HK1234747A1 - Salts and polymorphs of a substituted imidazopyridinyl-aminopyridine compound - Google Patents

Description

Salts and polymorphs of substituted imidazopyridinyl-aminopyridine compounds

RELATED APPLICATIONS

The present application claims priority and benefit from u.s.s.n. 61/982,692 filed 4/22 2014, the contents of which are incorporated herein by reference in their entirety.

Background

Cancer is the second leading cause of death in the united states, and heart disease alone exceeds it (Cancer Facts and regulations 2004, American Cancer Society, Inc.). Although recent advances in cancer diagnosis and treatment may be therapeutically effective if cancer is detected early, current drug therapies for metastatic disease are mostly palliative and rarely provide long-term cures. Even with the introduction of new chemotherapies into the market, there is a continuing need for new drugs that are effective for monotherapy or in combination with existing agents as first line therapy in the treatment of resistant tumors, as second line therapy and third line therapy.

Cancer cells are defined as heterogeneous. For example, within a single tissue or cell type, multiple mutational 'mechanisms' may lead to the development of cancer. Thus, heterogeneity often exists between cancer cells taken from the same tissue and the same type of tumor that have originated in different individuals. The commonly observed mutational 'mechanisms' associated with some cancers may be in one tissue type and anotherDifferent in (A) from (B)For exampleThe commonly observed 'mechanism' of mutations leading to colon cancer may be different from the commonly observed 'mechanism' leading to leukemia). Thus, it is often difficult to predict whether a particular cancer will respond to a particular chemotherapeutic agent (cancer medicine, 5 th edition, edited by Bast et al, b.c. Decker inc., Hamilton, Ontario).

The deregulation of components of the cell signaling pathway that regulate the growth and differentiation of normal cells results in the development of cell proliferative disorders and cancer. Mutations in cell signaling proteins can cause such proteins to be expressed or activated at inappropriate levels or at inappropriate times during the cell cycle, which in turn can lead to uncontrolled cell growth or changes in the properties of cell-cell junctions. For example, deregulation of receptor tyrosine kinases by mutation, gene rearrangement, gene amplification, and overexpression of both receptor and ligand has been implicated in the development and progression of human cancers.

The AKT protein family (members of which are also known as protein kinase b (pkb)) plays an important role in mammalian cell signaling. In humans, there are three genes in the AKT family: akt1, Akt2 and Akt 3. These genes are encoded by enzymes of the serine/threonine specific protein kinase family members. By inhibiting the apoptotic process, Akt1 is involved in the cell survival pathway. Akt1 also induces protein synthesis pathways and is therefore a key signaling pathway protein in the cellular pathway leading to skeletal muscle hypertrophy and general tissue growth. Akt2 is an important signaling molecule in the insulin signaling pathway and is required to induce glucose transport. The role of Akt3 is less clear, but appears to be expressed primarily in the brain.

By binding and modulating a number of downstream effector factors,for exampleThe nuclear factor-kappa B, Bcl-2 family of proteins and the murine twin 2 (MDM2), the AKT family regulates cell survival and metabolism. Akt1 is known to play a role in the cell cycle. Furthermore, activated Akt1 may be able to proliferate and survive cells that have been subjected to potential mutagenic effects and, therefore, may contribute to mutations in other genes. Akt1 also has been implicated in angiogenesis and tumor development. Research has shown thatThe absence of Akt1 is shown to enhance pathological angiogenesis and tumor growth associated with stromal abnormalities of the skin and blood vessels. Since Akt1 can block apoptosis, thereby promoting cell survival, Akt1 is a major factor in many types of cancer.

Thus, there is a need for novel compounds and methods for modulating the AKT gene and treating proliferative disorders, including cancer. The identification of the free bases and salts of these compounds and the solid forms (e.g., amorphous, crystalline, and mesogenic forms) of the free bases or salts of these compounds with optimized physical and chemical properties would advance the development of these compounds as pharmaceuticals. The most useful of these physical and chemical properties include: ease and reproducibility of preparation, crystallinity, non-hygroscopicity, water solubility, stability to visible and ultraviolet light, low degradation rates under accelerated stability conditions of temperature and humidity, low isomerization rates between isomeric forms, and safety for long-term administration to humans. The present application addresses these needs.

SUMMARY

The present application relates, at least in part, to solid state forms of substituted imidazopyridinyl-aminopyridine compounds (compound a):

(A)，

3- (3- (4- (1-aminocyclobutyl) phenyl) -5-phenyl-3H-imidazo [4,5-b ] pyridin-2-yl) pyridin-2-amine.

The present application also relates, at least in part, to salts of compound a.

The present application also relates, at least in part, to solid state forms of compound a free base or a salt of compound a.

In one embodiment, the salt of the compound is a mono-, di-, or tri-salt.

In one embodiment, the application relates to the HCl salt of compound a. In one embodiment, the HCl salt of compound a is a mono-, di-, or tri-HCl salt. In one embodiment, the HCl salt of compound a is a tri-HCl salt.

In one embodiment, the application relates to the mesylate salt of compound a: (a)Namely, it isMesylate salt). In one embodiment, the mesylate salt of compound a is a mono-, di-, or tri-salt. In one embodiment, the mesylate salt of compound a is a mesylate salt.

In one embodiment, the solid state form is an amorphous form. In another embodiment, the solid state form is a crystalline form. In another embodiment, the solid state form is a mesogenic form. In other embodiments, the solid state form is unsolvated. In other embodiments, the solid state form is a solvate.

In other embodiments, the solid of compound a free base or a salt of compound a is in a plurality of polymorphic forms.

In one embodiment, the solid form of compound a free base or the salt of compound a is a stable solid form. In one embodiment, the solid state form of compound a free base or a salt of compound a is a stable amorphous form. In another embodiment, the solid state form of compound a free base or a salt of compound a is a stable crystalline form. In another embodiment, the solid state form of compound a free base or a salt of compound a is a stable polymorph. In one embodiment, the solid state form of compound a free base or a salt of compound a is a stable mesogenic form.

In one embodiment, the polymorph of compound a free base is unsolvated. In another embodiment, the polymorph of compound a free base is a solvate. In one embodiment, the polymorph of the compound a salt is unsolvated. In another embodiment, the polymorph of a compound a salt is a solvate.

The present application also relates, at least in part, to polymorphic forms of compound a free base. In one embodiment, the polymorph of compound a free base is form 1. In some embodiments, form 1 has X-ray powder diffraction peaks at about 22.0 and 25.0 ° 2 Θ using Cu ka radiation. In some embodiments, form 1 has X-ray powder diffraction peaks at about 8.3, 17.1, 22.0, and 25.0 ° 2 θ using Cu ka radiation. In some embodiments, form 1 has X-ray powder diffraction peaks at about 8.3, 9.5, 12.9, 14.1, 15.2, 16.6, 17.1, 19.2, 19.4, 19.6, 21.2, 22.0, 22.4, and 25.0 ° 2 θ using Cu ka radiation. In some embodiments, form 1 is a solvate. In other embodiments, form 1 is a Dichloromethane (DCM) or Methyl Ethyl Ketone (MEK) solvate. In other embodiments, form 1 is a DCM hemisolvate or a MEK hemisolvate.

In another embodiment, the polymorph of compound a free base is form 2. In some embodiments, form 2 has X-ray powder diffraction peaks at about 18.4 and 19.3 ° 2 Θ using CuK α radiation. In some embodiments, form 2 has X-ray powder diffraction peaks at about 15.8, 18.4, 19.3, and 20.1 ° 2 θ using Cu ka radiation. In some embodiments, form 2 has X-ray powder diffraction peaks at about 8.3, 8.8, 11.6, 13.3, 15.8, 18.4, 19.3, 20.1, 20.9, 21.4, 23.2, 25.9, and 26.6 ° 2 θ using Cu ka radiation. In some embodiments, form 2 is unsolvated.

In another embodiment, the polymorph of compound a free base is form 3. In some embodiments, form 3 has X-ray powder diffraction peaks at about 15.1 and 23.4 ° 2 Θ using CuK α radiation. In some embodiments, form 3 has X-ray powder diffraction peaks at about 15.1, 18.8, 21.0, and 23.4 ° 2 Θ using Cu ka radiation. In some embodiments, form 3 has X-ray powder diffraction peaks at about 6.4, 7.6, 8.4, 11.7, 15.1, 16.7, 18.8, 21.0, and 23.4 ° 2 θ using Cu ka radiation. In some embodiments, form 3 is unsolvated.

In another embodiment, the polymorph of compound a free base is form 4. In some embodiments, form 4 has X-ray powder diffraction peaks at about 17 and 23 ° 2 θ using CuK α radiation. In some embodiments, form 4 has X-ray powder diffraction peaks at about 15, 17, 23, and 26 ° 2 Θ using Cu ka radiation. In some embodiments, form 4 has X-ray powder diffraction peaks at about 8, 14, 15, 17, 22, 23, and 26 ° 2 θ using Cu ka radiation. In some embodiments, form 4 is a solvate. In other embodiments, form 4 is a Tetrahydrofuran (THF) solvate. In other embodiments, form 4 is a THF hemisolvate.

The present application also relates, at least in part, to polymorphic forms of compound a mesylate salt. In one embodiment, the polymorph of compound a mesylate is form a. In some embodiments, form a has X-ray powder diffraction peaks at about 9.4 and 23.0 ° 2 Θ using Cu ka radiation. In some embodiments, form a has X-ray powder diffraction peaks at about 9.4, 15.5, 18.8, and 23.0 ° 2 Θ using Cu ka radiation. In some embodiments, form a has X-ray powder diffraction peaks at about 4.1, 7.8, 9.4, 10.1, 12.1, 15.5, 16.2, 18.8, 19.9, 21.1, 23.0, 25.1, and 27.4 ° 2 θ using Cu ka radiation.

In another embodiment, the polymorph of compound a mesylate is form B. In some embodiments, form B has X-ray powder diffraction peaks at about 6.2 and 14.3 ° 2 Θ using Cu ka radiation. In some embodiments, form B has X-ray powder diffraction peaks at about 6.2, 6.6, 14.3, and 15.3 ° 2 θ using Cu ka radiation. In some embodiments, form B has X-ray powder diffraction peaks at about 6.2, 6.6, 11.3, 14.3, 15.3, 22.8, and 26.9 ° 2 θ using Cu ka radiation.

In another embodiment, the polymorph of compound a mesylate is form C. In some embodiments, form C has X-ray powder diffraction peaks at about 20.3 and 22.8 ° 2 Θ using Cu ka radiation. In some embodiments, form C has X-ray powder diffraction peaks at about 17.6, 18.4, 19.3, 19.7, and 22.8 ° 2 θ using Cu ka radiation. In some embodiments, form C has X-ray powder diffraction peaks at about 6.2, 8.9, 9.8, 10.1, 13.7, 18.4, 19.3, 19.7, 22.8, and 26.8 ° 2 θ using Cu ka radiation.

In another embodiment, the polymorph of compound a mesylate is form D. In some embodiments, form D has X-ray powder diffraction peaks at about 14.5 and 23.0 ° 2 Θ using Cu ka radiation. In some embodiments, form D has X-ray powder diffraction peaks at about 5.9, 11.5, 14.5, 20.3, and 23.0 ° 2 θ using Cu ka radiation. In some embodiments, form D has X-ray powder diffraction peaks at about 5.4, 5.9, 11.5, 14.5, 17.9, 20.3, 23.0, 23.6, 24.0, 26.2, 27.8, and 28.9 ° 2 θ using Cu ka radiation.

In another embodiment, the polymorph of compound a mesylate is form E. In some embodiments, form E has X-ray powder diffraction peaks at about 20.9 and 21.9 ° 2 Θ using Cu ka radiation. In some embodiments, form E has X-ray powder diffraction peaks at about 13.7, 20.6, 20.9, 21.9, and 23.0 ° 2 Θ using Cu ka radiation. In some embodiments, form E has X-ray powder diffraction peaks at about 8.9, 11.3, 13.7, 16.5, 19.3, 20.6, 20.9, 21.9, 23.0, 23.8, and 26.2 ° 2 θ using Cu ka radiation.

In another embodiment, the polymorph of compound a mesylate is form F. In some embodiments, form F has X-ray powder diffraction peaks at about 16.7 and 17.0 ° 2 Θ using Cu ka radiation. In some embodiments, form F has X-ray powder diffraction peaks at about 16.7, 17.0, 19.5, 20.3, and 24.4 ° 2 θ using Cu ka radiation. In some embodiments, form F has X-ray powder diffraction peaks at about 4.8, 7.2, 15.6, 16.7, 17.0, 19.5, 20.3, 21.7, 24.0, and 24.4 ° 2 θ using Cu ka radiation.

In another embodiment, the polymorph of compound a mesylate is form G. In some embodiments, form G has X-ray powder diffraction peaks at about 5.8 and 22.1 ° 2 Θ using Cu ka radiation. In some embodiments, form G has X-ray powder diffraction peaks at about 5.8, 14.9, 16.3, 22.1, and 23.7 ° 2 θ using Cu ka radiation. In some embodiments, form G has X-ray powder diffraction peaks at about 5.8, 10.8, 14.9, 16.3, 17.7, 22.1, 23.1, 23.7, 24.5, and 26.5 ° 2 θ using Cu ka radiation.

In another embodiment, the polymorph of compound a mesylate is form H. In some embodiments, form H has X-ray powder diffraction peaks at about 10.9 and 22.8 ° 2 Θ using Cu ka radiation. In some embodiments, form H has X-ray powder diffraction peaks at about 6.1, 10.9, 12.4, 15.9, and 22.8 ° 2 θ using Cu ka radiation. In some embodiments, form H has X-ray powder diffraction peaks at about 6.1, 10.1, 10.9, 12.4, 15.7, 15.9, 16.4, 20.4, 20.8, and 22.8 ° 2 θ using Cu ka radiation.

In another embodiment, the polymorph of compound a mesylate is form I. In some embodiments, form I has X-ray powder diffraction peaks at about 5.2 and 10.5 ° 2 Θ using Cu ka radiation. In some embodiments, form I has X-ray powder diffraction peaks at about 5.2, 6.2, 10.5, 20.2, and 23.0 ° 2 θ using Cu ka radiation. In some embodiments, form I has X-ray powder diffraction peaks at about 5.2, 6.2, 10.5, 11.1, 13.6, 20.2, 22.0, 22.3, 23.0, and 23.8 ° 2 θ using Cu ka radiation.

In another embodiment, the polymorph of compound a mesylate is form J. In some embodiments, form J has X-ray powder diffraction peaks at about 17.0 and 22.8 ° 2 Θ using Cu ka radiation. In some embodiments, form J has X-ray powder diffraction peaks at about 14.6, 17.0, 21.9, 22.8, and 24.8 ° 2 θ using Cu ka radiation. In some embodiments, form J has X-ray powder diffraction peaks at about 14.6, 17.0, 19.7, 20.4, 21.9, 22.8, 24.8, 25.3, 26.7, and 27.7 ° 2 θ using Cu ka radiation.

In another embodiment, the polymorph of compound a mesylate is form K. In some embodiments, form K has X-ray powder diffraction peaks at about 9.2 and 10.0 ° 2 θ using CuK α radiation. In some embodiments, form K has X-ray powder diffraction peaks at about 9.2, 10.0, 15.7, 20.0, and 23.8 ° 2 θ using Cu ka radiation. In some embodiments, form K has X-ray powder diffraction peaks at about 4.1, 9.2, 10.0, 15.7, 17.5, 19.3, 20.0, 21.5, 23.2, and 23.8 ° 2 θ using Cu ka radiation.

The present application also relates, at least in part, to pharmaceutical compositions comprising compound a and a pharmaceutically acceptable diluent, excipient, or carrier. The present application also relates, at least in part, to pharmaceutical compositions comprising compound a free base or a salt of compound a and a pharmaceutically acceptable diluent, excipient, or carrier. In one embodiment, the salt is an HCl salt or a mesylate salt.

The present application also relates, at least in part, to pharmaceutical compositions comprising a stable solid state form of compound a free base and a pharmaceutically acceptable diluent, excipient or carrier. The present application also relates, at least in part, to pharmaceutical compositions comprising a stable solid state form of a salt of compound a and a pharmaceutically acceptable diluent, excipient, or carrier. In one embodiment, the solid state form is an amorphous form. In another embodiment, the solid state form is a crystalline form. In another embodiment, the solid state form is a mesogenic form. In other embodiments, the solid state form is unsolvated. In other embodiments, the solid state form is a solvate.

The present application also relates, at least in part, to pharmaceutical compositions comprising a crystalline form of compound a free base or a salt of compound a, and a pharmaceutically acceptable diluent, excipient, or carrier. The present application also relates, at least in part, to pharmaceutical compositions comprising a polymorph of compound a free base or a salt of compound a, and a pharmaceutically acceptable diluent, excipient, or carrier. In one embodiment, the polymorph is form 1,2, 3, or 4, or form a, B, C, D, E, F, G, H, I, J, or K.

The present application also relates, at least in part, to methods of preparing a salt of compound a, a solid state of compound a free base or a salt of compound a, an amorphous form of compound a free base or a salt of compound a, a polymorph of compound a free base or a salt of compound a, or a mesomorphic form of compound a free base or a salt of compound a.

The present application relates, at least in part, to a process for preparing a polymorph of compound a free base, the process comprising: dissolving compound a free base in a solvent to form a solution; and isolating compound a from the solution. In one embodiment, the method further comprises warming the solution during the dissolution of compound a. In one embodiment, the method further comprises stirring the solution during the dissolution of compound a. In one embodiment, the method further comprises cooling the solution to facilitate separation of compound a from the solution. In one embodiment, the method further comprises evaporating the solution to facilitate separation of compound a from the solution. In one embodiment, the method further comprises adding compound a seed polymorph to the solution prior to isolating compound a from the solution.

The present application relates, at least in part, to a process for preparing a polymorph of a salt of compound a, the process comprising: dissolving compound a free base in a first solvent to form a first solution; an acid is mixed with the first solution. In one embodiment, the acid is dissolved in a second solvent to form a second solution, and then the acid is mixed with the first solution. In one embodiment, the first solvent and the second solvent are the same; in another embodiment, the first solvent and the second solvent are different. In one embodiment, the mixing comprises adding the acid or the second solution to the first solution; in another embodiment, the mixing comprises adding the first solution to the acid or the second solution. In one embodiment, the mixing forms a third solution. In one embodiment, the mixing forms a first slurry. In one embodiment, the method further comprises warming the first solution. In one embodiment, the method further comprises warming the third solution or the first slurry. In one embodiment, the method further comprises agitating the third solution or the first slurry. In one embodiment, the method further comprises cooling the third solution or the first slurry. In one embodiment, the method further comprises stirring the third solution or the first slurry after the cooling. In one embodiment, the method further comprises evaporating the third solution. In one embodiment, the method further comprises adding a seed polymorph to the third solution to form a second slurry. In one embodiment, the method further comprises agitating the second slurry. In one embodiment, the method further comprises cooling the second slurry. In one embodiment, the method further comprises agitating the second slurry after the cooling. In one embodiment, the method further comprises filtering the third solution, the first slurry, or the second slurry. In one embodiment, the method further comprises drying the third solution, the first slurry, or the second slurry.

The present application also relates, at least in part, to a process for preparing a polymorph of a salt of compound a, the process comprising: dissolving compound a free base in a first solvent to form a compound a slurry; add acid to the compound a slurry. In one embodiment, the acid is dissolved in a second solvent to form a second solution, and then the acid is added to the compound a slurry. In one embodiment, the first solvent and the second solvent are the same; in another embodiment, the first solvent and the second solvent are different. In one embodiment, the acid or the second solution is added to the compound a slurry to form a third solution. In one embodiment, the acid or the second solution is added to the compound a slurry to form a first slurry. In one embodiment, the method further comprises warming the compound a slurry. In one embodiment, the method further comprises warming the third solution or the first slurry. In one embodiment, the method further comprises agitating the third solution or the first slurry. In one embodiment, the method further comprises cooling the third solution or the first slurry. In one embodiment, the method further comprises stirring the third solution or the first slurry after the cooling. In one embodiment, the method further comprises evaporating the third solution. In one embodiment, the method further comprises adding a third solvent to the third solution to form a second slurry. In one embodiment, the method further comprises adding a seed polymorph to the third solution to form a third slurry. In one embodiment, the method further comprises agitating the second slurry or the third slurry. In one embodiment, the method further comprises cooling the second slurry or the third slurry. In one embodiment, the method further comprises stirring the second slurry or the third slurry after the cooling. In one embodiment, the method further comprises filtering the third solution, the first slurry, the second slurry, or the third slurry. In one embodiment, the method further comprises drying the third solution, the first slurry, the second slurry, or the third slurry.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. In the specification, the singular forms also include the plural forms unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. It is admitted that the references cited herein are prior art. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

Other features and advantages of the present application will be apparent from the following detailed description, and from the claims.

Brief Description of Drawings

FIG. 1: image of crystals of Compound A free base

FIG. 2: XRPD of form 1 polymorph of compound a free base

FIG. 3: XRPD of forms 1,2 and 3 of Compound A free base

FIG. 4: XRPD of compound a free base form 1. (A) XRPD comparison of compound a free base form 1 before and after one week of storage at 40 ℃ and 75% RH; (B) XRPD comparison of compound a free base form 1 before and after one week of storage at 25 ℃ and 96% RH; (C) comparison of XRPD of form 1 of Compound A free base before and after GVS

FIG. 5: GVS isotherms of form 1 of Compound A free base

FIG. 6: HPLC of Compound A free base form 1

FIG. 7: of compound A as the free base¹H NMR. (A) Form 1 DCM solvate, (B) form 2, and (C) form 1 MEK solvate

FIG. 8: DSC and TGA thermograms of form 1 of Compound A free base

FIG. 9: structure representation of Compound A free base hemi-THF solvate

FIG. 10: images of crystals of compound a free base hemithf solvate

FIG. 11: hydrogen-bonded dimers of Compound A free base hemiTHF solvates

FIG. 12: hydrogen-bonded chains of dimers of Compound A free base hemiTHF solvates

FIG. 13: packaging of compound a free base hemithf solvate in a unit cell, looking down the b-axis of crystallization

FIG. 14: simulated XRPD of compound a free base hemithf solvate

FIG. 15: image of crystals of compound a HCl salt

FIG. 16: XRPD of Compound A HCl salt

FIG. 17: XRPD of polymorphic forms of Compound A MonoHCl salt (A) and Di-HCl salt (B)

FIG. 18: GVS isotherm of compound A HCl salt

FIG. 19: HPLC of the HCl salt of Compound A

FIG. 20: of compound A HCl salt before (A) and after (B) drying¹H NMR

FIG. 21: DSC and TGA thermogram of HCl salt of Compound A

FIG. 22: XRPD of Compound A Tris HCl salt (tris-HCl) after storage

FIG. 23: image of crystals of Compound A mesylate

FIG. 24: XRPD of Compound A mesylate

FIG. 25: XRPD of compound a mesylate. (A) Before and after storage at 40 ℃ and 75% RH (the upper three curves show XRPD after storage; the middle three curves show XRPD before storage; and the bottom curve shows XRPD of the free base of Compound A), (B) before and after GVS (the bottom curve shows XRPD before GVS), and (C) before and after storage at 40 ℃ and 75% RH (the bottom curve shows XRPD before storage)

FIG. 26: GVS of compound a mesylate. (A) Kinetic diagram, (B) isotherm diagram

FIG. 27 is a schematic view showing: HPLC of Compound A mesylate

FIG. 28: process for preparing compound A mesylate¹H NMR

FIG. 29: DSC and TGA thermogram of mesylate of Compound A

FIG. 30: XRPD of lyophilized compound a bis-mesylate salt

FIG. 31: process for preparing lyophilized Compound A Dimethanesulfonate¹H NMR

FIG. 32: XRPD of form A of Compound A mesylate

FIG. 33: compound A mesylate salt form A¹H NMR

FIG. 34: DSC of form A of Compound A mesylate

FIG. 35: TGA of form A of Compound A mesylate

FIG. 36: IR of form A of Compound A mesylate

FIG. 37: XRPD of form B of Compound A mesylate

FIG. 38: of Compound A mesylate in form B¹H NMR

FIG. 39: DSC of form B of Compound A mesylate

FIG. 40: TGA of form B of Compound A mesylate

FIG. 41: IR of form B of Compound A mesylate

FIG. 42: XRPD of form C of Compound A mesylate

FIG. 43: of form C of Compound A mesylate¹H NMR

FIG. 44: DSC of form C of Compound A mesylate

FIG. 45: TGA of form C of Compound A mesylate

FIG. 46: IR of form C of Compound A mesylate

FIG. 47: DSC of form A (A) and form B (B) of Compound A mesylate, and overlap of DSC of form A and form B (C)

FIG. 48: XRPD of form B of Compound A mesylate before and after heating

FIG. 49: XRPD of Compound A HCl salt

FIG. 50: XRPD of Compound A sulfate

FIG. 51: XRPD of Compound A mesylate

FIG. 52: XRPD of compound A maleate

FIG. 53: XRPD of Compound A phosphate

FIG. 54: XRPD of compound A L-glutamate

FIG. 55: XRPD of compound A L-tartrate

FIG. 56: XRPD of compound A mucate

FIG. 57: XRPD of Compound A citrate salt

FIG. 58: XRPD of compound A D-glucuronate

FIG. 59: XRPD of Compound A hippurate

FIG. 60: XRPD of compound A D-gluconate

FIG. 61: XRPD of compound A L-lactate

FIG. 62: XRPD of compound A L-ascorbate

FIG. 63: XRPD of Compound A succinate

FIG. 64: XRPD of Compound A acetate

FIG. 65: XRPD of the HCl salt of Compound A before and after storage at 40 ℃ and 75% RH (4 pairs of curves are shown, the lower curve in each pair of curves shows XRPD before storage)

FIG. 66: XRPD of Compound A sulfate before and after storage at 40 ℃ and 75% RH (the lower curve shows XRPD before storage)

FIG. 67: XRPD of Compound A mesylate salt before and after storage at 40 ℃ and 75% RH (4 pairs of curves are shown, the lower curve in each pair of curves shows XRPD before storage)

FIG. 68: XRPD of compound A maleate salt before and after storage at 40 ℃ and 75% RH (showing 3 pairs of curves, the lower curve in each pair showing XRPD before storage)

FIG. 69: XRPD of Compound A phosphate before and after storage at 40 ℃ and 75% RH (5 pairs of curves are shown, the lower curve in each pair shows XRPD before storage)

FIG. 70: XRPD of compound A L-tartrate before and after storage at 40 ℃ and 75% RH (the lower curve shows XRPD before storage)

FIG. 71: XRPD of the mucate salt of Compound A before and after storage at 40 ℃ and 75% RH (2 pairs of curves are shown, the lower curve in each pair shows XRPD before storage)

FIG. 72: XRPD of Compound A citrate before and after storage at 40 ℃ and 75% RH (the lower curve shows XRPD before storage)

FIG. 73: XRPD of compound A D-glucuronate before and after storage at 40 ℃ and 75% RH (the lower curve shows XRPD before storage)

FIG. 74: XRPD of Compound A hippurate before and after storage at 40 ℃ and 75% RH (2 pairs of curves are shown, the lower curve in each pair shows XRPD before storage)

FIG. 75: XRPD of compound A D-gluconate before and after storage at 40 ℃ and 75% RH (the lower curve shows XRPD before storage)

FIG. 76: XRPD of compound A L-lactate before and after storage at 40 ℃ and 75% RH (showing 3 pairs of curves, the lower curve in each pair showing XRPD before storage)

FIG. 77: XRPD of compound A L-ascorbate before and after storage at 40 ℃ and 75% RH (the lower curve shows XRPD before storage)

FIG. 78: XRPD of Compound A succinate before and after storage at 40 ℃ and 75% RH (the lower curve shows XRPD before storage)

FIG. 79: XRPD of Compound A acetate before and after storage at 40 ℃ and 75% RH (showing 3 pairs of curves, the lower curve in each pair showing XRPD before storage)

FIG. 80: MonoHCl salts of Compound A from THF (A), Ethyl acetate (B) and ethanol (C) and di-HCl salts of Compound A from ethanol (D)¹H NMR

FIG. 81: process for preparation of compound A disulfate from ethanol¹H NMR

FIG. 82: of the monomethanesulfonate salt of Compound A from THF (A), Ethyl acetate (B) and ethanol (C) and of the dimesylate salt of Compound A from THF (D)¹H NMR

FIG. 83: monomaleate salts of Compound A from Ethyl acetate (A) and ethanol (B) and dimaleate salts of Compound A from THF (C)¹H NMR

FIG. 84: of the monophosphates of Compound A from THF (A), Ethyl acetate (B) and ethanol (C) and of the diphosphates of Compound A from Ethyl acetate (D) and ethanol (E)¹H NMR

FIG. 85: process for preparation of compound A monotartrate from THF¹H NMR

FIG. 86: monomyxonate of Compound A from Ethyl acetate (A) and ethanol (B)¹H NMR

FIG. 87: process for preparing Compound A Monocitrate from ethanol¹H NMR

FIG. 88: process for preparation of A D-glucuronate salt of compound THF¹H NMR

FIG. 89: process for preparation of Compound A Monohippurate from Ethyl acetate (A) and ethanol (B)¹H NMR

FIG. 90: process for preparation of A D-gluconate Compound from THF¹H NMR

FIG. 91: process for preparation of compound A L-ascorbic acid salt from THF¹H NMR

FIG. 92: process for preparing succinate salt of compound A from ethanol¹H NMR

FIG. 93: from THF (A) Compound A mono L-lactate of Ethyl acetate (B) and ethanol (C)¹H NMR

FIG. 94: preparation of Compound A monoacetate from THF (A), Ethyl acetate (B) and ethanol (C)¹H NMR

FIG. 95: (A) XRPD of Compound A sulfate, and (B) XRPD of Compound A sulfate before and after storage at 40 ℃ and 75% RH (the upper three curves show XRPD after storage; the middle three curves show XRPD before storage; and the bottom curve shows XRPD of Compound A free base)

FIG. 96: form a compound a bis mesylate-XRPD analysis: hydration Screen and scaling Up

FIG. 97: compound A, Dimethanesulfonate-PLM assay

FIG. 98: compound A, form A, bis-mesylate-TG/DTA assay

FIG. 99: compound A, bis-mesylate salt-DSC analysis

FIG. 100: form a compound a bis mesylate-XRPD analysis: form A, compared to form A after heating to 150 ℃

FIG. 101: compound A bis-mesylate-DVS assay

FIG. 102: form a compound a bis mesylate-XRPD analysis: post-DVS analysis

FIG. 103: form a compound a bis mesylate-XRPD analysis: slurry in deionized water

FIG. 104: form A Compound A Dimethanesulfonate-HPLC purity analysis

FIG. 105: compound a, form a bis mesylate — HPLC purity: stability Studies at 40 ℃ and 75% RH

FIG. 106: compound a, form a bis mesylate — HPLC purity: stability study at ambient temperature

FIG. 107: compound a, form a bis mesylate — HPLC purity: stability study at 80 ℃

FIG. 108: form a compound a bis mesylate-XRPD analysis: stability testing at 40 ℃ and 75% RH, ambient temperature and 80 ℃

FIG. 109: form A Compound A Dimethanesulfonate salt¹H NMR spectroscopy

FIG. 110: form A Compound A Dimethanesulfonate-XRPD

FIG. 111: form A Compound A bis mesylate-XRPD-indicating peaks

FIG. 112: compound A, form A, bis-mesylate salt-XRPD-peak list

FIG. 113: form B compound a bis mesylate-XRPD analysis: hydration screening and scale-up

FIG. 114: compound A, Format B, bis-mesylate-PLM assay

FIG. 115: compound a, form B, bis mesylate-TG/DTA assay: after air drying for 2-3 days

FIG. 116: compound a, form B, bis mesylate-TG/DTA assay: vacuum drying for 1 day

Fig. 117: compound a, form B, bis mesylate-TG/DTA assay: drying at 50 deg.C for one day

FIG. 118: form B Compound A bis-mesylate-DSC analysis

FIG. 119: form B compound a bis mesylate-XRPD analysis: form A, compared to form B after heating to 250 ℃

FIG. 120: compound A, form B, bis mesylate-DVS assay

FIG. 121: form B compound a bis mesylate-XRPD analysis: post-DVS analysis

FIG. 122: form B compound a bis mesylate-XRPD analysis: slurry in deionized water

FIG. 123: form B Compound A bis-mesylate-HPLC analysis of purity

FIG. 124: form B compound a bis mesylate — HPLC purity: stability Studies at 40 ℃ and 75% RH

FIG. 125: form B compound a bis mesylate — HPLC purity: stability study at ambient temperature

FIG. 126: form B compound a bis mesylate — HPLC purity: stability study at 80 ℃ 80 DEG C

FIG. 127: form B compound a bis mesylate-XRPD analysis: stability testing-forms B, I and J, compared to form B at 40 ℃ and 75% RH, ambient temperature, and 80 ℃

FIG. 128: form B Compound A Dimethanesulfonate salt¹H NMR spectroscopy

FIG. 129: form B Compound A Dimethanesulfonate-XRPD

FIG. 130: form B Compound A bis mesylate-XRPD-peaks

FIG. 131: compound A, form B, bis-mesylate salt-XRPD-peak list

FIG. 132: form C Compound A Dimethanesulfonate-XRPD analysis

FIG. 133: compound A, Format C, bis-mesylate-PLM assay

FIG. 134: compound A, form C, bis-mesylate-TG/DTA assay

FIG. 135: compound A, form C, bis-mesylate-DSC analysis

FIG. 136: compound A, form C, bis mesylate-DVS assay

FIG. 137: form C compound a bis mesylate-XRPD analysis: post-DVS analysis

FIG. 138: form C compound a bis mesylate-XRPD analysis: slurry in deionized water

FIG. 139: form C Compound A Dimethanesulfonate-HPLC purity analysis

FIG. 140: form C compound a bis-mesylate salt — HPLC purity: stability Studies at 40 ℃ and 75% RH

FIG. 141: form C compound a bis-mesylate salt — HPLC purity: stability study at ambient temperature

FIG. 142: form C compound a bis-mesylate salt — HPLC purity: stability study at 80 ℃

FIG. 143: form C compound a bis mesylate-XRPD analysis: stability testing at 40 ℃ and 75% RH, ambient temperature and 80 ℃

FIG. 144: form C Compound A Dimethanesulfonate salt¹H NMR spectroscopy

FIG. 145: form C Compound A Dimethanesulfonate-XRPD

FIG. 146: compound A, form C, bis-mesylate-XRPD-indicated peaks

FIG. 147: compound A, form C, bis-mesylate salt-XRPD-peak list

Fig. 148: quenching experiment at-18 deg.C-XRPD analysis of the solid state of Compound A bis-mesylate in various solvents

FIG. 149: quenching experiment at-18 deg.C-XRPD analysis of the solid state of Compound A bis-mesylate in various solvents

FIG. 150: quenching experiment at-18 deg.C-solid form of Compound A bis-mesylate-PLM analysis of acetone: Water (90:10)

FIG. 151: quenching experiment at-18 deg.C-solid form of Compound A bis-mesylate-PLM analysis of acetone: water (50:50), 1, 4-dioxane: water (80:20) and ethanol

FIG. 152: quenching experiment at-18 deg.C-solid form of Compound A bis-mesylate-PLM analysis of ethanol: water (50:50), methanol and methanol: water (98:2)

Fig. 153: quenching experiments at-18 ℃ solid state of Compound A bis-mesylate-PLM analysis of 1-propanol: water (90:10), 1-propanol: water (50:50) and 2-propanol: water (90:10)

FIG. 154: quenching experiment at-18 deg.C-solid State of Compound A bis-mesylate-PLM analysis of tetrahydrofuran: Water (70:30)

FIG. 155: slow Cooling experiment (from 60 ℃ to 5 ℃ at 0.3 ℃/min) -XRPD analysis of the solid state of Compound A bis-mesylate in various solvents

FIG. 156: slow Cooling experiment (from 60 ℃ to 5 ℃ at 0.3 ℃/min) -XRPD analysis of the solid state of Compound A bis-mesylate in various solvents

FIG. 157: slow Cooling experiment (from 60 ℃ to 5 ℃ at 0.3 ℃/min), PLM analysis of Compound A dimethyl sulfonate in solid form, acetone: water (90:10), 1, 4-dioxane: water (80:20) and ethanol: water (90:10)

FIG. 158: slow Cooling experiment (from 60 ℃ to 5 ℃ at 0.3 ℃/min), PLM analysis of Compound A dimethyl sulphonate in solid form, ethanol: water (50:50), methanol and methanol: water (98:2)

FIG. 159: slow Cooling experiment (from 60 ℃ to 5 ℃ at 0.3 ℃/min) -PLM analysis of Compound A dimethyl sulphonate in solid form-methanol: water (80:20), 1-propanol and 1-propanol: water (90:10)

FIG. 160: slow Cooling experiment (from 60 ℃ to 5 ℃ at 0.3 ℃/min) -PLM analysis of Compound A bis-mesylate in solid form-1-propanol: water (50:50), 2-propanol: water (50:50), and tetrahydrofuran: water (70:30)

Fig. 161: anti-solvent (acetone) addition experiments in various solvents at ambient temperature-XRPD analysis of the solid state of compound a bis-mesylate salt

FIG. 162: anti-solvent (acetone) addition experiments in various solvents at ambient temperature-XRPD analysis of the solid state of compound a bis-mesylate salt

FIG. 163: antisolvent (acetone) addition experiments in various solvents at ambient temperature-solid state of Compound A bis-mesylate-PLM analysis of acetone: water (90:10), acetone: water (50:50) and acetonitrile: water (90:10)

FIG. 164: anti-solvent (acetone) addition experiments in various solvents at ambient temperature-solid state of Compound A dimethyl sulfonate-PLM analysis of acetonitrile: water (50:50), dimethyl sulfoxide and 1, 4-dioxane: water (80:20)

FIG. 165: antisolvent (acetone) addition experiments in various solvents at ambient temperature solid state of Compound A bis-mesylate-PLM analysis of ethanol: water (90:10), ethanol: water (50:50) and methanol

FIG. 166: anti-solvent (acetone) addition experiments in various solvents at ambient temperature solid state of compound A bis-mesylate salt PLM analysis of methanol: water (98:2), methanol: water (80:20) and 1-propanol: water (90:10)

FIG. 167: anti-solvent (acetone) addition experiments in various solvents at ambient temperature-solid state of Compound A bis-mesylate-1-propanol: water (50:50), 2-propanol: water (90:10) and 2-propanol: water (50:50) PLM analysis

FIG. 168: antisolvent (acetone) addition experiments in various solvents at ambient temperature-solid state of Compound A bis-mesylate-tetrahydrofuran, water (70:30) and PLM analysis of water

FIG. 169: evaporation experiments from various solvents-XRPD analysis of the solid state of Compound A bis-mesylate salt

FIG. 170: evaporation experiments from various solvents-XRPD analysis of the solid state of Compound A bis-mesylate salt

FIG. 171: evaporation experiments from various solvents solid state of Compound A bis-mesylate salt PLM analysis of acetone Water (95:5), acetone Water (90:10) and acetone Water (50:50)

FIG. 172: evaporation experiments from various solvents-solid form of Compound A bis-mesylate salt-PLM analysis of acetonitrile: water (90:10), acetonitrile: water (50:50), 1, 4-dioxane: water (80:20)

FIG. 173: evaporation experiments from various solvents-solid State of Compound A bis-mesylate-PLM analysis of ethanol, Water (50:50) and methanol

FIG. 174: evaporation experiments from various solvents solid-PLM analysis of Compound A dimethyl sulfonate Water (98:2), methanol Water (80:20) and 1-propanol Water (90:10)

FIG. 175: evaporation experiments from various solvents-solid form of Compound A bis-mesylate salt-PLM analysis of 1-propanol: water (50:50), 2-propanol: water (98:2) and 2-propanol: water (90:10)

FIG. 176: evaporation experiments from various solvents-PLM analysis of Compound A as a solid of the bis-mesylate salt, 2-propanol: water (50:50), tetrahydrofuran: water (95:5) and tetrahydrofuran: water (70:30)

FIG. 177: evaporation experiments from various solvents-solid-water PLM analysis of compound a bis-mesylate salt

FIG. 178: hydrated sieving experiment-XRPD analysis of a solid, low-concentration slurry of Compound A bis-mesylate salt in acetone and acetonitrile at 10 deg.C

FIG. 179: hydrated sieving experiment-XRPD analysis of a solid, low concentration slurry of Compound A bis-mesylate salt in 2-propanol at 10 deg.C

FIG. 180: hydrated sieving experiment-XRPD analysis of a solid, highly concentrated slurry of Compound A bis-mesylate salt in acetone and acetonitrile at 10 deg.C

FIG. 181: hydrated sieving experiment-XRPD analysis of a solid, highly concentrated slurry of Compound A bis-mesylate salt in 2-propanol at 10 deg.C

FIG. 182: hydrated sieving experiment-XRPD analysis of a solid, low-concentration slurry of Compound A bis-mesylate salt in acetone and acetonitrile at 25 deg.C

Fig. 183: hydrated sieving experiment-XRPD analysis of a solid, low concentration slurry of Compound A bis-mesylate salt in 2-propanol at 25 deg.C

Fig. 184: hydrated sieving experiment-XRPD analysis of a solid, highly concentrated slurry of Compound A bis-mesylate salt in acetone and acetonitrile at 25 deg.C

FIG. 185: hydrated sieving experiment-XRPD analysis of a solid, highly concentrated slurry of Compound A bis-mesylate salt in 2-propanol at 25 deg.C

Fig. 186: hydrated sieving experiment-XRPD analysis of a solid, low-concentration slurry of Compound A bis-mesylate salt in acetone and acetonitrile at 50 deg.C

FIG. 187: hydrated sieving experiment-XRPD analysis of a solid, low concentration slurry of Compound A bis-mesylate salt in 2-propanol at 50 deg.C

FIG. 188: hydrated sieving experiment-XRPD analysis of a solid, highly concentrated slurry of Compound A bis-mesylate salt in acetone and acetonitrile at 50 deg.C

FIG. 189: hydrated sieving experiment-XRPD analysis of a solid, highly concentrated slurry of Compound A bis-mesylate salt in 2-propanol at 50 deg.C

FIG. 190: form D compound a bis mesylate-XRPD analysis: hydration screening and scale-up

FIG. 191: compound A, Format D, Dimethanesulfonate-PLM assay

FIG. 192: compound A, form D, bis-mesylate-TG/DTA assay after air drying at ambient temperature for about 3 days

Fig. 193: compound A, form D, bis-mesylate-TG/DTA assay after 1 day vacuum drying at ambient temperature

FIG. 194: form D Compound A bis-mesylate-DSC analysis

FIG. 195: form D compound a bis mesylate-XRPD analysis: form A, form D, form I, form D after heating to 150 ℃ and form D after heating to 260 ℃

FIG. 196: compound A, form D, bis mesylate-DVS assay

FIG. 197: form D compound a bis mesylate-XRPD analysis: post-DVS analysis

FIG. 198: form D compound a bis mesylate-XRPD analysis: slurry in deionized water

Fig. 199: form D Compound A Dimethanesulfonate-HPLC purity analysis

Fig. 200: form D compound a bis-mesylate salt — HPLC purity: stability Studies at 40 ℃ and 75% RH

Fig. 201: form D compound a bis-mesylate salt — HPLC purity: stability study at ambient temperature

Fig. 202: form D compound a bis-mesylate salt — HPLC purity: stability study at 80 ℃

FIG. 203: form D compound a bis mesylate-XRPD analysis: stability testing at 40 ℃ and 75% RH, ambient temperature and 80 ℃

FIG. 204: form D Compound A Dimethanesulfonate salt¹H NMR spectroscopy

FIG. 205: form E compound a bis-mesylate-XRPD analysis: hydration screening and scale-up

FIG. 206: compound A, Format E, bis-mesylate-PLM assay

FIG. 207: compound A, form E, bis-mesylate-TG/DTA assay after air drying at ambient temperature for about 3 days

FIG. 208: compound A, form E, bis-mesylate-TG/DTA assay, after about 1 more day of vacuum drying at ambient temperature

FIG. 209: compound A, form E, bis-mesylate-TG/DTA assay after heating experiment (150 ℃ C.)

FIG. 210: compound A, form E, bis-mesylate-DSC analysis

FIG. 211: form E compound a bis-mesylate-XRPD analysis: form A, form E after heating to 150 ℃ and form E after heating to 260 ℃

FIG. 212: compound A, form E, bis mesylate-DVS assay

FIG. 213: form E compound a bis-mesylate-XRPD analysis: post-DVS analysis

FIG. 214: form E compound a bis-mesylate-XRPD analysis: slurry in deionized water

FIG. 215: form E Compound A Dimethanesulfonate-HPLC purity analysis

FIG. 216: form E compound a bis-mesylate salt — HPLC purity: stability Studies at 40 ℃ and 75% RH

FIG. 217: form E compound a bis-mesylate salt — HPLC purity: stability study at ambient temperature

FIG. 218: form E compound a bis-mesylate salt — HPLC purity: stability study at 80 ℃

FIG. 219: form E compound a bis-mesylate-XRPD analysis: stability testing at 40 ℃ and 75% RH, ambient temperature and 80 ℃

FIG. 220: form E Compound A Dimethanesulfonate salt¹H NMR spectroscopy

Fig. 221: compound A bis-mesylate-TG/DTA assay of form F

FIG. 222: compound A, form G, bis-mesylate-TG/DTA assay

FIG. 223: compound A, form H, bis-mesylate-TG/DTA assay

FIG. 224: form I compound a bis mesylate-XRPD analysis: hydration screening and scale-up

FIG. 225: compound A, Format I, bis-mesylate-PLM assay

FIG. 226: compound A bis-mesylate salt-TG/DTA assay of form I

FIG. 227: compound A, form I, bis-mesylate-DSC analysis

FIG. 228: compound A, form I, bis mesylate-DVS assay

Fig. 229: form I compound a bis mesylate-XRPD analysis: post-DVS analysis

FIG. 230: form I compound a bis mesylate-XRPD analysis: slurry in deionized water

FIG. 231: form I Compound A bis-mesylate-HPLC analysis of purity

FIG. 232: form I compound a bis mesylate — HPLC purity: stability Studies at 40 ℃ and 75% RH

FIG. 233: form I compound a bis mesylate — HPLC purity: stability study at ambient temperature

FIG. 234: form I compound a bis mesylate — HPLC purity: stability study at 80 ℃

FIG. 235: form I compound a bis mesylate-XRPD analysis: stability testing at 40 ℃ and 75% RH, ambient temperature and 80 ℃

FIG. 236: compound A, form I, bis-mesylate salt¹H NMR spectroscopy

FIG. 237: form J Compound A Dimethanesulfonate-XRPD analysis

FIG. 238: compound A bis-mesylate salt-TG/DTA assay of form J

FIG. 239: form D Compound A Dimethanesulfonate-XRPD

FIG. 240: form D Compound A bis mesylate-XRPD-peak

FIG. 241: form D Compound A bis-mesylate salt-XRPD-peak list

FIG. 242: form E Compound A Dimethanesulfonate-XRPD

FIG. 243: form E Compound A bis mesylate-XRPD-peak

FIG. 244: form E Compound A bis-mesylate salt-XRPD-peak list

FIG. 245: form F Compound A Dimethanesulfonate-XRPD

FIG. 246: form F Compound A bis mesylate-XRPD-indicated peaks

FIG. 247: form F Compound A bis-mesylate salt-XRPD-peak list

FIG. 248: form G Compound A Dimethanesulfonate-XRPD

FIG. 249: form G Compound A bis mesylate-XRPD-peak

FIG. 250: form G Compound A bis-mesylate salt-XRPD-peak list

FIG. 251: form H Compound A Dimethanesulfonate-XRPD

FIG. 252: form H Compound A bis mesylate-XRPD-peak

FIG. 253: form H Compound A bis-mesylate salt-XRPD-peak list

FIG. 254: form I Compound A Dimethanesulfonate-XRPD

FIG. 255: form I Compound A bis mesylate-XRPD-peaks

FIG. 256: compound A, form I, bis-mesylate salt-XRPD-peak list

FIG. 257: form J Compound A Dimethanesulfonate-XRPD

FIG. 258: form J Compound A bis mesylate-XRPD-peak

FIG. 259: compound A, form J, bis mesylate-XRPD-peak list

FIG. 260: form K Compound A Dimethanesulfonate-XRPD

FIG. 261: form K Compound A bis mesylate-XRPD-peak

FIG. 262: compound A, form K, bis-mesylate salt-XRPD-peak list

FIG. 263: XRPD comparison of all polymorphic forms of Compound A Disulfonate identified during polymorphic sieving, hydration sieving, and Scale-Up assessment

Detailed Description

Polymorph of compound a free base

Compound a may be dissolved and subsequently crystallized from a solvent described below, or mixtures thereof, to obtain the polymorphic forms of the present application. In some embodiments, a polymorph of compound a free base is prepared as follows: dissolving compound a free base in a solvent or mixture of solvents to form a solution, and separating compound a free base from the solution. In a specific embodiment of the present application, the solvent or mixture thereof is evaporated to yield compound a free base polymorph. Solvents suitable for preparing polymorphic forms of compound a free base include, but are not limited to, DCM, THF, dioxane, ethyl acetate, ethanol, IPAc, IPA, MEK, acetone, acetonitrile, nitromethane, water, and mixtures thereof. In particular embodiments, suitable solvents for preparing polymorphic forms of compound a free base are DCM, IPA, MEK, acetone, THF, IPAc, acetonitrile, dioxane, ethyl acetate and ethanol. For example, compound a free base is dissolved and subsequently crystallized from DCM, IPA, MEK, acetone, THF, IPAc or acetonitrile. The solvent may be anhydrous or may contain varying amounts of water(s) (ii)For example，0.1-0.5%，0.5-1%，1-5%，5-10%，10-20%，20-30%，30-40%，40-50%，50-60%，60-70%，70-80% and 80-90%).

In one embodiment, the process for preparing a polymorph of compound a free base further comprises warming the solution during dissolution of compound a. For example, the solution may be warmed to 20-30 deg.C, 30-40 deg.C, 40-50 deg.C, 50-60 deg.C, 60-70 deg.C, 70-80 deg.C, 80-90 deg.C, 90-100 deg.C, 100-. In one embodiment, the method further comprises stirring the solution during the dissolution of compound a. For example, the solution may be stirred for at least 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 60 minutes, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 36 hours, or 48 hours. In one embodiment, the method further comprises cooling the solution to facilitate separation of compound a from the solution. For example, the solution may be cooled to 100-90 deg.C, 90-80 deg.C, 80-70 deg.C, 70-60 deg.C, 60-50 deg.C, 50-40 deg.C, 40-30 deg.C, 30-20 deg.C, 20-10 deg.C, or 10-0 deg.C, or less than 0 deg.C. In one embodiment, the method further comprises evaporating the solution to facilitate separation of compound a free base from the solution. In one embodiment, the method further comprises adding compound a seed polymorph to the solution, followed by isolating compound a free base from the solution. In one embodiment, the isolating comprises filtering compound a free base from the solution. In one embodiment, the isolating further comprises drying compound a free base. For example, the drying may be carried out under any suitable conditions (b)For exampleAt a suitable temperature ofFor exampleAt a temperature lower than 0 ℃, 0-10 ℃, 10-20 ℃, 20-30 ℃, 30-40 ℃, 40-50 ℃, 50-60 ℃, 60-70 ℃, 70-80 ℃, 80-90 ℃, 90-100 ℃, 100-150 ℃, or 150-200 ℃ or more than 200 ℃.

In one embodiment, the polymorph of compound a free base is form 1. In some embodiments, form 1 has X-ray powder diffraction peaks at about 22.0 and 25.0 ° 2 Θ using CuK α radiation. In some embodiments, form 1 has X-ray powder diffraction peaks at about 8.3, 17.1, 22.0, and 25.0 ° 2 θ using Cu ka radiation. In some embodiments, form 1 has X-ray powder diffraction peaks at about 8.3, 9.5, 12.9, 14.1, 15.2, 16.6, 17.1, 19.2, 19.4, 19.6, 21.2, 22.0, and 25.0 ° 2 θ using CuK α radiation. In one embodiment, form 1 has an X-ray powder diffraction pattern substantially similar to that shown in figure 2.

In one embodiment, form 1 may be a solvate. In some embodiments, form 1 can be a Dichloromethane (DCM) or Methyl Ethyl Ketone (MEK) solvate. In other embodiments, form 1 can be a DCM hemisolvate or a MEK hemisolvate.

In one embodiment, form 1 can be isolated from IPA, MEK, or acetone.

In some embodiments, form 1 is stable at a temperature at or below 150 ℃, 140 ℃, 130 ℃, 120 ℃, 100 ℃, 90 ℃, 80 ℃, 70 ℃, 60 ℃, 50 ℃, 40 ℃, or 30 ℃. For example, form 1 is stable at 25 ℃. In some embodiments, form 1 is stable at or above 50% RH, 60% RH, 70% RH, 80% RH, or 90% RH. For example, form 1 is stable in the 0-96% RH range. For example, form 1 is stable at 96% RH.

In one embodiment, form 1 can be converted to other polymorphic forms. For example, form 1 may be converted to form 2 when heated.

In another embodiment, the polymorph of compound a free base is form 2. In some embodiments, form 2 has X-ray powder diffraction peaks at about 18.4 and 19.3 ° 2 Θ using CuK α radiation. In some embodiments, form 2 has X-ray powder diffraction peaks at about 15.8, 18.4, 19.3, and 20.1 ° 2 θ using Cu ka radiation. In some embodiments, form 2 has X-ray powder diffraction peaks at about 8.3, 8.8, 11.6, 13.3, 15.8, 18.4, 19.3, 20.1, 20.9, 21.4, 23.2, 25.9, and 26.6 ° 2 θ using Cu ka radiation. In one embodiment, form 2 has an X-ray powder diffraction pattern substantially similar to that shown in figure 3.

In some embodiments, form 2 is unsolvated.

In one embodiment, form 2 may be isolated from IPAc or acetonitrile.

In some embodiments, form 2 is stable at a temperature at or below 250 ℃, 240 ℃, 230 ℃, 220 ℃, 210 ℃, 200 ℃, 190 ℃, 180 ℃, 170 ℃, 160 ℃, 150 ℃, 140 ℃, 130 ℃, 120 ℃, 100 ℃, 90 ℃, 80 ℃, 70 ℃, 60 ℃, 50 ℃, 40 ℃, or 30 ℃. In some embodiments, form 2 is stable at or above 50% RH, 60% RH, 70% RH, 80% RH, or 90% RH. For example, form 2 is stable in the 0-96% RH range. For example, form 2 is stable at 96% RH.

In one embodiment, form 2 can be converted to other polymorphic forms. For example, form 2 may be converted to form 3 when melted and subsequently cooled.

In another embodiment, the polymorph of compound a free base is form 3. In some embodiments, form 3 has X-ray powder diffraction peaks at about 15.1 and 23.4 ° 2 Θ using CuK α radiation. In some embodiments, form 3 has X-ray powder diffraction peaks at about 15.1, 18.8, 21.0, and 23.4 ° 2 Θ using Cu ka radiation. In some embodiments, form 3 has X-ray powder diffraction peaks at about 6.4, 7.6, 8.4, 11.7, 15.1, 16.7, 18.8, 21.0, and 23.4 ° 2 θ using Cu ka radiation. In one embodiment, form 3 has an X-ray powder diffraction pattern substantially similar to that shown in figure 3.

In some embodiments, form 3 is unsolvated.

In some embodiments, form 3 is stable at a temperature at or below 250 ℃, 240 ℃, 230 ℃, 220 ℃, 210 ℃, 200 ℃, 190 ℃, 180 ℃, 170 ℃, 160 ℃, 150 ℃, 140 ℃, 130 ℃, 120 ℃, 100 ℃, 90 ℃, 80 ℃, 70 ℃, 60 ℃, 50 ℃, 40 ℃, or 30 ℃. In some embodiments, form 3 is stable at or above 50% RH, 60% RH, 70% RH, 80% RH, or 90% RH. For example, form 3 is stable in the 0-96% RH range. For example, form 3 is stable at 96% RH.

In another embodiment, the polymorph of compound a free base is form 4. In some embodiments, form 4 has X-ray powder diffraction peaks at about 17 and 23 ° 2 θ using CuK α radiation. In some embodiments, form 4 has X-ray powder diffraction peaks at about 15, 17, 23, and 26 ° 2 Θ using Cu ka radiation. In some embodiments, form 4 has X-ray powder diffraction peaks at about 8, 14, 15, 17, 22, 23, and 26 ° 2 θ using Cu ka radiation. In one embodiment, form 4 has an X-ray powder diffraction pattern substantially similar to that shown in figure 14.

In one embodiment, form 4 can be a solvate. In some embodiments, form 4 is a Tetrahydrofuran (THF) solvate. In other embodiments, form 4 is a THF hemisolvate.

In one embodiment, form 4 can be isolated from THF. For example, form 4 can be isolated from THF containing 5% water.

In some embodiments, form 4 is stable at a temperature at or below 250 ℃, 240 ℃, 230 ℃, 220 ℃, 210 ℃, 200 ℃, 190 ℃, 180 ℃, 170 ℃, 160 ℃, 150 ℃, 140 ℃, 130 ℃, 120 ℃, 100 ℃, 90 ℃, 80 ℃, 70 ℃, 60 ℃, 50 ℃, 40 ℃, or 30 ℃. In some embodiments, form 4 is stable at or above 50% RH, 60% RH, 70% RH, 80% RH, or 90% RH. For example, form 4 is stable in the 0-96% RH range. For example, form 4 is stable at 96% RH.

Salt of compound A

Compound a free base has three pKa values: 7.84, 4.69 and 2.82. Compound a can form mono-, di-and tri-salts. Acids that form salts with Compound A include, but are not limited to, HCl, H₂SO₄Methanesulfonic acid, maleic acid, phosphoric acid, L-glutamic acid, L-tartaric acid, galactaric acid, citric acid, D-glucuronic acid, hippuric acid, D-gluconic acid, L-lactic acid, L-ascorbic acid, succinic acid, and acetic acid. These acids form mono-, di-and tri-salts with compound a free base.

Salts of compound a may be prepared in a suitable solvent or mixture thereof. Solvents include, but are not limited to, THF, dioxane, ethyl acetate, ethanol, isopropyl acetate (IPAc), Isopropanol (IPA), MEK, acetone, acetonitrile, and nitromethane. Factors to be considered in selecting an appropriate solvent include, but are not limited to, solubility of compound a free base, stability of the salt in the solvent, solubility of the salt, and type of salt to be formed (Namely, it isMono-, di-, or tri-salts).

A salt of compound a may be formed by mixing compound a free base with an acid in a suitable solvent or mixture thereof. The mixture may be heated, for example, to promote dissolution of compound a free base or reaction between compound a free base and acid. The mixture may also be cooled, for example, to reduce undesirable side reactions or to reduce salt degradation. The amount of acid used for the reaction is determined by the type of salt to be formed: (Namely, it isMono-, di-, or tri-salts). The reaction time may be adjusted to complete the reaction. For example, the reaction time may be 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, 60 hours, or 72 hours. The reaction mixture may be cooled to facilitate salt precipitation and separation.

The salt of compound a can be purified by simple filtration or other purification methods known in the art (For exampleHPLC).

The salt of compound a may be water soluble. For example, the solubility of a salt of Compound A may be in the range of 0.01-0.05 mg/ml, 0.05-0.1 mg/ml, 0.1-0.5 mg/ml, 0.5-1.0 mg/ml, 1-5 mg/ml, 5-10 mg/ml, 10-20 mg/ml, 20-30 mg/ml, 30-40 mg/ml, 40-50 mg/ml, 50-75 mg/ml, or 75-100 mg/ml, or more than 100 mg/ml.

The salt of compound a may be amorphous or crystalline. The salt of compound a can form a variety of polymorphs. Amorphous salts of compound a may be converted to polymorphs. For example, after heating or under humid conditions (For example，>50% RH), amorphous salts of Compound A convertibleIn crystalline form. Amorphous salts may also lose counter ions (For exampleThe tri-salt is converted to the di-salt and/or mono-salt) and converted to the crystalline form. A polymorphic form of a salt of compound a may be converted to another polymorphic form.

Polymorphs of a salt of Compound A

Polymorphic forms of a salt of compound a may be formed by mixing compound a free base with an acid or a solution of an acid. In some embodiments, polymorphic forms of a salt of compound a may be prepared as follows: dissolving compound a free base in a first solvent to form a first solution; an acid is mixed with the first solution. In one embodiment, the acid is dissolved in a second solvent to form a second solution, and then the acid is mixed with the first solution. For example, the acids include, but are not limited to, HCl, H₂SO₄Methanesulfonic acid, maleic acid, phosphoric acid, L-glutamic acid, L-tartaric acid, galactaric acid, citric acid, D-glucuronic acid, hippuric acid, D-gluconic acid, L-lactic acid, L-ascorbic acid, succinic acid, and acetic acid. For example, the acid is HCl or methanesulfonic acid.

In one embodiment, the first solvent and the second solvent are the same; in another embodiment, the first solvent and the second solvent are different. For example, the first solvent is selected from THF, dioxane, ethyl acetate, ethanol, IPAc, IPA, MEK, acetone, acetonitrile, nitromethane, and methanol. The solvent may be anhydrous or may contain varying amounts of water(s) (ii)For example0.1-0.5%, 0.5-1%, 1-5%, 5-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, and 80-90%). For example, the first solvent is THF, ethyl acetate, ethanol or methanol. For example, the first solvent is a solvent containing water (C)For example0.1-0.5%, 0.5-1%, 1-5%, 5-10%, 10-20%) of methanol. For example, the second solvent is selected from THF, dioxane, ethyl acetate, ethanol, IPAc, IPA, MEK, acetone, acetonitrile, nitromethane, and methanol. For example, the second solvent is THF, ethyl acetate, ethanol or methanol. The solvent may be anhydrous or may contain varying amounts of water(s) (ii)For example，0.1-0.5%，0.5-1%，1-5%，5-10%，10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, and 80-90%). For example, the first and second solvents are the same and are each THF, ethyl acetate, ethanol, or methanol.

In one embodiment, the method further comprises warming the first solution. For example, the first solution can be warmed to 20-30 deg.C, 30-40 deg.C, 40-50 deg.C, 50-60 deg.C, 60-70 deg.C, 70-80 deg.C, 80-90 deg.C, 90-100 deg.C, 150 deg.C, 200 deg.C, or more than 200 deg.C.

In one embodiment, the mixing comprises adding the acid or the second solution to the first solution; in another embodiment, the mixing comprises adding the first solution to the acid or the second solution. In one embodiment, the mixing forms a third solution. In one embodiment, the mixing forms a first slurry. In one embodiment, the method further comprises warming the third solution or the first slurry. For example, the third solution or the first slurry may be warmed to 20-30 ℃, 30-40 ℃, 40-50 ℃, 50-60 ℃, 60-70 ℃, 70-80 ℃, 80-90 ℃, 90-100 ℃, 100-. In one embodiment, the method further comprises agitating the third solution or the first slurry. For example, the stirring is continued for at least 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 60 minutes, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 36 hours, or 48 hours. In one embodiment, the method further comprises cooling the third solution or the first slurry. For example, the third solution or the first slurry may be cooled to 100-90 ℃, 90-80 ℃, 80-70 ℃, 70-60 ℃, 60-50 ℃, 50-40 ℃, 40-30 ℃, 30-20 ℃, 20-10 ℃, or 10-0 ℃, or less than 0 ℃. In one embodiment, the method further comprises stirring the third solution or the first slurry after the cooling. For example, the stirring is continued for at least 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 60 minutes, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 36 hours, or 48 hours.

In one embodiment, the method further comprises evaporating the third solution.

In one embodiment, the method further comprises adding a seed polymorph to the third solution to form a second slurry. In one embodiment, the method further comprises agitating the second slurry. For example, the stirring is continued for at least 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 60 minutes, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 36 hours, or 48 hours. In one embodiment, the method further comprises cooling the second slurry. For example, the second slurry may be cooled to 100-90 ℃, 90-80 ℃, 80-70 ℃, 70-60 ℃, 60-50 ℃, 50-40 ℃, 40-30 ℃, 30-20 ℃, 20-10 ℃, or 10-0 ℃, or less than 0 ℃. In one embodiment, the method further comprises agitating the second slurry after the cooling. For example, the stirring is continued for at least 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 60 minutes, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 36 hours, or 48 hours.

In one embodiment, the method further comprises filtering the third solution, the first slurry, or the second slurry. The filtration can be carried out under any conditions. For example, the filtration may be at ambient temperature or at other suitable temperatures: (For exampleAt a temperature lower than 0 ℃, 0-10 ℃, 10-20 ℃, 20-30 ℃, 30-40 ℃, 40-50 ℃, 50-60 ℃, 60-70 ℃, 70-80 ℃, 80-90 ℃, 90-100 ℃, 100-150 ℃, or 150-200 ℃ or more than 200 ℃. In one embodiment, the method further comprises drying the third solution, the first slurry, or the second slurry. The drying may be carried out under any suitable conditions (a)For exampleAt a suitable temperature ofFor exampleBelow 0 ℃, 0-10 ℃, 10-20 ℃, 20-30 ℃, 30-40 ℃, 40-50 ℃, 50-60 ℃, 60-70 ℃, 70-80 ℃, 80-90 ℃, 90-100 ℃, 100-For exampleLess than 5 minutes, 10 minutes, 20 minutes, 30 minutes, 60 minutes, 2 hours, 4 hours, 8 hours, 12 hoursHours and 24 hours) and pressure: (For exampleAtmospheric pressure and vacuum)).

In another embodiment, polymorphic forms of a salt of compound a may be prepared as follows: dissolving compound a free base in a first solvent to form a compound a slurry; add acid to the compound a slurry. In one embodiment, the acid is dissolved in a second solvent to form a second solution, and then the acid is added to the compound a slurry. For example, the acids include, but are not limited to, HCl, H₂SO₄Methanesulfonic acid, maleic acid, phosphoric acid, L-glutamic acid, L-tartaric acid, galactaric acid, citric acid, D-glucuronic acid, hippuric acid, D-gluconic acid, L-lactic acid, L-ascorbic acid, succinic acid, and acetic acid. For example, the acid is HCl or methanesulfonic acid.

In one embodiment, the first solvent and the second solvent are the same; in another embodiment, the first solvent and the second solvent are different. For example, the first solvent is selected from THF, dioxane, ethyl acetate, ethanol, IPAc, IPA, MEK, acetone, acetonitrile, nitromethane, and methanol. The solvent may be anhydrous or may contain varying amounts of water(s) (ii)For example0.1-0.5%, 0.5-1%, 1-5%, 5-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, and 80-90%). For example, the first solvent is THF, ethyl acetate, ethanol or methanol. For example, the first solvent is a solvent containing water (C)For example0.1-0.5%, 0.5-1%, 1-5%, 5-10%, 10-20%) of methanol. For example, the second solvent is selected from THF, dioxane, ethyl acetate, ethanol, IPAc, IPA, MEK, acetone, acetonitrile, nitromethane, and methanol. For example, the second solvent is THF, ethyl acetate, ethanol or methanol. The solvent may be anhydrous or may contain varying amounts of water(s) (ii)For example0.1-0.5%, 0.5-1%, 1-5%, 5-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, and 80-90%). For example, the first and second solvents are the same and are each THF, ethyl acetate, ethanol, or methanol.

In one embodiment, the method further comprises warming the compound a slurry. For example, the compound A slurry can be warmed to 20-30 deg.C, 30-40 deg.C, 40-50 deg.C, 50-60 deg.C, 60-70 deg.C, 70-80 deg.C, 80-90 deg.C, 90-100 deg.C, 150 deg.C, 200 deg.C, or more than 200 deg.C. For example, the compound a slurry may be warmed to 55 ℃.

In one embodiment, the acid or the second solution is added to the compound a slurry to form a third solution. In one embodiment, the acid or the second solution is added to the compound a slurry to form a first slurry. In one embodiment, the method further comprises warming the third solution or the first slurry. For example, the third solution or the first slurry may be warmed to 20-30 ℃, 30-40 ℃, 40-50 ℃, 50-60 ℃, 60-70 ℃, 70-80 ℃, 80-90 ℃, 90-100 ℃, 100-. In one embodiment, the method further comprises agitating the third solution or the first slurry. For example, the stirring is continued for at least 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 60 minutes, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 36 hours, or 48 hours. In one embodiment, the method further comprises cooling the third solution or the first slurry. For example, the third solution or the first slurry may be cooled to 100-90 ℃, 90-80 ℃, 80-70 ℃, 70-60 ℃, 60-50 ℃, 50-40 ℃, 40-30 ℃, 30-20 ℃, 20-10 ℃, or 10-0 ℃, or less than 0 ℃. In one embodiment, the method further comprises stirring the third solution or the first slurry after the cooling. For example, the stirring is continued for at least 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 60 minutes, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 36 hours, or 48 hours.

In one embodiment, the method further comprises evaporating the third solution.

In one embodiment, the method further comprises adding a third solvent to the third solution to form a second slurry. For example, the third solvent may be any solvent that induces the formation of a slurry. For example, the firstThe trisolvent is selected from the group consisting of THF, dioxane, ethyl acetate, ethanol, IPAc, IPA, MEK, acetone, acetonitrile, nitromethane, and methanol. The third solvent may be anhydrous or may contain varying amounts of water(s) (ii)For example0.1-0.5%, 0.5-1%, 1-5%, 5-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, and 80-90%). For example, the third solvent is IPAc.

In one embodiment, the method further comprises adding a seed polymorph to the third solution to form a third slurry. In one embodiment, the method further comprises agitating the second slurry or the third slurry. For example, the stirring is continued for at least 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 60 minutes, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 36 hours, or 48 hours. In one embodiment, the method further comprises cooling the second slurry or the third slurry. For example, the second or third slurry may be cooled to 100-90 ℃, 90-80 ℃, 80-70 ℃, 70-60 ℃, 60-50 ℃, 50-40 ℃, 40-30 ℃, 30-20 ℃, 20-10 ℃, or 10-0 ℃, or less than 0 ℃. In one embodiment, the method further comprises stirring the second slurry or the third slurry after the cooling. For example, the stirring is continued for at least 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 60 minutes, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 36 hours, or 48 hours.

In one embodiment, the method further comprises filtering the third solution, the first slurry, the second slurry, or the third slurry. The filtration can be carried out under any conditions. For example, the filtration may be at ambient temperature or at other suitable temperatures: (For exampleAt a temperature lower than 0 ℃, 0-10 ℃, 10-20 ℃, 20-30 ℃, 30-40 ℃, 40-50 ℃, 50-60 ℃, 60-70 ℃, 70-80 ℃, 80-90 ℃, 90-100 ℃, 100-150 ℃, or 150-200 ℃ or more than 200 ℃. In one embodiment, the method further comprises drying the third solution, the first slurry, the second slurry, or the third slurry. The drying may be in any suitable stripIs carried out in the following mannerFor exampleAt a suitable temperature ofFor exampleBelow 0 ℃, 0-10 ℃, 10-20 ℃, 20-30 ℃, 30-40 ℃, 40-50 ℃, 50-60 ℃, 60-70 ℃, 70-80 ℃, 80-90 ℃, 90-100 ℃, 100-For exampleLess than 5 minutes, 10 minutes, 20 minutes, 30 minutes, 60 minutes, 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours), and a pressure (C: (A) ((B))For exampleAtmospheric pressure and vacuum)).

The present application also relates, at least in part, to polymorphic forms of compound a mesylate salt. In one embodiment, the polymorph of compound a mesylate is form a. In some embodiments, form a has X-ray powder diffraction peaks at about 9.4 and 23.0 ° 2 Θ using Cu ka radiation. In some embodiments, form a has X-ray powder diffraction peaks at about 9.4, 15.5, 18.8, and 23.0 ° 2 Θ using Cu ka radiation. In some embodiments, form a has X-ray powder diffraction peaks at about 4.1, 7.8, 9.4, 10.1, 12.1, 15.5, 16.2, 18.8, 19.9, 21.1, 23.0, 25.1, and 27.4 ° 2 θ using Cu ka radiation. In one embodiment, form a has an X-ray powder diffraction pattern substantially similar to that shown in figure 32.

In one embodiment, form a is compound a bis-mesylate.

In some embodiments, form a is stable at a temperature at or below 350 ℃, 325 ℃, 300 ℃, 275 ℃, 250 ℃, 200 ℃, 150 ℃, 100 ℃, or 50 ℃. In some embodiments, form a is stable at or below 325 ℃. In some embodiments, form a is stable at or above 50% RH, 60% RH, 70% RH, 80% RH, or 90% RH. For example, form A is stable in the 0-96% RH range.

In some embodiments, form a shows a sharp endotherm with an onset temperature of 305.9 ℃ and melting at 307.6 ℃ (fig. 34). In some embodiments, form a shows no significant weight loss until melting (fig. 35).

In one embodiment, form a can be produced as follows: dissolving compound a free base in THF; adding a solution of methanesulfonic acid in THF to the compound a free base solution to form a slurry; and filtering and drying the slurry.

In another embodiment, form a can be produced as follows: to the amorphous form of compound a bis-mesylate salt was added anhydrous methanol to prepare a slurry. The slurry was stirred at about 22 ℃ for about 2 days, after which the sample was filtered and allowed to dry at ambient temperature.

In one embodiment, the polymorph of compound a mesylate is form B. In some embodiments, form B has X-ray powder diffraction peaks at about 6.2 and 14.3 ° 2 Θ using Cu ka radiation. In some embodiments, form B has X-ray powder diffraction peaks at about 6.2, 6.6, 14.3, and 15.3 ° 2 θ using Cu ka radiation. In some embodiments, form B has X-ray powder diffraction peaks at about 6.2, 6.6, 11.3, 14.3, 15.3, 22.8, and 26.9 ° 2 θ using Cu ka radiation. In one embodiment, form B has an X-ray powder diffraction pattern substantially similar to that shown in figure 37.

In one embodiment, form B is compound a bis-mesylate.

In some embodiments, form B is stable at temperatures at or below 210 ℃, 205 ℃, 200 ℃, 150 ℃, 100 ℃, or 50 ℃. In some embodiments, form B is stable at or below 205 ℃. In some embodiments, form B is stable at or above 50% RH, 60% RH, 70% RH, 80% RH, or 90% RH. For example, form B is stable in the 0-96% RH range.

In some embodiments, form B shows a broad endotherm with an onset temperature of 182.6 ℃ and melting at 194.1 ℃ (fig. 39). In some embodiments, form B shows an exotherm with onset temperature of 199.3 ℃ with a peak at 204.5 ℃ (fig. 39). In some embodiments, form B shows a second endotherm with an onset temperature of 299.9 ℃ and a second melt at 302.3 ℃ (fig. 39). In some embodiments, form B shows weight loss at multiple temperatures (fig. 40).

In one embodiment, form B can be produced as follows: dissolving compound a free base in aqueous methanol to form a first slurry; adding methanesulfonic acid to the first slurry to form a solution; adding IPAc to the solution to form a second slurry; and filtering and drying the second slurry. For example, the methanesulfonic acid is neat methanesulfonic acid. For example, aqueous methanol may contain 2% water.

In another embodiment, form B can be produced as follows: to the amorphous form of compound a bis-mesylate salt was added 2-propanol having a water activity of 0.35 to prepare a slurry. The slurry was stirred at about 22 ℃ for about 3 days, after which the sample was filtered and allowed to dry at ambient temperature before characterization.

In one embodiment, the polymorph of compound a mesylate is form C. In some embodiments, form C has X-ray powder diffraction peaks at about 20.3 and 22.8 ° 2 Θ using Cu ka radiation. In some embodiments, form C has X-ray powder diffraction peaks at about 17.6, 18.4, 19.3, 19.7, 20.3, and 22.8 ° 2 θ using Cu ka radiation. In some embodiments, form C has X-ray powder diffraction peaks at about 6.2, 8.9, 9.8, 10.1, 13.7, 17.6, 18.4, 19.3, 19.7, 20.3, 22.8, and 26.8 ° 2 θ using Cu ka radiation. In one embodiment, form C has an X-ray powder diffraction pattern substantially similar to that shown in figure 42.

In one embodiment, form C is compound a bis-mesylate.

In some embodiments, form C is stable at a temperature at or below 400 ℃, 375 ℃, 350 ℃, 325 ℃, 300 ℃, 275 ℃, 250 ℃, 200 ℃, 150 ℃, 100 ℃, or 50 ℃. In some embodiments, form C is stable at or below 310 ℃. In some embodiments, form C is stable at or above 50% RH, 60% RH, 70% RH, 80% RH, or 90% RH. For example, form C is stable in the 0-96% RH range.

In some embodiments, form C shows a sharp endotherm with an onset temperature of 286.1 ℃ and melting at 288.5 ℃ (fig. 44). In some embodiments, form C showed no significant weight loss until melting (fig. 45).

In one embodiment, form C can be produced as follows: dissolving compound a free base in aqueous methanol to form a solution; adding methanesulfonic acid to the solution; adding compound a mesylate salt seed crystals to the solution: (For exampleSeeded form C crystals) to form a slurry; and filtering and drying the slurry. For example, the methanesulfonic acid is neat methanesulfonic acid. For example, aqueous methanol may contain 2% water.

In another embodiment, form C can be produced as follows: to form a, 2% aqueous methanol was added to form a slurry, the slurry was stirred, and the slurry was filtered and dried.

Characterization of polymorphs of the present application due to fluctuations in instrumentation and experimental conditions, as is well known in the art: (For exampleResults obtained by TGA, DSC, XRPD, PLM) may have slight differences from one measurement to another. For example, the X-ray powder diffraction peaks of polymorphs may shift from one measurement to another. That is, the X-ray powder diffraction peaks may have slightly different values from one measurement to another. However, polymorphic X-ray powder diffraction pattern (For exampleThe position, intensity and shape of the peaks) are substantially similar toFor exampleAt least 80%, 85%, 90%, or 95% pattern match with each other).

In one embodiment, form a has X-ray powder diffraction peaks at about 9.1 and 22.8 ° 2 θ using Cu ka radiation. In some embodiments, form a has X-ray powder diffraction peaks at about 9.1, 15.1, 16.0, 18.5, 22.8, and 22.9 ° 2 θ using Cu ka radiation. In some embodiments, form a has X-ray powder diffraction peaks at about 3.8, 7.6, 9.1, 9.9, 15.1, 16.0, 16.1, 18.5, 22.8, 22.9, and 23.2 ° 2 θ using Cu ka radiation. In one embodiment, form a has an X-ray powder diffraction pattern substantially similar to that shown in figure 110. In one embodiment, form a has X-ray powder diffraction peaks as shown in figure 112.

In one embodiment, form B has X-ray powder diffraction peaks at about 6.0 and 14.6 ° 2 θ using Cu ka radiation. In some embodiments, form B has X-ray powder diffraction peaks at about 6.0, 6.4, 11.1, 14.6, 15.1, and 23.7 ° 2 θ using Cu ka radiation. In some embodiments, form B has X-ray powder diffraction peaks at about 6.0, 6.4, 11.1, 14.6, 15.1, 17.3, 22.5, 22.7, 23.7, and 27.0 ° 2 θ using Cu ka radiation. In one embodiment, form B has an X-ray powder diffraction pattern substantially similar to that shown in figure 129. In one embodiment, form B has X-ray powder diffraction peaks as shown in figure 131.

In one embodiment, form C has X-ray powder diffraction peaks at about 20.1 and 22.6 ° 2 θ using Cu ka radiation. In some embodiments, form C has X-ray powder diffraction peaks at about 17.5, 18.2, 19.0, 19.6, 20.1, and 22.6 ° 2 θ using Cu ka radiation. In some embodiments, form C has X-ray powder diffraction peaks at about 12.5, 16.6, 17.5, 18.2, 19.0, 19.6, 20.1, 21.7, 22.6, 23.0, 23.6, 24.0, 26.6, and 27.2 ° 2 θ using Cu ka radiation. In one embodiment, form C has an X-ray powder diffraction pattern substantially similar to that shown in figure 145. In one embodiment, form C has an X-ray powder diffraction peak as shown in figure 147.

In one embodiment, the polymorph of compound a mesylate is form D. In some embodiments, form D has X-ray powder diffraction peaks at about 14.5 and 23.0 ° 2 Θ using Cu ka radiation. In some embodiments, form D has X-ray powder diffraction peaks at about 5.9, 11.5, 14.5, 20.3, and 23.0 ° 2 θ using Cu ka radiation. In some embodiments, form D has X-ray powder diffraction peaks at about 5.4, 5.9, 11.5, 14.5, 17.9, 20.3, 23.0, 23.6, 24.0, 26.2, 27.8, and 28.9 ° 2 θ using Cu ka radiation. In one embodiment, form D has X-ray powder diffraction peaks as shown in figure 241. In one embodiment, form D has an X-ray powder diffraction pattern substantially similar to that shown in figure 239.

In one embodiment, form D is compound a bis-mesylate.

In one embodiment, form D is birefringent, having a flat rod/plate-like morphology, as determined by PLM analysis, as shown in figure 191.

In one embodiment, form D has an initial broad endotherm (peak 103.2 ℃) that begins at about 50.3 ℃. In one embodiment, form D has a small endothermic/exothermic event between about 229 ℃ and 235 ℃. In one embodiment, form D has a final endotherm (peak 304.1 ℃) starting at about 300.9 ℃ (fig. 194).

In one embodiment, form D has a water content of about 3.8% as measured by Karl-Fischer titration.

In one embodiment, form D has an HPLC purity of 99.9% (fig. 199).

In one embodiment, form D is characterized as in graph 204¹H NMR spectrum.

In one embodiment, form D can be produced by: to the amorphous form of compound a bis-mesylate salt was added 2-propanol having 0.6 water activity to form a slurry, the slurry was stirred at about 22 ℃, and the slurry was filtered and dried.

In one embodiment, the polymorph of compound a mesylate is form E. In some embodiments, form E has X-ray powder diffraction peaks at about 20.9 and 21.9 ° 2 Θ using Cu ka radiation. In some embodiments, form E has X-ray powder diffraction peaks at about 13.7, 20.6, 20.9, 21.9, and 23.0 ° 2 Θ using Cu ka radiation. In some embodiments, form E has X-ray powder diffraction peaks at about 8.9, 11.3, 13.7, 16.5, 19.3, 20.6, 20.9, 21.9, 23.0, 23.8, and 26.2 ° 2 θ using Cu ka radiation. In one embodiment, form E has an X-ray powder diffraction peak as shown in figure 244. In one embodiment, form E has an X-ray powder diffraction pattern substantially similar to that shown in figure 242.

In one embodiment, form E is compound a bis-mesylate.

In one embodiment, form E is birefringent, has a long rod-like morphology, as determined by PLM analysis, as shown in figure 206.

In one embodiment, form E has a broad endotherm (peak 86.5 ℃) starting at about 45.9 ℃. In one embodiment, form E has an endothermic/exothermic event between about 189 ℃ and 215 ℃. In one embodiment, form E has a final endothermic event (peak 303.7 ℃) starting at about 299.1 ℃ (fig. 210).

In one embodiment, form E has a water content of about 6.2% as measured by Karl-Fischer titration.

In one embodiment, form E has an HPLC purity of 99.8% (fig. 215).

In one embodiment, form E is characterized as in graph 220¹H NMR spectrum.

In one embodiment, form E can be produced by: to the amorphous form of compound a bis-mesylate salt was added acetone with 0.89 water activity to form a slurry, the slurry was stirred at about 22 ℃, and the slurry was filtered and dried.

In one embodiment, the polymorph of compound a mesylate is form F. In some embodiments, form F has X-ray powder diffraction peaks at about 16.7 and 17.0 ° 2 Θ using Cu ka radiation. In some embodiments, form F has X-ray powder diffraction peaks at about 16.7, 17.0, 19.5, 20.3, and 24.4 ° 2 θ using Cu ka radiation. In some embodiments, form F has X-ray powder diffraction peaks at about 4.8, 7.2, 15.6, 16.7, 17.0, 19.5, 20.3, 21.7, 24.0, and 24.4 ° 2 θ using Cu ka radiation. In one embodiment, form F has X-ray powder diffraction peaks as shown in figure 247. In one embodiment, form F has an X-ray powder diffraction pattern substantially similar to that shown in figure 245.

In one embodiment, form F is compound a bis-mesylate.

In one embodiment, the polymorph of compound a mesylate is form G. In some embodiments, form G has X-ray powder diffraction peaks at about 5.8 and 22.1 ° 2 Θ using Cu ka radiation. In some embodiments, form G has X-ray powder diffraction peaks at about 5.8, 14.9, 16.3, 22.1, and 23.7 ° 2 θ using Cu ka radiation. In some embodiments, form G has X-ray powder diffraction peaks at about 5.8, 10.8, 14.9, 16.3, 17.7, 22.1, 23.1, 23.7, 24.5, and 26.5 ° 2 θ using Cu ka radiation. In one embodiment, form G has X-ray powder diffraction peaks as shown in figure 250. In one embodiment, form G has an X-ray powder diffraction pattern substantially similar to that shown in figure 248.

In one embodiment, form G is compound a bis-mesylate.

In one embodiment, the polymorph of compound a mesylate is form H. In some embodiments, form H has X-ray powder diffraction peaks at about 10.9 and 22.8 ° 2 Θ using Cu ka radiation. In some embodiments, form H has X-ray powder diffraction peaks at about 6.1, 10.9, 12.4, 15.9, and 22.8 ° 2 θ using Cu ka radiation. In some embodiments, form H has X-ray powder diffraction peaks at about 6.1, 10.1, 10.9, 12.4, 15.7, 15.9, 16.4, 20.4, 20.8, and 22.8 ° 2 θ using Cu ka radiation. In one embodiment, form H has an X-ray powder diffraction peak as shown in figure 253. In one embodiment, form H has an X-ray powder diffraction pattern substantially similar to that shown in figure 251.

In one embodiment, form H is compound a bis-mesylate.

In one embodiment, the polymorph of compound a mesylate is form I. In some embodiments, form I has X-ray powder diffraction peaks at about 5.2 and 10.5 ° 2 Θ using Cu ka radiation. In some embodiments, form I has X-ray powder diffraction peaks at about 5.2, 6.2, 10.5, 20.2, and 23.0 ° 2 θ using Cu ka radiation. In some embodiments, form I has X-ray powder diffraction peaks at about 5.2, 6.2, 10.5, 11.1, 13.6, 20.2, 22.0, 22.3, 23.0, and 23.8 ° 2 θ using Cu ka radiation. In one embodiment, form I has X-ray powder diffraction peaks as shown in figure 256. In one embodiment, form I has an X-ray powder diffraction pattern substantially similar to that shown in figure 254.

In one embodiment, form I is compound a bis-mesylate.

In one embodiment, form I is birefringent, has a rod-like morphology, as determined by PLM analysis, as shown in figure 225.

In one embodiment, form I has a small endothermic event (peak 235.7 ℃) starting at about 231.9 ℃. In one embodiment, form I has a final endotherm (peak 306.3 ℃) starting at about 303.7 ℃ (fig. 227).

In one embodiment, form I has a water content of about 0.8% as measured by Karl-Fischer titration.

In one embodiment, form I has an HPLC purity of 99.6% (fig. 231).

In one embodiment, form I is characterized by what is shown in figure 236¹H NMR spectrum.

In one embodiment, form I can be produced as follows: dissolving compound a, form a, as a bis-mesylate salt in anhydrous methanol. In one embodiment, the solution is evaporated in vacuo at about 50 ℃.

In one embodiment, the polymorph of compound a mesylate is form J. In some embodiments, form J has X-ray powder diffraction peaks at about 17.0 and 22.8 ° 2 Θ using Cu ka radiation. In some embodiments, form J has X-ray powder diffraction peaks at about 14.6, 17.0, 21.9, 22.8, and 24.8 ° 2 θ using Cu ka radiation. In some embodiments, form J has X-ray powder diffraction peaks at about 14.6, 17.0, 19.7, 20.4, 21.9, 22.8, 24.8, 25.3, 26.7, and 27.7 ° 2 θ using Cu ka radiation. In one embodiment, form J has X-ray powder diffraction peaks as shown in figure 259. In one embodiment, form J has an X-ray powder diffraction pattern substantially similar to that shown in figure 257.

In one embodiment, form J is compound a bis-mesylate.

In one embodiment, the polymorph of compound a mesylate is form K. In some embodiments, form K has X-ray powder diffraction peaks at about 9.2 and 10.0 ° 2 θ using Cu ka radiation. In some embodiments, form K has X-ray powder diffraction peaks at about 9.2, 10.0, 15.7, 20.0, and 23.8 ° 2 θ using Cu ka radiation. In some embodiments, form K has X-ray powder diffraction peaks at about 4.1, 9.2, 10.0, 15.7, 17.5, 19.3, 20.0, 21.5, 23.2, and 23.8 ° 2 θ using Cu ka radiation. In one embodiment, form K has an X-ray powder diffraction peak as shown in figure 262. In one embodiment, form K has an X-ray powder diffraction pattern substantially similar to that shown in figure 260.

In one embodiment, form K is compound a bis-mesylate.

All forms of the compounds of the present application are contemplated (For exampleFree base and salts, and amorphous, crystalline, polymorphic, and mesogenic forms thereof) in mixed or pure or substantially pure form, including racemic mixtures and mixtures of individual isomers. The racemic forms can be resolved by physical methods, e.g., separation or crystallization of the diastereomeric derivatives, or separation by chiral column chromatography or by supercritical fluid chromatography. The individual optical isomers can be obtained from the racemates by conventional methods, for example by salt formation with an optically active acid or base, followed byAnd (4) crystallizing. In addition, crystal polymorphisms may be present, but are not limited, and may be any single crystal form or mixture of crystal forms, or anhydrous or solvated: (For exampleDCM solvated, MEK solvated, THF solvated and hydrated) crystalline forms.

The terms "crystalline polymorph", "crystalline form", "polymorph" or "polymorphic form" refer to a compound wherein (a), (b), (c), (dFor exampleFree base, salt or solvate thereof) can be crystallized in different crystal packing arrangements and all have the same elemental composition crystal structure. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, crystal shapes, optoelectronic properties, stability and solubility. Crystallization solvent, crystallization rate, storage temperature, and other factors may cause a crystal form to dominate. Crystalline polymorphic forms of a compound may be prepared by crystallization under different conditions.

Furthermore, a compound of the present application (For exampleFree bases and salts, and amorphous, crystalline, polymorphic, and mesogenic forms thereof) may exist in hydrated or non-hydrated (anhydrous) forms or as solvates with other solvent molecules or in unsolvated forms. Non-limiting examples of hydrates include monohydrate, dihydrate, and the like。Non-limiting examples of solvates include DCM solvates, MEK solvates, THF solvates, and the like。

Some compounds of the present application (a)For exampleFree base and salts, as well as amorphous, crystalline, polymorphic, and mesogenic forms thereof) may exist in several tautomeric forms, and such tautomeric forms are included within the scope of the present application. "tautomers" refer to compounds whose structures differ significantly in the arrangement of atoms, but exist in an easy and rapid equilibrium. Tautomers can exist as mixtures of tautomeric sets in solution. In solid form, usually one tautomer predominates. It is to be understood that the compounds of the present application may be described as different tautomers. It is also understood that the compounds haveWhere tautomeric forms are present, all tautomeric forms are contemplated to be within the scope of the application, and the naming of the compounds does not exclude any tautomeric forms. Even though one tautomer may be described, the present application includes all tautomers of the compounds present.

The term "salt" as used herein is a pharmaceutically acceptable salt and can include acid addition salts including hydrochloride, hydrobromide, phosphate, sulfate, bisulfate, alkylsulfonate, arylsulfonate, acetate, benzoate, citrate, maleate, fumarate, succinate, lactate, tartrate, methanesulfonate, amino acid salts (salts of hydrochloric acid, sulfuric acid, hydrochloric acidFor exampleL-glutamate), galactaric (mucic) acid salts, citrate, glucuronate, hippurate, gluconate, and ascorbate; alkali metal cations, e.g. Na⁺、K⁺、Li⁺(ii) a Alkaline earth metal salts, e.g. Mg²⁺Or Ca²⁺(ii) a And organic amine salts.

As used herein, the terms "polymorph," "polymorphic form," "crystalline polymorph," and "crystalline form" and related terms herein refer to a crystalline form of the same molecule, and different polymorphs can have different physical properties, such as melting temperature, heat of fusion, solubility, dissolution rate, and/or vibrational spectrum, as a result of the arrangement or conformation of the molecules in the crystalline lattice. Differences in the physical properties exhibited by polymorphs affect pharmaceutical parameters such as storage stability, compressibility and density (important in formulation and product manufacture) and dissolution rate (an important factor in bioavailability). The difference in stability can also be due to chemical reactivity (For exampleDifferential oxidation, such that the dosage form discolors more rapidly when comprising one polymorph than when comprising another polymorph) or mechanical properties (For exampleOn storage, tablets crumble as the kinetically favored polymorph converts to the thermodynamically more stable polymorph) or both (b), (c), (dFor exampleTablets of one polymorph are more prone to breakage at high humidity). In extreme cases, due to dissolutionSolubility/solubility differences, some polymorphic transitions can lead to lack of efficacy, or in other extreme cases, can lead to toxicity. In addition, the physical properties of the crystals may be important in processing, e.g., one polymorph may be more likely to form solvates or may be difficult to filter and wash free of impurities: (For exampleParticle shape and size distribution may differ between polymorphs).

Polymorphic forms of the molecule can be obtained by a variety of methods, as known in the art. These methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, and sublimation.

Techniques for characterizing polymorphic forms include, but are not limited to, Differential Scanning Calorimetry (DSC), X-ray powder diffractometry (XRPD), single crystal X-ray diffractometry, vibrational spectroscopy (S) ((S))For exampleIR and raman spectroscopy), TGA, DTA, DVS, solid state NMR, thermal stage optical microscopy, Scanning Electron Microscopy (SEM), electron crystallography and quantitation analysis, Particle Size Analysis (PSA), surface area analysis, solubility studies, and dissolution studies.

The term "amorphous form" as used herein refers to a non-crystalline solid state form of a substance.

The terms "mesogenic form", "mesogenic form" or "mesogenic form" and related terms herein, as used herein, refer to a substance that exists in a state between a liquid and a solid state ((For exampleLiquid crystal). In the mesogenic form, the same molecules of a substance can be oriented in an organized manner (ii) ((iii))For exampleCrystalline), and the substance may flow like a liquid. The different types of mesomorphic forms exhibit distinct properties: (For exampleOptical properties (1)For exampleBirefringent) and can be distinguished by polarized light. Mesogens may or may not be identified by distinct XRPD peaks.

The term "solvate" as used herein refers to a solvent addition form containing a stoichiometric or non-stoichiometric amount of solvent. Some areCompounds have a tendency to trap a fixed molar ratio of solvent molecules in a crystalline solid state, thus forming solvates. If the solvent is water, the solvate formed is a hydrate, and when the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more water molecules with a substance in which water maintains its molecular state as H₂O, such combination being capable of forming one or more hydrates. For example, the solvate may be a Dichloromethane (DCM) solvate, methyl ethyl ketone (MEK solvate), or Tetrahydrofuran (THF) solvate.

The terms "unsolvated" or "desolvated" as used herein refer to a solid-state form of a material that is free of solvent (R) ((R))Example (b) Such asCrystalline, amorphous, and mesogenic forms).

The term "pure" as used herein refers to about 90-100%, preferably 95-100%, more preferably 98-100% (wt./wt.), or 99-100% (wt./wt.) pure compound;for exampleLess than about 10%, less than about 5%, less than about 2%, or less than about 1% impurities are present. Such impurities includeFor exampleDegradation products, oxidation products, solvents, and/or other undesirable impurities.

When at constant humidity: (For example10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90% and 95% RH), light exposure and temperature (RHFor exampleAt a temperature higher than 0 ℃,for example20 ℃, 25 ℃, 30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃, 55 ℃, 60 ℃, 65 ℃, and 70 ℃ for a period of time (C.) (For exampleOne, two, three and four weeks) when no significant amount of degradation products is observed, the compounds used herein are "stable". When degraded impurities appear or area percentage of existing impuritiesFor exampleAUC by HPLC) the compound is considered unstable under certain conditions. The amount of degradation growth over time is important in determining the stability of a compound.

The term "mixing" as used herein refers to combining, blending, stirring, vibrating, rotating, or agitating. The term "agitation" refers to mixing, vibrating, stirring, or rotating. The term "agitation" refers to mixing, vibrating, stirring, or rotating.

The terms "about" and "approximately" are synonymous unless expressly indicated otherwise. In one embodiment, "about" and "about" refer to an amount, value, or duration of a reference of ± 20%, ± 15%, ± 10%, ± 8%, ± 6%, ± 5%, ± 4%, ± 2%, ± 1%, or ± 0.5%. In another embodiment, "about" and "about" refer to the recited amount, value or duration ± 10%, ± 8%, ± 6%, ± 5%, ± 4%, or ± 2%. In yet another embodiment, "about" and "about" refer to the recited amount, value, or duration ± 5%.

When the terms "about" and "approximately" are used in reference to XRPD peaks, these terms refer to the referenced X-ray powder diffraction peaks + -0.3 deg. 2 theta, + -0.2 deg. 2 theta, or + -0.1 deg. 2 theta. In another embodiment, the terms "about" and "about" refer to the enumerated X-ray powder diffraction peaks. + -. 0.2 ℃ 2. theta. In another embodiment, the terms "about" and "about" refer to the listed X-ray powder diffraction peaks. + -. 0.1 ℃ 2. theta.

When the terms "about" and "about" are used in reference to a temperature or temperature range, these terms refer to the referenced temperature or temperature range ± 5 ℃,2 ℃, or ± 1 ℃. In another embodiment, the terms "about" and "approximately" refer to the referenced temperature or temperature range ± 2 ℃.

A compound of the present application (A)For exampleFree base and salts, and amorphous, crystalline, polymorphic, and mesogenic forms thereof) may also be prepared as prodrugs, e.g., pharmaceutically acceptable prodrugs. The terms "prodrug" and "prodrug" are used interchangeably herein and refer to any compound that releases the active parent drug in vivo. Since known prodrugs enhance numerous desirable qualities of drugs: (For exampleSolubility, bioavailability, manufacturing, etc.), the compounds of the present application can be delivered in prodrug form. Accordingly, this application is intended to encompass prodrugs of the presently claimed compounds, methods of delivering the prodrugs, and compositions containing the prodrugs. The term "prodrug" includes one or more promoieties(pro-moieties) (e.g., amino acid moieties or other water-solubilizing moieties) covalently linked to a compound of the present application. The compounds of the present application may be released from the promoiety via hydrolysis, oxidation, and/or enzymatic release mechanisms. In one embodiment, the prodrug compositions of the present application exhibit increased benefits of increased aqueous solubility, improved stability, and improved pharmacokinetic properties. The pro-moiety may be selected to give the desired prodrug properties. For example, the anterior component can be selected based on solubility, stability, bioavailability, and/or in vivo delivery or absorption,for exampleAmino acid moieties or other water-solubilizing moieties, such as phosphates. The term "prodrug" is also intended to include any covalently bonded carriers that release the active parent drug of the present application in vivo when such prodrug is administered to a subject. Prodrugs in the present application are prepared by altering functional groups present in the compound in such a way that the modification is cleaved (clear) to the parent compound, either conventionally processed or in vivo. Prodrugs include compounds of the present application wherein a hydroxy, amino, mercapto, carboxyl or carbonyl group is bonded to any group that can be cleaved in vivo to form a free hydroxy, free amino, free mercapto, free carboxyl or free carbonyl group, respectively.

Examples of prodrugs include, but are not limited to, esters of hydroxy functional groups in compounds of formula I: (For exampleAcetate, dialkylaminoacetate, formate, phosphate, sulfate, and benzoate derivatives) and carbamates (C:), (C), (For exampleN, N-dimethylaminocarbonyl), ester groups of carboxyl functions ((II)For exampleEthyl esters, morpholino ethanol esters), amino-functional enaminones and N-acyl derivatives ((II)For exampleN-acetyl) N-Mannich bases, Schiff bases, oximes, acetals, ketals and enol esters of ketone and aldehyde functional groups, etc., see Bundegaard, H. "Design of Prodrugs", pp.1-92, Elesevier, New York-Oxford (1985).

Synthesis of Compound A

Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations, including the use of protecting groups, are available from the relevant scientific literature or from standard reference texts in this field. Although not limited to any one or several sources, recognized reference texts for organic synthesis include: smith, M.B., advanced organic Chemistry of March, J.March: Reactions, Mechanisms, and Structure, 5 th edition; john Wiley & Sons: New York, 2001; and Greene, T.W., Wuts, P.G.M. Protective Groups in Organic Synthesis, 3 rd edition, John Wiley & Sons: New York, 1999.

Methods for preparing compound a are described in U.S. patent application publication No. 20110172203, which is incorporated herein by reference in its entirety.

Method of treatment

The present application provides methods for treating a cell proliferation disorder in a subject in need thereof by administering to a subject in need of such treatment a therapeutically effective amount of a compound of the present application: (For exampleFree base and salts, and amorphous, crystalline, polymorphic, and mesogenic forms thereof) or a pharmaceutically acceptable prodrug or metabolite thereof. The cell proliferative disorder can be a cancer or a precancerous condition. The present application also provides the use of a compound of the present application, or a pharmaceutically acceptable prodrug or metabolite thereof, in the manufacture of a medicament useful for treating a cell proliferative disorder.

The present application also provides methods of protecting a subject in need thereof from a cell proliferative disorder by administering to a subject in need of such treatment a therapeutically effective amount of a compound of the present application, or a pharmaceutically acceptable prodrug or metabolite thereof. The cell proliferative disorder can be a cancer or a precancerous condition. The present application also provides the use of a compound of the present application, or a pharmaceutically acceptable prodrug or metabolite thereof, in the manufacture of a medicament useful for preventing a cell proliferative disorder.

As used herein, a "subject in need thereof is a subject having a cell proliferative disorder, or a subject having an increased risk of developing a cell proliferative disorder relative to the majority population. The subject in need thereof can haveThere are pre-cancerous conditions. Preferably, the subject in need thereof has cancer. "subject" includes mammals. The mammal may beFor exampleAny of the mammals which are to be treated,example (b) Such asHuman, primate, bird, mouse, rat, poultry, dog, cat, cow, horse, goat, camel, sheep, or pig. Preferably, the mammal is a human.

The term "cell proliferative disorder" as used herein refers to a condition in which cells that are unregulated or abnormally growing or both may lead to the development of an unnecessary condition or disease, which may or may not be cancer. Exemplary cell proliferation disorders of the present application include a variety of conditions in which cell differentiation is dysregulated. Exemplary cell proliferative disorders include, but are not limited to, neoplasms, benign tumors, malignant tumors, pre-cancerous conditions, inflammatory diseases,In situTumors, encapsulated tumors, metastatic tumors, liquid tumors, solid tumors, immunological tumors, hematological tumors, cancer, carcinoma, leukemia, lymphoma, sarcoma, and rapidly differentiating cells. The term "rapidly differentiating cell" as used herein is defined as any cell that differentiates at a rate greater than or equal to that expected or observed in adjacent or juxtaposed cells within the same tissue. Cell proliferative disorders include precancers or precancerous conditions. Cell proliferative disorders include cancer. Preferably, the methods provided herein are used to treat or alleviate symptoms of cancer. The term "cancer" includes solid tumors as well as hematological and/or malignant tumors. "precancerous cells" or "precancerous cells" are cells of a cell proliferative disorder manifested as a precancerous or precancerous condition. A "cancer cell" or "cancerous cell" is a cell exhibiting a cell proliferative disorder of cancer. Any reproducible means of measurement can be used to identify cancerous or precancerous cells. Cancer cells or precancerous cells can be passed through a tissue sample: (For exampleBiopsy samples) are identified. Cancer cells or precancerous cells can be identified by using appropriate molecular markers.

Exemplary non-cancerous conditions or disorders include, but are not limited to, rheumatoid arthritis; inflammation; autoimmune diseases; a lymphoproliferative condition; acromegaly; rheumatoid spondylitis; osteoarthritis; gout, other arthritic conditions; sepsis; septic stroke; endotoxin stroke; gram negative sepsis; toxic stroke syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic pneumonia; inflammatory bowel disease; crohn's disease; psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; liver fibrosis; acute and chronic kidney disease; irritable bowel syndrome; pyresis; restenosis; cerebral malaria; stroke and ischemic injury; trauma to the nerve; alzheimer's disease; huntington's disease; parkinson's disease; acute and chronic pain; allergic rhinitis; allergic conjunctivitis; chronic heart failure; acute coronary syndrome; cachexia; malaria; leprosy; leishmaniasis; lyme disease; reiter syndrome; acute synovitis; muscle degeneration, bursitis; tendinitis; tenosynovitis; herniated, ruptured or herniated intervertebral discs; osteopetrosis (osteopetrosis); thrombosis; restenosis; silicosis; pulmonary sarcoidosis; bone resorption diseases, such as osteoporosis; graft-versus-host response; multiple sclerosis; lupus; fibromyalgia; AIDS and other viral diseases such as herpes zoster, herpes simplex I or II, influenza virus and cytomegalovirus; and diabetes.

Exemplary cancers include, but are not limited to, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphomas, anal cancers, anorectal cancers, cancers of the anal canal, appendiceal cancers, childhood cerebellar astrocytomas, childhood cerebral astrocytomas, basal cell carcinomas, skin cancers (non-melanoma), biliary cancers, extrahepatic bile duct cancers, intrahepatic bile duct cancers, bladder cancers, urinary bladder cancers, bone and joint cancers, osteosarcomas and malignant fibrous histiocytomas, brain cancers, brain tumors, brain stem gliomas, cerebellar astrocytomas, cerebral astrocytomas/gliomas, ependymomas, medulloblastomas, supratentorial primitive extraembryonic tumors, visual pathways and hypothalamic gliomas, breast cancers, bronchial adenomas/carcinoid tumors, gastrointestinal cancers, nervous system lymphomas, central nervous system cancers, central nervous system lymphoma, neck cancer, childhood cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorder, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, lymphoid neoplasms, mycosis fungoides, Seziary syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumors, extragonadal germ cell tumors, extrahepatic bile duct cancer, eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, stomach (gastric) cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, ovarian germ cell tumors, gestational trophoblastic glioma, head and neck cancer, hepatocellular (liver) cancer, hodgkin's lymphoma, hypopharynx cancer, intraocular melanoma, eye cancer, islet cell tumors (pancreatic endocrine), kaposi's sarcoma, kidney cancer, larynx cancer, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, lip and oral cancer, liver cancer, lung cancer, non-small cell lung cancer, AIDS-related lymphoma, non-Hodgkin's lymphoma, primary central nervous system lymphoma, Waldenstrom's macroglobulinemia, medulloblastoma, melanoma, intraocular (ocular) melanoma, Merck's cell cancer, malignant mesothelioma, metastatic squamous neck cancer, oral cancer, tongue cancer, multiple endocrine neoplasia syndrome, mycosis fungoides, myelodysplastic syndrome, myelodysplastic/myeloproliferative disorders, chronic myelogenous leukemia, acute myeloid leukemia, multiple myeloma, chronic myeloproliferative disorders, nasopharyngeal cancer, neuroblastoma, oral cancer, oropharyngeal cancer, ovarian cancer, ovarian epithelial cancer, low malignant potential tumors of the ovary, pancreatic cancer, islet cell pancreatic cancer, cancer of the paranasal sinuses and nasal cavities, parathyroid cancer, penile cancer, pharyngeal cancer, paragangliomas, pineal cell tumors and supratentorial primitive extraneural tumors, pituitary tumors, plasma cell neoplasms/multiple myeloma, pleuroperitoblastoma, prostate cancer, rectal cancer, renal pelvis and ureter, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland carcinoma, the ewing family of sarcoma tumors, kaposi's sarcoma, soft tissue sarcoma, uterine cancer, uterine sarcoma, skin cancer (non-melanoma), skin cancer (melanoma), mercker cell skin cancer, small intestine cancer, soft tissue sarcoma, squamous cell cancer, stomach (stomach) cancer, supratentorial primitive extraembryonic tumor, testicular cancer, laryngeal cancer, thymoma and carcinoma, thyroid cancer, transitional cell cancers of the renal pelvis and ureters and other urinary organs, gestational trophoblastic tumors, cancer of the urethra, endometrial uterine sarcoma, uterine corpus carcinoma, vaginal cancer, vulval cancer and wilms' tumor.

As used herein, "treatment" or "treating" describes the management and care of a patient for the purpose of combating a disease, condition, or disorder, and includes the administration of a compound of the present application, or a pharmaceutically acceptable prodrug or metabolite thereof, to alleviate a symptom or complication of the disease, condition, or disorder, or to eliminate the disease, condition, or disorder.

The compounds of the present application, or pharmaceutically acceptable prodrugs or metabolites thereof, may also be used for the prevention of a disease, condition, or disorder. As used herein, "prevent" or "prevention" describes reducing or eliminating the onset of symptoms or complications of a disease, condition, or disorder.

The term "alleviating" as used herein is used to describe the process of reducing the severity of signs or symptoms of a disorder. Importantly, the signs or symptoms can be reduced without elimination. In a preferred embodiment, administration of the pharmaceutical composition of the present application results in elimination of the signs or symptoms, however, elimination is not required. An effective dose is expected to reduce the severity of signs or symptoms. For example, if the severity of cancer is reduced within at least one of the multiple locations, the signs or symptoms of a condition (e.g., cancer) that may arise at the multiple locations are alleviated.

Treating cancer can result in a reduction in the size of the tumor. Reducing the size of a tumor may also be referred to as "tumor regression". Treatment of cancer can result in a reduction in tumor volume. Treatment of cancer results in a reduction in the number of tumors. Treatment of cancer can result in a reduction in the number of metastatic lesions in other tissues or organs distant from the primary tumor site. Treating cancer can result in an increase in the mean survival time of a population of treated subjects compared to a population receiving only the vector. Treating cancer can result in an increase in the mean survival time of a population of treated subjects compared to a population of untreated subjects. Treatment of cancer can result in an increase in the average survival time of a population of treated subjects compared to a population receiving monotherapy with a drug that is not a compound of the present application, or a pharmaceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof. Treating cancer can result in a reduction in mortality of a population of treated subjects compared to a population receiving only the vector. Treating cancer can result in a decreased mortality rate in a population of treated subjects compared to an untreated population. Treating cancer can result in a reduction in mortality of a population of treated subjects compared to a population receiving monotherapy with a drug that is not a compound of the present application, or a pharmaceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof. Treatment of cancer can result in a decrease in tumor growth rate. Treatment of cancer can result in reduced tumor regrowth. Treating or preventing cell proliferation disorders can result in a decrease in the rate of cell proliferation. Treating or preventing a cell proliferative disorder can result in a decrease in the proportion of proliferating cells. Treating or preventing a cell proliferative disorder can result in a reduction in the size of the area or region of cell proliferation. Treating or preventing a cell proliferative disorder can result in a reduction in the number or proportion of cells having an abnormal appearance or morphology.

As used herein, "monotherapy" refers to the administration of a single active or therapeutic compound to a subject in need thereof. Preferably, monotherapy will involve the administration of a therapeutically effective amount of the active compound. For example, cancer monotherapy involves administering to a subject in need of treatment for cancer a compound of the present application, or a pharmaceutically acceptable prodrug, metabolite, analog or derivative thereof. Monotherapy may be compared to combination therapy in which a combination of active compounds is administered, preferably with each component of the combination being present in a therapeutically effective amount. In one aspect, monotherapy using a compound of the present application, or a pharmaceutically acceptable prodrug or metabolite thereof, is more effective than combination therapy in inducing a desired biological effect.

As used herein, "combination therapy" or "co-treatment" includes the administration of a compound of the present application, or a pharmaceutically acceptable prodrug, metabolite, analog or derivative thereof, and at least a second agent as part of a particular treatment regimen, intended to provide a beneficial effect from the co-action of these therapeutic agents. The beneficial effects of the combination include, but are not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of the therapeutic agents. The combined administration of these therapeutic agents is usually carried out over a defined period of time (usually minutes, hours, days or weeks, depending on the combination chosen). "combination therapy" may (but is not generally) intended to encompass the administration of two or more of these therapeutic agents as part of a single monotherapy regimen which results, by chance or by chance, in a combination as used herein.

"combination therapy" is intended to include the administration of these therapeutic agents in a sequential manner, wherein each therapeutic agent is administered at a different time, as well as the administration of these therapeutic agents or at least two therapeutic agents in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or multiple single capsules for each therapeutic agent. Sequential or substantially simultaneous administration of each therapeutic agent may be accomplished by any suitable route, including, but not limited to, oral route, intravenous route, intramuscular route, and direct absorption through mucosal tissue. The therapeutic agents may be administered by the same route or by different routes. For example, a first therapeutic agent selected for combination may be administered by intravenous injection, while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. The order of administration of the therapeutic agents is not narrowly critical.

"combination therapy" also includes administration of the above therapeutic agents with other biologically active ingredients and non-drug treatments: (For exampleSurgical or radiation therapy). When combination therapy also includes non-drug treatment, the non-drug treatment can be carried out at any suitable time, so long as the combined co-action of the therapeutic agent and the non-drug treatment is achievedHas the beneficial effects. For example, where appropriate, beneficial effects are still achieved when non-drug treatment is temporarily removed from administration of the therapeutic agent, perhaps days or even weeks.

The compounds of the present application, or pharmaceutically acceptable prodrugs, metabolites, analogs or derivatives thereof, can be administered in combination with a second chemotherapeutic agent. The second chemotherapeutic agent (also referred to as an anti-neobiological agent or an anti-proliferative agent) may be an alkylating agent; (ii) an antibiotic; an antimetabolite; an antidote; an interferon; polyclonal or monoclonal antibodies; an EGFR inhibitor; a HER2 inhibitor; (ii) a histone deacetylase inhibitor; a hormone; a mitotic inhibitor; (ii) an MTOR inhibitor; (ii) a multi-kinase inhibitor; serine/threonine kinase inhibitors; tyrosine kinase inhibitors; VEGF/VEGFR inhibitors; taxanes or taxane derivatives, aromatase inhibitors, anthracyclines, microtubule-targeting drugs, topoisomerase poison drugs, inhibitors of molecular targets or enzymes: (inhibitors of molecular targets or enzymes)For exampleA kinase inhibitor), a cytidine analog drug or any chemotherapeutic, anti-neoplastic or anti-proliferative agent.

Pharmaceutical composition

The present application also provides pharmaceutical compositions comprising a salt of compound a, a solid state form of compound a free base or a salt of compound a, an amorphous form of compound a free base or a salt of compound a, a crystalline form of compound a free base or a salt of compound a, a polymorph of compound a free base or a salt of compound a, and/or a mesomorphic form of compound a free base or a salt of compound a.

A "pharmaceutical composition" is a formulation containing the free base, salt and/or solid state forms thereof of the present application in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is in any of a variety of forms including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler, or a vial. Active ingredient in unit dose of composition (For exampleThe free base, salts and solid state forms of the disclosed formulations) are in an effective amount and will depend on the particular treatment involvedAnd (6) changing. Those skilled in the art will recognize that routine variations in dosage are sometimes required, depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for topical or transdermal administration of the compounds of the present application include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable risk/benefit ratio.

"pharmaceutically acceptable excipient" refers to an excipient that can be used in the preparation of pharmaceutical compositions that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as for human pharmaceutical use. As used in the present specification and claims, "pharmaceutically acceptable excipient" includes both one and more than one such excipient.

The pharmaceutical compositions of the present application are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral,for exampleIntravenous, intradermal, subcutaneous, oral administration (For exampleInhalation), transdermal (topical) and transmucosal administration. Solutions or suspensions for parenteral, intradermal, or subcutaneous administration may include the following components: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants, such as ascorbic acid or sodium bisulfite; chelationAgents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates or phosphates, and agents for adjusting tonicity, such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, for example hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

The pharmaceutical compositions of the present application can be administered to a subject in a number of well-known methods currently used for chemotherapeutic treatment. For example, to treat cancer, the compounds of the present application can be injected directly into the tumor, into the bloodstream or body cavity or taken orally or applied through the skin using a patch. The selected dose should be sufficient to constitute an effective treatment, but not high enough to cause unacceptable side effects. The status of the disease condition is preferably closely monitored during and for a reasonable period of time after treatment: (For exampleCancer, precancer, etc.) and patient health.

The term "therapeutically effective amount" as used herein refers to an amount of a pharmaceutical agent that treats, ameliorates, or prevents an identified disease or condition, or exhibits a detectable therapeutic or inhibitory effect. The effect can be detected by any assay known in the art. For a subject, the exact effective amount will depend on the weight, size, and health of the subject; the nature and extent of the condition; and the therapy or combination of therapies selected for administration. A therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician. In a preferred aspect, the disease or condition to be treated is cancer. In another aspect, the disease or condition to be treated is a cell proliferative disorder.

For any compound, a therapeutically effective amount can be initially atFor exampleIn cell culture assays of neoplastic cells or in animal models (typically rat, mouse, rabbit, dog or pig). Animal models can also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes for administration to humans. Therapeutic/prophylactic efficacy and toxicity can be confirmed in cell cultures or experimental animals by standard pharmaceutical proceduresAnd then the step of determining the number of the first time,for example，ED₅₀(therapeutically effective dose in 50% of the population) and LD₅₀(the dose lethal to 50% of the population). The dose ratio of toxic to therapeutic effect is the therapeutic index and it can be expressed as the ratio LD₅₀/ED₅₀. Pharmaceutical compositions exhibiting a large therapeutic index are preferred. The dosage may vary within this range depending upon the dosage form employed, the severity of the patient, and the route of administration.

The dosage and administration are adjusted to provide a sufficient level of the active ingredient or to maintain the desired effect. Factors that may be considered include the severity of the disease state, the general health of the subject, the age, weight and sex of the subject, diet, time and frequency of administration, drug combination, severity of the response and tolerance/response to treatment. Long acting pharmaceutical compositions may be administered once every 3-4 days, weekly, or biweekly, depending on the half-life and clearance rate of the particular formulation.

Pharmaceutical compositions containing the free base, salt and/or solid state forms thereof of the present application may be manufactured in a generally known manner,for exampleBy means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Pharmaceutical compositions may be formulated in conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and/or auxiliaries which facilitate processing of the active ingredients into preparations which can be used pharmaceutically. Of course, the appropriate formulation will depend on the route of administration chosen.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (when water-soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL^TM(BASF, Parsippany, n.j.) or Phosphate Buffered Saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can beA solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens (parabens), chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions may be prepared as follows: the desired amount of active ingredient is incorporated in a suitable solvent with one or a combination of ingredients enumerated above, followed by filtered sterilization, as required. Generally, dispersions are prepared by incorporating the active ingredient in a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Oral compositions typically include an inert diluent or an edible pharmaceutically acceptable carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active ingredient may be incorporated into excipients and used in the form of tablets, lozenges or capsules. Oral compositions can also be prepared for use as a mouthwash using a fluid carrier, wherein the compound in the fluid carrier is administered orally, rinsed and expectorated or swallowed. Pharmaceutically compatible binders and/or auxiliary materials may be included as part of the composition. Tablets, pills, capsules, lozenges, and the like may contain any of the following ingredients or compounds of similar properties: binders, such as microcrystalline cellulose, gum tragacanth or gelatin; excipients, such as starch or lactose; disintegrants, for example alginic acid, Primogel or corn starch; lubricants, such as magnesium stearate or Sterotes; glidants, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; or a flavoring agent, such as peppermint, methyl salicylate, or orange flavoring.

For administration by inhalation, the active ingredient is in the form of an aerosol spray from a composition containing a suitable propellant(s) ((For exampleGas, such as carbon dioxide), or a nebulizer.

Systemic administration may also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active ingredient is formulated into ointments, salves, gels, or creams as generally known in the art.

The active ingredient may be prepared using pharmaceutically acceptable carriers that will protect the compound from rapid elimination by the body, such as controlled release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers may be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparing such formulations will be apparent to those skilled in the art. Materials are also commercially available from Alza corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

It is particularly advantageous to formulate oral or parenteral compositions in dosage unit form to facilitate administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suitable as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the present application is dictated by and directly dependent on the unique properties of the active ingredient and the particular therapeutic effect to be achieved.

In therapeutic applications, the dosage of the pharmaceutical composition used in accordance with the present application will vary depending upon the agent, the age, weight, and clinical condition of the patient to be treated, and the experience and judgment of the clinician or practitioner administering the treatment, among other factors affecting the selected dosage. Generally, the dose should be sufficient to result in slowing and preferably retrograde tumor growth and also preferably cause complete regression of the cancer. The dosage may range from about 0.01 mg/kg/day to about 5000 mg/kg/day. In a preferred aspect, the dosage may range from about 1 mg/kg/day to about 1000 mg/kg/day. In one aspect, the dose will be between about 0.1 mg/day to about 50 g/day; about 0.1 mg/day to about 25 g/day; about 0.1 mg/day to about 10 g/day; about 0.1 mg to about 3 g/day; or from about 0.1 mg to about 1 g/day, in single, divided or continuous doses (in kg for the weight of the patient), body surface area (in m)²Count) and age (in years), adjustable dose). An effective amount of a pharmaceutical agent is an amount that provides an objectively identifiable improvement to the record of a clinician or other qualified observer. For example, regression of a patient's tumor can be measured with reference to the diameter of the tumor. A decrease in tumor diameter indicates regression. Regression is also indicated by the inability of the tumor to recur after treatment has ceased. The term "dose-effective manner" as used herein refers to the amount of active ingredient that produces the desired biological effect in a subject or cell.

The pharmaceutical composition may be included in a container, package or dispenser with instructions for administration.

The compounds of the present application are capable of further salt formation. All such forms are also contemplated to be within the scope of the claimed application.

As used herein, "pharmaceutically acceptable salt" refers toA derivative of the compound of claim, wherein the parent compound is modified by making an acid or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (e.g., amines), alkali metal or organic salts of acidic residues (e.g., carboxylic acids), and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from the group consisting of: 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, acid carbonic acid, citric acid, ethylenediaminetetraacetic acid, ethanedisulfonic acid, 1, 2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, ethacrynic acid, hexylresorcinalic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, hydroxyethanesulfonic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, naphthalenesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, glycolic acid, succinic acid, sulfamic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and the commonly occurring amino acids,for exampleGlycine, alanine, phenylalanine, arginine and the like。

Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo- [2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, t-butylacetic acid, muconic acid, and the like. The application also includes when the acidic proton present in the parent compound is replaced by a metal ion,for exampleAn alkali metal ion, an alkaline earth ion or an aluminum ion, or a salt formed by coordinating with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine or the like.

It is to be understood that all references to pharmaceutically acceptable salts include the solvent addition forms (solvates) or crystalline forms (polymorphs) defined herein of the same salt.

The compounds of the present application may also be prepared as esters, e.g., pharmaceutically acceptable esters. For example, the carboxylic acid functionality in a compound may be converted to its corresponding ester,for exampleMethyl, ethyl or other esters. Alternatively, the alcohol group in the compound may be converted to its corresponding ester,for exampleAcetate, propionate or other ester.

The compounds of the present application may also be prepared as prodrugs, e.g., pharmaceutically acceptable prodrugs. The terms "prodrug" and "prodrug" are used interchangeably herein and refer to any compound that releases an active parent drug in vivo. Since known prodrugs enhance numerous desirable qualities of drugs: (For exampleSolubility, bioavailability, manufacturing, etc.), the compounds of the present application can be delivered in prodrug form. Accordingly, this application is intended to encompass prodrugs of the presently claimed compounds, methods of delivering the prodrugs, and compositions containing the prodrugs. "prodrug" is intended to include any covalently linked carrier that releases the active parent drug of the present application in vivo when such prodrug is administered to a subject. Prodrugs in the present application are prepared by modifying functional groups present in the compound in such a way that, upon routine manipulation or in vivo, the modification dissociates into the parent compound. Prodrugs include compounds of the present application wherein a hydroxy, amino, mercapto, carboxyl or carbonyl group is bonded to any group that can be cleaved in vivo to form a free hydroxy, free amino, free mercapto, free carboxyl or free carbonyl group, respectively.

Examples of prodrugs include, but are not limited to, esters of hydroxy functional groups in the compounds of the present application: (For exampleAcetate, dialkylaminoacetate, formate, phosphate, sulfate, and benzoate derivatives) and carbamates (C:), (C), (For exampleN, N-dimethylaminocarbonyl), esters of carboxyl functions (CFor exampleEthyl esters, morpholino ethanol esters), amino-functional enaminones and N-acyl derivativesArticle (A), (B), (C), (For exampleN-acetyl) N-Mannich bases, Schiff bases, oximes, acetals, ketals and enol esters of ketone and aldehyde functions, etc., see Bundegaard, H. Design of Prodrugs, pp.1-92, Elesevier, New York-Oxford (1985).

The pharmaceutical compositions of the present application are administered orally, nasally, transdermally, pulmonarily, inhalatively, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, and parenterally. In one embodiment, the compound is administered orally. Those skilled in the art will recognize certain advantages of a given route.

The dosage regimen utilizing the compounds will be selected in accordance with a variety of factors including the type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; a route of administration; renal and hepatic function of the patient; and the specific compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

Techniques for formulating and administering the compounds disclosed herein can be found in Remington: the Science and practice of Pharmacy, 19 th edition, Mack Publishing Co., Easton, Pa (1995). In one embodiment, the compounds described herein and pharmaceutically acceptable salts thereof are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compound will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the ranges described herein.

All percentages and ratios used herein are on a weight basis unless otherwise indicated. Other features and advantages of the present application will be apparent from the various embodiments. The examples provided illustrate the different components and methods that can be used to practice the present application. The examples do not limit the claimed application. Based on the disclosure, a skilled artisan can identify and employ other components and methods useful in practicing the present application.

Examples

Example 1: x-ray powder diffraction (XRPD)

1.1. Bruker AXS C2 GADDS

X-ray powder diffraction patterns were collected on a Bruker AXS C2 GADDS diffractometer using Cu ka radiation (40 kV, 40 mA), automated XYZ stage, laser video microscope for automated sample positioning and HiStar 2-dimensional area detector. X-ray optics consists of a single gobel multilayer mirror connected to a 0.3 mm pinhole collimator. Weekly performance tests were performed using a certified standard NIST1976 corendum (plate).

Beam divergence (Namely, it isThe effective size of the X-ray beam on the sample) is about 4 mm. A theta-theta continuous scan mode is used in which the sample-detector distance is 20 cm, resulting in an effective 2 theta range of 3.2 deg. -29.7 deg.. The sample is typically exposed to the X-ray beam for 120 seconds. The software for data collection was GADDS for WNT 4.1.16, data was analyzed and presented using Diffrac Plus EVA v11.0.0.2 or v13.0.0.2.

Environmental conditions

Samples run at ambient conditions were prepared as flat plate samples using the powder as received without grinding. Approximately 1-2 mg of sample was lightly pressed on the slide to obtain a flat surface.

Non-environmental conditions

Samples run under non-ambient conditions were mounted on a silicon wafer with a thermally conductive compound. The sample was then heated to the appropriate temperature at 10 ℃/min, followed by isothermal hold for 1 minute, before data collection was initiated.

1.2. Bruker AXS D8 Advance

X-ray powder diffraction patterns were collected on a Bruker D8 diffractometer using Cu ka radiation (40 kV, 40 mA), a theta-2 theta goniometer, and a divergence and acceptance slit of V4, a Ge monochromator, and a Lynxeye detector. The instrument was performance checked using the certified cornundum standard (NIST 1976). The software used for data collection was Diffrac Plus XRDCommander v2.5.0, data was analyzed and presented using Diffrac Plus EVA v11.0.0.0.2 or v13.0.0.2. Samples were run as flat plate samples at ambient conditions using the powder as received.

The warm and filled samples were cooled in a chamber cut into polished zero background (510) silicon wafers. The sample is rotated in its own plane during the analysis. Details of data collection are:

● angular extent: 2-42 degree 2 theta

● step size: 0.05 degree 2 theta

● Collection time: 0.5 sec/step

1.3. Bruker AXS D8 Advance

Variable temperature XRPD analysis was performed on Bruker D8 ADVANCE using Oxford Cryosystems Cryostream in capillary mode at 23, 115, 150 and 200 ℃. The sample was scanned between 3.0-50.0 ° 2 θ. The material was prepared in a capillary sample holder. The samples were then loaded into a Bruker D8 ADVANCE diffractometer and analyzed using the following experimental conditions:

start position [ ° 2 θ]	3.0000
		Final position [ ° 2 θ]	50.0000
Step size [ ° 2 θ]	0.0500
		Scanning step time s]	4
Type of diffractometer	Bruker D8 ADVANCE

1.4. Siemens D5000

XRPD analysis was performed on Siemens D5000, scanning the sample between 3.0-30.0 (or 50.0, to characterize the received material) degrees 2 θ. The material was gently pressed on a glass disc inserted into a sample holder. The samples were then loaded into a Siemens D5000 diffractometer operating in reflectance mode and analyzed using the following experimental conditions:

origin of original data	Siemens-binary V2 (. RAW)
		Start position [ ° 2 θ]	3.0000
Final position [ ° 2 θ]	30.0000 or 50.0000
		Step size [ ° 2 θ]	0.0200
Scanning step time s]	1
		Scanning type	Continuous
Slit type	Fixing
		Divergent slit size [ mm ]]	2.0000
Sample length [ mm ]]	Various kinds of
		Receiving slit size [ mm ]]	2.0000
Detector slit size mm]	0.2000
		Measurement of temperature [ ° c]	20.00
Anode material	Cu
		K-α1 [Å]	1.54060
K-α2 [Å]	1.54443
		K-β [Å]	1.39225
K-A2/K-A1 ratio	0.50000 (nominal)
		Generator settings	40 mA，40 kV
Type of diffractometer	Siemens D5000
		Focus ring (Foccusing Circle) diameter mm]	401.00
Diffracted beam monochromator	Graphite (II)
		Spin of spin	Is not limited to

Example 2:¹H NMR

NMR spectra were collected on a Bruker 400MHz instrument equipped with an autosampler and controlled by a DRX400 console. An automated experiment was obtained using a standard Bruker loaded experiment using ICON-NMR v4.0.4 run with Topspin v 1.3. For non-conventional spectroscopy, data were obtained by using Topspin alone. In DMSO-d unless otherwise stated₆To prepare a sample. Offline analysis was performed using ACD SpecManager v 12.00.

Implementation on Bruker AV400 (frequency: 400 MHz)¹H-NMR spectroscopic experiments. Experiments were conducted in deuterium oxide, each sample prepared to a concentration of about 10 mM.

Example 3: differential Scanning Calorimetry (DSC)

3.1. Mettler DSC 823e

DSC data was collected on a Mettler DSC 823e equipped with a 34-position autosampler. The instrument was calibrated for energy and temperature using certified indium. 0.5-3 mg of each sample was heated from 25 ℃ to 300 ℃ in a pinhole aluminum pan, typically at 10 ℃/min. A nitrogen purge of 50 ml/min was maintained over the sample. The instrument control and data analysis software was STARe v 9.20.

3.1. Seiko DSC6200

About 5 mg of material was weighed into an aluminum DSC pan and hermetically sealed with a perforated aluminum lid. The sample trays were then loaded in a Seiko DSC6200 instrument (equipped with a cooler) and held at 25 ℃. Once a stable heat flow response was obtained, the sample and reference were heated to about 360 ℃ at a scan rate of 10 ℃/minute and the resulting heat flow response was monitored.

Example 4: thermo-gravimetric analysis (TGA)

TGA data was collected on a MettlerTGA/SDTA 851e equipped with a 34-position auto-sampler. The instrument was temperature calibrated using certified indium. Typically 5-30 mg of each sample was loaded on a pre-weighed aluminum crucible and heated from ambient temperature to 350 ℃ at 10 ℃/min. A nitrogen purge of 50 ml/min was maintained over the sample. The instrument control and data analysis software was STARe v 9.20.

Approximately 5 mg of material was weighed into an open aluminum pan and loaded in a simultaneous thermal gravimetric/differential thermal analyzer (TG/DTA) and maintained at room temperature. The sample was then heated from 25 ℃ to 300 ℃ at a rate of 10 ℃/min, during which time the sample weight change was recorded, as well as any differential thermal events (DTA). At 100 cm³Flow rate per minute, nitrogen was used as purge gas.

Example 5: polarized Light Microscopy (PLM)

5.1. Leica LM/DM

The samples were studied on a Leica LM/DM polarized light microscope with a digital video camera for image capture. A small amount of each sample was placed on a glass slide, mounted in immersion oil, covered with a glass slide, and the individual particles were separated as well as possible. The sample was observed using appropriate magnification and partially polarized light in conjunction with a lambda false color filter.

5.1. Olympus BX50

The presence of birefringence was determined using an Olympus BX50 polarization microscope equipped with a Motic camera and image capture software (Motic Images Plus 2.0). All images were recorded using a 20 x objective unless stated otherwise.

Example 6: determination of chemical purity by HPLC

Purity analysis was performed on an Agilent HP1100 series system equipped with a diode array detector using the method detailed below and using ChemStation software vb.02.01-SR 1:

TABLE 1 HPLC METHOD PARAMETERS FOR CHEMICAL PURITY DETERMINATION

Example 7: specific gravity measurement vapor adsorption (GVS)

7.1. Inherent to SMS DVS

Adsorption isotherms were obtained using an SMS DVS intrinsic moisture adsorption analyzer controlled by DVS intrinsic control software v1.0.0.30. The sample temperature was maintained at 25 ℃ by instrument control. Humidity was controlled by a mixed flow of dry and wet nitrogen with a total flow rate of 200 ml/min. Relative humidity was measured by a calibrated Rotronic probe (dynamic range of 1.0-100% RH) placed near the sample. The weight change (mass relaxation) of the sample was continuously monitored by a microbalance (precision ± 0.005 mg) as the amount of strain in% RH.

Typically 5-20 mg of the sample is placed in a tared stainless steel basket of a sieve under ambient conditions. The samples were loaded and unloaded at 40% RH and 25 ℃ (typically room temperature conditions). Moisture sorption isotherms were performed as described below (4 scans resulted in 2 complete cycles). Standard isotherms were performed at 25 ℃ in the range of 0-90% RH at 10% RH intervals. Data Analysis was undertaken using DVS Analysis Suite v6.0.0.7, with Microsoft Excel.

TABLE 2 method parameters for SMS DVS intrinsic experiments

Parameter(s)	Value of
		Adsorption-scanning 1	40-90
Desorption/adsorption-Scan 2	90-0，0-40
		Interval (% RH)	10
Number of scans	4
		Flow rate (ml/min)	200
Temperature (. degree.C.)	25
		Stability (. degree.C./min)	0.2
Adsorption time (hours)	6 hours off time

The samples were recovered after completion of the isotherm and re-analyzed by XRPD.

7.2. Dynamic vapor adsorption (DVS)

Approximately 10 mg of the sample was placed in a sieve vapor adsorption balance pan and loaded on a DVS-1 dynamic vapor adsorption balance of Surface measurement systems. The samples were subjected to a ramp profile (ramping profile) of 0-90%, 90-0% Relative Humidity (RH), in increments of 10% for the anhydrous samples and 0-90%, 90-0%, 0-90%, 90-0% for the hydrated samples, holding the samples at each step until a stable weight had been achieved (99.5% step complete). The weight change during the adsorption/desorption cycle is plotted, which allows the hygroscopic properties of the sample to be determined.

Example 8: water determination by Karl Fischer titration (KF)

8.1. Mettler Toledo DL39 Coulometer

The water content of each sample was measured on a Mettler Toledo DL39 Coulometer using a Hydranal Coulomat AG reagent and an argon purge. A weighed solid sample is dissolved in a solvent and a volume is introduced into the container which corresponds to about 10 mg of sample per titration. Duplicate assays were performed.

8.2. Mettler Toledo C30 Compact Titrator

Initially, a blank sample containing only methanol was analyzed by KF (Mettler Toledo C30Compact Titrator) to determine the amount of white water before sample analysis. About 10-15 mg of solid material was accurately weighed in a vial. The material was then dissolved in methanol and the amount added was recorded. The resulting solution was then manually introduced into the titration chamber of Mettler Toledo C30Compact Titrator. The water content was calculated as a percentage and the data was printed.

Example 9: thermodynamic water solubility

9.1. Solubility in water

Aqueous solubility is determined by suspending sufficient compound in water to obtain a maximum final concentration of the parent free form of ≧ 10 mg/ml. The suspension was equilibrated at 25 ℃ for 24 hours, followed by measurement of the pH. The suspension was then filtered through a glass fibre C filter. The filtrate is then diluted by a suitable factor,for example,101. Quantitation was by HPLC with reference to a standard solution of about 0.25 mg/ml in DMSO. Different volumes of standards, diluted and undiluted sample solutions were injected. The solubility was calculated using the peak area determined by integrating the peaks found at the same retention time as the main peak in the standard injection.

TABLE 3 HPLC METHOD parameters for solubility measurement

The analysis was performed on an Agilent HP1100 series system equipped with a diode array detector and using the ChemStation software vB.02.01-SR 1.

9.2. High performance liquid chromatography-ultraviolet detection (HPLC-UV)

Purity and concentration analysis was performed using the following methods:

parameters of the instrument

Column:	watera Xbridge Shield RP18, 4.6 × 150 mm, 3.5 μm, part number 186003045
		Column temperature:	25℃
auto-sampler temperature:	5℃
		and (3) detection:	226 nm
mobile phase A:	95:5:0.1% Water methanol TFA
		Mobile phase B:	95:5:0.1% methanol, water, TFA
Gradient:	see the conditions in the table below
		Flow rate:	1.0 mL/min
Injection volume:	10 μL
		analysis time:	36 minutes
Rebalancing time:	4 minutes
		Data collection time:	36 minutes
Needle washing	100% methanol

Gradient condition

Time (minutes)	%A	%B
			0.0	100	0
2.0	100	0
			28.0	0	100
32.0	0	100
			32.1	100	0
36.0	100	0

Example 10: ion Chromatography (IC)

Data were collected on a Metrohm 761 Compact IC (for cations)/Metrohm 861Advanced Compact IC (for anions) using IC Net software v 2.3. Accurately weighed samples were prepared as stock solutions in appropriate dissolving solutions and diluted appropriately before testing. Quantification is achieved by comparison with standard solutions of known concentrations of the ions to be analysed.

TABLE 4 IC Process parameters for anion chromatography

Example 11: hot stage microscopy

The samples were analyzed by Polarized Light Microscopy (PLM) using a thermal phase instrument with a 10 x magnification lens. The temperature was ramped from 25 ℃ to 325 ℃ at 10 ℃/min.

Example 12: polymorph of compound a free base

Multiple polymorphic forms of compound a free base were prepared.

Form 1 is formed by separating compound a free base from Isopropanol (IPA), Methyl Ethyl Ketone (MEK), or acetone. Form 1 constitutes a rod-shaped birefringent particle (fig. 1). It was 99.3% chemically pure (fig. 6) with 0.01 equivalent of residual dioxane. Crystalline compound a free base is insoluble in water.

Form 1 can be a Dichloromethane (DCM) solvate containing 0.4-0.6 equivalents of DCM (FIG. 7A) or a MEK solvate containing 0.4-0.6 equivalents of MEK (FIG. 7C). Form 1 was stable at 25 ℃ and storage conditions of 0-96% RH (fig. 4B and C), and exhibited minimal water uptake (<0.8%, w/w) at 0-90% RH (fig. 5).

Form 1 exhibited a broad endotherm with onset temperature of-118 ℃ and melting at-207 ℃ (FIG. 8). Form 1 lost 8.8% (w/w) weight, which corresponds to 0.49 equivalents of DCM, over the temperature range of 110 ℃ and 150 ℃ (FIG. 8). Upon storage, minimal water absorption was observed for form 1 (fig. 5).

Form 1 released DCM at-110 ℃ and converted to unsolvated form 2 (fig. 3). Form 1 also converted to form 2 when stored at 40 ℃ and 75% RH (fig. 4A).

Form 2 is also formed by separating compound a free base from isopropyl acetate (IPAc) or acetonitrile. Form 2 did not contain any significant amount of solvent (fig. 7B). Form 2 melts at-210 ℃ and, when cooled, converts to form 3 (fig. 3).

Containing 5% H by slow evaporation₂Free base solution of O/THF mixture, growth form 4 (FIG. 10). Form 4 is a semi-THF solvate and has an asymmetric unit containing a separate molecule showing little disorder of compound a free base and half a molecule of THF. The disorder in compound a free base is at the amine group substituted on the cyclobutyl ring and is observed as elongated nitrogen ellipsoids. This type of disorder is observed when the amine groups are not conjugated by aromatic rings. Final R₁[I>2σ(I)]RMSD from planarity of 0.0267 was obtained by calculated least squares plane of 6-atom pyridine rings (C1-C5), where C5 showed the maximum deviation from planarity of-0.0463 (9) Å RMSD from planarity of 0.0083 was obtained by calculated least squares plane of 9-atom fused rings (C6-C11, N3, N4, N5), where C7 showedMaximum deviation from planarity is 0.016 (1) Å the dihedral angle between this plane and the previous plane is 20.27 (5) ° RMSD of 0.0015 from planarity is obtained by the calculated least squares plane of 6 atom benzene rings (C12-C17), where C16 shows maximum deviation from planarity of 0.0025 (9) Å the dihedral angle between this plane and the previous plane is 27.53 (2) °. RMSD of 0.0125 from planarity is obtained by the calculated least squares plane of 6 atom second benzene rings (C18-C23), where C23 shows maximum deviation from planarity of-0.0187 (8) the dihedral angle between this plane and the previous plane is 61.64 (4) ° cyclobutyl rings (C24-C27) take a typical (butterfly-like) structure, minimizing ring strain.

In form 4, compound a free base forms a dimer via the hydrogen bond N1-H1AB — N2[ D · · a = 3.051 (2) a ] of the nitrogen N2 of the amine group on the pyridine ring acting as donor and the nitrogen N1 of the pyridine ring on the symmetrically relevant molecule acting as acceptor (fig. 11). The dimer units of compound a free base are linked together by the amine substituent N6 of the cyclobutyl ring and a hydrogen bond N6-H6B-N2 [ D · · a = 3.284 (4) ] between the same groups in the relevant molecule, which leads to symmetry of the chains of compound a dimer units (fig. 12). Internal hydrogen bonds are also observed in the structure between the N1 nitrogen of the amine group on the pyridine ring and the nitrogen N4 of the nine-atom ring system, N1 — H1AA — N4 [ D · · a = 2.696 (2) a ] (fig. 11). An image of the packaging of compound a free base hemithf solvate in the unit cell is given in figure 13. There are no other unusual structural characteristics and the Fourier difference plot is featureless, showing maximum and minimum electron densities of 0.372 and-0.285 e A-3, respectively. A simulated XRPD pattern has been generated as a reference pattern for this material (fig. 14). The features of form 4 are provided in tables 5-13.

TABLE 5 Crystal data

TABLE 6

Diffraction meter	SuperNova, Daul, Cu at 0, Atlas
		Source of radiation	Supernova (Cu) X-ray, Cu K α
Data collection method	Phi and omega scanning
		Theta range of data collection	9.06-74.29 °
Range of indexes	-25≤h≤25，-15≤k≤15，-18≤l≤22
		Collected reflections	1688.5
Independent reflection	4679[R(int)=0.0375]
		Independently reflective covering	98.3%
Examining reflectance variables	N/A
		Absorption correction	Semi-empirical from equivalents
Maximum and minimum transmission	1.00000 and 0.73960
		Structural solution technology	Direct connection
Structural plan program	Bruker SHELXTL
		Refining technology	To F2Full matrix least squares
Refining procedure	Bruker SHELXTL
		Function of minimization	∑w(Fo 2-Fc 2)2
Data/limits/parameters	4679/1/335
		To F2Goodness of fit	1.010
Δ/σMaximum of	0.000
		Final R index
4292 data; i > 2 sigma (I)	R1=0.0474，wR2=0.1307
		All data	R1=0.0505，wR2=0.1348
Weighing process	Calculation w =1/[ sigma ]2(Fo 2)+(0.0900P2)+2.4199]Wherein P = (F)o 2+2Fc 2)/3
		Maximum diffraction peaks and holes	0.372 and-0.285 e Å-3

Summary of the refining

Ordered non-H atoms, XYZ	Free refining
		Ordered non-H atoms, U	Anisotropy of property
H atom (on carbon), XYZ	Idealized positions of riding on the attached atom
		H atom (on carbon), U	For the atom to be bonded, plural U (eq) are appropriate
H atom (on hetero atom), XYZ	Free refining except H6B DFIX N6
		H atom (on hetero atom), U	Isotropy
Disordered atom, OCC	Disorder, unmodeled of N6
		Disordered atom, XYZ	Disorder, unmodeled of N6
Disordered atom, U	Disorder, unmodeled of N6

TABLE 7 atomic coordinates (coordinates) and equivalent isotropic atomic substitution parameters (Å)²)

TABLE 8 selected bond length (A)

TABLE 9 selected Key Angle (^o)

TABLE 10 selected torsion Angle (^o)

TABLE 11 Anisotropic atom substitution parameters (Å)²)

TABLE 12 Hydrogen atom coordinates and Isotropic atom Displacement parameters (Å)²)

TABLE 13 selected Hydrogen bond information (Å & D)^o)

Example 13: preparation of Compound A salts and polymorphs

About 40-45 mg of compound a free base was accurately weighed and 50 volumes of the appropriate solvent was added. Solvents include dioxane, ethyl acetate, isopropyl acetate (IPAc), Isopropanol (IPA), Tetrahydrofuran (THF), Methyl Ethyl Ketone (MEK), acetone, ethanol, acetonitrile, and nitromethane. The sample was warmed to 50 ℃ for 1 hour, and various acid stock solutions were added (For exampleHCl, sulfuric acid, methanesulfonic acid, maleic acid, phosphoric acid, L-glutamic acid, L-tartaric acid, galactaric acid (mucic acid), citric acid, D-glucuronic acid, hippuric acid, D-gluconic acid, L-lactic acid, L-ascorbic acid, succinic acid, acetic acid). To form the monosalt, 1.1 equivalents of acid was added; to form the disalt, 2.1 equivalents of acid are added. The sample was held at 50 ℃ for an additional 2-3 hours, cooled to 0 ℃ at 0.1 ℃/min, and left at 0 ℃ overnight.

Example 14: polymorphs of a salt of Compound A

Various salts of compound a were prepared according to example 12, forming polymorphs with distinct XRPD patterns (fig. 49-64). Polymorphic forms of the salt of compound a were stable on storage (fig. 65-79).

Example 15: preparation of Compound A HCl salt and polymorphs

About 10 mg of compound a free base was accurately weighed and 50 volumes of the appropriate solvent was added. Solvents include dioxane, ethyl acetate, IPAc, IPA, THF, MEK, acetone, ethanol, acetonitrile and nitromethane. The samples were warmed to 50 ℃ for 1 hour, various HCl acid stock solutions were added (For exampleIn THF, ethyl acetate or ethanol). To form the monosalt, 1.1 equivalents of acid was added; and 2.1 equivalents of acid are added to form the disalt. The sample was held at 50 ℃ for an additional 4 hours, cooled to 0 ℃ at 0.1 ℃/min, and left at 0 ℃ overnight.

Example 16: preparation of Compound A HCl salt and polymorphs

HCl (1M in THF) (3.4 ml, 3.4 mmol, 3.3 equivalents) was added to a stirred suspension of compound a free base (450.3 mg, 1.04 mmol, 1 equivalent) and ethanol (22.5 ml, 50 relative volumes) over a period of 1 minute at 50 ℃. After addition of 3 ml of acid, the mixture became a solution, which remained in solution after complete addition. The mixture was stirred at 50 ℃ for 1 hour, then cooled to 0 ℃ at 0.1 ℃/min and stirred for an additional 5 hours. Aliquots were taken and the solids were isolated by vacuum filtration, suction dried and analyzed by XRPD to confirm the formation of the desired material. The remaining mixture was stirred at 0 ℃ for a further 4 hours. The solid was isolated by vacuum filtration, suction and dried at 30 ℃/5 mbar to give the desired material as a yellow solid. Table 14 shows the analysis of one polymorph of compound a HCl salt.

TABLE 14

Example 17: polymorphs of compound a HCl salt

In all solvents used, compound a formed a mono HCl salt. The mono HCl salt of compound a exhibited four distinct crystalline XRPD patterns (fig. 17A).

Compound a also formed a di-HCl salt in all solvents used. The di-HCl salt of compound a exhibited four distinct crystalline XRPD patterns (fig. 17B).

Compound a also formed a tri-HCl salt. XRPD showed the trihalochloride to be amorphous (fig. 16). Compound a tri-HCl salt is highly soluble in water. Stability studies showed that compound a, the tri-HCl salt, was partially converted to di-HCl salt and/or mono-HCl salt upon storage and exhibited distinct XRPD patterns (fig. 22).

Example 18: preparation of Compound A mesylate salt and polymorph

About 10 mg of compound a free base was weighed accurately and 50 volumes of the appropriate solvent were added. Solvents include dioxane, ethyl acetate, IPAc, IPA, THF, MEK, acetone, ethanol, acetonitrile and nitromethane. The sample was warmed to 50 ℃ for 1 hour, and various methanesulfonic acid stock solutions (were added: (1:)For exampleIn THF, ethyl acetate or ethanol). To form the monosalt, 1.1 equivalents of acid was added; and 2.1 equivalents of acid are added to form the disalt. The sample was placed at 50 ℃ for an additional 4 hours, cooled to 0 ℃ at 0.1 ℃/min, and left at 0 ℃ overnight.

Compound a mesylate salt polymorph was isolated from various solvents including, for example, THF, ethyl acetate, and ethanol. Compound a mesylate salt polymorph is highly soluble in water and is stable upon storage. No XRPD changes were observed for the polymorphic form of compound a mesylate salt prior to storage and after storage at 40 ℃ and 75% RH. Nor was any loss of methanesulfonic acid observed.

Example 19: preparation of Compound A mesylate salt and polymorph

Methanesulfonic acid (1M solution in THF) (3.4 ml, 3.4 mmol, 3.3 equivalents) was added to a stirred solution of compound a free base (450.1 mg, 1.04 mmol, 1 equivalent) in THF (22.5 ml, 50 relative volume) over a period of 1 minute at 50 ℃. A very thick precipitate formed and the stirring rate was increased to obtain a flowing suspension. The mixture was stirred at 50 ℃ for 1 hour, then cooled to 0 ℃ at 0.1 ℃/min and stirred for an additional 6 hours. Aliquots were taken and the solids were isolated by vacuum filtration, suction dried and analyzed by XRPD to confirm the formation of the desired material. The remaining mixture was stirred at 0 ℃ for a further 1 hour. The solid was isolated by vacuum filtration and dried with suction to give the desired material as a yellow solid. Table 15 shows the analysis of one polymorph of compound a mesylate.

Watch 15

Example 20: polymorph of Compound A bis-mesylate

Compound a bis-mesylate was lyophilized to yield an amorphous salt (fig. 30). The maturation of compound a bis-mesylate was carried out using various solvents under different conditions. 250mg of amorphous mesylate salt was slurried in 5 mL of the appropriate solvent. The temperature was cycled between 55 ℃ and 0 ℃ for 4 hours at each temperature. Between cycles, the temperature was adjusted to the next set temperature over 1 hour. The temperature cycle was repeated 4 times. Once the cycle was completed, the slurry was filtered and each separated solid was analyzed by XRPD. 23 solvents tested gave filterable solids. The XRPD patterns are summarized in table 16. Two distinct polymorphic forms of compound a bis-mesylate salt were identified.

TABLE 16

Solvent(s)	Polymorphic forms
		MeOH	Form A + form B (minor)
EtOH	Form A
		i-PrOH	Form B
EtOAc	Form B
		i-PrOAc	Form A
PrOAc	Form A
		BuOAc	Form A
THF	Form A
		2-MeTHF	Form A (high amorphous content)
Toluene	Solvates
		Acetonitrile	Form B
Benzonitrile	Form A
		Chloroform	Form B
1, 2-dichloroethane	Form B
		Hexafluorobenzene	Amorphous form
N-heptane	Amorphous form
		Isopropyl ether	Amorphous form
1, 2-dimethoxyethane	Form B
		Nitromethane	Form B
Isobutanol	Form B
		Acetone (II)	Form B
Methyl ethyl ketone	Form B
		Methyl isobutyl ketone	Form a (minor amount) + form B

Example 21: polymorph of Compound A bis-mesylate

Form A

A solution of compound A free base (41.06 g, 94.93 mmol, 1.0 equiv.) in THF (2.0L, 50 vol.) was treated with 1M methanesulfonic acid (208 mL, 208 mmol, 2.2 equiv.) in THF over the course of 3 min at 50 ℃. The resulting thick slurry was stirred at 50 ℃ for an additional 1 hour, then cooled to 20 ℃ and stirred at 20 ℃ for 17 hours. The resulting slurry was then filtered and the solid washed with THF (2X 300 mL) and dried under vacuum at 50 ℃ for 22 hours and at 20 ℃ for 48 hours. This gave compound a bismesylate as a pale yellow crystalline solid (58.1 g, 98% isolated yield). Alternatively, form a may be further slurried in anhydrous methanol at about 22 ℃ for up to about 48 hours to improve crystallinity.

Compound A bis-mesylate salt form A XRPD,¹H NMR, DSC, TGA, and IR data are provided as FIGS. 32-36. Form a XRPD pattern (fig. 32) by x-ray diffraction at 4.1, 7.8, 9.4, 10.1, 12.1, 15.5, 16.2, 18.8, 19.9, 21.1, 23.0, 25.1 and 27.4^o2 theta is distinguished by the observed single peak. Of the salt form A¹H NMR showed the presence of 2.41 ppm of the mesylate counterion, which corresponds to 1.87 equivalents. Ion chromatography measured 30.1% (wt) methanesulfonic acid, which corresponds to 1.94 equivalents (based on anhydrous). In that¹Residual THF was also observed in H NMR, which corresponds to OVI analysis by GC, measured as 2918 ppm THF. DSC (FIG. 34) shows a sharp endotherm with onset temperature of 305.9 ℃ and at 307Melting at 6 ℃. No significant weight loss event was observed in the TGA (figure 35) until a melting event was observed in the DSC experiment. The IR spectrum representing form a is given as fig. 36.

Additional characterization of form a is described below.

PLM analysis indicates that form a is birefringent, with needle-like morphology.

TGA shows a weight loss of about 1.47% below about 60 ℃, probably due to unbound solvent/water. No further weight loss was observed before degradation beyond about 300 ℃. DTA indicates a small endotherm beginning at about 92.2 deg.C (peak 96.1 deg.C) and a final sharp endotherm beginning at about 302.6 deg.C (peak 312.8 deg.C).

DSC analysis shows a small endothermic event starting at about 107.1 deg.C (peak 115.4 deg.C) and a final endotherm starting at about 305.1 deg.C (peak 308.2 deg.C).

Heating the form a sample to about 150 ℃, and performing XRPD analysis after heating to obtain a diffraction pattern consistent with form a. Further TG/DTA analysis was performed after heating to about 150 ℃, followed by allowing the sample to cool to ambient temperature. The analysis was consistent with the initial TG/DTA, again showing an endotherm at about 92.2 ℃. These heating experiments indicate that an endothermic event at about 92.2 ℃ may correspond to a solid-to-solid transition, wherein form a converts to a higher melting form above that temperature, i.e., a tautomeric relationship between form a and the high temperature form.

Further confirmation of this transformation was sought by variable temperature XRPD analysis (VT-XRPD) in which the sample of form a was placed in a capillary and XRPD analysis was performed at 23, 115, 150 and 200 ℃. At 23 ℃, the diffractogram was consistent with form a. At 150 and 200 ℃, a diffraction pattern different from form a was observed, indicating a conversion to a different polymorphic form. This different form is designated as form K. At 115 ℃ (transition temperature), a mixture of form a and form K was observed. VT-XRPD analysis confirmed the solid-to-solid transition at about 107.1 ℃ (peak 115.4 ℃), and the possible interconversion between the two forms.

The water content of about 1.1% was measured by Karl-Fischer titration.

An HPLC purity of 99.8% was observed.

HPLC concentration analysis indicated an aqueous solubility of about 383.4 mg/mL. XRPD analysis after slurrying form a in deionized water for about 24 hours indicated that form a converted to form E.

DVS analysis showed water absorption of about 2.4% up to 70% RH, indicating moderate hygroscopicity. No significant hysteresis was observed. XRPD analysis performed after DVS analysis gave a diffraction pattern consistent with form a, but some loss of crystallinity was observed.

No change in polymorphic form was observed after stability testing at 40 ℃/75% RH, 80 ℃ and at ambient temperature. HPLC analysis indicated a purity of about 99.8% (for 40 ℃/75% RH), about 99.8% (for 80 ℃) and about 99.7% (at ambient temperature).

Form B

Compound A free base (5.0 g, 11.56 mmol, 1.0 equiv.) in 2% H at 55 deg.C₂A slurry in O/MeOH (50 mL, 10 volumes) was treated with neat methanesulfonic acid (1.51 mL, 23.35 mmol, 2.02 equiv.). The resulting solution was stirred at 55 ℃ for 5 minutes. Adding over a period of 80 minutesi-PrOAc (95 mL), resulting in the formation of a thick slurry, which was cooled to 20 ℃ and stirred for 18 hours. Filtering the slurry, for wet cakei-PrOAc (50 mL) wash, followed by vacuum drying of the filter cake at 55 ℃ for 22 hours. The resulting solid was a white solid (7.07 g, 98% yield). By the reaction of_wForm B can be scaled up by slurrying amorphous compound a bis-mesylate in 2-propanol for about 72 hours at about 22 ℃ for 0.35.

XRPD of compound A bis-mesylate salt form B,¹H NMR, DSC, TGA, and IR data are provided as FIGS. 37-41. The XRPD pattern of form B (fig. 37) is distinguished by the dual peaks observed at 6.2 and 6.6 ° 2 θ. Of the salt form B¹H NMR (FIG. 38) showsThere was 2.39 ppm of the mesylate counterion, which corresponds to 1.91 equivalents. Ion chromatography measures 29.9% methanesulfonic acid, which corresponds to 1.92 equivalents of the mesylate salt (anhydrous basis). By passing¹H NMR observed residuali-PrOAc, corresponding to OVI analysis by GC, measuredi-PrOAc 32,783 ppm. DSC (FIG. 39) showed a broad endotherm with an onset temperature of 182.6 ℃ and melting at 194.1 ℃. The endotherm immediately followed by an exotherm with an onset temperature of 199.3 ℃ with a peak at 204.5 ℃. A second endotherm with an onset temperature of 299.9 ℃ and a second melting at 302.3 ℃ was observed. There were 3 separate weight loss events observed in TGA (figure 40). One event melting/recrystallization event observed in DSC: (<One corresponds to the melting/recrystallization event (-250 ℃) before 150 ℃), and the third occurs during the second endothermic event (-300 ℃). A representative IR spectrum of form B is given as figure 41.

Additional characterization of form B is described below.

PLM analysis indicates that form B is birefringent, with small rod/needle crystals.

TGA shows a 1.90% weight loss below about 50 ℃ followed by a 4.26% weight loss between about 50 and 130 ℃ and a further weight loss of 2.35% between about 130 and 190 ℃ after air drying at ambient temperature for 2-3 days. The DTA trace (trace) shows an initial endothermic event (peak 195.6 ℃) beginning at about 189.8 ℃, followed by an exothermic event at peak 205.7 ℃. A sharp endotherm (peak 306.8 ℃) beginning at about 303.6 ℃ was then observed. After drying under vacuum at ambient temperature for another 1 day, the TGA showed a 2.37% weight loss below about 60 ℃, followed by a 2.61% weight loss between about 60 ℃ and 140 ℃, and a further weight loss of 2.43% between about 140 ℃ and 200 ℃. The DTA trace shows an initial endothermic event (peak 193.6 ℃) beginning at about 187.3 ℃ followed by an exothermic event at peak 205.7 ℃. A sharp endotherm (peak 304.9 ℃) beginning at about 300.0 ℃ was then observed. After drying at 50 ℃ for another day, the TGA showed a weight loss of less than 0.81% at about 60 ℃, followed by a weight loss of 1.54% between about 60 ℃ and 140 ℃, and a further weight loss of 2.39% between about 140 ℃ and 200 ℃. The DTA trace shows an initial endothermic event (peak 195.0 ℃) beginning at about 189.3 ℃ followed by an exothermic event at peak 205.8 ℃. A sharp endotherm beginning at about 302.1 deg.C (peak 305.9 deg.C) was then observed.

To assess the thermal transition that occurred between about 190 ℃ and 210 ℃ (after dehydration/desolvation), a sample of form B was heated to about 250 ℃, and the resulting solid was subjected to a heated XRPD analysis. The diffraction pattern obtained was in accordance with form a.

DSC analysis shows a broad endotherm with a peak at about 108.6 ℃. A further endotherm beginning at about 172.6 ℃ (peak 186.4 ℃) was observed followed by an exotherm at peak 201.4 ℃. A final endotherm (peak 302.2 ℃) starting at about 298.1 ℃ was observed.

A water content of about 2.3% as measured by Karl-Fischer titration.

An HPLC purity of 99.7% was observed.

HPLC concentration analysis indicated an aqueous solubility of about 359 mg/mL. XRPD analysis after slurrying form B in deionized water for about 24 hours indicated that form B converted to form E.

DVS analysis indicates that some of the solvent present in form B may have been forced to be removed from the sample during the initial adsorption cycle (forced out of the sample). The desorption period indicated a gradual loss from 90% down to 0% RH. XRPD analysis performed after DVS analysis yielded diffraction patterns different from form B and all other forms previously identified. This form is designated as form J.

Form B remained unchanged with respect to the polymorphic form at ambient temperature but converted to form J at 40 ℃/75% RH and form I at 80 ℃ during the stability study. HPLC analysis indicated a purity of about 99.8% at 40 ℃/75% RH, about 99.8% at 80 ℃ and about 99.7% at ambient temperature.

Form C

Compound A free base (40.0 g, 92.48 mmol, 1.0 equiv.) in 2% H at 55 deg.C₂A slurry in O/MeOH (480 mL, 12 volumes) was treated with neat methanesulfonic acid (12.1 mL, 185.9 mmol, 2.01 equiv.) and the resulting solution was seeded with Compound A as the dimesylate salt form C. The resulting thin slurry was cooled to 50 ℃ over a 30 minute period for 1 hour, and then the mixture was cooled to 40 ℃ over a 45 minute period. The slurry was stirred at 40 ℃ for 1 hour, the heat source was removed to slowly cool the slurry to ambient temperature. After stirring at 20 ℃ for 19 hours, the slurry was filtered. The solid was dried under vacuum at 60 ℃ for 24 hours to give an off-white solid (41.52 g, 72% yield). Form C can be scaled up by slurrying compound a bis-mesylate in aqueous methanol (2% water) at 60 ℃.

XRPD of compound A bis-mesylate salt form C,¹H NMR, DSC, TGA data are provided as FIGS. 42-46. The XRPD pattern of form C (fig. 42) was distinguished by a single narrow peak observed at 6.2 ° 2 θ, followed by additional peaks starting at 8.9 °, 9.8 ° and 10.1 ° 2 θ. Of form C¹H NMR analysis (fig. 43) showed the presence of 2.41 ppm of the mesylate counterion, which corresponds to 1.92 equivalents. Ion chromatography measures 30.7% methanesulfonic acid, which corresponds to 1.99 equivalents of the mesylate salt (on an anhydrous basis). In that¹A small amount of residual MeOH was observed in the H NMR spectrum, corresponding to OVI analysis by GC, which was measured to be 552 ppm MeOH. DSC (fig. 44) showed a sharp endotherm with onset temperature of 286.1 ℃ and melting at 288.5 ℃. No significant weight loss event was observed in the TGA (figure 45) until a melting event was observed in the DSC experiment, consistent with decomposition of the sample. The IR spectrum of form C is provided as fig. 46.

DSCs of form a (fig. 47A) and form B (fig. 47B) were measured and shown in overlay (fig. 47C). A broad endotherm at about 190 ℃ followed by a sharp exotherm at 195 ℃ indicating a potential form change was observed in form B. The second endotherm occurred at 297 ℃, which is similar to the endotherm observed in form a.

The sample of form B was heated to 235 ℃, held for 15 minutes, and then cooled back to ambient temperature. XRPD analysis of the solid after heating showed that form B was no longer present (fig. 48), and the resulting pattern was consistent with the XRPD of form a.

Additional characterization of form C is described below.

PLM analysis indicates that form C is birefringent, with a small block morphology.

TG/DTA shows a sharp endotherm, starting at about 292.5 ℃ (peak 294.1 ℃), corresponding to 0.9% weight loss in the TGA trace.

DSC analysis shows a single endothermic event, starting at about 291.8 ℃ (peak 294.6 ℃).

The water content of about 0.3% was measured by Karl-Fischer titration.

An HPLC purity of 99.7% was observed.

HPLC concentration analysis indicated an aqueous solubility of about 367 mg/mL. XRPD analysis of the material after slurrying in deionized water for about 24 hours indicated that form C converted to form E.

DVS analysis indicates total water absorption of about 0.54% up to 90% RH, which indicates that the material is non-hygroscopic. XRPD analysis performed after DVS analysis indicated a diffraction pattern consistent with form C.

No change in polymorphic form was observed after stability testing at 40 ℃/75% RH, 80 ℃ and at ambient temperature. HPLC analysis indicated a purity of about 99.9% (for 40 ℃/75% RH), about 99.9% (for 80 ℃) and about 99.9% (at ambient temperature).

Observe that¹The H NMR spectrum was consistent with the material received.

Example 22: solubility in solvent

The amorphous form of compound a bis-mesylate was used as input material for solubility screening. The solubility values were estimated by solvent addition technique (solvent addition technique) to provide approximate values for generating slurries during subsequent experiments. About 15 mg of amorphous material was weighed into 24 vials. Each solvent was added to the appropriate vial in 10 aliquots of 10 μ l, 5 aliquots of 20 μ l, 3 aliquots of 100 μ l and 1 aliquot of 500 μ l or until the material was dissolved. Between additions, the sample was heated to 40 ℃. To a vial that already contained 1000 μ l of solvent but still had observable solid material, an additional aliquot of 1000 μ l of solvent was added. The solubility was calculated to be below this point if 2000 μ l of solvent had not dissolved the solids.

The selected solvent systems for solubility screening are shown in Table 177-1.

TABLE 17-1 solvent systems selected for solubility screening

	Solvent system	ICH class
			1	Acetone (II)	3
2	Acetonitrile	2
			3	1-Butanol	3
4	Cyclohexane	2
			5	Methylene dichloride	2
6	Dimethyl sulfoxide	3
			7	Diisopropyl ether	Is unknown
8	1, 4-dioxane	2
			9	Ethanol	3
10	2-Ethoxyethanol	2
			11	Ethyl acetate	3
12	N-heptane	3
			13	Acetic acid isopropyl ester	3
14	2-methyl THF	Is unknown
			15	Methanol	2
16	Methyl ethyl ketone	3
			17	Methyl isobutyl ketone	3
18	2-propanol	3
			19	Tert-butyl methyl ether	3
20	Tetrahydrofuran (THF)	2
			21	Toluene	2
22	Water (W)	N/A
			23	Acetone water (90:10)	3
24	2-propanol water (50:50)	3

The solubility of Compound A, the dimesylate salt, is shown in Table 17-2 below.

TABLE 17-2

Solvent system	Solubility (mg/mL), 40 deg.C
			Acetone (II)	< 8	Some solubility was observed, based on a very pale yellow solution
Acetonitrile	< 8	Some solubility was observed, based on a very pale yellow solution
			1-Butanol	< 8	Some solubility was observed, based on a very pale yellow solution
Cyclohexane	< 8	Colorless solution
			Methylene dichloride	< 8	Colorless solution
Dimethyl sulfoxide	About 126	Good solubility
			Diisopropyl ether	< 8	Colorless solution
1, 4-dioxane	< 8	Colorless solution
			Ethanol	< 8	Some solubility was observed, based on a very pale yellow solution
2-Ethoxyethanol	< 8	Some solubility was observed, based on a very pale yellow solution
			Ethyl acetate	< 8	Some solubility was observed, based on a very pale yellow solution
Heptane (Heptane)	< 8	Colorless solution
			Acetic acid isopropyl ester	< 8	Colorless solution
2-methyl THF	< 8	Colorless solution
			Methanol	About 40	Good solubility
Methyl ethyl ketone	< 8	Colorless solution
			Methyl isobutyl ketone	< 8	Colorless solution
2-propanol	About 25	Good solubility
			Tert-butyl methyl ether	< 8	Colorless solution
Tetrahydrofuran (THF)	< 8	Some solubility was observed, based on a very pale yellow solution
			Toluene	< 8	Colorless solution
Water (W)	About 769	Good solubility
			Acetone water (90:10)	About 16	Good solubility
2-propanol water (50:50)	About 400	Good solubility

Example 23: primary polymorph screening-selected solvent systems for polymorph screening

The solvent system listed in Table 18-1 was selected for polymorph sieving.

TABLE 18-1 solvent systems selected for polymorph sieving

	Solvent system			Solvent system
					1	Acetone (II)		16	Methanol
2	Acetone water (95:5)		17	Methanol water (98:2)
					3	Acetone water (90:10)		18	Methanol water (80:20)
4	Acetone water (50:50)		19	1-propanol
					5	Acetonitrile		20	1-propanol: water (90:10)
6	Acetonitrile water (90:10)		21	1-propanol: water (50:50)
					7	Acetonitrile water (50:50)		22	2-propanol
8	1-Butanol		23	2-propanol water (98:2)
					9	Dimethyl sulfoxide		24	2-propanol water (90:10)
10	1, 4-dioxane Water (80:20)		25	2-propanol water (50:50)
					11	Ethanol		26	Tetrahydrofuran (THF)
12	Ethanol water (90:10)		27	Tetrahydrofuran water (95:5)
					13	Ethanol water (50:50)		28	Tetrahydrofuran water (70:30)
14	2-Ethoxyethanol		29	Water (W)
					15	Ethyl acetate

Slow cooling experiment

About 150 mg of amorphous compound a was weighed in each of 29 vials, and an appropriate volume of solvent was added to prepare a slurry, which was stirred at 60 ℃ for about 48 hours to obtain a thermodynamically equilibrated system. The slurry was then filtered and the solution was divided into 3 portions. One portion was subjected to slow cooling from about 60 ℃ to 5 ℃ at a rate of 0.3 ℃/min with stirring. Any solid material was subsequently recovered and analyzed by PLM and XRPD. Fig. 155-160.

Quenching experiment

A quench experiment was performed in each of the 29 selected solvent systems using a saturated solution prepared as described in the slow cooling experiment by placing the solution in an environment of about 2 ℃ and about-18 ℃ for a minimum of 72 hours. Any solid material was subsequently recovered and analyzed by PLM and XRPD. Fig. 148 and 154.

Anti-solvent Addition Experiments (Anti-solvent Addition Experiments)

The anti-solvent addition experiment was conducted at ambient (about 22 ℃) by adding the anti-solvent (acetone) to a saturated filtered solution of amorphous compound a bis-mesylate salt in each of 29 selected solvent systems. Addition of the anti-solvent is continued until there is no further precipitation or until no more anti-solvent can be added to the vial. Any solid material was recovered and analyzed by PLM and XRPD. Fig. 161-168.

Evaporation experiment

The evaporation experiment was performed by evaporating the solution in each of the 29 solvent systems at ambient conditions (about 22 ℃) using a saturated solution prepared as described in the slow cooling experiment. After the solvent had evaporated to dryness, any solid material was subsequently recovered and analyzed by PLM and XRPD. FIG. 169-.

The results of the polymorph screening are shown in Table 18-2.

TABLE 18-2

As indicated in table 18-2:

from the cooling and evaporation experiments, form a was observed in methanol and methanol/water solvent systems.

Form B was observed by various experiments in ethanol, ethanol/water, methanol/water, 1-propanol/water, 2-propanol/water and acetonitrile/water solvent systems.

Form D was observed by various experiments in acetone/water, acetonitrile/water, 1, 4-dioxane/water, ethanol/water, methanol/water, 1-propanol/water, 2-propanol/water, tetrahydrofuran/water, and water.

Form G was observed in DMSO using acetone as the anti-solvent, added from the anti-solvent.

For several evaporation experiments amorphous material was observed.

Example 24: hydration screening

Based on chemical diversity, the solvents listed in table 19 were selected for hydration screening.

TABLE 19 solvents selected for hydration sieving

Solvent(s)	Class of solvents
		Acetone (II)	3
Acetonitrile	2
		2-propanol	3

The water activities shown in table 20 were calculated for the hydration sieve at 10 ℃, 25 ℃ and 50 ℃ in each solvent. The temperature is selected to cover the desired crystallization temperature range. Separate high (targeting 150 mg/mL) and low (targeting 75 mg/mL) slurry concentration experiments were performed.

TABLE 20 Water Activity calculated at 10 deg.C, 25 deg.C and 50 deg.C for each solvent

Hydration screening procedure

About 75-150 mg (solubility dependent) of amorphous compound a bis-mesylate material was weighed into each of 108 vials and slurried in each solvent, water system, with 6 different water activities at 10 ℃, 25 ℃ and 50 ℃. FIG. 178-189.

Low slurry concentration experiments were first performed, adding up to 1 mL of 0.1-0.6 water-active solvent to 75 mg. For 0.7-0.9 water activity, up to 100. mu.L of solvent was added to 75 mg. Second, a high slurry concentration experiment was performed, adding about the same volume of solvent to 150 mg.

The slurries were stirred at their partitioning temperature for about 48 hours, then separated and allowed to dry at ambient conditions, then analyzed by XRPD to identify the form of the resulting solid material. The material is more soluble in higher water-reactive solvent systems; thus, additional solids are added, if necessary, to form a slurry.

Example 25: alternative preparation of form a

About 13.3 mL of anhydrous methanol was added to 1 g of the amorphous form of compound a dimesylate to prepare a slurry. The slurry was stirred at about 22 ℃ for about 2 days, after which the sample was filtered and allowed to dry at ambient temperature before characterization.

Example 26: alternative preparation of form B

About 13.3 mL of 2-propanol having a water activity of 0.35 was added to 1 g of the amorphous form of compound a bis-mesylate salt to prepare a slurry. The slurry was stirred at about 22 ℃ for about 3 days, after which the sample was filtered and allowed to dry at ambient temperature before characterization.

Example 27: alternative preparation of form C

About 5 mL of 2% aqueous methanol was added to 1 g of compound a, form a, as a dimesylate salt, to prepare a slurry, which was stirred at about 60 ℃ for about 3 days. The sample was then filtered and allowed to dry at ambient temperature before characterization.

Example 28: preparation of form D

About 13.3 mL of 2-propanol having 0.6 water activity was added to 1 g of the amorphous form of compound a bis-mesylate salt to prepare a slurry. The slurry was stirred at about 22 ℃ for about 3 days. The sample was then filtered and allowed to dry at ambient temperature before characterization.

Example 29: preparation of form E

About 1.2 mL of 2-propanol having a water activity of 0.89 was added to 1 g of the amorphous form of compound a dimesylate to prepare a slurry. The slurry was stirred at about 22 ℃ for about 3 days, after which the sample was filtered and allowed to dry at ambient temperature before characterization.

Example 30: preparation of form I

Approximately 5 g of the received material compound a, form a, as the bis-mesylate salt, was dissolved in 50 mL of anhydrous methanol. The solution was then evaporated in a vacuum oven at about 50 ℃ to give a solid.

Example 31: stability test

Form A, form B, form C, form D, form E and form I were exposed to 40 ℃/75% RH, ambient light (about 22 ℃) and elevated temperature (80 ℃) for 1 week to determine stability. The resulting solid was analyzed by XRPD to determine if any formal change had occurred, and by HPLC to determine purity.

Example 32: water solubility study

The slurries of form a, form B, form C, form D, form E and form I were produced in deionized water and shaken at ambient temperature (about 22 ℃) for about 24 hours. The resulting solution was then analyzed by HPLC to determine water solubility. The remaining solids were analyzed by XRPD to determine if any formal changes had occurred during slurrification.

Example 33: characterization of form D

By the reaction of_wAmorphous compound a bis-mesylate material was slurried in 2-propanol at about 22 ℃ for about 72 hours in = 0.60, scale up form D (fig. 190).

PLM analysis indicated that the material was birefringent, with flat rod/plate-like morphology (fig. 191).

After air drying at ambient temperature for about 3 days, the TG/DTA showed an initial endotherm, which began at about 50.3 ℃ (peak 71.3 ℃), corresponding to a 7.10% weight loss in the TG trace. A further 1.24% progressive weight loss was observed between about 75 ℃ and 220 ℃. The DTA trace also shows a small endotherm/exotherm event between about 222 ℃ and 235 ℃, a small endotherm at about 281.4 ℃ and a final sharp endotherm beginning at about 307.3 ℃ (peak 310.7 ℃ (fig. 192). After vacuum drying at ambient temperature for another 1 day, the TG/DTA showed an initial endotherm, which began at about 45.1 ℃ (peak 63.7 ℃), corresponding to a 4.09% weight loss in the TG trace. A further progressive weight loss of 0.81% was observed between about 75 ℃ and 180 ℃. The DTA trace also shows a small endothermic/exothermic event between about 221 ℃ and 235 ℃ and a final sharp endotherm starting at about 306.0 ℃ (peak 309.8 ℃) (fig. 193).

To assess the forms obtained after dehydration and after the thermal transition that occurred between about 229 ℃ and 235 ℃, in one experiment the sample of form D was heated to about 150 ℃ and in a second experiment the sample of form D was heated to 260 ℃. XRPD analysis of the resulting solid after heating gave diffraction patterns consistent with form I and form a, respectively, for the 150 ℃ and 260 ℃ experiments (fig. 195).

DSC analysis showed an initial broad endotherm, which started at about 71.9 ℃ (peak 103.2 ℃). A small endothermic/exothermic event was observed between about 229 ℃ and 235 ℃. A final endotherm was observed, which started at about 300.9 ℃ (peak 304.1 ℃) (fig. 194).

The water content of about 3.8% was measured by Karl-Fischer titration.

An HPLC purity of 99.9% was observed (fig. 199).

HPLC concentration analysis indicated an aqueous solubility of about 352 mg/mL. XRPD analysis of the material after slurrying in deionized water for about 24 hours indicated that form D had converted to form E (fig. 198).

By DVS analysis, after dehydration at 0% RH, the second adsorption period appeared to indicate rehydration between 30% and 50% RH, with about 12% water uptake. Desorption isotherms, indicating that as the relative humidity decreased below 40% RH, water was progressively lost as the material was hydrated, so dehydration was observed (fig. 196). XRPD analysis performed after DVS analysis yielded a diffraction pattern consistent with form I (fig. 197).

During the stability study, form D remained unchanged for the polymorphic form at ambient temperature, but was converted to form J at 40 ℃/75% RH and to form I at 80 ℃ (figure 203). HPLC analysis indicated a purity of about 99.9% (fig. 200) at 40 ℃/75% RH, about 99.9% (fig. 202) at 80 ℃ and about 99.9% (fig. 201) at ambient.

Observe that¹The H NMR spectrum was consistent with the material received with a small amount of 2-propanol present. API: the ratio of 2-propanol was about 1:0.25 (fig. 204).

By characterization, form D was thus observed as a potential mixed hydrate and solvate.

Example 34: characterization of form E

By the reaction of_wAmorphous compound a bis-mesylate material was slurried in acetone for about 72 hours at about 22 ℃ in acetone, scaling up form E (figure 205).

PLM analysis indicated that the material was birefringent with long rod-like morphology (fig. 206).

After air drying at ambient temperature for about 3 days, the TG/DTA showed an initial endotherm, which began at about 45.9 ℃ (peak 71.9 ℃), corresponding to 7.7% weight loss in the TG trace. The DTA trace also shows an endothermic/exothermic event between about 192 ℃ and 220 ℃ and a final sharp endotherm starting at about 299.5 ℃ (peak 305.4 ℃) (fig. 207). After vacuum drying at ambient temperature for another 1 day, TG/DTA showed an initial endotherm, which began at about 39.8 ℃ (peak 59.8 ℃), corresponding to 4.8% weight loss in the TG trace. The DTA trace also shows an endothermic/exothermic event between about 192 ℃ and 220 ℃ and a final sharp endotherm beginning at about 301.4 ℃ (peak 305.0 ℃ (figure 208).

To assess the form obtained after dehydration of form E, the sample was heated to about 150 ℃ in one experiment and 260 ℃ in a second experiment. XRPD analysis after heating showed that form E remained unchanged for the 150 ℃ experiment, but was converted to form a at 260 ℃ (fig. 211). As a result, TG/DTA was performed again on the sample that had been heated to 150 ℃ and cooled back to ambient temperature (fig. 209). TG/DTA analysis showed thermal events consistent with the original form E sample before vacuum drying. This indicates that after dehydration, the material regains water/rehydration upon exposure to ambient conditions.

DSC analysis showed a broad endotherm, which started at about 58.1 ℃ (peak 86.5 ℃). An endothermic/exothermic event was observed between about 189 ℃ and 215 ℃. There was a final endothermic event that started at about 299.1 ℃ (peak 303.7 ℃) (graph 210).

KF analysis indicated a water content of about 6.2%.

An HPLC purity of 99.8% was observed (fig. 215).

HPLC concentration analysis indicated an aqueous solubility of about 347 mg/mL.

XRPD analysis of the material after slurrying in deionized water for about 24 hours indicated that form E remained unchanged (fig. 214).

During DVS analysis, the first adsorption period indicates that form E hydrate is non-hygroscopic. Dehydration occurs below 10% RH during the desorption period. During the second adsorption period, about 2.78% water uptake (corresponding to 1 molar equivalent of water) was observed below 20% RH (fig. 212 and 213). Another 5.5% water was then rapidly absorbed between 20% and 40% RH, which is likely indicative of further hydration.

Form E remained unchanged for the polymorphic form during the stability study at 40 ℃/75% RH and ambient. After storage at 80 ℃, some differences were observed by XRPD analysis compared to form E, probably due to dehydration during storage (figure 219). HPLC analysis indicated a purity of about 99.8% at 40 ℃/75% RH (fig. 216), about 99.8% at 80 ℃ (fig. 218), and about 99.7% at ambient temperature (fig. 217).

Observe that¹The H NMR spectrum was consistent with the received material (fig. 220).

By characterization, form E was thus observed to be a hydrate.

Example 35: characterization of form F

Form F was observed during hydration sieving in acetonitrile with 0.76 water activity at 25 ℃. Form F samples from hydration screens were analyzed by TG/DTA: TG/DTA from form F of the hydrated sieve showed an initial weight loss of 6.53% between about 25 and 120 ℃. Multiple endothermic and exothermic events were observed in DTA (fig. 221).

From limited characterization, form F may be a potential solvate/hydrate.

Example 36: characterization of form G

During polymorph sieving, form G was observed in DMSO, added by an anti-solvent (acetone). Form G samples from polymorphic sieving were analyzed by TG/DTA: TG/DTA from polymorph sieved form G showed a weight loss of 10.66% between about 25 and 200 ℃. Very small endothermic events were observed in DTA between 150 and 180 deg.C (FIG. 222).

From the data, form G could be DMSO solvate.

Example 37: characterization of form H

Form H was observed during hydration sieving in acetonitrile with 0.21 water activity at 50 ℃. Analysis of form H samples from hydration screens by TG/DTA: TG/DTA from hydrated sieved form H showed an initial weight loss of about 3.58% between about 25 and 60 ℃. A further weight loss of about 0.95% was observed between 60 and 240 ℃. The DTA trace shows an initial endotherm at about 45.8 ℃, an exotherm at about 202 ℃ and a final endotherm beginning at about 306.6 ℃ (peak 309.8 ℃) (fig. 223).

Form H may be a solvate/hydrate with limited characterization.

Example 38: characterization of form I

Form I was scaled up by evaporating a solution of compound a, the bis-mesylate salt in methanol at about 50 ℃ under vacuum (fig. 224).

PLM analysis indicated that the material was birefringent with rod-like morphology (fig. 225).

TG/DTA shows two very small endothermic events at about 96.3 ℃ and about 239.4 ℃. A final endotherm was then observed, which started at about 307.1 ℃ (peak 310.1 ℃). A small 0.4% weight loss was observed below about 60 ℃, which is likely due to unbound solvent/water (fig. 226).

DSC analysis showed a small endothermic event, beginning at about 231.9 ℃ (peak 235.7 ℃), followed by a final endotherm, beginning at about 303.7 ℃ (peak 306.3 ℃) (fig. 227).

The water content of about 0.8% was measured by Karl-Fischer titration.

An HPLC purity of 99.6% was observed (fig. 231).

HPLC concentration analysis indicated an aqueous solubility of about 368 mg/mL. XRPD analysis of the material after slurrying in deionized water for about 24 hours indicated that form I had converted to form E (fig. 230).

By DVS analysis, the adsorption period appears to indicate hydration above 40% RH, with about 10% water uptake between 40% and 50% RH. The desorption period indicates a progressive loss of water/dehydration below 50% RH (fig. 228-.

During the stability study, form I remained unchanged for the polymorphic form at ambient and 80 ℃ storage, but conversion to form J was observed for 40 ℃/75% RH storage (fig. 235). HPLC analysis indicated a purity of about 99.8% (fig. 232) at 40 ℃/75% RH, about 99.9% (fig. 234) at 80 ℃ and about 99.6% (fig. 233) at ambient temperature.

Observe that¹The H NMR spectrum was consistent with the material received (fig. 236).

By characterization, form I was thus observed to be anhydrous.

Example 39: characterization of form J

After DVS analysis of form B, further polymorphic forms were observed. This form is designated form J (fig. 237).

TGA shows about 2.76% weight loss below about 90 ℃. The DTA trace shows an initial endothermic event with a peak at about 76.3 ℃ and a small endothermic event with a peak at about 227.3 ℃ followed by an exothermic event with a peak at about 233.3 ℃. A sharp endotherm was then observed, which started at about 306.5 ℃ (peak 309.6 ℃) (fig. 238).

By limited characterization, form J may be a hydrate.

Example 40: summary of each of the characterized forms

A summary of the characterization of the successfully prepared forms is presented in table 21 below.

TABLE 21 summary of characterization of polymorphs

Characterization of the various forms led to additional forms identified after DVS analysis of form B, designated as form J. Variable temperature XRPD analysis of form a also indicated a different form at temperatures above about 107 ℃, designated form K.

Claims (69)

1. A polymorph of compound a mesylate salt selected from form a, form B, form C, form D, form E, form F, form G, form H, form I, form J, and form K, wherein:

said form a is characterized by X-ray powder diffraction peaks at about 9.4 and 23.0 degrees 2 theta using Cu ka radiation, or cuka radiation at 9.1 and 22.8 degrees 2 theta,

said form B is characterized by X-ray powder diffraction peaks at about 6.2 and 14.3 degrees 2 theta using Cu Ka radiation, or at 6.0 and 14.6 degrees 2 theta using CuKa radiation,

said form C is characterized by X-ray powder diffraction peaks at about 20.3 and 22.8 degrees 2 theta using Cu Ka radiation, or by X-ray powder diffraction peaks at 20.1 and 22.6 degrees 2 theta using Cu Ka radiation,

said form D is characterized by X-ray powder diffraction peaks at about 14.5 and 23.0 degrees 2 theta using Cu Ka radiation,

said form E is characterized by X-ray powder diffraction peaks at about 20.9 and 21.9 degrees 2-theta using Cu Ka radiation,

said form F is characterized by X-ray powder diffraction peaks at about 16.7 and 17.0 degrees 2 theta using Cu Ka radiation,

said form G is characterized by X-ray powder diffraction peaks at about 5.8 and 22.1 degrees 2 theta using Cu Ka radiation,

said form H is characterized by X-ray powder diffraction peaks at about 10.9 and 22.8 degrees 2 theta using Cu Ka radiation,

said form I characterized by X-ray powder diffraction peaks at about 5.2 and 10.5 degrees 2 theta using Cu Ka radiation,

said form J is characterized by X-ray powder diffraction peaks at about 17.0 and 22.8 degrees 2 θ using Cu Ka radiation, and

the crystalline form K is characterized by X-ray powder diffraction peaks at about 9.2 and 10.0 ° 2 Θ using Cu ka radiation.

2. The polymorph of claim 1 wherein said form a is characterized by X-ray powder diffraction peaks at about 9.4, 15.5, 18.8, and 23.0 ° 2 Θ using Cu ka radiation.

3. The polymorph of claim 2 wherein said form a is characterized by X-ray powder diffraction peaks at about 4.1, 7.8, 9.4, 10.1, 12.1, 15.5, 16.2, 18.8, 19.9, 21.1, 23.0, 25.1 and 27.4 ° 2 Θ using Cu ka radiation.

4. The polymorph of claim 1, wherein said form A is characterized by an X-ray powder diffraction pattern substantially similar to that shown in figure 32.

5. The polymorph of claim 1 wherein said form a is characterized by X-ray powder diffraction peaks at about 9.1, 15.1, 16.0, 18.5, 22.8, and 22.9 ° 2 Θ using Cu ka radiation.

6. The polymorph of claim 5 wherein said form A is characterized by X-ray powder diffraction peaks at about 3.8, 7.6, 9.1, 9.9, 15.1, 16.0, 16.1, 18.5, 22.8, 22.9, and 23.2 ° 2 θ using Cu Ka radiation.

7. The polymorph of claim 6, wherein said form A is characterized by X-ray powder diffraction peaks as shown in figure 112.

8. The polymorph of claim 1, wherein said form A is characterized by an X-ray powder diffraction pattern substantially similar to that shown in figure 110.

9. The polymorph of claim 1 wherein said form B is characterized by X-ray powder diffraction peaks at about 6.2, 6.6, 14.3, and 15.3 ° 2 θ using Cu Ka radiation.

10. The polymorph of claim 9 wherein said form B is characterized by X-ray powder diffraction peaks at about 6.2, 6.6, 11.3, 14.3, 15.3, 22.8, and 26.9 ° 2 Θ using Cu ka radiation.

11. The polymorph of claim 1, wherein said form B is characterized by an X-ray powder diffraction pattern substantially similar to that shown in figure 37.

12. The polymorph of claim 1 wherein said form B is characterized by X-ray powder diffraction peaks at about 6.0, 6.4, 11.1, 14.6, 15.1, and 23.7 ° 2 θ using Cu Ka radiation.

13. The polymorph of claim 12 wherein said form B is characterized by X-ray powder diffraction peaks at about 6.0, 6.4, 11.1, 14.6, 15.1, 17.3, 22.5, 22.7, 23.7, and 27.0 ° 2 Θ using Cu ka radiation.

14. The polymorph of claim 13, wherein said form B is characterized by X-ray powder diffraction peaks as shown in figure 131.

15. The polymorph of claim 1, wherein said form B is characterized by an X-ray powder diffraction pattern substantially similar to that shown in figure 129.

16. The polymorph of claim 1 wherein said form C is characterized by X-ray powder diffraction peaks at about 17.6, 18.4, 19.3, 19.7, and 22.8 ° 2 θ using Cu Ka radiation.

17. The polymorph of claim 16 wherein said form C is characterized by X-ray powder diffraction peaks at about 6.2, 8.9, 9.8, 10.1, 13.7, 18.4, 19.3, 19.7, 22.8, and 26.8 ° 2 Θ using Cu ka radiation.

18. The polymorph of claim 1, wherein said form C is characterized by an X-ray powder diffraction pattern substantially similar to that shown in figure 42.

19. The polymorph of claim 1 wherein said form C is characterized by X-ray powder diffraction peaks at about 17.5, 18.2, 19.0, 19.6, 20.1, and 22.6 ° 2 θ using Cu Ka radiation.

20. The polymorph of claim 19 wherein said form C is characterized by X-ray powder diffraction peaks at about 12.5, 16.6, 17.5, 18.2, 19.0, 19.6, 20.1, 21.7, 22.6, 23.0, 23.6, 24.0, 26.6 and 27.2 ° 2 Θ using Cu ka radiation.

21. The polymorph of claim 20, wherein said form C is characterized by X-ray powder diffraction peaks as shown in figure 147.

22. The polymorph of claim 1, wherein said form C is characterized by an X-ray powder diffraction pattern substantially similar to that shown in figure 145.

23. The polymorph of claim 1 wherein said form D is characterized by X-ray powder diffraction peaks at about 5.9, 11.5, 14.5, 20.3, and 23.0 ° 2 θ using Cu Ka radiation.

24. The polymorph of claim 23 wherein said form D is characterized by X-ray powder diffraction peaks at about 5.4, 5.9, 11.5, 14.5, 17.9, 20.3, 23.0, 23.6, 24.0, 26.2, 27.8, and 28.9 ° 2 Θ using Cu ka radiation.

25. The polymorph of claim 24, wherein said form D is characterized by X-ray powder diffraction peaks as shown in figure 241.

26. The polymorph of claim 1, wherein said form D is characterized by an X-ray powder diffraction pattern substantially similar to that shown in figure 239.

27. The polymorph of claim 1 wherein said form E is characterized by X-ray powder diffraction peaks at about 13.7, 20.6, 20.9, 21.9, and 23.0 ° 2 θ using Cu Ka radiation.

28. The polymorph of claim 27 wherein said form E is characterized by X-ray powder diffraction peaks at about 8.9, 11.3, 13.7, 16.5, 19.3, 20.6, 20.9, 21.9, 23.0, 23.8, and 26.2 ° 2 Θ using Cu ka radiation.

29. The polymorph of claim 28, wherein said form E is characterized by X-ray powder diffraction peaks as shown in figure 244.

30. The polymorph of claim 1, wherein said form E is characterized by an X-ray powder diffraction pattern substantially similar to that shown in figure 242.

31. The polymorph of claim 1 wherein said form F is characterized by X-ray powder diffraction peaks at about 16.7, 17.0, 19.5, 20.3, and 24.4 ° 2 θ using Cu Ka radiation.

32. The polymorph of claim 31 wherein said form F is characterized by X-ray powder diffraction peaks at about 4.8, 7.2, 15.6, 16.7, 17.0, 19.5, 20.3, 21.7, 24.0, and 24.4 ° 2 Θ using Cu ka radiation.

33. The polymorph of claim 32, wherein said form F is characterized by X-ray powder diffraction peaks as shown in figure 247.

34. The polymorph of claim 1, wherein said form F is characterized by an X-ray powder diffraction pattern substantially similar to that shown in figure 245.

35. The polymorph of claim 1 wherein said form G is characterized by X-ray powder diffraction peaks at about 5.8, 14.9, 16.3, 22.1, and 23.7 ° 2 θ using Cu Ka radiation.

36. The polymorph of claim 35 wherein said form G is characterized by X-ray powder diffraction peaks at about 5.8, 10.8, 14.9, 16.3, 17.7, 22.1, 23.1, 23.7, 24.5, and 26.5 ° 2 Θ using Cu ka radiation.

37. The polymorph of claim 36, wherein said form G is characterized by X-ray powder diffraction peaks as shown in figure 250.

38. The polymorph of claim 1 wherein said form G is characterized by an X-ray powder diffraction pattern substantially similar to that shown in figure 248.

39. The polymorph of claim 1 wherein said form H is characterized by X-ray powder diffraction peaks at about 6.1, 10.9, 12.4, 15.9, and 22.8 ° 2 θ using Cu Ka radiation.

40. The polymorph of claim 39 wherein said form H is characterized by X-ray powder diffraction peaks at about 6.1, 10.1, 10.9, 12.4, 15.7, 15.9, 16.4, 20.4, 20.8, and 22.8 ° 2 θ using Cu Ka radiation.

41. The polymorph of claim 40, wherein said form H is characterized by X-ray powder diffraction peaks as shown in figure 253.

42. The polymorph of claim 1, wherein said form H is characterized by an X-ray powder diffraction pattern substantially similar to that shown in figure 251.

43. The polymorph of claim 1 wherein said form I is characterized by X-ray powder diffraction peaks at about 5.2, 6.2, 10.5, 20.2, and 23.0 ° 2 θ using Cu Ka radiation.

44. The polymorph of claim 43 wherein said form I is characterized by X-ray powder diffraction peaks at about 5.2, 6.2, 10.5, 11.1, 13.6, 20.2, 22.0, 22.3, 23.0, and 23.8 ° 2 θ using Cu Ka radiation.

45. The polymorph of claim 44, wherein said form I is characterized by X-ray powder diffraction peaks as shown in figure 256.

46. The polymorph of claim 1, wherein said form I is characterized by an X-ray powder diffraction pattern substantially similar to that shown in figure 254.

47. The polymorph of claim 1 wherein said form J is characterized by X-ray powder diffraction peaks at about 14.6, 17.0, 21.9, 22.8, and 24.8 ° 2 θ using Cu Ka radiation.

48. The polymorph of claim 47, wherein said form J is characterized by X-ray powder diffraction peaks at about 14.6, 17.0, 19.7, 20.4, 21.9, 22.8, 24.8, 25.3, 26.7, and 27.7 ° 2 θ using Cu Ka radiation.

49. The polymorph of claim 48, wherein said form J is characterized by X-ray powder diffraction peaks as shown in figure 259.

50. The polymorph of claim 1, wherein said form J is characterized by an X-ray powder diffraction pattern substantially similar to that shown in figure 257.

51. The polymorph of claim 1 wherein said form K is characterized by X-ray powder diffraction peaks at about 9.2, 10.0, 15.7, 20.0, and 23.8 ° 2 Θ using Cu ka radiation.

52. The polymorph of claim 51, wherein said form K is characterized by X-ray powder diffraction peaks at about 4.1, 9.2, 10.0, 15.7, 17.5, 19.3, 20.0, 21.5, 23.2, and 23.8 ° 2 θ using Cu Ka radiation.

53. The polymorph of claim 52, wherein said form K is characterized by X-ray powder diffraction peaks as shown in figure 262.

54. The polymorph of claim 1, wherein said form K is characterized by an X-ray powder diffraction pattern substantially similar to that shown in figure 260.

55. A polymorph of compound a free base selected from form 1, form 2, form 3, and form 4, wherein:

said form 1 is characterized by an X-ray powder diffraction peak at about 22.0 and 25.0 degrees 2 theta using Cu ka radiation,

said form 2 is characterized by an X-ray powder diffraction peak at about 18.4 and 19.3 degrees 2 theta using Cu ka radiation,

said form 3 is characterized by an X-ray powder diffraction peak at about 15.1 and 23.4 degrees 2 theta using Cu Ka radiation, and

the crystalline form 4 is characterized by X-ray powder diffraction peaks at about 17 and 23 ° 2 Θ using Cu ka radiation.

56. The polymorph of claim 55, wherein said form 1 is characterized by X-ray powder diffraction peaks at about 8.3, 17.1, 22.0, and 25.0 ° 2 θ using Cu Ka radiation.

57. The polymorph of claim 56 wherein said form 1 is characterized by X-ray powder diffraction peaks at about 8.3, 9.5, 12.9, 14.1, 15.2, 16.6, 17.1, 19.2, 19.4, 19.6, 21.2, 22.0, 22.4 and 25.0 ° 2 θ using Cu Ka radiation.

58. The polymorph of claim 55, wherein said form 1 is characterized by an X-ray powder diffraction pattern substantially similar to that shown in figure 2.

59. The polymorph of claim 55 wherein said form 2 is characterized by X-ray powder diffraction peaks at about 15.8, 18.4, 19.3, and 20.1 ° 2 θ using Cu Ka radiation.

60. The polymorph of claim 59 wherein said form 2 is characterized by X-ray powder diffraction peaks at about 8.3, 8.8, 11.6, 13.3, 15.8, 18.4, 19.3, 20.1, 20.9, 21.4, 23.2, 25.9, and 26.6 ° 2 θ using Cu Ka radiation.

61. The polymorph of claim 55, wherein said form 2 is characterized by an X-ray powder diffraction pattern substantially similar to that shown in figure 3.

62. The polymorph of claim 55 wherein said form 3 is characterized by X-ray powder diffraction peaks at about 15.1, 18.8, 21.0, and 23.4 ° 2 θ using Cu Ka radiation.

63. The polymorph of claim 62, wherein said form 3 is characterized by X-ray powder diffraction peaks at about 6.4, 7.6, 8.4, 11.7, 15.1, 16.7, 18.8, 21.0, and 23.4 ° 2 θ using Cu Ka radiation.

64. The polymorph of claim 55, wherein said form 3 is characterized by an X-ray powder diffraction pattern substantially similar to that shown in figure 3.

65. The polymorph of claim 55, wherein said form 4 is characterized by X-ray powder diffraction peaks at about 15, 17, 23, and 26 ° 2 θ using Cu Ka radiation.

66. The polymorph of claim 65, wherein said form 4 is characterized by X-ray powder diffraction peaks at about 8, 14, 15, 17, 22, 23, and 26 ° 2 θ using Cu Ka radiation.

67. The polymorph of claim 55, wherein said form 4 is characterized by an X-ray powder diffraction pattern substantially similar to that shown in figure 14.

68. A pharmaceutical composition comprising a polymorph according to claim 1 or claim 55, and a pharmaceutically acceptable diluent, excipient or carrier.

69. A method of treating or preventing a cell proliferative disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the polymorph of claim 1 or claim 55.