 0.2 °2 ⁇ (e.g., 7.4 ⁇ 0.1, 13.3 ⁇ 0.1, 15.8 ⁇ 0.1, 16.3 ⁇ 0.1, 19.2 ⁇ 0.1, and 22.4 ⁇ 0.1 °2 ⁇ (e.g., 7.4, 13.3, 15.8, 16.3, 19.2, and 22.4 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form E comprises peaks at 7.4 ⁇ 0.2, 13.3 ⁇ 0.2, 15.8 ⁇ 0.2, 16.3 ⁇ 0.2, 19.2 ⁇ 0.2, and 22.4 ⁇ 0.2 °2 ⁇ (e.g., 7.4 ⁇ 0.1, 13.3 ⁇ 0.1, 15.8 ⁇ 0.1, 16.3 ⁇ 0.1, 19.2 ⁇ 0.1, and 22.4 ⁇ 0.1 °2 ⁇ (e.g., 7.4, 13.3, 15.8, 16.3, 19.2, and 22.4 °2 ⁇ )) using Cu K ⁇ radiation.
• Form E is characterized by an XRPD pattern substantially similar to that shown in FIG.5.
• Form E is characterized by an XRPD pattern comprising peaks at approximately the positions shown in the table below.
• Form E of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 173 ⁇ 20 °C (e.g., 173 ⁇ 10 °C (e.g., 173 ⁇ 5 °C (e.g., 173 ⁇ 4 °C (e.g., 173 ⁇ 3 °C (e.g., 173 ⁇ 2 °C (e.g., 173 ⁇ 1 °C (e.g., 173 ⁇ 0.5 °C)))))).
• a DSC curve having an endothermic peak at 173 ⁇ 20 °C (e.g., 173 ⁇ 10 °C (e.g., 173 ⁇ 5 °C (e.g., 173 ⁇ 4 °C (e.g., 173 ⁇ 3 °C (e.g., 173 ⁇ 2 °C (e.g., 173 ⁇ 1 °C (e.g., 173 ⁇
• Form E of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 173 °C.
• Thermogravimetric Analysis (TGA) Characterizations [0131] In some embodiments, Form E of Compound No.
• Form E of Compound No. 1 shows a weight loss of approximately 1.3% between about 34 °C and about 165 °C, as measured by TGA.
• Form F X-Ray Powder Diffraction (XRPD) Characterization
• the morphic form is Form F of Compound No. 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof.
• the morphic form is Form F of the hydrate of Compound No.1.
• the morphic form is Form F of Compound No.1.
• the present disclosure provides a form of Compound No.
• Form F characterized by an X-ray diffraction (“XRPD”) pattern comprising peaks at 5.5 ⁇ 0.2, 16.4 ⁇ 0.2, and 21.9 ⁇ 0.2 °2 ⁇ (e.g., 5.5 ⁇ 0.1, 16.4 ⁇ 0.1, and 21.9 ⁇ 0.1 °2 ⁇ (e.g., 5.5, 16.4, and 21.9 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• the XRPD pattern of Form F further comprises at least one peak selected from 7.2 ⁇ 0.2, 14.5 ⁇ 0.2, and 15.2 ⁇ 0.2 °2 ⁇ (e.g., 7.2 ⁇ 0.1, 14.5 ⁇ 0.1, and 15.2 ⁇ 0.1 °2 ⁇ (e.g., 7.2, 14.5, and 15.2 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form F further comprises at least two peaks selected from 7.2 ⁇ 0.2, 14.5 ⁇ 0.2, and 15.2 ⁇ 0.2 °2 ⁇ (e.g., 7.2 ⁇ 0.1, 14.5 ⁇ 0.1, and 15.2 ⁇ 0.1 °2 ⁇ (e.g., 7.2, 14.5, and 15.2 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form F further comprises peaks at 7.2 ⁇ 0.2, 14.5 ⁇ 0.2, and 15.2 ⁇ 0.2 °2 ⁇ (e.g., 7.2 ⁇ 0.1, 14.5 ⁇ 0.1, and 15.2 ⁇ 0.1 °2 ⁇ (e.g., 7.2, 14.5, and 15.2 °2 ⁇ )) using Cu K ⁇ radiation.
• the present disclosure provides a form of Compound No. 1 (“Form F”) characterized by an X-ray diffraction (“XRPD”) pattern comprising at least three peaks selected from 5.5 ⁇ 0.2, 7.2 ⁇ 0.2, 14.5 ⁇ 0.2, 15.2 ⁇ 0.2, 16.4 ⁇ 0.2, and 21.9 ⁇ 0.2 °2 ⁇ (e.g., 5.5 ⁇ 0.1, 7.2 ⁇ 0.1, 14.5 ⁇ 0.1, 15.2 ⁇ 0.1, 16.4 ⁇ 0.1, and 21.9 ⁇ 0.1 °2 ⁇ (e.g., 5.5, 7.2, 14.5, 15.2, 16.4, and 21.9 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• the XRPD pattern of Form F comprises at least four peaks selected from 5.5 ⁇ 0.2, 7.2 ⁇ 0.2, 14.5 ⁇ 0.2, 15.2 ⁇ 0.2, 16.4 ⁇ 0.2, and 21.9 ⁇ 0.2 °2 ⁇ (e.g., 5.5 ⁇ 0.1, 7.2 ⁇ 0.1, 14.5 ⁇ 0.1, 15.2 ⁇ 0.1, 16.4 ⁇ 0.1, and 21.9 ⁇ 0.1 °2 ⁇ (e.g., 5.5, 7.2, 14.5, 15.2, 16.4, and 21.9 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form F comprises at least five peaks selected from 5.5 ⁇ 0.2, 7.2 ⁇ 0.2, 14.5 ⁇ 0.2, 15.2 ⁇ 0.2, 16.4 ⁇ 0.2, and 21.9 ⁇ 0.2 °2 ⁇ (e.g., 5.5 ⁇ 0.1, 7.2 ⁇ 0.1, 14.5 ⁇ 0.1, 15.2 ⁇ 0.1, 16.4 ⁇ 0.1, and 21.9 ⁇ 0.1 °2 ⁇ (e.g., 5.5, 7.2, 14.5, 15.2, 16.4, and 21.9 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form F comprises peaks at 5.5 ⁇ 0.2, 7.2 ⁇ 0.2, 14.5 ⁇ 0.2, 15.2 ⁇ 0.2, 16.4 ⁇ 0.2, and 21.9 ⁇ 0.2 °2 ⁇ (e.g., 5.5 ⁇ 0.1, 7.2 ⁇ 0.1, 14.5 ⁇ 0.1, 15.2 ⁇ 0.1, 16.4 ⁇ 0.1, and 21.9 ⁇ 0.1 °2 ⁇ (e.g., 5.5, 7.2, 14.5, 15.2, 16.4, and 21.9 °2 ⁇ )) using Cu K ⁇ radiation.
• Form F is characterized by an XRPD pattern substantially similar to that shown in FIG.6.
• Form F is characterized by an XRPD pattern comprising peaks at approximately the positions shown in the table below. It is understood that the values in the table are approximate and subject to instrumental and experimental variations. Table 6: XRPD peak list for Form F
• Form F of Compound No. 1 is characterized by a DSC curve having at least one endothermic peak selected from 48 ⁇ 20, 80 ⁇ 20, 146 ⁇ 20, and 174 ⁇ 20 °C (e.g., 48 ⁇ 10, 80 ⁇ 10, 146 ⁇ 10, and 174 ⁇ 10 °C (e.g., 48 ⁇ 5, 80 ⁇ 5, 146 ⁇ 5, and 174 ⁇ 5 °C (e.g., 48 ⁇ 4, 80 ⁇ 4, 146 ⁇ 4, and 174 ⁇ 4 °C (e.g., 48 ⁇ 3, 80 ⁇ 3, 146 ⁇ 3, and 174 ⁇ 3 °C (e.g., 48 ⁇ 2, 80 ⁇ 2, 146 ⁇ 2, and 174 ⁇ 2 °C (e.g., 48 ⁇ 1, 80 ⁇ 1, 146 ⁇ 1, and 174 ⁇ 1 °C (e.g., 48 ⁇ 0.5, 80 ⁇ 20, 80 ⁇ 20, 146 ⁇ 20, and 174 ⁇ 20 °C (e.
• Form F of Compound No. 1 is characterized by a DSC curve having at least two endothermic peaks selected from 48 ⁇ 20, 80 ⁇ 20, 146 ⁇ 20, and 174 ⁇ 20 °C (e.g., 48 ⁇ 10, 80 ⁇ 10, 146 ⁇ 10, and 174 ⁇ 10 °C (e.g., 48 ⁇ 5, 80 ⁇ 5, 146 ⁇ 5, and 174 ⁇ 5 °C (e.g., 48 ⁇ 4, 80 ⁇ 4, 146 ⁇ 4, and 174 ⁇ 4 °C (e.g., 48 ⁇ 3, 80 ⁇ 3, 146 ⁇ 3, and 174 ⁇ 3 °C (e.g., 48 ⁇ 2, 80 ⁇ 2, 146 ⁇ 2, and 174 ⁇ 2 °C (e.g., 48 ⁇ 1, 80 ⁇ 1, 146 ⁇ 1, and 174 ⁇ 1 °C (e.g., 48 ⁇ 0.5, 80 ⁇ 0.5, 146 ⁇ 0.5, and 174
• Form F of Compound No. 1 is characterized by a DSC curve having at least three endothermic peaks selected from 48 ⁇ 20, 80 ⁇ 20, 146 ⁇ 20, and 174 ⁇ 20 °C (e.g., 48 ⁇ 10, 80 ⁇ 10, 146 ⁇ 10, and 174 ⁇ 10 °C (e.g., 48 ⁇ 5, 80 ⁇ 5, 146 ⁇ 5, and 174 ⁇ 5 °C (e.g., 48 ⁇ 4, 80 ⁇ 4, 146 ⁇ 4, and 174 ⁇ 4 °C (e.g., 48 ⁇ 3, 80 ⁇ 3, 146 ⁇ 3, and 174 ⁇ 3 °C (e.g., 48 ⁇ 2, 80 ⁇ 2, 146 ⁇ 2, and 174 ⁇ 2 °C (e.g., 48 ⁇ 1, 80 ⁇ 1, 146 ⁇ 1, and 174 ⁇ 1 °C (e.g., 48 ⁇ 0.5, 80 ⁇ 0.5, 146 ⁇ 0.5, and 174
• Form F of Compound No. 1 is characterized by a DSC curve having endothermic peaks at 48 ⁇ 20, 80 ⁇ 20, 146 ⁇ 20, and 174 ⁇ 20 °C (e.g., 48 ⁇ 10, 80 ⁇ 10, 146 ⁇ 10, and 174 ⁇ 10 °C (e.g., 48 ⁇ 5, 80 ⁇ 5, 146 ⁇ 5, and 174 ⁇ 5 °C (e.g., 48 ⁇ 4, 80 ⁇ 4, 146 ⁇ 4, and 174 ⁇ 4 °C (e.g., 48 ⁇ 3, 80 ⁇ 3, 146 ⁇ 3, and 174 ⁇ 3 °C (e.g., 48 ⁇ 2, 80 ⁇ 2, 146 ⁇ 2, and 174 ⁇ 2 °C (e.g., 48 ⁇ 1, 80 ⁇ 1, 146 ⁇ 1, and 174 ⁇ 1 °C (e.g., 48 ⁇ 0.5, 80 ⁇ 0.5, 146 ⁇ 0.5, and 174 ⁇ 0.5 0.5, and 174 ⁇
• Form F of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 48 °C. In some embodiments, Form F of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 80 °C. In some embodiments, Form F of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 144 °C.In some embodiments, Form F of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 146 °C. In some embodiments, Form F of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 174 °C.
• Form F of Compound No. 1 shows a weight loss of approximately 2-5% between about 33 ⁇ 20 °C (e.g., 33 ⁇ 10 °C (e.g., 33 ⁇ 5 °C (e.g., 33 ⁇ 4 °C (e.g., 33 ⁇ 3 °C (e.g., 33 ⁇ 2 °C (e.g., 33 ⁇ 1 °C (e.g., 33 ⁇ 0.5 °C)))))))))))))))))))))))))))))) and about 55 ⁇ 20 °C (e.g., 55 ⁇ 10 °C (e.g., 55 ⁇ 5 °C (e.g., 55 ⁇ 4 °C (e.g., 55 ⁇ 3 °C (e.g., 55 ⁇ 2 °C (e.g., 55 ⁇ 1 °C (e.g., 55 ⁇ 0.5 °C))))
• Form F of Compound No. 1 shows a weight loss of approximately 3.8% between about 33 °C and about 55 °C, as measured by TGA. [0153] In some embodiments, Form F of Compound No. 1 shows a weight loss of approximately 1-4% between about 55 ⁇ 20 °C (e.g., 55 ⁇ 10 °C (e.g., 55 ⁇ 5 °C (e.g., 55 ⁇ 4 °C (e.g., 55 ⁇ 3 °C (e.g., 55 ⁇ 2 °C (e.g., 55 ⁇ 1 °C (e.g., 55
• Form F of Compound No. 1 shows a weight loss of approximately 2.7% between about 55 °C and about 100 °C, as measured by TGA. [0155] In some embodiments, Form F of Compound No. 1 shows a weight loss of approximately 2-8% between about 33 ⁇ 20 °C (e.g., 33 ⁇ 10 °C (e.g., 33 ⁇ 5 °C (e.g., 33 ⁇ 4 °C (e.g., 33 ⁇ 3 °C (e.g., 33 ⁇ 2 °C (e.g., 33 ⁇ 1 °C (e.g., 33
• Form F of Compound No. 1 shows a weight loss of approximately 6.5% between about 33 °C and about 100 °C, as measured by TGA. [0157] In some embodiments, Form F of Compound No. 1 shows a weight loss of approximately 3.7% between about 33 °C and about 100 °C, as measured by TGA.
• Form G X-Ray Powder Diffraction (XRPD) Characterization
• the morphic form is Form G of Compound No. 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof.
• the morphic form is Form G of Compound No.1.
• the present disclosure provides a form of Compound No. 1 (“Form G”) characterized by an X-ray diffraction (“XRPD”) pattern comprising peaks at 4.0 ⁇ 0.2, 5.3 ⁇ 0.2, and 16.0 ⁇ 0.2 °2 ⁇ (e.g., 4.0 ⁇ 0.1, 5.3 ⁇ 0.1, and 16.0 ⁇ 0.1 °2 ⁇ (e.g., 4.0, 5.3, and 16.0 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• the XRPD pattern of Form G further comprises at least one peak selected from 7.1 ⁇ 0.2, 16.7 ⁇ 0.2, and 19.2 ⁇ 0.2 °2 ⁇ (e.g., 7.1 ⁇ 0.1, 16.7 ⁇ 0.1, and 19.2 ⁇ 0.1 °2 ⁇ (e.g., 7.1, 16.7, and 19.2 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form G further comprises at least two peaks selected from 7.1 ⁇ 0.2, 16.7 ⁇ 0.2, and 19.2 ⁇ 0.2 °2 ⁇ (e.g., 7.1 ⁇ 0.1, 16.7 ⁇ 0.1, and 19.2 ⁇ 0.1 °2 ⁇ (e.g., 7.1, 16.7, and 19.2 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form G further comprises peaks at 7.1 ⁇ 0.2, 16.7 ⁇ 0.2, and 19.2 ⁇ 0.2 °2 ⁇ (e.g., 7.1 ⁇ 0.1, 16.7 ⁇ 0.1, and 19.2 ⁇ 0.1 °2 ⁇ (e.g., 7.1, 16.7, and 19.2 °2 ⁇ )) using Cu K ⁇ radiation.
• the present disclosure provides a form of Compound No. 1 (“Form G”) characterized by an X-ray diffraction (“XRPD”) pattern comprising at least three peaks selected from 4.0 ⁇ 0.2, 5.3 ⁇ 0.2, 7.1 ⁇ 0.2, 16.0 ⁇ 0.2, 16.7 ⁇ 0.2, and 19.2 ⁇ 0.2 °2 ⁇ (e.g., 4.0 ⁇ 0.1, 5.3 ⁇ 0.1, 7.1 ⁇ 0.1, 16.0 ⁇ 0.1, 16.7 ⁇ 0.1, and 19.2 ⁇ 0.1 °2 ⁇ (e.g., 4.0, 5.3, 7.1, 16.0, 16.7, and 19.2 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• the XRPD pattern of Form G comprises at least four peaks selected from 4.0 ⁇ 0.2, 5.3 ⁇ 0.2, 7.1 ⁇ 0.2, 16.0 ⁇ 0.2, 16.7 ⁇ 0.2, and 19.2 ⁇ 0.2 °2 ⁇ (e.g., 4.0 ⁇ 0.1, 5.3 ⁇ 0.1, 7.1 ⁇ 0.1, 16.0 ⁇ 0.1, 16.7 ⁇ 0.1, and 19.2 ⁇ 0.1 °2 ⁇ (e.g., 4.0, 5.3, 7.1, 16.0, 16.7, and 19.2 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form G comprises at least five peaks selected from 4.0 ⁇ 0.2, 5.3 ⁇ 0.2, 7.1 ⁇ 0.2, 16.0 ⁇ 0.2, 16.7 ⁇ 0.2, and 19.2 ⁇ 0.2 °2 ⁇ (e.g., 4.0 ⁇ 0.1, 5.3 ⁇ 0.1, 7.1 ⁇ 0.1, 16.0 ⁇ 0.1, 16.7 ⁇ 0.1, and 19.2 ⁇ 0.1 °2 ⁇ (e.g., 4.0, 5.3, 7.1, 16.0, 16.7, and 19.2 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form G comprises peaks at 4.0 ⁇ 0.2, 5.3 ⁇ 0.2, 7.1 ⁇ 0.2, 16.0 ⁇ 0.2, 16.7 ⁇ 0.2, and 19.2 ⁇ 0.2 °2 ⁇ (e.g., 4.0 ⁇ 0.1, 5.3 ⁇ 0.1, 7.1 ⁇ 0.1, 16.0 ⁇ 0.1, 16.7 ⁇ 0.1, and 19.2 ⁇ 0.1 °2 ⁇ (e.g., 4.0, 5.3, 7.1, 16.0, 16.7, and 19.2 °2 ⁇ )) using Cu K ⁇ radiation.
• Form G is characterized by an XRPD pattern substantially similar to that shown in FIG.7.
• Form G is characterized by an XRPD pattern comprising peaks at approximately the positions shown in the table below. It is understood that the values in the table are approximate and subject to instrumental and experimental variations.
• Table 7 XRPD peak list for Form G Differential Scanning Calorimeter (DSC) Characterizations [0170] In some embodiments, Form G of Compound No.
• 1 is characterized by a DSC curve having at least one endothermic peak selected from 34 ⁇ 20, 175 ⁇ 20, and 182 ⁇ 20 °C (e.g., 34 ⁇ 10, 175 ⁇ 10, and 182 ⁇ 10 °C (e.g., 34 ⁇ 5, 175 ⁇ 5, and 182 ⁇ 5 °C (e.g., 34 ⁇ 4, 175 ⁇ 4, and 182 ⁇ 4 °C (e.g., 34 ⁇ 3, 175 ⁇ 3, and 182 ⁇ 3 °C (e.g., 34 ⁇ 2, 175 ⁇ 2, and 182 ⁇ 2 °C (e.g., 34 ⁇ 1, 175 ⁇ 1, and 182 ⁇ 1 °C (e.g., 34 ⁇ 0.5, 175 ⁇ 0.5, and 182 ⁇ 0.5 °C)))))))))).
• 34 ⁇ 20, 175 ⁇ 20, and 182 ⁇ 20 °C e.g., 34 ⁇ 10, 175
• Form G of Compound No. 1 is characterized by a DSC curve having at least two endothermic peaks selected from 34 ⁇ 20, 175 ⁇ 20, and 182 ⁇ 20 °C (e.g., 34 ⁇ 10, 175 ⁇ 10, and 182 ⁇ 10 °C (e.g., 34 ⁇ 5, 175 ⁇ 5, and 182 ⁇ 5 °C (e.g., 34 ⁇ 4, 175 ⁇ 4, and 182 ⁇ 4 °C (e.g., 34 ⁇ 3, 175 ⁇ 3, and 182 ⁇ 3 °C (e.g., 34 ⁇ 2, 175 ⁇ 2, and 182 ⁇ 2 °C (e.g., 34 ⁇ 1, 175 ⁇ 1, and 182 ⁇ 1 °C (e.g., 34 ⁇ 0.5, 175 ⁇ 0.5, and 182 ⁇ 0.5 °C))))))))).
• 34 ⁇ 20, 175 ⁇ 20, and 182 ⁇ 20 °C e.g.,
• Form G of Compound No. 1 is characterized by a DSC curve having endothermic peaks at 34 ⁇ 20, 175 ⁇ 20, and 182 ⁇ 20 °C (e.g., 34 ⁇ 10, 175 ⁇ 10, and 182 ⁇ 10 °C (e.g., 34 ⁇ 5, 175 ⁇ 5, and 182 ⁇ 5 °C (e.g., 34 ⁇ 4, 175 ⁇ 4, and 182 ⁇ 4 °C (e.g., 34 ⁇ 3, 175 ⁇ 3, and 182 ⁇ 3 °C (e.g., 34 ⁇ 2, 175 ⁇ 2, and 182 ⁇ 2 °C (e.g., 34 ⁇ 1, 175 ⁇ 1, and 182 ⁇ 1 °C (e.g., 34 ⁇ 0.5, 175 ⁇ 0.5, and 182 ⁇ 0.5 °C)))))))).
• 34 ⁇ 20, 175 ⁇ 20, and 182 ⁇ 20 °C e.g., 34 ⁇ 10, 1
• Form G of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 34 °C. In some embodiments, Form G of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 175 °C. In some embodiments, Form G of Compound No.1 is characterized by a DSC curve having an endothermic peak at 182 °C.
• TGA Thermogravimetric Analysis
• Form G of Compound No. 1 shows a weight loss of approximately 3.4% between about 33 °C and about 100 °C, as measured by TGA.
• Form H X-Ray Powder Diffraction (XRPD) Characterization [0176] In some embodiments, the morphic form is Form H of Compound No. 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof. [0177] In some embodiments, the morphic form is Form H of Compound No.1. [0178] In some embodiments, the present disclosure provides a form of Compound No.
• Form H characterized by an X-ray diffraction (“XRPD”) pattern comprising peaks at 4.6 ⁇ 0.2, 13.8 ⁇ 0.2, and 17.0 ⁇ 0.2 °2 ⁇ (e.g., 4.6 ⁇ 0.1, 13.8 ⁇ 0.1, and 17.0 ⁇ 0.1 °2 ⁇ (e.g., 4.6, 13.8, and 17.0 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• the XRPD pattern of Form H further comprises at least one peak selected from 5.6 ⁇ 0.2, 8.6 ⁇ 0.2, and 17.8 ⁇ 0.2 °2 ⁇ (e.g., 5.6 ⁇ 0.1, 8.6 ⁇ 0.1, and 17.8 ⁇ 0.1 °2 ⁇ (e.g., 5.6, 8.6, and 17.8 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form H further comprises at least two peaks selected from 5.6 ⁇ 0.2, 8.6 ⁇ 0.2, and 17.8 ⁇ 0.2 °2 ⁇ (e.g., 5.6 ⁇ 0.1, 8.6 ⁇ 0.1, and 17.8 ⁇ 0.1 °2 ⁇ (e.g., 5.6, 8.6, and 17.8 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form H further comprises peaks at 5.6 ⁇ 0.2, 8.6 ⁇ 0.2, and 17.8 ⁇ 0.2 °2 ⁇ (e.g., 5.6 ⁇ 0.1, 8.6 ⁇ 0.1, and 17.8 ⁇ 0.1 °2 ⁇ (e.g., 5.6, 8.6, and 17.8 °2 ⁇ )) using Cu K ⁇ radiation.
• the present disclosure provides a form of Compound No. 1 (“Form H”) characterized by an X-ray diffraction (“XRPD”) pattern comprising at least three peaks selected from 4.6 ⁇ 0.2, 5.6 ⁇ 0.2, 8.6 ⁇ 0.2, 13.8 ⁇ 0.2, 17.0 ⁇ 0.2, and 17.8 ⁇ 0.2 °2 ⁇ (e.g., 4.6 ⁇ 0.1, 5.6 ⁇ 0.1, 8.6 ⁇ 0.1, 13.8 ⁇ 0.1, 17.0 ⁇ 0.1, and 17.8 ⁇ 0.1 °2 ⁇ (e.g., 4.6, 5.6, 8.6, 13.8, 17.0, and 17.8 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• the XRPD pattern of Form H comprises at least four peaks selected from 4.6 ⁇ 0.2, 5.6 ⁇ 0.2, 8.6 ⁇ 0.2, 13.8 ⁇ 0.2, 17.0 ⁇ 0.2, and 17.8 ⁇ 0.2 °2 ⁇ (e.g., 4.6 ⁇ 0.1, 5.6 ⁇ 0.1, 8.6 ⁇ 0.1, 13.8 ⁇ 0.1, 17.0 ⁇ 0.1, and 17.8 ⁇ 0.1 °2 ⁇ (e.g., 4.6, 5.6, 8.6, 13.8, 17.0, and 17.8 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form H comprises at least five peaks selected from 4.6 ⁇ 0.2, 5.6 ⁇ 0.2, 8.6 ⁇ 0.2, 13.8 ⁇ 0.2, 17.0 ⁇ 0.2, and 17.8 ⁇ 0.2 °2 ⁇ (e.g., 4.6 ⁇ 0.1, 5.6 ⁇ 0.1, 8.6 ⁇ 0.1, 13.8 ⁇ 0.1, 17.0 ⁇ 0.1, and 17.8 ⁇ 0.1 °2 ⁇ (e.g., 4.6, 5.6, 8.6, 13.8, 17.0, and 17.8 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form H comprises peaks at 4.6 ⁇ 0.2, 5.6 ⁇ 0.2, 8.6 ⁇ 0.2, 13.8 ⁇ 0.2, 17.0 ⁇ 0.2, and 17.8 ⁇ 0.2 °2 ⁇ (e.g., 4.6 ⁇ 0.1, 5.6 ⁇ 0.1, 8.6 ⁇ 0.1, 13.8 ⁇ 0.1, 17.0 ⁇ 0.1, and 17.8 ⁇ 0.1 °2 ⁇ (e.g., 4.6, 5.6, 8.6, 13.8, 17.0, and 17.8 °2 ⁇ )) using Cu K ⁇ radiation.
• the present disclosure provides a form of Compound No. 1 (“Form H”), characterized by an XRPD pattern substantially similar to that shown in FIG.8.
• Form H is characterized by an XRPD pattern comprising peaks at approximately the positions shown in the table below. It is understood that the values in the table are approximate and subject to instrumental and experimental variations. Table 8: XRPD peak list for Form H
• the present disclosure provides a form of Compound No. 1 ("Form H"), characterized by a DSC curve having at least one endothermic peak selected from 62 ⁇ 20 and 153 ⁇ 20 °C (e.g., 62 ⁇ 10 and 153 ⁇ 10 °C (e.g., 62 ⁇ 5 and 153 ⁇ 5 °C (e.g., 62 ⁇ 4 and 153 ⁇ 4 °C (e.g., 62 ⁇ 3 and 153 ⁇ 3 °C (e.g., 62 ⁇ 2 and 153 ⁇ 2 °C (e.g., 62 ⁇ 1 and 153 ⁇ 1 °C (e.g., 62 ⁇ 0.5 and 153 ⁇ 0.5 °C)))))))))).
• Form H Differential Scanning Calorimeter
• Form H of Compound No. 1 is characterized by a DSC curve having endothermic peaks at 62 ⁇ 20 and 153 ⁇ 20 °C (e.g., 62 ⁇ 10 and 153 ⁇ 10 °C (e.g., 62 ⁇ 5 and 153 ⁇ 5 °C (e.g., 62 ⁇ 4 and 153 ⁇ 4 °C (e.g., 62 ⁇ 3 and 153 ⁇ 3 °C (e.g., 62 ⁇ 2 and 153 ⁇ 2 °C (e.g., 62 ⁇ 1 and 153 ⁇ 1 °C (e.g., 62 ⁇ 0.5 and 153 ⁇ 0.5 °C)))))))))).
• 62 ⁇ 20 and 153 ⁇ 20 °C e.g., 62 ⁇ 10 and 153 ⁇ 10 °C (e.g., 62 ⁇ 5 and 153 ⁇ 5 °C (e.g., 62
• Form H of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 62 °C. In some embodiments, Form H of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 153 °C.
• Form I X-Ray Powder Diffraction (XRPD) Characterization [0191] In some embodiments, the morphic form is Form I of Compound No. 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof. [0192] In some embodiments, the morphic form is Form I of the methanol solvate of Compound No.1. [0193] In some embodiments, the morphic form is Form I of Compound No. 1.
• the present disclosure provides a form of Compound No. 1 (“Form I”) characterized by an X-ray diffraction (“XRPD”) pattern comprising peaks at 5.1 ⁇ 0.2, 20.4 ⁇ 0.2, and 21.5 ⁇ 0.2 °2 ⁇ (e.g., 5.1 ⁇ 0.1, 20.4 ⁇ 0.1, and 21.5 ⁇ 0.1 °2 ⁇ (e.g., 5.1, 20.4, and 21.5 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• the XRPD pattern of Form I further comprises at least one peak selected from 17.0 ⁇ 0.2, 22.3 ⁇ 0.2, and 25.5 ⁇ 0.2 °2 ⁇ (e.g., 17.0 ⁇ 0.1, 22.3 ⁇ 0.1, and 25.5 ⁇ 0.1 °2 ⁇ (e.g., 17.0, 22.3, and 25.5 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form I further comprises at least two peaks selected from 17.0 ⁇ 0.2, 22.3 ⁇ 0.2, and 25.5 ⁇ 0.2 °2 ⁇ (e.g., 17.0 ⁇ 0.1, 22.3 ⁇ 0.1, and 25.5 ⁇ 0.1 °2 ⁇ (e.g., 17.0, 22.3, and 25.5 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form I further comprises peaks at 17.0 ⁇ 0.2, 22.3 ⁇ 0.2, and 25.5 ⁇ 0.2 °2 ⁇ (e.g., 17.0 ⁇ 0.1, 22.3 ⁇ 0.1, and 25.5 ⁇ 0.1 °2 ⁇ (e.g., 17.0, 22.3, and 25.5 °2 ⁇ )) using Cu K ⁇ radiation.
• the present disclosure provides a form of Compound No. 1 (“Form I”) characterized by an X-ray diffraction (“XRPD”) pattern comprising at least three peaks selected from 5.1 ⁇ 0.2, 17.0 ⁇ 0.2, 20.4 ⁇ 0.2, 21.5 ⁇ 0.2, 22.3 ⁇ 0.2, and 25.5 ⁇ 0.2 °2 ⁇ (e.g., 5.1 ⁇ 0.1, 17.0 ⁇ 0.1, 20.4 ⁇ 0.1, 21.5 ⁇ 0.1, 22.3 ⁇ 0.1, and 25.5 ⁇ 0.1 °2 ⁇ (e.g., 5.1, 17.0, 20.4, 21.5, 22.3, and 25.5 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• the XRPD pattern of Form I comprises at least four peaks selected from 5.1 ⁇ 0.2, 17.0 ⁇ 0.2, 20.4 ⁇ 0.2, 21.5 ⁇ 0.2, 22.3 ⁇ 0.2, and 25.5 ⁇ 0.2 °2 ⁇ (e.g., 5.1 ⁇ 0.1, 17.0 ⁇ 0.1, 20.4 ⁇ 0.1, 21.5 ⁇ 0.1, 22.3 ⁇ 0.1, and 25.5 ⁇ 0.1 °2 ⁇ (e.g., 5.1, 17.0, 20.4, 21.5, 22.3, and 25.5 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form I comprises at least five peaks selected from 5.1 ⁇ 0.2, 17.0 ⁇ 0.2, 20.4 ⁇ 0.2, 21.5 ⁇ 0.2, 22.3 ⁇ 0.2, and 25.5 ⁇ 0.2 °2 ⁇ (e.g., 5.1 ⁇ 0.1, 17.0 ⁇ 0.1, 20.4 ⁇ 0.1, 21.5 ⁇ 0.1, 22.3 ⁇ 0.1, and 25.5 ⁇ 0.1 °2 ⁇ (e.g., 5.1, 17.0, 20.4, 21.5, 22.3, and 25.5 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form I comprises peaks at 5.1 ⁇ 0.2, 17.0 ⁇ 0.2, 20.4 ⁇ 0.2, 21.5 ⁇ 0.2, 22.3 ⁇ 0.2, and 25.5 ⁇ 0.2 °2 ⁇ (e.g., 5.1 ⁇ 0.1, 17.0 ⁇ 0.1, 20.4 ⁇ 0.1, 21.5 ⁇ 0.1, 22.3 ⁇ 0.1, and 25.5 ⁇ 0.1 °2 ⁇ (e.g., 5.1, 17.0, 20.4, 21.5, 22.3, and 25.5 °2 ⁇ )) using Cu K ⁇ radiation.
• Form I is characterized by an XRPD pattern substantially similar to that shown in FIG.9.
• Form I is characterized by an XRPD pattern comprising peaks at approximately the positions shown in the table below. It is understood that the values in the table are approximate and subject to instrumental and experimental variations.
• Table 9 XRPD peak list for Form I Form J
• the morphic form is Form J of Compound No. 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof.
• the morphic form is Form J of the hydrate of Compound No.1.
• the morphic form is Form J of Compound No.1.
• the present disclosure provides a form of Compound No.
• Form J characterized by an X-ray diffraction (“XRPD”) pattern comprising peaks at 4.5 ⁇ 0.2, 17.9 ⁇ 0.2, and 22.5 ⁇ 0.2 °2 ⁇ (e.g., 4.5 ⁇ 0.1, 17.9 ⁇ 0.1, and 22.5 ⁇ 0.1 °2 ⁇ (e.g., 4.5, 17.9, and 22.5 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• the XRPD pattern of Form J further comprises at least one peak selected from 5.1 ⁇ 0.2, 10.4 ⁇ 0.2, and 16.0 ⁇ 0.2 °2 ⁇ (e.g., 5.1 ⁇ 0.1, 10.4 ⁇ 0.1, and 16.0 ⁇ 0.1 °2 ⁇ (e.g., 5.1, 10.4, and 16.0 °2 ⁇ )) using Cu K ⁇ radiation.
• 5.1 ⁇ 0.2, 10.4 ⁇ 0.2, and 16.0 ⁇ 0.2 °2 ⁇ e.g., 5.1 ⁇ 0.1, 10.4 ⁇ 0.1, and 16.0 ⁇ 0.1 °2 ⁇ (e.g., 5.1, 10.4, and 16.0 °2 ⁇ )
• the XRPD pattern of Form J further comprises at least two peaks selected from 5.1 ⁇ 0.2, 10.4 ⁇ 0.2, and 16.0 ⁇ 0.2 °2 ⁇ (e.g., 5.1 ⁇ 0.1, 10.4 ⁇ 0.1, and 16.0 ⁇ 0.1 °2 ⁇ (e.g., 5.1, 10.4, and 16.0 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form J further comprises peaks at 5.1 ⁇ 0.2, 10.4 ⁇ 0.2, and 16.0 ⁇ 0.2 °2 ⁇ (e.g., 5.1 ⁇ 0.1, 10.4 ⁇ 0.1, and 16.0 ⁇ 0.1 °2 ⁇ (e.g., 5.1, 10.4, and 16.0 °2 ⁇ )) using Cu K ⁇ radiation.
• the present disclosure provides a form of Compound No. 1 (“Form J”) characterized by an X-ray diffraction (“XRPD”) pattern comprising at least three peaks selected from 4.5 ⁇ 0.2, 5.1 ⁇ 0.2, 10.4 ⁇ 0.2, 16.0 ⁇ 0.2, 17.9 ⁇ 0.2, and 22.5 ⁇ 0.2 °2 ⁇ (e.g., 4.5 ⁇ 0.1, 5.1 ⁇ 0.1, 10.4 ⁇ 0.1, 16.0 ⁇ 0.1, 17.9 ⁇ 0.1, and 22.5 ⁇ 0.1 °2 ⁇ (e.g., 4.5, 5.1, 10.4, 16.0, 17.9, and 22.5 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• the XRPD pattern of Form J comprises at least four peaks selected from 4.5 ⁇ 0.2, 5.1 ⁇ 0.2, 10.4 ⁇ 0.2, 16.0 ⁇ 0.2, 17.9 ⁇ 0.2, and 22.5 ⁇ 0.2 °2 ⁇ (e.g., 4.5 ⁇ 0.1, 5.1 ⁇ 0.1, 10.4 ⁇ 0.1, 16.0 ⁇ 0.1, 17.9 ⁇ 0.1, and 22.5 ⁇ 0.1 °2 ⁇ (e.g., 4.5, 5.1, 10.4, 16.0, 17.9, and 22.5 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form J comprises at least five peaks selected from 4.5 ⁇ 0.2, 5.1 ⁇ 0.2, 10.4 ⁇ 0.2, 16.0 ⁇ 0.2, 17.9 ⁇ 0.2, and 22.5 ⁇ 0.2 °2 ⁇ (e.g., 4.5 ⁇ 0.1, 5.1 ⁇ 0.1, 10.4 ⁇ 0.1, 16.0 ⁇ 0.1, 17.9 ⁇ 0.1, and 22.5 ⁇ 0.1 °2 ⁇ (e.g., 4.5, 5.1, 10.4, 16.0, 17.9, and 22.5 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form J comprises peaks at 4.5 ⁇ 0.2, 5.1 ⁇ 0.2, 10.4 ⁇ 0.2, 16.0 ⁇ 0.2, 17.9 ⁇ 0.2, and 22.5 ⁇ 0.2 °2 ⁇ (e.g., 4.5 ⁇ 0.1, 5.1 ⁇ 0.1, 10.4 ⁇ 0.1, 16.0 ⁇ 0.1, 17.9 ⁇ 0.1, and 22.5 ⁇ 0.1 °2 ⁇ (e.g., 4.5, 5.1, 10.4, 16.0, 17.9, and 22.5 °2 ⁇ )) using Cu K ⁇ radiation.
• Form J is characterized by an XRPD pattern substantially similar to that shown in FIG.10.
• Form J is characterized by an XRPD pattern comprising peaks at approximately the positions shown in the table below. It is understood that the values in the table are approximate and subject to instrumental and experimental variations.
• Table 10 XRPD peak list for Form J Differential Scanning Calorimeter (DSC) Characterizations [0217] In some embodiments, Form J of Compound No.
• ⁇ 1 is characterized by a DSC curve having at least one endothermic peak selected from 137 ⁇ 20 and 166 ⁇ 20 °C (e.g., 137 ⁇ 10 and 166 ⁇ 10 °C (e.g., 137 ⁇ 5 and 166 ⁇ 5 °C (e.g., 137 ⁇ 4 and 166 ⁇ 4 °C (e.g., 137 ⁇ 3 and 166 ⁇ 3 °C (e.g., 137 ⁇ 2 and 166 ⁇ 2 °C (e.g., 137 ⁇ 1 and 166 ⁇ 1 °C (e.g., 137 ⁇ 0.5 and 166 ⁇ 0.5 °C))))))))))).
• 137 ⁇ 20 and 166 ⁇ 20 °C e.g., 137 ⁇ 10 and 166 ⁇ 10 °C (e.g., 137 ⁇ 5 and 166 ⁇ 5 °C (e.g., 137
• Form J of Compound No. 1 is characterized by a DSC curve having endothermic peaks at 137 ⁇ 20 and 166 ⁇ 20 °C (e.g., 137 ⁇ 10 and 166 ⁇ 10 °C (e.g., 137 ⁇ 5 and 166 ⁇ 5 °C (e.g., 137 ⁇ 4 and 166 ⁇ 4 °C (e.g., 137 ⁇ 3 and 166 ⁇ 3 °C (e.g., 137 ⁇ 2 and 166 ⁇ 2 °C (e.g., 137 ⁇ 1 and 166 ⁇ 1 °C (e.g., 137 ⁇ 0.5 and 166 ⁇ 0.5 °C)))))))).
• 137 ⁇ 20 and 166 ⁇ 20 °C e.g., 137 ⁇ 10 and 166 ⁇ 10 °C (e.g., 137 ⁇ 5 and 166 ⁇ 5 °C (e.g., 137 ⁇
• Form J of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 137 °C. In some embodiments, Form J of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 166 °C.
• Thermogravimetric Analysis (TGA) Characterizations [0220] In some embodiments, Form J of Compound No.
• Form J of Compound No. 1 shows a weight loss of approximately 1.1% between about 33 °C and about 75 °C, as measured by TGA.
• Form J of Compound No. 1 shows a weight loss of approximately 6-8% between about 75 ⁇ 20 °C (e.g., 75 ⁇ 10 °C (e.g., 75 ⁇ 5 °C (e.g., 75 ⁇ 4 °C (e.g., 75 ⁇ 3 °C (e.g., 75 ⁇ 2 °C (e.g., 75 ⁇ 1 °C (e.g., 75 ⁇ 0.5 °C)))))))))))))))))))))))))))))))))))))))))))))) and about 175 ⁇ 20 °C (e.g., 175 ⁇ 10 °C (e.g., 175 ⁇ 5 °C (e.g., 175 ⁇ 4 °C
• Form J of Compound No. 1 shows a weight loss of approximately 7.0% between about 75 °C and about 175 °C, as measured by TGA.
• Form J of Compound No. 1 shows a weight loss of approximately 7-10% between about 33 ⁇ 20 °C (e.g., 33 ⁇ 10 °C (e.g., 33 ⁇ 5 °C (e.g., 33 ⁇ 4 °C (e.g., 33 ⁇ 3 °C (e.g., 33 ⁇ 2 °C (e.g., 33 ⁇ 1 °C (e.g., 33 ⁇ 0.5 °C))))))))))))))))))))))))))))))))))))))))))))))))))))) and about 175 ⁇ 20 °C (e.g., 175 ⁇ 10 °C (e.g., 175 ⁇ 5 °C (e.g.
• Form J of Compound No. 1 shows a weight loss of approximately 8.2% between about 33 °C and about 175 °C, as measured by TGA.
• Form K X-Ray Powder Diffraction (XRPD) Characterization [0226] In some embodiments, the morphic form is Form K of Compound No. 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof. [0227] In some embodiments, the morphic form is Form K of Compound No.1. [0228] In some embodiments, the present disclosure provides a form of Compound No.
• Form K characterized by an X-ray diffraction (“XRPD”) pattern comprising peaks at 5.2 ⁇ 0.2, 17.0 ⁇ 0.2, and 20.5 ⁇ 0.2 °2 ⁇ (e.g., 5.2 ⁇ 0.1, 17.0 ⁇ 0.1, and 20.5 ⁇ 0.1 °2 ⁇ (e.g., 5.2, 17.0, and 20.5 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• the XRPD pattern of Form K further comprises at least one peak selected from 6.8 ⁇ 0.2, 21.6 ⁇ 0.2, and 22.4 ⁇ 0.2 °2 ⁇ (e.g., 6.8 ⁇ 0.1, 21.6 ⁇ 0.1, and 22.4 ⁇ 0.1 °2 ⁇ (e.g., 6.8, 21.6, and 22.4 °2 ⁇ )) using Cu K ⁇ radiation.
• 6.8 ⁇ 0.1, 21.6 ⁇ 0.1, and 22.4 ⁇ 0.1 °2 ⁇ e.g., 6.8, 21.6, and 22.4 °2 ⁇
• the XRPD pattern of Form K further comprises at least two peaks selected from 6.8 ⁇ 0.2, 21.6 ⁇ 0.2, and 22.4 ⁇ 0.2 °2 ⁇ (e.g., 6.8 ⁇ 0.1, 21.6 ⁇ 0.1, and 22.4 ⁇ 0.1 °2 ⁇ (e.g., 6.8, 21.6, and 22.4 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form K further comprises peaks at 6.8 ⁇ 0.2, 21.6 ⁇ 0.2, and 22.4 ⁇ 0.2 °2 ⁇ (e.g., 6.8 ⁇ 0.1, 21.6 ⁇ 0.1, and 22.4 ⁇ 0.1 °2 ⁇ (e.g., 6.8, 21.6, and 22.4 °2 ⁇ )) using Cu K ⁇ radiation.
• the present disclosure provides a form of Compound No. 1 (“Form K”) characterized by an X-ray diffraction (“XRPD”) pattern comprising at least three peaks selected from 5.2 ⁇ 0.2, 6.8 ⁇ 0.2, 17.0 ⁇ 0.2, 20.5 ⁇ 0.2, 21.6 ⁇ 0.2, and 22.4 ⁇ 0.2 °2 ⁇ (e.g., 5.2 ⁇ 0.1, 6.8 ⁇ 0.1, 17.0 ⁇ 0.1, 20.5 ⁇ 0.1, 21.6 ⁇ 0.1, and 22.4 ⁇ 0.1 °2 ⁇ (e.g., 5.2, 6.8, 17.0, 20.5, 21.6, and 22.4 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• the XRPD pattern of Form K comprises at least four peaks selected from 5.2 ⁇ 0.2, 6.8 ⁇ 0.2, 17.0 ⁇ 0.2, 20.5 ⁇ 0.2, 21.6 ⁇ 0.2, and 22.4 ⁇ 0.2 °2 ⁇ (e.g., 5.2 ⁇ 0.1, 6.8 ⁇ 0.1, 17.0 ⁇ 0.1, 20.5 ⁇ 0.1, 21.6 ⁇ 0.1, and 22.4 ⁇ 0.1 °2 ⁇ (e.g., 5.2, 6.8, 17.0, 20.5, 21.6, and 22.4 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form K comprises at least five peaks selected from 5.2 ⁇ 0.2, 6.8 ⁇ 0.2, 17.0 ⁇ 0.2, 20.5 ⁇ 0.2, 21.6 ⁇ 0.2, and 22.4 ⁇ 0.2 °2 ⁇ (e.g., 5.2 ⁇ 0.1, 6.8 ⁇ 0.1, 17.0 ⁇ 0.1, 20.5 ⁇ 0.1, 21.6 ⁇ 0.1, and 22.4 ⁇ 0.1 °2 ⁇ (e.g., 5.2, 6.8, 17.0, 20.5, 21.6, and 22.4 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form K comprises peaks at 5.2 ⁇ 0.2, 6.8 ⁇ 0.2, 17.0 ⁇ 0.2, 20.5 ⁇ 0.2, 21.6 ⁇ 0.2, and 22.4 ⁇ 0.2 °2 ⁇ (e.g., 5.2 ⁇ 0.1, 6.8 ⁇ 0.1, 17.0 ⁇ 0.1, 20.5 ⁇ 0.1, 21.6 ⁇ 0.1, and 22.4 ⁇ 0.1 °2 ⁇ (e.g., 5.2, 6.8, 17.0, 20.5, 21.6, and 22.4 °2 ⁇ )) using Cu K ⁇ radiation.
• Form K is characterized by an XRPD pattern substantially similar to that shown in FIG.11.
• Form K is characterized by an XRPD pattern comprising peaks at approximately the positions shown in the table below. It is understood that the values in the table are approximate and subject to instrumental and experimental variations.
• Table 11 XRPD peak list for Form K
• XRPD X-Ray Powder Diffraction
• the morphic form is Form L of Compound No. 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof.
• the morphic form is Form L of Compound No.1.
• the present disclosure provides a form of Compound No.
• Form L characterized by an X-ray diffraction (“XRPD”) pattern comprising peaks at 5.4 ⁇ 0.2, 7.8 ⁇ 0.2, and 19.3 ⁇ 0.2 °2 ⁇ (e.g., 5.4 ⁇ 0.1, 7.8 ⁇ 0.1, and 19.3 ⁇ 0.1 °2 ⁇ (e.g., 5.4, 7.8, and 19.3 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• the XRPD pattern of Form L further comprises at least one peak selected from 14.8 ⁇ 0.2, 15.3 ⁇ 0.2, and 16.6 ⁇ 0.2 °2 ⁇ (e.g., 14.8 ⁇ 0.1, 15.3 ⁇ 0.1, and 16.6 ⁇ 0.1 °2 ⁇ (e.g., 14.8, 15.3, and 16.6 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form L further comprises at least two peaks selected from 14.8 ⁇ 0.2, 15.3 ⁇ 0.2, and 16.6 ⁇ 0.2 °2 ⁇ (e.g., 14.8 ⁇ 0.1, 15.3 ⁇ 0.1, and 16.6 ⁇ 0.1 °2 ⁇ (e.g., 14.8, 15.3, and 16.6 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form L further comprises peaks at 14.8 ⁇ 0.2, 15.3 ⁇ 0.2, and 16.6 ⁇ 0.2 °2 ⁇ (e.g., 14.8 ⁇ 0.1, 15.3 ⁇ 0.1, and 16.6 ⁇ 0.1 °2 ⁇ (e.g., 14.8, 15.3, and 16.6 °2 ⁇ )) using Cu K ⁇ radiation.
• the present disclosure provides a form of Compound No.
• Form L characterized by an X-ray diffraction (“XRPD”) pattern comprising at least three peaks selected from 5.4 ⁇ 0.2, 7.8 ⁇ 0.2, 14.8 ⁇ 0.2, 15.3 ⁇ 0.2, 16.6 ⁇ 0.2, and 19.3 ⁇ 0.2 °2 ⁇ (e.g5.4 ⁇ 0.1, 7.8 ⁇ 0.1, 14.8 ⁇ 0.1, 15.3 ⁇ 0.1, 16.6 ⁇ 0.1, and 19.3 ⁇ 0.1 °2 ⁇ (e.g., 5.4, 7.8, 14.8, 15.3, 16.6, and 19.3 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• the XRPD pattern of Form L comprises at least four peaks selected from 5.4 ⁇ 0.2, 7.8 ⁇ 0.2, 14.8 ⁇ 0.2, 15.3 ⁇ 0.2, 16.6 ⁇ 0.2, and 19.3 ⁇ 0.2 °2 ⁇ (e.g5.4 ⁇ 0.1, 7.8 ⁇ 0.1, 14.8 ⁇ 0.1, 15.3 ⁇ 0.1, 16.6 ⁇ 0.1, and 19.3 ⁇ 0.1 °2 ⁇ (e.g., 5.4, 7.8, 14.8, 15.3, 16.6, and 19.3 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form L comprises at least five peaks selected from 5.4 ⁇ 0.2, 7.8 ⁇ 0.2, 14.8 ⁇ 0.2, 15.3 ⁇ 0.2, 16.6 ⁇ 0.2, and 19.3 ⁇ 0.2 °2 ⁇ (e.g5.4 ⁇ 0.1, 7.8 ⁇ 0.1, 14.8 ⁇ 0.1, 15.3 ⁇ 0.1, 16.6 ⁇ 0.1, and 19.3 ⁇ 0.1 °2 ⁇ (e.g., 5.4, 7.8, 14.8, 15.3, 16.6, and 19.3 °2 ⁇ )) using Cu K ⁇ radiation.
• the XRPD pattern of Form L comprises peaks at 5.4 ⁇ 0.2, 7.8 ⁇ 0.2, 14.8 ⁇ 0.2, 15.3 ⁇ 0.2, 16.6 ⁇ 0.2, and 19.3 ⁇ 0.2 °2 ⁇ (e.g5.4 ⁇ 0.1, 7.8 ⁇ 0.1, 14.8 ⁇ 0.1, 15.3 ⁇ 0.1, 16.6 ⁇ 0.1, and 19.3 ⁇ 0.1 °2 ⁇ (e.g., 5.4, 7.8, 14.8, 15.3, 16.6, and 19.3 °2 ⁇ )) using Cu K ⁇ radiation.
• Form L is characterized by an XRPD pattern substantially similar to that shown in FIG.12.
• Form L is characterized by an XRPD pattern comprising peaks at approximately the positions shown in the table below. It is understood that the values in the table are approximate and subject to instrumental and experimental variations. Table 12: XRPD peak list for Form L
• the present disclosure features a method of preparing a crystalline form of Compound No.1 or a pharmaceutically acceptable salt thereof.
• the present disclosure provides a method of preparing a crystalline form of Compound No. 1 or a pharmaceutically acceptable salt thereof, comprising one or more steps as described herein.
• the present disclosure provides a compound obtainable by, or obtained by, or directly obtained by a method for preparing a crystalline form of Compound No. 1 or a pharmaceutically acceptable salt thereof.
• the crystalline form of Compound No. 1 or the pharmaceutically acceptable salt thereof can be prepared by any suitable technique known in the art.
• compositions comprising a morphic form of Compound No. 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof described herein, and one or more pharmaceutically acceptable carriers or excipients.
• the pharmaceutical compositions containing active compounds of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes.
• compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen.
• Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
• suitable carriers include physiological saline, bacteriostatic water, Cremophor EL ⁇ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS).
• the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
• the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
• Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
• isotonic agents for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition.
• Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
• Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
• dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
• methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
• Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier.
• compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed.
• Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
• the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
• a binder such as microcrystalline cellulose, gum tragacanth or gelatin
• an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
• a lubricant such as magnesium stearate or Sterotes
• a glidant such as colloidal silicon dioxide
• the compounds are delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
• a suitable propellant e.g., a gas such as carbon dioxide, or a nebulizer.
• Systemic administration can also be by transmucosal or transdermal means.
• penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
• Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
• the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.
• the active compounds can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
• Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
• Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
• the specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.
• the dosages of the pharmaceutical compositions used in accordance with the disclosure vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage.
• the dose should be sufficient to result in slowing, and preferably regressing, the symptoms of the disease and also preferably causing complete regression of the disease.
• the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.
• Methods of Use [0265] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject, comprising administering to the subject a pharmaceutically effective amount of a form of Compound No. 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof. [0266] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject, comprising administering to the subject a pharmaceutically effective amount of a form of Compound No.
• the present disclosure provides a form of Compound No. 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof for use in treating or preventing cancer in a subject.
• the present disclosure provides a form of Compound No.1 (e.g., Form A, Form, B, Form C, Form, D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, or Form L), the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof for use in treating or preventing cancer in a subject.
• the present disclosure provides use of a form of Compound No. 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing cancer in a subject.
• the present disclosure provides use of a form of Compound No.
• Form A of Compound No. 1 e.g., Form A, Form, B, Form C, Form, D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, or Form L
• Form A of Compound No. 1 is administered.
• Form B of Compound No. 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof is administered.
• Form D of Compound No. 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof is administered.
• Form E of Compound No. 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof is administered.
• Form F of Compound No. 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof is administered.
• Form G of Compound No. 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof is administered.
• Form I of Compound No. 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof is administered.
• Form J of Compound No. 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof is administered.
• Form K of Compound No. 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof is administered.
• Form L of Compound No. 1, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof is administered.
• the subject is a mammal.
• the subject is a human.
• the subject is a mouse.
• the compounds of the disclosure inhibit or modulate the activity of a receptor tyrosine kinase, in particular extracellular mutants of ErbB-receptors, such as, but not limited to, EGFR- Viii, EGFR-Vii, EGFR-Vvi, EGFR-A289V and EGFR-G598V and HER2-S310F.
• a receptor tyrosine kinase in particular extracellular mutants of ErbB-receptors, such as, but not limited to, EGFR- Viii, EGFR-Vii, EGFR-Vvi, EGFR-A289V and EGFR-G598V and HER2-S310F.
• the compounds and compositions of the disclosure can be useful as a medicament, i.e.
• the present disclosure provides a method of prevention or treatment of a mammal, for example, a human, suffering from cancer, as detailed below.
• prevention refers to reducing or eliminating the onset of the symptoms or complications of a disease (e.g., cancer).
• Such prevention comprises the step of administering a therapeutically effective amount of a compound of Formula I or salt thereof (or of a pharmaceutical composition containing a compound of Formula I or salt thereof) to said mammal, for example, a human.
• treatment or “treating” is intended to encompass therapy and cure.
• Such treatment comprises the step of administering a therapeutically effective amount of a compound of Formula I or salt thereof (or of a pharmaceutical composition containing a compound of Formula I or salt thereof) to said mammal, for example, a human.
• a therapeutically effective amount of a compound of Formula I or salt thereof or of a pharmaceutical composition containing a compound of Formula I or salt thereof
• the disclosure provides the use of the compounds of the disclosure or pharmaceutically acceptable salts or stereoisomers thereof or a pharmaceutical composition thereof for the prevention or treatment of cancer, as detailed below, in a mammal, for example a human.
• the present disclosure is directed to a method of inhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of an EGFR), comprising administering the subject in need thereof a therapeutically effective amount of a compound described herein.
• the present disclosure is directed to a method of inhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of an EGFR), comprising administering the subject in need thereof a composition described herein.
• an oncogenic variant of an ErbB receptor e.g., an oncogenic variant of an EGFR
• the present disclosure is directed to a method of preventing or treating cancer, comprising administering the subject in need thereof a therapeutically effective amount of a compound described herein.
• the present disclosure is directed to a method of preventing or treating cancer, comprising administering the subject in need thereof a composition described herein.
• the present disclosure is directed to a compound described herein for use in the inhibition of an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of an EGFR).
• an oncogenic variant of an ErbB receptor e.g., an oncogenic variant of an EGFR
• the present disclosure is directed to a compound described herein for use in the prevention or treatment of cancer.
• the present disclosure is directed to a composition described herein for use in the inhibition of an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of an EGFR).
• the present disclosure is directed to a composition described herein for use in the prevention or treatment of cancer.
• the present disclosure is directed to use of a compound described herein in the manufacture of a medicament for inhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of an EGFR).
• an oncogenic variant of an ErbB receptor e.g., an oncogenic variant of an EGFR
• the present disclosure is directed to use of a compound described herein in the manufacture of a medicament for preventing or treating cancer.
• the compound is selected from the compounds described in Tables 1 and 2, pharmaceutically acceptable salts thereof, and stereoisomers thereof.
• the compound is selected from the compounds described in Tables 1 and 2 and pharmaceutically acceptable salts thereof.
• the compound is selected from the compounds described in Tables 1 and 2.
• cancer is a solid tumor.
• the cancer is a bladder cancer, a breast cancer, a cervical cancer, a colorectal cancer, an endometrial cancer, a gastric cancer, a glioblastoma (GBM), a head and neck cancer, a lung cancer, a non-small cell lung cancer (NSCLC), or any subtype thereof.
• the cancer is glioblastoma (GBM) or any subtype thereof.
• the cancer is glioblastoma.
• the cancer, or a tumor or a cell thereof expresses an oncogenic variant of an ErbB receptor.
• the oncogenic variant of the ErbB receptor comprises an allosteric mutation.
• the oncogenic variant of an ErbB receptor is is an allosteric variant of the ErbB receptor.
• the ErbB receptor is an an epidermal growth factor receptor (EGFR) or a human epidermal growth factor receptor 2 (HER2) receptor.
• the ErbB receptor is an epidermal growth factor receptor (EGFR).
• the ErbB receptor is a HER2 receptor.
• the cancer, or a tumor or a cell thereof expresses an oncogenic variant of an epidermal growth factor receptor (EGFR).
• EGFR epidermal growth factor receptor
• the oncogenic variant of EGFR is an allosteric variant of EGFR.
• the oncogenic variant of EGFR comprises an allosteric mutation.
• the cancer, or a tumor or a cell thereof expresses an oncogenic variant of a HER2 receptor.
• the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor.
• the oncogenic variant of the HER2 receptor comprises an allosteric mutation.
• the oncogenic variant of an EGFR comprises an EGFR variant III (EGFR-Viii) mutation.
• the oncogenic variant of EGFR comprises an EGFR variant II (EGFR-Vii) mutation.
• the oncogenic variant of EGFR comprises an EGFR variant VI (EGFR-Vvi) mutation.
• the oncogenic variant of an EGFR comprises a substitution of a valine (V) for an alanine (A) at position 289 of SEQ ID NO: 1.
• the oncogenic variant of EGFR comprises a substitution of a valine (V) for a glycine (G) at position 598 of SEQ ID NO: 1.
• the cancer, or a tumor or a cell thereof expresses an oncogenic variant of an EGFR and wherein the oncogenic variant of EGFR is an allosteric variant of EGFR, the oncogenic variant of an EGFR comprises a modification of a structure of the EGFR, wherein the oncogenic variant of an EGFR is a capable of forming a covalently linked dimer, wherein the covalently linked dimer is constitutively active and wherein the covalently linked dimer enhances an activity of EGFR when contacted to a Type I ErbB inhibitor.
• the modification of the structure of the EGFR comprises a modification of one or more of a nucleic acid sequence, an amino acid sequence, a secondary structure, a tertiary structure, and a quaternary structure.
• the oncogenic variant comprises a mutation, a splicing event, a post-translational process, a conformational change or any combination thereof.
• the modification of the structure of the EGFR occurs within a first cysteine rich (CR1) and/or second cysteine rich (CR2) region of EGFR.
• the first cysteine rich (CR1) and/or second cysteine rich (CR2) region of EGFR comprises amino acid residues T211-R334 and/or C526-S645 of SEQ ID NO: 1, respectively.
• the oncogenic variant of an EGFR generates a physical barrier to formation of a disulfide bond within the CR1 and/or the CR2 region. In some embodiments, the oncogenic variant of an EGFR removes a physical barrier to formation of a disulfide bond within the CR1 and/or the CR2 region.
• the oncogenic variant of an EGFR comprises one or more free or unpaired Cysteine (C) residues located at a dimer interface of the EGFR. In some embodiments, the oncogenic variant of an EGFR comprises one or more free or unpaired Cysteine (C) residues at a site selected from the group consisting of C190-C199, C194-C207, C215-C223, C219-C231, C232-C240, C236-C248, C251-C260, C264-C291, C295-C307, C311-C326, C329-C333, C506- C515, C510-C523, C526-C535, C539-C555, C558-C571, C562-C579, C582-C591, C595-C617, C620-C628 and C624-C636 according to SEQ ID NO: 1.
• the modification occurs within 10 angstroms or less of an intramolecular disulfide bond at a site selected from the group consisting of C190-C199, C194-C207, C215-C223, C219-C231, C232-C240, C236-C248, C251-C260, C264-C291, C295-C307, C311-C326, C329-C333, C506-C515, C510-C523, C526- C535, C539-C555, C558-C571, C562-C579, C582-C591, C595-C617, C620-C628 and C624- C636 according to SEQ ID NO: 1.
• the cancer, or a tumor or a cell thereof expresses an oncogenic variant of EGFR and the oncogenic variant of EGFR is a mutation of EGFR, a nucleotide sequence encoding the oncogenic variant of an EGFR comprises a deletion or the substitution comprises one or more amino acids that encode an adenosine triphosphate (ATP) binding site.
• the ATP binding site comprises amino acids E746 to A750 of SEQ ID NO: 1.
• the ATP binding site or the deletion or substitution thereof comprises K858 of SEQ ID NO: 1.
• the deletion comprises K858 of SEQ ID NO: 1.
• an arginine (R) is substituted for the lysine (K) at position 858 (K858R) of SEQ ID NO: 1.
• the cancer, or a tumor or a cell thereof expresses an oncogenic variant of an EGFR and wherein the oncogenic variant of EGFR is an allosteric variant of EGFR, a nucleotide sequence encoding the oncogenic variant of an EGFR comprises an insertion within a sequence encoding exon 20 or a portion thereof.
• the sequence encoding exon 20 or a portion thereof comprises a sequence encoding KEILDEAYVMASVDNPHVCAR (SEQ ID NO: 7).
• the sequence encoding exon 20 or a portion thereof comprises a sequence encoding a C-helix, a terminal end of the C-helix or a loop following the C- helix.
• the insertion comprises the amino acid sequence of ASV, SVD, NPH, or FQEA.
• the sequence encoding exon 20 or a portion thereof comprises one or more of: (a) an insertion of the amino acid sequence ASV between positions V769 and D770 of SEQ ID NO: 1; (b) an insertion of the amino acid sequence SVD between positions D770 and N771 of SEQ ID NO: 1; (c) an insertion of the amino acid sequence NPH between positions H773 and V774 of SEQ ID NO: 1; (d) an insertion of the amino acid sequence FQEA between positions A763 and Y764 of SEQ ID NO: 1; (e) an insertion of the amino acid sequence PH between positions H773 and V774 of SEQ ID NO: 1; (f) an insertion of the amino acid G between positions D770 and N771 of SEQ ID NO: 1; (g) an insertion of the amino acid H between positions H773 and V774 of SEQ ID NO: 1; (h) an insertion of the amino acid sequence HV between positions V774 and C775 of S
• the cancer, or a tumor or a cell thereof expresses an oncogenic variant of an EGFR and wherein the oncogenic variant of EGFR is an allosteric variant of EGFR, the oncogenic variant of an EGFR comprises EGFR-Vii, EGFR-Vvi, EGFR-R222C, EGFR- R252C, EGFR-R252P, EGFR-R256Y, EGFR-T263P, EGFR-Y270C, EGFR-A289T, EGFR- A289V, EGFR-A289D, EGFR-H304Y, EGFR-G331R, EGFR-P596S, EGFR-P596L, EGFR- P596R, EGFR-G598V, EGFR-G598A, EGFR-G614D, EGFR-C620Y, EGFR-C614W, EGFR-
• the cancer, or a tumor or a cell thereof expresses one or more of: (a) a wild type human epidermal growth factor receptor 2 (HER2) receptor or an oncogenic variant of a HER-2 receptor.
• HER2 human epidermal growth factor receptor 2
• the cancer, or a tumor or a cell thereof expresses a wild type HER- 2 receptor, the wild type HER2 receptor comprises the amino acid sequence of SEQ ID NO: 2, 3, 4, 5, or 6.
• the cancer, or a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor, the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor.
• the cancer, or a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a phenylalanine (F) for a serine (S) at position 310 of SEQ ID NO: 2 or 5.
• F phenylalanine
• S serine
• the cancer, or a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a tyrosine (Y) for a serine (S) at position 310 of SEQ ID NO: 2 or 5.
• the cancer, or a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a glutamine (Q) for an arginine (R) at position 678 of SEQ ID NO: 2 or 5.
• the cancer, or a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a leucine (L) for a valine (V) at position 777 of SEQ ID NO: 2 or 5.
• the cancer, or a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a methionine (M) for a valine (V) at position 777 of SEQ ID NO: 2 or 5.
• M methionine
• V valine
• the cancer, or a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of an isoleucine (I) for a valine (V) at position 842 of SEQ ID NO: 2 or 5.
• the cancer, or a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of an alanine (A) for a leucine (L) at position 755 of SEQ ID NO: 2 or 5.
• the cancer, or a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a proline (P) for a leucine (L) at position 755 of SEQ ID NO: 2 or 5.
• the cancer, or a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises a substitution of a serine (S) for a leucine (L) at position 755 of SEQ ID NO: 2 or 5.
• the cancer, or a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, a nucleotide sequence encoding the oncogenic variant of a HER2 receptor comprises an insertion within a sequence encoding exon 20 or a portion thereof.
• the sequence encoding exon 20 or a portion thereof comprises a sequence encoding KEILDEAYVMAGVGSPYVSR(SEQ ID NO: 8).
• the sequence encoding exon 20 or a portion thereof comprises a sequence encoding a C-helix, a terminal end of the C- helix or a loop following the C-helix.
• the insertion comprises the amino acid sequence of GSP or YVMA.
• the sequence encoding exon 20 or a portion thereof comprises one or more of: (a) an insertion of the amino acid sequence YVMA between positions A775 and G776 of SEQ ID NO: 2; (b) an insertion of the amino acid sequence GSP between positions P780 and Y781 of SEQ ID NO: 2; (c) an insertion of the amino acid sequence YVMA between positions A771 and Y772 of SEQ ID NO: 2; (d) an insertion of the amino acid sequence YVMA between positions A775 and G776 of SEQ ID NO: 2; (e) an insertion of the amino acid V between positions V777 and G778 of SEQ ID NO: 2; (f) an insertion of the amino acid V between positions V777 and G778 of SEQ ID NO: 2; (g) a substitution of the amino acid sequence AVGCV for the GV between positions 776 and 777 of SEQ ID NO: 2; (h) a substitution of the amino acid sequence LC for the G
• the cancer, or a tumor or a cell thereof expresses an oncogenic variant of a HER-2 receptor and wherein the oncogenic variant of a HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of a HER2 receptor comprises HER2- 16, HER2-C311R, HER2-S310F, p95-HER2-M611 or any combination thereof.
• the cancer, or a tumor or a cell thereof expresses an oncogenic variant of a HER-4 receptor.
• the oncogenic variant of the HER-4 receptor is an allosteric variant of the HER4 receptor.
• the oncogenic variant of a HER4 receptor comprises deletion of exon 16 (HER4- ⁇ 16).
• the cancer, or a tumor or a cell thereof expresses an oncogenic variant of an EGFR, wherein the sequence encoding the oncogenic variant of the EGFR comprises a deletion of exon 20 or a portion thereof and wherein the the cancer, the tumor or the cell thereof does not comprise a second oncogenic variation in a sequence other than exon 20 of EGFR.
• the second oncogenic variation comprises a sequence encoding one or more of an EGFR kinase domain (KD), BRAF, NTRK, and KRAS.
• the cancer, or a tumor or a cell thereof expresses an oncogenic variant of an EGFR, wherein the sequence encoding the oncogenic variant of the EGFR comprises a deletion of exon 20 or a portion thereof and wherein the the cancer, the tumor or the cell thereof does not comprise a marker indicating responsiveness to immunotherapy.
• the oncogenic variant e.g., allosteric variant
• the oncogenic mutation e.g., allosteric mutation
• FDA Food and Drug Aministration
• the subject prior to the treatment with the compound of the present disclosure, is treated with a therapeutic agent different from the compound of the present disclosure.
• the cancer, or a tumor or a cell thereof is insensitive or resistant to treatment with a therapeutic agent different from the compound of the present disclosure.
• the cancer, or a tumor or a cell thereof is insensitive or resistant to treatment with a Type I inhibitor.
• the cancer, or a tumor or a cell thereof is insensitive or resistant to treatment with one or more of gefinitinib, erlotinib, afatinib, osimertinib, necitunumab, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, afatinib, sapitinib, dacomitinib, canertinib, pelitinib, WZ4002, WZ8040, WZ3146, CO-1686 and AZD9291.
• the subject has an adverse reaction to treatment with a therapeutic agent different from the compound of the present disclosure.
• the subject has an adverse reaction to treatment with a Type I inhibitor.
• the subject has an adverse reaction to treatment with one or more of gefinitinib, erlotinib, afatinib, osimertinib, necitunumab, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, afatinib, sapitinib, dacomitinib, canertinib, pelitinib, WZ4002, WZ8040, WZ3146, CO-1686 and AZD9291.
• the adverse reaction is an activation of the oncogenic variant of an EGFR and wherein the oncogenic variant comprises a mutation in an extracellular domain of the receptor. In some embodiments, the adverse reaction is an activation of the oncogenic variant of a HER-2 Receptor and wherein the oncogenic variant comprises a mutation in an extracellular domain of the receptor. [0349] In some embodiments, the method further comprises administering to the subject in need thereof a therapeutically effective amount of a non-Type I inhibitor. In some embodiments, the non-Type I inhibitor comprises a small molecule Type II inhibitor. [0350] In some embodiments, the method further comprises administering to the subject in need thereof a therapeutically effective amount of a non-Type I inhibitor.
• the non-Type I inhibitor comprises a small molecule Type II inhibitor.
• the compound is used in combination with a therapeutically effective amount of a non-Type I inhibitor.
• the non-Type I inhibitor comprises a small molecule Type II inhibitor.
• the composition further comprises a non-Type I inhibitor.
• the non-Type I inhibitor comprises a small molecule Type II inhibitor.
• the therapeutically effective amount reduces a severity of a sign or symptom of the cancer.
• the sign of the cancer comprises a tumor grade and wherein a reduction of the severity of the sign comprises a decrease of the tumor grade.
• the sign of the cancer comprises a tumor metastasis and wherein a reduction of the severity of the sign comprises an elimination of the metastasis or a reduction in the rate or extent the metastasis.
• the sign of the cancer comprises a tumor volume and wherein a reduction of the severity of the sign comprises an elimination of the tumor or a reduction in the volume.
• the symptom of the cancer comprises pain and wherein a reduction of the severity of the sign comprises an elimination or a reduction in the pain.
• the therapeutically effective amount induces a period of remission.
• the therapeutically effective amount improves a prognosis of the subject.
• a use (or method of prevention or treatment) of a subject comprises administering to a subject in need of such prevention or treatment a therapeutically effective amount of a compound of the disclosure or pharmaceutically acceptable salts thereof or a pharmaceutical composition thereof by targeting allosteric and/or oncogenic variants of EGFR and HER-2 receptor.
• Definitions [0361] It is understood that the compounds described herein include the compounds themselves, as well as their salts, and their solvates, if applicable.
• a salt for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted benzene compound.
• Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).
• the terms “approximately” and “about” are synonymous.
• “approximately” and “about” refer to the recited amount, value, dose, or duration ⁇ 20%, ⁇ 15%, ⁇ 10%, ⁇ 8%, ⁇ 6%, ⁇ 5%, ⁇ 4%, ⁇ 2%, ⁇ 1%, or ⁇ 0.5%. In some embodiments, “approximately” and “about” refer to the listed amount or duration ⁇ 10%, ⁇ 8%, ⁇ 6%, ⁇ 5%, ⁇ 4%, or ⁇ 2%. In some embodiments, “approximately” and “about” refer to the listed amount, value, dose, or duration ⁇ 5%.
• “approximately” and “about” refer to the listed amount, value, dose, or duration ⁇ 2%. In some embodiments, “approximately” and “about” refer to the listed amount, value, dose, or duration ⁇ 1%.
• the term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt. Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted benzene compound.
• Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion.
• the substituted benzene compounds also include those salts containing quaternary nitrogen atoms.
• the compounds of the present disclosure can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules.
• Nonlimiting examples of hydrates include monohydrates and dihydrates.
• Nonlimiting examples of solvates include ethanol solvates and acetone solvates.
• the expressions “one or more of A, B, or C,” “one or more A, B, or C,” “one or more of A, B, and C,” “one or more A, B, and C,” “selected from the group consisting of A, B, and C”, “selected from A, B, and C”, and the like are used interchangeably and all refer to a selection from a group consisting of A, B, and/or C, i.e., one or more As, one or more Bs, one or more Cs, or any combination thereof, unless indicated otherwise.
• compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.
• any description of a method of treatment or prevention includes use of a crystalline form of Compound No. 1 or a pharmaceutically acceptable salt thereof to prepare a medicament to treat or prevent such condition.
• the treatment or prevention includes treatment or prevention of human or non-human animals including rodents and other disease models.
• any description of a method of treatment includes use of a crystalline form of Compound No. 1 or a pharmaceutically acceptable salt thereof to provide such treatment as is described herein. It is to be further understood, unless otherwise stated, any description of a method of treatment includes use of a crystalline form of Compound No.
• the term “subject” refers to a subject having a disease or having an increased risk of developing the disease.
• a “subject” includes a mammal.
• the mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig.
• the subject can also be a bird or fowl.
• the mammal is a human.
• the term “subject in need thereof” can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein.
• a subject in need thereof can also be one who is suffering from a disease or disorder disclosed herein.
• a subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large).
• a subject in need thereof can have a refractory or resistant a disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment).
• the subject in need thereof may be resistant at start of treatment or may become resistant during treatment.
• the subject in need thereof received and failed all known effective therapies for a disease or disorder disclosed herein.
• the subject in need thereof received at least one prior therapy.
• treating describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder.
• the term “treat” can also include treatment of a cell in vitro or an animal model.
• a crystalline form of Compound No. 1 or a pharmaceutically acceptable salt thereof can or may also be used to prevent a relevant disease, condition or disorder, or used to identify suitable candidates for such purposes.
• preventing describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.
• solubility refers to the property of a polymorph (e.g., Form A, B, C, D, E, F, G, H, I, J, K, or L) disclosed herein to dissolve in a liquid solvent and form a homogeneous solution.
• solubility is expressed as a concentration, either by mass of solute per unit volume of solvent (e.g., g of solute per kg of solvent, g per dL (100 mL), mg/ml, etc.), molarity, molality, mole fraction, or other similar descriptions of concentration.
• concentration either by mass of solute per unit volume of solvent (e.g., g of solute per kg of solvent, g per dL (100 mL), mg/ml, etc.), molarity, molality, mole fraction, or other similar descriptions of concentration.
• the maximum equilibrium amount of solute that can dissolve per amount of solvent is the solubility of that solute in that solvent under the specified conditions, including temperature, pressure, pH,
• “stable” refers to a polymorph that maintains purity, appearance, and/or analytical parameters over a defined time and temperature as compared to the polymorph as isolated.
• the “stable” polymorph exhibits less than about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% impurity over a set period of time (e.g., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, one week, two weeks, three weeks, one month, two months, three months, or four months).
• the term “pharmaceutical composition” is a formulation containing the compounds of the present disclosure in a form suitable for administration to a subject.
• the pharmaceutical composition is in bulk or in unit dosage form.
• the unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial.
• the quantity of active ingredient (e.g, a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved.
• active ingredient e.g, a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof
• the dosage will also depend on the route of administration.
• routes of administration A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transderrnal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalations!, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like.
• Dosage forms for the topical or transderrnal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
• the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.
• the term “pharmaceutically acceptable” refers to those compounds, anions, cations, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/'risk ratio.
• the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use.
• a “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.
• the term “therapeutically effective amount” refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art.
• the precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.
• the term “pharmaceutically acceptable salts” refer to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof
• the pharmaceutically acceptable salt of a compound is also a. prodrug of the compound.
• pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like.
• the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
• such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxy benzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucolieptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric
• compositions include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-l -carboxylic acid, 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like.
• the present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N- methylglucamine, and the like.
• a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
• an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N- methylglucamine, and the like.
• the ratio of the compound to the cation or anion of the salt can be 1: 1, or any ration other than 1:1, e.g., 3:1, 2: 1, 1:2, or 1:3.
• the compounds, or pharmaceutically acceptable salts thereof are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally.
• the compound is administered orally.
• One skilled in the art will recognize the advantages of certain routes of administration.
• the dosage regimen utilizing the compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient, the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient, and the particular compound or salt thereof employed.
• An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
• the compounds described herein, and the pharmaceutically acceptable salts thereof are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent.
• suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions.
• the compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.
• Embodiment 1 A morphic form of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
• Embodiment 2 The morphic form of embodiment 1, wherein the morphic form is a crystalline form.
• Embodiment 3 The morphic form of embodiment 1 or 2, wherein the morphic form is Form A, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof.
• Embodiment 4. The morphic form of embodiment 3, wherein Form A is characterized by an X-ray diffraction (“XRPD”) pattern comprising peaks at 4.840.2, 5.6.40.2, and 17.640.2 °20 (e.g., 4.840.1, 5.6-40.1, and 17.6 - 0.1 °20 (e.g., 4.8, 5.6, and 17.6 °20)) using Cu Ka radiation.
• XRPD X-ray diffraction
• Embodiment 5 The morphic form of embodiment 4, wherein Form A further comprises at least one peak selected from 9.640.2, 20.040.2, and 24.640.2 °20 (e.g., 9.6 ⁇ 0.1, 20.040.1, and 24.640.1 °20 (e.g., 9.6, 20.0, and 24.6 : 20) ) using Cu Ka radiation.
• 9.640.2, 20.040.2, and 24.640.2 °20 e.g., 9.6 ⁇ 0.1, 20.040.1, and 24.640.1 °20 (e.g., 9.6, 20.0, and 24.6 : 20)
• Embodiment 6 The morphic form of embodiment 3, wherein Form A is characterized by an X-ray diffraction (“XRPD”) patern comprising at least three peaks selected from 4.8.40.2, 5.640.2, 9.640.2, 17.6.40.2, 20.0.0.2. and 24.640.2 °20 (e.g., 4.840.1, 5.640.1, 9.640.1, 17.640.1 , 20.04.0.1, and 24.640.1 °29 (e.g., 4.8, 5.6, 9.6, 17.6, 20.0, and 24.6 °20)) using Cu Ka radiation.
• XRPD X-ray diffraction
• Embodiment ? The morphic form of embodiment 3, wherein Form A is characterized by an XRPD pattern substantially similar to that shown in FIG. 1.
• Embodiment 8 The morphic form of embodiment 3, wherein Form A is characterized by a DSC curve having at least one endothermic peak selected from 76 4 20, 141 4 20, 156 ⁇ 20, and 170 ⁇ 20 °C (e.g., 76 ⁇ 10, 141 ⁇ 10, 156 ⁇ 10, and 170 ⁇ 10 °C (e.g., 76 ⁇ 5, 141 ⁇ 5, 156 ⁇ 5, and 170 ⁇ 5 °C (e.g., 76 ⁇ 4, 141 ⁇ 4, 156 ⁇ 4, and 170 ⁇ 4 °C (e.g., 76 ⁇ 3, 141 ⁇ 3, 156 ⁇ 3, and 170 ⁇ 3 °C (e.g., 76 ⁇ 2, 141 ⁇ 2, 156 ⁇ 2, and 170 ⁇ 2 °C (e.g., 76 ⁇ 1, 141 ⁇ 1, 156 ⁇ 1, and 170 ⁇ 1 °C (e.g., 76 ⁇ 0.5,
• Embodiment 9 The morphic form of embodiment 1 or 2, wherein the morphic form is Form B, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof, [0399] Embodiment 10.
• XRPD X-ray diffraction
• Embodiment 11 The morphic form of embodiment 10, wherein Form B further comprises at least one peak selected from 3.2 ⁇ 0.2, 13.4 ⁇ 0.2, and 17.7 ⁇ 0.2 °20 (e.g., 3.2 ⁇ 0.1, 13.4 ⁇ 0.1, and 17.7 ⁇ 0,l °20 (e.g., 3.2, 13.4, and 17.7 °20)) using Cu Ka radiation.
• Form B further comprises at least one peak selected from 3.2 ⁇ 0.2, 13.4 ⁇ 0.2, and 17.7 ⁇ 0.2 °20 (e.g., 3.2 ⁇ 0.1, 13.4 ⁇ 0.1, and 17.7 ⁇ 0,l °20 (e.g., 3.2, 13.4, and 17.7 °20)) using Cu Ka radiation.
• Embodiment 12 The morphic form of embodiment 9, wherein Form B is characterized by an X-ray diffraction (“XRPD”) pattern comprising at least three peaks selected from 3.2 ⁇ 0.2, 6.5 0.2. 13.4 ⁇ 0.2, 16.7. 6.2. 17 7 - 0 2. and 18.6 ⁇ 0.2 °20 (e.g., 3.2 ⁇ 0.1, 6.5.04. 13.4 ⁇ 0.1, 16.7 ⁇ 0. 1, 17.7 ⁇ 0.1, and 18.6 ⁇ 0.1 °20 (e.g., 3.2, 6.5, 13.4, 16.7, 17.7, and 18.6 °20)) using Cu Ka radiation.
• XRPD X-ray diffraction
• Embodiment 13 The morphic form of embodiment 9, wherein Form B is characterized by an XRPD pattern substantially similar to that shown in FIG. 2,
• Embodiment 14 The morphic form of embodiment 9, wherein Form B is characterized by a DSC curve having at least one endothermic peak selected from 155 ⁇ 20 and 176 ⁇ 20 °C (e.g., 155 ⁇ 10 and 176 ⁇ 10 °C (e.g., 155 ⁇ 5 and 176 ⁇ 5 °C (e.g., 155 ⁇ 4 and 176 ⁇ 4 °C (e.g., 155 ⁇ 3 and 176 ⁇ 3 °C (e.g., 155 ⁇ 2 and 176 ⁇ 2 °C (e.g., 155 ⁇ 1 and 176 ⁇ 1 °C (e.g., 155 ⁇ 0.5 and 176 ⁇ 0.5 :: C)) ))))))))).
• 155 ⁇ 20 and 176 ⁇ 20 °C e.g., 155 ⁇ 10 and 176 ⁇ 10 °C (e.g., 155 ⁇ 5 and
• Embodiment 15 The morphic form of embodiment 1 or 2, wherein the morphic form is Form C, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof.
• Embodiment 16 The morphic form of embodiment 15, wherein Form C is characterized by an X-ray diffraction (“XRPD”) pattern comprising peaks at 16.1 ⁇ 0.2, 16.7 ⁇ 0.2, and 19. H0.2 c 20 (e.g., 16. l ⁇ 0.1, 16.7 ⁇ 0.1, and 19. l ⁇ 0.1 °26 (e.g., 16.1, 16.7, and 19.1 °20)) using Cu Ka radiation.
• XRPD X-ray diffraction
• Form C further comprises at least one peak selected from 4.0 ⁇ 0.2, 12.6 ⁇ 0.2, and 14.1 ⁇ 0.2 °2 ⁇ (e.g., 4.0 ⁇ 0.1, 12.6 ⁇ 0.1, and 14.1 ⁇ 0.1 °2 ⁇ (e.g., 4.0, 12.6, and 14.1 °2 ⁇ )) using Cu K ⁇ radiation.
• 4.0 ⁇ 0.2, 12.6 ⁇ 0.2, and 14.1 ⁇ 0.2 °2 ⁇ e.g., 4.0 ⁇ 0.1, 12.6 ⁇ 0.1, and 14.1 ⁇ 0.1 °2 ⁇ (e.g., 4.0, 12.6, and 14.1 °2 ⁇ )
• Embodiment 19 The morphic form of embodiment 15, wherein Form C is characterized by an X-ray diffraction (“XRPD”) pattern comprising at least three peaks selected from 4.0 ⁇ 0.2, 12.6 ⁇ 0.2, 14.1 ⁇ 0.2, 16.1 ⁇ 0.2, 16.7 ⁇ 0.2, and 19.1 ⁇ 0.2 °2 ⁇ (e.g., 4.0 ⁇ 0.1, 12.6 ⁇ 0.1, 14.1 ⁇ 0.1, 16.1 ⁇ 0.1, 16.7 ⁇ 0.1, and 19.1 ⁇ 0.1 °2 ⁇ (e.g., 4.0, 12.6, 14.1, 16.1, 16.7, and 19.1 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• Embodiment 20 The morphic form of embodiment 15, wherein Form C is characterized by a DSC curve having an endothermic peak at 181 ⁇ 20 °C (e.g., 181 ⁇ 10 °C (e.g., 181 ⁇ 5 °C (e.g., 181 ⁇ 4 °C (e.g., 181 ⁇ 3 °C (e.g., 181 ⁇ 2 °C (e.g., 181 ⁇ 1 °C (e.g., 181 ⁇ 0.5 °C)))))))).
• Embodiment 21 Embodiment 21.
• Embodiment 22 The morphic form of embodiment 21, wherein Form D is characterized by an X-ray diffraction (“XRPD”) pattern comprising peaks at 15.3 ⁇ 0.2, 19.3 ⁇ 0.2, and 23.5 ⁇ 0.2 °2 ⁇ (e.g., 5.3 ⁇ 0.1, 19.3 ⁇ 0.1, and 23.5 ⁇ 0.1 °2 ⁇ (e.g., 5.3, 19.3, and 23.5 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• Form D further comprises at least one peak selected from 5.4 ⁇ 0.2, 9.7 ⁇ 0.2, and 18.8 ⁇ 0.2 °2 ⁇ (e.g., 5.4 ⁇ 0.1, 9.7 ⁇ 0.1, and 18.8 ⁇ 0.1 °2 ⁇ (e.g., 5.4, 9.7, and 18.8 °2 ⁇ )) using Cu K ⁇ radiation.
• 5.4 ⁇ 0.2, 9.7 ⁇ 0.2, and 18.8 ⁇ 0.2 °2 ⁇ e.g., 5.4 ⁇ 0.1, 9.7 ⁇ 0.1, and 18.8 ⁇ 0.1 °2 ⁇ (e.g., 5.4, 9.7, and 18.8 °2 ⁇ )
• Embodiment 25 The morphic form of embodiment 21, wherein Form D is characterized by an X-ray diffraction (“XRPD”) pattern comprising at least three peaks selected from 5.4 ⁇ 0.2, 9.7 ⁇ 0.2, 15.3 ⁇ 0.2, 18.8 ⁇ 0.2, 19.3 ⁇ 0.2, and 23.5 ⁇ 0.2 °2 ⁇ (e.g., 5.4 ⁇ 0.1, 9.7 ⁇ 0.1, 15.3 ⁇ 0.1, 18.8 ⁇ 0.1, 19.3 ⁇ 0.1, and 23.5 ⁇ 0.1 °2 ⁇ (e.g., 5.4, 9.7, 15.3, 18.8, 19.3, and 23.5 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• Embodiment 26 The morphic form of embodiment 21, wherein Form D is characterized by a DSC curve having at least one endothermic peak selected from 128 ⁇ 20, 149 ⁇ 20, and 175 ⁇ 20 °C (e.g., 128 ⁇ 10, 149 ⁇ 10, and 175 ⁇ 10 °C (e.g., 128 ⁇ 5, 149 ⁇ 5, and 175 ⁇ 5 °C (e.g., 128 ⁇ 4, 149 ⁇ 4, and 175 ⁇ 4 °C (e.g., 128 ⁇ 3, 149 ⁇ 3, and 175 ⁇ 3 °C (e.g., 128 ⁇ 2, 149 ⁇ 2, and 175 ⁇ 2 °C (e.g., 128 ⁇ 1, 149 ⁇ 1, and 175 ⁇ 1 °C (e.g., 128 ⁇ 0.5, 149 ⁇ 0.5, and 175 ⁇ 0.5 °C)))))))))))))))).
• Embodiment 27 The morphic form of embodiment 1 or 2, wherein the morphic form is Form E, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof.
• Embodiment 28 The morphic form of embodiment 27, wherein Form E is characterized by an X-ray diffraction (“XRPD”) pattern comprising peaks at 7.4 ⁇ 0.2, 15.8 ⁇ 0.2, and 16.3 ⁇ 0.2 °2 ⁇ (e.g., 7.4 ⁇ 0.1, 15.8 ⁇ 0.1, and 16.3 ⁇ 0.1 °2 ⁇ (e.g., 7.4, 15.8, and 16.3 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• Embodiment 30 The morphic form of embodiment 28, wherein Form E further comprises at least one peak selected from 13.3 ⁇ 0.2, 19.2 ⁇ 0.2, and 22.4 ⁇ 0.2 °2 ⁇ (e.g., 13.3 ⁇ 0.1, 19.2 ⁇ 0.1, and 22.4 ⁇ 0.1 °2 ⁇ (e.g., 13.3, 19.2, and 22.4 °2 ⁇ )) using Cu K ⁇ radiation.
• 13 ⁇ 0.2, 19.2 ⁇ 0.2, and 22.4 ⁇ 0.2 °2 ⁇ e.g., 13.3 ⁇ 0.1, 19.2 ⁇ 0.1, and 22.4 ⁇ 0.1 °2 ⁇ (e.g., 13.3, 19.2, and 22.4 °2 ⁇ )) using Cu K ⁇ radiation.
• Embodiment 31 The morphic form of embodiment 27, wherein Form E is characterized by an X-ray diffraction (“XRPD”) pattern comprising at least three peaks selected from 7.4 ⁇ 0.2, 13.3 ⁇ 0.2, 15.8 ⁇ 0.2, 16.3 ⁇ 0.2, 19.2 ⁇ 0.2, and 22.4 ⁇ 0.2 °2 ⁇ (e.g., 7.4 ⁇ 0.1, 13.3 ⁇ 0.1, 15.8 ⁇ 0.1, 16.3 ⁇ 0.1, 19.2 ⁇ 0.1, and 22.4 ⁇ 0.1 °2 ⁇ (e.g., 7.4, 13.3, 15.8, 16.3, 19.2, and 22.4 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• Embodiment 32 The morphic form of embodiment 27, wherein Form E is characterized by a DSC curve having an endothermic peak at 173 ⁇ 20 °C (e.g., 173 ⁇ 10 °C (e.g., 173 ⁇ 5 °C (e.g., 173 ⁇ 4 °C (e.g., 173 ⁇ 3 °C (e.g., 173 ⁇ 2 °C (e.g., 173 ⁇ 1 °C (e.g., 173 ⁇ 0.5 °C)))))))).
• Embodiment 33 Embodiment 33.
• Embodiment 34 The morphic form of embodiment 33, wherein Form F is characterized by an X-ray diffraction (“XRPD”) pattern comprising peaks at 5.5 ⁇ 0.2, 16.4 ⁇ 0.2, and 21.9 ⁇ 0.2 °2 ⁇ (e.g., 5.5 ⁇ 0.1, 16.4 ⁇ 0.1, and 21.9 ⁇ 0.1 °2 ⁇ (e.g., 5.5, 16.4, and 21.9 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• Form F further comprises at least one peak selected from 7.2 ⁇ 0.2, 14.5 ⁇ 0.2, and 15.2 ⁇ 0.2 °2 ⁇ (e.g., 7.2 ⁇ 0.1, 14.5 ⁇ 0.1, and 15.2 ⁇ 0.1 °2 ⁇ (e.g., 7.2, 14.5, and 15.2 °2 ⁇ )) using Cu K ⁇ radiation.
• 7.2 ⁇ 0.2, 14.5 ⁇ 0.2, and 15.2 ⁇ 0.2 °2 ⁇ e.g., 7.2 ⁇ 0.1, 14.5 ⁇ 0.1, and 15.2 ⁇ 0.1 °2 ⁇ (e.g., 7.2, 14.5, and 15.2 °2 ⁇ )
• Embodiment 37 The morphic form of embodiment 33, wherein Form F is characterized by an X-ray diffraction (“XRPD”) pattern comprising at least three peaks selected from 5.5 ⁇ 0.2, 7.2 ⁇ 0.2, 14.5 ⁇ 0.2, 15.2 ⁇ 0.2, 16.4 ⁇ 0.2, and 21.9 ⁇ 0.2 °2 ⁇ (e.g., 5.5 ⁇ 0.1, 7.2 ⁇ 0.1, 14.5 ⁇ 0.1, 15.2 ⁇ 0.1, 16.4 ⁇ 0.1, and 21.9 ⁇ 0.1 °2 ⁇ (e.g., 5.5, 7.2, 14.5, 15.2, 16.4, and 21.9 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• Embodiment 38 The morphic form of embodiment 33, wherein Form F is characterized by a DSC curve having at least one endothermic peak selected from 48 ⁇ 20, 80 ⁇ 20, 146 ⁇ 20, and 174 ⁇ 20 °C (e.g., 48 ⁇ 10, 80 ⁇ 10, 146 ⁇ 10, and 174 ⁇ 10 °C (e.g., 48 ⁇ 5, 80 ⁇ 5, 146 ⁇ 5, and 174 ⁇ 5 °C (e.g., 48 ⁇ 4, 80 ⁇ 4, 146 ⁇ 4, and 174 ⁇ 4 °C (e.g., 48 ⁇ 3, 80 ⁇ 3, 146 ⁇ 3, and 174 ⁇ 3 °C (e.g., 48 ⁇ 2, 80 ⁇ 2, 146 ⁇ 2, and 174 ⁇ 2 °C (e.g., 48 ⁇ 1, 80 ⁇ 1, 146 ⁇ 1, and 174 ⁇ 1 °C (e.g., 48 ⁇ 0.5, 80 ⁇ 0.5, 146 ⁇ 20, and 174
• Embodiment 39 The morphic form of embodiment 1 or 2, wherein the morphic form is Form G, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof.
• Embodiment 40 The morphic form of embodiment 39, wherein Form G is characterized by an X-ray diffraction (“XRPD”) pattern comprising peaks at 4.0 ⁇ 0.2, 5.3 ⁇ 0.2, and 16.0 ⁇ 0.2 °2 ⁇ (e.g., 4.0 ⁇ 0.1, 5.3 ⁇ 0.1, and 16.0 ⁇ 0.1 °2 ⁇ (e.g., 4.0, 5.3, and 16.0 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• Form G further comprises at least one peak selected from 7.1 ⁇ 0.2, 16.7 ⁇ 0.2, and 19.2 ⁇ 0.2 °2 ⁇ (e.g., 7.1 ⁇ 0.1, 16.7 ⁇ 0.1, and 19.2 ⁇ 0.1 °2 ⁇ (e.g., 7.1, 16.7, and 19.2 °2 ⁇ )) using Cu K ⁇ radiation.
• Embodiment 42 Embodiment 42.
• Form G is characterized by an X-ray diffraction (“XRPD”) pattern comprising at least three peaks selected from 4.0 ⁇ 0.2, 5.3 ⁇ 0.2, 7.1 ⁇ 0.2, 16.0 ⁇ 0.2, 16.7 ⁇ 0.2, and 19.2 ⁇ 0.2 °2 ⁇ (e.g., 4.0 ⁇ 0.1, 5.3 ⁇ 0.1, 7.1 ⁇ 0.1, 16.0 ⁇ 0.1, 16.7 ⁇ 0.1, and 19.2 ⁇ 0.1 °2 ⁇ (e.g., 4.0, 5.3, 7.1, 16.0, 16.7, and 19.2 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• Embodiment 44 The morphic form of embodiment 39, wherein Form G is characterized by an XRPD pattern substantially similar to that shown in FIG.7. [0433] Embodiment 44.
• Embodiment 45 The morphic form of embodiment 1 or 2, wherein the morphic form is Form H, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof.
• Embodiment 46 The morphic form of embodiment 45, wherein Form H is characterized by an X-ray diffraction (“XRPD”) pattern comprising peaks at 4.6 ⁇ 0.2, 13.8 ⁇ 0.2, and 17.0 ⁇ 0.2 °2 ⁇ (e.g., 4.6 ⁇ 0.1, 13.8 ⁇ 0.1, and 17.0 ⁇ 0.1 °2 ⁇ (e.g., 4.6, 13.8, and 17.0 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• Embodiment 48 The morphic form of embodiment 46, wherein Form H further comprises at least one peak selected from 5.6 ⁇ 0.2, 8.6 ⁇ 0.2, and 17.8 ⁇ 0.2 °2 ⁇ (e.g., 5.6 ⁇ 0.1, 8.6 ⁇ 0.1, and 17.8 ⁇ 0.1 °2 ⁇ (e.g., 5.6, 8.6, and 17.8 °2 ⁇ )) using Cu K ⁇ radiation.
• Embodiment 48 Embodiment 48.
• Embodiment 49 The morphic form of embodiment 45, wherein Form H is characterized by an X-ray diffraction (“XRPD”) pattern comprising at least three peaks selected from 4.6 ⁇ 0.2, 5.6 ⁇ 0.2, 8.6 ⁇ 0.2, 13.8 ⁇ 0.2, 17.0 ⁇ 0.2, and 17.8 ⁇ 0.2 °2 ⁇ (e.g., 4.6 ⁇ 0.1, 5.6 ⁇ 0.1, 8.6 ⁇ 0.1, 13.8 ⁇ 0.1, 17.0 ⁇ 0.1, and 17.8 ⁇ 0.1 °2 ⁇ (e.g., 4.6, 5.6, 8.6, 13.8, 17.0, and 17.8 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• Embodiment 50 The morphic form of embodiment 45, wherein Form H is characterized by a DSC curve having at least one endothermic peak selected from 62 ⁇ 20 and 153 ⁇ 20 °C (e.g., 62 ⁇ 10 and 153 ⁇ 10 °C (e.g., 62 ⁇ 5 and 153 ⁇ 5 °C (e.g., 62 ⁇ 4 and 153 ⁇ 4 °C (e.g., 62 ⁇ 3 and 153 ⁇ 3 °C (e.g., 62 ⁇ 2 and 153 ⁇ 2 °C (e.g., 62 ⁇ 1 and 153 ⁇ 1 °C (e.g., 62 ⁇ 0.5 and 153 ⁇ 0.5 °C))))))))))).
• 62 ⁇ 20 and 153 ⁇ 20 °C e.g., 62 ⁇ 10 and 153 ⁇ 10 °C (e.g., 62 ⁇ 5 and 153
• Embodiment 51 The morphic form of embodiment 1 or 2, wherein the morphic form is Form I, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof.
• Embodiment 52 The morphic form of embodiment 51, wherein Form I is characterized by an X-ray diffraction (“XRPD”) pattern comprising peaks at 5.1 ⁇ 0.2, 20.4 ⁇ 0.2, and 21.5 ⁇ 0.2 °2 ⁇ (e.g., 5.1 ⁇ 0.1, 20.4 ⁇ 0.1, and 21.5 ⁇ 0.1 °2 ⁇ (e.g., 5.1, 20.4, and 21.5 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• Embodiment 54 The morphic form of embodiment 52, wherein Form I further comprises at least one peak selected from 17.0 ⁇ 0.2, 22.3 ⁇ 0.2, and 25.5 ⁇ 0.2 °2 ⁇ (e.g., 17.0 ⁇ 0.1, 22.3 ⁇ 0.1, and 25.5 ⁇ 0.1 °2 ⁇ (e.g., 17.0, 22.3, and 25.5 °2 ⁇ )) using Cu K ⁇ radiation.
• Embodiment 54 Embodiment 54.
• Embodiment 51 wherein Form I is characterized by an X-ray diffraction (“XRPD”) pattern comprising at least three peaks selected from 5.1 ⁇ 0.2, 17.0 ⁇ 0.2, 20.4 ⁇ 0.2, 21.5 ⁇ 0.2, 22.3 ⁇ 0.2, and 25.5 ⁇ 0.2 °2 ⁇ (e.g., 5.1 ⁇ 0.1, 17.0 ⁇ 0.1, 20.4 ⁇ 0.1, 21.5 ⁇ 0.1, 22.3 ⁇ 0.1, and 25.5 ⁇ 0.1 °2 ⁇ (e.g., 5.1, 17.0, 20.4, 21.5, 22.3, and 25.5 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• Embodiment 56 The morphic form of embodiment 1 or 2, wherein the morphic form is Form J, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof.
• Embodiment 57 Embodiment 57.
• Embodiment 56 wherein Form J is characterized by an X-ray diffraction (“XRPD”) pattern comprising peaks at 4.5 ⁇ 0.2, 17.9 ⁇ 0.2, and 22.5 ⁇ 0.2 °2 ⁇ (e.g., 4.5 ⁇ 0.1, 17.9 ⁇ 0.1, and 22.5 ⁇ 0.1 °2 ⁇ (e.g., 4.5, 17.9, and 22.5 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• Embodiment 59 The morphic form of embodiment 57, wherein Form J further comprises at least one peak selected from 5.1 ⁇ 0.2, 10.4 ⁇ 0.2, and 16.0 ⁇ 0.2 °2 ⁇ (e.g., 5.1 ⁇ 0.1, 10.4 ⁇ 0.1, and 16.0 ⁇ 0.1 °2 ⁇ (e.g., 5.1, 10.4, and 16.0 °2 ⁇ )) using Cu K ⁇ radiation.
• Embodiment 59 Embodiment 59.
• Embodiment 60 The morphic form of embodiment 56, wherein Form J is characterized by an X-ray diffraction (“XRPD”) pattern comprising at least three peaks selected from 4.5 ⁇ 0.2, 5.1 ⁇ 0.2, 10.4 ⁇ 0.2, 16.0 ⁇ 0.2, 17.9 ⁇ 0.2, and 22.5 ⁇ 0.2 °2 ⁇ (e.g., 4.5 ⁇ 0.1, 5.1 ⁇ 0.1, 10.4 ⁇ 0.1, 16.0 ⁇ 0.1, 17.9 ⁇ 0.1, and 22.5 ⁇ 0.1 °2 ⁇ (e.g., 4.5, 5.1, 10.4, 16.0, 17.9, and 22.5 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• Embodiment 61 The morphic form of embodiment 56, wherein Form J is characterized by a DSC curve having at least one endothermic peak selected from 137 ⁇ 20 and 166 ⁇ 20 °C (e.g., 137 ⁇ 10 and 166 ⁇ 10 °C (e.g., 137 ⁇ 5 and 166 ⁇ 5 °C (e.g., 137 ⁇ 4 and 166 ⁇ 4 °C (e.g., 137 ⁇ 3 and 166 ⁇ 3 °C (e.g., 137 ⁇ 2 and 166 ⁇ 2 °C (e.g., 137 ⁇ 1 and 166 ⁇ 1 °C (e.g., 137 ⁇ 0.5 and 166 ⁇ 0.5 °C)))))))).
• Embodiment 62 The morphic form of embodiment 1 or 2, wherein the morphic form is Form K, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof.
• Embodiment 63 The morphic form of embodiment 62, wherein Form K is characterized by an X-ray diffraction (“XRPD”) pattern comprising peaks at 5.2 ⁇ 0.2, 17.0 ⁇ 0.2, and 20.5 ⁇ 0.2 °2 ⁇ (e.g., 5.2 ⁇ 0.1, 17.0 ⁇ 0.1, and 20.5 ⁇ 0.1 °2 ⁇ (e.g., 5.2, 17.0, and 20.5 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• Embodiment 65 The morphic form of embodiment 63, wherein Form K further comprises at least one peak selected from 6.8 ⁇ 0.2, 21.6 ⁇ 0.2, and 22.4 ⁇ 0.2 °2 ⁇ (e.g., 6.8 ⁇ 0.1, 21.6 ⁇ 0.1, and 22.4 ⁇ 0.1 °2 ⁇ (e.g., 6.8, 21.6, and 22.4 °2 ⁇ )) using Cu K ⁇ radiation.
• 6.8 ⁇ 0.1, 21.6 ⁇ 0.1, and 22.4 ⁇ 0.1 °2 ⁇ e.g., 6.8, 21.6, and 22.4 °2 ⁇
• Embodiment 66 The morphic form of embodiment 62, wherein Form K is characterized by an X-ray diffraction (“XRPD”) pattern comprising at least three peaks selected from 5.2 ⁇ 0.2, 6.8 ⁇ 0.2, 17.0 ⁇ 0.2, 20.5 ⁇ 0.2, 21.6 ⁇ 0.2, and 22.4 ⁇ 0.2 °2 ⁇ (e.g., 5.2 ⁇ 0.1, 6.8 ⁇ 0.1, 17.0 ⁇ 0.1, 20.5 ⁇ 0.1, 21.6 ⁇ 0.1, and 22.4 ⁇ 0.1 °2 ⁇ (e.g., 5.2, 6.8, 17.0, 20.5, 21.6, and 22.4 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• Embodiment 67 The morphic form of embodiment 1 or 2, wherein the morphic form is Form L, the solvate thereof, the hydrate thereof, or the pharmaceutically acceptable salt thereof.
• Embodiment 68 Embodiment 68.
• Embodiment 69 The morphic form of embodiment 67, wherein Form L is characterized by an X-ray diffraction (“XRPD”) pattern comprising peaks at 5.4 ⁇ 0.2, 7.8 ⁇ 0.2, and 19.3 ⁇ 0.2 °2 ⁇ (e.g., 5.4 ⁇ 0.1, 7.8 ⁇ 0.1, and 19.3 ⁇ 0.1 °2 ⁇ (e.g., 5.4, 7.8, and 19.3 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• Embodiment 70 The morphic form of embodiment 68, wherein Form L further comprises at least one peak selected from 14.8 ⁇ 0.2, 15.3 ⁇ 0.2, and 16.6 ⁇ 0.2 °2 ⁇ (e.g., 14.8 ⁇ 0.1, 15.3 ⁇ 0.1, and 16.6 ⁇ 0.1 °2 ⁇ (e.g., 14.8, 15.3, and 16.6 °2 ⁇ )) using Cu K ⁇ radiation.
• 14.8 ⁇ 0.2, 15.3 ⁇ 0.2, and 16.6 ⁇ 0.2 °2 ⁇ e.g., 14.8 ⁇ 0.1, 15.3 ⁇ 0.1, and 16.6 ⁇ 0.1 °2 ⁇ (e.g., 14.8, 15.3, and 16.6 °2 ⁇ )) using Cu K ⁇ radiation.
• Embodiment 71 The morphic form of embodiment 67, wherein Form L is characterized by an X-ray diffraction (“XRPD”) pattern comprising at least three peaks selected from 5.4 ⁇ 0.2, 7.8 ⁇ 0.2, 14.8 ⁇ 0.2, 15.3 ⁇ 0.2, 16.6 ⁇ 0.2, and 19.3 ⁇ 0.2 °2 ⁇ (e.g5.4 ⁇ 0.1, 7.8 ⁇ 0.1, 14.8 ⁇ 0.1, 15.3 ⁇ 0.1, 16.6 ⁇ 0.1, and 19.3 ⁇ 0.1 °2 ⁇ (e.g., 5.4, 7.8, 14.8, 15.3, 16.6, and 19.3 °2 ⁇ )) using Cu K ⁇ radiation.
• XRPD X-ray diffraction
• Embodiment 72 The morphic form of any preceding embodiments, which is at least 90, 95, 96, 97, 98, or 99% pure.
• Embodiment 73 A pharmaceutical composition comprising a therapeutically effective amount of any one, or combination, of the morphic forms of any preceding embodiments and a pharmaceutically acceptable excipient.
• Embodiment 74 A method of inhibiting an oncogenic variant of an ErbB receptor, comprising administering to the subject in need thereof a therapeutically effective amount of the morphic form of any one of the preceding embodiments.
• Embodiment 75 Embodiment 75.
• Embodiment 76 A method of preventing or treating cancer, comprising administering to the subject in need thereof a therapeutically effective amount of the morphic form of any one of the preceding embodiments.
• Embodiment 77 A method of preventing or treating cancer, comprising administering to the subject in need thereof the pharmaceutical composition of any one of the preceding embodiments.
• Embodiment 78 A method of preventing or treating cancer, comprising administering to the subject in need thereof the pharmaceutical composition of any one of the preceding embodiments.
• a method of preventing or treating cancer comprising: i) identifying a subject candidate as the subject in need of the treatment when that at least one oncogenic variant of an ErbB receptor is present in the subject; and ii) administering to the subject in need of the treatment a therapeutically effective amount of the morphic form of any one of the preceding embodiments.
• Embodiment 79. A method of preventing or treating cancer, comprising: i) identifying a subject candidate as the subject in need of the treatment when that at least one oncogenic variant of an ErbB receptor is present in the subject; and ii) administering to the subject in need of the treatment the pharmaceutical composition of any one of the preceding embodiments.
• Embodiment 80 Embodiment 80.
• a method of preventing or treating cancer comprising: i) identifying a subject candidate as the subject in need of the treatment when that at least one oncogenic variant of an ErbB receptor is present in a biological sample from the subject; and ii) administering to the subject in need of the treatment a therapeutically effective amount of the morphic form of any one of the preceding embodiments.
• Embodiment 81 A method of preventing or treating cancer, comprising: i) identifying a subject candidate as the subject in need of the treatment when that at least one oncogenic variant of an ErbB receptor is present in a biological sample from the subject; and ii) administering to the subject in need of the treatment the pharmaceutical composition of any one of the preceding embodiments.
• Embodiment 82 A method of preventing or treating cancer, comprising administering to the subject in need thereof a therapeutically effective amount of the morphic form of any one of the preceding embodiments when that at least one oncogenic variant of an ErbB receptor is identified as being present in the subject.
• Embodiment 83 A method of preventing or treating cancer, comprising administering to the subject in need thereof the morphic form of any one of the preceding embodiments when that at least one oncogenic variant of an ErbB receptor is identified as being present in the subject.
• Embodiment 84 A method of preventing or treating cancer, comprising administering to the subject in need thereof the morphic form of any one of the preceding embodiments when that at least one oncogenic variant of an ErbB receptor is identified as being present in the subject.
• a method of preventing or treating cancer comprising administering to the subject in need thereof a therapeutically effective amount of the morphic form of any one of the preceding embodiments when that at least one oncogenic variant of an ErbB receptor is identified as being present in a biological sample from the subject.
• Embodiment 85 A method of preventing or treating cancer, comprising administering to the subject in need thereof the pharmaceutical composition of any one of the preceding embodiments when that at least one oncogenic variant of an ErbB receptor is identified as being present in a biological sample from the subject.
• Embodiment 86 The morphic form of any one of the preceding embodiments for use in the inhibition of an oncogenic variant of an ErbB receptor.
• Embodiment 87 The pharmaceutical composition of any one of the preceding embodiments for use in the inhibition of an oncogenic variant of an ErbB receptor.
• Embodiment 88 The morphic form of any one of the preceding embodiments for use in the prevention or treatment of cancer.
• Embodiment 89 The pharmaceutical composition of any one of the preceding embodiments for use in the prevention or treatment of cancer.
• Embodiment 90 The morphic form of any one of the preceding embodiments for use in the prevention or treatment of cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor is present in the subject.
• Embodiment 91 The pharmaceutical composition of any one of the preceding embodiments for use in the prevention or treatment of cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor is present in the subject.
• Embodiment 92 The morphic form of any one of the preceding embodiments for use in the prevention or treatment of cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor is present in a biological sample from the subject,
• Embodiment 93 The pharmaceutical composition of any one of the preceding embodiments for use in the prevention or treatment of cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor is present in a biological sample from the subject.
• Embodiment 94 Use of the morphic form of any one of the preceding embodiments in the manufacture of a medicament for inhibiting an oncogenic variant of an ErbB receptor.
• Embodiment 95 Use of the morphic form of any one of the preceding embodiments in the manufacture of a medicament for preventing or treating cancer.
• Embodiment 96 The morphic form, pharmaceutical composition, method, or use of any one of the preceding embodiments, wherein the cancer is a solid tumor.
• Embodiment 97 The morphic form, pharmaceutical composition, method, or use of any one of the preceding embodiments, wherein the cancer is a bladder cancer, a breast cancer, a cervical cancer, a colorectal cancer, an endometrial cancer, a gastric cancer, a glioblastoma (GBM), a head and neck cancer, a lung cancer, a non-small cell lung cancer (NSCLC), or any subtype thereof.
• the cancer is a bladder cancer, a breast cancer, a cervical cancer, a colorectal cancer, an endometrial cancer, a gastric cancer, a glioblastoma (GBM), a head and neck cancer, a lung cancer, a non-small cell lung cancer (NSCLC), or any subtype thereof.
• GBM glioblastoma
• NSCLC non-small cell lung cancer
• Embodiment 98 The morphic form, pharmaceutical composition, method, or use of any one of the preceding embodiments, wherein the cancer is glioblastoma (GBM) or any subtype thereof.
• GBM glioblastoma
• Embodiment 99 The morphic form, pharmaceutical composition, method, or use of any one of the preceding embodiments, wherein the cancer is glioblastoma.
• Embodiment 100 The morphic form, pharmaceutical composition, method, or use of any one of the preceding embodiments, wherein the cancer or a tumor or a cell thereof expresses an oncogenic variant of an epidermal growth factor receptor (EGER).
• EGER epidermal growth factor receptor
• Embodiment 101 The niorphic form, pharmaceutical composition, method, or use of any one of the preceding embodiments, wherein the oncogenic variant is an oncogenic variant in an ErbB receptor.
• Embodiment 102 The morphic form, pharmaceutical composition, method, or use of any one of the preceding embodiments, wherein the oncogenic variant in the ErbB receptor is an allosteric variant.
• Embodiment 103 The morphic form, pharmaceutical composition, method, or use of any one of the preceding embodiments, wherein the oncogenic variant is an oncogenic variant in an epidermal growth factor receptor (EGER).
• EGER epidermal growth factor receptor
• Embodiment 104 The morphic form, pharmaceutical composition, method, or use of any one of the preceding embodiments, wherein the oncogenic variant in the EGFR is an allosteric variant.
• Embodiment 105 The morphic form, pharmaceutical composition, method, or use of any one of the preceding embodiments, wherein the oncogenic variant is an oncogenic variant of a HER2 receptor.
• Embodiment 106 The morphic form, pharmaceutical composition, method, or use of any one of the preceding embodiments, wherein the oncogenic variant in the HER2 receptor is an allosteric variant.
• Embodiment 107 The morphic form, pharmaceutical composition, method, or use of any one of the preceding embodiments, wherein the oncogenic variant is an oncogenic variant in a HER-4 receptor.
• Embodiment 108 The morphic form, pharmaceutical composition, method, or use of any one of the preceding embodiments, wherein the subject or the cancer is insensitive or resistant to treatment with one or more of gefimtimb, erlotinib, afatinib, osimertinib, and necitunumab.
• Embodiment 109 The morphic form, pharmaceutical composition, method, or use of any one of the preceding embodiments, wherein the sequence encoding the oncogenic variant of the EGFR comprises a deletion of exon 20 or a portion thereof and wherein the cancer, tumor or ceil thereof does not comprise an oncogenic variation in a sequence encoding one or more of an EGFR kinase domain (KD), BRAE NTRK, and KRAS or wherein.
• KD EGFR kinase domain
• BRAE NTRK BRAE NTRK
• KRAS KRAS
• Embodiment 110 The niorphic form, pharmaceutical composition, method, or use of any one of the preceding embodiments, wherein the sequence encoding the oncogenic variant of the EGFR comprises a deletion of exon 20 or a portion thereof and wherein the cancer, tumor or cell thereof does not comprise a marker indicating responsiveness to immunotherapy.
• Embodiment 111 The morphic form, pharmaceutical composition, method, or use of any one of the preceding embodiments, wherein the oncogenic variant or the oncogenic mutation is detected by a Food and Drug Administration (FDA) -approved diagnosis.
• FDA Food and Drug Administration
• Embodiment 1 12. The morphic form, pharmaceutical composition, method, or use of any one of the preceding embodiments, wherein the subject has an adverse reaction to treatment with a Type I inhibitor.
• Embodiment 113 The morphic form, pharmaceutical composition, method, or use of any one of the preceding embodiments, wherein the subject has an adverse reaction to treatment with one or more of gefinitinib, erlotinib, afatinib, osimertinib, necitunumab, crizotmib, alectinib, ceritmib, dabrafenib, trametimb, afatinib, sapitmib, dacomitinib, canertinib, pelitinib, WZ4002, WZ8040, WZ3146, CO- 1686 and AZD9291.
• X-ray Powder Diffractometer XRPD analysis was performed using a Broker D8 Advance X-ray powder diffractometer. Analysis was performed using parameters as set forth below.
• DSC Differential Scanning Calorimetric
• TGA Thermal Gravimetric Analysis
• DVS Dynamic Vapor Sorption
• Karl Fischer Analysis Karl Fischer analysis was performed using Mettler Toledo Coulometric KF Titrator C30 using the coulometric method.
• PLM Polarized Light Microscopy
• NMR analysis was performed using Bruker Avance-AV 400M at a frequency of 400 MHz, a 5 mm PABBO BB-1H/D probe, 8 scanes, a temperature of 297.6 K, and a relaxation delay of 1 second.
• a crystalline form of the present disclosure may be prepared according to one or more of the protocols as described herein.
• Protocol I Equilibration with solvents at 25°C for 2 weeks. About 20 mg of Form A was equilibrated in a suitable amount of a solvent at 25 °C for 2 weeks with a stirring plate. The obtained suspension were filtered.
• Protocol 2 Equilibration with solvents at 50°C for 1 week. About 30 nig of Form A was equilibrated in a suitable amount of a solvent at 50 °C for 1 week with a stirring plate. The obtained suspension were filtered.
• Protocol 3 Equilibration with solvents under a temperature cycle. .About 30 mg of Form A was equilibrated in a suitable amount of a solvent under a temperature cycle between 5 °C to 50 °C at a heating/cooling rate of 0.2 °C/min for 10 cycles.
• Protocol 4 Crystallization at room temperature by slow evaporation. About 10 mg of Form A was dissolved in a suitable amount of a solvent. The obtained solution was filtered by 0.45 gm nylon filter. The filtered solution was then slowly evaporated under ambient condition.
• Protocol 5 Crystallization under nitrogen flow by fast evaporation. About 10 nig of Form A was dissolved in a suitable amount of a solvent. The obtained solution was filtered by 0.45 tini nylon filter. The filtered solution was then fast evaporated under nitrogen flow.
• Protocol 6 Crystallization from hot saturated solutions by slow cooling. About 2.0 mg of Form A was dissolved in the minimal amount of a selected solvent at 50 °C. The obtained solution was filtered by 0.45 uni nylon filter. The filtered solution was then cooled to 5 °C at 0.1 °C/min. Precipitates were collected by filtration.
• Protocol 7 Crystallization from hot saturated solutions by fast cooling. About 20 mg of Form A was dissolved in a minimal amount of a selected solvent at 50 °C. The obtained solution was filtered by 0.45 pm nylon filter. The filtered solution were then put at 5 °C and stirred at a rate of 400 rpm. Precipitates were collected by filtration.
• Protocol 8 Precipitation by addition of anti-solvent. About 20 mg of Form A w r as dissolved in a minimal amount of a good solvent. The solutions were filtered. Anti-solvent was added into the filtered solution slowly. Precipitates were collected by filtration. When cloudy sample were obtained from an anti-solvent experiment, slow evaporation experiments were conducted at. 25 °C.
• Protocol 9 Variable relative humidity experiment. Form F was investigated by variable humidity XRPD experiments. Form F converted to a new crystalline form, assigned as Form L, in 0% RH. Form L reverted to Form F in > 10% RH. This suggests that the Form L is a metastable anhydrate and is only stable in about 0% RH. See Example 8 for more details.
• Example 4 Competetive equilibration experiments
• Competitive equilibration experiments were conducted to determine thermodynamic relationships of anhydrate polymorphs. The experiments were conducted in 5 solvent systems at 25 °C as shown below in Table B.
• Form C and Form F showed pH dependent solubility and similar solubility profile in these aqueous media. They showed good solubility (> 2mg/mL) in pH 1.0 HO solution, pH 4.5 acetate buffer (50 mM) and in SGF. They showed low solubility (about 20pg/mL) m pH 6.8 phosphate buffer (50 mM) and ( ⁇ 10 pg/mL) in pure water. Both of them degraded in FeSSIF'-vl and FaSSIF-vl.
• Table D the sample was cloudy in pH 4.5 acetate buffer.
• Form F was investigated by variable humidity XRPD experiments. See, e.g., Table F.
• Form F converted to a new crystaHme form, assigned as Form L, in 0% RH.
• Form L reverted to Form F in > 10%RH. Tins suggests that the Form L is a metastable anhydrate and is only stable in close to 0%RH.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Epidemiology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Priority Applications (9)

Applications Claiming Priority (2)

Publications (1)

Family

ID=83691602

Family Applications (1)

Country Status (10)

Cited By (5)

Citations (2)

• 2022
  • 2022-09-21 CA CA3231697A patent/CA3231697A1/en active Pending
  • 2022-09-21 MX MX2024003475A patent/MX2024003475A/es unknown
  • 2022-09-21 AU AU2022352658A patent/AU2022352658A1/en active Pending
  • 2022-09-21 CN CN202280075401.6A patent/CN119110799A/zh active Pending
  • 2022-09-21 WO PCT/US2022/044232 patent/WO2023049168A1/en not_active Ceased
  • 2022-09-21 EP EP22789775.8A patent/EP4405350A1/en active Pending
  • 2022-09-21 JP JP2024517482A patent/JP2024534517A/ja active Pending
  • 2022-09-21 IL IL311354A patent/IL311354A/en unknown
  • 2022-09-21 KR KR1020247013097A patent/KR20240099193A9/ko active Pending
  • 2022-09-21 US US18/693,733 patent/US20240425492A1/en active Pending

Patent Citations (2)

Non-Patent Citations (5)

Also Published As

Similar Documents

Legal Events