Crystalline form of multi-tyrosine kinase inhibitor, method of preparation, and use thereof

Abstract

To provide a novel anti-cancer compound and a method for treating cancer.SOLUTION: The present invention relates to crystalline forms of N-(3 -fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-di carboxamide (Compound 1), pharmaceutical compositions comprising the crystalline form, processes for preparing the crystalline form and methods of use thereof.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to crystal forms of multi-tyrosine kinase inhibitors. In particular, the present invention relates to a crystal form of the multi-tyrosine kinase inhibitor N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, a pharmaceutical composition containing the crystal form, a method for preparing the crystal form, and methods of using them.

Background Art

[0002] International Publication No. WO2009 / 026717A discloses compounds having inhibitory activity against multiple protein tyrosine kinases, for example, inhibitory activity against VEGF receptor kinase and HGF receptor kinase. In particular, the disclosed N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) is a multi-tyrosine kinase inhibitor and shows strong inhibition of a series of tyrosine kinases closely related to RET, CBL, CHR4q12, DDR, Trk, etc., which are major regulators of signal transduction pathways leading to cell proliferation, survival, and tumor progression.

Chemical Formula

[0003] Compound 1 shows tumor regression in multiple human xenograft tumor models in mice and is currently in human clinical trials as a single agent therapy and as a combination therapy for treating a wide range of solid tumors. Compound 1 is currently in a Phase 1 clinical trial for patients with advanced cancer and a Phase 2 trial for patients with advanced liposarcoma and non-small cell lung cancer (NSCLC).

[0004] However, although amorphous small-scale chemically synthesized compound 1 is disclosed in Example 52 (Compound 147) of WO2009 / 026717A, in order to prepare the API of compound 1 in high quality and in large quantities, the crystalline form of compound 1 is usually required, whereby process impurities can be eliminated by recrystallization. In practice, it is difficult to predict with confidence which crystalline form of a particular compound is stable, reproducible, and suitable for drug processing. It is even more difficult to predict whether a particular crystalline solid form will be produced with the desired physical properties for formulation.

[0005] For all of the foregoing reasons, there is a great need to produce a crystalline form of compound 1 that provides improvements in the manufacture of pharmaceutical compositions. The present invention advantageously addresses one or more of these needs.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Summary of the Invention

[0007] This application discloses an invention for addressing the aforementioned problems and needs by providing its crystalline form. The inventors of the present invention have surprisingly found that it is very difficult to obtain a single phase of the crystalline form of N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (hereinafter referred to as Compound 1). After making great efforts to conduct systematic solid form screening research, the inventors of the present invention obtained several crystalline materials of Compound 1, Materials A - L, and Forms C, D, and H. However, only three crystalline forms (Forms C, D, and H) existed with phase homogeneity, and all other forms were composed of disordered multiple phases. Finally, the inventors of the present invention found that only Form D has excellent physical properties suitable for formulations and can be manufactured on a large commercial scale with high quality and good reproducibility.

[0008] In a first aspect of the present invention, provided herein is a crystalline form of Compound 1.

[0009] In one embodiment, the crystalline forms of Compound 1 are referred to as Form C, Form D, and Form H.

[0010] In one embodiment, the crystalline form of Compound 1, referred to as Form D, has a powder X-ray diffraction pattern (XRPD) that includes diffraction peaks having °2θ angular values independently selected from the group consisting of 7.8 ± 0.2°, 14.3 ± 0.2°, and 17.2 ± 0.2°.

[0011] In one embodiment, the crystalline form (Form D) of Compound 1 can be a single crystal.

[0012] In one embodiment, the crystalline form of Compound 1 is referred to as Form C.

[0013] In one embodiment, the crystalline form of Compound 1 is referred to as Form H.

[0014] In another embodiment, the crystalline form of Compound 1 has an XRPD pattern substantially as shown in FIG. 1A, FIG. 2A(1), FIG. 3B, FIG. 3C or FIG. 3D.

[0015] In a second aspect of the invention, there is provided a pharmaceutical composition for use in the method, comprising a therapeutically effective amount of a crystalline form of Compound 1 and a pharmaceutically acceptable excipient. In one embodiment, the crystalline form of Compound 1 is selected from Form C, Form D and Form H.

[0016] In a third aspect of the invention, there is provided a method for inhibiting multi-tyrosine kinase activity in a cell, the method comprising contacting a cell in which inhibition of multi-tyrosine kinase activity is desired with a therapeutically effective amount of a crystalline form of Compound 1. In one embodiment, the crystalline form of Compound 1 is selected from Form C, Form D and Form H.

[0017] In a fourth aspect of the invention, there is provided a method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of Compound 1. In one embodiment, the cancer is a cancer associated with multi-tyrosine kinase. In one embodiment, the multi-tyrosine kinase-related cancer is lung cancer, including non-small cell lung cancer (NSCLC). In one embodiment, the crystalline form of Compound 1 is selected from Form C, Form D and Form H.

[0018] In a fifth aspect of the invention, there is provided a method for preparing a crystalline form of Compound 1. In one embodiment, the crystalline form of Compound 1 is selected from Form C, Form D and Form H. BRIEF DESCRIPTION OF THE DRAWINGS

[0019]

Figure 1A

Figure 1B

Figure 2A-1

Figure 2A-2

Figure 2B

Figure 2C

Figure 3A

Figure 3B

Figure 3C

Figure 3D

Figure 3E

Figure 3F

Figure 3G

Mode for Carrying Out the Invention

[0020] The present invention relates to a crystalline form of Compound 1. In particular, the present invention relates to a crystalline form selected from Form C, Form D, or Form H of Compound 1, a pharmaceutical composition containing the crystalline form, a method for preparing the crystalline form, and a method of using the same.

[0021] In one embodiment, the crystalline form of Compound 1 is referred to as Form C, Form D, and Form H.

[0022] In one embodiment, the crystalline form of Compound 1 is referred to as Form D and has a powder X-ray diffraction (XRPD) pattern including diffraction peaks having °2θ angular values independently selected from the group consisting of 7.8 ± 0.2°, 14.3 ± 0.2°, and 17.2 ± 0.2°.

[0023] In one embodiment, the crystalline form of Compound 1 is referred to as Form D and has a powder X-ray diffraction (XRPD) pattern including diffraction peaks having °2θ angular values independently selected from the group consisting of 7.8 ± 0.2°, 14.3 ± 0.2°, 17.2 ± 0.2°, and 21.7 ± 0.2°.

[0024] In one embodiment, the crystalline form of Compound 1 is referred to as Form D and has a powder X-ray diffraction (XRPD) pattern including diffraction peaks having °2θ angular values independently selected from the group consisting of 7.8 ± 0.2°, 14.3 ± 0.2°, 17.2 ± 0.2°, 21.7 ± 0.2°, and 26.4 ± 0.2°.

[0025] In another embodiment, Form D has a powder X-ray diffraction pattern comprising diffraction peaks having 2θ angle values independently selected from the group consisting of 7.8 ± 0.2°, 14.3 ± 0.2°, 16.6 ± 0.2°, 17.2 ± 0.2°, 19.3 ± 0.2°, 21.7 ± 0.2° and 26.4 ± 0.2°.

[0026] In another embodiment, Form D has a powder X-ray diffraction pattern comprising diffraction peaks having 2θ angle values independently selected from the group consisting of 7.8 ± 0.2°, 14.3 ± 0.2°, 16.6 ± 0.2°, 17.2 ± 0.2°, 19.3 ± 0.2°, 21.7 ± 0.2°, 23.3 ± 0.2°, 26.4 ± 0.2° and 28.2 ± 0.2°.

[0027] In another embodiment, Form D has a powder X-ray diffraction pattern comprising diffraction peaks having 2θ angle values independently selected from the group consisting of 6.50 ± 0.2°, 7.8 ± 0.2°, 14.3 ± 0.2°, 16.6 ± 0.2°, 17.2 ± 0.2°, 19.3 ± 0.2°, 21.7 ± 0.2°, 23.3 ± 0.2°, 25.7 ± 0.2°, 26.4 ± 0.2° and 28.2 ± 0.2°.

[0028] In another embodiment, Form D has an XRPD pattern substantially as shown in Figure 1A.

[0029] In another embodiment, Form D is characterized by having a broad and small endotherm with a maximum peak at about 57°C to 62°C (starting at about 20°C to 22°C), followed by a sharp endotherm with a peak maximum at about 180°C (starting at about 178°C) by differential scanning calorimetry (DSC). In another embodiment, Form D has a DSC thermogram substantially as shown in Figure 1B.

[0030] In one embodiment, Form D of Compound 1 can be a single crystal, and the crystal structure data is summarized in Table 1B. As shown in Figure 2B, the single crystal structure of Compound 1 Form D belongs to the P-1 space group and the triclinic system. It can be seen that the terminal long alkyl chain has a large ellipsoid, indicating high mobility due to disordered atoms. Also, refer to Figure 2C, there are several channels around the alkyl chain in the crystal packing.

[0031] Table 1B Crystal Data and Structure Refinement of Compound 1 Form D (Single Crystal)

Table 1-1

Table 1-2

[0032] In another embodiment, Form D has an XRPD pattern substantially as shown in Figure 2A(1).

[0033] In one embodiment, Form D has an XRPD pattern substantially as shown in Figure 3C. In another embodiment, Form D has a DSC and / or TGA substantially as shown in Figure 3F.

[0034] In one embodiment, the crystal form of Compound 1 is called Form C. In another embodiment, Form C has an XRPD pattern substantially as shown in Figure 3B.

[0035] In one embodiment, the crystal form of Compound 1 is called Form H. In another embodiment, Form H has an XRPD pattern substantially as shown in Figure 3D.

[0036] In one embodiment, the crystal form of the present invention is a crystal form that is at least 40%, 50%, 60%, 70%, 80%, 90% or 95% purified.

[0037] In a second aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of Compound 1 and a pharmaceutically acceptable excipient for use in the method. In one embodiment, the crystalline form of Compound 1 is selected from Form C, Form D, and Form H. In another embodiment, the crystalline form of Compound 1 is Form D.

[0038] The crystalline form of Compound 1 can be formulated by any method well known in the art and can be prepared for administration by any route including, but not limited to, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or rectal. In certain embodiments, the crystalline form of Compound 1 is administered intravenously in a hospital. In one embodiment, the administration can be by the oral route.

[0039] The characteristics of the carrier will depend on the route of administration. As used herein, the term "pharmaceutically acceptable" refers to a non-toxic substance that is compatible with biological systems such as cells, cell cultures, tissues, or organisms and does not interfere with the effectiveness of the biological activity of the active ingredient(s). Thus, the composition can include, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The preparation of pharmaceutically acceptable formulations is described, for example, in Remington’s Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0040] In one embodiment, the pharmaceutical composition of the present invention comprises 95% of crystalline form of Compound 1. In another embodiment, the pharmaceutical composition of the present invention comprises at least 95% of the crystalline form of Compound 1. In another embodiment, the pharmaceutical composition of the present invention comprises at least 90% of the crystalline form of Compound 1. In another embodiment, the pharmaceutical composition of the present invention comprises at least 80% of the crystalline form of Compound 1. In another embodiment, the pharmaceutical composition of the present invention comprises at least 70% of the crystalline form of Compound 1. In another embodiment, the pharmaceutical composition of the present invention comprises at least 60% of the crystalline form of Compound 1. In another embodiment, the pharmaceutical composition of the present invention comprises at least 50% of the crystalline form of Compound 1.

[0041] A pharmaceutical composition comprising the crystalline form of Compound 1 can be used in the methods of use described herein.

[0042] In a third aspect of the present invention, there is provided a method for inhibiting multi-tyrosine kinase activity in a cell, the method comprising contacting a cell in which inhibition of multi-tyrosine kinase activity is desired with a therapeutically effective amount of the crystalline form of Compound 1. In one embodiment, the crystalline form of Compound 1 is selected from Form C, Form D, and Form H. In another embodiment, the crystalline form of Compound 1 is Form D.

[0043] In a fourth aspect of the present invention, there is provided a method for treating cancer in a subject in need of treatment for cancer, the method comprising administering to the subject a therapeutically effective amount of the crystalline form of Compound 1.

[0044] The compositions and methods provided herein can be used for the treatment of a wide variety of cancers. Examples of specific types of cancer include, but are not limited to, breast cancer, lung cancer including non-small cell lung cancer (NSCLC), colon cancer, rectal cancer, bladder (urothelial) cancer, prostate cancer, leukemia, kidney (renal) cancer, glioma, sarcoma including leiomyosarcoma, liver (hepatocellular) cancer, ovarian cancer, and gastric cancer.

[0045] In one embodiment, the cancer is a multi-tyrosine kinase-related cancer.

[0046] In one embodiment, the multi-tyrosine kinase-related cancers are NSCLC, liposarcoma, urothelial cancer, and oral cancer. In certain embodiments, the cancer is non-small cell lung cancer.

[0047] The active compound is contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount to the patient without causing serious toxic effects to the treated patient. In one embodiment, for all of the above conditions, the dosage of the active compound ranges from about 0.6 to 1800 mg per day, for example, 5 to 1000 mg per day, and as a further example, ranges from 50 to 200 mg per day of the recipient. In one embodiment, the active compound is administered at a dosage of 150 mg, preferably orally, preferably in a continuous 21-day cycle. A typical topical dosage ranges from 0.01 to 3 weight / weight % in a suitable carrier. The effective dosage range of a pharmaceutically acceptable derivative can be calculated based on the weight of the parent compound being delivered. If the derivative is active by itself, the effective dosage can be estimated as described above using the weight of the derivative, or by other means known to those skilled in the art.

[0048] In some embodiments of the methods described herein, prior to treatment with the compositions or methods of the invention, the patient has been treated with one or more of chemotherapy, targeted anti-cancer agents, radiation therapy, and surgery, and optionally, the prior treatment has failed, and / or the patient has had surgery, and optionally, the surgery has failed, and / or the patient has been treated with a platinum-based chemotherapeutic agent, and optionally, the patient has previously been determined to be non-responsive to treatment with a platinum-based chemotherapeutic agent, and / or the patient has been treated with a kinase inhibitor, and optionally, the prior treatment with the kinase inhibitor has failed, and / or the patient has been treated with one or more other therapeutic agents(s).

[0049] In one embodiment, the multi-tyrosine kinase inhibitor is orally administered once a day. In one embodiment, the crystalline form of Compound 1 is orally administered twice a day. In one embodiment, the crystalline form of Compound 1 is orally administered once a day. In one embodiment, the crystalline form of Compound 1 is selected from Form C, Form D, and Form H. In another embodiment, the crystalline form of Compound 1 is Form D.

[0050] One of ordinary skill in the art will understand that the ability of a test compound in combination or a given combination to treat or prevent a disorder can be predicted by both in vivo and in vitro tests using suitable known and generally acceptable cell and / or animal models.

[0051] One of ordinary skill in the art will further understand that human clinical trials, including first-in-human trials, dose-range finding trials, and efficacy trials in healthy patients and / or patients suffering from a given disorder, can be completed according to methods well known in the clinical and medical arts.

[0052] In a fifth aspect of the present invention, provided herein is a method for preparing crystalline Form D of N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1), comprising any one of the following procedures: 1) Dissolve N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide in acetone, heat to reflux, and cool with stirring to obtain Form D. 2) N-(3-Fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, form D is dissolved in acetone using form D as a seed crystal, heated to reflux, cooled with stirring to obtain form D. 3) N-(3-Fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide is ground in an organic solvent at ambient temperature, the slurry is filtered, and the organic solvent is exchanged with fresh organic solvent to obtain form D, where the organic solvent is selected from acetone, ACN, CHCl3, MTBE, DMF, EtOH, nitromethane, or a mixture thereof. 4) N-(3-Fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide is dissolved in THF, evaporated, dissolved in EtOAc, and precipitated to obtain form D. 5) N-(3-Fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide is ground in IPA at about 40 °C, the slurry is filtered, and the IPA is exchanged with fresh IPA to obtain form D.

[0053] In one embodiment, the method for preparing crystalline form D of N-(3-Fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide includes any one of the following procedures: 1) N-(3-Fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, in Form D, is dissolved in acetone using the Form D as a seed crystal, heated to reflux, cooled with stirring to obtain Form D, heated to reflux for 1 - 2 hours, cooled to an internal temperature of 20 ± 5 °C for at least 24 hours, filtered, the filter cake is washed with acetone, and dried under vacuum at 45 °C to obtain Form D. 2) N-(3-Fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide is milled at ambient temperature in an organic solvent, after about 24 hours the slurry is filtered, and the organic solvent is exchanged with fresh organic solvent to obtain Form D, where the organic solvent is selected from acetone, ACN, CHCl3, MTBE, DMF, EtOH, nitromethane, or mixtures thereof. 3) N-(3-Fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide is dissolved in THF, evaporated, dissolved in EtOAc, stirred, and precipitated to obtain Form D. 4) N-(3-Fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide is milled in IPA at about 40 °C, after about 24 hours the slurry is filtered, and the IPA is exchanged with fresh IPA to obtain Form D.

[0054] In another embodiment, the organic solvent is selected from CHCl3 / MTBE (50 / 50, v / v) and DMF / ACN (30 / 70, v / v). In another embodiment, the resulting slurry is milled for up to about 2.5 weeks.

[0055] Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, patent applications, and publications referred to herein are incorporated herein by reference.

[0056] As used herein, "Compound 1" refers to N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.

[0057] As used herein, "crystalline form of Compound 1" refers to the crystalline form of N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.

[0058] For materials showing a unique crystalline XRPD pattern, when no other character type is yet associated with the compound, consecutive roman alphabet letters are assigned as the default designation. This designation is tentatively associated with the term "material" until the phase purity obtained by indexing the XRPD pattern is determined and the chemical identity obtained by proton nuclear magnetic resonance spectroscopy (1H NMR) is determined. If the characteristic data is consistent with a unique crystalline form consisting of a single phase, the material is further designated as a "form" with the same letter designation (i.e., Material C becomes Form C). In the present invention, the XRPD pattern of a "form" of a compound can be successfully indexed. However, the XRPD pattern of a "material" cannot be indexed, and a "material" is a somewhat disordered crystalline material or a mixture.

[0059] As used herein, the term "Form C" or "crystalline Form C", when used alone, refers to crystalline Form C of N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide. Also, the term "Form D" or "crystalline Form D" has the same meaning as "Form C" or "crystalline Form C".

[0060] As used herein, "multi-tyrosine kinase-related disease or disorder" refers to a disease or disorder associated with or mediated by oncogenic mutations in RET, CBL, CHR4q12, DDR and / or Trk.

[0061] As used herein, the terms "subject", "individual", or "patient" are used interchangeably and refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the subject experiences and / or exhibits at least one symptom of the disease or disorder to be treated and / or prevented. In some embodiments, the subject is suspected of having a multi-tyrosine kinase-related cancer.

[0062] As used herein, a "therapeutically effective amount" of a crystalline form of Compound 1 is an amount sufficient to alleviate symptoms, or reduce symptoms in any way, or halt or arrest the progression of a condition, or negatively regulate or inhibit the activity of multi-tyrosine kinase. Such an amount can be administered as a single dose or according to a dosing schedule, whereby the amount is effective.

[0063] As used herein, "treatment" refers to any modality that alleviates or beneficially modifies the symptoms or pathology of a condition, disorder, or disease. Treatment also encompasses any pharmaceutical use of the compositions herein.

[0064] As used herein, "alleviation of the symptoms of a particular disorder by administration of a particular pharmaceutical composition" refers to any reduction, whether permanent or temporary, persistent or transient, that may result from or be related to the administration of the composition.

[0065] As used herein, the term "about" when used to modify a numerically defined parameter (e.g., the dosage of crystalline form of Compound 1 or its pharmaceutically acceptable salts detailed herein, or the length of treatment time described herein) means that the parameter can vary up to 10% above or below the numerical value recited for that parameter. For example, a dosage of about 5 mg / kg can vary between 4.5 mg / kg and 5.5 mg / kg. The "about" used at the beginning of a list of parameters means to modify each parameter. For example, about 0.5 mg, 0.75 mg, or 1.0 mg means about 0.5 mg, about 0.75 mg, or about 1.0 mg. Similarly, about 5% or more, 10% or more, 15% or more, 20% or more, and 25% or more means about 5% or more, about 10% or more, about 15% or more, about 20% or more, or about 25% or more.

[0066] As used herein, the term "about" when used in connection with XRPD peak positions means the inherent peak variability that depends on the calibration of the instrument, the method used to prepare the crystalline form of the invention, the age of the crystalline form, and the type of instrument used for the analysis. The variability of the instrument used for XRPD analysis was about ±0.2 o 2θ.

[0067] As used herein, the term "about" when used with respect to the onset of the DSC endothermic peak means the inherent peak variability that depends on the calibration of the equipment, the method used to prepare the samples of the present invention, and the type of equipment used in the analysis. The variability of the equipment used in the DSC analysis was about ±2 °C.

[0068] General methods Unless otherwise specified, in the illustrated embodiments, the general methods outlined below were used.

[0069] I. Crystallization techniques The crystalline forms of the present invention can be prepared using a variety of methods well known to those skilled in the art, including crystallization or recrystallization from a suitable solvent or sublimation. A wide variety of techniques can be used, including those of the illustrated embodiments, for crystallization or recrystallization involving evaporation of a water-miscible or water-immiscible solvent, seeding of a supersaturated solvent mixture, lowering the temperature of a solvent mixture, or lyophilization of a solvent mixture.

[0070] In the present invention, crystallization can be carried out with or without seed crystals. The seed crystals can be derived from any previous batch of the desired crystalline form. The addition of seed crystals may not affect the preparation of the crystalline forms in the present invention.

[0071] The samples were recovered after completion of the isotherm and reanalyzed by XRPD.

[0072] [Table 2]

[0073] The following examples are intended to further illustrate certain embodiments of the present invention and are not intended to limit the scope of the present invention.

[0074] Example 1 Preparation of N-(3-Fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)

[0075] This example shows the preparation of N-(3-Fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1).

[0076] Step 1: N-((6-Bromopyridin-3-yl)methyl)-2-methoxyethan-1-amine (Compound 1A)

Chem.

[0077] Molecular sieves (0.3 w / w) were added to a stirred solution of 2-methoxyethylamine (3.0 eq) in dichloromethane (DCM) (12 vol), and the mixture was stirred at 25 ± 5 °C for 2 h under a nitrogen atmosphere. The water content of the reaction mass was monitored by Karl Fischer analysis until the water content limit reached 0.5% w / w. Once the water content limit was reached, the reaction mass was cooled to 5 ± 5 °C, and 6-bromonicotinaldehyde (1.0 eq) was added lot by lot to the above reaction mass at 5 ± 5 °C over 30 min. The reaction mass was stirred at 5 ± 5 °C for 30 ± 5 min, and acetic acid (1.05 eq) was added dropwise at 5 ± 5 °C. After the addition was complete, the mass was slowly warmed to 25 ± 5 °C and stirred for 8 h to obtain Compound 1A. Imine formation was monitored by HPLC.

[0078] Step 2: tert-Butyl ((6-bromopyridin-3-yl)methyl)(2-methoxyethyl)carbamate (Compound 1B)

Chem.

[0079] The charged compound 1A (1.0 equivalent) in THF (5.0 vol) was added, and the reaction mass was stirred at 25 ± 5 °C for 30 minutes under a nitrogen atmosphere. The reaction mass was cooled to a temperature of about 10 ± 5 °C. Di-tert-butyl dicarbonate (1.2 equivalents) was added to the reaction mass at 10 ± 5 °C under a nitrogen atmosphere, the temperature of the reaction mass was raised to 25 ± 5 °C, and the reaction mass was raised for about 2 hours. The progress of the reaction was monitored by HPLC. After completion of the IPC, a prepared solution of taurine (1.5 equivalents) in 2 Maq NaOH (3.1 vol) was charged and stirred at 10 ± 5 °C for 16 to 18 hours. The reaction mass was further diluted with 1 M aqueous NaOH solution (3.7 vol), and the layers were separated. The aqueous layer was extracted with DCM (2 × 4.7 vol), and the extracts were combined with the organic layer. The combined organic layer was washed with 1 M aqueous NaOH solution (3.94 vol), then with water (2 × 4.4 vol), and dried over sodium sulfate (2.0 w / w). The filtrate was concentrated under reduced pressure at less than 40 °C until no distillate was observed. Tetrahydrofuran (THF) was sequentially added (1 × 4 vol and 1 × 6 vol), and concentrated under reduced pressure at less than 40 °C until no distillate was observed to obtain Compound 1B as a pale yellow syrup solution.

[0080] Step 3: tert-Butyl ((6-(7-chlorothieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl)(2-methoxyethyl)carbamate (Compound 1C)

Chemical formula

[0081] To a stirred solution of 7-chlorothieno[3,2-b]pyridine (1.05 equivalents) in tetrahydrofuran (7 vol), n-butyllithium (2.5 M in hexane) was added dropwise at -15 ± 10 °C, and stirred at the same temperature for 90 minutes under a nitrogen atmosphere. Zinc chloride (1.05 equivalents) was added to the reaction mass at -15 ± 10 °C. The reaction mass was slowly warmed to 25 ± 5 °C and stirred for 45 minutes under a nitrogen atmosphere to obtain Compound 1C. The progress of the reaction was monitored by HPLC.

[0082] Step 4: tert-Butyl ((6-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl)(2-methoxyethyl)carbamate (Compound 1D)

Chemical formula

[0083] 3-Fluoro-4-hydroxybenzenaminium chloride (1.2 equivalents) in DMSO (3.9 vol) at 25 ± 5 °C was charged under a nitrogen atmosphere, and the reaction mass was stirred at 25 ± 5 °C until a clear solution was observed. t-BuOK was added lot by lot under a nitrogen atmosphere at 25 ± 10 °C. The reaction mass temperature was raised to 45 ± 5 °C and maintained for 30 minutes under a nitrogen atmosphere. Compound 1C was charged lot by lot under a nitrogen atmosphere at 45 ± 5 °C and stirred at 45 ± 5 °C for 10 minutes. The reaction mixture was heated to 100 ± 5 °C and stirred for 2 hours. The reaction mass was monitored by HPLC.

[0084] After completion of the reaction, the reaction mass was cooled to 10 ± 5 °C and quenched with cold water (20 vol) at 10 ± 5 °C. The mass temperature was raised to 25 ± 5 °C and stirred for 7 - 8 hours. The obtained crude product of Compound 1D was collected by filtration and washed with 2 vol of water. The crude Compound 1D material was taken up in water (10 vol) and stirred at 25 ± 5 °C for a maximum of 20 minutes. The reaction mass was heated to 45 ± 5 °C, stirred at 45 ± 5 °C for 2 - 3 hours, filtered, and dried under vacuum.

[0085] The crude Compound 1D was taken up in MTBE (5 vol) at 25 ± 5 °C and stirred at 25 ± 5 °C for about 20 minutes. The reaction mass temperature was raised to 45 ± 5 °C, stirred at 45 ± 5 °C for 3 - 4 hours, and then cooled to 20 ± 5 °C. The reaction mass was stirred at 20 ± 5 °C for about 20 minutes, filtered, subsequently washed with a water (0.5 vol) bed, and dried under vacuum.

[0086] The crude material was dissolved in acetone (10 vol) at 25 ± 5 °C and stirred at 25 ± 5 °C for about 2 hours. The reaction mixture was filtered through a celite bed and washed with acetone (2.5 vol). The filtrate was slowly diluted with water (15 vol) at 25 ± 5 °C. The reaction mass was stirred at 25 ± 5 °C for 2 - 3 hours, filtered, washed with water (2 vol) on the bed, and dried in vacuo to obtain Compound 1D as a brown solid.

[0087] Step 5: 1 - ((4 - ((2 - (5 - (((tert - butoxycarbonyl)(2 - methoxyethyl)amino)methyl)pyridin - 2 - yl)thieno[3,2 - b]pyridin - 7 - yl)oxy)-3 - fluorophenyl)carbamoyl)cyclopropane - 1 - carboxylic acid (Compound 1E)

Chemical formula

[0088] To a solution of Compound 1D (1.0 equivalent) in tetrahydrofuran (7 vol) was added an aqueous potassium carbonate solution (1.0 equivalent) in water (8 vol). The solution was cooled to 5 ± 5 °C and stirred for about 60 minutes. While stirring, triethylamine (2.0 equivalents) was separately added at 5 ± 5 °C to a solution of 1,1 - cyclopropanedicarboxylic acid (2.0 equivalents) in tetrahydrofuran (8 vol), followed by the addition of thionyl chloride (2.0 equivalents), and the mixture was stirred for about 60 minutes. The mass of the acid chloride was slowly added to the Compound 1D solution at 5 ± 5 °C. The temperature was raised to 25 ± 5 °C and stirred for 3.0 hours. The reaction was monitored by HPLC analysis.

[0089] After the reaction was completed, the mass was diluted with ethyl acetate (5.8 vol), water (5.1 vol), 10% (w / w) aqueous hydrochloric acid solution (0.8 vol) and 25% (w / w) aqueous sodium chloride solution (2 vol). The aqueous layer was separated and extracted with ethyl acetate (2 × 5 vol). The combined organic layers were washed with 0.5 M aqueous sodium bicarbonate solution (7.5 vol). The organic layer was treated with Darco activated carbon (0.5 w / w) and sodium sulfate (0.3 w / w) at 25 ± 5 °C for 1.0 hour. The organic layer was filtered through celite and washed with tetrahydrofuran (5.0 vol). The filtrate was concentrated under vacuum to about 3 vol at below 50 °C and co-distilled with ethyl acetate (2 x 5 vol) under vacuum to about 3.0 vol at below 50 °C. The organic layer was cooled to 15 ± 5 °C, stirred for about 60 minutes, filtered, and the solid was washed with ethyl acetate (2.0 vol). The material was dried under vacuum at 40 ± 5 °C until the water content was less than 1% to obtain Compound 1E as a brown solid.

[0090] Step 6: tert-Butyl ((6-(7-(2-Fluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxamido)phenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl)(2-methoxyethyl)carbamate (Compound 1F)

Chemical Structure

[0091] Pyridine (1.1 eq) was added to a suspension of Compound 1E (1.0 eq) in tetrahydrofuran (10 vol) and cooled to 5 ± 5 °C. Thionyl chloride (2.0 eq) was added and stirred for about 60 minutes. The formation of the resulting acid chloride was confirmed by HPLC analysis after quenching the sample with methanol. Separately, an aqueous potassium carbonate solution (2.5 eq) (7.0 vol of water) was added to a solution of 4-fluoroaniline (3.5 eq) in tetrahydrofuran (10 vol), cooled to 5 ± 5 °C, and stirred for about 60 minutes. The temperature of the acid chloride mass at 5 ± 5 °C was raised to a temperature of about 25 ± 5 °C and stirred for 3 minutes. The reaction was monitored by HPLC analysis.

[0092] After the reaction was completed, the solution was diluted with ethyl acetate (25 vol), and the organic layer was separated and washed with 1 M aqueous sodium hydroxide solution (7.5 vol), 1 M aqueous hydrochloric acid solution (7.5 vol), and 25% (w / w) aqueous sodium chloride solution (7.5 vol). The organic layer was dried and filtered through sodium sulfate. The filtrate was concentrated to about 3 vol under vacuum below 50 °C and co-distilled with ethyl acetate (3 x 5 vol) to about 3.0 vol under vacuum below 50 °C. Ethyl acetate (5 vol) and MTBE (10 vol) were added, heated to 50 ± 5 °C, and stirred for 30 to 60 minutes. The mixture was cooled to 15 ± 5 °C, stirred for about 30 minutes, filtered, and the solid was washed with ethyl acetate (2.0 vol). The MGB3 content was analyzed by HPLC analysis. The material was dried under vacuum at 40 ± 5 °C until the water content reached about 3.0% to obtain Compound 1F as a brown solid.

[0093] Step 7: N-(3-Fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)

Chemical formula

[0094] Concentrated hydrochloric acid (0.5 vol) was added to a mixture of Compound 1F in glacial acetic acid (3.5 vol), and the mixture was stirred at 25 ± 5 °C for 1.0 hour. The reaction was monitored by HPLC analysis.

[0095] After the reaction was completed, the mass was added to water (11 vol) and stirred at 20 ± 5 °C for 30 minutes. The pH was adjusted to 3.0 ± 0.5 using 10% (w / w) aqueous sodium bicarbonate solution and stirred at 20 ± 5 °C for about 3.0 hours. The mass was filtered and washed with water (4 × 5.0 vol), and the pH of the filtrate was confirmed each time. The material was dried under vacuum at 50 ± 5 °C until the water content reached about 10%.

[0096] The crude compound 1 was taken up in ethyl acetate (30 vol), heated to 70 ± 10 °C, stirred for 1.0 hour, cooled to 25 ± 5 °C, filtered, and washed with ethyl acetate (2 vol). The material was dried under vacuum at 45 ± 5 °C for 6.0 hours.

[0097] The crude compound 1 was taken up in polished-filtered tetrahydrofuran (30 vol) and pre-washed Amberlyst A-21 ion exchange resin, and stirred at 25 ± 5 °C until the solution became clear. After obtaining a clear solution, the resin was filtered and washed with polished-filtered tetrahydrofuran (15 vol). The filtrate was concentrated by about 50% under vacuum below 50 °C, co-distilled with polished-filtered IPA (3 × 15.0 vol), and concentrated to a maximum of 50% under vacuum below 50 °C. Charge-polished-filtered IPA (15 vol) was added, and the solution was concentrated to about 20 vol under vacuum below 50 °C. The reaction mass was heated to 80 ± 5 °C, stirred for 60 minutes, and cooled to 25 ± 5 °C. The resulting reaction mass was stirred at 25 ± 5 °C for about 20 hours. The reaction mass was cooled to 0 ± 5 °C, stirred for 4 - 5 hours, filtered, and washed with polished-filtered IPA (2 vol). The material was dried under vacuum at 45 ± 5 °C until the water content was about 2% to obtain the desired product, compound 1. 1 H-NMR (400 MHz, DMSO-d6): δ 10.40 (s, 1H), 10.01 (s, 1H), 8.59 - 8.55 (m, 1H), 8.53 (d, J = 5.6 Hz, 1H), 8.32 (s, 1H), 8.23 (d, J = 8.0 Hz, 1H), 7.96 - 7.86 (m, 2H), 7.70 - 7.60 (m, 2H), 7.56 - 7.43 (m, 2H), 7.20 - 7.11 (m, 2H), 6.66 (d, J = 5.6 Hz, 1H), 3.78 (s, 2H), 3.41 (t, J = 5.6 Hz, 2H), 3.25 (s, 3H), 2.66 (t, J = 5.6 Hz, 2H), 1.48 (s, 4H) ppm. MS: M / e 630 (M + 1) + 。

[0098] Example 2 Preparation of Crystal Form D of N-(3-Fluoro-4-((2-(5-(((2-Methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

[0099] Example 2A: Preparation of Crystal Form D of Compound 1 To a 50 L reactor, 7.15 Kg of Compound 1, 40 g of Form D as seed crystals, and 21 L of acetone (≥99%) were added. The mixture was heated to reflux (about 56 °C) for 1 - 2 hours. The mixture was stirred at an internal temperature of 20 ± 5 °C for at least 24 hours. The suspension was filtered and the filter cake was washed with 7 L of acetone. The wet cake was dried under vacuum at 45 °C to obtain 5.33 kg of Compound 1 in the desired Form D.

[0100] Powder X-ray Diffraction (XRPD) The XRPD pattern was collected using a PANalytical X’Pert PRO MPD diffractometer with an incident beam of Cu radiation generated using a long fine focus source of au Optix. An elliptically inclined multilayer mirror was used to pass the CuKa X-rays through the specimen and focus them onto the detector. Prior to analysis, a silicon specimen (NIST SRM640e) was analyzed to confirm that the observed position of the Si Ill peak was in agreement with the NIST-certified position. The specimen of each sample was sandwiched between films of 3 μm thickness and analyzed in transmission geometry. A beam stop, short automatic scattering extension, and automatic scattering knife edge were used to minimize the background generated by air. A solar slit diffract beau1s for the incident monochromator was used to minimize the spread due to axial divergence. The diffraction pattern was collected using a scanning position-sensitive detector (X’Celerator) placed at a position 240 mm from the specimen and data collector software v.2.2b. The XRPD pattern was created using Pattern Match v2.3.6.

[0101] The characteristics of the obtained Compound 1 were examined using a powder X-ray diffraction (XRPD) pattern, indicating that Compound 1 is in crystalline form D of Compound 1 (Compound 1 Form D). Refer to Figure 1A. The obtained XRPD pattern is substantially the same as that shown in Figure 3C.

[0102] Differential scanning calorimetry (DSC) DSC was performed using a Mettler Toledo DSC3+ differential scanning calorimeter. Temperature calibration was carried out using octane, phenyl salicylate, indium, tin, and zinc. The sensitivity of TAWN was 11.9. The sample was placed in an aluminum DSC pan, covered, and the weight was accurately recorded. A weighed aluminum pan configured as the sample pan was placed on the reference side of the cell. Before sample analysis, holes were made in the lid of the pan. The method name of the thermogram is an abbreviation of the start temperature, end temperature, and heating rate. For example, -30-250-10 means "from ambient temperature to 250 °C at 10 °C / min". The nitrogen flow rate was 50.0 mL / min. Since this instrument is at the same pressure as the atmosphere, it does not provide the gas pressure value required by the USP.

[0103] A broad and small endotherm with a peak maximum of about 57 °C to 62 °C (start about 20 °C to 22 °C) and a subsequent sharp endotherm with a peak maximum of about 180 °C (start about 178 °C) were observed. These events may be due to the loss of volatile substances and melt, respectively (see Figure 1B).

[0104] In another embodiment, Form D was prepared as follows. Specified material O was suspended in 600 μL of acetone. Initial dissolution was observed, followed by reprecipitation. Since the purpose of the experiment was to obtain a suspension containing sufficient solids to slurry, separate, and collect XRPD data, the amount of the suspended substance was not measured. Based on the solubility of Form D in acetone, a very rough estimate of the experimental scale was about 80 - 100 mg. The suspension was stirred at ambient temperature for about 2.5 weeks, and then the solid was isolated by centrifugation with filtration. The XRPD data appeared to be consistent with Form D. Next, the sample was dried in a vacuum oven at about 40 °C for about 2.5 hours. The XRPD pattern of the final solid was consistent with Form D.

[0105] Example 2B: Preparation of Compound 1, Form D 427.0 mg of Compound 1 was dissolved in 5 mL of THF to obtain a clear brown solution. The resulting solution was filtered, and the filtrate was evaporated under a nitrogen stream. A sticky solid was obtained, which was vacuum dried at room temperature for about 5 minutes, but still a sticky brown solid was obtained. It was dissolved in 0.2 mL of EtOAc and sonicated to dissolve. The reaction mixture was stirred at room temperature for 15 minutes, and a solid settled out. 0.4 mL of EtOAc was added to the resulting solid, and the mixture was stirred at room temperature for 21 hours and 40 minutes to obtain a suspension. The solid was separated from the mother liquor by centrifugation, and then the resulting solid was resuspended in 0.6 mL of EtOAc and stirred at room temperature for 2 days. The solid was isolated by centrifugation to obtain Compound 1 in the desired Form D.

[0106] The obtained Compound 1 was characterized using a powder X-ray diffraction (XRPD) pattern, which indicated that Compound 1 was in crystalline Form D of Compound 1 (Compound 1, Form D).

[0107] Example 2C: Preparation of Compound 1, Form D Single crystal X-ray diffraction data of Compound 1 were collected at 180 K on a Rigaku XtaLAB PRO 007HF(Mo) diffractometer using MoKα radiation (λ = 0.71073 Å). Data reduction and empirical absorption correction were performed using the CrysAlisPro program. This structure was solved by a dual space algorithm using the SHELXT program. All non-hydrogen atoms could be located directly from the difference Fourier map. Framework hydrogen atoms were geometrically placed and constrained to the parent atoms using a riding model. The final structure refinement was carried out using the SHELXL program by minimizing the sum of the squares of the deviations of F2 using a full matrix method.

[0108] Preparation of Compound 1 Polymorph D (Single Crystal) Compound 1 Polymorph D was dissolved in a mixture of acetone / ACN (1 / 2), and the concentration of Compound 1 was about 7 mg / mL. Block single crystals were obtained.

[0109] The obtained single crystals of Compound 1 Polymorph D were characterized using XRPD patterns. See Figure 2A. The crystal structure data are summarized in Table 1B. The refined single crystal structure is shown in Figure 2B. The single crystal structure of Compound 1 Polymorph D belongs to the P-1 space group and the triclinic system. It was found that the terminal long alkyl chains have large ellipsoids, indicating high mobility due to disordered atoms.

[0110] The theoretically calculated XRPD from the single crystal structure is essentially similar to the experimental XRPD (Figure 2A). Due to the orientation priority, disorder, and the temperature tested, some small peaks are absent or shifted (180 K for single crystal data and 293 K for experimental data).

[0111] Table 1B Crystal Data and Structure Refinement Compound 1 Polymorph D (Single Crystal)

Table 3-1

Table 3-2

[0112] Example 3 Solid screen of N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)

[0113] The solid screen of Compound 1 was carried out. The solids, when separated in sufficient amounts, were characterized by powder X-ray diffraction (XRPD) patterns. The XRPD patterns were compared with each other. Additionally, other spectra or methods such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and dynamic vapor sorption (DVS) were used to characterize or investigate the obtained solids.

[0114] Powder X-ray diffraction (XRPD) XRPD pattern overlays were created using PatternMatch versions 2.3.6 and 3.0.4. Figures labeled "Image by PatternMatchv3.0.4" were generated using unvalidated versions of the software and are considered non-cGMP representations.

[0115] Transmission mode XRPD The XRPD pattern was collected using an incident beam of Cu radiation generated using the long fine focus source of Optix on a PANalytical X’Pert PRO MPD diffractometer. An elliptically inclined multilayer mirror was used to focus the CuKα X-ray radiation through the sample onto the detector. Prior to analysis, a silicon specimen (NIST SRM640d) was analyzed to confirm that the observed position of the Si(111) peak was in agreement with the NIST certified position. The specimen of the sample was sandwiched between films of 3 μm thickness and analyzed in transmission geometry. A beam stop, short anti-scatter extension, and anti-scatter knife edge were used to minimize the background generated by air. A solar slit for the incident and diffracted beam were used to minimize the broadening due to axial divergence. The diffraction pattern was collected using a scanning position sensitive detector (X’Celerator) located at a position 240 mm from the sample and the Data Collector software v2.2b.

[0116] Reflection mode XRPD The VT-XRPD pattern was collected using an incident beam of CuKα radiation generated using a long fine focus source and a nickel filter on a PANalytical X’Pert PRO MPD diffractometer. The diffractometer was configured using a symmetric Bragg-Brentano geometry. The data was collected and analyzed using the Data Collector software v2.2b. Prior to analysis, a silicon specimen (NIST SRM640d) was analyzed to confirm that the observed position of the Si(111) peak was in agreement with the NIST certified position. The specimen of the sample was packed into a nickel-coated copper well. A scatter guard slit (SS) was used to minimize the background generated by air. A solar slit for the incident and diffracted beam were used to minimize the broadening due to axial divergence. The diffraction pattern was collected using a scanning position sensitive detector (X’Celerator) located at a position 240 mm from the sample and the Data Collector software v2.2b.

[0117] Variable temperature XRPD Using an Anton Paar temperature and humidity chamber (THC), in-situ reflection mode XRPD patterns were collected as a function of temperature. The temperature of the specimen was changed with a Peltier thermoelectric device placed directly beneath the specimen holder and monitored with a platinum-100 resistance sensor placed in the specimen holder. The thermoelectric device was powered and controlled by an Anton Paar TCU50 connected to a data collector.

[0118] Polarizing microscope (PLM) Samples were observed using a Leica MZ12.5 stereomicroscope equipped with a first-order red compensator. To display the samples, various objective lenses in the range of usually 0.8 to 10 times magnification were used in crossed polarization. The selected samples were observed in mineral oil. The selected samples were analyzed using a Leica DM LP microscope equipped with a SPOT Insight color digital camera. Each sample was placed on a slide glass, a cover glass was placed over the sample, and a drop of mineral oil was added to cover the sample by capillary action. Each sample was observed using crossed polarizers and a first-order red compensator at magnifications of 20x0.40NA and 40x0.74NA. Images were captured using SPOT software (v.4.5.9). A micron bar was inserted into each image as a reference for particle size.

[0119] Differential scanning calorimetry (DSC) DSC analysis was performed using TA Instruments 2920 and Q2000 differential scanning calorimeters. Temperature calibration was performed using NIST-traceable indium metal. The samples were placed in aluminum DSC pans, covered, and the weights were accurately recorded. A weighed aluminum pan configured as the sample pan, T0C or T0CHSMP (Tzero crimped or Tzero hermetic seal with a manual pinhole pan, respectively) was placed on the reference side of the cell. The method code of the thermogram is an abbreviation of the starting temperature, ending temperature, and heating rate. For example, -30-250-10 means "-30°C to 250°C, 10°C / min".

[0120] Thermogravimetric analysis (TGA) The TG analysis was performed using a TA Instruments 2950 thermogravimetric analyzer. Temperature calibration was performed using nickel and Alumel (trademark). Each sample was placed in an aluminum pan and inserted into the TG furnace. The furnace was heated under nitrogen purge. The method code of the thermogram is an abbreviation of the starting temperature, ending temperature, and heating rate. For example, 25-350-10 means "25 °C to 350 °C, 10 °C / min".

[0121] Dynamic vapor sorption (DVS) Automated vapor sorption (VS) data were collected using a VTISGA-100 vapor sorption analyzer. NaCl and PVP were used as calibration standards. The samples were not dried before analysis. Sorption and desorption data were collected in the range of 5% to 95% RH in 10% RH increments under nitrogen purge. The equilibrium criterion used for the analysis was a weight change of less than 0.0100% in 5 minutes, and the maximum equilibrium time was 3 hours. The data on the initial moisture content of the samples were not corrected.

[0122] Indexing Computational studies, i.e., indexing and structure refinement, were performed under the "SSCI non-cGMP activity procedure". The agreement between the allowed peak positions and the observed peaks indicates the determination of a consistent unit cell. Indexing was performed using X’Pert High Score Plus 2.2a (2.2.1) and proprietary SSCI software. No attempts were made to confirm tentative index solutions within the scope of this work for molecular packing.

[0123] Example 3A: Preparation of Material A, Material B (including Material O), and Material O of Compound 1 The XRPD patterns of Materials A and B (observed for Compound 1 including Material O and Material O) are shown in Figure 3G.

[0124] Example 3B: Screening of Stable Forms of Compound 1 The material B (including material O) of compound 1 obtained in Example 3A was milled in various solvents containing a solvent system with high water activity to target potential hydrates. The experiments were mainly carried out at ambient temperature. To achieve sufficient solubility, the selected experiments were carried out at about 40 °C. To change the impurity profile of compound 1, most of the slurry was filtered after about 24 hours and the solvent was exchanged with a new solvent (adjusting the ratio as necessary). The resulting slurry was milled for up to 2.5 weeks. The conditions and results of the stable form screen are summarized in Table 2A.

[0125] Table 2A Stable form screen of compound 1

Table 4-1

Table 4-2

[0126] Example 3C: Polymorph screen of compound 1 (solution method) The material B (including material O) of compound 1 obtained in Example 3A was subjected to various solution crystallization techniques such as evaporation, vapor diffusion, cooling to ambient temperature or below, slurry, and solvent / antisolvent precipitation aimed at the formation of metastable forms. Both non-aqueous solvents and solvent systems with high water activity were used. The conditions and results of the polymorph screen (solution experiments) are summarized in Table 2B.

[0127] Table 2B Polymorph screen of compound 1 (solution method)

Table 5-1

Table 5-2

[0128] Material J was manufactured under both selected aqueous and non-aqueous conditions. Material J is crystalline. Short-term vacuum drying at approximately 40 °C revealed the presence of another material (designated as Material M).

[0129] Example 3C: Drying Experiment of Compound 1 Crystal Form Limited non-solvent-based experiments were conducted on materials generated during the stable form screen and included short-term vacuum drying at high temperature. The conditions and results of the drying experiments are summarized in Table 2C. Table 2C Non-solvent-based Experiments

Table 6

[0130] Example 3D: Powder X-ray Diffraction (XRPD) Patterns of Solid Forms of Compound 1 Several materials with unique XRPD patterns were produced in Examples 3A - 3E. The unique materials were designated as Forms C, D, H, and Materials A, B, E, F, G, J, K, L, N, and O. The XRPD patterns of the forms are shown in Figure 3A. The patterns of the other observed materials are shown in Figure 3B.

[0131] Furthermore, the successful indexing of the XRPD patterns of Form C (derived from dioxane), Form D, and Form H indicates that Forms C, D, and H are composed of single crystal phases. See Figures 3B, 3C, and 3D individually. Also, the TGA and DSC thermograms of Form D generated in acetone are shown in Figure 3F.

[0132] The XRPD patterns of Materials A - L could not be indexed, indicating that Materials A - L are crystalline materials with a certain degree of disorder or mixture. Refer to Figure 3E. Here, Material E was observed in a single experiment conducted with isopropyl alcohol. The sample was generated by cooling and probably contains another material, perhaps called Material G. Material F was generated, in medium and high water activities, mostly as a mixture with another material, perhaps called Material G. Material G, observed as a mixture with Material F, was generated only in solvent systems with higher water activity. Material K has an XRPD pattern similar to that of Material G.

[0133] Example 2E: Slurry Interconversion Experiments To investigate the relationships between selected materials generated during screening, limited slurry interconversion experiments were carried out. The experiments were performed by slurrying seeds of the target solid at ambient temperature in two different solvent systems. All materials were vacuum dried (at about 40 °C for about 2.5 hours) prior to slurrying. Solvent conditions were chosen to achieve sufficient solubility of the materials tested. Both non - aqueous conditions and solvent systems with high water activity were utilized. The results are summarized in Table 2D.

[0134] Slurries of Forms C, D, and H were carried out in ethyl acetate, but the results were not conclusive. The experiment gave a mixture of Form C and Form D, and while it was shown that Form H is thermodynamically the least stable under these conditions, the relative stability of C and D remains unclear. Comparison of the XRPD peak intensities of the mixture suggests that Form C may be in excess. However, this could have been caused by the selective transition of Form H to Form C. Therefore, the relative stability of Form C and Form D is unknown. Material F was obtained from a slurry of seeds of Materials F, G, and J in tetrahydrofuran / water (40 / 60). Table 2D Slurry Interconversion Experiments [Table 7] (a) The slurry was carried out for about 42 hours using a vacuum-dried starting material (about 40 °C, about 2.5 hours). (b) The solid was stirred in a solvent saturated with the slurry for about 3 hours, and the solvent was replaced with an ethyl acetate solution.

[0135] Example 2H: Preliminary Physical Stability Evaluation of Form D A preliminary physical stability evaluation of Form D was performed. The data are summarized in Table 2E.

[0136] In the experiment, Form D was shown not to change even when subjected to RH stresses of about 43% and about 75% and short-term vacuum drying at about 40 °C. The XRPD patterns of the stressed materials showed no significant peak shifts compared to the untreated samples. The XRPD pattern of Form D obtained from the high-moisture-activity slurry is consistent with the pattern of the untreated material. However, a small shift of the selected peaks was observed, probably due to hydration. Table 2E Preliminary Stability Evaluation of Form D

Table 8

[0137] Although the present invention has been described in connection with its specific embodiments, those embodiments are further modifiable, and this application is generally intended to cover any variations, uses, or modifications of the present invention in accordance with the principles of the present invention, including departures from the present disclosure that fall within the known or customary practice of the art to which the present invention pertains and that come within the scope of the essential features shown above and of the following appended claims.

Claims

1. A crystalline form of N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.

2. 2. The crystalline form of claim 1, wherein the crystalline form is designated as Form D.

3. 3. The crystalline form of claim 2, wherein Form D has an X-ray powder diffraction pattern (XRPD) comprising diffraction peaks having °2θ angle values ​​independently selected from the group consisting of 7.8±0.2°, 14.3±0.2°, and 17.2±0.2°.

4. 3. The crystalline form of claim 2, wherein Form D has an X-ray powder diffraction pattern (XRPD) comprising diffraction peaks having °2θ angle values ​​independently selected from the group consisting of 7.8±0.2°, 14.3±0.2°, 17.2±0.2°, and 21.7±0.2°.

5. 3. The crystalline form of claim 2, wherein Form D has an X-ray powder diffraction pattern (XRPD) comprising diffraction peaks having °2θ angle values ​​independently selected from the group consisting of 7.8±0.2°, 14.3±0.2°, 17.2±0.2°, 21.7±0.2°, and 26.4±0.2°.

6. 3. The crystalline form of claim 2, wherein Form D has an X-ray powder diffraction pattern (XRPD) comprising diffraction peaks having °2θ angle values ​​independently selected from the group consisting of 7.8±0.2°, 14.3±0.2°, 16.6±0.2°, 17.2±0.2°, 19.3±0.2°, 21.7±0.2°, and 26.4±0.2°.

7. 3. The crystalline form of claim 2, wherein Form D has an X-ray powder diffraction pattern (XRPD) comprising diffraction peaks having °2θ angle values ​​independently selected from the group consisting of 7.8±0.2°, 14.3±0.2°, 16.6±0.2°, 17.2±0.2°, 19.3±0.2°, 21.7±0.2°, 23.3±0.2°, 26.4±0.2°, and 28.2±0.2°.

8. 3. The crystalline form of claim 2, wherein Form D has an X-ray powder diffraction pattern (XRPD) comprising diffraction peaks having °2θ angle values ​​independently selected from the group consisting of 6.50±0.2°, 7.8±0.2°, 14.3±0.2°, 16.6±0.2°, 17.2±0.2°, 19.3±0.2°, 21.7±0.2°, 23.3±0.2°, 25.7±0.2°, 26.4±0.2°, and 28.2±0.2°.

9. 3. The crystalline form of claim 2, wherein Form D has an XRPD pattern substantially as shown in Figure 1A.

10. 3. The crystalline form of claim 2, wherein Form D is characterized by an endotherm with a maximum peak at about 180°C (onset about 178°C) by differential scanning calorimetry (DSC).

11. 3. The crystalline form of claim 2, wherein Form D has a DSC thermogram substantially as shown in Figure 1B.

12. 3. The crystalline form of claim 2, wherein Form D has an XRPD pattern substantially as shown in Figure 2A(1) or Figure 3C.

13. A pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.

14. 14. The pharmaceutical composition of claim 13, wherein the crystalline form is Form D.

15. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of any one of claims 2 to 12.

16. The pharmaceutical composition according to any one of claims 13 to 15, further comprising at least one pharmaceutically acceptable excipient and / or diluent.

17. 13. A method for inhibiting multi-tyrosine kinase activity in a cell, comprising contacting the cell in which inhibition of multi-tyrosine kinase activity is desired with a therapeutically effective amount of a crystalline form of any one of claims 1 to 12.

18. 1. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form of N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.

19. 19. The method of claim 18, wherein the therapeutically effective amount of the crystalline form is about 5 to 1000 mg per day.

20. 20. The method of claim 19, wherein the therapeutically effective amount of the crystalline form is about 50-200 mg per day.

21. 19. The method of claim 18, wherein the cancer is lung cancer, including non-small cell lung cancer (NSCLC).

22. 19. The method of claim 18, wherein the cancer is bladder cancer.

23. 19. The method of claim 18, wherein the cancer is renal cancer.

24. 19. The method of claim 18, wherein the cancer is ovarian cancer.

25. 19. The method of claim 18, wherein the cancer is gastric cancer.

26. 19. The method of claim 18, wherein the cancer is liver cancer.

27. 19. The method of claim 18, wherein the cancer is glioma.

28. 19. The method of claim 18, wherein the cancer is breast cancer.

29. 19. The method of claim 18, wherein the cancer is a sarcoma.

30. 30. The method of claim 29, wherein the sarcoma is a leiomyosarcoma.

31. 19. The method of claim 18, wherein the cancer is a multi-tyrosine kinase associated cancer.

32. 10. A process for preparing the crystalline form of claim 1, comprising: 1) dissolving N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide in acetone, heating to reflux and cooling with stirring to obtain Form D; 2) dissolving N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, Form D, in acetone as a crystalline seed, heating to reflux and cooling with stirring to obtain Form D; 3) Triturating N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide in an organic solvent at ambient temperature, filtering the slurry, and replacing the organic solvent with fresh organic solvent to obtain Form D, wherein the organic solvent is selected from the group consisting of acetone, ACN, CHCl ３ , MTBE, DMF, EtOH, nitromethane, or mixtures thereof to obtain Form D; 4) dissolving N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide in THF, evaporating, dissolving in EtOAc and precipitating to obtain Form D; and 5) triturating N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide in IPA at about 40° C., filtering the slurry, and replacing the IPA with fresh IPA to obtain Form D.

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