Malate salt of n- (4- { [ 6, 7-bis (methyloxy) quin0lin-4-yl] oxy}phenyl)-n' - (4 -fluorophenyl) cyclopropane-1,1-dicarboxamid e, and crystalline forms therof for the treatment of cancer.

N-(4-{[6,7-BIS(METHYLOXY)QUINOLIN-4YL]OXY}PHENYL)-Ν'-(4-FLUOROPHENYL)CYCLOPROPANE-1,1DICARBOXAMIDE MALATE SALT AND ITS CRYSTALLINE FORMS FOR THE TREATMENT OF CANCER

Field of Invention

This description relates to N(4-{{6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-Ν'-(4fluorophenyl)cyclopropane-1,1-dicarboxamide malate salts and forms crystalline and amorphous of N-(4-{{6,7bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-Ν'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide malate salts. N(4([6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-Ν'-(4fluorophenyl)cyclopropane-1,1-dicarboxamide malate salts include one of (1) (L)-malate salt, (2) the (D)-malate salt, (3) the (D,L)-malate salt and (4) mixtures thereof. The description also refers to pharmaceutical compositions comprising at least one N—(4—{[6,7—bis(methyloxy)quinolin-4-yl]oxy}phenyl)-Ν'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide malate salt .

The description also relates to pharmaceutical compositions comprising a crystalline or amorphous form of at least one N-(4-{[6,7bis(methyloxy)quinolin-4-yloxy}phenyl)-N'-(4) malate salt. -fluorophenyl)cyclopropane-1,1-dicarboxamide.

ίη/ΖΖΠΖ/Β/ΥΙΛΙ

The description also relates to methods of treating cancer comprising administering at least one N-(4-([6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)Ν'-(4) malate salt. -fluorophenyl)cyclopropane-1,1-dicar-boxamide.

The disclosure also relates to methods of treating cancer comprising administering a crystalline or amorphous form of at least one N-(4-{[6,7bis(methyloxy)quinolin-4-yl]oxy}phenyl)- malate salt. N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.

Background of the Invention

Traditionally, dramatic improvements in cancer treatment are associated with the identification of therapeutic agents that act through new mechanisms. A mechanism that can be exploited in cancer treatment is the modulation of protein kinase activity because signal transduction through the activation of protein kinases is responsible for many of the characteristics of tumor cells. Signal transduction of protein kinases is of particular importance, for example, in thyroid, gastric, head and neck, lung, breast, prostate and colorectal cancers, as well as in the growth and proliferation of cancer cells. brain tumor.

Protein kinases can be categorized as receptor type or non-receptor type. Tyrosine kinases binding HGF to c-Met induces receptor activation through autophosphorylation that results in an increase in receptor-dependent signaling, which promotes cell invasion and growth. Anti-HGF antibodies or HGF antagonists have been shown to inhibit tumor metastasis in vivo (See: Maulik et al Cytokine & Growth Factor Reviews 2002 13, 41-59). Overexpression of c-Met, VEGER2 and/or Ret has been demonstrated in a wide variety of tumor types including breast tumor, colon tumor, kidney tumor, lung tumor, squamous cell myeloid leukemia, hemangiomas, melanomas, astrocytic tumor (including glioblastoma, giant cell glioblastoma, gliosarcoma and glioblastoma with oligodendroglial components). The Ret protein is a transmembrane receptor with tyrosine kinase activity. Ret is mutated in most familial forms of medullary thyroid cancer. These mutations activate the function of Ret kinases and convert it into an oncogenic product.

Inhibition of EGF, VEGF and ephrin signal transduction will prevent cell proliferation and angiogenesis, two key cellular processes necessary for tumor growth and survival (Matter A. Drug Disc. Technol. 2001 6, 1005-1024). KDR kinase (referring to tyrosine kinase, receptor-like, bbhb domain ίη/ΖΖΠΖ/Β/ΥΙΛΙ insertion kinases) and flt-4 (fms-like tyrosine kinase-4) are both growth factor receptors. vascular endothelial (VEGF). Inhibition of EGF, VEGF and ephrin signal transduction will prevent angiogenesis and cell proliferation, two key cellular processes necessary for tumor survival and growth (Matter A. Drug Disc. Technol. 2001 6, 1005-1024). EGF and VEGF receptors are desirable targets for small molecule inhibition.

Accordingly, small molecule compounds that specifically inhibit, regulate and/or modulate the signal transduction of kinases, including particularly Ret, c-Met and VEGFR2 described above, are particularly desirable as a means to treat or prevent disease states associated with angiogenesis and abnormal cell proliferation. One of these small molecules is N-(4-{ [6,7-bis(methyloxy)quinolin-4yl]oxy)phenyl)-Ν' -(4-fluorophenyl)-cyclopropane-1,1dicarboxamide, which has the chemical structure :

<img file="MX2022014444A_D0001.tif" />

WO 2005/030140 describes the synthesis of N-(4{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-Ν'-(4-fluorophenyl) cyclopropane-1, 1-dicarboxamide ( Example 12, 37, 38 and

48) and also describes the therapeutic activity of this molecule to inhibit, regulate and/or modulate the signal transduction of kinases, (Tests, Table 4, entry 289). Example 48 is in paragraph [0353] in WO 2005/030140.

In addition to therapeutic efficiency, the drug developer strives to provide a suitable form of the therapeutic agent that has properties that relate to processing, production, storage stability and/or utility as a drug. Therefore, the discovery of a form that possesses some or all of these desired properties is vital to drug development.

Applicants have found a salt form of the drug N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-Ν' -(4-fluorophenyl)cyclopropane-1,1- dicarboxamide having properties suitable for use in a pharmaceutical composition for the treatment of a proliferative disease such as cancer. The new form of salt of the invention exists in crystalline and amorphous forms.

Brief Description of the Invention

This description relates to N(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4fluorophenyl)cyclopropane-1,1-dicarboxamide malate salts as described herein, pharmaceutical compositions thereof as described herein and uses thereof as described herein.

ίη/ΖΖΠΖ/Β/ΥΙΛΙ

Ί

Another aspect relates to crystalline and amorphous forms of N-(4-{[6,7-bis-(methyloxy)quinolin-4-yl]oxy}phenyl)-Ν'-(4-fluorophenyl) malate salts. -cyclopropane-1,1dicarboxamide as described herein, pharmaceutical compositions thereof as described herein, and uses thereof as described herein.

Brief Description of the Figures

Figure 1 shows the experimental XRPD pattern for Crystalline Compound (I), Form Nl at 25°C.

Figure 2 shows the NMR spectrum¹³C solid state of crystalline Compound (I), Form Nl.

Figure 3 shows the NMR spectrum¹⁵Solid state N of Crystalline Compound (I), Form Nl.

Figure 4 shows the NMR spectrum¹⁹Solid state F of Crystalline Compound (I), Form Nl.

Figure 5 shows the thermal gravimetric analysis (TGA) of Crystalline Compound (I), Form Nl.

Figure 6 shows differential scanning calorimetry (DSC) of Crystalline Compound (I), Form Nl.

Figure 7 shows the moisture absorption of Crystalline Compound (I), Form Nl.

Figure 8 shows the experimental XRPD pattern for Crystalline Compound (I), Form N-2 at 25°C.

Figure 9 shows the RNM spectrum¹³C state solid ίη/ΖΖΠΖ/Β/ΥΙΛΙ ίΠ/77Ω7/Β/ΥΙΛΙ of Crystalline Compound (I), Form N-2.

Figure 10 shows the NMR spectrum¹⁵Solid state N of Crystalline Compound (I), Form N-2.

Figure 11 shows the NMR spectrum¹⁹Solid state F of Crystalline Compound (I), Form N-2.

Figure 12 shows the thermal gravimetric analysis (TGA) of Crystalline Compound (I), Form N-2.

Figure 13 shows differential scanning calorimetry (DSC) of Crystalline Compound (I), Form N-2.

Figure 14 shows the moisture absorption of Crystalline Compound (I), Form N-2.

Figure 15 shows the experimental and simulated XRPD patterns for Crystalline Compound (III), Form Nl at room temperature.

Figure 16 shows the NMR spectrum¹³C solid state of crystalline Compound (III), Form Nl.

Figure 17 shows the NMR spectrum¹⁵Solid state N of crystalline Compound (III), Form Nl.

Figure 18 shows the NMR spectrum¹⁹Solid state F of crystalline Compound (III), Form Nl.

Figure 19 shows the thermal gravimetric analysis (TGA) of the crystalline Compound (III), Form Nl.

Figure 20 shows differential scanning calorimetry (DSC) of Crystalline Compound (III), Form Nl.

Figure 21 shows the moisture absorption of ίη/ΖΖΠΖ/Β/ΥΙΛΙ

Crystalline compound (III), Form Nl.

Figure 22 shows the XRPD pattern of amorphous Compound (I) at room temperature.

Figure 23 shows the NMR spectrum¹³C solid state of amorphous Compound (I).

Figure 24 shows the NMR spectrum¹⁵Solid state N of amorphous Compound (I).

Figure 25 shows the NMR spectrum¹⁹F solid state of amorphous Compound (I).

Figure 26 shows the differential scanning calorimetry (DSC) of the amorphous Compound (I).

Figure 27 shows the moisture absorption of the amorphous Compound (I).

Detailed description of the invention

This description relates to improvements in the physicochemical properties of N-(4-[6,7-bis(methyloxy)quinolin-4-yl]oxyphenyl)-Ν'-(4-fluorophenyl)cyclopropane-1,1dicarboxamide, therefore that this compound may be suitable for drug development. Described herein are N-(4-{[6,7-bis(methyloxy)-quinolin-4yl]oxy}phenyl)-Ν'-(4-fluorophenyl)cyclopropane-1,1dicarboxamide malate salts. New solid state forms of these salts are also described. The malate salts, as well as their crystalline and amorphous forms described herein each represent separate aspects of the disclosure.

Although malate salts and their solid state forms are described herein, the invention also relates to new compositions containing the described salts and solid state forms. The therapeutic uses of the salts and solid state forms described as well as the therapeutic compositions containing them represent separate aspects of the description. The characteristics used to characterize the salts and their solid state forms are described in the following examples. These techniques, alone or in combination, can be used to characterize the salts and their solid state forms described herein. Salts and their solid state forms can also be characterized by reference to the figures described.

N-(4-{[6,7-bis(methyloxy)quinolin-4yl]oxy}phenyl)-Ν'-(4-fluorophenyl)-cyclopropane-1,1dicarboxamide was found to have a Ret enzyme IC50 value of approximately 5.2 nM (nanomolar) and a c-Met enzyme IC50 value of approximately 1.3 nM (nanomolar). The assay that was used to measure this c-Met activity is described in paragraph [0458] in WO2005-030140.

The biochemical activity of RET was assessed using a Luciferase-Coupled Chemiluminescent Kinase (LCCA) assay format as described in WO2005-030140. Kinase activity was measured as the percentage of ATP remaining after the kinase reaction. The remaining ίΠ/ΖΖηΖ/Ε/ΥΙΛΙ ATP was detected by luciferasaluciferin-coupled chemiluminescence. Specifically, the reaction was initiated by mixing the test compounds, ΑΤΡ 2μΜ, poly-EY ΙμΜ and 15nM RET (baculovirus-expressed human RET kinase domain M700-D1042 with a (His)6 tag at the N-terminus). in a 20uL assay buffer (20mM Tris-HCL pH 7.5, 10mM MgCl, 0.01% Triton X-100, ImM DTT, MnCl₂ 3mM). The mixture was incubated at room temperature for 2 hours after which 20 uL of the luciferase-luciferin mixture was added and the chemiluminescent signal was read using a Wallac Victor reader.². The luciferase-luciferin mixture consists of 50 mM HEPES, pH 7.8, 8.5 μg/mL oxalic acid (pH 7.8), 5 mM DTT, 0.4% Triton X-100, 0.25 mg/mL coenzyme A, AMP 63 μΜ , 28 pg/mL of luciferin and 40,000 light units/mL of luciferase.

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-Ν'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide Malate Salts

This description relates to N(4—{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4fluorophenyl)cyclopropane-1,1-dicarboxamide malate salts. These malate salts are a combination of N-(4-{{6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1dicarboxamide with malic acid which forms a 1:1 malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-phenyl)-Ν' (4-fluorophenyl)cyclopropane-1,1- dicarboxamide.

ίη/ΖΖΠΖ/Β/ΥΙΛΙ

Malic acid has the following structure:

ΏH-OH

Λ Χ,ΟΗ

HO p

EITHER

Due to its chiral carbon, there are two enantiomers of malic acid, (L)-malic acid and (D)-malic acid.

(L)-malic acid has the following structure:

<img file="MX2022014444A_D0002.tif" />

EITHER

There are several names or designations for (L)-malic acid that are known in the art. These include butanedioic acid, hydroxy-, (2S)-(9CI); butanedioic acid, hydroxy-, (S)-; malic acid, L-(8CI); malic acid, 1-(3CI); (-)-(S)-malic acid; (-)-hydroxysuccinic acid; (-) (L)-malic acid; (-)-malic acid; (2S)-2hydroxybutanedioic acid; (2S)-2-hydroxysuccinic acid; (S)-malic acid; apple acid; L-(-)-malic acid; (L)malic acid; NSC 9232; S-(-)-malic acid; and S-2hydroxybutanedioic acid.

(D) Malic acid has the following structure:

Pi H_zaOH/A. ho o

There are several names or designations for (D)-malic acid that are known in the art.

ίη/ΖΖΠΖ/Β/ΥΙΛΙ

These include butanedioic acid, 2-hydroxy acid, (2R)-, butanedioic acid, hydroxy- acid, (2R) acid (9CI); butanedioic acid, hydroxy acid-, (R)-; (+)-malic; (2R)-2-hydroxybutanedioic acid; (2R)-malic acid; (R)-(+)-malic acid; (R)-malic acid; D-(+)-2hydroxysuccinic acid; D-(+)-malic acid; and D-malic acid.

As discussed above, the chemical structure of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-phenyl)Ν'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide is

<img file="MX2022014444A_D0003.tif" />

There are no quinal carbons in its chemical structure.

There are several names for N-(4-{[6,7-bis(methyloxy)-quinolin-4yl]oxy}phenyl)-Ν'-(4-fluorophenyl)cyclopropane-1,1dicarboxamide that are publicly known, and some of These various names and designations include 1,1-cyclopropanedicarboxamide, 1,1-cyclopropanedicarboxamide, Ν'[4-[(6,7-dimethoxy-4-quino-linyl)oxy]phenyl]-N(4fluorophenyl)- and 1,1- cyclopropanedi-carboxamide, N-[4-[(6,7dimethoxy-4-quinolinyl)oxy]phenyl]-Ν'-(4-fluorophenyl)-(9CI).

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-Ν'-(4-fluorophenyl)cyclopropane-1,1dicarboxamide can be prepared according to any of several ίΠ/ ΖΖηΖ/Ε/ΥΙΛΙ different methodologies, either on a per gram scale (&lt;1 kg) or a per kilogram scale (&gt;1 kg). A gram-scale method is set forth in WO 2005-030140, which describes the synthesis of N-(4-{[6,7-bis(methyloxy)quinolin-4-i1]oxy}phenyl)-Ν'-(4fluorophenyl )cyclopropane-1,1-dicar-boxamide (Examples 25, 37, 38 and 48), which is hereby incorporated by reference. Alternatively, N-(4-{[6,7-bis(methyloxy)quinolin-4yl]oxy}phenyl)-Ν'-(4-fluoro-phenyl)cyclopropane-1,1dicarboxamide, which includes the active compounds, They can be prepared on a kilogram scale using the procedure set forth in Example I below.

This description relates to N(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-Ν'-(4fluorophenyl)cyclopropane-1,1-dicarboxamide malate salts:

N-(4-{{6,7-bis(methyloxy)quinolin-4-yl]oxy[phenyl)-Ν'-(4-fluorophenyl)cyclo-propane1,1-dicarboxamide (L)-malate salt , (compound (I));

N-(4-{{6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-Ν'-(4-fluorophenyl)cyclo-propane1,1-dicarboxamide (D)-malate salt , (compound (II)); and N-(4-[6,7-bis(methyloxy)quinolin-4-i1]oxy}phenyl)-Ν'-(4-fluorophenyl)cyclo-propane1,1-dicarboxamide (DL)-malate salt (compound (III)).

Each has improved properties over N- (4-{ [6,7-bis(methyloxy)quinolin-4-yl]oxy[-phenyl)-Ν' -(4ίη/ΖΖΠΖ/Β/ΥΙΛΙ fluorophenyl)cyclopropane- 1,1-dicarboxamide and its other salts. The names used herein to characterize a specific form, for example N-2 etc., are not intended to be limited to exclude any other substance possessing similar or identical physical and chemical characteristics, but rather these names are used as identifiers. only to be interpreted in accordance with the characterization information presented herein.

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-Ν'-(4-fluorophenyl)cyclopropane-1,1dicarboxamide malate salts, and in particular Compound (I), has a preferred combination of pharmaceutical properties for development. Under the conditions of 25°C/60% relative humidity (RH) and 40°C/60% relative humidity, Compound (I) showed no change in the test, purity, humidity and dissolution. The DSC/TGA shows that Compound (I) is stable up to 185°C. No solvent losses were observed. Water uptake by (L)-malate salt was reversible with slight hysteresis. The amount of water taken was calculated to be approximately 0.60% by weight at 90% relative humidity. The (L)-malate salt was synthesized in good yield and purity &gt;90% and has sufficient solubility for use in a pharmaceutical composition. The amount of water associated with this salt was calculated to be approximately 0.5 wt % by Karl Fischer analysis and correlates with the ίη/ΖΖΠΖ/Ε/ΥΙΛΙ analysis by TGA and GVS. N-(4{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (D)-malate salt will have the same properties as N-(4-{[6,7bis(methyloxy)quinolin-4-yl]oxy}phenyl)-Ν'-(4-fluorophenyl)cyclopropane-1 (L)-malate salt, 1-dicarboxamide).

The salt of Compound (I) itself, and separately its crystalline and amorphous forms, exhibit beneficial properties over the free base and the other salts of N-(4{[6,7-bis(methyloxy)quinolin-4- yl]oxy}-phenyl)-N-(4fluorophenyl)cyclopropane-1,1-dicarboxamide. For example, the hydrochloride salt of N-(4-{[6,7-bis-(methyloxy)quinolin-4yl]oxy}phenyl)-N'-(4-fluorophenyl)-cyclopropane-1,1dicarboxamide exhibits undesirable sensitivity to humidity, phase change to exposure to high humidity (75% humidity) and high temperature (40 °C) . The maleate salt has low solubility. Tartrate salt has low crystallinity and low solubility. The phosphate salt exhibited an 8% weight gain due to Η absorption₂Ο, the highest among the salts tested.

The water solubility of the various salts was determined using 10 mg of solids per mL of water. The salts were prepared in a salt test by reacting an acetone solution of the free base with concentrated tetrahydrofuran (THF) solutions of a variety of ίη/ΖΖΠΖ/Β/ΥΙΛΙ acids in approximately a 1:1 molar ratio. Table 1 below summarizes the water solubility and other data relating to the free base and each salt.

Table 1

<td></td><td>Solubility (mg/ml)</td><td></td>

<td>free base</td><td> «0.001</td><td>very low solubility</td>

<td>Propionate</td><td> «0.001</td><td>no salt formation; free base and acid mixture</td>

<td>Acetate</td><td> «0.001</td><td>no salt formation; free base and acid mixture</td>

<td>Succinated</td><td> 0.010</td><td>no salt formation; free base and acid mixture</td>

<td>Benzoate</td><td> 0.005</td><td>no salt formation; free base and acid mixture</td>

<td>L-Lactate</td><td> 0.015</td><td>Amorphous, salt</td>

<td>Pyrroglutamate</td><td> 0.44</td><td>Amorphous, salt</td>

<td>Glycolate</td><td> 0.016</td><td>Amorphous, salt</td>

<td>L-Ascorbate</td><td> 0.053</td><td>Crystalline salt, low solubility</td>

<td>Sulfate</td><td> 0.004</td><td>Crystalline salt, low solubility</td>

<td>Tosylate</td><td> 0.007</td><td>Crystalline salt, low solubility</td>

ίΠ/77Ω7/Β/ΥΙΛΙ

<td>Malonate</td><td> 0.003</td><td>Crystalline salt, low solubility</td>

<td>2, 5- didroxybenzoate</td><td> «0.001</td><td>Crystalline salt, low solubility</td>

<td>Fumarate</td><td> 0.008</td><td>Crystalline salt, low solubility</td>

<td>Citrate</td><td> 0.002</td><td>Crystalline salt, low solubility</td>

<td>mesylate</td><td> 0.175</td><td>crystalline salt; Possible formation of sulfonic acid when produced with alcohol.</td>

<td>Esylate</td><td> 0.194</td><td>Crystalline salt, possible formation of sulfonic acid when produced with alcohol.</td>

<td>Benzene- sulfonate</td><td> 0.039</td><td>Crystalline salt, possible formation of sulfonic acid when produced with alcohol.</td>

<td>Chloride</td><td> 0.070</td><td>Crystalline but hygroscopic; possible hydrate formation. Change in XRPD pattern upon exposure to humidity.</td>

<td>Maleate</td><td> 0.005</td><td>Crystalline salt, possible hydrate formation; low solubility; different XRPD pattern observed in upscaling (possible issue of polymorphism).</td>

ίη/ΖΖΠΖ/Β/ΥΙΛΙ

<td>Phosphate</td><td> 0.026</td><td>Crystalline but Hygroscopic</td>

<td>L-tartrate</td><td> 0.014</td><td>Low degree of crystallinity; Hygroscopic.</td>

<td>(L)-Malate</td><td> 0.059</td><td>Crystalline; not Hygroscopic if indication of hydrate formation. Adequate solubility, and chemical/physical stability.</td>

Another aspect of this description relates to crystalline forms of Compound (I), including the Nl and/or N-2 crystalline form of Compound (I) as described herein. Each form of Compound (I) is a separate aspect of the description. Similarly, another aspect of this disclosure relates to crystalline forms of Compound (II), including the Nl and/or N-2 crystalline form of Compound (II) as described herein. Each of which is also a separate aspect of the description. As is known in the art, the crystalline (D)malate salt will form the same crystalline form and have the same properties as the crystalline Compound (I). See WO 2008/083319, which discusses the properties of crystalline enantiomers. Mixtures of the crystalline forms of Compounds (I) and (II) are another aspect of the description.

The crystalline Nl forms of Compounds (I) and (II) as described herein can be characterized ίη/ΖΖΠΖ/Β/ΥΙΛΙ by at least one of the following:

(i) an NMR spectrum¹³solid state C with peaks at 18.1, 42.9, 44.5, 70.4, 123.2, 156.2, 170.8, 175.7 and 182.1 ppm, +0.2 ppm;

(ii) an NMR spectrum¹³C solid state substantially in accordance with the pattern shown in Figure 2;

(iii) an x-ray powder diffraction pattern (CuKaX=l.5418Á) comprising four or more peaks selected from: 6.4, 9.0, 12.0, 12.8, 13.5, 16.9, 19.4,

21.5, 22.8, 25.1 and 27.6°2θ ± 0.2°2θ, where the measurement of the crystalline form is at room temperature;

(iv) an x-ray powder diffraction (XRPD) spectrum substantially in accordance with the pattern shown in Figure 1;

(v) an NMR spectrum¹⁵Solid state N with peaks at 118.6, 119.6, 120.7, 134.8, 167.1, 176.0 and 180 ppm, +0.2 ppm; and/or (vi) an NMR spectrum¹⁵N solid state substantially in accordance with the pattern shown in Figure 3.

Other solid state properties that can be used to characterize the crystalline Nl forms of Compounds (I) and (II) are shown in the figures and are discussed in the examples below. For the crystalline ίη/ΖΖΠΖ/Β/ΥΙΛΙ Compound (I), the phase of this solid and the degree of crystallinity remains unchanged after exposure to 7.5% relative humidity at 40°C for 1 week.

The N-2 crystalline forms of Compounds (I) and (II) as described herein can be characterized by at least one of the following:

(i) an NMR spectrum¹³solid-state C with peaks at 23.0, 25.9, 38.0, 54.4, 56.11, 41.7, 69.7, 102.0, 122.5, 177.3, 179.3, 180.0, and 180.3, ± 0.2 ppm;

(ii) an NMR spectrum¹³C solid state substantially in accordance with the pattern shown in Figure 9;

(iii) an x-ray powder diffraction pattern (CuKaX=l.5418Á) comprising four or more peaks selected from: 6.4, 9.1, 12.0, 12.8, 13.7, 17.1, 20.9, 21.9, 22.6 and 23.7°2θ ± 0.2°2θ, where the measurement of the crystalline form is at room temperature;

(iv) an x-ray powder diffraction (XRPD) spectrum substantially in accordance with the pattern shown in Figure 8;

(v) an RMA spectrum¹⁵solid-state N with peaks at 118.5, 120.8, 135.1, 167.3, and 180.1 ppm; and/or (vi) an NMR spectrum¹⁵N solid state substantially in accordance with the pattern shown in Figure 10.

ίη/ΖΖΠΖ/Β/ΥΙΛΙ

Other solid state properties that can be used to characterize the crystalline N-2 forms of Compounds (I) and (II) are shown in the figures and are discussed in the examples below.

In another embodiment, the description relates to a crystalline form of Compound (I), as described herein in any of the aspects and/or embodiments, is substantially the pure Nl form.

In another embodiment, the description relates to a crystalline form of Compound (I), as described herein in any of the aspects and/or embodiments, is substantially the pure N-2 form.

The description also refers to amorphous forms of Compounds (I) and (II). The preparation and solid state properties and characteristics of the amorphous form of Compound (I) are described in the following examples. The amorphous forms of Compounds (I) and (II) represent another aspect of the description.

A further aspect of the description relates to mixtures of Compound (I) and Compound (II). The mixtures can have a weight % from greater than zero to less than 100 weight % of Compound (I) and from less than 100 weight % to a weight % greater than zero of Compound (II), based on the total weight of Compound (I) and Compound (II). In other embodiments, the mixture comprises from about 1 to about 99% by weight of Compound (I) and from about 99 to about 1% by weight of Compound (II), based on the total weight of Compound (I) and the Compound (II) in the mixture. In a further embodiment, the mixture comprises from about 90% by weight to less than 100% by weight of Compound (I) and from a % by weight greater than zero to about 10% by weight of the

Compound (II), based on the total weight of Compound (I) and Compound (II). Accordingly, the mixture may have ΙΙΟ% by weight of Compound (I); 11-20% by weight of Compound (I); 21-30% by weight of Compound (I); 31-40% by weight of Compound (I); 41-50% by weight of Compound (I); 51-60% by weight of Compound (I); 61-70% by weight of Compound (I); 71-80% by weight of Compound (I); 81-90% by weight of

Compound (I); or 91-99% by weight of Compound (I) with the remaining percentage by weight of the malate salt which is that of Compound (II).

Another aspect of this disclosure relates to crystalline forms of the N-(4-[6,7bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl) (DL)-malate salt. ) cyclopropane-1, 1-dicarboxamide, Compound (III). (DL)-malate salt is prepared from racemic malic acid. The crystalline Nl form of Compound (III) as described herein can be characterized by at least one of the following:

ίη/ΖΖΠΖ/Β/ΥΙΛΙ (i) an NMR spectrum¹³Solid state C with four or more peaks selected from 20.8, 26.2, 44.8, 55.7, 70.7, 100.4, 101.0, 114.7, 115.2, 116.0, 119.7, 120.4, 121.6, 124.4, 136.9, 138.9, 141. 1, 145.7, 150.3, 156.5 , 157.6, 159.6, 165.2, 167.4, 171.2, 176.3, 182.1 ppm, + 0.2 ppm;

(ii) an NMR spectrum¹³C solid state substantially in accordance with the pattern shown in Figure 16;

(iii) an x-ray powder diffraction pattern (CuKaX=l.5418Á) comprising four or more 2Θ values ​​selected from: 12.8, 13.5, 16.9, 19.4, 21.5, 22.8, 25.1, and 27.6, ±0.2°2θ , where the measurement of the crystalline form is at room temperature;

(iv) an x-ray powder diffraction (XRPD) spectrum substantially in accordance with the pattern shown in Figure 15;

(v) an NMR spectrum¹⁵Solid state N with peaks at 119.6, 134.7 and 175.5 ppm, ± 0.2 ppm; and/or (vi) an NMR spectrum¹⁵N solid state substantially in accordance with the pattern shown in Figure 17.

Other solid state properties that can be used to characterize the crystalline Nl form of Compound (III) are shown in the figures and are discussed in the examples below. In one embodiment, the Nl form of ίη/ΖΖΠΖ/Β/ΥΙΛΙ

Compound (III) is characterized by unit cell parameters approximately equal to the following:

Cell dimensions a = 14.60Á b = 5.20Á c = 3 9.0 9Á a = 90.0° β = 90.4° γ = 90.0°

Space group: P2i/n

Molecules of Compound (I)/unit cell: 4

Volume = 2969 Á³

Density (calculated) = 1.422 g/cm³

The unit cell parameters of the Nl form of Compound (III) were measured at a temperature of about 25°C, for example, room temperature.

Each of the crystalline Nl and N-2 forms of the

Compounds (I) and (II) and the Nl crystalline form of Compound (III) have unique characteristics that can distinguish them from each other. These characteristics can be understood by comparing the physical properties of the solid state forms that are present in the later examples. For example, Table 2 lists the characteristic XRPD peak positions (°2θ±0.2°2θ) for crystalline compound (III), Form Nl and Forms Nl and N-2 of crystalline compound (I). Amorphous shapes do not present ίη/ΖΖΠΖ/Β/ΥΙΛΙ reflection peaks in their XRPD patterns.

Table 2

Diffraction peak positions, characteristic (degrees 2Θ+0.2) at RT, based on the pattern collected with a diffractometer (CuKa) with a rotating capillary.

<td>Compound (I) Form Nl</td><td>Compound (I) Form N-2</td><td>Compound (III) Form Nl</td>

<td> 6.4</td><td> 6.4</td><td> 6.4</td>

<td> 9.0</td><td> 9.1</td><td> 9.1</td>

<td> 12.0</td><td> 12.0</td><td> 12.1</td>

<td> 12.8</td><td> 12.8</td><td> 12.8</td>

<td> 13.5</td><td> 13.7</td><td> 13.6</td>

<td> 16.9</td><td> 17.1</td><td> 17.1</td>

<td> 19.4*</td><td> 20.9*</td><td> 19.3</td>

<td> 21.5*</td><td> 21.9*</td><td> 21.4</td>

<td> 22.8*</td><td> 22.6</td><td> 22.8</td>

<td> 25.1*</td><td> 23.7</td><td> 24.1</td>

<td> 27.6*</td><td> —</td><td> 27.6</td>

unique deflections between Compound (I), Form Nl and Compound (I), Form N-2.

Unique reflections between Forms Nl and N-2 of the crystalline compound (II) are designated by an asterisk ίη/ΖΖΠΖ/Β/ΥΙΛΙ (*). As discussed above, Compound (II) is an enantiomer of Compound (I) and thus, Compound (II), Form Nl will have the same characteristic reflection pattern and unique peaks as those listed in Table 2 for Compound (I), Form Nl. Likewise, Compound (II), Form N-2 will have the same characteristic reflection pattern and unique peaks as those listed in Table 2 for Compound (I), Form N-2. Compounds (I) and (II) are distinct from each other based on their absolute stereochemistry, i.e., (L)-malate salt versus (D)-malate salt, respectively. The crystalline compound (III), Form Nl, is distinct as the salt of (D,L)-malate.

The characteristic solid-state NMR peaks can also serve to distinguish the crystalline and amorphous forms described herein. For example, Table 3 lists the NMR peaks¹³C solid state characteristics for crystalline Compound (III), Form Nl; Crystalline compound (I), Forms Nl and N-2 and the amorphous form of Compound (I).

ίη/ΖΖΠΖ/Ε/ΥΙΛΙ

Table 3

<td colspan="4">Solid State Carbon-13 NMR Resonances (ppm, +0.2 ppm)</td>

<td>(I) Form Nl</td><td>(I) Form N-2</td><td>(III) Form N- 1</td><td>(YO), Amorphous</td>

<td> 18.1</td><td> 23.0</td><td> 20.8</td><td> 27.2</td>

<td> 42.9</td><td> 25.9</td><td> 26.2</td><td> 33.8</td>

<td> 44.5</td><td> 38.0</td><td> 44.8</td><td> 142.9</td>

<td> 54.4</td><td> 54.4</td><td> 70.7</td><td> —</td>

<td> 56.1</td><td> 56.1</td><td> 114.7</td><td> —</td>

<td> 70.4</td><td> 41.7</td><td> 141.1</td><td> —</td>

<td> 123.2</td><td> 69.7</td><td> 145.7</td><td> —</td>

<td> 156.2</td><td> 102.0</td><td> 176.3</td><td> —</td>

<td> 170.8</td><td> 122.5</td><td> 182.1</td><td> —</td>

<td> 175.7</td><td> 177.3</td><td> —</td><td> —</td>

<td> 182.1</td><td> 179.3</td><td> —</td><td> —</td>

<td> —</td><td> 180.0</td><td> —</td><td> —</td>

<td> --</td><td> 180.3</td><td> —</td><td> —</td>

NMR Spectra¹⁹F and¹⁵N solid states, as discussed below, provide data for similar characterization and comparison. As discussed above, being an enantiomer of Compound (I), the crystalline Forms Nl and N-2 and the amorphous form of Compound (II) will have the same solid state NMR resonances, and unique peaks between them, as those listed in Table 3 for Forms Nl and N-2 of the crystalline compound (I) ·

Pharmaceutical Compositions and Treatment Methods

Another aspect of this description relates to a pharmaceutical composition comprising at least one Compound (I), Compound (II), Compound (III), or combinations thereof, and a pharmaceutically acceptable excipient. The amount of Compound (I), Compound (II), Compound (III), or combinations thereof in the pharmaceutical composition may be a therapeutically effective amount. Compound (I), Compound (II), or Compound (III) may be present individually in the pharmaceutical composition as one of the solid state forms discussed above or combinations thereof. Crystalline forms are preferred solid state forms. Accordingly, another aspect of this description relates to a dispersion or solid pharmaceutical composition comprising at least one of a therapeutically effective amount of a crystalline form of Compound (I), Compound (II), Compound (III), or combinations thereof, and a pharmaceutically acceptable excipient.

Another aspect of this description relates to a method of treating cancer comprising administering to a subject in need thereof, at least one of Compound (I), Compound (II ), Compound (III) or combinations of these. The amount of Compound (I), Compound (II), or combinations thereof administered may be a therapeutically effective amount. Compound (I), Compound (II), or Compound (III) may be administered individually as one of the solid state forms discussed above or combinations thereof. The crystalline forms are preferred solid state forms, with Crystalline Compound (I), Forms Nl or N-2 being preferred. Accordingly, another aspect of this description relates to a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of at least one of Compound (I), Compound (II), Compound (III), or combinations thereof, wherein Compound (I), Compound (II), or Compound (III) is present in a crystalline form. In another aspect of this disclosure, the method of treatment may be practiced by administering a pharmaceutical composition of at least one of Compound (I), Compound (II), Compound (III) or combinations thereof as discussed above.

Another aspect of this description relates to a method of treating cancer, as discussed above, where the cancer is treated stomach cancer, esophageal carcinoma, kidney cancer, liver cancer, ovarian carcinoma, cervical carcinoma, bowel cancer large intestine, small intestine cancer, brain cancer (including astrocytic tumor, including glioblastoma, giant cell glioblastoma, gliosarcoma and alioblastoma with oligodendroglial components), lung cancer (including non-small cell lung cancer), bone cancer, prostate carcinoma, pancreatic carcinoma, skin carcinoma, bone cancer, lymphoma, solid tumors, Hodgkin's disease, non-Hodgkin's lymphoma or thyroid cancer (including medullary thyroid cancer).

Tyrosine kinase inhibitors have also been used to treat non-small cell lung cancer (NSCLC). Gefitinib and Erlotinib are angiogenesis inhibitors that target receptors for an epidermal growth factor called tyrosine kinase. Erlotinib and Gefitinib are currently being used to treat NSCLC. Another aspect of this disclosure relates to a method of treating non-small cell lung cancer (NSCLC) in a subject, the method comprising administering to the subject in need of treatment a therapeutically effective amount of N-(4-{ [6 ,7bis(methyloxy)quinolin-4-yl]oxy}-phenyl)-Ν'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, or a pharmaceutically acceptable salt thereof, optionally in combination with ίη/ΖΖΠΖ/Ε /ΥΙΛΙ

Erlotinib or Gefitinib. In another embodiment, the combination is with Erlotinib.

Another aspect of this description relates to a method of treating non-small cell lung cancer (NSCLC) in a subject, the method comprising administering to the subject in need of treatment a therapeutically effective amount of Erlotinib or Gefitinib in combination with at least one of Compound (I), Compound (II), Compound (III) or combinations thereof. Compound (I), Compound (II), or Compound (III) may be administered individually as one of the solid state forms discussed above or combinations thereof. Crystalline forms are preferred solid state forms. Accordingly, another aspect of this disclosure relates to a method of treating non-small cell lung cancer (NSCLC) in a subject, the method comprising administering to the subject in need of treatment, a therapeutically effective amount of Erlotinib or Gefitinib in combination with at least one of Compound (I), Compound (II), Compound (III), or combinations thereof, wherein Compound (I), Compound (II), o Compound (III) is present in a crystalline form. In another aspect of this disclosure, this method of treatment can be practiced by administering a pharmaceutical composition of at least one of Compound (I), ίΠ/77Ω7/Β/ΥΙΛΙ

Compound (II), Compound (III) or combinations of these as discussed above. Another embodiment, the combination administered in this method is Erlotinib with at least one of Compound (I), Compound (II), Compound (III), or combinations of these.

Another aspect of this description relates to a method of treating an astrocytic tumor (including glioblastoma, giant cell glioblastoma, gliosarcoma, and glioblastoma with oligodendroglial components in a subject) in a subject, the method comprising administering to the subject in need of the treatment a therapeutically effective amount of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-Ν'-(4-fluorophenyl)cyclopropane-1,1dicarboxamide.

Another aspect of this description relates to a method of treating an astrocytic tumor (including glioblastoma, giant cell glioblastoma, gliosarcoma, and glioblastoma with oligodendroglial components in a subject) in a subject, the method comprising administering to the subject in need of the treatment a therapeutically effective amount of at least one of Compound (I), Compound (II), Compound (III) or combinations thereof. Compound (I), Compound (II), or Compound (III) can be administered individually as one of the solid state forms discussed above or combinations of ίη/ΖΖΠΖ/Β/ΥΙΛΙ these. Crystalline forms are preferred solid state forms. Accordingly, another aspect of this description relates to a method of treating an astrocytic tumor comprising administering to a subject in need thereof a therapeutically effective amount of at least one of Compound (I), Compound (II), Compound (III ), or combinations thereof, wherein Compound (I), Compound (II), or Compound (III) is present in a crystalline form. In another aspect of this disclosure, this method of treatment may be practiced by administering a pharmaceutical composition of at least one of Compound (I), Compound (II), Compound (III) or combinations thereof as discussed above.

Another aspect of this description relates to a method of treating thyroid cancer (including medullary thyroid cancer) in a subject, the method comprising administering to the subject in need of treatment N-(4{[6,7-bis(methyloxy )quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, or a pharmaceutically acceptable salt thereof. The amount administered may be a therapeutically effective amount.

Another aspect of the description relates to a method of treating thyroid cancer (including medullary thyroid cancer) in a subject, the method comprising administering to the subject in need of treatment at least one of Compound (I), Compound (II) , Compound (III) or combinations thereof. Compound (I), Compound (II), or Compound (III) may be administered individually as one of the solid state forms discussed above or combinations thereof. Crystalline forms are preferred solid state forms. Accordingly, another aspect of this description relates to a method of treating thyroid cancer comprising administering to a subject in need thereof a therapeutically effective amount of at least one of Compound (I), Compound (II), Compound (III ), or combinations thereof, wherein Compound (I), Compound (II), or Compound (III) is present in a crystalline form. In another aspect of this disclosure, this method of treatment can be practiced by administering a pharmaceutical composition of at least one of Compound (I), Compound (II), Compound (III) or combinations thereof as discussed above.

Another aspect of this description relates to a method of treating diseases or disorders associated with uncontrolled, normal and/or unwanted cellular activities. This method administers, to a subject in need thereof, at least one of Compound (I), Compound Compound (III) or combinations thereof. The amount of Compound (I), Compound (II), or combinations of these administered may be a therapeutically effective amount. Compound (I), Compound (II), or Compound (III) may be administered individually as one of the solid state forms discussed above or combinations thereof. Crystalline forms are preferred solid state forms.

Accordingly, another aspect of this description relates to a method of treating diseases or disorders associated with uncontrolled, normal and/or unwanted cellular activities comprising administering to a subject in need thereof a therapeutically effective amount of at least one of the Compound ( I) Compound (II), Compound (III), or combinations thereof, wherein Compound (I), Compound (II), or Compound (III) is present in a crystalline form. In another aspect of this disclosure, the method of treatment may be practiced by administering a pharmaceutical composition of at least one of Compound (I), Compound (II), Compound (III) or combinations thereof as discussed above. Another aspect of this description relates to a method of treating diseases or disorders associated with uncontrolled, normal and/or unwanted cellular activities. This method administers, to a subject in need thereof, a crystalline form of Compound (I), Compound (II), or any combination of Compound (I) and (II). The amount of the ίη/ΖΖΠΖ/Β/ΥΙΛΙ

Compound (I), Compound (II), or any combination of Compound (I) and (II) administered may be a therapeutically effective amount.

Another aspect of this disclosure relates to the use of the N-(4-{[6,7-bis(methyloxy)quinolin-4yl]oxy}phenyl)-Ν'-(4-fluorophenyl)cyclopropane-1 malate salt. ,1-dicarboxamide, according to any of the previous modalities for the preparation of a medicine for the treatment of a disease or disorder analyzed above. When dissolved, a crystalline or amorphous form according to this description loses its solid state structure, and is therefore referred to as a solution of, for example, Compound (I). At least one crystalline form described herein can be used to prepare at least one liquid formulation in which at least one crystalline form is dissolved and/or suspended in accordance with the description.

A pharmaceutical composition as discussed above may be any dosage form containing the active Compound (I), Compound and (II) and/or Compound (III) including solid state forms thereof (referred to below). as active compounds). The pharmaceutical composition may be, for example, a tablet, capsule, liquid suspension, injectable, topical or transdermal. The pharmaceutical compositions generally contain from about 1% to about 99% by weight of the active compounds, or a crystalline form of the active compounds, and from 99% to 1% by weight of a suitable pharmaceutical excipient. In one example, the composition will be between about 5% and about 75% by weight of the active compound, with the remainder being suitable pharmaceutical excipients or other adjuvants, as discussed below.

A therapeutically effective amount of the active compounds, or a crystalline or amorphous form of the active compounds, according to this disclosure for inhibiting, regulating and/or modulating the signal transduction of kinases (discussed herein with respect to pharmaceutical compositions) is refers to an amount sufficient to treat a patient suffering from any of a variety of cancers associated with abnormal cell proliferation and angiogenesis. A therapeutically effective amount according to this disclosure is a therapeutically useful amount for the treatment or prevention of the disease states and disorders discussed herein. Compounds (I), (II) and/or (III) (including their solid state forms), have therapeutic activity to inhibit, regulate and/or modulate kinase signal transduction, as described in WO2005-030140 . N-(4-{[6,7bis(methyloxy)quinolin-4-yl]oxy} phenyl)-Ν'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.

ίη/ΖΖΠΖ/Β/ΥΙΛΙ ίη/ΖΖΠΖ/Β/ΥΙΛΙ

The actual amount required for the treatment of any particular patient will depend on a variety of factors, including the disease state being treated and its severity, the specific pharmaceutical composition employed; the patient's age, body weight, general health, sex, and diet; the mode of administration; administration time; the route of administration; and the rate of excretion of the active compounds, or a crystalline form of the active compounds, according to this description; the duration of treatment; any of the drugs used in combination or coincident with the specific compound used; other factors well known in medical techniques. These factors are discussed in Goodman and Gilman's The Pharmacological Basis of Therapeutics, Tenth Edition, A. Gilman, J.Hardman and L. Limbird, eds., McGrawHill Press, 155-173, 2001, which is incorporated herein by reference. The active compounds, or a crystalline form of the active compounds, according to this description and the pharmaceutical compositions comprising them, can be used in combination with other anticancer agents that are generally administered to a patient who is treated with cancer. They may also be co-formulated with one or more of these agents in an individual pharmaceutical composition.

Depending on the type of pharmaceutical composition, the pharmaceutically acceptable carrier may be chosen from any or a combination of carriers known in the art. The choice of pharmaceutically acceptable carrier depends partially on the desired method of administration to be used. For a pharmaceutical composition of this description, that is, one of the active compounds, or a crystalline form of the active compounds, of this description, a carrier must be chosen to substantially maintain the particular form of the active compounds, whether it is crystalline or not. In other words, the carrier must not substantially alter the form in which the active compounds are. Nor must the carrier be otherwise incompatible with the form of the active compounds, such as by producing any undesirable biological effects or otherwise interacting detrimentally with any of the other components of the pharmaceutical composition.

The pharmaceutical compositions of this disclosure can be prepared by methods known in the art of pharmaceutical formulation, For example, see Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pennsylvania, 1990). In a solid dosage form, Compound (I) is mixed with at least one pharmaceutically acceptable excipient, such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, such as starches, lactose, sucrose, glucose , mannitol and silicic acid, (b) binders, such as cellulose derivatives, starch, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia gum, (c) humectants, such as glycerol, (d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates and sodium carbonate, (e) solution retarders, such as paraffin, (f) absorption accelerators, such as, for example, quaternary ammonium compounds, (g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate, magnesium stearate and the like (h) adsorbers, such as, for example, kaolin and bentonite, and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Known pharmaceutically acceptable adjuvants in pharmaceutical formulation may also be used in the pharmaceutical compositions of this disclosure. These include, but are not limited to, preservatives, humectants, suspending agents, sweeteners, flavorings, flavorings, emulsifiers and dispersants. Prevention of the action of microorganisms can be ensured by various ίη/ΖΖΠΖ/Β/ΥΙΛΙ antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. If desired, a pharmaceutical composition of this description may also contain minor amounts of auxiliary substances, such as wetting or emulsifying agents, pH buffering agents and antioxidants, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, and butylated hydroxytoluene.

Solid dosage forms as described above can be prepared with coatings and coatings, such as enteric coatings and others well known in the art. They may contain opacifying agents, and may also be of such a composition that they release the active compound(s) in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds may also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

The suspensions, in addition to the active compounds, may contain suspending agents, such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, ίη/ΖΖΠΖ/Β/ΥΙΛΙ and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar- agar and tragacanth, or mixtures of these substances, and the like.

Compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the active compounds, or a crystalline form of the active compounds, with, for example, suitable non-irritant excipients or carriers, such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary temperatures, but liquid at body temperature and therefore melt, while they are in a suitable body cavity and release the active component therein.

Because the active compounds, or a crystalline form of the active compounds, are maintained during their preparation, solid dosage forms are preferred for the pharmaceutical composition of this disclosure. Solid dosage forms for oral administration, including capsules, tablets, pills, powders and granules, are particularly preferred. In these solid dosage forms, the active compounds, mixed with at least one inert pharmaceutically acceptable excipient (also known as a pharmaceutically acceptable carrier). Administration of the active compounds, or a crystalline form of the active compounds, in pure form or in an appropriate pharmaceutical composition, can be carried out by any of the accepted modes of administration or agents to serve for similar utilities. In this way, the administration can be, for example, orally, nasally, parenterally (intravenously, intramuscularly or subcutaneously), topically, transdermally, intravaginally, intravesically, intracystemally, or rectally, in the form of solid, semisolid, powder. lyophilized, or liquid dosage forms, such as, for example, tablets, suppositories, pills, hard and soft elastic gelatin capsules, powders, solutions, suspensions or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise doses. A preferable route of administration is oral administration, using a convenient dosage regimen that can be adjusted according to the degree of severity of the disease state being treated.

General Preparation Methods of Crystalline Forms

Crystalline forms can be prepared by a variety of methods including, but not limited to, for example , crystallization or recrystallization in a suitable mixture of solvents; sublimation; growth of a melt; solid state transformation of another phase; crystallization of a supercritical fluid; and jet spray. Techniques for crystallization or recrystallization of crystalline forms from a solvent mixture include, but are not limited to, for example, evaporation of the solvent, lowering the temperature of the solvent mixture, seeding crystals from a supersaturated solvent mixture of the compound. and/or get out of it; seeding crystals of a supersaturated solvent mixture of the compound and/or a salt thereof; freeze drying of the solvent mixture; and the addition of antisolvents (countersolvents) to the solvent mixture. High-performance crystallization techniques can be used to prepare crystalline forms that include polymorphic substances.

Drug crystals, including polymorphic substances, preparation methods, and characterization of drug crystals are discussed in Solid-State Chemistry of Drugs, SR Byrn, RR Pfeiffer, and JG Stowell, 2^n.d. Ed, SSCI, West Lafayette, Indiana (1999).

In a crystallization technique in which the solvent is employed, the solvents are typically chosen based on one or more factors, including but not limited to, for example, solubility of the compound; crystallization technique used; and vapor pressure of the solvent. Combinations of solvents can be used. For example, the compound can be solubilized in a first solvent to give a solution to which the antisolvent is then added to decrease the solubility of Compound (I) in the solution and precipitate the formation of crystals. A bbhb ίη/ΖΖΠΖ/Ε/ΥΙΛΙ ίη/ΖΖΠΖ/Ε/ΥΙΛΙ antisolvent is a solvent in which a compound has low solubility.

In a method that can be used when preparing crystals, Compound (I), Compound (II) and/or Compound (III) can be suspended and/or stirred in a suitable solvent to give a thick suspension, which can be heated to promote dissolution. The term slurry, as used herein, means a saturated solution of the compound, wherein the solution may contain an additional amount of compound to give a heterogeneous mixture of compound and solvent at a given temperature.

Seed crystals can be added to any crystallization mixture to promote crystallization. Seeding may be employed to control the growth of a particular polymorphic substance and/or to control the particle size distribution of the crystalline product. Therefore, the calculation of the number of seeds needed depends on the size of the seed available and the desired size of an average particle of product as described, for example, in Programmed Cooling Batch Crystallizers, JW Mullin and J.

Nyvlt, Chemical Engineering Science, 1971, 26, 3690377. In general, small seed sizes are needed to effectively control crystal growth in the batch. Small seeds can be generated by sieving, grinding or micronizing large crystals or by microcrystallizing a solution. In grinding or micronizing crystals, care must be taken to avoid changing the crystallinity of the desired crystalline form (i.e., changing to an amorphous or other polymorphic form).

A cooled crystallization mixture can be filtered under vacuum and the isolated solid product washed with a suitable solvent, such as, for example, cold recrystallization solvent. After it is washed, the product can be dried under a nitrogen purge to give the desired crystalline form. The product may be analyzed by a suitable analytical or spectroscopic technique, including but not limited to, for example, differential scanning calorimetry (DSC), x-ray powder diffraction (XRPD): and thermogravimetric analysis (TGA) to ensure that the crystalline form of the compound has been formed. The resulting crystalline form can be produced in an amount greater than about 70% by weight of isolated yield, based on the weight of the compound originally used in the crystallization process, and preferably greater than about 90% by weight of isolated yield. .

Optionally, the product can be deagglomerated by being co-ground or by passing through a mesh sieve.

The features and advantages of this description can be more easily understood by those skilled in the art by reading the following detailed description. It will be appreciated that certain features of the invention that are, for reasons of clarity, described above and below in the context of separate embodiments, may also be combined to form a further embodiment. Conversely, various features of this description that are, for the sake of brevity, described in the context of an individual modality, may also be combined to form sub-combinations thereof. The description is further illustrated by the following examples, which are not to be considered as limiting the description in scope or spirit to the specific procedures described therein.

The definitions set forth herein take precedence over the definitions set forth in any patent, patent application and/or patent application publication incorporated herein by reference. All measurements are subject to experimental error and are within the spirit of the invention.

As used herein, amorphous refers to a solid form of a molecule and/or ion that is not crystalline. An amorphous solid does not exhibit a definitive x-ray diffraction pattern with a sharp maximum.

As used herein, the term "substantially pure" means the crystalline form of Compound (I) referred to as containing at least about 90% by weight based on the weight of this crystalline form. The term at least about 90% by weight, while not intended 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, about 91, about 92 , approximately 93, approximately 94, approximately 95, approximately 96, approximately 97, approximately 98, approximately 99 and approximately 100% by weight. The % is referred to based on the weight of the crystalline form. The remainder of the crystalline form of Compound (I) may comprise other forms of Compound (I) and/or reaction impurities and/or processing impurities that arise, for example, when the crystalline form is prepared. The presence of reaction impurities and/or processing impurities can be determined by analytical techniques known in the art, such as, for example, chromatography, nuclear magnetic resonance spectroscopy, mass spectroscopy and/or infrared spectroscopy.

Preparatory Examples

Example 1: Preparation of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-Ν'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and the salt of (L)-malate thereof (Compound (I)).

The synthetic route used for the preparation of N(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4fluorophenyl)cyclopropane-1,1-dicarboxamide and the salt of (L) malate thereof is represented in reaction scheme 1: Reaction Scheme 1

<img file="MX2022014444A_D0004.tif" />

<img file="MX2022014444A_D0005.tif" />

2.C· Lundma

<img file="MX2022014444A_D0006.tif" />

<img file="MX2022014444A_D0007.tif" />

The process shown in Reaction Scheme 1 is described in more detail below.

1.1 Preparation of 4—Chloro-6,7—dimethoxy—quinoline

A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol (1 L, 10.0 kg) and acetonitrile (64.0 L). The resulting mixture was heated to approximately 65°C and phosphorus oxychloride (POCl3, 50.0 kg) was added. After the addition of POCl3, the temperature of the reaction mixture was increased to approximately 80 °C. The reaction was judged complete (approximately 9.0 hours) when &lt;2% of the starting material remained (in high-performance liquid chromatography [HPLC] analysis of the process). The reaction mixture was cooled to approximately 10°C and then quenched in a cooled solution of dichloromethane (DCM, 238.0 kg), NH₄30% OH (135.0 kg) and ice (440.0 kg). The resulting mixture was heated to approximately 14°C, and the phases were separated. The organic phase was washed with water (40.0 kg) and concentrated by vacuum distillation with the removal of solvent (approximately 190.0 kg). Methyl t-butyl ether (MTBE, 50.0 kg) was added to the batch, and the mixture was cooled to approximately 10°C, during which time the product crystallized. The solids were recovered by centrifugation, washed with n-heptane (20.0 kg) and dried at approximately 40 °C to give the title compound (8.0 kg).

1.2 Preparation of 6,7-Dimethyl-4-(4-nitro-phenoxy)-quinoline A reactor was sequentially charged with 4-chloro6,7-dimethoxy-quinoline (8.0 kg), 4-nitrophenol (7.0 kg), 4-dimethylaminopyridine ( 0.9 kg), and 2,6-lutidine (40.0 kg). The reactor contents were heated to approximately 147°C. When the reaction was complete (&lt;5% starting material remaining as determined by in-process HPLC analysis, approximately 20 hours), the reactor contents were allowed to cool to approximately 25°C. Methanol (26.0 kg) was added, followed by potassium carbonate (3.0 kg) dissolved in water (50.0 kg). The reactor contents were stirred for approximately 2 hours. The resulting solid precipitate was filtered, washed with water (67.0 kg) and dried at 25°C for about 12 hours to give the title compound (4.0 kg).

1.3 Preparation of 4-(6,7-Dimethoxy-quinoline-4-yloxy)phenylamine

A solution containing potassium formate (5.0 kg), formic acid (3.0 kg) and water (16.0 kg) was added to a mixture of 6,7-dimethoxy-4-(4-nitro-phenoxy)-quinoline (4.0 kg). ), 10% palladium on carbon (50% water, wet, 0.4 kg) in tetrahydrof urane (40.0 kg) that has been heated to approximately 60 °C. The addition was carried out such that the temperature of the reaction mixture remained approximately 60°C. When the reaction was judged complete as determined using in-process HPLC analysis (&lt;2% starting material remaining, typically 15 hours), the reactor contents were filtered. The filtrate was concentrated by vacuum distillation at approximately 35°C to half its original volume, resulting in precipitation of the product. The product was recovered by filtration, washed with water (12.0 kg) and dried under vacuum at approximately 50°C to give the title compound (3.0 kg; 97% AUC).

ίη/ΖΖΠΖ/Β/ΥΙΛΙ

1.4 Preparation of 1-(4-fluoro-phenyl-carbamoyl)-cyclopropanecarboxylic acid

Triethylamine (8.0 kg) was added to a cooled (approximately 4°C) solution of commercially available cyclopropane-1,1dicarboxylic acid (2 1, 10.0 kg) in THF (63.0 kg) at a rate such that the temperature of the batch does not exceed 10°C. The solution was stirred for approximately 30 minutes, and then thionyl chloride (9.0 kg) was added, maintaining the batch temperature below 10°C. When the addition was completed, a solution of 4-fluoroaniline (9.0 kg) in THF (25.0 kg) was added at a rate such that the temperature of the batch does not exceed 10°C. The mixture was stirred for approximately 4 hours and then diluted with isopropyl acetate (87.0 kg). This solution was washed sequentially with aqueous sodium hydroxide (2.0 kg dissolved in 50.0 L of water), water (40.0 L), and aqueous sodium chloride (10.0 kg dissolved in 40.0 L of water). The organic solution was concentrated by vacuum distillation followed by the addition of heptane, which resulted in precipitation of solid. The solid was recovered by centrifugation and then dried at approximately 35°C under vacuum to give the title compound. (10.0kg) .

1.5 Preparation of 1-(4-fluoro-phenylcarbamoyl)cyclopropanecarbonyl chloride

Oxalyl chloride (1.0 kg) was added to a solution of 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (2.0 kg) in a mixture of THF (11 kg) and N,Ndimethylformamide (DMF; 0.02 kg) at a speed such that the temperature of the batch does not exceed 30°C. This solution was used in the next step without further processing. 1.6 Preparation of N-(4{[6,7-bis(methyloxy)quinolin-4-yl]oxy)phenyl)-Ν' -(4-fluorophenyl)cyclopropane-1,1-dicarboxamide The solution from the previous step containing 1-(4-fluoro-phenyIcarbamoyl)cyclopropanecarbonyl chloride was added to a mixture of 4-(6,7dimethoxy-quinoline-4-yloxy)-phenylamine (3.0 kg) and potassium carbonate (4.0 kg) in THF (27.0 kg ) and water (13.0 kg) at a rate such that the temperature of the batch does not exceed 30°C. The mixture was stirred at 15-30°C for approximately 10 hours which resulted in precipitation of the product. The product was recovered by filtration, washed with a pre-produced solution of THF (11.0 kg) and water (24.0 kg), and dried at about 65°C under vacuum for about 12 hours to give the title compound (base free, 5.0 kg). NMR-¹H (400 MHz, dg-DMSO) : δ 10.2 (s, 1H), 10.05 (s, 1H), 8.4 (s, 1H), 7.8 (m, 2H), 7.65 (m, 2H), 7.5 (s, 1H), 7.35 (s, 1H), 7.25 (m, 2H), 7.15 (m, 2H), 6.4 (s, 1H), 4.0 (d, 6H), 1.5 (s, 4H). LC/MS: M+H= 502.

ίη/ΖΖΠΖ/Β/ΥΙΛΙ ίη/ΖΖΠΖ/Β/ΥΙΛΙ

1.7 Preparation of N-(4{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'~(4-fluorophenyl)cyclopropane-1,1- (L)-malate salt dicarboxamide, (Compound (I))

A solution of (L)-malic acid (2.0 kg) in water (2.0 kg) was added to a free base solution of [4-(6,7dimethoxy-quinoline-4—yloxy)—phenyl]-amide(4-fluoro -phenyl)cyclopropane-1,1-dicarboxylic acid amide (1 5, 5.0 kg) in ethanol, maintaining a batch temperature of approximately 25°C. Carbon (0.5 kg) and thiol-silica (0.1 kg) were then added, and the resulting mixture was heated to approximately 78 °C, at which point water (6.0 kg) was added. The reaction mixture was then filtered, followed by the addition of isopropanol (38.0 kg), and allowed to cool to approximately 25°C. The product was recovered by filtration and washed with isopropanol (20.0 kg) and dried at approximately 65 ° C to give Compound (I) (5.0 kg). Example 2: Preparation of Crystalline Compound (I), Form Nl

A solution was prepared by adding tetrahydrofuran (12 mL/g-volume-LR limiting reagent); 1.20 L) and N-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (100 g; 1.00 equiv; 100.00 g) and (L)-malic acid (1.2 equiv (molar); 32.08 g) to a 1 L reactor. Water (0.5317 mL/gvolume-LR; 53.17 mL) was added and the solution was heated to 60°C and kept at that temperature for one hour until the solids were completely dissolved. The solution was passed through a wax filter.

At 60°C, acetonitrile (12 mL/g-volumeLR; 1.20 L) was added over a period of 8 hours. The solution was kept at 60°C for 10 hours. The solution was then cooled to 20°C and held for 1 hour. The solids were filtered and washed with acetonitrile (12 mL/g-volume-LR; 1.20 L). The solids were dried at 60°C (25 mm Hg) for 6 hours to give Compound (I), Form Nl (108 g; 0.85 equiv; 108.00 g; 85.22% yield) as a white crystalline solid.

Example 3: Alternate Preparation of Crystalline Compound (I), Form Nl

A solution was prepared with 190 mL of tetrahydrofuran (110 mL), methyl isobutyl ketone, and 29 mL of water. Then, 20 mL of this solution was transferred into an amber bottle, and then saturated by adding N-(4-{[6,7bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-Ν'-(4fluorophenyl )cyclopropane-1,1-dicarboxamide, (L)-malate until a thick suspension was formed, and aged for at least 2 h with stirring at room temperature. The solids were removed by filtration through a Buchner funnel, producing a clear, saturated solution.

Separately, a powder mixture was produced with known quantities from two lots of Compound (I): (1) ίη/ΖΖΠΖ/Β/ΥΙΛΙ

300 mg of lot 1, which contained approximately 41% of Compound (I), Form Nl and 59% of Compound (I), Form N-2 by Raman spectroscopy analysis, and (2) 200 mg of lot 2, which has a XPRD pattern similar to Compound (I), Form N-2.

The powder mixture of Compound (I), Form Nl and the Compound. (I), Form N-2 was added to the saturated solution, and the thick suspension was aged under magnetic stirring at room temperature for 25 days. The slurry was then sampled and filtered through a Buchner funnel to obtain 162 mg of the wet cake. The wet cake was dried in a vacuum oven at 45°C to give 128 mg of the crystalline compound (I) in Form Nl.

Example 4: Preparation of Crystalline Compound (I), Form N2

4.1 Preparation of Crystalline Compound (I), Form N-2 Seed Crystals

A solution was prepared by combining 20 ml of acetone and 300 mg of the free base N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-Ν' -(4-fluorophenyl )cyclopropane-1,1dicarboxamide in a 25 ml screw cap bottle. Then, 0.758 ml of a concentrated 0.79M (L)-malic acid solution was added to the flask with magnetic stirring. The solution was then allowed to stir for 24 hours at room temperature. The sample was then filtered by suction with a 0.45 μιη PTFE filter cartridge and dried in vacuo at room temperature overnight.

4.2 Preparation of Crystalline Compound (I), Form N-2.

N-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-Ν'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (48 g; 1.00 equiv; 48.00 g) and tetrahydrofuran (16.5 mL/g-volume-LR; 792.00 mL). The water content was adjusted to 1 wt% water. The solution was heated to 60°C. Once dissolved, the solution was passed through a wax filter to provide the first solution.

In a separate reactor, (L) malic acid (1.2 equiv (molar); 15.40 g) was dissolved in methyl isobutyl ketone (10 mL/g-volume-LR; 480.00 mL) and tetrahydrofuran (1 mL/g-volume-LR ; 48.00 mL). Then, 50 mL of the (L)-malic acid solution was added to the first solution at 50°C. Seed crystals (1%, 480 mg) were added and the malic acid solution was added at 50 °C dropwise using an addition funnel (1.3 ml/min (3 h)). The slurry was kept at 50°C for 18 hours and then cooled to 25°C for 30 minutes. The solids were filtered, and washed with 20% tetrahydrofuran/methyl isobutyl ketone (10V, 480 mL). The solids were dried under vacuum at 60°C for 5 hours to give Compound (I) (55.7 g; 0.92 equiv; 55.70 g; 91.56% yield) as an off-white crystalline solid.

ίη/ΖΖΠΖ/Β/ΥΙΛΙ

Example 5: Preparation of Crystalline Compound (III), Form Nl

A 1 ml aliquot of N-(4-{[6,7-bis(methyloxy)-quinolin-4-yloxy}phenyl)-Ν'-(4fluorophenyl)cyclopropane-1 (DL)-malic acid salt, 1-Dicarboxamide, slurried in tetrahydrof urane (THF), was heated to 60°C on a hot plate in a half-dram flask. Then, tetrahydrofuran was added drop by drop until an almost clear solution was obtained. The flask was capped, removed from the hot plate, and equilibrated at room temperature without stirring. Crystallization was evident after several hours and the solution was allowed to stand overnight to allow completion. Several drops of the resulting thick suspension were placed on a glass slide for microscopic analysis. The crystalline material consisted of many elongated plates ranging up to 60 microns in the longest dimension.

Alternative Preparation of Crystalline Compound (III) Form Nl

N-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-Ν'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (15 g) was added to a reactor. ; 1.00 equiv; 15.00 g) and tetrahydrofuran (16.5 mL/g-volume-LR; 792.00 mL). The water content was adjusted to 1 wt% water. The solution was heated to 60°C. Once dissolved, the solution was passed through a wax filter to provide the first solution.

In a separate reactor, malic acid (DL) (1.2 equiv (molar); 4.53 g) was dissolved in methyl isobutyl ketone (8 mL/g-volume-LR; 120.00 mL) and tetrahydrofuran (1 mL/g-volume-LR ; 15.00 mL). Then, 20 mL of the solution was added to the first solution at 50°C. The malic acid solution was added dropwise at 50°C using an addition funnel (1.3 ml/min (3 h)). The slurry was kept at 50°C for 18 hours and then cooled to 25°C for 30 minutes. The solids were filtered, and washed with 20% THF/MIBK (10V, 150 mL). The solids were dried under vacuum at 60°C for 5 hours to give Compound (III) (15.52 g; 86.68% yield) as an off-white solid.

Example 6: Preparation of Amorphous Compound (I)

A solution was prepared with 5 g of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-Ν'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (L)-malate and 250 mL of a 1:1 (v:v) mixture of methanol and dichloromethane. The hazy solution was filtered through a 0.45 micron filter to produce a clear, yellowish solution. The solution was pumped through the nozzle of the spray dryer at a rate of 12.9 cc/min, and atomized by nitrogen gas fed at a rate of 10.9 L/min. The temperature at the cyclone inlet was set to 65°C to dry the wet ίη/ΖΖΠΖ/Ε/ΥΙΛΙ ίη/ΖΖΠΖ/Β/ΥΙΛΙ droplets. Dry amorphous powder (1.5 g) was collected (yield = 30%).

Examples of Characterization

I. NMR Spectra in Dimethyl Sulfoxide Solution 1.1 Compound (I), Form Nl

NMR-³H (400 MHz, d₆-DMSO) : δ 1.48 (s, 1H), 2.42-2.48 (m, 1H), 2.60-2.65 (m, 1H), 3.93-3.96 (m, 6H), 4.25-4.30 (dd, 1 H, J = 5, 8 Hz), 6.44 (d, 1H, J = 5 Hz, 1H), 7.12-7.19 (m,

2H), 7.22-7.26 (m, 2H), 7.40 (s, 1H), 7.51 (s, 1H), 7.63-7.68 (m, 2H), 7.76-7.80 (m, 2H), 8.46-8.49 (m, 1H), 10.08 (s,

11H), 10.21 (s, 1H).

NMR-¹³C (dg-DMSO): 15.36, 31.55, 55.64, 55.67,

66.91, 99.03, 102.95, 107.66, 114.89, 115.07, 115.11, 121.17, 122.11 122.32, 122.39, 135.15, 136.41, 146.25, 148.7, 149.28, 149.38, 152.54, 157.03, 159.42, 160.02, 168.07, 171.83,

174.68 .

1.2 Compound (I), Form N-2

RME-iR (400 MHz, d₆-DMSO) : δ 1.48 (s, 1H), 2.42-2.48 (m, 1H), 2.60-2.65 (m,1H), 3.93-3.96 (m, 6H), 4.25-4.30 (dd, 1 H, J = 5, 8 Hz), 6.44 (d, J = 5 Hz, 1H), 7.12-7.19 (m, 2H), 7.22-7.26 (m, 2H), 7.40 (s, 1H), 7.51 (s, 1H), 7.63-7.68 (m, 2H), 7.76-7.80 (m, 2H), 8.46-8.49 (m, 1H), 10.08 (s, 1H),

10.21 (s, 1H).

NMR-¹³C (d₆-DMS0) : 15.36, 31.55, 55.64, 55.67,

66.91, 99.03, 102.95, 107.66, 114.89, 115.07, 115.11, 121.17, ίη/ΖΖΠΖ/Β/ΥΙΛΙ

122.11, 122.32, 122.39, 135.15, 136.41, 146.25, 148.7,

149.28, 149.38, 152.54, 157.03, 159.42, 160.02, 168.07,

171.83, 174.68.

1.3 Compound (III), Form Nl

iH-NMR (400 MHz, dg-DMSO): δ 1.48 (s, 1H), 2.42-2.48 (m, 1H), 2.60-2.65 (m, 1H), 3.93-3.96 (m, 6H), 4.25-4.30 (dd, 1H, J = 5, 8 Hz), 6.44 (d, J = 5 Hz, 1H), 7.12-7.19 (m, 2H), 7.22-7.26 (m, 2H), 7.40 (s, 1H), 7.51 (s, 1H), 7.63-7.68 (m, 2H), 7.76-7.80 (m, 2H), 8.46-8.49 (m, 1H), 10.08 (s, 1H),

10.21 (s, 1H).

NMR-¹³C (d₆-DMSO) : 15.36, 31.55, 55.64, 55.67,

66.91 , 99.03, 102.95, 107.66, 114.89, 115.07, 115.11, 121.17, 122.11, 122.32, 122.39, 135.15, 136.41, 146.25, 148.7,

149.28 , 149.38, 152.54, 157.03, 159.42, 160.02, 168.07,

171.83 , 174.68.

Characterization of the Solid State Forms of N-(4-{[6,7bis(methyloxy)quinolin-4-yl]oxy}phenyl)-Ν' -(4fluorophenyl)cyclopropane-1,1-dicarboxamide, malate II Studies of X-ray Powder Diffraction (XRPD)

X-ray powder diffraction (XRPD) patterns were collected on a Bruker AXS C2 GADDS diffractometer equipped with an automated XYZ stage, video-laser microscope for sample placement, and a HiStar two-dimensional area detector. The radiation source used was copper (Cu Ka = 1.5406 Á), where the voltage was set to 40 kV and ίη/ΖΖΠΖ/Β/ΥΙΛΙ the current was set to 40 mA, the X-ray optics consisted of a multilayer mirror Single gobel coupled with a 0.3 mm pinhole collimator. The beam divergence, that is, the effective size of the X-ray beam in the sample, was approximately 4 mm. A 0-0 continuous scan mode was used with a sample-detector distance of 20 cm giving an effective interval of 3.2^either29.8°. Run samples under ambient conditions (approximately 18°C ​​to approximately 25°C) were prepared as flat plate specimens using as-received powder without grinding. Approximately 1-2 mg of the sample was lightly pressed on a glass slide to obtain a flat surface. Typically, the sample will be exposed to the x-ray beam for 120 seconds. The beam divergence (i.e. the effective x-ray spot size) gives a value of approximately 4 mm. Alternatively, powder samples were placed in sealed glass capillaries of 1 mm or less in diameter; the capillary was rotated during data collection at a sample-detector distance of 15 cm. Data were collected for 3^20^35° with a sample exposure time of at least 2000 seconds. The resulting two-dimensional diffraction areas were integrated to create a traditional, 1-dimensional XRPD pattern with a step size of 0.02 °20 in the range 3 to 35⁰20 ± 0.2 ⁰twenty. The software used for ίη/ΖΖΠΖ/Β/ΥΙΛΙ data collection was GADDS for WNT 4.1.16 and data were analyzed and presented using Diffrac Plus EVA v 9.0.0.2 or 13.0.0.2.

II.1 Compound (I), Form Nl

Figure 1 shows the experimental XRPD pattern of Crystalline Compound (I), Form Nl acquired at room temperature (approximately 25 °C). A list of the peaks is shown in Table 2 above. The 2Θ values ​​at 19.4, 21.5, 22.8, 25.1, and 27.6 ( + 0.2°2θ) are useful for characterizing crystalline Compound (I), Form Nl. The complete list of peaks, or a subset thereof, may be sufficient to characterize crystalline Compound (I), Form Nl.

II.2 Compound (I), Form N-2

Figure 8 shows the experimental XRPD pattern of crystalline Compound (I), Form N-2 acquired at room temperature (approximately 25°C). A list of the peaks is shown in Table 2 above. The 2Θ values ​​at 20.9 and 21.9 (± 0.2°2θ) are useful to characterize the

Crystalline compound (I), Form N-2. The complete list of peaks, or a subset thereof, may be sufficient to characterize crystalline Compound (I), Form N-2.

II.3 Compound (III), Form Nl

Figure 15 shows the simulated and experimental XRPD pattern of Crystalline Compound (III), Form Nl, ίη/ΖΖΠΖ/Β/ΥΙΛΙ acquired at 25°C using a rotating capillary sample. A list of the peaks is shown in Table 2 above. The complete list of peaks, or a subset thereof, may be sufficient to characterize crystalline Compound (III), Form N-2.

II.4 Amorphous Compound (I)

Figure 22 shows the experimental XRPD pattern of amorphous Compound (I) acquired at room temperature (approximately 25°C). The spectra are characterized by a broad peak and the absence of sharp peaks, which is consistent with an amorphous material.

III. Single Crystal X-ray Study for Compound (III), Form Nl

Data were collected on a Bruker-Nonius CAD4 serial diffractometer. Unit cell parameters were obtained through least squares analysis of the experimental diffractometer settings of 25 high-angle reflections. Intensities were measured using Cu Κα radiation (λ = 1.5418 Á) at a constant temperature with the Θ-2Θ variable scan technique and were corrected for Lorentz polarization factors only. Background counts were collected at the ends of the scan for the middle of the scan time. Alternatively, single crystal data were collected on a Bruker-Nonius Kappa CCD 2000 system using Cu ίη/ΖΖΠΖ/Β/ΥΙΛΙ radiation

Κα (λ, = 1.5418 Á) . Indexing and processing of the measured intensity data was carried out with the HKL2000 software package (Otwinowski, Z. &amp; Minor, W. (1997) in Macromolecular Crystallography, eds. Cárter, WC Jr &amp; Sweet, RM (Academia, NY), Vol. 276, pp.307-326) in the Collect program suite (Collect Data collection and Processing user interface: Collect: Data collection software, R. Hooft, Nonius BV, 1998). Alternatively, single crystal data were collected on a Bruker-AXS APEX2 CCD system using Cu Κα radiation (λ= 1.5418 Á). Indexing and processing of the measured intensity data was carried out with the APEX2 Data collection and processing user interface: APEX2 software package/program suite.

User Manual, vi.27). Where indicated, crystals were cooled in the cold stream of an Oxford cryogenic system (Oxford Cryosystems Cryostream cooler: J. Cosier and AM Glazer, J. Appl. Cryst., 1986, 19, 105) during data collection.

The structures were solved by direct methods and refined based on the observed reflections using either the SDP software package (SDP, Structure Determination Package, Enraf-Nonius, Bohemia NY 11716. Scattering factors, including f' and f'^r , in the SDP software were taken from the International Tables for Crystalloqraphy, Kynoch Press, Birminqham, England, 1974; Vol IV, Tables

2.2Α and 2.3.1) with minor local modifications or the crystallographic packages (MAXUS solution and refinement software suite: S. Mackay, CJ Gilmore, C. Edwards, M. Tremayne, N. Stewart, K. Shankland. maXus: a computer program for the solution and refinement of crystal structures from diffraction data) or SHELXTL (APEX2 Data collection and processing user interface: APEX2 User Manual, vi.27).

The derived atomic parameters (coordinates and temperature factors) were refined through full-matrix least squares. The function minimized in the refinements was Ew(IF_either I - IF_cYO)² · R is defined as The IF_either IIF_c | | /EIF_either I while R_w = [Ew (I Fo I - I Fc I)²/Ew ( I Fo I²] ^1/2 where w is an appropriate weighting function based on errors in the observed intensities. Difference maps were examined at all stages of refinement. Hydrogens were introduced into the idealized positions with isotropic temperature factors, but the parameters of the hydrogens were not varied.

Hybrid, simulated , 80). Cell parameters at room temperature were obtained by performing cell refinement using the program

CellRefine.xls. The inputs to the program include the 2-boob position of ca. 10 reflections, obtained from the experimental powder pattern at room temperature; The corresponding Miller indices, hkl, were assigned based on the single crystalline data collected at low temperature. A new (hybrid) XRPD was calculated (by either of the software programs, Alex or LatticeView) by inserting the molecular structure determined at low temperature into the room temperature cell obtained in the first step of the procedure. The molecules are inserted in a way that retains the size and shape of the molecule and the position of the molecules with respect to the origin of the cell, but, allows the intermolecular distances to expand with the cell.

A single crystal, measuring 40 x 30 x 10 microns, was selected from the slurry of crystals described in Example 5 for single crystal diffraction analysis. The selected crystal was fixed to a thin glass fiber with a small amount of light grease, and mounted at room temperature in a Bruker ApexII single crystal diffractometer equipped with a rotating copper anode.

Crystalline Compound (III), Form Nl is characterized by unit cell parameters approximately equal to those reported in Table 4. The unit cell parameters were measured at a temperature of approximately 25°C.

bbhb ίη/ΖΖΠΖ/Β/ΥΙΛΙ

Table 4 a = 14.60 Á b = 5.20 Á c = 39.09 Á a = 90.0 ° β = 90.4 ° γ = 90.0° Space group R2i/n Molecules of Compound (I)/unit cell: 4 Volume = 2969 Á³

Structure refinement and solution was routine in the monoclinic space group, P2i/n, with four formula units in the unit cell. The structure contains N-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-N'(4-fluorophenyl)cyclopropane-1,1-dicarboxamide cations, protonated in the quinoline nitrogen atom, and individually ionized anions of malic acid, in a 1:1 ratio. Additionally, the crystal contained a 1:1 ratio of (L)-malic acid ions to (D)-malic acid ions. Table 5 shows the fractional atomic coordinates for ίη/ΖΖΠΖ/Β/ΥΙΛΙ

Compound (III), Form Nl calculated at a temperature of approximately 25°C.

Based on the single crystal X-ray data, crystalline Compound (III), Form Nl can be characterized by a simulated and/or by an observed pattern of XRPD substantially in accordance with the experimental patterns shown in Figure 15.

Table 5

Fractional Atomic Coordinates for Compound (III), Form

Nl Calculated at a temperature of approximately 25°C

<td>Atom</td><td>x</td><td>AND</td><td>Z</td><td>Atom</td><td>x</td><td>AND</td><td>Z</td>

<td> 01</td><td> 0.30601</td><td> -0.52166</td><td> 0.22875</td><td>C40</td><td> 0.25712</td><td> -0.35516</td><td> 0.17574</td>

<td> 02</td><td> 0.29518</td><td> 0.12504</td><td> 0.09391</td><td>C41</td><td> 0.63543</td><td> 0.13842</td><td> 0.29041</td>

<td> 03</td><td> 0.19041</td><td> -0.53232</td><td> 0.18147</td><td>C42</td><td> 0.22703</td><td> 0.46640</td><td> 0.06306</td>

<td>F5</td><td> -0.07307</td><td> 2.12170</td><td> -0.08811</td><td>C43</td><td> 0.34559</td><td> 1.01717</td><td> -0.10021</td>

<td> 06</td><td> 0.18186</td><td> 1.20500</td><td> -0.03241</td><td>C44</td><td> 0.39312</td><td> 1.20834</td><td> -0.08137</td>

<td> 07</td><td> 0.57137</td><td> 0.22739</td><td> 0.23473</td><td>C45</td><td> 0.48224</td><td> 0.32340</td><td> 0.15059</td>

<td> 08</td><td> 0.58700</td><td> -0.17911</td><td> 0.24998</td><td> 046</td><td> 0.77400</td><td> 0.04784</td><td> 0.34652</td>

<td> 09</td><td> 0.41742</td><td> 0.76377</td><td> -0.04319</td><td>C47</td><td> 0.79349</td><td> 0.09920</td><td> 0.31966</td>

<td>N10</td><td> 0.28649</td><td> 0.82210</td><td> -0.01420</td><td>H10</td><td> 0.22646</td><td> 0.91057</td><td> -0.01479</td>

ίη/ΖΖΠΖ/Β/ΥΙΛΙ

<td>Atom</td><td>x</td><td>AND</td><td>Z</td><td>Atom</td><td>x</td><td>AND</td><td>Z</td>

<td> 011</td><td> 0.87391</td><td> 0.22086</td><td> 0.31241</td><td>H16</td><td> 0.24790</td><td> 1.42164</td><td> -0.10317</td>

<td>N12</td><td> 0.46887</td><td> 0.17029</td><td> 0.17613</td><td>H19</td><td> -0.04176</td><td> 1.82973</td><td> -0.03893</td>

<td>C13</td><td> 0.29647</td><td> 0.64886</td><td> 0.01247</td><td>H20</td><td> 0.16347</td><td> 1.73025</td><td> -0.13083</td>

<td>C14</td><td> 0.31416</td><td> 1.08187</td><td> -0.06304</td><td>H22</td><td> 0.43179</td><td> -0.17902</td><td> 0.22447</td>

<td> 015</td><td> 0.33900</td><td> -0.02207</td><td> 0.14761</td><td>H23</td><td> 0.17093</td><td> 0.73524</td><td> 0.03244</td>

<td>N16</td><td> 0.20651</td><td> 1.40640</td><td> -0.08267</td><td>H27</td><td> 0.21953</td><td> -0.24212</td><td> 0.12962</td>

<td>C17</td><td> 0.40079</td><td> -0.01723</td><td> 0.17602</td><td>H29</td><td> 0.07954</td><td> 1.50390</td><td> -0.03492</td>

<td>C18</td><td> 0.29743</td><td> 0.29956</td><td> 0.06604</td><td>H30</td><td> 0.04671</td><td> 2.05817</td><td> -0.13354</td>

<td>C19</td><td> 0.00418</td><td> 1.80556</td><td> -0.05680</td><td>H33</td><td> 0.41851</td><td> 0.16255</td><td> 0.04395</td>

<td>C20</td><td> 0.11925</td><td> 1.73626</td><td> -0.11097</td><td>H34</td><td> 0.43433</td><td> 0.41859</td><td> 0.10106</td>

<td>C21</td><td> 0.22556</td><td> 1.24019</td><td> -0.05791</td><td>H38</td><td> 0.41440</td><td> 0.45648</td><td> -0.00227</td>

<td>C22</td><td> 0.39150</td><td> -0.17467</td><td> 0.20389</td><td>H41</td><td> 0.61062</td><td> 0.02238</td><td> 0.31086</td>

<td>C23</td><td> 0.22558</td><td> 0.63870</td><td> 0.03619</td><td>H42</td><td> 0.17752</td><td> 0.45794</td><td> 0.07911</td>

<td> 024</td><td> 0.62714</td><td> 0.39565</td><td> 0.29760</td><td>H45</td><td> 0.53033</td><td> 0.44239</td><td> 0.15049</td>

<td>C25</td><td> 0.34591</td><td> 0.87438</td><td> -0.03961</td><td>H31a</td><td> 0.76754</td><td> 0.12071</td><td> 0.26693</td>

<td> 026</td><td> 0.36467</td><td> -0.51389</td><td> 0.25773</td><td>H31b</td><td> 0.74726</td><td> -0.15247</td><td> 0.28137</td>

<td> 027</td><td> 0.26562</td><td> -0.20277</td><td> 0.14859</td><td>H43a</td><td> 0.30237</td><td> 1.06909</td><td> -0.12187</td>

<td> 028</td><td> 0.35380</td><td> 0.15272</td><td> 0.12054</td><td>H43b</td><td> 0.36868</td><td> 0.85693</td><td> -0.10836</td>

<td> 029</td><td> 0.07365</td><td> 1.60604</td><td> -0.05443</td><td>H44a</td><td> 0.45563</td><td> 1.18725</td><td> -0.07495</td>

<td> 030</td><td> 0.04897</td><td> 1.92890</td><td> -0.11212</td><td>H44b</td><td> 0.38932</td><td> 1.39942</td><td> -0.08846</td>

<td> 031</td><td> 0.73841</td><td> 0.04517</td><td> 0.28641</td><td>H26a</td><td> 0.35958</td><td> -0.37184</td><td> 0.27147</td>

<td> 032</td><td> 0.32089</td><td> -0.35160</td><td> 0.20385</td><td>H2 6b</td><td> 0.42813</td><td> -0.55605</td><td> 0.25348</td>

<td> 033</td><td> 0.36641</td><td> 0.29052</td><td> 0.04302</td><td>H26c</td><td> 0.34954</td><td> -0.66814</td><td> 0.27571</td>

ίΠ/ΖΖηΖ/Ε/ΥΙΛΙ

<td>Atom</td><td>x</td><td>AND</td><td>Z</td><td>Atom</td><td>x</td><td>AND</td><td>Z</td>

<td>C34</td><td> 0.42458</td><td> 0.32272</td><td> 0.12143</td><td>H35a</td><td> 0.08189</td><td> -0.39941</td><td> 0.15398</td>

<td>C35</td><td> 0.11723</td><td> -0.54030</td><td> 0.15742</td><td>H35b</td><td> 0.06671</td><td> -0.68838</td><td> 0.16269</td>

<td>C36</td><td> 0.12933</td><td> 1.59042</td><td> -0.08228</td><td>H35c</td><td> 0.13276</td><td> -0.61095</td><td> 0.13323</td>

<td>C37</td><td> -0.00344</td><td> 1.93494</td><td> -0.08547</td><td>Hll</td><td> 0.88836</td><td> 0.21926</td><td> 0.28968</td>

<td>C38</td><td> 0.36439</td><td> 0.47245</td><td> 0.01586</td><td>H12</td><td> 0.50720</td><td> 0.16494</td><td> 0.19477</td>

<td>C39</td><td> 0.59040</td><td> 0.05797</td><td> 0.25625</td><td>H24</td><td> 0.61522</td><td> 0.45898</td><td> 0.27789</td>

IV. Solid State Nuclear Magnetic Resonance (SSNMR)

All solid-state NMR-13 measurements were performed with a Bruker DSX-400 400 MHz NMR spectrometer. High-resolution spectra were obtained using high-power proton decoupling and the TPPM pulse sequence and ramp amplitude cross-polarization (RAMP-CP) with magic angle spin (MAS) at approximately 12 kHz (A.E. Bennett et al. , J. Chem. Phys., 1995, 103, 6951), (G. Metz, X. Wu and SO Smith J. Magn. Reson. A, . 1994, 110, 219-227). Approximately 70 mg of the sample, packaged in a can-type design zirconia rotor, was used for each experiment. The chemical changes (δ) are referred to external adamantane with the high frequency resonance that is set to 38.56 ppm (WL Earl and DL VanderHart, J. Magn. Reson., 1982, 48, 35-54).

IV. 1 Compound (I), Form Nl

The NMR spectrum¹³ίη/ΖΖΠΖ/Ε/ΥΙΛΙ Solid State C

Crystalline Compound (I), Form Nl is shown in Figure 2. In full view of peaks, a subset of them may be sufficient to characterize Crystalline Compound (I), Form Nl.

NMR Peaks¹³C SS: 18.1, 20.6, 26.0, 42.9, 44.5,

54.4, 55.4, 56.1, 70.4, 99.4, 100.1, 100.6, 114.4, 11.4.9, 115.8, 119.6, 120.1, 121.6, 123.2, 124.1, 136.4, 138.6, 40.6, 145.4, 150.1, 150.9, 156.2, 157.4, 159.4, 164.9, 167.1,

170.8, 175.7, and 182.1 ppm, ± 0.2 ppm.

Figure 3 shows the NMR spectrum¹⁵Solid state N of Crystalline Compound (I), Form Nl. The spectrum shows peaks at 118.6, 119.6, 120.7, 134.8, 167.1, 176.0, and 180 ppm, + 0.2 ppm. The complete list of peaks, or a subset thereof, may be sufficient to characterize crystalline Compound (I), Form Nl.

Figure 4 shows the NMR spectrum¹⁹Solid state F of Crystalline Compound (I), Form Nl. The spectrum shows a peak at -121.6, -120.8, and -118.0 ppm, ± 0.2 ppm.

IV.2 Compound (I), Form N-2

The NMR spectrum¹³C solid state of Crystalline Compound (I), Form N-2 is shown in Figure 9. The complete list of peaks, or a subset thereof, may be sufficient to characterize Crystalline Compound (1), Form N-2 .

NMR Peaks¹³C SS: 20.5, 21.8, 23.0, 25.9, 26.4, ίη/ΖΖΠΖ/Β/ΥΙΛΙ

38.0 , 41.7, 54.7, 55.8, 56.2, 56.6, 69.7, 99.4, 100.0, 100.4,

100.8, 102.3, 114.5, 115.5, 116.7, 119.0, 120.2, 121.1,

121.2, 122.1, 122.9, 124.5, 136.0, 137.3, 138.1, 138.9,

139.5, 140.2, 144.9, 145.7, 146.1, 150.7, 156.7, 157.7,

159.6, 159.7, 165.1, 167.0, 168.0, 171.5, 177.3, 179.3,

180.0, and 180.3 ppm, ± 0.2 ppm.

Figure 10 shows the NMR spectrum¹⁵Solid state N of Crystalline Compound (I), Form N-2. The spectrum shows peaks at 118.5, 120.8, 135.1, 167.3, and 180.1 ppm, ± 0.2 ppm. The complete list of peaks, or a subset thereof, may be sufficient to characterize crystalline Compound (I), Form N-2.

Figure 11 shows the NMR spectrum¹⁹Solid state F of Crystalline Compound (I), Form N-2. The spectrum shows peaks at -121.0 and -119.1 ppm, ± 0.2 ppm. These peaks, individually or together, may be sufficient to characterize crystalline Compound (I), Form N-2.

IV.3 Compound (III), Form Nl

The NMR spectrum¹³C solid state of Crystalline Compound (III), Form Nl is shown in Figure 16. The complete list of peaks, or a subset thereof, may be sufficient to characterize Crystalline Compound (III), Form Nl.

RRMN Peaks¹³C SS: 20.8, 26.2, 44.8, 55.7, 70.7, ίη/ΖΖΠΖ/Β/ΥΙΛΙ

100.4, 101.0, 114.7, 115.2, 116.0, 119.7, 120.4, 121.6,

124.4, 136.9, 138.9, 141.1, 145.7, 150.3, 156.5, 157.6,

159.6, 165.2, 167.4, 171.2, 176.3, and 182.1 ppm, ± 0.2 ppm.

Figure 17 shows the NMR spectrum¹⁵Solid state N of crystalline Compound (III), Form Nl. The spectrum shows peaks at 119.6, 134.7, and 175.5 ppm, ± 0.2 ppm. The complete list of peaks, or a subset thereof, may be sufficient to characterize crystalline Compound (III), Form Nl.

Figure 18 shows the MRN spectrum¹⁹Solid state F of crystalline Compound (III), Form Nl. The spectrum shows a peak at -120.5 ppm, ± 0.2 ppm.

IV.4 Compound (I), Amorphous

Figure 23 shows the NMR spectrum¹³C solid state of amorphous Compound (I). The complete list of peaks, or a subset thereof, may be sufficient to characterize the amorphous Compound (I).

NMR Peaks¹³C SS (ppm): 12.2, 17.8, 20.3, 21.8, 27.2, 33.8, 41.7, 56.9, 69.9, 99.9, 102.2, 115.6, 122.2,

134.4, 137.8, 142.9, 149.1, 150.9, 157.3, 159.7, 167.0,

171.7, 173.1, 177.4, and 179.5 ppm, ± 0.2 ppm.

Figure 24 shows the NMR spectrum¹⁵N solid state amorphous Compound (1). The spectrum shows peaks at 120.8, 131.8, 174.7, and 178.3 ppm, ± 0.2 ppm. The complete list of peaks, or a subset thereof, may be sufficient to characterize the amorphous Compound (I).

Figure 25 shows the NMR spectrum¹⁹Solid state F of amorphous Compound (I). The spectrum shows a peak at -118.9 ppm, + 0.2 ppm.

V. Thermal Characterization Measurements

Thermal Gravimetric Analysis (TGA)

TGA measurements were performed on a TA Instruments* model Q500 or 2950, ​​which employs an open tray arrangement. The sample (approximately 10-30 mg) was placed in a pre-tared platinum tray. The weight of the sample was measured accurately and recorded to one thousandth of a milligram by the instrument. The oven was purged with nitrogen gas at 100 mL/min. Data were collected between room temperature and 300°C at 10°C/min heating rate.

Analysis by Differential Scanning Calorimetry (DSC)

DSC measurements were performed on a TA Instruments* model Q2000, Q1000, or 2920, using open tray exposure. The sample (approximately 26 mg) was weighed into an aluminum pan and recorded accurately to one hundredth of a milligram, and transferred to the DSC. The instrument was purged with nitrogen gas at 50mL/min. Data were collected between room temperature and 300°C at 10°C/min heating rate. The graph was made with the endothermic peaks pointing towards ίη/ΖΖΠΖ/Β/ΥΙΛΙ ίη/ΖΖΠΖ/Ε/ΥΙΛΙ below.

V .l Compound (I), Form Nl

Figure 5 shows the TGA thermogram for Crystalline Compound (I), Form Nl, showing a weight loss of approximately 0.4 wt% at a temperature of 170°C.

Figure 6 shows the DSC thermogram for Crystalline Compound (I), Form Nl, showing a melting point of approximately 187°C.

V .2 Compound (I), Form N-2

Figure 12 shows the TGA thermogram for Crystalline Compound (I), Form N-2, showing a weight loss of approximately 0.1 wt% at a temperature of 170°C.

Figure 13 shows the DSC thermogram for Crystalline Compound (I), Form N-2, showing a melting point of approximately 186°C.

V .3 Compound (III), Form Nl

Figure 19 shows the TGA thermogram for Crystalline Compound (III), Form Nl, showing a weight loss of approximately 0.2 wt% at a temperature of 170°C.

Figure 20 shows the DSC thermogram for Crystalline Compound (III), Form Nl, showing a melting point of approximately 186°C.

ίη/ΖΖΠΖ/Β/ΥΙΛΙ

V .2 Compound (I), Amorphous

Figure 26 shows the DSC for Crystalline Compound (I).

SAW . Moisture Vapor Isotherm Measurements

Moisture absorption isotherms were collected on a VTI SGA-100 symmetric vapor analyzer using approximately 10 mg of the sample. The sample was dried at 60 °C until a loss rate of 0.0005 wt%/min was obtained for 10 minutes. The sample was tested at 25°C and 3 or 4, 5, 15, 25, 35, 45, 50, 65, 75, 85, and 95% relative humidity. Equilibrium at each relative humidity was achieved when the rate of 0.0003 wt%/min for 35 minutes or a maximum of 600 minutes was achieved.

VI .1 Compound (I), Form Nl

Figure 7 shows the moisture vapor isotherm for Crystalline Compound (I), Form Nl.

VI .2 Compound (I), Form Nl

Figure 14 shows the moisture vapor isotherm of crystalline Compound (I), Form N-2.

VI .3 Compound (III), Form Nl

Figure 21 shows the moisture vapor isotherm of crystalline Compound (III), Form Nl.

VI .4 Compound (I), Amorphous

Figure 27 shows the moisture vapor isotherm of the amorphous Compound (I).

The foregoing description has been presented in some detail by way of illustration and example, for purposes of clarity and understanding. The invention has been described with reference to various specific preferred embodiments and techniques, however, it should be understood that many variations and modifications can be made as long as they remain within the spirit and scope of the invention. It will be obvious to one skilled in the art that changes and modifications can be made within the scope of the appended claims. Therefore, it will be understood that the foregoing description is intended to be illustrative and not restrictive. The scope of the invention must therefore be determined not by reference to the foregoing description, but is instead determined by reference to the following appended claims, together with the full scope of equivalents to which these claims are entitled.

It is stated that in relation to this date, the best method known to the applicant to put the aforementioned invention into practice is the one that is clear from the present description of the invention.