WO2023131234A1 - Formes cristallines d'un inhibiteur d'atr - Google Patents

Formes cristallines d'un inhibiteur d'atr Download PDF

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Publication number
WO2023131234A1
WO2023131234A1 PCT/CN2023/070683 CN2023070683W WO2023131234A1 WO 2023131234 A1 WO2023131234 A1 WO 2023131234A1 CN 2023070683 W CN2023070683 W CN 2023070683W WO 2023131234 A1 WO2023131234 A1 WO 2023131234A1
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Prior art keywords
crystalline form
compound
xrpd pattern
peaks
dsc thermogram
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PCT/CN2023/070683
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English (en)
Inventor
Zhongyang SHI
Jian Wang
Feifei YANG
Lei Wang
Bo Shan
Jay Mei
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Shanghai Antengene Corporation Limited
Antengene Discovery Limited
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Publication of WO2023131234A1 publication Critical patent/WO2023131234A1/fr

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    • 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
    • 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

Definitions

  • the present disclosure generally relates to crystalline forms of Compound I, as well as pharmaceutical compositions comprising these crystalline forms and methods of treatment by administration of these crystalline forms or the pharmaceutical compositions.
  • ATR also known as FRAP-Related Protein 1; FRP1, MEC1, SCKL, SECKL1 protein kinase
  • FRP1, MEC1, SCKL, SECKL1 protein kinase is a member of the PI3-Kinase like kinase (PIKK) family of proteins involved in repair and maintenance of the genome and its stability. It is essential to the viability of replicating cells and is activated during S-phase to regulate firing of replication origins and to repair damaged replication forks. Therefore, ATR inhibitors have the potential to be an efficient way in cancer treatment.
  • PIKK PI3-Kinase like kinase
  • Compound I and pharmaceutically acceptable salts thereof are potent ATR inhibitor:
  • compositions which are capable of inhibiting ATR protein kinase.
  • Methods for use of such compounds for treatment of various diseases or conditions, such as cancer, are also provided.
  • the present disclosure provides a crystalline form B of Compound I, characterized by an XRPD pattern comprising one or more peaks at 5.91, 18.06, and 18.30 ( ⁇ 0.2° 2 ⁇ ) .
  • the present disclosure provides a crystalline form C of Compound I, characterized by an XRPD pattern comprising one or more peaks at 5.85, 17.52, 19.2 and 23.59 ( ⁇ 0.2° 2 ⁇ ) .
  • the present disclosure provides a crystalline form D of Compound I, characterized by an XRPD pattern comprising one or more peaks at 5.39, 18.12 and 18.32 ( ⁇ 0.2° 2 ⁇ ) .
  • the present disclosure provides a crystalline form E of Compound I, characterized by an XRPD pattern comprising one or more peaks at 17.29, 17.58, and 19.80 ( ⁇ 0.2° 2 ⁇ ) .
  • the present disclosure provides a crystalline form F of Compound I, characterized by an XRPD pattern comprising one or more peaks at 17.93, 18.19, and 19.80 ( ⁇ 0.2° 2 ⁇ ) .
  • the present disclosure provides a crystalline form G of the maleate of Compound I, characterized by an XRPD pattern comprising one or more peaks at 18.30, 18.72 and 24.73 ( ⁇ 0.2° 2 ⁇ ) .
  • the present disclosure provides a crystalline form H of the fumarate of Compound I, characterized by an XRPD pattern comprising one or more peaks at 6.37, 7.65, 17.48 and 19.40 ( ⁇ 0.2° 2 ⁇ ) .
  • the present disclosure provides a crystalline form I of the mesylate of Compound I, characterized by an XRPD pattern comprising one or more peaks at 16.62, 17.37, 18.09, 19.75 and 20.42 ( ⁇ 0.2° 2 ⁇ ) .
  • the present disclosure provides a crystalline form J of the phosphate of Compound I, characterized by an XRPD pattern comprising one or more peaks at 18.03, 18.22, 18.96, 19.64 and 19.93 ( ⁇ 0.2° 2 ⁇ ) .
  • the present disclosure provides a crystalline form K of the phosphate of Compound I, characterized by an XRPD pattern comprising one or more peaks at 10.67, 18.00, 19.35 and 25.71 ( ⁇ 0.2° 2 ⁇ ) .
  • the present disclosure provides a crystalline form L of the benzene sulfonate of Compound I, characterized by an XRPD pattern comprising one or more peaks at 7.83, 15.66, 19.84 and 20.52 ( ⁇ 0.2° 2 ⁇ ) .
  • the present disclosure provides a crystalline form M of the benzene sulfonate of Compound I, characterized by an XRPD pattern comprising one or more peaks at 11.42, 16.40 and 16.89 ( ⁇ 0.2° 2 ⁇ ) .
  • the present disclosure provides a crystalline form N of the p-tosylate of Compound I, characterized by an XRPD pattern comprising one or more peaks at 8.11, 16.11, 16.51, 17.01, 18.29 and 20.50 ( ⁇ 0.2° 2 ⁇ ) .
  • the present disclosure provides a crystalline form O of the ethanedisulfonate of Compound I, characterized by an XRPD pattern comprising one or more peaks at 7.62, 19.63, 20.06, 21.29 and 21.66 ( ⁇ 0.2° 2 ⁇ ) .
  • the present disclosure provides a crystalline form P of the oxalate of Compound I, characterized by an XRPD pattern comprising one or more peaks at 9.35, 16.77, 18.68 and 19.07 ( ⁇ 0.2° 2 ⁇ ) .
  • the present disclosure provides a crystalline form Q of the ethanesulfonate of Compound I, characterized by an XRPD pattern comprising one or more peaks at 9.24, 19.44 and 19.66 ( ⁇ 0.2° 2 ⁇ ) .
  • the present disclosure provides a crystalline form R of the hydrobromide of Compound I, characterized by an XRPD pattern comprising one or more peaks at 9.23, 16.84, 25.53 and 27.23 ( ⁇ 0.2° 2 ⁇ ) .
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising Compound I or a salt of Compound I and a pharmaceutically acceptable excipient, wherein Compound I or the salt of Compound I is in a crystalline form of the present disclosure.
  • the present disclosure provides a method for treating cancer, comprising administering an effective amount of the crystalline forms of Compound I or a salt of Compound I of the present disclosure or the pharmaceutical composition of the present disclosure to a subject in need thereof.
  • the present disclosure provides use of the crystalline forms of Compound I or a salt of Compound I of the present disclosure or the pharmaceutical composition of the present disclosure in the manufacture of a medicament in the prevention or treatment of a cancer.
  • the present disclosure provides a method for inhibiting ATR kinase in a subject in need thereof, comprising administering an effective amount of the crystalline forms of Compound I or a salt of Compound I of the present disclosure or the pharmaceutical composition of the present disclosure to the subject.
  • Fig. 1A shows a XRPD pattern of crystalline form B.
  • Fig. 1B shows a TGA thermogram of crystalline form B.
  • Fig. 1C shows a DSC thermogram of crystalline form B.
  • Fig. 1D shows the 1 H NMR of crystalline form B.
  • Fig. 2A shows a XRPD pattern of crystalline form C.
  • Fig. 2B shows a TGA thermogram of crystalline form C.
  • Fig. 2C shows a DSC thermogram of crystalline form C.
  • Fig. 2D shows the 1 H NMR of crystalline form C.
  • Fig. 2E shows a DVS diagram of crystalline form C.
  • Fig. 2F shows the XRPD patterns of crystalline form C before and after DVS analysis.
  • Fig. 2G shows a XRPD overlay of crystalline form C tested for physical stability under various conditions.
  • Fig. 2H shows a HPLC overlay of crystalline form C tested for chemical stability under various conditions.
  • Fig. 3A shows a XRPD pattern of crystalline form D.
  • Fig. 3B shows a TGA thermogram of crystalline form D.
  • Fig. 3C shows a DSC thermogram of crystalline form D.
  • Fig. 3D shows the 1 H NMR of crystalline form D.
  • Fig. 4A shows a XRPD pattern of crystalline form E.
  • Fig. 4B shows a TGA thermogram of crystalline form E.
  • Fig. 4C shows a DSC thermogram of crystalline form E.
  • Fig. 4D shows the 1 H NMR of crystalline form E.
  • Fig. 5A shows a XRPD pattern of crystalline form F.
  • Fig. 5B shows a TGA thermogram of crystalline form F.
  • Fig. 5C shows a DSC thermogram of crystalline form F.
  • Fig. 5D shows the 1 H NMR of crystalline form F.
  • Fig. 6A shows a XRPD overlay of crystalline forms B, C and D in competitive slurry experiment in acetone.
  • Fig. 6B shows a XRPD overlay of crystalline forms B, C and D in competitive slurry experiment in ACN.
  • Fig. 8A shows a XRPD pattern of crystalline form G.
  • Fig. 8B shows a TGA thermogram of crystalline form G.
  • Fig. 8C shows a DSC thermogram of crystalline form G.
  • Fig. 8D shows the 1 H NMR of crystalline form G.
  • Fig. 9A shows a XRPD pattern of crystalline form H.
  • Fig. 9B shows a TGA thermogram of crystalline form H.
  • Fig. 9C shows a DSC thermogram of crystalline form H.
  • Fig. 9D shows the 1 H NMR of crystalline form H.
  • Fig. 10A shows a XRPD pattern of crystalline form I.
  • Fig. 10B shows a TGA thermogram of crystalline form I.
  • Fig. 10C shows a DSC thermogram of crystalline form I.
  • Fig. 10D shows the 1 H NMR of crystalline form I.
  • Fig. 11A shows a XRPD pattern of crystalline form J.
  • Fig. 11B shows a TGA thermogram of crystalline form J.
  • Fig. 11C shows a DSC thermogram of crystalline form J.
  • Fig. 11D shows the 1 H NMR of crystalline form J.
  • Fig. 12A shows a XRPD pattern of crystalline form K.
  • Fig. 12B shows a TGA thermogram of crystalline form K.
  • Fig. 12C shows a DSC thermogram of crystalline form K.
  • Fig. 12D shows the 1 H NMR of crystalline form K.
  • Fig. 13A shows a XRPD pattern of crystalline form L.
  • Fig. 13B shows a TGA thermogram of crystalline form L.
  • Fig. 13C shows a DSC thermogram of crystalline form L.
  • Fig. 13D shows the 1 H NMR of crystalline form L.
  • Fig. 14A shows a XRPD pattern of crystalline form M.
  • Fig. 14B shows a TGA thermogram of crystalline form M.
  • Fig. 14C shows a DSC thermogram of crystalline form M.
  • Fig. 14D shows the 1 H NMR of crystalline form M.
  • Fig. 15A shows a XRPD pattern of crystalline form N.
  • Fig. 15B shows a TGA thermogram of crystalline form N.
  • Fig. 15C shows a DSC thermogram of crystalline form N.
  • Fig. 15D shows the 1 H NMR of crystalline form N.
  • Fig. 16A shows a XRPD pattern of crystalline form O.
  • Fig. 16B shows a TGA thermogram of crystalline form O.
  • Fig. 16C shows a DSC thermogram of crystalline form O.
  • Fig. 16D shows the 1 H NMR of crystalline form O.
  • Fig. 17A shows a XRPD pattern of crystalline form P.
  • Fig. 17B shows a TGA thermogram of crystalline form P.
  • Fig. 17C shows a DSC thermogram of crystalline form P.
  • Fig. 17D shows the 1 H NMR of crystalline form P.
  • Fig. 18A shows a XRPD pattern of crystalline form Q.
  • Fig. 18B shows a TGA thermogram of crystalline form Q.
  • Fig. 18C shows a DSC thermogram of crystalline form Q.
  • Fig. 18D shows the 1 H NMR of crystalline form Q.
  • Fig. 19A shows a XRPD pattern of crystalline form R.
  • Fig. 19B shows a TGA thermogram of crystalline form R.
  • Fig. 19C shows a DSC thermogram of crystalline form R.
  • Fig. 19D shows the 1 H NMR of crystalline form R.
  • Fig. 20A –Fig. 20C show DVS diagrams of crystalline forms G, H and I, respectively.
  • Fig. 21A –Fig. 21C show the XRPD patterns of crystalline forms G, H and I before and after DVS analysis, respectively.
  • Fig. 22 shows the dynamic solubility diagrams of crystalline forms C, G, H and I.
  • Fig. 23 shows XRPD overlays of crystalline form G tested for solubility in various mediums: (A) in H 2 O, (B) in FaSSIF, (C) FeSSIF.
  • Fig. 24 shows XRPD overlays of crystalline form H tested for solubility in various mediums: (A) in H 2 O, (B) in SGF, (C) in FaSSIF, (D) FeSSIF.
  • Fig. 25 shows XRPD overlays of crystalline form I tested for solubility in various mediums: (A) in FaSSIF, (B) FeSSIF.
  • Fig. 26 shows XRPD overlays of crystalline form C tested for solubility in various mediums: (A) in H 2 O, (B) in SGF, (C) in FaSSIF, (D) FeSSIF.
  • Fig. 27 shows XRPD overlays of crystalline form G tested for physical stability under various conditions: (A) 25°C/60%RH/1 week and 25°C/60%RH/4 weeks, (B) 40°C/75%RH/1 week and 40°C/75%RH/4 weeks, and (C) 80°C/1 day and 80°C/22 days.
  • Fig. 28 shows XRPD overlays of crystalline form H tested for physical stability under various conditions: (A) 25°C/60%RH/1 week and 25°C/60%RH/4 weeks, (B) 40°C/75%RH/1 week and 40°C/75%RH/4 weeks, and (C) 80°C/1 day and 80°C/22 days.
  • Fig. 29 shows XRPD overlays of crystalline form I tested for physical stability under various conditions: (A) 25°C/60%RH/1 week and 25°C/60%RH/4 weeks, (B) 40°C/75%RH/1 week and 40°C/75%RH/4 weeks, and (C) 80°C/1 day and 80°C/22 days.
  • Fig. 30A –Fig. 30C show PLM diagrams of crystalline forms G, H and I, respectively.
  • Fig. 31 shows a XRPD pattern of starting crystalline form A.
  • Compound I refers to a compound having the following structure:
  • crystal form As used herein, the terms “crystal form” , “crystalline form” and “Form” interchangeably refer to a crystal structure (or polymorph) having a particular molecular packing arrangement in the crystal lattice. Crystalline forms can be identified and distinguished from each other by one or more characterization techniques including, for example, X-ray powder diffraction (XRPD) , single crystal X-ray diffraction, differential scanning calorimetry (DSC) , thermogravimetric analysis (TGA) , and/or dynamic vapor sorption (DVS) .
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • DVD dynamic vapor sorption
  • crystalline Form [X] of Compound I refers to unique crystalline forms that can be identified and distinguished from each other by one or more characterization techniques including, for example, X-ray powder diffraction (XRPD) , single crystal X-ray diffraction, differential scanning calorimetry (DSC) , thermogravimetric analysis (TGA) , and/or dynamic vapor sorption (DVS) .
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • DVD dynamic vapor sorption
  • the novel crystalline forms are characterized by an X-ray powder diffractogram having one or more signals at one or more specified two-theta values (° 2 ⁇ ) .
  • solvate refers to a crystal form comprising one or more molecules of the compound of the present disclosure and, incorporated into the crystal lattice, one or more molecules of a solvent or solvents in stoichiometric or nonstoichiometric amounts.
  • solvent water
  • solvate is referred to as a “hydrate. ”
  • XRPD refers to the analytical characterization method of X-ray powder diffraction.
  • X-ray powder diffractogram X-ray powder diffraction pattern
  • XRPD pattern XRPD pattern
  • an X-ray powder diffractogram may include one or more broad signals; and for a crystalline material, an X-ray powder diffractogram may include one or more signals, each identified by its angular value as measured in degrees 2 ⁇ (° 2 ⁇ ) , depicted on the abscissa of an X-ray powder diffractogram.
  • a “peak” as used herein refers to a point in the XRPD pattern where the intensity as measured in counts is at a local maximum.
  • One of ordinary skill in the art would recognize that one or more signals (or peaks) in an XRPD pattern may overlap and may, for example, not be apparent to the naked eye. Indeed, one of ordinary skill in the art would recognize that some art-recognized methods are capable of and suitable for determining whether a signal exists in a pattern, such as Rietveld refinement.
  • the repeatability of the measured angular values is in the range of ⁇ 0.2° 2 ⁇ , i.e., the angular value can be at the recited angular value + 0.2 degrees two-theta, the angular value -0.2 degrees two-theta, or any value between those two end points (angular value +0.2 degrees two-theta and angular value -0.2 degrees two-theta) .
  • the repeatability of the measured angular values is in the range of ⁇ 0.1° 2 ⁇ .
  • peak intensities refers to relative signal intensities within a given X-ray powder diffractogram. Factors that can affect the relative signal or peak intensities include sample thickness and preferred orientation (e.g., the crystalline particles are not distributed randomly) .
  • an X-ray powder diffractogram is “substantially similar to that in [aparticular] Figure” when at least 90%, such as at least 95%, at least 98%, or at least 99%, of the peaks in the two diffractograms overlap.
  • substantially similarity one of ordinary skill in the art will understand that there may be variation in the intensities and/or signal positions in XRPD diffractograms even for the same crystalline form.
  • the signal maximum values in XRPD diffractograms (in degrees two-theta (°2 ⁇ ) referred to herein) generally mean that value is identified as ⁇ 0.2 degrees 2 ⁇ of the reported value, an art-recognized variance. In some embodiments, the signal variance is identified as ⁇ 0.1 degrees 2 ⁇ of the reported value.
  • the terms “about” and “substantially” indicate with respect to features such as endotherms, endothermic peak, exotherms, baseline shifts, etc., that their values can vary.
  • “about” or “substantially” means that typical peak position and intensity variability are taken into account.
  • the peak positions (2 ⁇ ) will show some inter-apparatus variability, typically as much as 0.2°. Occasionally, the variability could be higher than 0.2° depending on apparatus calibration differences.
  • amorphous refers to a solid form of a molecule, atom, and/or ions that is not crystalline. An amorphous solid does not display a definitive X-ray diffraction pattern.
  • substantially pure when used in reference to a form, means a compound having a purity greater than 90 weight %, including greater than 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99 weight %, and also including equal to about 100 weight %of Compound I, based on the weight of the compound.
  • the remaining material comprises other form (s) of the compound, and/or reaction impurities and/or processing impurities arising from its preparation.
  • a crystalline form of Compound I may be deemed substantially pure in that it has a purity greater than 90 weight %, as measured by means that are at this time known and generally accepted in the art, where the remaining less than 10 weight %of material comprises other form (s) of Compound I and/or reaction impurities and/or processing impurities.
  • composition refers to a formulation containing the compound or crystalline forms thereof provided herein in a form suitable for administration to a subject.
  • 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 herein includes both one and more than one such excipient.
  • pharmaceutically acceptable excipient also encompasses “pharmaceutically acceptable carrier” and “pharmaceutically acceptable diluent” .
  • the term “therapeutically effective amount” refers to an amount of a molecule, compound, or composition comprising the molecule or compound 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; the rate of administration; the therapeutic or combination of therapeutics selected for administration; and the discretion of the prescribing physician.
  • Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.
  • a “subject” refers to a human and a non-human animal.
  • a non-human animal include all vertebrates, e.g., mammals, such as non-human primates (particularly higher primates) , dog, rodent (e.g., mouse or rat) , guinea pig, cat, and non-mammals, such as birds, amphibians, reptiles, etc.
  • the subject is a human.
  • the subject is an experimental animal or animal suitable as a disease model.
  • the present disclosure relates to a crystalline form B of Compound I, characterized by an X-ray powder diffractogram (XRPD) pattern comprising one or more peaks at 5.91, 18.06, and 18.30 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form B further comprises one or more peaks at 11.80, 17.74, 19.92, 23.73 and 24.95 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form B further comprises one or more peaks at 10.77, 12.62, 16.35, 17.48, 20.24, 23.40, 25.42 and 29.01 ( ⁇ 0.2° 2 ⁇ ) .
  • the crystalline form B is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
  • the crystalline form B is characterized by an XRPD pattern comprising one or more peaks as shown in Fig. 1A. In some embodiments, crystalline form B is characterized by an XRPD pattern substantially as shown in Fig. 1A.
  • the crystalline form B is characterized by a thermogravimetric analysis (TGA) thermogram substantially as shown in Fig. 1B.
  • TGA thermogravimetric analysis
  • the crystalline form B is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset temperature of about 247.0°C.
  • DSC differential scanning calorimetry
  • the crystalline form B is characterized by a DSC thermogram substantially as shown in Fig. 1C.
  • the crystalline form B is in substantially pure form. In another embodiment, the crystalline form B has a purity of at least 80wt%, at least 85wt%, at least 86wt%, at least 87wt%, at least 88wt%, at least 89wt%, at least 90wt%, at least 91wt%, at least 92wt%, at least 93wt%, at least 94wt%, at least 95wt%, at least 96wt%, at least 97wt%, at least 98wt%, or at least 99wt%.
  • the present disclosure relates to a crystalline form C of Compound I characterized by an XRPD pattern comprising one or more peaks at 5.85, 17.52, 19.2 and 23.59 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form C further comprises one or more peaks at 10.41, 11.67, 15.63 and 18.17 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form C further comprises one or more peaks at 16.84, 17.09, 17.25, 20.36, 25.80 and 29.50 ( ⁇ 0.2° 2 ⁇ ) .
  • the crystalline form C is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
  • the crystalline form C is characterized by an XRPD pattern comprising one or more peaks as shown in Fig. 2A. In some embodiments, crystalline form C is characterized by an XRPD pattern substantially as shown in Fig. 2A.
  • the crystalline form C is characterized by a TGA thermogram substantially as shown in Fig. 2B.
  • the crystalline form C is characterized by a DSC thermogram having an endotherm with an onset temperature of about 248.3°C.
  • the crystalline form C is characterized by a DSC thermogram substantially as shown in Fig. 2C.
  • the crystalline form C is in substantially pure form. In another embodiment, the crystalline form C has a purity of at least 80wt%, at least 85wt%, at least 86wt%, at least 87wt%, at least 88wt%, at least 89wt%, at least 90wt%, at least 91wt%, at least 92wt%, at least 93wt%, at least 94wt%, at least 95wt%, at least 96wt%, at least 97wt%, at least 98wt%, or at least 99wt%.
  • the present disclosure relates to a crystalline form D of Compound I, characterized by an XRPD pattern comprising one or more peaks at 5.39, 18.12 and 18.32 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form D further comprises one or more peaks at 10.53, 16.64, and 23.53 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form D further comprises one or more peaks at 15.56, 16.21, 18.56, 19.00 and 23.92 ( ⁇ 0.2° 2 ⁇ ) .
  • the crystalline form D is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
  • the crystalline form D is characterized by an XRPD pattern comprising one or more peaks as shown in Fig. 3A. In some embodiments, crystalline form D is characterized by an XRPD pattern substantially as shown in Fig. 3A.
  • the crystalline form D is characterized by a TGA thermogram substantially as shown in Fig. 3B.
  • the crystalline form D is characterized by a DSC thermogram having an endotherm with an onset temperature of about 245.3°C.
  • the crystalline form D is characterized by a DSC thermogram substantially as shown in Fig. 3C.
  • the crystalline form D is in substantially pure form. In another embodiment, the crystalline form D has a purity of at least 80wt%, at least 85wt%, at least 86wt%, at least 87wt%, at least 88wt%, at least 89wt%, at least 90wt%, at least 91wt%, at least 92wt%, at least 93wt%, at least 94wt%, at least 95wt%, at least 96wt%, at least 97wt%, at least 98wt%, or at least 99wt%.
  • the present disclosure relates to a crystalline form E of Compound I characterized by an XRPD pattern comprising one or more peaks at 17.29, 17.58, and 19.80 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form E further comprises one or more peaks at 4.39, 10.05, 18.16, and 23.66 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form E further comprises one or more peaks at 13.16, 16.86, 18.68, and 19.53 ( ⁇ 0.2° 2 ⁇ ) .
  • the crystalline form E is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
  • the crystalline form E is characterized by an XRPD pattern comprising one or more peaks as shown in Fig. 4A. In some embodiments, crystalline form E is characterized by an XRPD pattern substantially as shown in Fig. 4A.
  • the crystalline form E is characterized by a thermogravimetric analysis (TGA) thermogram substantially as shown in Fig. 4B.
  • TGA thermogravimetric analysis
  • the crystalline form E is characterized by a DSC thermogram having endotherms with onset temperatures of about 101.1°C and 229.7°C.
  • the crystalline form E is characterized by a DSC thermogram having an exothermal with an onset temperature of about 149.2°C.
  • the crystalline form E is characterized by a DSC thermogram substantially as shown in Fig. 4C.
  • the crystalline form E is a NMP solvate. In some embodiments, the molar ratio between NMP and the Compound I is about 0.9: 1.
  • the crystalline form E is in substantially pure form. In some embodiments, the crystalline form E has a purity of at least 80wt%, at least 85wt%, at least 86wt%, at least 87wt%, at least 88wt%, at least 89wt%, at least 90wt%, at least 91wt%, at least 92wt%, at least 93wt%, at least 94wt%, at least 95wt%, at least 96wt%, at least 97wt%, at least 98wt%, or at least 99wt%.
  • the present disclosure relates to a crystalline form F of Compound I, characterized by an XRPD pattern comprising one or more peaks at 17.93, 18.19, and 19.80 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form F further comprises one or more peaks at 16.70, 18.96, 20.41, 24.95, and 27.68 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form F further comprises one or more peaks at 6.11, 12.19, 12.80, and 18.96 ( ⁇ 0.2° 2 ⁇ ) .
  • the crystalline form F is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
  • the crystalline form F is characterized by an XRPD pattern comprising one or more peaks as shown in Fig. 5A. In some embodiments, crystalline form F is characterized by an XRPD pattern substantially as shown in Fig. 5A.
  • the crystalline form F is characterized by a TGA thermogram substantially as shown in Fig. 5B.
  • the crystalline form F is characterized by a differential scanning calorimetry (DSC) thermogram having endotherms with onset temperatures of about 79.7°C, 220.8°C and 249.1°C.
  • DSC differential scanning calorimetry
  • the crystalline form F is characterized by a DSC thermogram having an exothermal with an onset temperature of about 222.3°C.
  • the crystalline form F is characterized by a DSC thermogram substantially as shown in Fig. 5C.
  • the crystalline form F is a hydrate.
  • the crystalline form F is in substantially pure form. In some embodiments, the crystalline form F has a purity of at least 80wt%, at least 85wt%, at least 86wt%, at least 87wt%, at least 88wt%, at least 89wt%, at least 90wt%, at least 91wt%, at least 92wt%, at least 93wt%, at least 94wt%, at least 95wt%, at least 96wt%, at least 97wt%, at least 98wt%, or at least 99wt%.
  • the present disclosure relates to a crystalline form G of the maleate of Compound I, characterized by an XRPD pattern comprising one or more peaks at 18.30, 18.72 and 24.73 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form G further comprises one or more peaks at 6.89, 14.17, 15.36 and 24.73 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form G further comprises one or more peaks at 16.5, 21.13, 25.73, 26.94 and 28.83 ( ⁇ 0.2° 2 ⁇ ) .
  • the crystalline form G is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
  • the crystalline form G is characterized by an XRPD pattern comprising one or more peaks as shown in Fig. 8A. In some embodiments, crystalline form G is characterized by an XRPD pattern substantially as shown in Fig. 8A.
  • the crystalline form G is characterized by a TGA thermogram substantially as shown in Fig. 8B.
  • the crystalline form G is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset temperature of about 158.0°C.
  • DSC differential scanning calorimetry
  • the crystalline form G is characterized by a DSC thermogram substantially as shown in Fig. 8C.
  • the crystalline form G is an anhydrate. In some embodiments, the molar ratio between maleic acid and the Compound I is about 1: 1.
  • the crystalline form G is in substantially pure form. In some embodiments, the crystalline form G has a purity of at least 80wt%, at least 85wt%, at least 86wt%, at least 87wt%, at least 88wt%, at least 89wt%, at least 90wt%, at least 91wt%, at least 92wt%, at least 93wt%, at least 94wt%, at least 95wt%, at least 96wt%, at least 97wt%, at least 98wt%, or at least 99wt%.
  • the present disclosure relates to a crystalline form H of the fumarate of Compound I, characterized by an XRPD pattern comprising one or more peaks at 6.37, 7.65, 17.48 and 19.40 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form H further comprises one or more peaks at 12.72, 13.70, 21.45 and 22.79 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form H further comprises one or more peaks at 9.00, 15.41, 18.14, 27.25 and 28.00 ( ⁇ 0.2° 2 ⁇ ) .
  • the crystalline form H is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
  • the crystalline form H is characterized by an XRPD pattern comprising one or more peaks as shown in Fig. 9A. In some embodiments, crystalline form H is characterized by an XRPD pattern substantially as shown in Fig. 9A.
  • the crystalline form H is characterized by a TGA thermogram substantially as shown in Fig. 9B.
  • the crystalline form H is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset temperature of about 201.1°C.
  • DSC differential scanning calorimetry
  • the crystalline form H is characterized by a DSC thermogram substantially as shown in Fig. 9C.
  • the crystalline form H is an anhydrate. In some embodiments, the molar ratio between fumaric acid and the Compound I is about 1: 1.
  • the crystalline form H is in substantially pure form. In some embodiments, the crystalline form H has a purity of at least 80wt%, at least 85wt%, at least 86wt%, at least 87wt%, at least 88wt%, at least 89wt%, at least 90wt%, at least 91wt%, at least 92wt%, at least 93wt%, at least 94wt%, at least 95wt%, at least 96wt%, at least 97wt%, at least 98wt%, or at least 99wt%.
  • the present disclosure relates to a crystalline form I of the mesylate of Compound I, characterized by an XRPD pattern comprising one or more peaks at 16.62, 17.37, 18.09, 19.75 and 20.42 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form I further comprises one or more peaks at 9.04, 15.73, 19.36, 21.75 and 24.07 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form I further comprises one or more peaks at 10.68, 22.14, 26.04, 29.08 and 30.84 ( ⁇ 0.2° 2 ⁇ ) .
  • the crystalline form I is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
  • the crystalline form I is characterized by an XRPD pattern comprising one or more peaks as shown in Fig. 10A. In some embodiments, crystalline form I is characterized by an XRPD pattern substantially as shown in Fig. 10A.
  • the crystalline form I is characterized by a TGA thermogram substantially as shown in Fig. 10B.
  • the crystalline form I is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset temperature of about 251.0°C.
  • DSC differential scanning calorimetry
  • the crystalline form I is characterized by a differential scanning calorimetry (DSC) thermogram having an exotherm with an onset temperature of about 257.9°C.
  • DSC differential scanning calorimetry
  • the crystalline form I is characterized by a DSC thermogram substantially as shown in Fig. 10C.
  • the crystalline form I is an anhydrate. In some embodiments, the molar ratio between methylsulfonic acid and the Compound I is about 1: 1.
  • the crystalline form I is in substantially pure form. In some embodiments, the crystalline form I has a purity of at least 80wt%, at least 85wt%, at least 86wt%, at least 87wt%, at least 88wt%, at least 89wt%, at least 90wt%, at least 91wt%, at least 92wt%, at least 93wt%, at least 94wt%, at least 95wt%, at least 96wt%, at least 97wt%, at least 98wt%, or at least 99wt%.
  • the present disclosure relates to a crystalline form J of the phosphate of Compound I, characterized by an XRPD pattern comprising one or more peaks at 18.03, 18.22, 18.96, 19.64 and 19.93 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form J further comprises one or more peaks at 11.67, 17.45, 22.56 and 24.22 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form J further comprises one or more peaks at 4.99, 9.35, 10.26, 16.14, 21.94 and 23.10 ( ⁇ 0.2° 2 ⁇ ) .
  • the crystalline form J is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
  • the crystalline form J is characterized by an XRPD pattern comprising one or more peaks as shown in Fig. 11A. In some embodiments, crystalline form J is characterized by an XRPD pattern substantially as shown in Fig. 11A.
  • the crystalline form J is characterized by a TGA thermogram substantially as shown in Fig. 11B.
  • the crystalline form J is characterized by a differential scanning calorimetry (DSC) thermogram having endotherms with peak temperatures of about 129.3°C, 200.1°C and 235.3°C.
  • DSC differential scanning calorimetry
  • the crystalline form J is characterized by a DSC thermogram substantially as shown in Fig. 11C.
  • the molar ratio between phosphoric acid and the Compound I is about 0.5: 1.
  • the crystalline form J is in substantially pure form. In some embodiments, the crystalline form J has a purity of at least 80wt%, at least 85wt%, at least 86wt%, at least 87wt%, at least 88wt%, at least 89wt%, at least 90wt%, at least 91wt%, at least 92wt%, at least 93wt%, at least 94wt%, at least 95wt%, at least 96wt%, at least 97wt%, at least 98wt%, or at least 99wt%.
  • the present disclosure relates to a crystalline form K of the phosphate of Compound I, characterized by an XRPD pattern comprising one or more peaks at 10.67, 18.00, 19.35 and 25.71 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form K further comprises one or more peaks at 4.18, 15.90, 16.64, 18.48 and 18.86 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form K further comprises one or more peaks at 19.71, 20.14, 23.39, 24.95 and 27.14 ( ⁇ 0.2° 2 ⁇ ) .
  • the crystalline form K is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
  • the crystalline form K is characterized by an XRPD pattern comprising one or more peaks as shown in Fig. 12A. In some embodiments, crystalline form K is characterized by an XRPD pattern substantially as shown in Fig. 12A.
  • the crystalline form K is characterized by a TGA thermogram substantially as shown in Fig. 12B.
  • the crystalline form K is characterized by a differential scanning calorimetry (DSC) thermogram having endotherms with peak temperatures of about 101.1°C, 127.2°C, 141.6°C, 171.8°C and 220.8°C.
  • DSC differential scanning calorimetry
  • the crystalline form K is characterized by a DSC thermogram substantially as shown in Fig. 12C.
  • the molar ratio between phosphoric acid and the Compound I is about 1.1: 1.
  • the crystalline form K is in substantially pure form. In some embodiments, the crystalline form K has a purity of at least 80wt%, at least 85wt%, at least 86wt%, at least 87wt%, at least 88wt%, at least 89wt%, at least 90wt%, at least 91wt%, at least 92wt%, at least 93wt%, at least 94wt%, at least 95wt%, at least 96wt%, at least 97wt%, at least 98wt%, or at least 99wt%.
  • the present disclosure relates to a crystalline form L of the benzene sulfonate of Compound I, characterized by an XRPD pattern comprising one or more peaks at 7.83, 15.66, 19.84 and 20.52 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form L further comprises one or more peaks at 15.97, 17.28, 17.84, 18.09 and 19.11 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form L further comprises one or more peaks at 14.08, 16.59, 19.39, 21.50, 22.32 and 24.99 ( ⁇ 0.2° 2 ⁇ ) .
  • the crystalline form L is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
  • the crystalline form L is characterized by an XRPD pattern comprising one or more peaks as shown in Fig. 13A. In some embodiments, crystalline form L is characterized by an XRPD pattern substantially as shown in Fig. 13A.
  • the crystalline form L is characterized by a TGA thermogram substantially as shown in Fig. 13B.
  • the crystalline form L is characterized by a differential scanning calorimetry (DSC) thermogram having endotherms with peak temperatures of about 167.3°C and 177.1°C.
  • DSC differential scanning calorimetry
  • the crystalline form L is characterized by a DSC thermogram substantially as shown in Fig. 13C.
  • the molar ratio between benzene sulfonic acid and the Compound I is about 0.9: 1.
  • the crystalline form L is in substantially pure form. In some embodiments, the crystalline form L has a purity of at least 80wt%, at least 85wt%, at least 86wt%, at least 87wt%, at least 88wt%, at least 89wt%, at least 90wt%, at least 91wt%, at least 92wt%, at least 93wt%, at least 94wt%, at least 95wt%, at least 96wt%, at least 97wt%, at least 98wt%, or at least 99wt%.
  • the present disclosure relates to a crystalline form M of the benzene sulfonate of Compound I, characterized by an XRPD pattern comprising one or more peaks at 11.42, 16.40 and 16.89 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form M further comprises one or more peaks at 17.90, 18.65, 21.16, 21.85 and 22.92 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form M further comprises one or more peaks at 7.89, 15.78, 19.52, 20.76 and 24.72 ( ⁇ 0.2° 2 ⁇ ) .
  • the crystalline form M is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
  • the crystalline form M is characterized by an XRPD pattern comprising one or more peaks as shown in Fig. 14A. In some embodiments, crystalline form M is characterized by an XRPD pattern substantially as shown in Fig. 14A.
  • the crystalline form M is characterized by a TGA thermogram substantially as shown in Fig. 14B.
  • the crystalline form M is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset temperature of about 225.9°C.
  • DSC differential scanning calorimetry
  • the crystalline form M is characterized by a differential scanning calorimetry (DSC) thermogram having an exotherm with an onset temperature of about 247.7°C.
  • DSC differential scanning calorimetry
  • the crystalline form M is characterized by a DSC thermogram substantially as shown in Fig. 14C.
  • the molar ratio between benzene sulfonic acid and the Compound I is about 0.9: 1.
  • the crystalline form M is in substantially pure form. In some embodiments, the crystalline form M has a purity of at least 80wt%, at least 85wt%, at least 86wt%, at least 87wt%, at least 88wt%, at least 89wt%, at least 90wt%, at least 91wt%, at least 92wt%, at least 93wt%, at least 94wt%, at least 95wt%, at least 96wt%, at least 97wt%, at least 98wt%, or at least 99wt%.
  • the present disclosure relates to a crystalline form N of the p-tosylate of Compound I, characterized by an XRPD pattern comprising one or more peaks at 8.11, 16.11, 16.51, 17.01, 18.29 and 20.50 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form N further comprises one or more peaks at 11.13, 21.13, 22.33 and 23.12 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form N further comprises one or more peaks at 11.84, 13.75, 14.09, 23.80 and 27.62 ( ⁇ 0.2° 2 ⁇ ) .
  • the crystalline form N is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
  • the crystalline form N is characterized by an XRPD pattern comprising one or more peaks as shown in Fig. 15A. In some embodiments, crystalline form N is characterized by an XRPD pattern substantially as shown in Fig. 15A.
  • the crystalline form N is characterized by a TGA thermogram substantially as shown in Fig. 15B.
  • the crystalline form N is characterized by a differential scanning calorimetry (DSC) thermogram having endotherms with peak temperatures of about 52.5°C and 261.8°C.
  • DSC differential scanning calorimetry
  • the crystalline form N is characterized by a differential scanning calorimetry (DSC) thermogram having an exotherm with an peak temperature of about 264.8°C.
  • DSC differential scanning calorimetry
  • the crystalline form N is characterized by a DSC thermogram substantially as shown in Fig. 15C.
  • the molar ratio between toluenesulfonic acidand the Compound I is about 1: 1.
  • the crystalline form N is in substantially pure form. In some embodiments, the crystalline form N has a purity of at least 80wt%, at least 85wt%, at least 86wt%, at least 87wt%, at least 88wt%, at least 89wt%, at least 90wt%, at least 91wt%, at least 92wt%, at least 93wt%, at least 94wt%, at least 95wt%, at least 96wt%, at least 97wt%, at least 98wt%, or at least 99wt%.
  • the present disclosure relates to a crystalline form O of the ethanedisulfonate of Compound I, characterized by an XRPD pattern comprising one or more peaks at 7.62, 19.63, 20.06, 21.29 and 21.66 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form O further comprises one or more peaks at 8.86, 11.82, 15.26, 15.55, 15.92 and 23.96 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form O further comprises one or more peaks at 17.74, 18.67, 23.41, 24.70 and 26.66 ( ⁇ 0.2° 2 ⁇ ) .
  • the crystalline form O is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
  • the crystalline form O is characterized by an XRPD pattern comprising one or more peaks as shown in Fig. 16A. In some embodiments, crystalline form O is characterized by an XRPD pattern substantially as shown in Fig. 16A.
  • the crystalline form O is characterized by a TGA thermogram substantially as shown in Fig. 16B.
  • the crystalline form O is characterized by a differential scanning calorimetry (DSC) thermogram having endotherms with peak temperatures of about 91.2°C, 198.1°C, 277.3°C and 286.5°C.
  • DSC differential scanning calorimetry
  • the crystalline form O is characterized by a DSC thermogram substantially as shown in Fig. 16C.
  • the molar ratio between ethanedisulfonic acid and the Compound I is about 0.9: 1.
  • the crystalline form O is in substantially pure form. In some embodiments, the crystalline form O has a purity of at least 80wt%, at least 85wt%, at least 86wt%, at least 87wt%, at least 88wt%, at least 89wt%, at least 90wt%, at least 91wt%, at least 92wt%, at least 93wt%, at least 94wt%, at least 95wt%, at least 96wt%, at least 97wt%, at least 98wt%, or at least 99wt%.
  • the present disclosure relates to a crystalline form P of the oxalate of Compound I, characterized by an XRPD pattern comprising one or more peaks at 9.35, 16.77, 18.68 and 19.07 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form P further comprises one or more peaks at 12.45, 19.88, 21.50 and 23.60 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form P further comprises one or more peaks at 20.71, 22.59, 24.00 and 28.70 ( ⁇ 0.2° 2 ⁇ ) .
  • the crystalline form P is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
  • the crystalline form P is characterized by an XRPD pattern comprising one or more peaks as shown in Fig. 17A. In some embodiments, crystalline form P is characterized by an XRPD pattern substantially as shown in Fig. 17A.
  • the crystalline form P is characterized by a TGA thermogram substantially as shown in Fig. 17B.
  • the crystalline form P is characterized by a differential scanning calorimetry (DSC) thermogram having endotherms with peak temperatures of about 116.2°C, 182.9°C, 214.7°C and 235.2°C.
  • DSC differential scanning calorimetry
  • the crystalline form P is characterized by a DSC thermogram substantially as shown in Fig. 17C.
  • the molar ratio between oxalic acid and the Compound I is about 0.8: 1.
  • the crystalline form P is in substantially pure form. In some embodiments, the crystalline form P has a purity of at least 80wt%, at least 85wt%, at least 86wt%, at least 87wt%, at least 88wt%, at least 89wt%, at least 90wt%, at least 91wt%, at least 92wt%, at least 93wt%, at least 94wt%, at least 95wt%, at least 96wt%, at least 97wt%, at least 98wt%, or at least 99wt%.
  • the present disclosure relates to a crystalline form Q of the ethanesulfonate of Compound I, characterized by an XRPD pattern comprising one or more peaks at 9.24, 19.44 and 19.66 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form Q further comprises one or more peaks at 5.17, 16.40, 17.33, 17.89, 18.57 and 22.48 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form Q further comprises one or more peaks at 6.80, 14.28, 15.59 and 20.71 ( ⁇ 0.2° 2 ⁇ ) .
  • the crystalline form Q is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
  • the crystalline form Q is characterized by an XRPD pattern comprising one or more peaks as shown in Fig. 18A. In some embodiments, crystalline form Q is characterized by an XRPD pattern substantially as shown in Fig. 18A.
  • the crystalline form Q is characterized by a TGA thermogram substantially as shown in Fig. 18B.
  • the crystalline form Q is characterized by a differential scanning calorimetry (DSC) thermogram having endotherms with peak temperatures of about 72.5°C, 161.2°C, 167.2°C and 242.0°C.
  • DSC differential scanning calorimetry
  • the crystalline form Q is characterized by a DSC thermogram substantially as shown in Fig. 18C.
  • the molar ratio between ethanesulfonic acid and the Compound I is about 1: 1.
  • the crystalline form Q is in substantially pure form. In some embodiments, the crystalline form Q has a purity of at least 80wt%, at least 85wt%, at least 86wt%, at least 87wt%, at least 88wt%, at least 89wt%, at least 90wt%, at least 91wt%, at least 92wt%, at least 93wt%, at least 94wt%, at least 95wt%, at least 96wt%, at least 97wt%, at least 98wt%, or at least 99wt%.
  • the present disclosure relates to a crystalline form R of the hydrobromide of Compound I, characterized by an XRPD pattern comprising one or more peaks at 9.23, 16.84, 25.53 and 27.23 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form R further comprises one or more peaks at 5.54, 17.61, 17.89 and 19.39 ( ⁇ 0.2° 2 ⁇ ) .
  • the XRPD pattern of crystalline form R further comprises one or more peaks at 11.06, 14.21, 14.61, 15.92, 23.1218.49 and 27.83 ( ⁇ 0.2° 2 ⁇ ) .
  • the crystalline form R is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
  • the crystalline form R is characterized by an XRPD pattern comprising one or more peaks as shown in Fig. 19A. In some embodiments, crystalline form R is characterized by an XRPD pattern substantially as shown in Fig. 19A.
  • the crystalline form R is characterized by a TGA thermogram substantially as shown in Fig. 19B.
  • the crystalline form R is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with a peak temperature of about 101.2°C.
  • DSC differential scanning calorimetry
  • the crystalline form R is characterized by a differential scanning calorimetry (DSC) thermogram having exotherms with peak temperatures of about 162.5°C and 209.2°C.
  • DSC differential scanning calorimetry
  • the crystalline form R is characterized by a DSC thermogram substantially as shown in Fig. 19C.
  • the molar ratio between hydrobromic acid and the Compound I is about 1.2: 1.
  • the crystalline form R is in substantially pure form. In some embodiments, the crystalline form R has a purity of at least 80wt%, at least 85wt%, at least 86wt%, at least 87wt%, at least 88wt%, at least 89wt%, at least 90wt%, at least 91wt%, at least 92wt%, at least 93wt%, at least 94wt%, at least 95wt%, at least 96wt%, at least 97wt%, at least 98wt%, or at least 99wt%.
  • Compound I can be synthesized according to methods known to persons skilled in the art, such as the synthetic procedures described in Example 1.
  • compositions comprising Compound I or a salt of Compound I, wherein Compound I or the salt of Compound I is in a crystalline form selected from the group consisting of: the crystalline form B, the crystalline form C, the crystalline form D, the crystalline form E, the crystalline form F, the crystalline form G, the crystalline form H, the crystalline form I, the crystalline form J, the crystalline form K, the crystalline form L, the crystalline form M, the crystalline form N, the crystalline form O, the crystalline form P, the crystalline form Q, and the crystalline form R of the present disclosure.
  • compositions comprising Compound I or a salt of Compound I, wherein Compound I or the salt of Compound I is in a crystalline form selected from the group consisting of: the crystalline form B, the crystalline form C, the crystalline form D, the crystalline form E, the crystalline form F, the crystalline form G, the crystalline form H, the crystalline form I, the crystalline form J, the crystalline form K, the crystalline form L, the crystalline form M, the crystalline form N, the crystalline form O, the crystalline form P, the crystalline form Q and the crystalline form R of the present disclosure, and at least one pharmaceutical acceptable excipient.
  • At least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of Compound I is in crystalline form B.
  • At least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of Compound I is in crystalline form C.
  • At least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of Compound I is in crystalline form D.
  • At least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of Compound I is in crystalline form E.
  • At least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of Compound I is in crystalline form F.
  • At least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form G.
  • At least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form H.
  • At least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form I.
  • At least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form J.
  • At least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form K.
  • At least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form L.
  • At least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form M.
  • At least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form N.
  • At least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form O.
  • At least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form P.
  • At least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form Q.
  • At least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form R.
  • Solvents are generally selected based on solvents recognized by persons skilled in the art as safe to be administered to a mammal including humans.
  • safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water.
  • Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300) , etc. and mixtures thereof.
  • suitable excipients may include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol) ; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, dis
  • suitable excipients may include one or more stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present disclosure or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament) .
  • stabilizing agents i.e., surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present disclosure or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament
  • the active pharmaceutical ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly- (methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • a “liposome” is a small vesicle composed of various types of lipids, phospholipids and/or surfactant which is useful for delivery of a drug (such as the compounds disclosed herein and, optionally, a chemotherapeutic agent) to a mammal including humans.
  • a drug such as the compounds disclosed herein and, optionally, a chemotherapeutic agent
  • the components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes.
  • compositions provided herein can be in any form that allows for the composition to be administered to a subject, including, but not limited to a human, and formulated to be compatible with an intended route of administration.
  • compositions provided herein may be supplied in bulk or in unit dosage form depending on the intended administration route.
  • powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets may be acceptable as solid dosage forms
  • emulsions, syrups, elixirs, suspensions, and solutions may be acceptable as liquid dosage forms.
  • emulsions and suspensions may be acceptable as liquid dosage forms
  • solutions, sprays, dry powders, and aerosols may be acceptable dosage form.
  • powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches may be acceptable dosage form.
  • pessaries, tampons, creams, gels, pastes, foams and spray may be acceptable dosage form.
  • the quantity of active ingredient in a unit dosage form of composition is a therapeutically effective amount and is varied according to the particular treatment involved.
  • therapeutically effective amount refers to an amount of a molecule, compound, or composition comprising the molecule or compound 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; the rate of administration; the therapeutic or combination of therapeutics selected for administration; and the discretion of the prescribing physician.
  • Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.
  • compositions of the present disclosure may be in a form of formulation for oral administration.
  • the pharmaceutical compositions of the present disclosure may be in the form of tablet formulations.
  • suitable pharmaceutically-acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid.
  • Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case using conventional coating agents and procedures well known in the art.
  • the pharmaceutical compositions of the present disclosure may be in a form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • the pharmaceutical compositions of the present disclosure may be in the form of aqueous suspensions, which generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate) , or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • suspending agents such as sodium
  • the aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid) , coloring agents, flavoring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame) .
  • preservatives such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid) , coloring agents, flavoring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame) .
  • the pharmaceutical compositions of the present disclosure may be in the form of oily suspensions, which generally contain suspended active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin) .
  • the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • the pharmaceutical compositions of the present disclosure may be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
  • Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavoring and preservative agents.
  • the pharmaceutical compositions provided herein may be in the form of syrups and elixirs, which may contain sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, a demulcent, a preservative, a flavoring and/or coloring agent.
  • sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, a demulcent, a preservative, a flavoring and/or coloring agent.
  • compositions of the present disclosure may be in a form of formulation for injection administration.
  • the pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents, which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1, 3-butanediol or prepared as a lyophilized powder.
  • a non-toxic parenterally acceptable diluent or solvent such as a solution in 1, 3-butanediol or prepared as a lyophilized powder.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono-or diglycerides.
  • fatty acids such as oleic acid may likewise be used in the preparation of injectables.
  • compositions of the present disclosure may be in a form of formulation for inhalation administration.
  • the pharmaceutical compositions of the present disclosure may be in the form of aqueous and nonaqueous (e.g., in a fluorocarbon propellant) aerosols containing any appropriate solvents and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
  • the carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol) , innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.
  • compositions of the present disclosure may be in a form of formulation for topical or transdermal administration.
  • the pharmaceutical compositions provided herein may be in the form of creams, ointments, gels and aqueous or oily solutions or suspensions, which may generally be obtained by formulating an active ingredient with a conventional, topically acceptable excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • a conventional, topically acceptable excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • compositions provided herein may be formulated in the form of transdermal skin patches that are well known to those of ordinary skill in the art.
  • excipients and carriers are generally known to those skilled in the art and are thus included in the present disclosure.
  • excipients and carriers are described, for example, in “Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991) , in “Remington: The Science and Practice of Pharmacy” , Ed. University of the Sciences in Philadelphia, 21 st Edition, LWW (2005) , which are incorporated herein by reference.
  • the pharmaceutical compositions of the present disclosure can be formulated as a single dosage form.
  • the amount of the compounds provided herein in the single dosage form will vary depending on the subject treated and particular mode of administration.
  • the pharmaceutical compositions of the present disclosure can be formulated so that a dosage of between 0.001-1000 mg/kg body weight/day, for example, 0.01-800 mg/kg body weight/day, 0.01-700 mg/kg body weight/day, 0.01-600 mg/kg body weight/day, 0.01-500 mg/kg body weight/day, 0.01-400 mg/kg body weight/day, 0.01-300 mg/kg body weight/day, 0.1-200 mg/kg body weight/day, 0.1-150 mg/kg body weight/day, 0.1-100 mg/kg body weight/day, 0.5-100 mg/kg body weight/day, 0.5-80 mg/kg body weight/day, 0.5-60 mg/kg body weight/day, 0.5-50 mg/kg body weight/day, 1-50 mg/kg body weight/day, 1-45 mg/kg body weight/day, 1-40 mg/kg body weight/day, 1-35 mg/kg body weight/day, 1-30 mg/kg body weight/day, 1-25 mg/kg body weight/day of the
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
  • routes of administration and dosage regimes see Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board) , Pergamon Press 1990, which is specifically incorporated herein by reference.
  • the pharmaceutical compositions of the present disclosure can be formulated as short-acting, fast-releasing, long-acting, and sustained-releasing. Accordingly, the pharmaceutical formulations of the present disclosure may also be formulated for controlled release or for slow release.
  • compositions comprising one or more molecules or compounds of the present disclosure or pharmaceutically acceptable salts thereof and a veterinary carrier.
  • Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.
  • an article for distribution can include a container having deposited therein the compositions in an appropriate form.
  • suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass) , sachets, ampoules, plastic bags, metal cylinders, and the like.
  • the container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package.
  • the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
  • compositions may also be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use.
  • sterile liquid carrier for example water
  • Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
  • compositions comprise one or more compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, as a first active ingredient, and a second active ingredient.
  • the second active ingredient has complementary activities to the compound provided herein such that they do not adversely affect each other.
  • Such ingredients are suitably present in combination in amounts that are effective for the purpose intended.
  • the second active ingredient can include:
  • antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas) ; antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea and gemcitabine) ; antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin) ; antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorel
  • cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene) , oestrogen receptor down regulators (for example fulvestrant) , antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate) , LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin) , progestogens (for example megestrol acetate) , aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase such as finasteride;
  • antioestrogens for example tamoxifen, toremifene, raloxifene, droloxifene and
  • anti-invasion agents for example c-Src kinase family inhibitors like 4- (6-chloro-2, 3-methylenedioxyanilino) -7- [2- (4-methylpiperazin-1-yl) ethoxy] -5-tetrahydropyran-4-yloxyquinazoline (AZD0530) and N- (2-chloro-6-methylphenyl) -2- ⁇ 6- [4- (2-hydroxyethyl) piperazin-1-yl] -2-methylpyrimidin-4-ylamino ⁇ thiazole-5-carboxamide (dasatinib, BMS-354825) , and metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function) ;
  • anti-invasion agents for example c-Src kinase family inhibitors like 4- (6-chloro-2, 3-methylenedioxyanilino) -7- [2- (4-
  • inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [Herceptin TM ] and the anti-erbBl antibody cetuximab [C225] ) ; such inhibitors also include, for example, tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-amine (gefitinib, ZD 1839) , N- (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy) quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N- (3-chloro-4-fluorophenyl) -7
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin TM ) and VEGF receptor tyrosine kinase inhibitors such as 4- (4-bromo-2-fluoroanilino) -6-methoxy-7- (1-methylpiperidin-4- ylmethoxy) quinazoline (ZD6474; Example 2 within WO 01/32651) , 4- (4-fluoro-2-methylindol-5-yloxy) -6-methoxy-7- (3-pyrrolidin-1-ylpropoxy) quinazoline (AZD2171; Example 240 within WO 00/47212) , vatalanib (PTK787; WO 98/35985) and SU11248 (sunitinib; WO 01/60814) , and compounds that work by other mechanisms (for example linom
  • vascular damaging agents such as combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
  • antisense therapies such as ISIS 2503, an anti-ras antisense agent
  • gene therapy approaches including approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
  • immunotherapeutic approaches including ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte -macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-trtnsfected tumour cell lines and approaches using anti-idiotypic antibodies.
  • cytokines such as interleukin 2, interleukin 4 or granulocyte -macrophage colony stimulating factor
  • the present disclosure provides crystalline forms of Compound I or a salt of Compound I, which are capable of inhibiting ATR kinase.
  • the inhibitory properties of crystalline forms of Compound I or a salt of Compound I may be demonstrated using the test procedures set out herein.
  • crystalline forms of Compound I or a salt of Compound I may be used in the treatment (therapeutic or prophylactic) of conditions or diseases in a subject which are mediated by ATR kinase.
  • the crystalline forms of Compound I or a salt of Compound I can be used as anti-tumour agents. In some embodiments, the crystalline forms of Compound I or a salt of Compound I can be used as anti-proliferative, apoptotic and/or anti-invasive agents in the containment and/or treatment of solid and/or liquid tumour disease. In certain embodiments, the crystalline forms of Compound I or a salt of Compound I are useful in the prevention or treatment of those tumours which are sensitive to inhibition of ATR. In certain embodiments, the crystalline forms of Compound I or a salt of Compound I are useful in the prevention or treatment of those tumours which are mediated alone or in part by ATR.
  • the crystalline forms of Compound I or a salt of Compound I are useful for the treatment of proliferative diseases, including malignant diseases such as cancer as well as non-malignant diseases such as inflammatory diseases, obstructive airways diseases, immune diseases or cardiovascular diseases.
  • the crystalline forms of Compound I or a salt of Compound I are useful for the treatment of cancer, for example but not limited to, haematologic malignancies such as leukaemia, multiple myeloma, lymphomas such as Hodgkin's disease, non-Hodgkin's lymphomas (including mantle cell lymphoma) , and myelodysplastic syndromes, and also solid tumours and their metastases such as breast cancer, lung cancer (non-small cell lung cancer (NSCL) , small cell lung cancer (SCLC) , squamous cell carcinoma) , endometrial cancer, tumours of the central nervous system such as gliomas, dysembryoplastic neuroepithelial tumour, glioblastoma multiforme, mixed gliomas, medulloblastoma, retinoblastoma, neuroblastoma, germinoma and teratoma, cancers of the gastrointestinal tract such as gastric cancer, o
  • the crystalline forms of Compound I or a salt of Compound I are useful for the treatment of autoimmune and/or inflammatory diseases, for example but not limited to, allergy, Alzheimer's disease, acute disseminated encephalomyelitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune hemolytic and thrombocytopenic states, autoimmune hepatitis, autoimmune inner ear disease, bullous pemphigoid, coeliac disease, chagas disease, chronic obstructive pulmonary disease, chronic Idiopathic thrombocytopenic purpura (ITP) , churg-strauss syndrome, Crohn's disease, dermatomyositis, diabetes mellitus type 1, endometriosis, Goodpasture's syndrome (and associated glomerulonephritis and pulmonary hemorrhage) , graves' disease, guillain
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total) , whether detectable or undetectable. “Therapy” can also mean prolonging survival as compared to expected survival if not receiving it.
  • Those in need of therapy include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
  • the term “therapy” also encompasses prophylaxis unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be interpreted in a corresponding manner.
  • prophylaxis or “prophylactic” is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the disease and secondary prophylaxis whereby the disease has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the disease.
  • treatment is used synonymously with “therapy” .
  • treat can be regarded as “applying therapy” where “therapy” is as defined herein.
  • the present disclosure provides use of the crystalline form of the present disclosure or the pharmaceutical composition of the present disclosure for use in therapy, for example, for use in therapy associated with ATR kinase.
  • the present disclosure provides use of the crystalline form of the present disclosure or the pharmaceutical composition of the present disclosure, in the manufacture of a medicament for treating cancer.
  • the present disclosure provides use of the crystalline form of the present disclosure or the pharmaceutical composition of the present disclosure, in the manufacture of a medicament for treating cancer.
  • the present disclosure provides a crystalline form of the present disclosure or a pharmaceutical composition of the present disclosure, for use in the treatment of cancer.
  • the crystalline forms of Compound I or a salt of Compound I can be used further combination with other biologically active ingredients (such as, but not limited to, a second and different antineoplastic agent) and non-drug therapies (such as, but not limited to, surgery or radiation treatment) .
  • the crystalline forms of Compound I or a salt of Compound I can be used in combination with other pharmaceutically active compounds, or non-drug therapies, preferably compounds that are able to enhance the effect of the crystalline forms of Compound I or a salt of Compound I.
  • the crystalline forms of Compound I or a salt of Compound I can be administered simultaneously (as a single preparation or separate preparation) or sequentially to the other therapies.
  • a combination therapy envisions administration of two or more drugs/treatments during a single cycle or course of therapy.
  • the crystalline forms of Compound I or a salt of Compound I are used in combination with one or more of traditional chemotherapeutic agents, which encompass a wide range of therapeutic treatments in the field of oncology. These agents are administered at various stages of the disease for the purposes of shrinking tumors, destroying remaining cancer cells left over after surgery, inducing remission, maintaining remission and/or alleviating symptoms relating to the cancer or its treatment.
  • the crystalline forms of Compound I or a salt of Compound I are used in combination with one or more targeted anti-cancer agents that modulate protein kinases involved in various disease states.
  • the crystalline forms of Compound I or a salt of Compound I are used in combination with one or more targeted anti-cancer agents that modulate non-kinase biological targets, pathway, or processes.
  • the crystalline forms of Compound I or a salt of Compound I are used in combination with one or more of other anti-cancer agents that include, but are not limited to, gene therapy, RNAi cancer therapy, chemoprotective agents (e.g., amfostine, mesna, and dexrazoxane) , drug-antibody conjugate (e.g brentuximab vedotin, ibritumomab tioxetan) , cancer immunotherapy such as Interleukin-2, cancer vaccines (e.g., sipuleucel-T) or monoclonal antibodies (e.g., Bevacizumab, Alemtuzumab, Rituximab, Trastuzumab, etc) .
  • other anti-cancer agents include, but are not limited to, gene therapy, RNAi cancer therapy, chemoprotective agents (e.g., amfostine, mesna, and dexrazoxane)
  • the crystalline forms of Compound I or a salt of Compound I are used in combination with one or more anti-inflammatory agent including but not limited to NSAIDs, non-specific and COX-2 specific cyclooxgenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptors antagonists, immunosuppressants and methotrexate.
  • one or more anti-inflammatory agent including but not limited to NSAIDs, non-specific and COX-2 specific cyclooxgenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptors antagonists, immunosuppressants and methotrexate.
  • the crystalline forms of Compound I or a salt of Compound I are used in combination with radiation therapy or surgeries.
  • Radiation is commonly delivered internally (implantation of radioactive material near cancer site) or externally from a machine that employs photon (x-ray or gamma-ray) or particle radiation.
  • the combination therapy further comprises radiation treatment
  • the radiation treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and radiation treatment is achieved.
  • the present disclosure provides a method for treating diseases associated with ATR kinase in a subject in need thereof, comprising administering an effective amount of the crystalline forms of Compound I or a salt of Compound I of the present disclosure or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present disclosure to the subject.
  • Mixed polymer A polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxy propyl methyl cellulose and methyl cellulose (mixed with equivalent mass)
  • Mixed polymer B polycaprolactone, polyethylene polyol, polymethyl methacrylate, sodium alginate and hydroxyethyl cellulose (mixed with equivalent mass)
  • DVS curve was determined on DVS Intrinsic of SMS (Surface Measurement Systems) .
  • the relative humidity at 25°C was calibrated with deliquescence points of LiCl, Mg (NO 3 ) 2 and KCl.
  • the DVS measurement was conducted under the following conditions shown in Table 13.
  • Crystalline form B of Compound I can be obtained by methods such as Method C, Method D, Method E or Method F.
  • the XRPD pattern of crystalline form B of Compound I is shown in Fig. 1A.
  • the peaks, interplanar spacings and intensities are shown in Table 15.
  • the TGA thermogram of crystalline form B of Compound I indicates that crystalline form B had a 2.10%weight loss when heated to 210°C.
  • the DSC thermogram of crystalline form B of Compound I reveals a mild exothermal with onset temperature at 214.8°C and a sharp endotherm with onset temperature at 247.0°C.
  • Fig. 1D shows the 1 H NMR of crystalline form B of Compound I, and no solvent was detected. It is deduced that crystalline form B of Compound I is an anhydrate.
  • Crystalline form C of Compound I can be obtained by methods such as Method A, Method B, Method C, Method D, Method E, Method G or Method H.
  • the XRPD pattern of crystalline form C of Compound I is shown in Fig. 3A.
  • the peaks, interplanar spacings and intensities are shown in Table 16.
  • the TGA thermogram of crystalline form C of Compound I indicates that crystalline form C had a 1.1%weight loss when heated to 210°C.
  • the DSC thermogram of crystalline form C reveals a sharp endotherm with onset temperature at 249.2°C.
  • Fig. 2D shows the 1 H NMR of crystalline form C of Compound I, and no solvent was detected. It is deduced that crystalline form C of Compound I is an anhydrate.
  • Crystalline form D of Compound I can be obtained by Method A.
  • the XRPD pattern of crystalline form D of Compound I is shown in Fig. 3A.
  • the peaks, interplanar spacings and intensities are shown in Table 17.
  • the TGA thermogram of crystalline form D of Compound I indicates that crystalline form D had a 7.0%weight loss when heated to 200°C.
  • the DSC thermogram of crystalline form D reveals a sharp endotherm with onset temperature at 245.3°C.
  • Fig. 3D shows the 1 H NMR of crystalline form D of Compound I, and trace residual solvent was detected. It is deduced that crystalline form D of Compound I is a hydrate or an anhydrate.
  • Crystalline form E of Compound I can be obtained by methods such as Method A or Method D.
  • the XRPD pattern of crystalline form E of Compound I is shown in Fig. 4A.
  • the peaks, interplanar spacings and intensities are shown in Table 18.
  • the TGA thermogram of crystalline form E of Compound I indicates that crystalline form E had a 4.2%weight loss when heated to 80°C, and a 29.8%weight loss when further heated to 150°C.
  • the DSC thermogram of crystalline form E of Compound I reveals endotherms with onsets temperatures at 101.1°C and 229.7°C, and an exotherm with onset temperature at 149.2°C.
  • Fig. 4D shows the 1 H NMR of crystalline form E of Compound I, and NMP solvent was detected. It is deduced that crystalline form E of Compound I is a NMP solvate.
  • Crystalline form F of Compound I can be obtained by methods such as Method C, Method D, Method F, Method G, Method H or Method I.
  • the XRPD pattern of crystalline form F of Compound I is shown in Fig. 5A.
  • the peaks, interplanar spacings and intensities are shown in Table 19.
  • the TGA thermogram of crystalline form F of Compound I indicates that crystalline form F had a 6.7%weight loss when heated to 100°C.
  • the DSC thermogram of crystalline form F of Compound I reveals endotherms with onsets temperatures at 79.7°C, 220.8°C and 249.1°C, and an exotherm with onset temperature at 222.3°C.
  • Fig. 5D shows the 1 H NMR of crystalline form F of Compound I. It is deduced that crystalline form F of Compound I is a hydrate.
  • Crystalline form C was evaluated for its hygroscopicity under DVS experiment at 25°C. DVS results are shown in Fig. 2E. Crystalline form C showed 0.25%weight gain at 25°C/80%RH, indicating that it is slightly hygroscopic. XRPD patterns for crystalline form C before and after DVS experiment showed no changes (see Fig. 2F) .
  • Crystalline form C samples were tested under 80°C/Sealed/1 day, 25°C/60%RH/Open/1 week and 40°C/75%RH/Open/1 week for stability studies. Solid samples under different conditions were investigated with XRPD for their physical stability, and with HPLC for their chemical stability. Results are shown in Table 20. XRPD results are shown in Fig. 2G. HPLC results are shown in Table 21 and Fig. 2H. Under 80°C/Sealed/1 day, 25°C/60%RH/Open/1 week and 40°C /75%RH/Open/1 week, crystalline form C showed no transformation or purity decrease, demonstrating its good stability.
  • Example 5.1 Crystalline forms B, C and D
  • Results are summarized in Table 22. Results of XRPD analysis are shown in Fig. 6A and Fig. 6B.
  • Example 5.2 Crystalline forms C, D and F
  • Results are summarized in Table 23. Results of XRPD analysis are shown in Fig. 7A and Fig. 7B.
  • DVS curve was determined on DVS Intrinsic of SMS (Surface Measurement Systems) .
  • the relative humidity at 25°C was calibrated with deliquescence points of LiCl, Mg (NO 3 ) 2 and KCl.
  • the DVS measurement was conducted under the following conditions shown in Table 27.
  • Crystalline form G of the maleate of Compound I can be obtained by suspending and stirring the starting crystalline form A of Compound I and equimolar maleic acid in EtOAc at room temperature for 3 days and drying the solid under vacuum at room temperature for 12 hours.
  • the XRPD pattern of crystalline form G of the maleate of Compound I is shown in Fig. 8A.
  • the peaks, interplanar spacings and intensities are shown in Table 30.
  • the TGA thermogram of crystalline form G of the maleate of Compound I indicates that crystalline form G had a 5.3%weight loss when heated to 150°C.
  • the DSC thermogram of crystalline form G of the maleate of Compound I reveals an endotherm with an onset temperature at 158.0°C.
  • Fig. 8D shows the 1 H NMR of crystalline form G of the maleate of Compound I. It is deduced that crystalline form G of the maleate of Compound I is an anhydrate, and the molar ratio between maleic acid and the Compound I is about 1: 1.
  • the UPLC results as shown in Table 31 indicate that the purity of crystalline form G is 98.38%.
  • Crystalline form H of the fumarate of Compound I can be obtained by suspending and stirring the starting crystalline form A of Compound I and equimolar fumaric acid in EtOAc at room temperature for 3 days and drying the solid under vacuum at room temperature for 12 hours.
  • the XRPD pattern of crystalline form H of the fumarate of Compound I is shown in Fig. 9A.
  • the peaks, interplanar spacings and intensities are shown in Table 32.
  • the TGA thermogram of crystalline form H of the fumarate of Compound I indicates that crystalline form H had a 4.6%weight loss when heated to 150°C.
  • the DSC thermogram of crystalline form H of the fumarate of Compound I reveals an endotherm with an onset temperature at 201.1°C.
  • Fig. 9D shows the 1 H NMR of crystalline form H of the fumarate of Compound I. It is deduced that crystalline form H of the fumarate of Compound I is an anhydrate, and the molar ratio between fumaric acid and the Compound I is about 1: 1.
  • the UPLC results as shown in Table 33 indicate that the purity of crystalline form H is 99.11%.
  • the PLM diagram reveals significant melting occurs at around 200°C.
  • Crystalline form I of the mesylate of Compound I can be obtained by suspending and stirring the starting crystalline form A of Compound I and equimolar methanesulfonic acid in EtOAc at room temperature for 3 days and drying the solid under vacuum at room temperature for 12 hours.
  • the XRPD pattern of crystalline form I of the mesylate of Compound I is shown in Fig. 10A.
  • the peaks, interplanar spacings and intensities are shown in Table 34.
  • the TGA thermogram of crystalline form I of the mesylate of Compound I indicates that crystalline form I had a 2.2%weight loss when heated to 240°C.
  • the DSC thermogram of crystalline form I of the mesylate of Compound I reveals an endotherm with an onset temperature at 251.0°C, and an exotherm with a peak temperature at 257.9°C.
  • Fig. 10D shows the 1 H NMR of crystalline form I of the mesylate of Compound I.
  • crystalline form I of the mesylate of Compound I is an anhydrate, and the molar ratio between methylsulfonic acid and the Compound I is about 1: 1.
  • the UPLC results as shown in Table 35 indicate that the purity of crystalline form I is 98.75%.
  • the PLM diagram reveals significant melting occurs at around 257°C.
  • Crystalline form J of the phosphate of Compound I can be obtained by suspending and stirring the starting crystalline form A of Compound I and equimolar phosphoric acid in EtOAc at room temperature for 2 days and drying the solid under vacuum at room temperature for 12 hours.
  • the XRPD pattern of crystalline form J of the phosphate of Compound I is shown in Fig. 11A.
  • the peaks, interplanar spacings and intensities are shown in Table 36.
  • the TGA thermogram of crystalline form J of the phosphate of Compound I indicates that crystalline form J had a 3.7%weight loss when heated to 150°C.
  • the DSC thermogram of crystalline form J of the phosphate of Compound I reveals endotherms with peak temperatures at 129.3°C, 200.1°C and 235.3°C.
  • Fig. 11D shows the 1 H NMR of crystalline form J of the phosphate of Compound I. It is deduced that molar ratio between phosphoric acid and the Compound I is about 0.5: 1.
  • the UPLC results as shown in Table 37 reveal that the purity of crystalline form J is 99.72%.
  • Example 6.5 Crystalline form K of the phosphate of Compound I
  • Crystalline form K of the phosphate of Compound I can be obtained by suspending and stirring the starting crystalline form A of Compound I and equimolar phosphoric acid in EtOAc at room temperature for 2 days and drying the solid under vacuum at room temperature for 12 hours.
  • the XRPD pattern of crystalline form K of the phosphate of Compound I is shown in Fig. 12A.
  • the peaks, interplanar spacings and intensities are shown in Table 38.
  • the TGA thermogram of crystalline form K of the phosphate of Compound I indicates that crystalline form K had a 5.7%weight loss when heated to 150°C.
  • the DSC thermogram of crystalline form K of the phosphate of Compound I reveals endotherms with peak temperatures at 101.1°C, 127.2°C, 141.6°C, 171.8°C and 220.8°C.
  • Fig. 12D shows the 1 H NMR of crystalline form K of the phosphate of Compound I. It is deduced that molar ratio between phosphoric acid and the Compound I is about 1.1: 1.
  • the UPLC results as shown in Table 39 reveal that the purity of crystalline form J is 98.95%.
  • Crystalline form L of the benzene sulfonate of Compound I can be obtained by suspending and stirring the starting crystalline form A of Compound I and equimolar benzenesulfonic acid in the EtOAc system at room temperature, followed by centrifugation and drying the solid under vacuum at room temperature for 12 hours.
  • the XRPD pattern of crystalline form L of the benzene sulfonate of Compound I is shown in Fig. 13A.
  • the peaks, interplanar spacings and intensities are shown in Table 40.
  • the TGA thermogram of crystalline form L of the benzene sulfonate of Compound I indicates that crystalline form L had a 6.4%weight loss when heated to 200°C.
  • the DSC thermogram of crystalline form L of the benzene sulfonate of Compound I reveals endotherms with peak temperatures at 167.3°C and 177.1°C.
  • Fig. 13D shows the 1 H NMR of crystalline form L of the benzene sulfonate of Compound I. It is deduced that molar ratio between benzene sulfonic acid and the Compound I is about 0.9: 1.
  • the UPLC results as shown in Table 41 reveal that the purity of crystalline form L is 99.07%.
  • Crystalline form M of the benzene sulfonate of Compound I can be obtained by suspending and stirring the starting crystalline form A of Compound I and equimolar benzenesulfonic acid in 2-MeTHF system at room temperature, followed by centrifugation and drying the solid under vacuum at room temperature for 12 hours.
  • the XRPD pattern of crystalline form K of the benzene sulfonate of Compound I is shown in Fig. 14A.
  • the peaks, interplanar spacings and intensities are shown in Table 42.
  • the TGA thermogram of crystalline form M of the benzene sulfonate of Compound I indicates that crystalline form M had a 3.0%weight loss when heated to 200°C.
  • the DSC thermogram of crystalline form K of the benzene sulfonate of Compound I reveals an endotherm with an onset temperature at 225.9°C, and an exotherm with a peak temperature at 247.7°C.
  • Fig. 14D shows the 1 H NMR of crystalline form M of the benzene sulfonate of Compound I. It is deduced that molar ratio between benzene sulfonic acid and the Compound I is about 0.9: 1.
  • the UPLC results as shown in Table 43 reveal that the purity of crystalline form L is 99.05%.
  • Crystalline form N of the p-tosylate of Compound I can be obtained by suspending and stirring the starting crystalline form A of Compound I and equimolar p-toluenesulfonic acid in EtOAc at room temperature for 3 days and drying the solid under vacuum at room temperature for 12 hours.
  • the XRPD pattern of crystalline form N of the tosylate of Compound I is shown in Fig. 15A.
  • the peaks, interplanar spacings and intensities are shown in Table 42.
  • the TGA thermogram of crystalline form N of the p-tosylate of Compound I indicates that crystalline form N had a 3.6%weight loss when heated to 200°C.
  • the DSC thermogram of crystalline form N of the p-tosylate of Compound I reveals endotherms with peak temperatures at 52.5°C and 261.8°C, and an exotherm with a peak temperature at 264.8°C.
  • Fig. 15D shows the 1 H NMR of crystalline form N of the p-tosylate of Compound I. It is deduced that molar ratio between p-toluenesulfonic acid and the Compound I is about 1: 1.
  • the UPLC results as shown in Table 43 reveal that the purity of crystalline form N is 99.12%.
  • Crystalline form O of the ethanedisulfonate of Compound I can be obtained by suspending and stirring the starting crystalline form A of Compound I and equimolar ethanedisulfonic acid in EtOAc at room temperature for 3 days and drying the solid under vacuum at room temperature for 12 hours.
  • the XRPD pattern of crystalline form O of the ethanedisulfonate of Compound I is shown in Fig. 16A.
  • the peaks, interplanar spacings and intensities are shown in Table 44.
  • the TGA thermogram of crystalline form O of the ethanedisulfonate of Compound I indicates that crystalline form O had a 6.3%weight loss when heated to 250°C.
  • the DSC thermogram of crystalline form O of the ethanedisulfonate of Compound I reveals endotherms with peak temperatures at 591.2°C, 198.1°C, 277.3°C and 286.5°C.
  • Fig. 16D shows the 1 H NMR of crystalline form O of the ethanedisulfonate of Compound I. It is deduced that molar ratio between ethanedisulfonate and the Compound I is about 0.9: 1.
  • the UPLC results as shown in Table 45 reveal that the purity of crystalline form N is 98.77%.
  • Crystalline form P of the oxalate of Compound I can be obtained by suspending and stirring the starting crystalline form A of Compound I and equimolar oxalic acid in EtOAc at room temperature for 3 days and drying the solid under vacuum at room temperature for 12 hours.
  • the XRPD pattern of crystalline form P of the oxalate of Compound I is shown in Fig. 17A.
  • the peaks, interplanar spacings and intensities are shown in Table 45.
  • the TGA thermogram of crystalline form P of the oxalate of Compound I indicates that crystalline form P had a 1.7%weight loss when heated to 150°C.
  • the DSC thermogram of crystalline form P of the oxalate of Compound I reveals endotherms with peak temperatures at 116.2°C, 182.9°C, 214.7°C and 235.2°C.
  • Fig. 17D shows the 1 H NMR of crystalline form P of the oxalate of Compound I. It is deduced that molar ratio between oxalic acid and the Compound I is about 0.8: 1.
  • the UPLC results as shown in Table 46 reveal that the purity of crystalline form N is 98.89%.
  • Example 6.11 Crystalline form Q of the ethanesulfonate of Compound I
  • Crystalline form Q of the ethanesulfonate of Compound I can be obtained by suspending and stirring the starting crystalline form A of Compound I and equimolar ethanesulfonic acid in 2-MeTHF at room temperature for 3 days and drying the solid under vacuum at room temperature for 12 hours.
  • the XRPD pattern of crystalline form Q of the ethanesulfonate of Compound I is shown in Fig. 18A.
  • the peaks, interplanar spacings and intensities are shown in Table 47.
  • the TGA thermogram of crystalline form Q of the ethanesulfonate of Compound I indicates that crystalline form Q had a 7.5%weight loss when heated to 160°C.
  • the DSC thermogram of crystalline form Q of the ethanesulfonate of Compound I reveals endotherms with peak temperatures at 72.5°C, 161.2°C, 167.2°C and 242.0°C.
  • Fig. 18D shows the 1 H NMR of crystalline form Q of the ethanesulfonate of Compound I. It is deduced that molar ratio between ethanesulfonic acid and the Compound I is about 1: 1.
  • the UPLC results as shown in Table 48 reveal that the purity of crystalline form Q is 98.80%.
  • Crystalline form R of the hydrobromide of Compound I can be obtained by suspending and stirring the starting crystalline form A of Compound I and equimolar hydrobromic acid in EtOAc at room temperature for 2 days and drying the solid under vacuum at room temperature for 12 hours.
  • the XRPD pattern of crystalline form R of the hydrobromide of Compound I is shown in Fig. 19A.
  • the peaks, interplanar spacings and intensities are shown in Table 49.
  • the TGA thermogram of crystalline form R of the hydrobromide of Compound I indicates that crystalline form R had a 9.0%weight loss when heated to 150°C.
  • the DSC thermogram of crystalline form R of the hydrobromide of Compound I reveals an endotherm with a peak temperature at 101.2°C, and exotherms with peak temperatures at about 162.5°C and 209.2°C.
  • Fig. 19D shows the 1 H NMR of crystalline form R of the hydrobromide of Compound I. It is deduced that molar ratio between hydrobromic acid and the Compound I is about 1.2: 1.
  • the UPLC results as shown in Table 50 reveal that the purity of crystalline form R is 98.75%.
  • Crystalline forms G, H and I were evaluated for their hygroscopicity under DVS experiment at 25°C. DVS results are shown in Fig. 20A –Fig. 20C. Crystalline forms G, H and I showed 0.47%, 0.28%, 0.69%weight gain at 25°C/80%RH, respectively, indicating that they are slightly hygroscopic. XRPD patterns for crystalline forms G, H and I before and after DVS experiment showed no changes (see Fig. 21A, 21B and 21C, respectively) .
  • Crystalline forms C, G, H and I were evaluated for their dynamic solubilities in water and biosolvents SGF, FaSSIF and FeSSIF at 37°C according to a test procedure as follows:
  • NA The amount of remaining solids after centrifugation is too low to be tested by XRPD.
  • Crystalline form G It showed no purity decrease under 25°C/60%RH/Open/4 weeks, it showed slight purity decrease under 40°C/75%RH/Open/4 weeks, and it showed significant purity decrease under 80°C/Sealed/22 days.
  • Crystalline form H It showed no purity decrease under 25°C/60%RH/Open/4 weeks and 40°C/75%RH/Open/4 weeks, it showed slight purity decrease under 80°C/Sealed/22 days.
  • Crystalline form I did not undergo crystal transformation or decrease in purity under all conditions and showed better physical and chemical stability.
  • Crystalline form G may be degraded under high temperature and high temperature and high humidity conditions, and Crystalline form H may be degraded if placed under high temperature conditions for a long time.
  • Detection of ATR kinase activity utilized the Mobility shift assay to measure the phosphorylation of the substrate protein FAM-RAD17 (GL, Cat. No. 514318, Lot. No. P19042-MJ524315) .
  • the assay was developed and conducted at Chempartner. Compound I was dissolved in 100%DMSO at concentration of 20 mM, then conducted the assay as follows:
  • ATR kinase (Eurofins, Cat. No. 14-953, Lot. No. D14JP007N) into Kinase base buffer (50 mM HEPES, pH 7.5; 0.0015%Brij-35; 0.01%Triton) to prepare 2 x enzyme solution, then add 10 ⁇ l of 2x enzyme solution to each well of the 384-well assay plate, incubate at room temperature for 10 min.
  • stop buffer 100 mM HEPES, pH 7.5; 0.015%Brij-35; 0.2%Coating Reagent #3; 50 mM EDTA
  • Percent inhibition (max-conversion) / (max-min) *100wherein “max” stands for DMSO control; “min” stands for low control.
  • X means concentration in a format not transformed to logarithms.
  • the IC50 value for Compound I in this assay was 16 nM.
  • CCG Assay 2 Tumor Cell Anti-proliferation Assay (CTG Assay)
  • Human colorectal cancer cells HT-29 (HTB-38) and LoVo (CCL-229) were selected for the CTG assay, the two cell lines were originally obtained from the American Type Culture Collection (ATCC) .
  • ATCC American Type Culture Collection
  • Add FBS and appropriate additives into base medium to prepare complete medium then briefly rinse the cell layer with 0.25% (w/v) Trypsin-0.038% (w/v) EDTA solution to remove all traces of serum that contains trypsin inhibitor, after that, add appropriate volume of Trypsin-EDTA solution to flask and observe cells under an inverted microscope until cell layer is dispersed, at last, add appropriate volume of complete growth medium and aspirate cells by gently pipetting.

Abstract

La divulgation concerne diverses formes cristallines de composés (I) ou d'un sel de composé (I), ainsi que des compositions pharmaceutiques, des méthodes de fabrication et des méthodes d'utilisation de ceux-ci. Ces formes cristallines sont utiles dans le traitement de maladies et de troubles associés à la kinase ATR.
PCT/CN2023/070683 2022-01-06 2023-01-05 Formes cristallines d'un inhibiteur d'atr WO2023131234A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019154365A1 (fr) * 2018-02-07 2019-08-15 南京明德新药研发有限公司 Inhibiteur d'atr et son application
WO2019178590A1 (fr) * 2018-03-16 2019-09-19 Board Of Regents, The University Of Texas System Inhibiteurs hétérocycliques de la kinase atr
WO2020049017A1 (fr) * 2018-09-07 2020-03-12 Merck Patent Gmbh Dérivés de 5-morpholin-4-yl-pyrazolo[4,3-b]pyridine
WO2022002245A1 (fr) * 2020-07-03 2022-01-06 Shanghai Antengene Corporation Limited Inhibiteurs d'atr et leurs utilisations

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019154365A1 (fr) * 2018-02-07 2019-08-15 南京明德新药研发有限公司 Inhibiteur d'atr et son application
WO2019178590A1 (fr) * 2018-03-16 2019-09-19 Board Of Regents, The University Of Texas System Inhibiteurs hétérocycliques de la kinase atr
WO2020049017A1 (fr) * 2018-09-07 2020-03-12 Merck Patent Gmbh Dérivés de 5-morpholin-4-yl-pyrazolo[4,3-b]pyridine
WO2022002245A1 (fr) * 2020-07-03 2022-01-06 Shanghai Antengene Corporation Limited Inhibiteurs d'atr et leurs utilisations

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