WO2023131234A1

WO2023131234A1 - Crystalline forms of an atr inhibitor

Info

Publication number: WO2023131234A1
Application number: PCT/CN2023/070683
Authority: WO
Inventors: Zhongyang SHI; Jian Wang; Feifei YANG; Lei Wang; Bo Shan; Jay Mei
Original assignee: Shanghai Antengene Corporation Limited; Antengene Discovery Limited
Priority date: 2022-01-06
Filing date: 2023-01-05
Publication date: 2023-07-13

Abstract

Disclosed are various crystalline of compound (I) or salt of compound (I), as well as pharmaceutical compositions, methods of making and methods of using the same. These crystalline forms are useful in the treatment of diseases and disorders associated with ATR kinase.

Description

CRYSTALLINE FORMS OF AN ATR INHIBITOR

FIELD OF THE DISCLOSURE

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.

BACKGROUND OF THE DISCLOSURE

ATR (also known as FRAP-Related Protein 1; 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.

Compound I and pharmaceutically acceptable salts thereof are potent ATR inhibitor:

Many compounds can exist in different crystalline forms, or polymorphs, which exhibit different physical, chemical, and spectroscopic properties. In certain case of drugs, certain solid forms may be more bioavailable than others, while others may be more stable under manufacturing, storage, and biological conditions. In order to ensure the quality, safety and efficacy of the drug during manufacture, it is important to have one polymorph of a compound that exhibits certain desirable physical and chemical (including spectroscopic) properties.

Accordingly, there is a strong need for one or more crystalline forms of Compound I or salts of Compound I that have an acceptable balance of these properties.

SUMMARY OF THE DISCLOSURE

The present disclosure provides crystalline forms of Compound I or a salt of Compound I:

including several anhydrous, hydrate and solvate forms, and solid state forms thereof, pharmaceutical 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.

In one aspect, 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° 2θ) .

In another aspect, 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° 2θ) .

In a further aspect, 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° 2θ) .

In a further aspect, 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° 2θ) .

In a further aspect, 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° 2θ) .

In a further aspect, 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° 2θ) .

In a further aspect, 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° 2θ) .

In a further aspect, 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° 2θ) .

In a further aspect, 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° 2θ) .

In a further aspect, 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° 2θ) .

In a further aspect, 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° 2θ) .

In a further aspect, 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° 2θ) .

In a further aspect, 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° 2θ) .

In a further aspect, 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° 2θ) .

In a further aspect, 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° 2θ) .

In a further aspect, 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° 2θ) .

In a further aspect, 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° 2θ) .

In another aspect, the present disclosure provides 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.

In a further aspect, 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.

In a further aspect, 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.

In a further aspect, 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.

BRIEF DESCRIPTION OF THE DRAWINGS

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 ¹H 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 ¹H 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 ¹H 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 ¹H 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 ¹H 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. 7A shows a XRPD overlay of crystalline forms C, D and F in competitive slurry experiment in MeOH/H ₂O (a _w=0-0.6) .

Fig. 7B shows a XRPD overlay of crystalline forms C, D and F in competitive slurry experiment in MeOH/H ₂O (a _w=0.8-1.0) .

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 ¹H 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 ¹H 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 ¹H 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 ¹H 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 ¹H 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 ¹H 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 ¹H 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 ¹H 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 ¹H 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 ¹H 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 ¹H 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 ¹H 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 ₂O, (B) in FaSSIF, (C) FeSSIF.

Fig. 24 shows XRPD overlays of crystalline form H tested for solubility in various mediums: (A) in H ₂O, (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 ₂O, (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℃/60%RH/1 week and 25℃/60%RH/4 weeks, (B) 40℃/75%RH/1 week and 40℃/75%RH/4 weeks, and (C) 80℃/1 day and 80℃/22 days.

Fig. 28 shows XRPD overlays of crystalline form H tested for physical stability under various conditions: (A) 25℃/60%RH/1 week and 25℃/60%RH/4 weeks, (B) 40℃/75%RH/1 week and 40℃/75%RH/4 weeks, and (C) 80℃/1 day and 80℃/22 days.

Fig. 29 shows XRPD overlays of crystalline form I tested for physical stability under various conditions: (A) 25℃/60%RH/1 week and 25℃/60%RH/4 weeks, (B) 40℃/75%RH/1 week and 40℃/75%RH/4 weeks, and (C) 80℃/1 day and 80℃/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.

DETAILED DESCRIPTION OF THE DISCLOSURE

Reference will now be made in detail to certain embodiments of the present disclosure, examples of which are illustrated in the accompanying structures and formulas. While the present disclosure will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the present disclosure to those embodiments. On the contrary, the present disclosure is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present disclosure as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present disclosure. The present disclosure is in no way limited to the methods and materials described. In the event that one or more of the incorporated references and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, the present disclosure controls. All references, patents, patent applications cited in the present disclosure are hereby incorporated by reference in their entireties.

It is appreciated that certain features of the present disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the present disclosure, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable sub-combination. It must be noted that, as used in the specification and the appended claims, the singular forms “a, ” “an, ” and “the” include plural forms of the same unless the context clearly dictates otherwise. Thus, for example, reference to “a compound” includes a plurality of compounds.

Definitions

As used herein, the term “Compound I” refers to a compound having the following structure:

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) . Accordingly, as used herein, the term “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) . In some embodiments, 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 (° 2θ) .

As used herein, the term “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. When the solvent is water, the solvate is referred to as a “hydrate. ”

As used herein, the term “XRPD” refers to the analytical characterization method of X-ray powder diffraction. As used herein, the terms “X-ray powder diffractogram” , “X-ray powder diffraction pattern” , “XRPD pattern” interchangeably refer to an experimentally obtained pattern plotting signal positions (on the abscissa) versus signal intensities (on the ordinate) . For an amorphous material, 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 2θ (° 2θ) , 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° 2θ, 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) . In some embodiments, the repeatability of the measured angular values is in the range of ±0.1° 2θ.

The term “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) .

As used herein, 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. In determining “substantial 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. Thus, those of ordinary skill in the art will understand that the signal maximum values in XRPD diffractograms (in degrees two-theta (°2θ) referred to herein) generally mean that value is identified as ±0.2 degrees 2θof the reported value, an art-recognized variance. In some embodiments, the signal variance is identified as ±0.1 degrees 2θ of the reported value.

As used herein, the terms “about” and “substantially” indicate with respect to features such as endotherms, endothermic peak, exotherms, baseline shifts, etc., that their values can vary. With reference to X-ray diffraction peak positions, “about” or “substantially” means that typical peak position and intensity variability are taken into account. For example, one skilled in the art will appreciate that the peak positions (2θ) 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. Further, one skilled in the art will appreciate that relative peak intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be taken as qualitative measure only. For DSC, variation in the temperatures observed will depend upon the rate of temperature change as well as sample preparation technique and the particular instrument employed. Thus, the endotherm/melting point values reported herein relating to DSC/TGA thermograms can vary ± 5℃ (and still be considered to be characteristic of the particular crystalline form described herein) . When used in the context of other features, such as, for example, percent by weight (%by weight) , reaction temperatures, the term “about” indicates a variance of ± 5%.

As used herein “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.

As used herein, “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. For example, 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.

As used herein, the term “pharmaceutical composition” refers to a formulation containing the compound or crystalline forms thereof provided herein in a form suitable for administration to a subject.

As used herein, 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. The term “pharmaceutically acceptable excipient” also encompasses “pharmaceutically acceptable carrier” and “pharmaceutically acceptable diluent” .

As used herein, 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.

As used herein, a “subject” refers to a human and a non-human animal. Examples of 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. In a preferred embodiment, the subject is a human. In some embodiments, the subject is an experimental animal or animal suitable as a disease model.

Crystalline Forms

preparation methods for making the compounds, pharmaceutical compositions containing them and various uses of the disclosed compounds.

Crystalline Form B of Compound I

In one aspect, 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° 2θ) . In some embodiments, 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° 2θ) . In some embodiments, 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° 2θ) .

In some embodiments, the crystalline form B is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

In some embodiments, 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.

In some embodiments, the crystalline form B is characterized by a thermogravimetric analysis (TGA) thermogram substantially as shown in Fig. 1B.

In some embodiments, the crystalline form B is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset temperature of about 247.0℃.

In some embodiments, the crystalline form B is characterized by a DSC thermogram substantially as shown in Fig. 1C.

In some embodiments, 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%.

Crystalline Form C of Compound I

In one aspect, 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° 2θ) . In some embodiments, 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° 2θ) . In some embodiments, 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° 2θ) .

In some embodiments, the crystalline form C is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

In some embodiments, 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.

In some embodiments, the crystalline form C is characterized by a TGA thermogram substantially as shown in Fig. 2B.

In some embodiments, the crystalline form C is characterized by a DSC thermogram having an endotherm with an onset temperature of about 248.3℃.

In some embodiments, the crystalline form C is characterized by a DSC thermogram substantially as shown in Fig. 2C.

In some embodiments, 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%.

Crystalline Form D of Compound I

In one aspect, 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° 2θ) . In some embodiments, the XRPD pattern of crystalline form D further comprises one or more peaks at 10.53, 16.64, and 23.53 (± 0.2° 2θ) . In some embodiments, 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° 2θ) .

In some embodiments, the crystalline form D is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

In some embodiments, 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.

In some embodiments, the crystalline form D is characterized by a TGA thermogram substantially as shown in Fig. 3B.

In some embodiments, the crystalline form D is characterized by a DSC thermogram having an endotherm with an onset temperature of about 245.3℃.

In some embodiments, the crystalline form D is characterized by a DSC thermogram substantially as shown in Fig. 3C.

In some embodiments, 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%.

Crystalline Form E of Compound I

In one aspect, 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° 2θ) . In some embodiments, 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° 2θ) . In some embodiments, 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° 2θ) .

In some embodiments, the crystalline form E is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

In some embodiments, 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.

In some embodiments, the crystalline form E is characterized by a thermogravimetric analysis (TGA) thermogram substantially as shown in Fig. 4B.

In some embodiments, the crystalline form E is characterized by a DSC thermogram having endotherms with onset temperatures of about 101.1℃ and 229.7℃.

In some embodiments, the crystalline form E is characterized by a DSC thermogram having an exothermal with an onset temperature of about 149.2℃.

In some embodiments, the crystalline form E is characterized by a DSC thermogram substantially as shown in Fig. 4C.

In some embodiments, 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.

In some embodiments, 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%.

Crystalline Form F of Compound I

In one aspect, 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° 2θ) . In some embodiments, 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° 2θ) . In some embodiments, 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° 2θ) .

In some embodiments, the crystalline form F is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

In some embodiments, 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.

In some embodiments, the crystalline form F is characterized by a TGA thermogram substantially as shown in Fig. 5B.

In some embodiments, the crystalline form F is characterized by a differential scanning calorimetry (DSC) thermogram having endotherms with onset temperatures of about 79.7℃, 220.8℃ and 249.1℃.

In some embodiments, the crystalline form F is characterized by a DSC thermogram having an exothermal with an onset temperature of about 222.3℃.

In some embodiments, the crystalline form F is characterized by a DSC thermogram substantially as shown in Fig. 5C.

In some embodiments, the crystalline form F is a hydrate.

In some embodiments, 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%.

Crystalline Form G of the maleate of Compound I

In one aspect, 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° 2θ) . In some embodiments, 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° 2θ) . In some embodiments, 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° 2θ) .

In some embodiments, the crystalline form G is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

In some embodiments, 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.

In some embodiments, the crystalline form G is characterized by a TGA thermogram substantially as shown in Fig. 8B.

In some embodiments, the crystalline form G is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset temperature of about 158.0℃.

In some embodiments, the crystalline form G is characterized by a DSC thermogram substantially as shown in Fig. 8C.

In some embodiments, the crystalline form G is an anhydrate. In some embodiments, the molar ratio between maleic acid and the Compound I is about 1: 1.

In some embodiments, 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%.

Crystalline Form H of the fumarate of Compound I

In one aspect, 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° 2θ) . In some embodiments, 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° 2θ) . In some embodiments, 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° 2θ) .

In some embodiments, the crystalline form H is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

In some embodiments, 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.

In some embodiments, the crystalline form H is characterized by a TGA thermogram substantially as shown in Fig. 9B.

In some embodiments, the crystalline form H is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset temperature of about 201.1℃.

In some embodiments, the crystalline form H is characterized by a DSC thermogram substantially as shown in Fig. 9C.

In some embodiments, the crystalline form H is an anhydrate. In some embodiments, the molar ratio between fumaric acid and the Compound I is about 1: 1.

In some embodiments, 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%.

Crystalline Form I of the mesylate of Compound I

In one aspect, 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° 2θ) . In some embodiments, 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° 2θ) . In some embodiments, 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° 2θ) .

In some embodiments, the crystalline form I is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

In some embodiments, 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.

In some embodiments, the crystalline form I is characterized by a TGA thermogram substantially as shown in Fig. 10B.

In some embodiments, the crystalline form I is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset temperature of about 251.0℃.

In some embodiments, the crystalline form I is characterized by a differential scanning calorimetry (DSC) thermogram having an exotherm with an onset temperature of about 257.9℃.

In some embodiments, the crystalline form I is characterized by a DSC thermogram substantially as shown in Fig. 10C.

In some embodiments, the crystalline form I is an anhydrate. In some embodiments, the molar ratio between methylsulfonic acid and the Compound I is about 1: 1.

In some embodiments, 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%.

Crystalline Form J of the phosphate of Compound I

In one aspect, 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° 2θ) . In some embodiments, 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° 2θ) . In some embodiments, 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° 2θ) .

In some embodiments, the crystalline form J is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

In some embodiments, 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.

In some embodiments, the crystalline form J is characterized by a TGA thermogram substantially as shown in Fig. 11B.

In some embodiments, the crystalline form J is characterized by a differential scanning calorimetry (DSC) thermogram having endotherms with peak temperatures of about 129.3℃, 200.1℃ and 235.3℃.

In some embodiments, the crystalline form J is characterized by a DSC thermogram substantially as shown in Fig. 11C.

In some embodiments, the molar ratio between phosphoric acid and the Compound I is about 0.5: 1.

In some embodiments, 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%.

Crystalline Form K of the phosphate of Compound I

In one aspect, 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° 2θ) . In some embodiments, 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° 2θ) . In some embodiments, 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° 2θ) .

In some embodiments, the crystalline form K is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

In some embodiments, 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.

In some embodiments, the crystalline form K is characterized by a TGA thermogram substantially as shown in Fig. 12B.

In some embodiments, the crystalline form K is characterized by a differential scanning calorimetry (DSC) thermogram having endotherms with peak temperatures of about 101.1℃, 127.2℃, 141.6℃, 171.8℃ and 220.8℃.

In some embodiments, the crystalline form K is characterized by a DSC thermogram substantially as shown in Fig. 12C.

In some embodiments, the molar ratio between phosphoric acid and the Compound I is about 1.1: 1.

In some embodiments, 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%.

Crystalline Form L of the benzene sulfonate of Compound I

In one aspect, 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° 2θ) . In some embodiments, 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° 2θ) . In some embodiments, 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° 2θ) .

In some embodiments, the crystalline form L is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

In some embodiments, 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.

In some embodiments, the crystalline form L is characterized by a TGA thermogram substantially as shown in Fig. 13B.

In some embodiments, the crystalline form L is characterized by a differential scanning calorimetry (DSC) thermogram having endotherms with peak temperatures of about 167.3℃ and 177.1℃.

In some embodiments, the crystalline form L is characterized by a DSC thermogram substantially as shown in Fig. 13C.

In some embodiments, the molar ratio between benzene sulfonic acid and the Compound I is about 0.9: 1.

In some embodiments, 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%.

Crystalline Form M of the benzene sulfonate of Compound I

In one aspect, 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° 2θ) . In some embodiments, 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° 2θ) . In some embodiments, 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° 2θ) .

In some embodiments, the crystalline form M is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

In some embodiments, 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.

In some embodiments, the crystalline form M is characterized by a TGA thermogram substantially as shown in Fig. 14B.

In some embodiments, the crystalline form M is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset temperature of about 225.9℃.

In some embodiments, the crystalline form M is characterized by a differential scanning calorimetry (DSC) thermogram having an exotherm with an onset temperature of about 247.7℃.

In some embodiments, the crystalline form M is characterized by a DSC thermogram substantially as shown in Fig. 14C.

In some embodiments, 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%.

Crystalline Form N of the p-tosylate of Compound I

In one aspect, 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° 2θ) . In some embodiments, 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° 2θ) . In some embodiments, 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° 2θ) .

In some embodiments, the crystalline form N is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

In some embodiments, 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.

In some embodiments, the crystalline form N is characterized by a TGA thermogram substantially as shown in Fig. 15B.

In some embodiments, the crystalline form N is characterized by a differential scanning calorimetry (DSC) thermogram having endotherms with peak temperatures of about 52.5℃ and 261.8℃.

In some embodiments, the crystalline form N is characterized by a differential scanning calorimetry (DSC) thermogram having an exotherm with an peak temperature of about 264.8℃.

In some embodiments, the crystalline form N is characterized by a DSC thermogram substantially as shown in Fig. 15C.

In some embodiments, the molar ratio between toluenesulfonic acidand the Compound I is about 1: 1.

In some embodiments, 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%.

Crystalline Form O of the ethanedisulfonate of Compound I

In one aspect, 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° 2θ) . In some embodiments, 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° 2θ) . In some embodiments, 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° 2θ) .

In some embodiments, the crystalline form O is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

In some embodiments, 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.

In some embodiments, the crystalline form O is characterized by a TGA thermogram substantially as shown in Fig. 16B.

In some embodiments, the crystalline form O is characterized by a differential scanning calorimetry (DSC) thermogram having endotherms with peak temperatures of about 91.2℃, 198.1℃, 277.3℃ and 286.5℃.

In some embodiments, the crystalline form O is characterized by a DSC thermogram substantially as shown in Fig. 16C.

In some embodiments, the molar ratio between ethanedisulfonic acid and the Compound I is about 0.9: 1.

In some embodiments, 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%.

Crystalline Form P of the oxalate of Compound I

In one aspect, 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° 2θ) . In some embodiments, 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° 2θ) . In some embodiments, 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° 2θ) .

In some embodiments, the crystalline form P is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

In some embodiments, 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.

In some embodiments, the crystalline form P is characterized by a TGA thermogram substantially as shown in Fig. 17B.

In some embodiments, the crystalline form P is characterized by a differential scanning calorimetry (DSC) thermogram having endotherms with peak temperatures of about 116.2℃, 182.9℃, 214.7℃ and 235.2℃.

In some embodiments, the crystalline form P is characterized by a DSC thermogram substantially as shown in Fig. 17C.

In some embodiments, the molar ratio between oxalic acid and the Compound I is about 0.8: 1.

In some embodiments, 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%.

Crystalline Form Q of the ethanesulfonate of Compound I

In one aspect, 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° 2θ) . In some embodiments, 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° 2θ) . In some embodiments, 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° 2θ) .

In some embodiments, the crystalline form Q is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

In some embodiments, 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.

In some embodiments, the crystalline form Q is characterized by a TGA thermogram substantially as shown in Fig. 18B.

In some embodiments, the crystalline form Q is characterized by a differential scanning calorimetry (DSC) thermogram having endotherms with peak temperatures of about 72.5℃, 161.2℃, 167.2℃ and 242.0℃.

In some embodiments, the crystalline form Q is characterized by a DSC thermogram substantially as shown in Fig. 18C.

In some embodiments, the molar ratio between ethanesulfonic acid and the Compound I is about 1: 1.

In some embodiments, 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%.

Crystalline Form R of the hydrobromide of Compound I

In one aspect, 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° 2θ) . In some embodiments, 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° 2θ) . In some embodiments, 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° 2θ) .

In some embodiments, the crystalline form R is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

In some embodiments, 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.

In some embodiments, the crystalline form R is characterized by a TGA thermogram substantially as shown in Fig. 19B.

In some embodiments, the crystalline form R is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with a peak temperature of about 101.2℃.

In some embodiments, the crystalline form R is characterized by a differential scanning calorimetry (DSC) thermogram having exotherms with peak temperatures of about 162.5℃ and 209.2℃.

In some embodiments, the crystalline form R is characterized by a DSC thermogram substantially as shown in Fig. 19C.

In some embodiments, the molar ratio between hydrobromic acid and the Compound I is about 1.2: 1.

In some embodiments, 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%.

Synthesis of Compound I

Compound I can be synthesized according to methods known to persons skilled in the art, such as the synthetic procedures described in Example 1.

Pharmaceutical Compositions

In a further aspect, there is provided pharmaceutical 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.

In another aspect, there is provided pharmaceutical 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.

In some embodiments, at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of Compound I is in crystalline form B.

In some embodiments, at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of Compound I is in crystalline form C.

In some embodiments, at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of Compound I is in crystalline form D.

In some embodiments, at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of Compound I is in crystalline form E.

In some embodiments, at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of Compound I is in crystalline form F.

In some embodiments, at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form G.

In some embodiments, at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form H.

In some embodiments, at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form I.

In some embodiments, at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form J.

In some embodiments, at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form K.

In some embodiments, at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form L.

In some embodiments, at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form M.

In some embodiments, at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form N.

In some embodiments, at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form O.

In some embodiments, at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form P.

In some embodiments, at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form Q.

In some embodiments, at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form R.

The particular excipient used in the pharmaceutical compositions provided herein will depend upon the means and purpose for which the compounds of the present disclosure is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe to be administered to a mammal including humans. In general, 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.

In some embodiments, 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, disaccharides and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes) ; and/or non-ionic surfactants such as TWEEN ^TM, PLURONICS ^TM or polyethylene glycol (PEG) .

In some embodiments, 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) . 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. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980) . 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. The components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes.

The pharmaceutical 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.

A variety of routes are contemplated for the pharmaceutical compositions provided herein, and accordingly the pharmaceutical composition provided herein may be supplied in bulk or in unit dosage form depending on the intended administration route. For example, for oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets may be acceptable as solid dosage forms, and emulsions, syrups, elixirs, suspensions, and solutions may be acceptable as liquid dosage forms. For injection administration, emulsions and suspensions may be acceptable as liquid dosage forms, and a powder suitable for reconstitution with an appropriate solution as solid dosage forms. For inhalation administration, solutions, sprays, dry powders, and aerosols may be acceptable dosage form. For topical (including buccal and sublingual) or transdermal administration, powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches may be acceptable dosage form. For vaginal administration, 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. As used herein, 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.

In some embodiments, the pharmaceutical compositions of the present disclosure may be in a form of formulation for oral administration.

In certain embodiments, 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.

In certain embodiments, 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.

In certain embodiments, 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. 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) .

In certain embodiments, 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.

In certain embodiments, 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.

In certain embodiments, 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.

In some embodiments, the pharmaceutical compositions of the present disclosure may be in a form of formulation for injection administration.

In certain embodiments, 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. 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. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.

In some embodiments, the pharmaceutical compositions of the present disclosure may be in a form of formulation for inhalation administration.

In certain embodiments, 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.

In some embodiments, the pharmaceutical compositions of the present disclosure may be in a form of formulation for topical or transdermal administration.

In certain embodiments, 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.

In certain embodiments, the pharmaceutical 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.

Besides those representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the present disclosure. Such 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.

In some embodiments, 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.

In some embodiments, 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 crystalline forms of Compound I provided herein, or a pharmaceutically acceptable salt thereof, can be administered. In some instances, 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. For further information on 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.

In some embodiments, 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.

In a further aspect, there is also provided veterinary 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.

The pharmaceutical compositions or veterinary compositions may be packaged in a variety of ways depending upon the method used for administering the drug. For example, 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. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings. The 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. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.

In a further aspect, there is also provided pharmaceutical 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.

In some embodiments, 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.

In some embodiments, the second active ingredient can include:

(i) 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 vinorelbine and taxoids like paclitaxel and taxotere) ; and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecins) ;

(ii) 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;

(iii) 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) ;

(iv) inhibitors of growth factor function: for example such inhibitors 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- (3-morpholinopropoxy) quinazolin-4-amine (CI 1033) and erbB2 tyrosine kinase inhibitors such as lapatinib) , inhibitors of the hepatocyte growth factor family, inhibitors of the platelet-derived growth factor family such as imatinib, inhibitors of serine/threonine kinases (for example Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006) ) and inhibitors of cell signalling through MEK and/or Akt kinases;

(v) 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 linomide, inhibitors of integrin ανβ3 function and angiostatin) ] ;

(vi) 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;

(vii) antisense therapies, such as ISIS 2503, an anti-ras antisense agent;

(viii) 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

(ix) 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.

Method of treatment of disease

In an aspect, 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.

Accordingly, 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.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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, oesophagal cancer, hepatocellular (liver) carcinoma, cholangiocarcinomas, colon and rectal carcinomas, cancers of the small intestine, pancreatic cancers, cancers of the skin such as melanomas (in particular metastatic melanoma) , thyroid cancers, cancers of the head and neck and cancers of the salivary glands, prostate, testis, ovary, cervix, uterus, vulva, bladder, kidney (including renal cell carcinoma, clear cell and renal oncocytoma) , squamous cell carcinomas, sarcomas such as osteosarcoma, chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, Ewing's sarcoma, gastrointestinal stromal tumour (GIST) , Kaposi's sarcoma, and paediatric cancers such as rhabdomyosarcomas and neuroblastomas.

In some embodiments, 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-barre syndrome, hashimoto's disease, hidradenitis suppurativa, idiopathic thrombocytopenic purpura, interstitial cystitis, irritable bowel syndrome, lupus erythematosus, morphea, multiple sclerosis, myasthenia gravis, narcolepsy, neuromyotonia, Parkinson's disease, pemphigus vulgaris, pernicious anaemia, polymyositis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, schizophrenia, septic shock, scleroderma, Sjogren's disease, systemic lupus erythematosus (and associated glomerulonephritis) , temporal arteritis, tissue graft rejection and hyperacute rejection of transplanted organs, vasculitis (ANCA-associated and other vasculitides) , vitiligo, and Wegener's granulomatosis.

As used herein, the term “therapy” is intended to have its normal meaning of dealing with a disease in order to entirely or partially relieve one, some or all of its symptoms, or to correct or compensate for the underlying pathology, thereby achieving beneficial or desired clinical results. For purposes of this disclosure, 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.

As used herein, the term “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.

The term “treatment” is used synonymously with “therapy” . Similarly the term “treat” can be regarded as “applying therapy” where “therapy” is as defined herein.

In a further aspect, 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.

In a further aspect, 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.

In another aspect, 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.

In some embodiments, 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) . For instance, 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. In general, a combination therapy envisions administration of two or more drugs/treatments during a single cycle or course of therapy.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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) .

In some embodiments, 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.

In some embodiments, 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. Where 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.

Accordingly, in a further aspect, 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.

EXAMPLES

For the purpose of illustration, the following examples are included. However, it is to be understood that these examples do not limit the present disclosure and are only meant to suggest a method of practicing the present disclosure. Persons skilled in the art will recognize that the chemical reactions described may be readily adapted to prepare a number of other compounds of the present disclosure, and alternative methods for preparing the compounds of the present disclosure are deemed to be within the scope of the present disclosure. For example, the synthesis of non-exemplified compounds according to the present disclosure may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents and building blocks known in the art other than those described, and/or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the present disclosure.

Example 1: Synthesis of Compound I

Method 1:

Step 1. tert-butyl 5- { [4- (1-methanesulfonylcyclopropyl) -6- [ (3R) -3-methylmorpholin -4-yl] pyrimidin-2-yl] amino} -3-methyl-1H-pyrazole-1-carboxylate

To a solution of (3R) -4- [2-chloro-6- (1-methanesulfonylcyclopropyl) pyrimidin-4-yl] -3-methylmorpholine (100 mg, 0.30 mmol) and tert-butyl 5-amino-3-methyl-1H -pyrazole-1-carboxylate (89.2 mg, 0.45 mmol) in Dioxane (5 mL) was added Cs ₂CO ₃ (196.4 mg, 0.60 mmol) , Xant-Phos (17.4 mg, 0.03 mmol) and Pd ₂ (dba) ₃ (24.4 mg, 0.03 mmol) . The mixture was stirred at 100 ℃ for 6 h under nitrogen atmosphere.

LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (40 mL) , then washed with water and brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE : EA = 1: 1, V/V) to afford the desired product (130 mg, yield: 87%) . LC/MS (ESI) : m/z 493 [M+H] ⁺.

Step 2. 4- (1-methanesulfonylcyclopropyl) -N- (3-methyl-1H-pyrazol-5-yl) -6- [ (3R) -3-methylmorpholin-4-yl] pyrimidin-2-amine (Compound I)

To a solution of tert-butyl 5- { [4- (1-methanesulfonylcyclopropyl) -6- [ (3R) -3-methyl morpholin-4-yl] pyrimidin-2-yl] amino} -3-methyl-1H-pyrazole-1-carboxylate (120 mg, 0.24 mmol ) in DCM (2 mL) was added HCl solution (4 M in dioxane, 2 mL) . The mixture was stirred at room temperature (RT) for 2 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated under vacuo. The residue was purified by Prep-HPLC (C18, 10-95%MeCN in H ₂O with 0.1%ammonia) to give the desired product (32.6 mg, yield: 34%) . LC/MS (ESI) m/z: 393 [M+H] ⁺. ¹H NMR (400 MHz, DMSO) δ 9.21 (s, 1H) , 6.31 (s, 1H) , 6.15 (s, 1H) , 4.40 (s, 1H) , 4.02 (d, J = 11.7 Hz, 1H) , 3.93 (d, J = 8.1 Hz, 1H) , 3.73 (d, J = 11.3 Hz, 1H) , 3.58 (dd, J = 11.6, 2.9 Hz, 2H) , 3.25 (s, 3H) , 3.16 (d, J = 10.8 Hz, 1H) , 2.19 (s, 3H) , 1.58 (s, 2H) , 1.47 (s, 2H) , 1.20 (d, J = 6.7 Hz, 3H) .

Method 2:

Step 1. tert-butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylate

To a solution of 3-methyl-1H-pyrazol-5-amine (25 g, 257.41 mmol) in THF (800 mL) at 0 ℃ was added NaH (60%, 10.81 g, 270.28 mmol) portion wise. After stirring at 0 ℃ for 30 min, (Boc) ₂O (58.99 g, 270.28 mmol) was added in one portion. The mixture was stirred at room temperature for 1 h. TLC showed the reaction was complete. The reaction mixture was poured into saturated NH ₄Cl aqueous solution and extracted with DCM (600 mL×2) twice. The combined organic layer was separated, then washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE : EA = 2: 1, V/V) to give the desired product (19 g, yield: 37.42%) . ¹HNMR (400 MHz, CDCl ₃) δ 5.59 (d, J = 0.9 Hz, 1H) , 3.89 (s, 2H) , 2.44 (d, J = 0.9 Hz, 3H) , 1.62 (s, 9H) .

Step 2. (R) -tert-butyl 5-methyl-3- ( (4- (3-methylmorpholino) -6- (1- (methyl sulfonyl) cyclopropyl) pyrimidin-2-yl) amino) -1H-pyrazole-1-carboxylate

To a solution of (3R) -4- [2-chloro-6- (1-methanesulfonylcyclopropyl) pyrimidin-4-yl] -3-methylmorpholine (15.0 g, 45.20 mmol) and tert-butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylate (10.7 g, 54.24 mmol) in Dioxane (600 mL) were added BrettPhos-Pd-G3 (906 mg, 4.41 mmol) and Cs ₂CO ₃ (29.45 g, 90.4 mmol) . The mixture was stirred at 100 ℃ overnight under N ₂ atmosphere. The reaction mixture was diluted with EA (1.0 L) , then washed with water and brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by column chromatography on silica gel (DCM : MeOH = 20 : 1, V/V) to afford the desired product (17 g, yield: 76%) . LC/MS (ESI) : m/z 493 [M+H] ⁺.

Step 3. (R) -N- (3-methyl-1H-pyrazol-5-yl) -4- (3-methylmorpholino) -6- (1- (methylsulfonyl) cyclopropyl) pyrimidin-2-amine (Compound I)

A mixture of (R) -tert-butyl 5-methyl-3- ( (4- (3-methylmorpholino) -6- (1- (methyl sulfonyl) cyclopropyl) pyrimidin-2-yl) amino) -1H-pyrazole-1-carboxylate (17.0 g, 34.51 mmol) in HCl solution (4.0 M in dioxane, 100.0 mL) was stirred at room temperature for 12h. The reaction mixture was concentrated under reduced pressure to dryness, the residue was diluted with EA (200 mL) and saturated NaHCO ₃ aqueous solution (200 mL) . The resulting mixture was stirred at room temperature overnight. The organic layer was separated, then washed with brine, dried over anhydrous Na ₂SO ₄, filtered and concentrated. The residue was purified by Prep-HPLC (C ₁₈, 10-95%, MeOH in H ₂O with 0.1%HCOOH) to give the desired product (10 g, yield: 73 %) . LC/MS (ESI) : m/z 393 [M+H] ⁺. ¹H NMR (400 MHz, DMSO) δ 11.78 (s, 1H) , 9.10 (s, 1H) , 6.23 (d, J = 29.9 Hz, 2H) , 4.38 (s, 1H) , 4.07 –3.87 (m, 2H) , 3.73 (d, J = 11.4 Hz, 1H) , 3.58 (dd, J = 11.5, 2.9 Hz, 1H) , 3.43 (td, J = 11.8, 2.9 Hz, 1H) , 3.26 (s, 3H) , 3.13 (td, J = 12.9, 3.7 Hz, 1H) , 2.19 (s, 3H) , 1.19 (d, J = 6.7 Hz, 3H) .

Example 2: Preparation of crystalline forms of Compound I

The following abbreviations have been used in the examples:

MeOH	methanol
EtOH	ethanol
IPA	isopropanol
MIBK	methyl isobutyl ketone
EtOAc	ethyl acetate
IPAc	isopropyl acetate
MTBE	methyl tert-butyl ether

THF	tetrahydrofuran
2-MeTHF	2-methyltetrahydrofuran
CPME	cyclopentyl methyl ether
ACN	acetonitrile
DCM	dichloromethane
DMSO	dimethyl sulfoxide

Method A (Addition of anti-solvent) :

20 mg of starting crystalline form A (a mixture of crystalline forms B and D of Compound I, XRPD shown in Fig. 31) of Compound I were weighed into a 20 ml vial, and was added 0.4-3.0 mL selected good solvents. The mixture was stirred at 50℃ and filtered to obtain a clear solution. Selected anti-solvent was added into the obtained clear solutions under stirring until solids precipitated. Precipitates were collected. If no solids precipitated upon addition of 10 ml anti-solvent, the solution was stirred at 5℃ or evaporated at room temperature. Crystalline samples were investigated by XRPD. Results were shown in Table 1.

Table 1. Crystallization by addition of anti-solvent

*: no solids precipitated upon addition of anti-solvent. The solution was stirred at 5℃ and was still clear, and then was allowed to evaporate at room temperature to precipitate solids.

Method B (Addition of anti-anti-solvent) :

15 mg of starting crystalline form A of Compound I were weighed into a 3 ml vial, and was added 0.4-3.0 mL selected good solvents to give clear solutions. The clear solutions were added into selected anti-solvents dropwise under stirring. The precipitated solids were centrifuged and were investigated by XRPD. Results were shown in Table 2.

Table 2. Crystallization by addition of anti-anti-solvent

*: no solids precipitated upon addition of anti-anti-solvent. The solution was stirred at 5℃ and solids precipitated.

^#: no solids precipitated upon addition of anti-anti-solvent. The solution was stirred at 5℃ and was still clear, and then was allowed to evaporate at room temperature to precipitate solids.

Method C (Slow evaporation) :

15 mg of starting crystalline form A of Compound I were weighed into a 5 ml vial, and was added 3.0 mL selected solvents. The solutions were shaken and filtered, and the filtrates were allowed to slowly evaporate at room temperature. The solids obtained were collected and investigated by XRPD. Results were shown in Table 3.

Table 3. Crystallization by slow evaporation

Solvent (v/v)	Crystalline Form (s)
MeOH	C
Acetone	C
THF	F
CAN	C
CHCl ₃	B
DCM	C
2-MeTHF	C
THF/H ₂O (4: 1)	F

Method D (Slow cooling) :

15-45 mg starting crystalline form A of Compound I were weighed into a 3 ml vial, and was added 2.0 mL selected solvents. The solution was stirred at 50℃ for 16 hours and filtered. The filtrate was put into a biochemical incubator and was allowed to cool from 50℃ to 5℃ at a rate of 0.1℃/min. The solids obtained were collected and investigated by XRPD. Results were shown in Table 4.

Table 4. Crystallization by slow cooling

Solvent (v/v)	Crystalline Form (s)
EtOH	C
IPA	C
MIBK ^#	B
EtOAc ^#	C
2-MeTHF ^#	C
ACN/H ₂O (1: 1)	F
MeOH/Anisole (1: 1) *	D+F
Acetone/THF (1: 1)	C

*: no solids precipitated upon slowly cooling to 5℃. The solution was kept at -20℃ and solids precipitated.

^#: no solids precipitated upon slowly cooling to 5℃. The solution was kept at -20℃ and was still clear, and then was allowed to evaporate at room temperature to precipitate solids.

Method E (Vapor-liquid diffusion) :

15 mg of starting crystalline form A of Compound I were weighed into a 3 ml vial, and was added 0.4-2.0 mL selected solvents. The solutions were shaken and filtered, and the filtrates were transferred into a new 4 ml vial and sealed with a PE cover with a hole. 4 ml selected anti-solvents were added into a 20 ml vial. The 4 ml vial was put into the 20 ml vial, which was sealed and placed at room temperature. Crystalline samples were investigated by XRPD. Results were shown in Table 5.

Table 5. Crystallization by Vapor-liquid diffusion

*: clear solutions were obtained upon vapor-liquid diffusion at room temperature for 8 days, and were allowed to evaporate at room temperature.

^#: clear solutions were obtained upon vapor-liquid diffusion at room temperature for 8 days, and were allowed to evaporate at room temperature and then subject to dry under vacuum at room temperature.

Method F (Polymer induction) :

15 mg of starting crystalline form A of Compound I were weighed into a 3 ml vial, and were added 1.6-2.0 ml selected solvents. The solutions were shaken and filtered with PTFE filter film with a pore size of 0.45 μm. The filtrates were added ～2 mg mixed polymers and were sealed with film having four holes. The filtrates were placed at room temperature and allowed to slowly evaporate. Crystalline samples were investigated by XRPD. Results were shown in Table 6.

Table 6. Crystallization by polymer induction

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)

Method G (Slurry stirring at room temperature) :

15 mg of starting crystalline form A of Compound I were weighed into a HPLC vial, and were added 0.5 ml selected solvents. The suspensions were magnetically stirred (～1000 rpm) at room temperature for about 6 days. The solids were centrifuged and investigated by XRPD. Results were shown in Table 7.

Table 7. Crystallization by slurry stirring at room temperature

Solvent (v/v)	Crystalline Form (s)
MeOH	C
EtOH	C
Acetone	C
MIBK	B+D
2-MeTHF	B+D
1, 4-Dioxane	B+C+D

CPME	B+D
DCM	C
H ₂O	F
1, 4-Dioxane/MEK (1: 1)	C
IPA/CPME (1: 1)	B+D
EtOAc/Acetone (1: 1)	C
THF/n-Heptane (1: 1)	B+D
IPAc/DCM (1: 1)	C
DMSO/MTBE (1: 4) *	C
Acetone/CAN (1: 1)	C
MeOH/H ₂O (a _w～0.2, 937: 63)	C
MeOH/H ₂O (a _w～0.4, 844: 156)	C
MeOH/H ₂O (a _w～0.6, 696: 304)	F
MeOH/H ₂O (a _w～0.8, 430: 570)	F

*: clear solution was obtained upon stirring at room temperature for 3 days. The solution was then stirred at 5℃ for 4 days and solids precipitated.

Method H (Slurry stirring at 50℃) :

15 mg of starting crystalline form A of Compound I were weighed into a HPLC vial, and were added 0.5 ml selected solvents. The suspensions were magnetically stirred (～1000 rpm) at 50℃ for about 3 days. The solids were centrifuged and investigated by XRPD. Results were shown in Table 8.

Table 8. Crystallization by slurry stirring at 50℃

Solvent (v/v)	Crystalline Form (s)
EtOH	C
MTBE	B+D
IPAc	C
MEK	C
2-MeTHF	C
ACN	C
Anisole	C
CHCl ₃	C
MeOH/EtOAc (1: 1)	C
THF/Toluene (1: 1)	C
ACN/EtOH (1: 1)	C

IPAc/CPME (1: 1)	C
MeOH/CHCl ₃ (1: 1)	Amorphous
EtOAc/2-MeTHF (1: 1)	C
ACN/H ₂O (1: 1)	F
2-MeTHF/CPME (1: 1)	C
1, 4-Dioxane/MeOH (1: 1) *	C
EtOH/MIBK (1: 1)	C

*: clear solution was obtained upon stirring at 50℃ for 3 days. The solution was then stirred at room temperature for 3 days and solids precipitated.

Method I (Vapor-solid diffusion) :

15 mg of starting crystalline form A of Compound I were weighed into a 3 ml vial. 4 ml selected solvents were added into a 20 ml vial. The 3 ml vial was put into the 20 ml vial, which was sealed and placed at room temperature. Solids were collected after 8 days. Crystalline samples were investigated by XRPD. Results were shown in Table 9.

Table 9. Crystallization by Vapor-solid diffusion

Solvent	Crystalline Form (s)
H ₂O	F
DCM	C
EtOH	B+D
MeOH	C
ACN	B+D
THF	B+D
CHCl ₃	B+C+D
Acetone	B+D

Example 3: Characterization of crystalline forms of Compound I

General Methods

X-ray Powder Diffraction (XRPD)

XRPD analysis of all crystalline forms of Compound I was measured under the following conditions shown in Table 10.

Table 10. XRPD parameters

Thermal Gravimetric Analyses (TGA)

TGA analysis of all crystalline forms of Compound I was performed on TA Q5000/Discovery 5500 thermogravimetric analyzer under the following conditions shown in Table 11.

Table 11. TGA parameters

Instrument	TA Q5000/Discovery 5500
Method	Linear heating
Sample Plate	Aluminum, open
Temperature Range	RT～350℃
Heating Rate
	10℃/min
Atmosphere	Nitrogen

Differential Scanning Calorimetry (DSC)

DSC analysis of all crystalline forms of Compound I was performed on TA Q2000/Discovery 2500 differential scanning calorimeter under the following conditions shown in Table 12.

Table 12. DSC parameters

Instrument	TA Q2000/Discovery 2500
Method	Linear heating
Sample Plate	Aluminum, covered
Temperature Range	25℃ ～300℃
Heating Rate
	10℃ /min
Atmosphere	Nitrogen

Dynamic Vapor Sorption (DVS)

DVS curve was determined on DVS Intrinsic of SMS (Surface Measurement Systems) . The relative humidity at 25℃ 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.

Table 13. DVS parameters

Ultra Performance Liquid Chromatography (UPLC)

Purity and solubility were measured on a Waters UPLC under the following conditions shown in Table 14.

Table 14. UPLC measurement conditions

Example 3.1: Crystalline form B of Compound I

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.

Table 15. XRPD of crystalline form B

The TGA thermogram of crystalline form B of Compound I, as shown in Fig. 1B, indicates that crystalline form B had a 2.10%weight loss when heated to 210℃. In addition, as shown in Fig. 1C, the DSC thermogram of crystalline form B of Compound I reveals a mild exothermal with onset temperature at 214.8℃ and a sharp endotherm with onset temperature at 247.0℃. Fig. 1D shows the ¹H 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.

Example 3.2: Crystalline form C of Compound I

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.

Table 16. XRPD of crystalline form C

The TGA thermogram of crystalline form C of Compound I, as shown in Fig. 2B, indicates that crystalline form C had a 1.1%weight loss when heated to 210℃. In addition, as shown in Fig. 2C, the DSC thermogram of crystalline form C reveals a sharp endotherm with onset temperature at 249.2℃. Fig. 2D shows the ¹H 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.

Example 3.3: Crystalline form D of Compound I

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.

Table 17. XRPD of crystalline form D

The TGA thermogram of crystalline form D of Compound I, as shown in Fig. 3B, indicates that crystalline form D had a 7.0%weight loss when heated to 200℃. In addition, as shown in Fig. 3C, the DSC thermogram of crystalline form D reveals a sharp endotherm with onset temperature at 245.3℃. Fig. 3D shows the ¹H 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.

Example 3.4: Crystalline form E of Compound I

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.

Table 18. XRPD of crystalline form E

The TGA thermogram of crystalline form E of Compound I, as shown in Fig. 4B, indicates that crystalline form E had a 4.2%weight loss when heated to 80℃, and a 29.8%weight loss when further heated to 150℃. In addition, as shown in Fig. 4C, the DSC thermogram of crystalline form E of Compound I reveals endotherms with onsets temperatures at 101.1℃ and 229.7℃, and an exotherm with onset temperature at 149.2℃. Fig. 4D shows the ¹H 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.

Example 3.5: Crystalline form F of Compound I

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.

Table 19. XRPD of crystalline form F

The TGA thermogram of crystalline form F of Compound I, as shown in Fig. 5B, indicates that crystalline form F had a 6.7%weight loss when heated to 100℃. In addition, as shown in Fig. 5C, the DSC thermogram of crystalline form F of Compound I reveals endotherms with onsets temperatures at 79.7℃, 220.8℃ and 249.1℃, and an exotherm with onset temperature at 222.3℃. Fig. 5D shows the ¹H NMR of crystalline form F of Compound I. It is deduced that crystalline form F of Compound I is a hydrate.

Example 4: Evaluation of crystalline form C of Compound I

Example 4.1: Hygroscopicity

Crystalline form C was evaluated for its hygroscopicity under DVS experiment at 25℃. DVS results are shown in Fig. 2E. Crystalline form C showed 0.25%weight gain at 25℃/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) .

Example 4.2: Stability

Crystalline form C samples were tested under 80℃/Sealed/1 day, 25℃/60%RH/Open/1 week and 40℃/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℃/Sealed/1 day, 25℃/60%RH/Open/1 week and 40℃ /75%RH/Open/1 week, crystalline form C showed no transformation or purity decrease, demonstrating its good stability.

Table 20. Stability of crystalline form C

Test #	Condition	Purity (Area %)	Transformation
1	start	99.40	No
2	80℃/Sealed/1 day	99.45	No
3	25℃/60%RH/Open/1 week	99.36	No
4	40℃/75%RH/Open/1 week	99.34	No

Table 21. HPLC result of crystalline form C

Example 5: Crystalline form transformation

Example 5.1: Crystalline forms B, C and D

Competitive slurry experiments were set up in acetone and CAN for crystalline forms B, C and D at both room temperature and 50℃:

1) 10-15 mg starting crystalline form A was weighed into a HPLC vial and was added 1 ml solvents. The mixture was magnetically stirred at room temperature or 50℃ for 2 days, followed by filtration (PTFE filter film of 0.45μm) , providing clear saturated solution;

2) 5 mg crystalline form B and crystalline form C was respectively weighed into new HPLC vials, and were added the clear saturated solution in step 1) , providing slurries;

3) The slurries were magnetically stirred at room temperature or 50℃ for 11 days, and were added ～5mg crystalline form D;

4) The slurries were magnetically stirred at room temperature or 50℃ for 3 days. Solids were collected and analyzed by XRPD analysis.

Results are summarized in Table 22. Results of XRPD analysis are shown in Fig. 6A and Fig. 6B.

Table 22. Summary of results from competitive slurry experiments

Example 5.2: Crystalline forms C, D and F

Competitive slurry experiments were set up in MeOH/H ₂O at different water activities for crystalline forms C, D and F:

1) 10-15 mg starting crystalline form A was weighed into a HPLC vial and was added 1 ml solvents. The mixture was magnetically stirred at room temperature for 3 hours, followed by filtration (PTFE filter film of 0.45μm) , providing clear saturated solution;

2) 5 mg crystalline forms C, D and F were respectively weighed into new HPLC vials, and were added the clear saturated solution in step 1) , providing slurries;

3) The slurries were magnetically stirred at room temperature for 3-10 days. Solids were collected and analyzed by XRPD analysis.

Results are summarized in Table 23. Results of XRPD analysis are shown in Fig. 7A and Fig. 7B.

*Water content in solution was measured by KF, and water activity was calculated

It can be seen that at room temperature, the mixture of crystalline forms C, D and F converted to crystalline form C at a _w of 0-0.6, and converted to crystalline form F at a _w of 0.8-1.0, suggesting that the critical a _w for transformation between crystalline form C and crystalline form F is 0.6-0.8.

Example 6: Characterization of crystalline forms of salts of Compound I

General Methods

X-ray Powder Diffraction (XRPD)

XRPD analysis of all crystalline forms of salts of Compound I was measured under the following conditions shown in Table 24.

Table 24. XRPD parameters

Thermal Gravimetric Analyses (TGA)

TGA analysis of all crystalline forms of salts was performed on TA Q5000/Discovery 5500 thermogravimetric analyzer under the following conditions shown in Table 25.

Table 25. TGA parameters

Instrument	TA Q5000/Discovery 5500
Method	Linear heating
Sample Plate	Aluminum, open
Temperature Range	RT～ Set Terminal Temperature
Heating Rate
	10℃/min
Atmosphere	Nitrogen

Differential Scanning Calorimetry (DSC)

DSC analysis of all crystalline forms of salts was performed on TA Q2000/Discovery 2500 differential scanning calorimeter under the following conditions shown in Table 26.

Table 26. DSC parameters

Instrument	TA Q2000/Discovery 2500
Method	Linear heating
Sample Plate	Aluminum, covered
Temperature Range	25℃ ～ Set Terminal Temperature
Heating Rate
	10℃ /min
Atmosphere	Nitrogen

Dynamic Vapor Sorption (DVS)

DVS curve was determined on DVS Intrinsic of SMS (Surface Measurement Systems) . The relative humidity at 25℃ 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.

Table 27. DVS parameters

Ultra Performance Liquid Chromatography (UPLC)

Purity was measured on a Waters UPLC under the following conditions shown in Table 28.

Table 28. Purity measurement conditions

Solubility and molar ratio were measured on a Waters UPLC under the following conditions shown in Table 29.

Table 29. Solubility and molar ratio measurement conditions

Example 6.1: Crystalline form G of the maleate of Compound I

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.

Table 30. XRPD of crystalline form G

The TGA thermogram of crystalline form G of the maleate of Compound I, as shown in Fig. 8B, indicates that crystalline form G had a 5.3%weight loss when heated to 150℃. In addition, as shown in Fig. 8C, the DSC thermogram of crystalline form G of the maleate of Compound I reveals an endotherm with an onset temperature at 158.0℃. Fig. 8D shows the ¹H 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%.

Table 31. UPLC results of crystalline form G

Relative Retention Time	Purity [Area%]
0.85	0.30
0.90	0.06
1.00	98.38
1.02	0.40
1.07	0.06
1.08	0.05
1.24	0.74

Example 6.2: Crystalline form H of the fumarate of Compound I

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.

Table 32. XRPD of crystalline form H

The TGA thermogram of crystalline form H of the fumarate of Compound I, as shown in Fig. 9B, indicates that crystalline form H had a 4.6%weight loss when heated to 150℃. In addition, as shown in Fig. 9C, the DSC thermogram of crystalline form H of the fumarate of Compound I reveals an endotherm with an onset temperature at 201.1℃. Fig. 9D shows the ¹H 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℃.

Table 33. UPLC results of crystalline form H

Relative Retention Time	Purity [Area%]
1.00	99.11
1.02	0.40
1.07	0.08
1.24	0.41

Example 6.3: Crystalline form I of the mesylate of Compound I

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.

Table 34. XRPD of crystalline form I

The TGA thermogram of crystalline form I of the mesylate of Compound I, as shown in Fig. 10B, indicates that crystalline form I had a 2.2%weight loss when heated to 240℃. In addition, as shown in Fig. 10C, the DSC thermogram of crystalline form I of the mesylate of Compound I reveals an endotherm with an onset temperature at 251.0℃, and an exotherm with a peak temperature at 257.9℃. Fig. 10D shows the ¹H NMR of crystalline form I of the mesylate of Compound I. It is deduced that 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℃.

Table 35. UPLC results of crystalline form I

Relative Retention Time	Purity [Area%]
0.90	0.05
1.00	98.75
1.02	0.41
1.07	0.06
1.08	0.05
1.24	0.68

Example 6.4: Crystalline form J of the phosphate of Compound I

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.

Table 36. XRPD of crystalline form J

The TGA thermogram of crystalline form J of the phosphate of Compound I, as shown in Fig. 11B, indicates that crystalline form J had a 3.7%weight loss when heated to 150℃. In addition, as shown in Fig. 11C, the DSC thermogram of crystalline form J of the phosphate of Compound I reveals endotherms with peak temperatures at 129.3℃, 200.1℃ and 235.3℃. Fig. 11D shows the ¹H 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%.

Table 37. UPLC results of crystalline form J

Relative Retention Time	Purity [Area%]
1.00	99.72
1.02	0.21
1.23	0.08

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.

Table 38. XRPD of crystalline form K

The TGA thermogram of crystalline form K of the phosphate of Compound I, as shown in Fig. 12B, indicates that crystalline form K had a 5.7%weight loss when heated to 150℃. In addition, as shown in Fig. 12C, the DSC thermogram of crystalline form K of the phosphate of Compound I reveals endotherms with peak temperatures at 101.1℃, 127.2℃, 141.6℃, 171.8℃ and 220.8℃. Fig. 12D shows the ¹H 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%.

Table 39. UPLC results of crystalline form K

Relative Retention Time	Purity [Area%]
1.00	98.95
1.02	0.38
1.07	0.05
1.23	0.62

Example 6.6: Crystalline form L of the benzene sulfonate of Compound I

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.

Table 40. XRPD of crystalline form L

The TGA thermogram of crystalline form L of the benzene sulfonate of Compound I, as shown in Fig. 13B, indicates that crystalline form L had a 6.4%weight loss when heated to 200℃. In addition, as shown in Fig. 13C, the DSC thermogram of crystalline form L of the benzene sulfonate of Compound I reveals endotherms with peak temperatures at 167.3℃ and 177.1℃. Fig. 13D shows the ¹H 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%.

Table 41. UPLC results of crystalline form L

Relative Retention Time	Purity [Area%]
1.00	99.07
1.02	0.38
1.24	0.54

Example 6.7: Crystalline form M of the benzene sulfonate of Compound I

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.

Table 42. XRPD of crystalline form K

The TGA thermogram of crystalline form M of the benzene sulfonate of Compound I, as shown in Fig. 14B, indicates that crystalline form M had a 3.0%weight loss when heated to 200℃. In addition, as shown in Fig. 14C, the DSC thermogram of crystalline form K of the benzene sulfonate of Compound I reveals an endotherm with an onset temperature at 225.9℃, and an exotherm with a peak temperature at 247.7℃. Fig. 14D shows the ¹H 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%.

Table 41. UPLC results of crystalline form L

Relative Retention Time	Purity [Area%]
0.90	0.05
1.00	99.05
1.02	0.37
1.07	0.06
1.08	0.05
1.24	0.42

Example 6.8: Crystalline form N of the p-tosylate of Compound I

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.

Table 42. XRPD of crystalline form N

The TGA thermogram of crystalline form N of the p-tosylate of Compound I, as shown in Fig. 15B, indicates that crystalline form N had a 3.6%weight loss when heated to 200℃. In addition, as shown in Fig. 15C, the DSC thermogram of crystalline form N of the p-tosylate of Compound I reveals endotherms with peak temperatures at 52.5℃ and 261.8℃, and an exotherm with a peak temperature at 264.8℃. Fig. 15D shows the ¹H 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%.

Table 43. UPLC results of crystalline form N

Relative Retention Time	Purity [Area%]
0.90	0.06
1.00	99.12
1.02	0.35
1.07	0.05
1.08	0.05
1.24	0.36

Example 6.9: Crystalline form O of the ethanedisulfonate of Compound I

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.

Table 44. XRPD of crystalline form O

The TGA thermogram of crystalline form O of the ethanedisulfonate of Compound I, as shown in Fig. 16B, indicates that crystalline form O had a 6.3%weight loss when heated to 250℃. In addition, as shown in Fig. 16C, the DSC thermogram of crystalline form O of the ethanedisulfonate of Compound I reveals endotherms with peak temperatures at 591.2℃, 198.1℃, 277.3℃ and 286.5℃. Fig. 16D shows the ¹H 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%.

Table 45. UPLC results of crystalline form O

Relative Retention Time	Purity [Area%]
0.90	0.06
1.00	98.77

Relative Retention Time	Purity [Area%]
1.02	0.39
1.07	0.06
1.08	0.05
1.24	0.68

Example 6.10: Crystalline form P of the oxalate of Compound I

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.

Table 45. XRPD of crystalline form P

The TGA thermogram of crystalline form P of the oxalate of Compound I, as shown in Fig. 17B, indicates that crystalline form P had a 1.7%weight loss when heated to 150℃. In addition, as shown in Fig. 17C, the DSC thermogram of crystalline form P of the oxalate of Compound I reveals endotherms with peak temperatures at 116.2℃, 182.9℃, 214.7℃ and 235.2℃. Fig. 17D shows the ¹H 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%.

Table 46. UPLC results of crystalline form P

Relative Retention Time	Purity [Area%]
1.00	98.89
1.02	0.38
1.08	0.05
1.23	0.69

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.

Table 47. XRPD of crystalline form Q

The TGA thermogram of crystalline form Q of the ethanesulfonate of Compound I, as shown in Fig. 18B, indicates that crystalline form Q had a 7.5%weight loss when heated to 160℃. In addition, as shown in Fig. 18C, the DSC thermogram of crystalline form Q of the ethanesulfonate of Compound I reveals endotherms with peak temperatures at 72.5℃, 161.2℃, 167.2℃ and 242.0℃. Fig. 18D shows the ¹H 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%.

Table 48. UPLC results of crystalline form Q

Relative Retention Time	Purity [Area%]
0.90	0.05
1.00	98.80
1.02	0.38
1.07	0.06
1.08	0.06
1.20	0.05

Relative Retention Time	Purity [Area%]
1.24	0.60

Example 6.12: Crystalline form R of the hydrobromide of Compound I

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.

Table 49. XRPD of crystalline form R

The TGA thermogram of crystalline form R of the hydrobromide of Compound I, as shown in Fig. 19B, indicates that crystalline form R had a 9.0%weight loss when heated to 150℃. In addition, as shown in Fig. 19C, the DSC thermogram of crystalline form R of the hydrobromide of Compound I reveals an endotherm with a peak temperature at 101.2℃, and exotherms with peak temperatures at about 162.5℃ and 209.2℃. Fig. 19D shows the ¹H 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%.

Table 50. UPLC results of crystalline form Q

Relative Retention Time	Purity [Area%]
0.86	0.07
1.00	98.75
1.02	0.40
1.07	0.05
1.09	0.09
1.21	0.09
1.23	0.55

Example 7: Evaluation of crystalline forms of salts of Compound I

Example 7.1: Hygroscopicity

Crystalline forms G, H and I were evaluated for their hygroscopicity under DVS experiment at 25℃. 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℃/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) .

Example 7.2: Dynamic Solubility

Crystalline forms C, G, H and I were evaluated for their dynamic solubilities in water and biosolvents SGF, FaSSIF and FeSSIF at 37℃ according to a test procedure as follows:

1) Weighed 25 mg of crystalline forms C, G, H and I, respectively, into 5 mL glass vials, and added 4 mL of corresponding medium (H ₂O, SGF, FaSSIF and FeSSIF) . The initial feeding concentration is 5 mg/mL.

2) Mixed by rotation at 25 rpm on a rotary incubator at 37 ℃. The sampling points were at 1, 4, and 24 hours.

3) At each sampling point, took about 0.8 mL of suspension into a centrifuge tube, and centrifuged (12000 rpm, 5 min, 37 ℃) to separate the solid.

4) The supernatant was filtered through a PTFE filter membrane with a pore size of 0.45 μm. The filtrate was used to test the UPLC solubility and pH, and the solid was tested for XRPD.

The dynamic solubility evaluation results of each crystalline form are summarized in Table 51. The solubility curve is shown in Fig. 22 (the dotted line indicates that the sample is dissolved) , and the XRPD results of the solid samples separated from each sampling point are shown in Figs. 23 -26.

The results show:

1) In the four mediums, the solubilities of crystalline forms G, H and I are higher than that of crystalline form C.

2) In H ₂O and SGF, the solubilities of crystalline forms G and I are higher than that of crystalline forms H. In FeSSIF, there was no significant difference in the solubility of crystalline forms G, H and I.

3) The remaining solids of crystalline forms G, H and I after solubility tests in FaSSIF and FeSSIF transformed into crystalline form F, indicating that disproportionation occurred for the crystalline forms G, H and I in the above mediums. No change was observed for crystalline form C after 24 hours in the four mediums.

Table 51. Solubility results of crystalline forms C, G, H and I

S: Solubility (mg/mL) , calculated as free base.

--: The sample was dissolved and XRPD test was not performed.

NA: The amount of remaining solids after centrifugation is too low to be tested by XRPD.

FC: Crystalline transformation of the sampled solids.

NOTE: Clear dissolutions were observed after 1 h for crystalline forms G and I in H ₂O and SGF and crystalline form H in SGF and FaSSIF, so additional ～20 mg solids were added.

Example 7.3: Stability

Stability studies were carried out for samples of crystalline forms G, H and I under conditions of 80℃/Sealed/1 day, 80℃/Sealed/22 days, 25℃/60%RH/Open/1 week, 25℃/60%RH/Open/4 weeks, 40℃/75%RH/Open/1 week and 40℃/75%RH/Open/4 weeks. Solid samples separated from different conditions were investigated with XRPD for physical stability, and with UPLC for chemical stability. Results are summarized in Table 52. XRPD results are shown in Figs. 27-29. UPLC results are shown in Tables 53-55.

XRPD results show that no crystalline form transformation occurred for crystalline forms G, H and I under all the conditions.

UPLC results show:

a) Crystalline form G: It showed no purity decrease under 25℃/60%RH/Open/4 weeks, it showed slight purity decrease under 40℃/75%RH/Open/4 weeks, and it showed significant purity decrease under 80℃/Sealed/22 days.

b) Crystalline form H: It showed no purity decrease under 25℃/60%RH/Open/4 weeks and 40℃/75%RH/Open/4 weeks, it showed slight purity decrease under 80℃/Sealed/22 days.

c) Crystalline form I: No significant purity decrease was observed under all the conditions.

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.

Table 52. Stability of crystalline forms G, H and I

*: Retested after 39 days under 5 ℃/Sealed.

#: The samples obtained in the first sampling were placed under 5 ℃/Sealed for about 10 days, and then tested for XRPD and UPLC purity after being placed under corresponding conditions for 3 weeks.

Table 53. HPLC result of crystalline form G

Table 54. HPLC result of crystalline form H

Table 55. HPLC result of crystalline form I

Example 7.4 Crystal morphology

The crystal morphology of crystalline forms G, H and I was observed by PLM, and the results are summarized in Fig. 30. The results show that the crystalline forms G and I are irregular crystal particles with agglomeration, crystalline form H is a rod-like or needle-like crystal.

Example 8 Biochemical Assays

Assay 1: ATR inhibition assay

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:

1) Transfer 80 μl 20mM compound to 40μl of 100%DMSO in a 96-well plate.

2) Serially dilute the compound by transferring 20μl to 60μl of 100%DMSO in the next well and so forth for a total of 10 concentrations.

3) Add 100 μl of 100%DMSO to two empty wells for no compound control and no enzyme control in the same 96-well plate. Mark the plate as source plate.

4) Transfer 40 μl of compound from source plate to a new 384-well plate as the intermediate plate.

5) Transfer 60 nl compounds to assay plate by Echo.

6) Add 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 μl of 2x enzyme solution to each well of the 384-well assay plate, incubate at room temperature for 10 min.

7) Add FAM-RAD17 and ATP (Sigma, Cat. No. A7699-1G, CAS No. 987-65-5) in the kinase base buffer to prepare 2x peptide solution, then add 10μl to the assay plate.

8) Incubate at 28℃ for specified period of time. Add 40 μl of stop buffer (100 mM HEPES, pH 7.5; 0.015%Brij-35; 0.2%Coating Reagent #3; 50 mM EDTA) to stop reaction.

9) Collect data on Caliper. Convert conversion values to inhibition values.

Percent inhibition = (max-conversion) / (max-min) *100wherein “max” stands for DMSO control; “min” stands for low control.

Fit the data in XLFit excel add-in version 5.4.0.8 to obtain IC50 values. Equation used is:

Y=Bottom + (Top-Bottom) / (1+ (IC50/X) ^HillSlope)

wherein X means concentration in a format not transformed to logarithms.

The IC50 value for Compound I in this assay was 16 nM.

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) . 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. Collect and count numbers with Vi-cell XR and adjust cell density, seed cells into 96-well opaque-walled clear bottom tissue-culture treated plates in the CO2 incubator for 20-24 hours. Compound I was at 10 mM in DMSO. Then Compound I was added to the cell media in 3-fold serial dilutions, the final DMSO concentration is 0.5%. Incubate plates for 96h at 5%CO ₂, 37℃. Before the measurement, transfer the appropriate volume of CellTiter-Glo Buffer into the amber bottle containing CellTiter-Glo substrate to reconstitute the lyophilized enzyme/substrate mixture, mix gently, this forms the CellTiter-Glo Reagent (Promega Cat. No. G7573) . Equilibrate the plate and its contents to room temperature for approximately 30 minutes, then add 100 μL of CellTiter-Glo Reagent to the assay plate, mix contents for 2 minutes on an orbital shaker to induce cell lysis, incubate at room temperature for 10 minutes to stabilize luminescent signal, at last paste the clear bottom with white back seal and record luminescence with Enspire. IC ₅₀ and GI ₅₀ values were calculated with XLFit curve fitting software using 4 Parameter Logistic Model Y=Bottom + (Top-Bottom) / (1+ (IC50/X) ^HillSlope) .

The IC50 (Y=50%) values for Compound I in this assay was 401 nM.

The foregoing description is considered as illustrative only of the principles of the present disclosure. Further, since numerous modifications and changes will be readily apparent to those skilled in the art, it is not desired to limit the invention to the exact construction and process shown as described above. Accordingly, all suitable modifications and equivalents may be considered to fall within the scope of the invention as defined by the claims that follow.

Claims

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° 2θ) .
The crystalline form B of claim 1, wherein the XRPD pattern further comprises one or more peaks at 11.80, 17.74, 19.92, 23.73 and 24.95 (±0.2° 2θ) .
The crystalline form B of claim 1 or 2, wherein the XRPD pattern 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° 2θ) .
The crystalline form B of any of claims 1-3, characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
The crystalline form B of any of claims 1-4, characterized by an XRPD pattern substantially as shown in Fig. 1A.
The crystalline form B of any of claims 1-5, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset temperature of about 247.0℃.
The crystalline form B of claim 13, characterized by a DSC thermogram substantially as shown in Fig. 1C.
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° 2θ) .
The crystalline form C of claim 8, wherein the XRPD pattern further comprises one or more peaks at 10.41, 11.67, 15.63 and 18.17 (±0.2° 2θ) .
The crystalline form C of claim 8 or 9, wherein the XRPD pattern further comprises one or more peaks at 16.84, 17.09, 17.25, 20.36, 25.80 and 29.50 (±0.2° 2θ) .
The crystalline form C of any of claims 8-10, characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
The crystalline form C of any of claims 8-11, characterized by an XRPD pattern substantially as shown in Fig. 2A.
The crystalline form C of any of claims 8-12, characterized by a DSC thermogram having an endotherm with an onset temperature of about 248.3℃.
The crystalline form C of claim 13, characterized by a DSC thermogram substantially as shown in Fig. 2C.
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° 2θ) .
The crystalline form D of claim 15, wherein the XRPD pattern further comprises one or more peaks at 10.53, 16.64, and 23.53 (±0.2° 2θ) .
The crystalline form D of claim 15 or 16, wherein the XRPD pattern further comprises one or more peaks at 15.56, 16.21, 18.56, 19.00 and 23.92 (±0.2° 2θ) .
The crystalline form D of any of claims 15-17, characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
The crystalline form D of any of claims 15-18, characterized by an XRPD pattern substantially as shown in Fig. 3A.
The crystalline form D of any of claims 15-19, characterized by a DSC thermogram having an endotherm with an onset temperature of about 245.3℃.
The crystalline form D of claim 20, characterized by a DSC thermogram substantially as shown in Fig. 3C.
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° 2θ) .
The crystalline form E of claim 22, wherein the XRPD pattern further comprises one or more peaks at 4.39, 10.05, 18.16, and 23.66 (±0.2° 2θ) .
The crystalline form E of claim 22 or 23, wherein the XRPD pattern further comprises one or more peaks at 13.16, 16.86, 18.68, and 19.53 (±0.2° 2θ) .
The crystalline form E of any of claims 22-24, characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
The crystalline form E of any of claims 22-25, characterized by an XRPD pattern substantially as shown in Fig. 4A.
The crystalline form E of any of claims 22-26, characterized by a DSC thermogram having endotherms with onset temperatures of about 101.1℃ and 229.7℃.
The crystalline form E of any of claims 22-27, characterized by a DSC thermogram having an exothermal with an onset temperature of about 149.2℃.
The crystalline form E of any of claims 22-28, characterized by a DSC thermogram substantially as shown in Fig. 4C.
The crystalline form E of any of claims 22-29, wherein the crystalline form E is a NMP solvate.
The crystalline form E of claim 30, wherein the molar ratio between NMP and the Compound I is about 0.9: 1.
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° 2θ) .
The crystalline form F of claim 32, wherein the XRPD pattern further comprises one or more peaks at 16.70, 18.96, 20.41, 24.95, and 27.68 (±0.2° 2θ) .
The crystalline form F of claim 32 or 33, wherein the XRPD pattern further comprises one or more peaks at 6.11, 12.19, 12.80, and 18.96 (±0.2° 2θ) .
The crystalline form F of any of claims 32-34, characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
The crystalline form F of any of claims 32-35, characterized by an XRPD pattern substantially as shown in Fig. 5A.
The crystalline form F of any of claims 32-36, characterized by a DSC thermogram having endotherms with onset temperatures of about 79.7℃, 220.8℃ and 249.1℃.
The crystalline form F of any of claims 32-37, characterized by a DSC thermogram having an exothermal with an onset temperature of about 222.3℃.
The crystalline form F of any of claims 32-38, characterized by a DSC thermogram substantially as shown in Fig. 5C.
The crystalline form F of any of claims 32-39, wherein the crystalline form F is a hydrate.
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° 2θ) .
The crystalline form G of claim 41, wherein the XRPD pattern further comprises one or more peaks at 6.89, 14.17, 15.36 and 24.73 (±0.2° 2θ) .
The crystalline form G of claim 41 or 42, wherein the XRPD pattern further comprises one or more peaks at 16.5, 21.13, 25.73, 26.94 and 28.83 (±0.2° 2θ) .
The crystalline form G of any of claims 41-43, characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
The crystalline form G of any of claims 41-44, characterized by an XRPD pattern substantially as shown in Fig. 8A.
The crystalline form G of any of claims 41-45, characterized by a DSC thermogram having an endotherm with an onset temperature of about 158.0℃.
The crystalline form G of any of claims 41-46, characterized by a DSC thermogram substantially as shown in Fig. 8C.
The crystalline form G of claim 41, wherein the molar ratio between maleic acid and the Compound I is about 1: 1.
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° 2θ) .
The crystalline form H of claim 49, wherein the XRPD pattern further comprises one or more peaks at 12.72, 13.70, 21.45 and 22.79 (±0.2° 2θ) .
The crystalline form H of claim 49 or 50, wherein the XRPD pattern further comprises one or more peaks at 9.00, 15.41, 18.14, 27.25 and 28.00 (±0.2° 2θ) .
The crystalline form H of any of claims 49-51, characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
The crystalline form H of any of claims 49-52, characterized by an XRPD pattern substantially as shown in Fig. 9A.
The crystalline form H of any of claims 49-53, characterized by a DSC thermogram having an endotherm with an onset temperature of about 201.1℃.
The crystalline form H of any of claims 49-54, characterized by a DSC thermogram substantially as shown in Fig. 9C.
The crystalline form H of claim 49, wherein the molar ratio between fumaric acid and the Compound I is about 1: 1.
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° 2θ) .
The crystalline form I of claim 57, wherein the XRPD pattern further comprises one or more peaks at 9.04, 15.73, 19.36, 21.75 and 24.07 (±0.2° 2θ) .
The crystalline form I of claim 57 or 58, wherein the XRPD pattern further comprises one or more peaks at 10.68, 22.14, 26.04, 29.08 and 30.84 (±0.2° 2θ) .
The crystalline form I of any of claims 57-59, characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
The crystalline form I of any of claims 57-60, characterized by an XRPD pattern substantially as shown in Fig. 10A.
The crystalline form I of any of claims 57-61, characterized by a DSC thermogram having an endotherm with an onset temperature of about 251.0℃.
The crystalline form I of any of claims 57-62, characterized by a DSC thermogram having an exotherm with an onset temperature of about 257.9℃.
The crystalline form I of any of claims 57-63, characterized by a DSC thermogram substantially as shown in Fig. 10C.
The crystalline form I of claim 57, wherein the molar ratio between methylsulfonic acid and the Compound I is about 1: 1.
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° 2θ) .
The crystalline form J of claim 66, wherein the XRPD pattern further comprises one or more peaks at 11.67, 17.45, 22.56 and 24.22 (±0.2° 2θ) .
The crystalline form J of claim 66 or 67, wherein the XRPD pattern further comprises one or more peaks at 4.99, 9.35, 10.26, 16.14, 21.94 and 23.10 (±0.2° 2θ) .
The crystalline form J of any of claims 66-68, characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
The crystalline form J of any of claims 66-69, characterized by an XRPD pattern substantially as shown in Fig. 11A.
The crystalline form J of any of claims 66-70, characterized by a DSC thermogram having endotherms with peak temperatures of about 129.3℃, 200.1℃ and 235.3℃.
The crystalline form J of any of claims 66-71, characterized by a DSC thermogram substantially as shown in Fig. 11C.
The crystalline form J of claim 66, wherein the molar ratio between phosphoric acid and the Compound I is about 0.5: 1.
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° 2θ) .
The crystalline form K of claim 74, wherein the XRPD pattern further comprises one or more peaks at 4.18, 15.90, 16.64, 18.48 and 18.86 (±0.2° 2θ) .
The crystalline form K of claim 74 or 75, wherein the XRPD pattern further comprises one or more peaks at 19.71, 20.14, 23.39, 24.95 and 27.14 (±0.2° 2θ) .
The crystalline form K of any of claims 74-76, characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
The crystalline form K of any of claims 74-77, characterized by an XRPD pattern substantially as shown in Fig. 12A.
The crystalline form K of any of claims 74-78, characterized by a DSC thermogram having endotherms with peak temperatures of about 101.1℃, 127.2℃, 141.6℃, 171.8℃ and 220.8℃.
The crystalline form K of any of claims 74-79, characterized by a DSC thermogram substantially as shown in Fig. 12C.
The crystalline form K of claim 74, wherein the molar ratio between phosphoric acid and the Compound I is about 1.1: 1.
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° 2θ) .
The crystalline form L of claim 82, wherein the XRPD pattern further comprises one or more peaks at 15.97, 17.28, 17.84, 18.09 and 19.11 (±0.2° 2θ) .
The crystalline form L of claim 82 or 83, wherein the XRPD pattern further comprises one or more peaks at 14.08, 16.59, 19.39, 21.50, 22.32 and 24.99 (±0.2° 2θ) .
The crystalline form L of any of claims 82-84, characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
The crystalline form L of any of claims 82-85, characterized by an XRPD pattern substantially as shown in Fig. 13A.
The crystalline form L of any of claims 82-86, characterized by a DSC thermogram having endotherms with peak temperatures of about 167.3℃ and 177.1℃.
The crystalline form L of any of claims 82-87, characterized by a DSC thermogram substantially as shown in Fig. 13C.
The crystalline form L of claim 82, wherein the molar ratio between benzenesulfonic acid and the Compound I is about 0.9: 1.
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° 2θ) .
The crystalline form M of claim 90, wherein the XRPD pattern further comprises one or more peaks at 17.90, 18.65, 21.16, 21.85 and 22.92 (±0.2° 2θ) .
The crystalline form M of claim 90 or 91, wherein the XRPD pattern further comprises one or more peaks at 7.89, 15.78, 19.52, 20.76 and 24.72 (±0.2° 2θ) .
The crystalline form M of any of claims 90-92, characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
The crystalline form M of any of claims 90-93, characterized by an XRPD pattern substantially as shown in Fig. 14A.
The crystalline form M of any of claims 90-94, characterized by a DSC thermogram having an endotherm with an onset temperature of about 225.9℃.
The crystalline form M of any of claims 90-95, characterized by a DSC thermogram having an exotherm with an onset temperature of about 247.7℃.
The crystalline form M of any of claims 90-96, characterized by a DSC thermogram substantially as shown in Fig. 14C.
The crystalline form M of claim 90, wherein the molar ratio between benzenesulfonic acid and the Compound I is about 0.9: 1.
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° 2θ) .
The crystalline form N of claim 99, wherein the XRPD pattern further comprises one or more peaks at 11.13, 21.13, 22.33 and 23.12 (±0.2° 2θ) .
The crystalline form N of claim 99 or 100, wherein the XRPD pattern further comprises one or more peaks at 11.84, 13.75, 14.09, 23.80 and 27.62 (±0.2° 2θ) .
The crystalline form N of any of claims 99-101, characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
The crystalline form N of any of claims 99-102, characterized by an XRPD pattern substantially as shown in Fig. 15A.
The crystalline form N of any of claims 99-103, characterized by a DSC thermogram having endotherms with peak temperatures of about 52.5℃ and 261.8℃.
The crystalline form N of any of claims 99-104, characterized by a DSC thermogram having an exotherm with an peak temperature of about 264.8℃.
The crystalline form N of any of claims 99-105, characterized by a DSC thermogram substantially as shown in Fig. 15C.
The crystalline form N of claim 99, wherein the molar ratio between p-toluenesulfonic acid and the Compound I is about 1: 1.
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° 2θ) .
The crystalline form O of claim 108, wherein the XRPD pattern further comprises one or more peaks at 8.86, 11.82, 15.26, 15.55, 15.92 and 23.96 (±0.2° 2θ) .
The crystalline form O of claim 108 or 109, wherein the XRPD pattern further comprises one or more peaks at 17.74, 18.67, 23.41, 24.70 and 26.66 (±0.2° 2θ) .
The crystalline form O of any of claims 108-110, characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
The crystalline form O of any of claims 108-111, characterized by an XRPD pattern substantially as shown in Fig. 16A.
The crystalline form O of any of claims 108-112, characterized by a DSC thermogram having endotherms with peak temperatures of about 91.2℃, 198.1℃, 277.3℃ and 286.5℃.
The crystalline form O of any of claims 108-113, characterized by a DSC thermogram substantially as shown in Fig. 16C.
The crystalline form O of claim 108, wherein the molar ratio between ethanedisulfonic acid and the Compound I is about 0.9: 1.
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° 2θ) .
The crystalline form P of claim 116, wherein the XRPD pattern further comprises one or more peaks at 12.45, 19.88, 21.50 and 23.60 (±0.2° 2θ) .
The crystalline form P of claim 116 or 117, wherein the XRPD pattern further comprises one or more peaks at 20.71, 22.59, 24.00 and 28.70 (±0.2° 2θ) .
The crystalline form P of any of claims 116-118, characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
The crystalline form P of any of claims 116-119, characterized by an XRPD pattern substantially as shown in Fig. 17A.
The crystalline form P of any of claims 116-120, characterized by a DSC thermogram having endotherms with peak temperatures of about 116.2℃, 182.9℃, 214.7℃ and 235.2℃.
The crystalline form P of any of claims 116-121, characterized by a DSC thermogram substantially as shown in Fig. 17C.
The crystalline form P of claim 116, wherein the molar ratio between oxalic acid and the Compound I is about 0.8: 1.
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° 2θ) .
The crystalline form Q of claim 124, wherein the XRPD pattern further comprises one or more peaks at 5.17, 16.40, 17.33, 17.89, 18.57 and 22.48 (±0.2° 2θ) .
The crystalline form Q of claim 124 or 125, wherein the XRPD pattern further comprises one or more peaks at 6.80, 14.28, 15.59 and 20.71 (±0.2° 2θ) .
The crystalline form Q of any of claims 124-126, characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
The crystalline form Q of any of claims 124-127, characterized by an XRPD pattern substantially as shown in Fig. 18A.
The crystalline form Q of any of claims 124-128, characterized by a DSC thermogram having endotherms with peak temperatures of about 72.5℃, 161.2℃, 167.2℃ and 242.0℃.
The crystalline form Q of any of claims 124-129, characterized by a DSC thermogram substantially as shown in Fig. 18C.
The crystalline form Q of claim 124, wherein the molar ratio between ethanesulfonic acid and the Compound I is about 1: 1.
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° 2θ) .
The crystalline form R of claim 132, wherein the XRPD pattern further comprises one or more peaks at 5.54, 17.61, 17.89 and 19.39 (±0.2° 2θ) .
The crystalline form R of claim 132 or 133, wherein the XRPD pattern further comprises one or more peaks at 11.06, 14.21, 14.61, 18.49 and 27.83 (±0.2° 2θ) .
The crystalline form R of any of claims 132-134, characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:
The crystalline form R of any of claims 132-135, characterized by an XRPD pattern substantially as shown in Fig. 19A.
The crystalline form R of any of claims 132-136, characterized by a DSC thermogram having an endotherm with a peak temperature of about 101.2℃.
The crystalline form R of any of claims 132-137, characterized by a DSC thermogram having exotherms with peak temperatures of about 162.5℃ and 209.2℃.
The crystalline form R of any of claims 132-138, characterized by a DSC thermogram substantially as shown in Fig. 19C.
The crystalline form R of claim 132, wherein the molar ratio between hydrobromic acid and the Compound I is about 1.2: 1.
The crystalline form of any of claims 1-140 in substantially pure form.
The crystalline form of claim 141, wherein the crystalline form has a purity of at least 90wt%.
A pharmaceutical composition comprising Compound I and a pharmaceutically acceptable excipient, wherein Compound I is in a crystalline form selected from the group consisting of: the crystalline form B of any of claims 1-7, the crystalline form C of any of claims 8-14, the crystalline form D of any of claims 15-21, the crystalline form E of any of claims 22-31, and the crystalline form F of any of claims 32-40.
The pharmaceutical composition of claim 143, wherein at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of Compound I is in crystalline form B.
The pharmaceutical composition of claim 143, wherein at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of Compound I is in crystalline form C.
The pharmaceutical composition of claim 143 wherein at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of Compound I is in crystalline form D.
The pharmaceutical composition of claim 143, wherein at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of Compound I is in crystalline form E.
The pharmaceutical composition of claim 143, wherein at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of Compound I is in crystalline form F.
A pharmaceutical composition comprising a salt of Compound I and a pharmaceutically acceptable excipient, wherein the salt of Compound I is in a crystalline form selected from the group consisting of: the crystalline form G of any of claims 41-48, the crystalline form H of any of claims 49-56, the crystalline form I of any of claims 57-65, the crystalline form J of any of claims 66-73, the crystalline form K of any of claims 74-81, the crystalline form L of any of claims 82-89, the crystalline form M of any of claims 90-98, the crystalline form N of any of claims 99-107, the crystalline form O of any of claims 108-115, the crystalline form P of any of claims 116-123, the crystalline form Q of any of claims 124-131 and the crystalline form R of any of claims 132-140.
The pharmaceutical composition of claim 149, wherein at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form G.
The pharmaceutical composition of claim 149, wherein at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form H.
The pharmaceutical composition of claim 149, wherein at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form I.
The pharmaceutical composition of claim 149, wherein at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form J.
The pharmaceutical composition of claim 149, wherein at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form K.
The pharmaceutical composition of claim 149, wherein at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form L.
The pharmaceutical composition of claim 149, wherein at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form M.
The pharmaceutical composition of claim 149, wherein at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form N.
The pharmaceutical composition of claim 149, wherein at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form O.
The pharmaceutical composition of claim 149, wherein at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form P.
The pharmaceutical composition of claim 149, wherein at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form Q.
The pharmaceutical composition of claim 149, wherein at least 85%, 90%, 95%, 99%, 99.5%, 99.9%or 99.99%of the salt of Compound I is in crystalline form R.
A method for treating cancer, comprising administering an effective amount of the crystalline form of Compound I or a salt of Compound I of any one of claims 1-142 or the pharmaceutical composition of any of claims 143-161 to a subject in need thereof.
Use of the crystalline form of Compound I or a salt of Compound I of any one of claims 1-142 or the pharmaceutical composition of any of claims 143-161 in the manufacture of a medicament for treating cancer.
The crystalline form of Compound I or a salt of Compound I of any one of claims 1-142 or the pharmaceutical composition of any of claims 143-161, for use in the treatment of cancer.
A method for inhibiting ATR kinase in a subject in need thereof, comprising administering an effective amount of the crystalline form of Compound I or a salt of Compound I of any one of claims 1-142 or the pharmaceutical composition of any of claims 143-161 to the subject.