HK1231054B - Malate salt of n-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-n'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms therof - Google Patents

Description

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide malate and its crystalline form

This application is a divisional application based on a patent application with an application date of January 15, 2010, a priority date of January 16, 2009, application number 201080012656.5 (PCT/US2010/021194), and an invention name of "Malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and its crystalline form for cancer treatment".

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No. 61/145,421, filed January 16, 2009, which is incorporated herein by reference.

Technical Field

The present disclosure relates to a malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and to crystalline and amorphous forms of a malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide. The malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide includes one of the following: (1) (L)-malate, (2) (D)-malate, (3) (D,L)-malate, and (4) a mixture thereof. The present disclosure also relates to pharmaceutical compositions comprising at least one malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.

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

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

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

Background Art

Traditionally, significant improvements in cancer treatment have been associated with the identification of therapeutic agents that act through novel mechanisms. One mechanism that can be exploited in cancer treatment is the modulation of protein kinase activity, as signal transduction via protein kinase activation is responsible for many of the characteristics of tumor cells. Protein kinase signal transduction is particularly relevant to the growth and proliferation of, for example, thyroid cancer, gastric cancer, head and neck cancer, lung cancer, breast cancer, prostate cancer, and colorectal cancer, as well as brain tumor cells.

Protein kinases can be classified as either receptor-type or non-receptor-type. Receptor-type tyrosine kinases comprise a large number of transmembrane receptors with diverse biological activities. For a detailed discussion of receptor-type tyrosine kinases, see Plowman et al., DN&P 7(6):334-339, 1994. Because protein kinases and their ligands play key roles in a wide variety of cellular activities, deregulation of protein kinase enzymatic activity can lead to altered cellular properties, such as uncontrolled cell growth associated with cancer. In addition to oncological indications, altered kinase signaling is implicated in many other pathological conditions, including, for example, immune disorders, cardiovascular diseases, inflammatory diseases, and degenerative diseases. Therefore, protein kinases are attractive targets for small molecule drug discovery. Particularly attractive targets for small molecule modulation associated with anti-angiogenic and anti-proliferative activities include the receptor-type tyrosine kinases Ret, c-Met, and VEGFR2.

The kinase c-Met is the prototypic member of a subfamily of heterodimeric receptor tyrosine kinases (RTKs) that includes Met, Ron, and Sea. The endogenous ligand for c-Met is hepatocyte growth factor (HGF), a potent inducer of angiogenesis. HGF binding to c-Met induces receptor activation through autophosphorylation, leading to increased receptor-dependent signaling, which promotes cell growth and invasion. 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, VEGFR2 and/or Ret has been demonstrated in a variety of tumor types, including breast tumors, colon tumors, kidney tumors, lung tumors, squamous cell tumors, myeloid leukemias, hemangiomas, melanomas, astrocytomas (including glioblastomas, giant cell glioblastomas, gliosarcoma and glioblastomas with oligodendroglial components). The Ret protein is a transmembrane receptor with tyrosine kinase activity. Ret is mutated in most familial forms of medullary thyroid carcinoma. These mutations activate the kinase function of Ret and convert it into an oncogene product.

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

Therefore, small molecule compounds that specifically inhibit, regulate, and/or modulate signal transduction by kinases (particularly including the aforementioned Ret, c-Met, and VEGFR2) are particularly desirable as a method for treating or preventing conditions associated with abnormal cell proliferation and angiogenesis. One such small molecule is N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, which has the following chemical structure:

WO 2005/030140 describes the synthesis of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Examples 12, 37, 38, and 48). This molecule is also disclosed as having therapeutic activity that inhibits, regulates, and/or modulates kinase signal transduction (Assays, Table 4, Entry 289). Example 48 is in paragraph [0353] of WO 2005/030140.

In addition to therapeutic efficacy, drug developers attempt to provide a suitable form of a therapeutic agent that has properties that are relevant to processing, manufacturing, storage stability, and/or usefulness as a drug. Therefore, finding a form that has some or all of these desired properties is crucial to drug development.

Applicants have discovered salt forms of the drug N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide that possess properties suitable for use in pharmaceutical compositions for the treatment of proliferative diseases, such as cancer. The novel salt forms of the present invention exist in both crystalline and amorphous forms.

SUMMARY OF THE INVENTION

The present disclosure relates to the malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide described herein, its pharmaceutical compositions described herein, and its uses described herein.

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

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the experimental XRPD pattern of crystalline Compound (I) Form N-1 at 25°C.

Figure 2 shows the solid- ^state13C NMR spectrum of crystalline Compound (I) Form N-1.

Figure 3 shows the solid-state ¹⁵ N NMR spectrum of crystalline Compound (I) Form N-1.

Figure 4 shows the solid- ^state19F NMR spectrum of crystalline Compound (I) Form N-1.

FIG5 shows the thermogravimetric analysis (TGA) of Form N-1 crystalline Compound (I).

Figure 6 shows the differential scanning calorimetry (DSC) analysis of crystalline Compound (I) Form N-1.

FIG7 shows the water adsorption of Form N-1 crystalline Compound (I).

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

Figure 9 shows the solid- ^state13C NMR spectrum of crystalline Compound (I) Form N-2.

Figure 10 shows the solid-state ¹⁵ N NMR spectrum of crystalline Compound (I) Form N-2.

Figure 11 shows the solid- ^state19F NMR spectrum of crystalline Compound (I) Form N-2.

Figure 12 shows the thermogravimetric analysis (TGA) of crystalline Compound (I) Form N-2.

Figure 13 shows the differential scanning calorimetry (DSC) analysis of crystalline Compound (I) Form N-2.

FIG14 shows the water adsorption of Form N-2 crystalline Compound (I).

Figure 15 shows the experimental and simulated XRPD patterns of crystalline Compound (III) Form N-1 at room temperature.

Figure 16 shows the solid- ^state13C NMR spectrum of crystalline Compound (III) Form N-1.

Figure 17 shows the solid-state ¹⁵ N NMR spectrum of crystalline Compound (III) Form N-1.

Figure 18 shows the solid- ^state19F NMR spectrum of crystalline Compound (III) Form N-1.

FIG19 shows the thermogravimetric analysis (TGA) of Form N-1 of crystalline Compound (III).

Figure 20 shows the differential scanning calorimetry (DSC) analysis of Form N-1 crystalline Compound (III).

FIG21 shows the water adsorption of Form N-1 crystalline Compound (III).

FIG22 shows the XRPD pattern of amorphous Compound (I) at room temperature.

Figure 23 shows the solid-state ¹³ C NMR spectrum of amorphous Compound (I).

Figure 24 shows the solid-state ¹⁵ N NMR spectrum of amorphous Compound (I).

Figure 25 shows the solid-state ¹⁹ F NMR spectrum of amorphous Compound (I).

FIG26 shows differential scanning calorimetry (DSC) of amorphous Compound (I).

FIG27 shows the water adsorption of amorphous Compound (I).

Detailed Description of the Invention

The present disclosure relates to improvements in the biochemical properties of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, thereby making the compound suitable for drug development. Disclosed herein are malate salts of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide. The present disclosure also discloses novel solid-state forms of these salts. The malate salts and their crystalline and amorphous forms disclosed herein each represent a separate aspect of the present disclosure. While the present disclosure describes malate salts and their solid-state forms, the present disclosure also relates to novel compositions containing the disclosed salts and solid-state forms. The therapeutic uses of the salts and solid-state forms, and therapeutic compositions containing them, represent separate aspects of the present disclosure. Techniques used to characterize the salts and their solid-state forms are described in the following examples. These techniques can be used alone or in combination to characterize the salts and their solid-state forms disclosed herein. The salts and their solid-state forms can also be characterized with reference to the figures disclosed herein.

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide was found to have an enzyme Ret IC ₅₀ value of approximately 5.2 nM (nanomolar) and an enzyme c-Met IC ₅₀ value of approximately 1.3 nM (nanomolar). The assay for measuring this c-Met activity is described in WO2005-030140, paragraph [0458].

RET biochemical activity was assessed using the luciferase-coupled chemiluminescent kinase assay (LCCA) format described in WO2005-030140. Kinase activity was measured as the percentage of ATP remaining after the kinase reaction. Remaining ATP was detected by luciferase-luciferin-coupled chemiluminescence. Specifically, the reaction was initiated by mixing the test compound (2 μM ATP, 1 μM poly-EY ₎ , and 15 nM RET (baculovirus-expressed human RET kinase domain M700-D1042 with a (His)6 tag at the N-terminus) in 20 μL of assay buffer (20 mM Tris-HCl pH 7.5, 10 mM _MgCl₂ , 0.01% Triton X-100, 1 mM DTT, ₃ mM MnCl₂). The mixture was incubated at ambient temperature for 2 hours, followed by the addition of 20 μL of the luciferase-luciferin mixture, and the chemiluminescent signal was read using a Wallac Victor ² reader. The luciferase-luciferin mixture consisted of 50 mM HEPES, pH 7.8, 8.5 ug/mL oxalic acid (pH 7.8), 5 mM DTT, 0.4% Triton X-100, 0.25 mg/mL Coenzyme A, 63 μM AMP, 28 μg/mL luciferin, and 40,000 units of light/mL luciferase.

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

The present disclosure relates to malate salts of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide. These malate salts are combinations of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and malic acid, which form a 1:1 malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.

Malic acid has the following structure:

Due to its chiral carbon, malic acid exists as two enantiomers, (L)-malic acid and (D)-malic acid.

(L)-Malic acid has the following structure:

(L)-malic acid is known in the art by a number of designations or names. These include (2S)-(9CI)-hydroxy-butanedioic acid; (S)-hydroxy-butanedioic acid; L-(8CI)-malic acid; l-(3CI)-malic acid; (-)-(S)-malic acid; (-)-hydroxysuccinic acid; (-)-(L)-malic acid; (-)-malic acid; (2S)-2-hydroxybutanedioic acid; (2S)-2-hydroxysuccinic acid; (S)-malic acid; malic acid; L-(-)-malic acid; (L)-malic acid; NSC 9232; S-(-)-malic acid; and S-2-hydroxybutanedioic acid.

(D)-Malic acid has the following structure:

(D)-malic acid is known in the art by a number of designations or names. These include (2R)-2-hydroxysuccinic acid, (2R)-(9CI)-hydroxysuccinic acid; (R)-hydroxy-succinic acid; (+)-malic acid; (2R)-2-hydroxysuccinic acid; (2R)-malic acid; (R)-(+)-malic acid; (R)-malic acid; D-(+)-2-hydroxysuccinic 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)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide is

There are no chiral carbon atoms in its chemical structure. N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide is known by several names, some of which include N'-[4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-N-(4-fluorophenyl)-1,1-cyclopropanedicarboxamide and N-[4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-N'-(4-fluorophenyl)-(9CI)-1,1-cyclopropanedicarboxamide.

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide can be prepared on a gram scale (<1 kg) or a kilogram scale (>1 kg) according to any of several different methods. Gram-scale methods are described in WO 2005-030140, which describes the synthesis of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Examples 25, 37, 38, and 48), which is incorporated herein by reference. Alternatively, N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, including the active compound, can be prepared on a kilogram scale using the method described in Example 1 below.

The present disclosure relates to the malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:

(L)-malate of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound (I));

(D)-malate of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound (II)); and

(DL)-malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound (III)).

Each compound has improved properties relative to N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and its other salts. The names used herein to characterize a specific form, such as "N-2," are not intended to exclude any other substances having similar or identical physical and chemical characteristics, but rather these names are used as pure identifiers to be interpreted in light of the characterization information provided herein.

The malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, particularly Compound (I), exhibits a preferred combination of pharmaceutical properties for development. Compound (I) exhibited no changes in assay, purity, moisture, or solubility at 25°C/60% relative humidity (RH) and 40°C/60% RH. DSC/TGA analysis showed that Compound (I) was stable up to 185°C. No solvent loss was observed. Water absorption by the (L)-malate salt was reversible with slight hysteresis. The amount of water absorbed was calculated to be approximately 0.60% by weight at 90% RH. The (L)-malate salt was synthesized in good yield and >90% purity and possessed sufficient solubility for use in pharmaceutical compositions. Karl Fischer analysis, combined with TGA and GVS analysis, indicated that the amount of water associated with the salt was approximately 0.5% by weight. The (D)-malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide will have the same properties as the (L)-malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.

Compound (I) salts themselves and their individual crystalline and amorphous forms exhibit beneficial properties relative to the free base and other salts of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide. For example, the hydrochloride salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide exhibits undesirable moisture sensitivity, changing phase upon exposure to high humidity (75% humidity) and elevated temperature (40°C). The maleate salt exhibits low solubility. The tartaric acid salt exhibits low crystallinity and solubility. The phosphate salt exhibits an 8% weight gain due to the highest H ₂ O^- absorption of the salts tested.

The water solubility of the different salts was determined using 10 mg solid/mL water. In a salt screen, salts were prepared by reacting an acetone solution of the free base with a tetrahydrofuran (THF) stock solution of an approximately 1:1 molar ratio of the acid range. Table 1 below lists water solubility and other data related to the free base and individual salts.

Table 1

Another aspect of the present disclosure relates to crystalline forms of compound (I), including the N-1 and/or N-2 crystalline forms of compound (I) as described herein. Each form of compound (I) is a separate aspect of the present disclosure. Similarly, another aspect of the present disclosure relates to crystalline forms of compound (II), including the N-1 and/or N-2 crystalline forms of compound (II) as described herein. Each of these is also a separate aspect of the present disclosure. It is known in the art that crystalline (D) malate will form the same crystalline form as crystalline compound (I) and have the same properties. See WO 2008/083319 for a discussion of the properties of crystalline enantiomers. Mixtures of crystalline forms of compounds (I) and (II) are another aspect of the present disclosure.

The N-1 crystalline form of compounds (I) and (II) described herein may be characterized by at least one of the following:

(i) a solid-state ¹³ C NMR spectrum having 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) the solid-state ¹³ C NMR spectrum is essentially consistent with the pattern shown in Figure 2 ;

(iii) an x-ray powder diffraction pattern comprising four or more peaks selected from the group consisting of 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, wherein the measurement of the crystalline form is at ambient room temperature;

(iv) the x-ray powder diffraction (XRPD) spectrum is essentially consistent with the pattern shown in Figure 1;

(v) a solid-state ¹⁵ N NMR spectrum having peaks at 118.6, 119.6, 120.7, 134.8, 167.1, 176.0, and 180 ppm ± 0.2 ppm; and/or

(vi) The solid-state ¹⁵ N NMR spectrum is essentially consistent with the pattern shown in FIG3 .

Additional solid state properties useful for characterizing Form N-1 of Compounds (I) and (II) are shown in the Figures and discussed in the Examples below. For crystalline Compound (I), the solid state phase and crystallinity remained unchanged after exposure to 75% RH at 40°C for one week.

The N-2 crystalline form of compounds (I) and (II) described herein may be characterized by at least one of the following:

(i) a solid-state ¹³ C NMR spectrum having 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) the solid-state ¹³ C NMR spectrum is essentially consistent with the pattern shown in Figure 9 ;

(ii) an x-ray powder diffraction pattern comprising four or more peaks selected from the group consisting of 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, wherein the measurement of the crystalline form is at ambient room temperature;

(iv) the x-ray powder diffraction (XRPD) spectrum is essentially consistent with the pattern shown in Figure 8;

(v) a solid-state ¹⁵ N NMR spectrum having peaks at 118.5, 120.8, 135.1, 167.3, and 180.1 ppm; and/or

(vi) The solid-state ¹⁵ N NMR spectrum is essentially consistent with the pattern shown in Figure 10;

Additional solid state properties useful in characterizing Form N-2 of Compounds (I) and (II) are shown in the Figures and discussed in the Examples below.

In another embodiment, the present disclosure relates to a crystalline form of Compound (I) as described herein in any aspect and/or embodiment, which is substantially pure Form N-1.

In another embodiment, the present disclosure relates to a crystalline form of Compound (I) as described herein in any aspect and/or embodiment, which is substantially pure Form N-2.

The present disclosure also relates 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 present disclosure.

Another aspect of the present disclosure relates to a mixture of compound (I) and compound (II). The mixture can have a compound (I) greater than 0% weight to less than 100% weight based on compound (I) and compound (II) gross weight and a compound (II) less than 100% weight to greater than 0% weight. In other embodiments, the mixture comprises a compound (I) of about 1% weight to about 99% weight based on compound (I) and compound (II) gross weight in the mixture and a compound (II) of about 99% weight to about 1% weight. In another embodiment, the mixture comprises a compound (I) less than 100% weight based on compound (I) and compound (II) gross weight and a compound (II) greater than 0% weight to about 10% weight. Thus, the mixture may have 1-10% 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 weight percentages of malate being weight percentages of compound (II).

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

(i) a solid ^state13C NMR spectrum having 4 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) the solid-state ¹³ C NMR spectrum is essentially consistent with the pattern shown in Figure 16 ;

(iii) a powder x-ray diffraction pattern comprising 4 or more 2θ values selected from the group consisting of 12.8, 13.5, 16.9, 19.4, 21.5, 22.8, 25.1, and 27.6 ± 0.2° 2θ, wherein the measurement of the crystalline form is at room temperature;

(iv) the x-ray powder diffraction (XRPD) spectrum is essentially consistent with the pattern shown in FIG15 ;

(v) a solid-state ¹⁵ N NMR spectrum having peaks at 119.6, 134.7, and 175.5 ppm ± 0.2 ppm; and/or

(vi) The solid-state ¹⁵ N NMR spectrum is generally consistent with the pattern shown in FIG17 .

Other solid state properties that can be used to characterize the N-1 crystalline form of compound (III) are shown in the figures and discussed in the examples below. In one embodiment, the N-1 form of compound (III) is characterized by unit cell parameters approximately equal to the following:

Unit cell size:

α＝90.0°

β＝90.4°

γ＝90.0°

Space group: P2 ₁ /n

Molecules/unit cell of compound (I): 4

Density (calculated) = 1.422 g/cm ³

The unit cell parameters of Form N-1 of Compound (III) are measured at a temperature of about 25°C, for example, at ambient or room temperature.

The N-1 and N-2 crystalline forms of compounds (I) and (II), and the N-1 crystalline form of compound (III), each have unique characteristics that distinguish them from one another. These characteristics can be understood by comparing the physical properties of the solid forms shown in the following examples. For example, Table 2 lists the characteristic XRPD peak positions (°2θ±0.2°2θ) of the N-1 form of crystalline compound (III) and the N-1 and N-2 forms of crystalline compound (I). The amorphous form does not exhibit reflection peaks in its XRPD pattern.

Table 2

Characteristic diffraction peak positions at room temperature (°2θ±0.2), based on patterns collected with a diffractometer (CuKα) with a spinning capillary.

*Unique reflection between N-1 type compound (I) and N-2 type compound (I).

The unique reflections between the N-1 and N-2 forms of crystalline Compound (II) are indicated by an asterisk (*). As discussed above, Compound (II) is an enantiomer of Compound (I), and therefore, Form N-1 of Compound (II) will have the same characteristic reflection pattern and unique peaks as listed in Table 2 for Form N-1 of Compound (I). Similarly, Form N-2 of Compound (II) has the same characteristic reflection pattern and unique peaks as listed in Table 2 for Form N-2 of Compound (I). Compound (I) and Compound (II) differ from each other in terms of their absolute stereochemistry, i.e., (L)-malate versus (D)-malate, respectively. Form N-1 of crystalline Compound (III) is distinguished as the (D,L)-malate salt.

Characteristic peaks from solid-state NMR can also be used to distinguish between crystalline and amorphous forms disclosed herein. For example, Table 3 lists characteristic solid-state ¹³ C NMR peaks for Form N-1 crystalline Compound (III), Forms N-1 and N-2 crystalline Compound (I), and an amorphous form of Compound (I).

Table 3

The solid-state ¹⁹ F and ¹⁵ N NMR spectra discussed below provide data for similar comparison and characterization. As discussed above, as enantiomers of Compound (I), the N-1 and N-2 crystalline forms and the amorphous form of Compound (II) will have the same solid-state NMR resonances and unique peaks therebetween as listed in Table 3 for the N-1 and N-2 crystalline forms of Compound (I).

Pharmaceutical compositions and methods of treatment

Another aspect of the present disclosure relates to a pharmaceutical composition comprising at least one of compound (I), compound (II), compound (III) or a combination thereof and a pharmaceutically acceptable excipient. The amount of compound (I), compound (II), compound (III) or a combination thereof in the pharmaceutical composition can be a therapeutically effective amount. Compound (I), compound (II) or compound (III) can be present in the pharmaceutical composition as one of the solid forms discussed above or a combination thereof. Crystalline forms are preferred solid forms. Therefore, another aspect of the present disclosure relates to a solid or dispersion pharmaceutical composition comprising at least one crystalline form of compound (I), compound (II), compound (III) or a combination thereof in a therapeutically effective amount and a pharmaceutically acceptable excipient.

Another aspect of the present disclosure relates to a method for treating cancer, the method comprising administering to a subject in need thereof at least one of compound (I), compound (II), compound (III) or a combination thereof. The dosage of compound (I), compound (II) or a combination thereof can be a therapeutically effective amount. Compound (I), compound (II) or compound (III) can be administered alone or in combination as one of the solid forms discussed above. Crystalline forms are preferred solid forms, and preferably N-1 or N-2 type crystalline compound (I). Therefore, another aspect of the present disclosure relates to a method for treating cancer, the method comprising administering to a subject in need thereof at least one of compound (I), compound (II), compound (III) or a combination thereof in a therapeutically effective amount, wherein compound (I), compound (II) or compound (III) exists in a crystalline form. In another aspect of the present disclosure, the method of treatment can be implemented by administering a pharmaceutical composition such as at least one of compound (I), compound (II), compound (III) or a combination thereof discussed above.

Another aspect of the present disclosure relates to a method of treating cancer as discussed above, wherein the cancer being treated is gastric cancer, esophageal cancer, kidney cancer, liver cancer, ovarian cancer, cervical cancer, colorectal cancer, small intestine cancer, brain cancer (including astrocytomas, including glioblastomas, giant cell glioblastomas, gliosarcoma and glioblastomas with oligodendroglial components), lung cancer (including non-small cell lung cancer), bone cancer, prostate cancer, pancreatic cancer, skin cancer, bone cancer, lymphoma, solid tumors, Hodgkin's disease, non-Hodgkin's lymphoma or thyroid cancer 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 the receptor of epidermal growth factor (called tyrosine kinase). Erlotinib and gefitinib are currently used to treat NSCLC. Another aspect of the present disclosure relates to a method for treating non-small cell lung cancer (NSCLC) in a subject, the method comprising administering to a subject in need of treatment an effective amount of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide or a pharmaceutically acceptable salt thereof, optionally in combination with erlotinib or gefitinib. In another embodiment, the combination is in combination with erlotinib.

Another aspect of the present disclosure relates to a method for treating non-small cell lung cancer (NSCLC) in a subject, the method comprising administering to a 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 a combination thereof. Compound (I), compound (II) or compound (III) can be administered alone as one of the solid forms discussed above or as a combination thereof. A crystalline form is a preferred solid form. Therefore, another aspect of the present disclosure relates to a method for treating non-small cell lung cancer (NSCLC) in a subject, the method comprising administering to a 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 a combination thereof, wherein compound (I), compound (II) or compound (III) is present in a crystalline form. In another aspect of the present disclosure, this method of treatment can be implemented by administering a pharmaceutical composition such as at least one of compound (I), compound (II), compound (III) or a combination thereof discussed above. In another embodiment, the composition administered in this method is a combination of erlotinib and at least one of Compound (I), Compound (II), Compound (III), or a combination thereof.

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

Another aspect of the present disclosure relates to a method for treating an astrocytoma (including a glioblastoma, giant cell glioblastoma, gliosarcoma, and a glioblastoma with an oligodendroglial component) in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of at least one of compound (I), compound (II), compound (III), or a combination thereof. Compound (I), compound (II), or compound (III) can be administered alone or in combination as one of the solid forms discussed above. Crystalline forms are preferred solid forms. Therefore, another aspect of the present disclosure relates to a method for treating an astrocytoma, the method comprising administering to a subject in need thereof a therapeutically effective amount of compound (I), compound (II), compound (III), or a combination thereof, wherein compound (I), compound (II), or compound (III) exists in a crystalline form. In another aspect of the present disclosure, this method of treatment can be implemented by administering a pharmaceutical composition such as at least one of compound (I), compound (II), compound (III), or a combination thereof discussed above.

Another aspect of the present disclosure relates to a method for treating thyroid cancer (including medullary thyroid cancer) in a subject, comprising administering to a 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 can be a therapeutically effective amount.

Another aspect of the present disclosure relates to a method for treating thyroid cancer (including medullary thyroid cancer) in a subject, the method comprising administering to a subject in need thereof at least one of compound (I), compound (II), compound (III) or a combination thereof. Compound (I), compound (II) or compound (III) can be administered alone or in combination as one of the solid forms discussed above. Crystalline forms are preferred solid forms. Therefore, another aspect of the present disclosure relates to a method for treating thyroid cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of compound (I), compound (II), compound (III) or a combination thereof, wherein compound (I), compound (II) or compound (III) exists in a crystalline form. In another aspect of the present disclosure, this method of treatment can be implemented by administering a pharmaceutical composition such as at least one of compound (I), compound (II), compound (III) or a combination thereof discussed above.

Another aspect of the present disclosure relates to a method for treating a disease or disorder associated with uncontrolled, abnormal, and/or harmful cellular activity. This method administers at least one of Compound (I), Compound (II), Compound (III), or a combination thereof to a subject in need thereof. The amount of Compound (I), Compound (II), or a combination thereof administered can be a therapeutically effective amount. Compound (I), Compound (II), or Compound (III) can be administered alone as one of the solid-state forms discussed above or as a combination thereof. A crystalline form is a preferred solid-state form.

Therefore, another aspect of the present disclosure relates to a method for treating a disease or disorder associated with uncontrolled, abnormal and/or harmful cell activity, the method comprising administering to a subject in need thereof a therapeutically effective amount of at least one of Compound (I), Compound (II), Compound (III) or a combination thereof, wherein Compound (I), Compound (II) or Compound (III) is present in a crystalline form. In another aspect of the present disclosure, this method of treatment can be implemented by administering a pharmaceutical composition such as at least one of Compound (I), Compound (II), Compound (III) or a combination thereof discussed above. Another aspect of the present disclosure relates to a method for treating a disease or disorder associated with uncontrolled, abnormal and/or harmful cell activity. This method administers a crystalline form of Compound (I), Compound (II) or any combination of Compounds (I) and (II) to a subject in need thereof. The amount of Compound (I), Compound (II) or any combination of Compounds (I) and (II) administered can be a therapeutically effective amount.

Another aspect of the present disclosure relates to the use of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide malate salt of any of the above embodiments for the manufacture of a medicament for treating a disease or disorder discussed above. Upon dissolution, the crystalline or amorphous form of the present disclosure loses its solid state structure and is therefore referred to, for example, as a solution of Compound (I). At least one crystalline form disclosed herein can be used to prepare at least one liquid formulation in which at least one crystalline form of the present disclosure is dissolved and/or suspended.

For example, the pharmaceutical composition discussed above can be any pharmaceutical form containing active compound (I), compound (II) and/or compound (III), including solid forms thereof, hereinafter referred to as active compound. The pharmaceutical composition can be, for example, a tablet, capsule, liquid suspension, injectable, topical or transdermal formulation. The pharmaceutical composition generally contains from about 1% by weight to about 99% by weight of the active compound or a crystalline form of the active compound and from 99% by weight to 1% by weight of a suitable pharmaceutical excipient. In one embodiment, the composition is between about 5% by weight and about 75% by weight of the active compound, with the remainder being suitable pharmaceutical excipients or other adjuvants, as discussed below.

According to the present disclosure, a "therapeutically effective amount of an active compound or a crystalline or amorphous form of an active compound" (discussed herein with respect to pharmaceutical compositions) that inhibits, regulates, and/or modulates kinase signaling 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 the present disclosure is a therapeutic amount that is therapeutically useful for treating or preventing the conditions and disorders discussed herein. Compounds (I), (II), and/or (III), including solid-state forms thereof, have therapeutic activity for inhibiting, regulating, and/or modulating kinase signaling, as described in WO2005-030140. N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.

The actual amount required to treat any particular patient depends on a variety of factors, including the condition being treated and its severity; the specific pharmaceutical composition used; the patient's age, weight, general health, sex, and diet; the mode of administration; the time of administration; the route of administration; and the rate of excretion of the active compound or crystalline form of the active compound of the present disclosure; the duration of treatment; any drugs used in combination or concomitantly with the specific compound used; and other such factors well known in the medical arts. These factors are discussed in "The Pharmacological Basis of Therapeutics" by Goodman and Gilman, 10th Edition, A. Gilman, J. Hardman, and L. Limbird, eds., McGraw-Hill Press, 155-173, 2001, which is incorporated herein by reference. The active compounds or crystalline forms of the active compounds of the present disclosure and pharmaceutical compositions containing them can be used in combination with anticancer agents or other agents typically administered to patients undergoing treatment for cancer. They can also be formulated together with one or more such agents in a single pharmaceutical composition.

Depending on the type of pharmaceutical composition, a pharmaceutically acceptable carrier can be selected from any one or combination of carriers known in the art. The selection of a pharmaceutically acceptable carrier depends in part on the desired method of administration to be used. For pharmaceutical compositions of the present disclosure, that is, one of the active compounds of the present disclosure or the crystalline forms of the active compounds, the carrier should be selected so as to substantially maintain the specific form of the active compound, whether or not it is crystalline. In other words, the carrier should not substantially change the form of the active compound. The carrier should also not be incompatible with the form of the active compound in other aspects, for example, producing any undesirable biological effects or interacting with any other components of the pharmaceutical composition in a harmful manner.

The pharmaceutical compositions of the present 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, Pa., 1990). In solid dosage forms, 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 starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, such as cellulose derivatives, starch, alginates, gelatin, polyvinyl pyrrolidone, sucrose and gum arabic; (c) humectants, such as glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, cross-linked sodium carboxymethyl cellulose, complex silicates and sodium carbonate; (e) solution retarding agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate, magnesium stearate, etc.; (h) adsorbents, such as kaolin and bentonite; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate or mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Pharmaceutically acceptable adjuvants known in the field of pharmaceutical preparations can also be used for pharmaceutical compositions of the present invention. These include but are not limited to preservatives, wetting agents, suspending agents, sweeteners, flavorings, aromatics, emulsifiers and dispersants. By various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc., it is possible to ensure that microbial action is inhibited. It is also possible to expect that isotonic agents, such as sugar, sodium chloride, etc., are included. If necessary, pharmaceutical compositions of the present invention may also contain a small amount of auxiliary substances, such as wetting agents or emulsifiers, pH buffers and antioxidants (e.g., citric acid, sorbitan monolaurate, triethanolamine oleate and butylated hydroxytoluene).

The above-mentioned solid dosage forms can be prepared with coatings and shells, such as enteric coatings and others known in the art. They may contain opacifiers and may also be compositions that allow them to release the active compound in a delayed manner in certain parts of the intestinal tract. Examples of embedding compositions that can be used are polymeric substances and waxes. If appropriate, the active compound can also be in microencapsulated form with one or more of the above-mentioned excipients.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances.

Compositions for rectal administration are, for example, suppositories, which can be prepared by mixing the active compound or a crystalline form of the active compound with, for example, suitable non-irritating excipients or carriers (e.g., cocoa butter, polyethylene glycol or a suppository wax) which are solid at ordinary temperatures but liquid at body temperature and therefore melt in the appropriate body cavity to release the active ingredient therein.

Because the crystalline form of active compound or active compound is maintained during its preparation, solid dosage form is preferred for pharmaceutical composition of the present disclosure. It is particularly preferred for solid dosage form for oral administration, which includes capsules, tablets, pills, powders and granules. In these solid dosage forms, active compound is mixed with at least one inert, pharmaceutically acceptable excipient (also referred to as pharmaceutically acceptable carrier). Active compound or active compound crystalline form in pure form or in suitable pharmaceutical composition can be carried out by any acceptable mode of administration or medicament for similar applications. Therefore, administration can be, for example, oral, nasal, parenteral (intravenous, intramuscular or subcutaneous), local, transdermal, intravaginal, intravesical, intracisternal or rectal mode, with solid, semisolid, lyophilized powder or liquid dosage form (for example, tablet, suppository, pill, soft elastic and hard gelatin capsule, powder, solution, suspension or aerosol etc.), preferably with the unit dosage form suitable for simple and accurate dosage administration. A preferred route of administration is oral administration, using a convenient dosage regimen that can be adjusted according to the severity of the disease to be treated.

General preparation method of crystalline form

Crystalline forms can be prepared by a variety of methods, including, but not limited to, crystallization or recrystallization from a suitable solvent mixture; sublimation; growth from a melt; solid-state transformation from another phase; crystallization from a supercritical fluid; and spraying. Techniques for crystallizing or recrystallizing crystalline forms from solvent mixtures include, but are not limited to, for example, solvent evaporation; lowering the temperature of the solvent mixture; crystal seeding of a supersaturated solvent mixture of the compound and/or its salt; crystal seeding of a supersaturated solvent mixture of the compound and/or its salt; freeze drying of the solvent mixture; and addition of an antisolvent to the solvent mixture. Crystalline forms, including polymorphs, can be prepared using high-throughput crystallization techniques.

Crystals of drugs (including polymorphs), methods of preparation, and characterization of drug crystals are discussed in Solid-State Chemistry of Drugs, S. R. Byrn, R. R. Pfeiffer, and J. G. Stowell, 2nd ed., SSCI, West Lafayette, Indiana (1999).

In crystallization techniques that utilize a solvent, the solvent is generally selected based on one or more factors, including, but not limited to, the solubility of the compound, the crystallization technique used, and the vapor pressure of the solvent. Combinations of solvents may be used. For example, the compound may be solubilized in a first solvent to provide a solution, and then an antisolvent may be added to reduce the solubility of the compound in the solution and precipitate the crystals. An antisolvent is a solvent in which the compound has low solubility.

In the method for preparing crystals, compound (I), compound (II) and/or compound (III) may be suspended and/or stirred in a suitable solvent to obtain a slurry, and the slurry may be heated to promote dissolution. As used herein, the term "slurry" refers to a saturated solution of a compound, wherein the solution may contain an additional amount of the compound to obtain a heterogeneous mixture of the compound and the solvent at a given temperature.

Seeds can be added to any crystallization mixture to promote crystallization. Seeding can be used to control the growth of a specific polymorph and/or to control the grain size distribution of the crystallized product. Therefore, the calculation of the amount of required seed crystals depends on the size of the available seed crystals and the desired size of the average product particles, as described in "Programmed Cooling Batch Crystallizers", J.W.Mullin and J.Nyvlt, Chemical Engineering Science, 1971, 26, 3690377. Small-sized seed crystals are generally required to effectively control the crystal growth in the batch. Small-sized seed crystals can be produced by screening, grinding or micronizing large crystals, or by solution microcrystallization. During crystal grinding or micronization, care should be taken to avoid changes in crystallinity from the desired crystalline form (i.e., becoming amorphous or other polymorphs).

The cooled crystallization mixture can be filtered under vacuum, and the separated solid product can be washed with a suitable solvent (e.g., a cold recrystallization solvent). After washing, the product can be dried under a nitrogen purge to obtain the desired crystalline form. The product can be analyzed by suitable spectroscopy or analytical techniques, 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 of an isolated yield greater than about 70% by weight based on the weight of the compound initially used in the crystallization process, preferably greater than about 90% by weight isolated yield. The product can optionally be deblocked by co-grinding or by passing through a mesh screen.

After reading the following detailed description, those skilled in the art will more readily appreciate the features and advantages of the present disclosure. It should be understood that, for clarity reasons, certain features of the present disclosure described above and below in the context of separate embodiments may also be combined to form a single embodiment. Conversely, for brevity reasons, different features of the present disclosure described in the context of a single embodiment may also be combined to form sub-combinations thereof. The present disclosure is further illustrated by the following examples, which should not be construed as limiting the scope or spirit of the present disclosure to the specific procedures described therein.

Definitions set forth herein take precedence over 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 non-crystalline molecular and/or ionic solid form. Amorphous solids do not exhibit a well-defined X-ray diffraction pattern with sharp maxima.

As used herein, the term "substantially pure" refers to a crystalline form of the compound (I) in question that contains at least about 90% by weight based on the weight of such a crystalline form. While not intended to limit the applicability of the teachings equivalent to the scope of the claims, the term "at least about 90% by weight" includes, but is not limited to, for example, about 90% by weight, about 91% by weight, about 92% by weight, about 93% by weight, about 94% by weight, about 95% by weight, about 96% by weight, about 97% by weight, about 98% by weight, about 99% by weight, and about 100% by weight based on the weight of the crystalline form in question. The remaining crystalline form of compound (I) may include other forms of compound (I) and/or reaction impurities and/or processing impurities that occur when, for example, preparing this crystalline form. The presence of reaction impurities and/or processing impurities can be determined by analytical techniques known in the art (e.g., chromatography, nuclear magnetic resonance spectroscopy, mass spectrometry, and/or infrared spectroscopy).

Preparation Example

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

The synthetic route for preparing N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and its (L)-malate salt is depicted in Scheme 1:

Solution 1

The method shown in Scheme 1 is described in more detail below.

1.1 Preparation of 4-chloro-6,7-dimethoxy-quinoline

6,7-Dimethoxy-quinolin-4-ol (1 L, 10.0 kg) and acetonitrile (64.0 L) were added sequentially to the reactor. 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 raised to approximately 80°C. The reaction was considered complete (approximately 9.0 hours) when <2% starting material remained (in-process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 10°C and then quenched into a cold solution of dichloromethane (DCM, 238.0 kg), 30% _NH₄OH (135.0 kg), and ice (440.0 kg). The resulting mixture was warmed to approximately 14°C, and the phases were separated. The organic phase was washed with water (40.0 kg) and concentrated by vacuum distillation, while removing the solvent (approximately 190.0 kg). To this batch was added methyl-tert-butyl ether (MTBE, 50.0 kg) and the mixture was cooled to about 10° C. during which time the product crystallized. The solid was recovered by centrifugation, washed with n-heptane (20.0 kg) and dried at about 40° C. to give the title compound (8.0 kg).

1.2 Preparation of 6,7-dimethyl-4-(4-nitro-phenoxy)-quinoline

4-Chloro-6,7-dimethoxyquinoline (8.0 kg), 4-nitrophenol (7.0 kg), 4-dimethylaminopyridine (0.9 kg), and 2,6-lutidine (40.0 kg) were added to the reactor in sequence. The reactor contents were heated to approximately 147°C. Upon completion of the reaction (<5% residual starting material as determined by in-process HPLC analysis, approximately 20 hours), the reactor contents were cooled 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 approximately 12 hours to provide the title compound (4.0 kg).

1.3 Preparation of 4-(6,7-dimethoxy-quinolin-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 tetrahydrofuran (40.0 kg) heated to approximately 60°C. The addition was performed so that the temperature of the reaction mixture remained at approximately 60°C. When the reaction was deemed complete (<2% starting material remaining, typically 1.5 hours) as determined by in-process HPLC analysis, the reactor contents were filtered. The filtrate was concentrated by vacuum distillation at approximately 35°C to half its initial volume, which resulted in the product precipitate. The product was recovered by filtration, washed with water (12.0 kg), and dried under vacuum at approximately 50°C to yield the title compound (3.0 kg; 97% AUC).

1.4 Preparation of 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid

Triethylamine (8.0 kg) was added to a cooled (approximately 4°C) solution of commercially available cyclopropane-1,1-dicarboxylic acid (2 1, 10.0 kg) in THF (63.0 kg) at a rate such that the batch temperature did not exceed 10°C. The solution was stirred for approximately 30 minutes, then thionyl chloride (9.0 kg) was added, maintaining the batch temperature below 10°C. Upon completion of the addition, a solution of 4-fluoroaniline (9.0 kg) in THF (25.0 kg) was added at a rate such that the batch temperature did not exceed 10°C. The mixture was stirred for approximately 4 hours, 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 a solid precipitate. The solid was recovered by centrifugation and then dried under vacuum at about 35°C to give the title compound (10.0 kg).

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,N-dimethylformamide (DMF; 0.02 kg) at such a rate that the batch temperature did 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)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

The solution containing 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride from the previous step was added to a mixture of 4-(6,7-dimethoxy-quinolin-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 batch temperature did not exceed 30°C. Upon completion of the reaction (typically within 10 minutes), water (74.0 kg) was added. The mixture was stirred at 15-30°C for approximately 10 hours, resulting in the precipitation of the product. The product was recovered by filtration, washed with a pre-prepared solution of THF (11.0 kg) and water (24.0 kg), and dried under vacuum at approximately 65°C for approximately 12 hours to provide the title compound (free base, 5.0 kg). ^1H NMR(400MHz,d ₆ -DMSO): δ10.2(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.

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

A solution of (L)-malic acid (2.0 kg) in water (2.0 kg) was added to a solution of cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]amide (4-fluoro-phenyl)-amide free base (1.5, 5.0 kg) in ethanol, maintaining the batch temperature at approximately 25°C. Carbon (0.5 kg) and thiosilica (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 isopropyl alcohol (38.0 kg) and allowed to cool to approximately 25°C. The product was recovered by filtration, washed with isopropyl alcohol (20.0 kg), and dried at approximately 65°C to provide Compound (I) (5.0 kg).

Example 2: Preparation of Type N-1 Crystalline Compound (I)

A solution was prepared by adding tetrahydrofuran (12 mL/g-bulk-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 (mol); 32.08 g) to a 1 L reactor. Water (0.5317 mL/g-bulk-LR; 53.17 mL) was added, and the solution was heated to 60°C and maintained at this temperature for 1 hour until the solids were completely dissolved. The solution was passed through a Polish filter.

Acetonitrile (12 mL/g-bulk-LR; 1.20 L) was added at 60° C. over a period of 8 hours. The solution was maintained at 60° C. for 10 hours. The solution was then cooled to 20° C. and maintained for 1 hour. The solid was filtered and washed with acetonitrile (12 mL/g-bulk-LR; 1.20 L). The solid was dried at 60° C. (25 mm Hg) for 6 hours to provide Compound (I) Form N-1 (108 g; 0.85 equiv; 108.00 g; 85.22% yield) as a white crystalline solid.

Example 3: Alternative Preparation of Form N-1 Crystalline Compound (I)

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

Powder mixtures were prepared separately using two batches of known amounts of Compound (I): (1) 300 mg of Batch 1, containing approximately 41% N-1 Form Compound (I) and 59% N-2 Form Compound (I) (as analyzed by Raman spectroscopy), and (2) 200 mg of Batch 2, having an XPRD pattern similar to that of N-2 Form Compound (I).

The mixture of N-1 type compound (I) and N-2 type compound (I) powders was added to the saturated solution and the slurry was aged for 25 days at room temperature under magnetic stirring. The slurry was then sampled and filtered through a Buchner funnel to obtain 162 mg of a wet cake. The wet cake was dried in a vacuum oven at 45 ° C to obtain 128 mg of N-1 type crystalline compound (I).

Example 4: Preparation of Type N-2 Crystalline Compound (I)

4.1 Preparation of Type N-2 Crystalline Compound (I) 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)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide in a 25 ml screw-cap vial. Next, 0.758 ml of a 0.79 M (L)-malic acid stock solution was added to the vial under magnetic stirring. The solution was then left stirring at ambient temperature for 24 hours. The sample was then suction filtered using a 0.45 μm PTFE cartridge and dried overnight in a vacuum at ambient temperature.

4.2 Preparation of Type N-2 Crystalline Compound (I)

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

In a separate reactor, (L)-malic acid (1.2 equiv (mol); 15.40 g) was dissolved in methyl isobutyl ketone (10 mL/g-bulk-LR; 480.00 mL) and tetrahydrofuran (1 mL/g-bulk-LR; 48.00 mL). Next, 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 dropwise via an addition funnel at 50°C (1.3 ml/min (3 hours)). The slurry was maintained at 50°C for 18 hours and then cooled to 25°C over 30 minutes. The solid was filtered and washed with 20% tetrahydrofuran/methyl isobutyl ketone (10V, 480 mL). The solid was dried at 60° C. under vacuum for 5 hours to afford Compound (I) (55.7 g; 0.92 eq; 55.70 g; 91.56% yield) as an off-white crystalline solid.

Example 5: Preparation of Type N-1 Crystalline Compound (III)

In a half dram bottle, a 1 ml aliquot of the (DL)-malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide slurried in tetrahydrofuran (THF) was heated to 60°C on a hot plate. Next, tetrahydrofuran was added dropwise until an almost clear solution was obtained. The bottle was capped, removed from the hot plate and equilibrated at ambient temperature without stirring. Crystallization was evident after a few hours and the solution was left overnight to complete crystallization. A few drops of the resulting slurry were placed on a glass slide for microscopic analysis. The crystalline material consisted of numerous elongated plates with the longest dimension ranging up to 60 micrometers.

Alternative preparation of N-1 type crystalline compound (III)

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

In a separate reactor, (DL)-malic acid (1.2 equiv (mol); 4.53 g) was dissolved in methyl isobutyl ketone (8 mL/g-bulk-LR; 120.00 mL) and tetrahydrofuran (1 mL/g-bulk-LR; 15.00 mL). Next, 20 mL of the solution was added to the first solution at 50°C. The malic acid solution was added dropwise at 50°C via an addition funnel (1.3 ml/min (3 hours)). The slurry was maintained at 50°C for 18 hours and then cooled to 25°C over 30 minutes. The solid was filtered and washed with 20% THF/MIBK (10 V, 150 mL). The solid was dried at 60°C under vacuum 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)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (L)-malate and 250 mL of a 1:1 (v:v) mixture of methanol and dichloromethane. The cloudy solution was filtered through a 0.45 micron filter to give a clear, slightly yellowish solution. The solution was pumped through a spray dryer nozzle 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 droplets. A dried amorphous powder (1.5 g) was collected (yield = 30%).

Characterization Examples

I. NMR Spectrum in Dimethyl Sulfoxide Solution

I.1 N-1 type compound (I)

^1H NMR(400MHz,d ₆ -DMSO): δ1.48(s,4H),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＝5,8Hz),6.44(d,1H,J＝5Hz,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).

^13C NMR(d ₆ -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.

I.2 N-2 type compound (I)

^1H NMR(400MHz,d ₆ -DMSO): δ1.48(s,4H),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＝5,8Hz),6.44(d,J＝5Hz,1H),7.12-7.1 9(m,2H),7.22-7.26(m,2H),7.40(s,1H),7.51(s,1H),7.63-7.68(m,2 H),7.76-7.80(m,2H),8.46-8.49(m,1H),10.08(s,1H),10.21(s,1H).

^13C NMR(d ₆ -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.

I.3 N-1 type compound (III)

^1H NMR(400MHz,d ₆ -DMSO): δ1.48(s,4H),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＝5,8Hz),6.44(d,J＝5Hz,1H),7.12-7.1 9(m,2H),7.22-7.26(m,2H),7.40(s,1H),7.51(s,1H),7.63-7.68(m,2 H),7.76-7.80(m,2H),8.46-8.49(m,1H),10.08(s,1H),10.21(s,1H).

^13C NMR(d ₆ -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.

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

II. Powder X-ray Diffraction (XRPD) Studies

X-ray powder diffraction (XRPD) patterns were collected on a Bruker AXS C2 GADDS diffractometer equipped with an automated XYZ stage, a laser video microscope for automated sample positioning, and a HiStar 2-dimensional area detector. The radiation source used was a copper source with a voltage set at 40 kV and a current set at 40 mA. The X-ray optics consisted of a single multilayer mirror coupled to a 0.3 mm pinhole collimator. The beam divergence, i.e., the effective size of the X-ray beam at the sample, was approximately 4 mm. A θ-θ continuous scan mode was used with a sample-to-detector distance of 20 cm, which yielded an effective 2θ range of 3.2°-29.8°. Flat plate samples were prepared under ambient conditions (approximately 18°C to 25°C) using the received powder without grinding. Approximately 1-2 mg of sample was gently pressed onto a glass slide to obtain a flat surface. Samples were typically exposed to the X-ray beam for 120 seconds. The beam divergence, i.e., the effective size of the X-ray spot, was approximately 4 mm. Alternatively, powder samples were placed in sealed glass capillaries with a diameter of 1 mm or less, and the capillary was rotated at a sample-to-detector distance of 15 cm during data collection. Data were collected for 3 ≤ 2θ ≤ 35° with a sample exposure time of at least 2000 seconds. The resulting two-dimensional diffraction arcs were integrated to generate a conventional 1-dimensional XRPD pattern over the range of 3 to 35° 2θ ± 0.2° 2θ using a step size of 0.02° 2θ. The software used for data collection was GADDS (for WNT 4.1.16), and the data were analyzed and displayed using Diffrac Plus EVA v9.0.0.2 or v13.0.0.2.

II.1 N-1 type compound (I)

Figure 1 shows an experimental XRPD pattern of Form N-1 crystalline Compound (I) obtained at room temperature (about 25°C). A list of peaks is shown in Table 2 above. 2θ values at 19.4, 21.5, 22.8, 25.1, and 27.6 (±0.2° 2θ) can be used to characterize Form N-1 crystalline Compound (I). The entire list of peaks, or a subset thereof, may be sufficient to characterize Form N-1 crystalline Compound (I).

II.2 N-2 type compound (I)

Figure 8 shows an experimental XRPD pattern of Form N-2 crystalline Compound (I) obtained at room temperature (about 25°C). The peak list is shown in Table 2 above. The 2θ values at 20.9 and 21.9 (±0.2° 2θ) can be used to characterize Form N-2 crystalline Compound (I). The entire peak list or a subset thereof may be sufficient to characterize Form N-2 crystalline Compound (I).

II.3 N-1 type compound (III)

Figure 15 shows the experimental and simulated XRPD patterns of Form N-1 crystalline Compound (III) obtained with a spinning capillary sample at 25°C. The list of peaks is shown above in Table 2. The entire list of peaks or a subset thereof may be sufficient to characterize Form N-2 crystalline Compound (III).

II.4 Amorphous compound (I)

Figure 22 shows the experimental XRPD pattern of amorphous Compound (I) obtained at room temperature (about 25°C). The spectrum is characterized by broad peaks and a lack of sharp peaks, which is consistent with an amorphous material.

III. Single crystal X-ray studies of N-1 type compound (III)

Data were collected on a Bruker-Nonius CAD4 series diffractometer. Unit cell parameters were determined by least-squares analysis using a 25° high-angle reflection as the experimental diffractometer setting. Intensity was measured using Cu Kα radiation at a constant temperature using a θ-2θ variable scanning technique and corrected for the Lorentz polarization factor only. Background counts were collected at the end of the scan for half the scan time. Alternatively, single crystal data were collected on a Bruker-Nonius Kappa CCD 2000 system using Cu Kα radiation. Indexing and processing of the measured intensity data were performed using the HKL2000 software package (Otwinowski, Z. & Minor, W. (1997), Macromolecular Crystallography, eds. Carter, WC Jr & Sweet, RM (Academic, NY), Vol. 276, pp. 307-326) in the Collect suite (Collect Data collection and processing user interface: Collect: Data collection software, R. Hooft, Nonius BV, 1998). Alternatively, single crystal data were collected using CuKα radiation on a Bruker-AXS APEX2 CCD system. Indexing and processing of the measured intensity data were performed using the APEX2 software package/suite (APEX2 Data collection and processing user interface: APEX2 User Manual, v1.27). Where indicated, crystals were cooled in the cold stream of an Oxford cryo system (Oxford Cryosystems Cryostream cooler: J. Cosier and AM Glazer, J. Appl. Cryst., 1986, 19 , 105) during data collection.

The structure was solved by direct methods and refined according to the observed reflections using the SDP software package (SDP, Structure Determination Package, Enraf-Nonius, Bohemia NY 11716. The scattering coefficients (including f' and f") in the SDP software were taken from "International Tables for Crystallography", Kynoch Press, Birmingham, England, 1974; Vol IV, Tables 2.2A and 2.3.1) with minor local modifications or using the crystallographic packages MAXUS (maXus Solution and Refinement Software Group: S. Mackay, C.J. 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, v1.27).

The derived atomic parameters (coordinates and temperature factors) were refined using a complete matrix least squares method. The function minimized during the refinement was _Σw (| _Fo |-| _Fc |) ² . R was defined as Σ|| _Fo |-| _Fc ||/Σ| _Fo |, with _Rw = [ _Σw (| _Fo |-| _Fc |) ² / _Σw | _Fo | ² ] ^1/2 , where w is a suitable weighting function based on the error in the observed intensities. Difference maps were examined at all stages of the refinement. Hydrogens were introduced at idealized positions using isotropic temperature factors, but the hydrogen parameters were not changed.

The "hybrid" simulated powder X-ray pattern was generated as described in the literature (Yin.S.; Scaringe, R.P.; DiMarco, J.; Galella, M. and Gougoutas, J.Z., American Pharmaceutical Review, 2003, 6, 2, 80). The room temperature unit cell parameters were obtained by unit cell modification using the CellRefine.xls program. The program input included the 2-θ positions of about 10 reflections obtained from the laboratory temperature powder pattern, and the corresponding Miller indices hkl were assigned based on single crystal data collected at low temperature. The new (hybrid) XRPD was calculated (by either the software program Alex or LatticeView) by inserting the molecular structure determined at low temperature into the room temperature unit cell obtained in the first step of the method. The molecules were inserted in a manner that maintained the size and shape of the molecules and the molecular positions relative to the unit cell origin but allowed the intermolecular distances to expand as the unit cell expanded.

Single crystals measuring 40 x 30 x 10 microns were selected for single crystal diffraction analysis from the slurry of crystals described in Example 5. The selected crystals were fixed to fine glass fibers with a small amount of non-sticky grease and mounted at room temperature on a Bruker Apex II single crystal diffractometer equipped with a rotating copper anode.

Crystalline Compound (III) Form N-1 is characterized by unit cell parameters approximately equal to those listed in Table 4. The unit cell parameters are measured at a temperature of about 25°C.

Table 4

The structural solution and revision are conventional in the monoclinic space group P2 ₁ /n, which has four formula units in the unit cell. This structure contains a 1:1 ratio of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide cation protonated at the quinoline nitrogen atom and a monoionized malate anion. Additionally, the crystals contain a 1:1 ratio of (L)-malate to (D)-malate ions. Table 5: Fractional atomic coordinates of the N-1 form of compound (III) calculated at approximately 25°C.

Based on the single crystal X-ray data, Form N-1 crystalline Compound (III) can be characterized by a simulated powder x-ray diffraction (XRPD) pattern substantially consistent with the simulated pattern shown in FIG15 and/or by an observed XRPD pattern substantially consistent with the experimental pattern shown in FIG15.

Table 5

Fractional atomic coordinates of N-1 type compound (III) calculated at a temperature of about 25°C

IV. Solid-State Nuclear Magnetic Resonance (SSNMR)

All solid-state C-13 NMR measurements were performed using a Bruker DSX-400, 400 MHz NMR spectrometer. High-resolution spectra were acquired at approximately 12 kHz using high-power proton decoupling and a TPPM pulse sequence with ramp-amplified orthogonal polarization (RAMP-CP) utilizing magic angle spinning (MAS) (A.E. Bennett et al., J. Chem. Phys., 1995, 103, 6951) (G. Metz, X. Wu, and S.O. Smith, J. Magn. Reson. A, 1994, 110, 219-227). Each experiment used approximately 70 mg of sample loaded onto a zirconia rotor in a cartridge design. Chemical shifts (δ) were referenced to external adamantane, with the high-frequency resonance set to 38.56 ppm (W.L. Earl and D.L. VanderHart, J. Magn. Reson., 1982, 48, 35-54).

IV.1 N-1 type compound (I)

Figure 2 shows the solid ^state13C NMR spectrum of crystalline Compound (I) Form N-1.The entire peak list or a subset thereof may be sufficient to characterize crystalline Compound (I) Form N-1.

SS ¹³ C NMR peaks: 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, 114.9, 115.8, 119.6, 120.1, 121.6, 123.2, 124.1, 136.4, 138.6, 140.6, 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 solid-state ¹⁵ N NMR spectrum of crystalline Compound (I) Form N-1. The spectrum shows peaks at 118.6, 119.6, 120.7, 134.8, 167.1, 176.0, and 180 ppm ± 0.2 ppm. The entire peak list or a subset thereof may be sufficient to characterize crystalline Compound (I) Form N-1.

Figure 4 shows the solid-state ¹⁹ F NMR spectrum of Form N-1 crystalline Compound (I). The spectrum shows peaks at -121.6, -120.8, and -118.0 ppm ± 0.2 ppm.

IV.2 N-2 type compound (I)

Figure 9 shows the solid ^state13C NMR spectrum of crystalline Compound (I) Form N-2.The entire peak list or a subset thereof may be sufficient to characterize crystalline Compound (I) Form N-2.

SS ¹³ C NMR peaks: 20.5, 21.8, 23.0, 25.9, 26.4, 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, 1 24.5, 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 solid-state ¹⁵ N NMR spectrum 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 entire peak list or a subset thereof may be sufficient to characterize crystalline Compound (I) Form N-2.

Figure 11 shows the solid-state ¹⁹ F NMR spectrum of crystalline Compound (I) Form N-2. The spectrum shows peaks at -121.0 and -119.1 ppm ± 0.2 ppm. These peaks, alone or in combination, are sufficient to characterize crystalline Compound (I) Form N-2.

IV.3 N-1 type compound (III)

Figure 16 shows the solid ^state13C NMR spectrum of crystalline Compound (III) Form NI.The entire peak list or a subset thereof may be sufficient to characterize crystalline Compound (III) Form NI.

SS ¹³ C NMR peaks: 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, and 182.1 ppm, ±0.2 ppm.

Figure 17 shows the solid-state ¹⁵ N NMR spectrum of crystalline Compound (III) Form N-1. The spectrum shows peaks at 119.6, 134.7, and 175.5 ppm ± 0.2 ppm. The entire peak list or a subset thereof may be sufficient to characterize crystalline Compound (III) Form N-1.

Figure 18 shows the solid-state ¹⁹ F NMR spectrum of Form N-1 crystalline Compound (III). The spectrum shows a peak at -120.5 ppm ± 0.2 ppm.

IV.4 Amorphous compound (I)

Figure 23 shows the solid ^state13C NMR spectrum of amorphous Compound (I).The entire peak list or a subset thereof may be sufficient to characterize amorphous Compound (I).

SS ¹³ C NMR peaks (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 solid-state ¹⁵ N NMR spectrum of amorphous Compound (I). The spectrum shows peaks at 120.8, 131.8, 174.7, and 178.3 ppm ± 0.2 ppm. The entire peak list or a subset thereof may be sufficient to characterize amorphous Compound (I).

Figure 25 shows the solid-state ¹⁹ F NMR spectrum of amorphous Compound (I). The spectrum shows a peak at -118.9 ppm ± 0.2 ppm.

V. Thermal Characterization Measurements

Thermogravimetric analysis (TGA)

TGA measurements were performed on a TA Instruments ^™ model Q500 or 2950 using an open pan setup. Samples (approximately 10-30 mg) were placed in pre-tared platinum pans. The sample weight was accurately weighed and recorded by the instrument to the nearest thousandth of a milligram. The furnace was purged with nitrogen at 100 mL/min. Data were collected between room temperature and 300°C at a heating rate of 10°C/min.

Differential scanning calorimetry (DSC) analysis

DSC measurements were performed on a TA Instruments ^™ model Q2000, Q1000, or 2920 using an open pan setup. Samples (approximately 2-6 mg) were weighed into an aluminum pan, recorded to the nearest hundredth of a milligram, and transferred to the DSC. The instrument was purged with nitrogen at 50 mL/min. Data were collected between room temperature and 300°C at a heating rate of 10°C/min. Plots were plotted with the endothermic peak facing downward.

V.1 N-1 type compound (I)

FIG5 shows a TGA thermogram of crystalline Compound (I) Form N-1, which shows a weight loss of about 0.4% by weight at a temperature of 170°C.

FIG6 shows the DSC thermogram of Form N-1 crystalline Compound (I), which shows a melting point of about 187°C.

V.2 N-2 type compound (I)

FIG12 shows a TGA thermogram of crystalline Compound (I) Form N-2, which shows a weight loss of about 0.1% by weight at a temperature of 170°C.

FIG13 shows the DSC thermogram of crystalline Compound (I) Form N-2, which shows a melting point of about 186°C.

V.3 N-1 type compound (III)

FIG19 shows a TGA thermogram of crystalline Compound (III) Form N-1, which shows a weight loss of about 0.2% by weight at a temperature of 170°C.

FIG20 shows the DSC thermogram of Form N-1 crystalline Compound (III), which shows a melting point of approximately 186° C.

V.2 Amorphous compound (I)

Figure 26 shows the DSC of crystalline Compound (I).

VI. Water Vapor Isotherm Measurement

Moisture sorption isotherms were collected in a VTI SGA-100 Symmetric Vapor Analyzer using approximately 10 mg of sample. Samples were dried at 60°C until a loss rate of 0.0005% wt/min was achieved over 10 minutes. Samples were tested at 25°C and 3 or 4, 5, 15, 25, 35, 45, 50, 65, 75, 85, and 95% relative humidity. Equilibrium was achieved at each relative humidity, reaching a rate of 0.0003% wt/min for 35 minutes or a maximum of 600 minutes.

VI.1 N-1 type compound (I)

FIG7 shows the water vapor isotherm of crystalline Compound (I) Form N-1.

VI.2 N-1 type compound (I)

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

VI.3 N-1 type compound (III)

Figure 21 shows the water vapor isotherm of crystalline Compound (III) Form N-1.

VI.4 Amorphous compound (I)

FIG27 shows the water vapor isotherm of amorphous Compound (I).

For purposes of clarity and understanding, the foregoing disclosure has been described in some detail by way of illustration and example. The present invention has been described with reference to various specific and preferred embodiments and techniques. However, it will be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention. It will be apparent to those skilled in the art that variations and modifications may be implemented within the scope of the claims. Therefore, it will be understood that the foregoing description is intended to be illustrative and not restrictive. Therefore, the scope of the present invention should not be determined by reference to the foregoing description, but rather by reference to the claims, along with the full scope of equivalents to such claims.

Claims (7)

1. N-(4-{[6,7-bis(methyloxy)quinoline-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (L)-malate, wherein the salt is of the N-2 crystalline form, and the N-2 form is characterized by at least one of the following: (i) The solid-state ^13C NMR spectrum has peaks at 23.0, 25.9, 38.0, 41.7, 69.7, 102.0, 122.5, 177.3, 179.3, 180.0 and 180.3 ± 0.2 ppm; (ii) X-ray powder diffraction patterns (CuKα) include 2θ values at 20.9 ± 0.2°2θ and 21.9 ± 0.2°2θ, 12.0 ± 0.2°2θ, 12.8 ± 0.2°2θ, and 23.7 ± 0.2°2θ, where the crystalline form was measured at ambient room temperature; and/or (iii) The solid-state ¹⁵ N NMR spectrum has peaks at 118.5, 120.8, 135.1, 167.3 and 180.1 ppm. 2. The N-(4-{[6,7-bis(methyloxy)quinoline-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (L)-malate of claim 1, wherein the salt is of the N-2 crystalline form, and the N-2 form is characterized by at least one of the following: (i) The solid-state ^13C NMR spectrum is basically consistent with the pattern shown in Figure 9; (ii) The X-ray powder diffraction pattern is basically consistent with the pattern shown in Figure 8; and/or (iii) The solid-state ¹⁵ N NMR spectrum is basically consistent with the pattern shown in Figure 10. 3. The N-(4-{[6,7-bis(methyloxy)quinoline-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (L)-malate of any one of claims 1-2, wherein the salt is of the N-2 type based on at least 90% by weight of the salt. 4. A pharmaceutical composition comprising N-(4-{[6,7-bis(methyloxy)quinoline-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (L)-malate of any one of claims 1-3 and a pharmaceutically acceptable excipient. 5. Use of the N-(4-{[6,7-bis(methyloxy)quinoline-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (L)-malate of any one of claims 1-3 in the manufacture of a medicament for treating cancer. 6. Use of the crystalline form of the (L)-malate of N-(4-{[6,7-bis(methyloxy)quinoline-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide according to any one of claims 1-3 for the manufacture of a medicament for treating thyroid cancer in a subject. 7. Use of the crystalline form of the (L)-malate of N-(4-{[6,7-bis(methyloxy)quinoline-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide according to any one of claims 1-3 for the manufacture of a medicament for treating glioblastoma in a subject.