阅读说明：本技术 一种盐的结晶性固体形式、制备工艺和使用方法 (Crystalline solid form of a salt, process for preparation and method of use ) 是由 K·沙 C·M·布雷泽 于 2018-05-26 设计创作，主要内容包括：本发明涉及可以用于治疗癌症的化合物N-{4-[(6,7-二甲氧基喹啉-4-基)氧基]苯基}-N′-(4-氟苯基)环丙烷-1,1-二羧酰胺的盐及其溶剂化物的新型结晶性固体形式,所述溶剂化物包括水合物。还公开了包含所述结晶性固体形式的药物组合物和制备所述结晶性固体形式的工艺,以及使用它们治疗癌症,特别是肾细胞癌(RCC)和甲状腺髓样癌(MTC)的方法。(The present invention relates to novel crystalline solid forms of the salt of the compound N- {4- [ (6, 7-dimethoxyquinolin-4-yl) oxy ] phenyl } -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide and solvates thereof, including hydrates, that are useful in the treatment of cancer. Also disclosed are pharmaceutical compositions comprising the crystalline solid forms and processes for preparing the crystalline solid forms, as well as methods of using them to treat cancer, particularly Renal Cell Carcinoma (RCC) and Medullary Thyroid Carcinoma (MTC).)

A crystalline solid salt of N- {4- [ (6, 7-dimethoxyquinolin-4-yl) oxy ] phenyl } -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (compound 1), wherein the salt is selected from the group consisting of:

n- {4- [ (6, 7-dimethoxyquinolin-4-yl) oxy ] phenyl } -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (Compound 1) pyruvate;

n- {4- [ (6, 7-dimethoxyquinolin-4-yl) oxy ] phenyl } -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (compound 1) glutarate; and

n- {4- [ (6, 7-dimethoxyquinolin-4-yl) oxy ] phenyl } -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (Compound 1) isethionate monohydrate.

2. Crystalline solid N- {4- [ (6, 7-dimethoxyquinolin-4-yl) oxy ] phenyl } -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (compound 1) · -pyruvate salt of claim 1 characterized as form 14 wherein the crystalline solid comprises compound 1 and pyruvate in a 1: 1 molar ratio.

3. The crystalline solid compound 1-pyruvate of claim 2 characterized as form 14, wherein the form 14 is characterized by one or more peaks on the 2 Θ scale in an XRPD pattern selected from the group consisting of: 7.84, 8.81, 11.58, 15.67, 16.30, 16.55, 17.67, 17.92, 18.00, 18.20, 18.62, 19.66, 20.54, 20.75, 23.84, 26.35, and 26.42 degrees.

4. The crystalline solid compound 1-pyruvate of claim 2 or claim 3 characterized as form 14, wherein the form 14 is characterized by peaks at 8.81, 11.58, 17.67, 18.00, 23.84, and 26.35 degrees on the 2 Θ scale in an X-ray powder diffraction pattern.

5. The crystalline solid compound 1-pyruvate according to any one of claims 2-4, characterized as form 14, wherein the form 14 is characterized by an XRPD pattern according to figure 5.

6. The crystalline solid compound 1-pyruvate salt of claim 2 characterized as form 14, wherein the form 14 is characterized by a thermal event having a peak temperature of about 183 ℃ in a Differential Scanning Calorimetry (DSC) thermogram recorded at 10 ℃/min.

7. The crystalline solid compound 1-pyruvate salt according to claim 2 characterized as form 14, wherein the form 14 is characterized by a broad endothermic peak with an onset temperature of about 157 ℃ as measured by thermogravimetric differential thermal analysis (TG/DTA) with an accompanying weight loss of about 11.4%.

8. The crystalline solid compound 1-pyruvate salt of claim 2 characterized as form 14, wherein the form 14 is characterized by a total weight gain between 0% relative humidity and 80% relative humidity of about 0.10% w/w as measured by Dynamic Vapor Sorption (DVS).

9. The crystalline solid N- {4- [ (6, 7-dimethoxyquinolin-4-yl) oxy ] phenyl } -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (compound 1) glutarate salt of claim 1 characterized as form 20, wherein the crystalline solid comprises compound 1 and glutarate in a 1: 1 molar ratio.

10. The crystalline solid compound 1-glutarate salt according to claim 9, characterized as form 20, wherein the form 20 is characterized by one or more peaks on the 2 Θ scale in the X-ray powder diffraction pattern selected from the group consisting of: 8.06, 11.77, 19.97, 20.21, 22.27, 23.11, 23.17, 25.81, 25.87, 26.00, and 26.06 degrees.

11. The crystalline solid compound 1-glutarate salt according to claim 9 or claim 10, characterized as form 20, wherein the form 20 is characterized by peaks at 8.06, 11.77, 20.21, 22.27, 23.11, 25.81, 25.87, and 26.00 degrees on the 2 Θ scale in an X-ray powder diffraction pattern.

12. The crystalline solid compound 1-glutarate salt according to any one of claims 9-11, characterized as form 20, wherein said form 20 is characterized by an XRPD pattern according to figure 7.

13. The crystalline solid compound 1-glutarate salt according to claim 9, characterized as form 20, wherein the form 20 is characterized by a thermal event having a peak temperature of about 176 ℃ in a Differential Scanning Calorimetry (DSC) thermogram recorded at 10 ℃/min.

14. The crystalline solid compound 1-glutarate salt according to claim 9, characterized by form 20, wherein the form 20 is characterized by an endothermic peak with an onset temperature of about 175 ℃ as measured by thermogravimetric differential thermal analysis (TG/DTA), with an accompanying weight loss of about 0.5%.

15. The crystalline solid compound 1-glutarate salt according to claim 9, characterized by form 20, wherein the form 20 is characterized by a total weight gain between 0% relative humidity and 80% relative humidity, as measured by Dynamic Vapor Sorption (DVS), of about 0.08% w/w.

16. Crystalline solid N- {4- [ (6, 7-dimethoxyquinolin-4-yl) oxy ] phenyl } -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (Compound 1) · isethionate monohydrate according to claim 1, characterized by form 27, wherein said crystalline solid comprises Compound 1 and isethionate in a 1: 1 molar ratio.

17. The crystalline solid compound 1-isethionate monohydrate according to claim 16 characterized by form 27, wherein said form 27 is characterized by one or more peaks on the 2-theta scale in an X-ray powder diffraction pattern selected from the group consisting of: 6.56, 12.39, 12.59, 13.14, 16.57, 17.55, 21.68, 23.66, 24.33, 26.09, 26.53, 26.69, and 27.40 degrees.

18. The crystalline solid compound 1-isethionate monohydrate according to claim 16 or claim 17, characterized by form 27, wherein said form 27 is characterized by peaks at 12.39, 12.59, 17.55, 21.68, 23.66, 24.33 and 26.09 degrees on the 2-theta scale in an X-ray powder diffraction pattern.

19. The crystalline solid compound 1-isethionate monohydrate according to any one of claims 16-18 characterized by form 27, wherein said form 27 is characterized by an XRPD pattern according to figure 9.

20. The crystalline solid compound 1-isethionate monohydrate according to claim 16 characterized by form 27, wherein said form 27 is characterized by a first thermal event with a peak temperature of about 80 ℃ and a second thermal event with a peak temperature of about 203 ℃ in a Differential Scanning Calorimetry (DSC) thermogram recorded at 10 ℃/min.

21. The crystalline solid compound 1-isethionate monohydrate according to claim 16 characterized by form 27, wherein said form 27 is characterized by a first endotherm with an onset temperature of about 49C and a second endotherm with an onset temperature of about 196C as measured by thermogravimetric differential thermal analysis (TG/DTA), said first endotherm being accompanied by a weight loss of about 3%, said second endotherm being not accompanied by a weight loss.

22. The crystalline solid compound 1-isethionate monohydrate according to claim 16, characterized by form 27, wherein said form 27 is characterized by a total weight gain of about 2.4% w/w between 20% and 80% relative humidity as measured by Dynamic Vapor Sorption (DVS).

23. A pharmaceutical composition comprising a therapeutically effective amount of a substantially pure crystalline solid form of a salt of compound 1 as described in any one of claims 1 to 22 and a pharmaceutically acceptable carrier.

24. A pharmaceutical composition comprising a mixture of a therapeutically effective amount of a crystalline solid form of a salt of compound 1 as described in any one of claims 1-22 and a pharmaceutically acceptable carrier.

25. A method of treating cancer comprising administering to a subject a therapeutically effective amount of a crystalline solid form of a salt of compound 1 of any one of claims 1-22.

26. A method of treating cancer comprising administering to a subject the pharmaceutical composition of any one of claims 23-24.

27. The method of any one of claims 25-26, wherein the cancer is selected from thyroid cancer, gastric cancer, esophageal cancer, renal cancer, liver cancer, ovarian cancer, cervical cancer, bladder cancer, large bowel cancer, small bowel cancer, brain cancer, lung cancer, bone cancer, prostate cancer, pancreatic cancer, skin cancer, bone cancer, lymphoma, solid tumor, hodgkin's disease, or non-hodgkin's lymphoma.

28. The method of claim 27, wherein the thyroid cancer is medullary thyroid cancer.

29. The method of claim 27, wherein the renal cancer is renal cell carcinoma.

30. The method of claim 27, wherein the liver cancer is hepatocellular carcinoma.

31. The method of claim 27, wherein the brain cancer is astrocytoma.

32. The method of claim 31, wherein the astrocytoma is selected from the group consisting of glioblastoma, giant cell glioblastoma, and gliosarcoma.

33. The method of claim 32, wherein the glioblastoma has an oligodendrocyte component.

34. The method of claim 27, wherein the lung cancer is non-small cell lung cancer.

35. The method of claim 27, wherein the prostate cancer is castration-resistant prostate cancer.

36. A method of treating a disease or disorder associated with uncontrolled, abnormal and/or unwanted cellular activities caused by cMET or RET overexpression, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one solid form of compound 1 of any one of claims 1 to 22.

37. A method of treating a disease or disorder associated with uncontrolled, abnormal and/or unwanted cellular activities caused by cMET or RET overexpression, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of the pharmaceutical composition of any one of claims 1-22.

Technical Field

The present invention relates to novel crystalline solid forms of the salt of the compound N- {4- [ (6, 7-dimethoxyquinolin-4-yl) oxy ] phenyl } -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide and solvates (including hydrates) thereof, which are useful in the treatment of cancer. Also disclosed are pharmaceutical compositions comprising the crystalline solid forms and processes for preparing the crystalline solid forms, as well as methods of using them to treat cancer, particularly Renal Cell Carcinoma (RCC) and Medullary Thyroid Carcinoma (MTC).

Background

Commonly assigned PCT patent publication No. WO2005/030140, which is incorporated herein by reference in its entirety, discloses novel inhibitors of multiple Receptor Tyrosine Kinases (RTKs) involved in tumor growth and angiogenesis, pathological bone remodeling, and cancer metastasis progression. In particular, the compound N- {4- [ (6, 7-dimethoxyquinolin-4-yl) oxy ] phenyl } -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide is specifically described as an RTK inhibitor in WO 2005/030140. N- {4- [ (6, 7-dimethoxyquinolin-4-yl) oxy ] phenyl } -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide is also known in the art as cabozantinib. The chemical structure of N- {4- [ (6, 7-dimethoxyquinolin-4-yl) oxy ] phenyl } -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (cabozantinib) is represented by compound 1.

The enzyme Ret IC has been found for Compound 1₅₀A value of about 5.2nM (dihydrate), enzyme c-Met IC₅₀The value was about 1.3nM (dihydrate). An assay for measuring such c-Met activity is described in paragraph [0458 ] of WO2005/030140]As described therein.

In initial development experiments, compound 1 (free base) was found to be a BCS class II compound with low solubility and high permeability. Since compound 1 was observed to have low solubility in water, it was initially considered unsuitable for the development of solid oral dosage forms, and drug development was therefore focused on finding salts with suitable hygroscopicity, thermal stability, chemical stability, physical stability, and solubility.

The malate salt of compound 1, as described in WO 2010/083414 (the entire contents of which are incorporated herein by reference), was later identified as providing an acceptable combination of crystallinity, solubility and stability compared to the free base of compound 1. 11/29/2012, N- {4- [ (6, 7-dimethoxyquinolin-4-yl) oxy]S-malic acid salts of phenyl } -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (also known as cabozantinib or) Approved by the U.S. food and drug administration for the treatment of progressive, metastatic Medullary Thyroid Carcinoma (MTC). In 12 months 2013, the European Committee for pharmaceuticals (CHMP) for proposed indications for progressive, unresectable, locally advanced or metastatic MTC submitted to the European drug administration or EMAHas issued a positive opinion. Recently, cabozinib in the form of S-malate was approved as a candidate in 2015Can be used for treating advanced renal cell carcinoma.

In addition to therapeutic efficacy, applicants continue to strive to provide one or more suitable forms of compound 1 that have advantageous properties with respect to processing, manufacturing, storage stability, and/or usefulness as a pharmaceutical. Thus, the discovery of new crystalline solid forms of compound 1 having some or all of these desired properties remains crucial for drug development. Thus, disclosed herein are novel crystalline solid forms of compound 1 that may be used in pharmaceutical compositions for the treatment of proliferative diseases such as cancer.

Summary of The Invention

These needs and others are met by the present invention, which is directed to novel crystalline solid forms of a salt of compound 1, as well as pharmaceutical compositions containing such crystalline solid forms, methods of using such crystalline solid forms, and processes for preparing such crystalline solid forms. Crystalline solid forms include solvated solid forms, including hydrates. Among other uses, the crystalline solid form of compound 1 can be used to prepare pharmaceutical compositions expected to be useful for treating cancer. Accordingly, one aspect of the present invention relates to a pharmaceutical composition in solid form comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of compound 1.

As indicated previously, compound 1 inhibits a variety of Receptor Tyrosine Kinases (RTKs) involved in tumor growth and angiogenesis, pathological bone remodeling, and cancer metastasis progression. Thus, the crystalline solid form of compound 1 is useful for treating cancer. Accordingly, another aspect of the present invention relates to a method for treating cancer comprising administering to a subject a therapeutically effective amount of a solid form of compound 1 as disclosed herein. The invention also relates to a process for preparing crystalline solid forms of compound 1.

The solid forms are summarized in table 1.

TABLE 1: n- {4- [ (6, 7-Dimethoxyquinolin-4-yl) oxy]Novel crystalline solid forms of a salt of phenyl } -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide

A total of 27 forms were observed during the screening. One of the modes (form 8) is associated with the free base. The remaining 26 solids were evaluated for their crystallinity, solvation state, stoichiometry, ease of manufacture, deliquescence, desolvation stability, molecular weight, and acceptability/tolerability for oral administration. Water solubility and optical microscopy were also determined.

In a particular aspect, the present invention relates to a crystalline solid salt of N- {4- [ (6, 7-dimethoxyquinolin-4-yl) oxy ] phenyl } -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (compound 1), wherein the salt is selected from the group consisting of: n- {4- [ (6, 7-dimethoxyquinolin-4-yl) oxy ] phenyl } -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (Compound 1) pyruvate; n- {4- [ (6, 7-dimethoxyquinolin-4-yl) oxy ] phenyl } -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (compound 1) glutarate; and N- {4- [ (6, 7-dimethoxyquinolin-4-yl) oxy ] phenyl } -N' - (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (Compound 1) isethionate monohydrate.

Forms 14, 19 and 20 (pyruvate, glutarate and isethionate) were prepared on a 250-1000mg scale and confirmed to be identical to the forms observed in the initial screen. These three salts are also prepared by XRPD, DSC, TG/DTA, DVS and¹h NMR microscopy for full characterization. Their crystal habit was also investigated. Compound 1 pyruvate and glutarate are irregular particles with low aspect ratio, while compound 1 isethionate shows a crystal habit of needle-like morphology.

The salt forms described herein have a number of advantageous properties. Examples of such advantageous properties include lower molecular weight (resulting in higher activity/weight ratio), higher solubility, improved filterability and flowability due to particle morphology/aspect ratio, and lower hygroscopicity. In addition, many of the salts described herein are natural human metabolites and therefore well tolerated in the body.

Drawings

Fig. 1 is a graph showing XRPD spectra of forms 1, 2, and 3.

Fig. 2 is a graph showing XRPD spectra of forms 4, 5 and 6.

Fig. 3 is a graph showing XRPD spectra for forms 7, 8 and 9.

Fig. 4 is a graph showing XRPD spectra for forms 10, 11 and 12.

Fig. 5 is a graph showing XRPD spectra for forms 13, 14 and 15.

Fig. 6 is a graph showing XRPD spectra for forms 16, 17 and 18.

Fig. 7 is a graph showing XRPD spectra for forms 19, 20 and 21.

Fig. 8 is a graph showing XRPD spectra for forms 22, 23 and 24.

Fig. 9 is a graph showing XRPD spectra for forms 25, 26 and 27.

FIG. 10 is a TG/DTA curve of form 1.

FIG. 11 is a TG/DTA curve of form 2.

FIG. 12 is a TG/DTA curve of form 3.

FIG. 13 is a TG/DTA curve of form 5.

FIG. 14 is a TG/DTA curve of form 6.

FIG. 15 is a TG/DTA curve of form 7.

FIG. 16 is a TG/DTA curve of form 9.

FIG. 17 is a TG/DTA curve of form 10.

FIG. 18 is a TG/DTA curve of form 11.

FIG. 19 is a TG/DTA curve of form 12.

FIG. 20 is a TG/DTA curve of form 13.

FIG. 21 is a TG/DTA curve of form 15.

FIG. 22 is a TG/DTA curve of form 16.

FIG. 23 is a TG/DTA curve of form 17.

FIG. 24 is a TG/DTA curve of form 18.

FIG. 25 is a TG/DTA curve of form 21.

FIG. 26 is a TG/DTA curve of form 22.

FIG. 27 is a TG/DTA curve of form 24.

FIG. 28 is a TG/DTA curve of form 25.

FIG. 29 is a TG/DTA curve of form 26.

FIG. 30 is a photograph of form 1 in DMSO-d₆NMR spectrum of (1).

FIG. 31 is a photograph of form 2 in DMSO-d₆NMR spectrum of (1).

FIG. 32 is a photograph of form 3 in DMSO-d₆NMR spectrum of (1).

FIG. 33 is a photograph of form 5 in DMSO-d₆NMR spectrum of (1).

FIG. 34 is a photograph of form 6 in DMSO-d₆NMR spectrum of (1).

FIG. 35 is a photograph of form 7 in DMSO-d₆NMR spectrum of (1).

FIG. 36 is a photograph of form 8 in DMSO-d₆NMR spectrum of (1).

FIG. 37 is a photograph of form 9 in DMSO-d₆NMR spectrum of (1).

FIG. 38 is a photograph of form 10 in DMSO-d₆NMR spectrum of (1).

FIG. 39 is a photograph of form 11 in DMSO-d₆NMR spectrum of (1).

FIG. 40 is a photograph of form 12 in DMSO-d₆NMR spectrum of (1).

FIG. 41 is a photograph of form 13 in DMSO-d₆NMR spectrum of (1).

FIG. 42 is a photograph of form 15 in DMSO-d₆NMR spectrum in (1).

FIG. 43 is a photograph of form 16 in DMSO-d₆NMR spectrum in (1).

FIG. 44 is a photograph of form 17 in DMSO-d₆NMR spectrum of (1).

FIG. 45 is a photograph of form 18 in DMSO-d₆NMR spectrum of (1).

FIG. 46 is a photograph of form 19 in DMSO-d₆NMR spectrum of (1).

FIG. 47 is a photograph of form 21 in DMSO-d₆NMR spectrum of (1).

FIG. 48 is a photograph of form 22 in DMSO-d₆NMR spectrum of (1).

FIG. 49 is a photograph of form 23 in DMSO-d₆NMR spectrum of (1).

FIG. 50 is a photograph of form 24 in DMSO-d₆NMR spectrum of (1).

FIG. 51 is a photograph of form 25 in DMSO-d₆NMR spectrum of (1).

FIG. 52 is a photograph of form 26 in DMSO-d₆NMR spectrum of (1).

Figure 53A is an XRPD spectrum of form 14, compound 1 pyruvate.

Figure 53B is a DSC trace of form 14, compound 1 pyruvate.

FIG. 53C is a TG/DTA thermogram of form 14, Compound 1 pyruvate.

Figure 53D is a DVS isotherm of form 14, compound 1 pyruvate.

Figure 53E is an XRPD spectrum of form 14, compound 1 pyruvate, before DVS (top panel) and after DVS (bottom panel).

FIG. 53F is an FT-IR spectrum of form 14, compound 1 pyruvate.

FIG. 53G is of form 14, Compound 1 pyruvate¹H NMR(DMSO-d⁶) Spectrum of light.

Figure 54A is an XRPD spectrum of form 20, compound 1 glutarate salt.

Figure 54B is a DSC trace of form 20, compound 1 glutarate.

Figure 54C is a TG/DTA thermogram of form 20, compound 1 glutarate.

Figure 54D is a DVS isotherm of form 20, compound 1 glutarate.

Figure 54E is an XRPD spectrum of form 20, compound 1 glutarate before DVS (top panel) and after DVS (bottom panel).

Figure 54F is an Infrared (IR) spectrum of form 20, compound 1 glutarate salt.

FIG. 54G is of form 20, compound 1 glutarate¹H NMR(DMSO-d⁶) Spectrum of light.

Figure 55A is an XRPD spectrum of form 27, compound 1 isethionate monohydrate.

Figure 55B is a DSC trace of form 27, compound 1 isethionate monohydrate.

Figure 55C is a TG/DTA thermogram of form 27, compound 1 isethionate monohydrate.

Figure 55D is a DVS isotherm of form 27, compound 1 isethionate monohydrate.

Figure 55E is an XRPD spectrum of form 27, compound 1 isethionate monohydrate before DVS (top panel) and after DVS (bottom panel).

Figure 55F is an Infrared (IR) spectrum of form 27, compound 1 isethionate monohydrate.

FIG. 55G is of form 27, Compound 1 isethionate monohydrate¹H NMR (DMSO-d⁶) Spectrum of light.

Detailed Description

Definition of

The processes described herein can be used to prepare the compositions of the present invention. The amounts and characteristics of the components used in each process will be as described herein.

When describing the compounds, compositions, methods, and processes of the present invention, the following terms have the following meanings, unless otherwise indicated.

The term "solvate" means a complex or aggregate formed from one or more solute molecules (i.e., crystalline compound 1) and one or more solvent molecules. Such solvates typically have a substantially fixed molar ratio of solute to solvent. This term also includes clathrates, which include clathrates containing water. Representative solvents include, for example, water, methanol, ethanol, isopropanol, acetic acid, and the like. When the solvent is water, the solvate formed is a hydrate.

By "therapeutically effective amount" is meant an amount sufficient to effect treatment when administered to a subject in need thereof. The amount of a "compound of the invention" that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the age of the subject being treated, and the like. A therapeutically effective amount can be routinely determined by one of ordinary skill in the art based on his own knowledge and this disclosure. Thus, a "therapeutically effective amount" of compound 1 is an amount sufficient to treat a subject suffering from any of a variety of cancers associated with abnormal cellular proliferation and angiogenesis. A therapeutically effective amount according to the present disclosure is an amount that has a therapeutic effect on the treatment or prevention of the disease states and conditions discussed herein. Compound 1 (including the solid forms disclosed herein) has therapeutic activity for inhibiting, managing and/or modulating kinase signaling as described in WO 2005/030140.

As used herein, "Treating" or "treatment" means Treating a disease state (characterized by abnormal cell proliferation and invasion) in a human and includes at least one of: (i) preventing the disease state in a human, particularly when such human is predisposed to the disease state but has not yet been diagnosed with the disease state; (ii) inhibiting the disease state, i.e., arresting its development; and (iii) alleviating, i.e., causing regression of, the disease state.

The term "pharmaceutically acceptable" refers to materials that are not biologically or otherwise undesirable. For example, the term "pharmaceutically acceptable carrier" refers to a material that can be incorporated into a composition and administered to a subject without causing undesirable biological effects or interacting in a deleterious manner with other components of the composition. Such pharmaceutically acceptable materials typically meet required standards for toxicological and manufacturing testing and include those materials identified by the U.S. food and drug administration as suitable inactive ingredients.

The term "dosage form" refers to physically discrete units suitable for administration to a subject, i.e., each unit contains a predetermined amount of a compound of the invention calculated to produce the desired therapeutic effect, either alone or in combination with one or more additional units. For example, such unit dosage forms can be capsules, tablets, pills, and the like.

As used herein, "amorphous" refers to a non-crystalline solid form of molecules and/or ions. Amorphous solids do not show a well-defined X-ray diffraction pattern with sharp maxima.

The term "substantially pure" as used herein means that the solid form of compound 1 referred to contains at least about 90% by weight, based on the weight of such solid form. The term "at least about 90 wt%", while not intending to limit the applicability of the doctrine of equivalents to the scope of the claims, includes, but is not limited to, for example, about 90 wt%, about 91 wt%, about 92 wt%, about 93 wt%, about 94 wt%, about 95 wt%, about 96 wt%, about 97 wt%, about 98 wt%, about 99 wt%, and about 100 wt%, based on the weight of the referenced solid form. The remainder of the solid form of compound 1 may comprise one or more other solid forms of compound 1 and/or reaction impurities and/or processing impurities such as occur when preparing crystalline forms. The presence of reaction impurities and/or processing impurities can be determined by analytical techniques known in the art, for example, chromatography, nuclear magnetic resonance spectroscopy, mass spectrometry, and/or infrared spectroscopy.

As used herein, "crystalline solid" refers to a compound or composition in which the structural units are arranged in a fixed geometric pattern or lattice, so that the crystalline solid has a rigid long-range order. The structural units constituting the crystalline structure may be atoms, molecules or ions. Crystalline solids exhibit a defined melting point.

As used herein, "european pharmacopoeia classification" is a system for classifying compound 1 based on hygroscopicity. The classification was determined according to table 2:

TABLE 2: classification of european pharmacopoeia

Classification	Weight gain at 80% RH (25 ℃ C.)
		Non-hygroscopic	＜0.2％
Slightly hygroscopic	More than or equal to 0.2 percent and less than 2 percent
		Is hygroscopic	More than or equal to 2 percent and less than 15 percent
Is very easy to absorb moisture	≥15％
		Deliquescence is easy	Absorb enough water to form a liquid

The hygroscopicity of a compound can be determined using procedures known to those skilled in the art such as, but not limited to, Dynamic Vapor Sorption (DVS).

In addition, unless otherwise specified, structures described herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, in which one or more hydrogen atoms are replaced by deuterium or tritium or one or more carbon atoms are replaced by deuterium or tritium¹³C-or¹⁴C-enriched carbon substituted compound 1 is within the scope of the present invention. Such compounds may be used, for example, as analytical tools, probes in bioassays, or compounds with improved therapeutic properties.