A crystalline form of (S,E)-4-(dimethylamino)-N-(3-(4-(2-hydroxy-1-phenylethylamino)-6-phenylfuro[2,3-d]pyrimidin-5-yl)phenyl)but-2-enamide free base

Abstract

Disclosed herein are specific crystalline forms of (S,E)-4-(dimethylamino)-N-(3-(4-(2-hydroxy-1-phenylethanamineyl)-6-phenylfuro[2,3-d]pyrimidin-5-yl)phenyl)but-2-enamide (ABT-101) free base, pharmaceutical compositions and capsules comprising the same, and medical applications thereof. The crystalline forms of ABT-101 free base can exhibit unexpected stability and improved pharmacokinetic properties compared to other forms or salts thereof, thereby allowing the compound to be more suitable for pharmaceutical development and to meet the requirements for bioavailability and drug efficacy.

Description

TECHNICAL FIELD

[0001] CROSS-REFERENCE: This application claims priority to and the benefit of U.S. Provisional Application No. 63 218 504, filed July 6, 2021, the contents of which are incorporated herein by reference.

[0002] The present invention relates to novel crystalline forms of (S,E)-4-(dimethylamino)-N-(3-(4-(2-hydroxy-l-phenylethylamino)-6-phenylfuro[2,3-d]pyrimidin-5-yl)phenyl)but-2-enamide (ABT-101) free base, pharmaceutical compositions comprising the same, and capsules, and methods of using the crystalline forms to treat cancer. BACKGROUND

[0003] Epidermal growth factor receptor (EGFR) is a subfamily of four closely related receptor tyrosine kinases: EGFR, HER2, HER3, and HER4. Binding of EGF ligand to the extracellular domain of EGFR leads to activation of the intracellular protein-tyrosine kinase activity. As a result, autophosphorylation of several tyrosine residues occurs in the C-terminal domain of EGFR. (Kamath, S. Buolamwini, J. K., Med. Res. Rev. 2006, 26, 569-594).

[0004] Targeted therapies against EFGR and HER2 are now standard treatment regimens for patients suffering from cancer. More specifically, several EGFR kinase inhibitors such as Gefitinib and Erlotinib have been used to treat non-small cell lung cancer (NSCLC). However, only 10-20% of NSCLC patients respond to Gefitinib treatment, which is mainly due to drug resistance caused by T790M mutation in EGFR kinase. In addition, HER2 exon 20 insertion is also a common mutation present in 1-3% of NSCLC patients (J. Med. Chem. 2019, 62, 10108-10123). Although there are currently no EGFR or HER2 directed therapies approved as treatments specific to these mutations, therefore, there is great interest in developing EGFR kinase inhibitors, especially EGFR kinase inhibitors that can inhibit the activity of EGFR mutants (e.g., T790M mutants) and HER2 exon 20 insertion, as anticancer drugs.

[0005] Accordingly, several fused bicyclic or tricyclic compounds including ABT-101 that can be used to inhibit the activity of EGFR are disclosed in U.S. Patent Application No. 8,507,502 B2, which is incorporated herein by reference in its entirety. Nonetheless, there has been little discussion of the differences between aspects of the crystalline forms of these compounds. SUMMARY

[0006] The present application is based on the discovery that certain crystalline forms of (S,E)-4-(dimethylamino)-N-(3-(4-(2-hydroxy-1-phenylethylamino)-6-phenylfuro[2,3-d]pyrimidin-5-yl)phenyl)but-2-enamide (ABT-101) free base exhibit unexpected stability and improved pharmacokinetic properties.

[0007] Accordingly, the present application provides a crystalline form of (S,E)-4-(dimethylamino)-N-(3-(4-(2-hydroxy-1-phenylethylamino)-6-phenylfuro[2,3-d]pyrimidin-5-yl)phenyl)but-2-enamide (ABT-101) free base characterized by an X-ray powder diffraction pattern comprising peaks at 4.8°±0.2°, 9.5°±0.2°, 10.2°±0.2°, 12.5°±0.2°, 15.0°±0.2°, 18.4°±0.2°, and 20.8°±0.2° in terms of values of Bragg's angle 2Θ.

[0008] Further, the crystalline form provided herein is characterized by an X-ray powder diffraction pattern further comprising a peak at 8.7°±0.2° in terms of values of Bragg's angle 2Θ.

[0009] Further, the crystalline form provided herein is characterized by an X-ray powder diffraction pattern further comprising a peak at 19.4°±0.2° in terms of values of Bragg's angle 2Θ.

[0010] Further, the crystalline form provided herein is characterized by an X-ray powder diffraction pattern further comprising a peak at 23.1°±0.2° in terms of values of Bragg's angle 2Θ.

[0011] Further, the crystalline form provided herein has a melting point temperature of 170°C to 195°C.

[0012] Further, the crystalline form provided herein has a melting enthalpy of 75°C to 85°C.

[0013] The present application provides a pharmaceutical composition comprising the crystalline form provided herein and a pharmaceutically acceptable carrier or excipient.

[0014] In another aspect, the present application provides a capsule comprising the pharmaceutical composition provided herein.

[0015] Further, the capsule provided herein comprises 0.1 mg to 200 mg of the crystalline form.

[0016] Further, the capsule provided herein comprises 25 mg to 100 mg of the crystalline form.

[0017] Further, the capsule provided herein comprises 50 mg to 100 mg of the crystalline form.

[0018] The present application provides a method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a crystalline form provided herein.

[0019] Furthermore, the crystalline forms provided herein are EGFR inhibitors, HER2 inhibitors or tumor-agnostic inhibitors.

[0020] Furthermore, according to the method of the present application, wherein the cancer is peritoneal cancer, small intestine cancer, non-small cell lung cancer (NSCLC), neuroendocrine cancer, salivary gland cancer, bladder cancer, breast cancer, cervical cancer, cholangiocarcinoma, esophageal cancer, stomach cancer, early gastric cancer, colorectal cancer, prostate cancer, ovarian cancer, head and neck cancer, endometrial cancer, renal cancer, melanoma cancer, sarcoma cancer, pancreatic cancer, small cell lung cancer (SCLC), leukemia cancer, brain cancer or thyroid cancer.

[0021] Thus, the present application acts in that specific crystalline forms of ABT-101 free base can exhibit unexpected stability and improved pharmacokinetic properties compared to other forms or salts thereof, thereby allowing the compound to be more suitable for pharmaceutical development and to meet the requirements for bioavailability and drug efficacy. BRIEF DESCRIPTION OF DRAWINGS

[0022] In order to make the above and other objects, characteristics, advantages and embodiments of the present application more apparent, the following describes the drawings:

[0023] Figure 1 DSC curve of a crystalline form of ABT-101 free base is illustrated;

[0024] Figure 2a and 2b DSC thermogram of a crystalline form of ABT-101 free base obtained is illustrated;

[0025] Figure 3 XRPD pattern of a crystalline form of ABT-101 free base (01BP-063-184) is illustrated;

[0026] Figure 4 XRPD pattern of a crystalline form of ABT-101 free base is illustrated;

[0027] Figure 5 Comparison results of amorphous (00BP-081-154) and crystalline (01BP-063-120) free forms of ABT-101 are illustrated. DETAILED DESCRIPTION

[0028] DEFINITIONS

[0029] The terms used in the specification generally have their ordinary meanings in the art, and specific terms are to be interpreted as is customary in the art, and specific terms will be described under the heading "Definitions" below to assist in the understanding of the relevant description of the application. The same term should have the same scope and meaning in the same context and in the same situation. In addition, there is more than one way to refer to the same thing; thus, the terms discussed herein can be substituted with alternative terms and synonyms, and the specification does not have any special meaning or significance whether or not a term is specified or discussed herein. Synonyms for certain terms are provided herein, but the use of one or more synonyms does not imply that other synonyms are excluded.

[0030] As used herein, "a" and "the" can also be construed as "one or more" unless otherwise indicated by context. Additionally, in the context of the specification and appended claims, "intermediate" and "inner" include "located in" unless otherwise indicated by context; and the projectile tip direction is defined as "up" or "down" unless otherwise indicated by context. Furthermore, the specification can be provided with headings and subheadings, but such headings and subheadings are not to interpret the scope of the application.

[0031] The term "crystalline" as used herein can refer to molecules or external planes with regular repeating arrangement. Crystal forms can differ in thermodynamic stability, physical parameters, X-ray structure, and process of preparation.

[0032] The term "amorphous" as used herein can refer to a form of a compound or a salt or molecular complex of a compound that lacks long-range order of crystallization, where the X-ray diffraction pattern lacks Bragg reflections.

[0033] The term "solid form" as used herein can refer to crystalline solid forms or phases, including crystalline free base, crystalline salt, or co-crystal; and amorphous phases, including amorphous dispersions.

[0034] As used herein, unless otherwise indicated, the term "treatment" means reversing, alleviating, inhibiting or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. Unless otherwise indicated, the term "treatment" refers to the act of "treating" as that term is defined immediately above.

[0035] The term "effective amount" or "therapeutically effective amount" as used herein refers to the amount of a compound or combination of compounds sufficient to achieve an intended application including, but not limited to, the treatment of a disease. A therapeutically effective amount can vary depending upon the intended application (in vitro or in vivo), or the individual or disease condition being treated (e.g., the weight, age and gender of the individual, the severity of the disease condition, the manner of administration, etc.), all of which can readily be determined by one of skill in the art. The term also applies to a dose that will induce a particular response in target cells, such as a reduction in platelet adhesion and / or cell migration. The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether the compounds are administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system in which the compounds are carried.

[0036] In one embodiment, the present application provides a crystalline form of (S,E)-4- (dimethylamino)-N-(3-(4-(2-hydroxy-1-phenylethylamino)-6-phenylfuro[2,3-d]pyrimidin-5- yl)phenyl)but-2-enamide (ABT-101, represented by Formula I) free base.

[0037]

[0038] The crystalline form is characterized by an X-ray powder diffraction pattern comprising peaks at 2-theta values of 4.8°±0.2°, 9.5°±0.2°, 10.2°±0.2°, 12.5°±0.2°, 15.0°±0.2°, 18.4°±0.2°, and 20.8°±0.2°.

[0039] Preferably, the crystalline form provided herein is characterized by an X-ray powder diffraction pattern further comprising a peak at a 2-theta value of 8.7°±0.2°.

[0040] Preferably, the crystalline form provided herein is characterized by an X-ray powder diffraction pattern further comprising a peak at a 2-theta value of 19.4°±0.2°.

[0041] Preferably, the crystalline form provided herein is characterized by an X-ray powder diffraction pattern further comprising a peak at a 2-theta value of 23.1°±0.2°.

[0042] In another embodiment, the crystalline form is characterized by an X-ray powder diffraction pattern comprising a peak selected from the group consisting of 4.8°±0.2°, 8.7°±0.2°, 9.5°±0.2°, 10.2°±0.2°, 12.5°±0.2°, 15.0°±0.2°, 18.4°±0.2°, 19.4°±0.2°, 20.8°±0.2°, and 23.1°±0.2°, wherein the peak positions are measured in 2.

[0043] It is known in the art that X-ray powder diffraction (XPRD) patterns can be obtained with one or more measurement errors that are dependent on the measurement conditions, such as the equipment used, sample preparation, or the instrument. In particular, it is well known that the intensities of X-ray powder diffraction patterns can vary with the measurement conditions and sample preparation. For example, one skilled in the art of X-ray powder diffraction will recognize that the relative intensities of peaks can vary depending on the orientation of the sample tested and based on the type and settings of the instrument used. One skilled in the art will also recognize that the position of reflections can be affected by the exact height at which the sample is placed in the diffractometer, the flatness of the sample surface, and the zero calibration of the diffractometer. Accordingly, one skilled in the art will appreciate that the diffraction pattern data presented herein should not be interpreted as absolute, and that any crystalline form that provides a powder diffraction pattern that is substantially the same as the powder diffraction patterns disclosed herein falls within the scope of the present application. For additional information, see Jenkins and Snyder, Introduction to X-Ray Powder Diffractometry, John Wiley & Sons, 1996.

[0044] In one embodiment, the crystalline form provided herein has a melting point temperature of 170 °C to 195 °C; more particularly, the melting point temperature is, for example, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, or 195 °C. In one embodiment, the crystalline form provided herein has a melting enthalpy of 75 °C to 85 °C; more particularly, the melting enthalpy is, for example, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, or 85 °C. In each of the foregoing embodiments, the melting point temperature and melting enthalpy characterizing the crystalline form of the present application are analyzed by differential scanning calorimetry (DSC) including modulated differential scanning calorimetry or temperature modulated differential scanning calorimetry.

[0045] In one embodiment, the present application provides pharmaceutical compositions comprising the crystalline forms provided herein and a pharmaceutically acceptable carrier or excipient. More specifically, the pharmaceutical compositions are EGFR inhibitors, HER2 inhibitors, or inhibitors of indeterminate tumor types. Where desired, the pharmaceutical compositions contain a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, penetration enhancers, solubilizers or adjuvants. In some embodiments, the concentration of the crystalline form of ABT-101 free base provided in the pharmaceutical compositions of the present application is independently less than, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, or 0.001%, w / w, w / v, or v / v, relative to the total mass or volume of the pharmaceutical composition. In some embodiments, the concentration of the crystalline form of ABT-101 free base provided in the pharmaceutical compositions of the present application is independently greater than, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, or 0.001%, w / w, w / v, or v / v, relative to the total mass or volume of the pharmaceutical composition.

[0046] Examples of suitable fillers for use in the pharmaceutical compositions disclosed herein include, but are not limited to, lactose monohydrate, talc, calcium carbonate (e.g., granular or powdered), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0047] Examples of lubricants for use in the pharmaceutical compositions disclosed herein include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium stearyl fumarate, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, or mixtures thereof. Additional lubricants include, for example, colloidal silica, condensed aerosol of synthetic silica, silicified microcrystalline cellulose, or mixtures thereof.

[0048] Examples of disintegrants that can be used in the pharmaceutical compositions disclosed herein include, but are not limited to, croscarmellose sodium, alginic acid, calcium carbonate, microcrystalline cellulose, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other alginates, other celluloses, gums, or mixtures thereof.

[0049] In another aspect, the present application provides a capsule comprising the pharmaceutical composition. Further, the capsule provided herein comprises 0.1 mg to 200 mg of the crystalline form of ABT-101 free base; more particularly, the amount of the crystalline form is, for example, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg. Preferably, the capsule provided herein comprises 25 mg to 100 mg of the crystalline form of ABT-101 free base; more particularly, the amount of the crystalline form is, for example, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 mg. More preferably, the capsule provided herein comprises 50 mg to 100 mg of the crystalline form of ABT-101 free base; more particularly, the amount of the crystalline form is, for example, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 mg.

[0050] Pharmaceutical compositions of the present application suitable for oral administration can be presented as discrete units such as capsules, sachets, or tablets; or a liquid or aerosol spray, each containing a predetermined amount of the active ingredient, as powders or granules, solutions or suspensions, liquid or non-aqueous solutions, oil-in-water emulsions, or water-in-oil emulsions. Pharmaceutical compositions of the present application also include powders, powders for reconstitution, suspensions, solutions, emulsions, microemulsions, microspheres, liposomes, and / or elixirs for oral ingestion, as well as liquid dosage forms for oral ingestion. Such dosage forms can be prepared using any pharmaceutical method known in the art, but all methods include the step of bringing into association (one or more) active ingredients with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.

[0051] The present application provides a method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a crystalline form of ABT-101 free base.

[0052] In some embodiments, the crystalline form of ABT-101 free base administered is an EGFR inhibitor, a HER2 inhibitor, or an undetermined tumor type inhibitor.

[0053] In selected embodiments, the crystalline form of ABT-101 free base is administered in a single dose. The single dose of the crystalline form of ABT-101 free base can also be used to treat an acute condition. In selected embodiments, the crystalline form of ABT-101 free base is administered in multiple doses. The dosing can be about once, twice, three times, four times, five times, six times, or more than six times per day. The dosing can be about once a month, once every two weeks, once a week, or once every other day. In other embodiments, the crystalline form of ABT-101 free base is administered about once a day to about 6 times a day. In another embodiment, the administration of the crystalline form of ABT-101 free base is for less than about 7 days. In yet another embodiment, the administration is for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, the continuous dosing is achieved and maintained for as long as needed.

[0054] Administration of the active pharmaceutical ingredient of the present application can continue for as long as needed. In selected embodiments, the crystalline form of ABT-101 free base is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the crystalline form of ABT-101 free base is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In selected embodiments, the crystalline form of ABT-101 free base is chronically administered on a continuous basis, e.g., to obtain a long-term effect treatment. In some embodiments, an effective dose of the crystalline form of ABT-101 free base is in the range of about 1 mg to about 500 mg, about 10 mg to about 300 mg, about 20 mg to about 250 mg, about 25 mg to about 200 mg, about 10 mg to about 200 mg, about 20 mg to about 150 mg, about 30 mg to about 120 mg, about 10 mg to about 90 mg, about 20 mg to about 80 mg, about 30 mg to about 70 mg, about 40 mg to about 60 mg, about 45 mg to about 55 mg, about 48 mg to about 52 mg, about 50 mg to about 150 mg, about 60 mg to about 140 mg, about 70 mg to about 130 mg, about 80 mg to about 120 mg, about 90 mg to about 110 mg, about 95 mg to about 105 mg, about 150 mg to about 250 mg, about 160 mg to about 240 mg, about 170 mg to about 230 mg, about 180 mg to about 220 mg, about 190 mg to about 210 mg, about 195 mg to about 205 mg, or about 198 to about 202 mg. In some embodiments, an effective dose of the crystalline form of ABT-101 free base is about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg. In some embodiments, an effective dose of the crystalline form of ABT-101 free base is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, or 500 mg.

[0055] Furthermore, according to the method of the present application, wherein the cancer is peritoneal cancer, small intestine cancer, non-small cell lung cancer (NSCLC), neuroendocrine cancer, salivary gland cancer, bladder cancer, breast cancer, cervical cancer, cholangiocarcinoma, esophageal cancer, stomach cancer, early gastric cancer, colorectal cancer, prostate cancer, ovarian cancer, head and neck cancer, endometrial cancer, renal cancer, melanoma cancer, sarcoma cancer, pancreatic cancer, small cell lung cancer (SCLC), leukemia cancer, brain cancer, or thyroid cancer.

[0056] Notwithstanding that the numerical ranges and parameters setting forth the broadest scope of the application are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Moreover, all ranges disclosed herein are to be understood to encompass both the logical upper and lower limits (i.e., if a range is from 1 to 10, then it also implies that the range is from 10 to 1). Also, it should be understood that every maximum numerical limitation given throughout this specification includes every lower numerical limitation, as if such lower numerical limitations were expressly written herein. Every minimum numerical limitation given throughout this specification includes every higher numerical limitation, as if such higher numerical limitations were expressly written herein. Values given for optimized parameters are understood to be approximate, as it is not possible to test every availability of every vendor and every lot of every vendor. Also, it should be understood that every upper numerical limitation given throughout this specification includes every lower numerical limitation, as if such lower numerical limitations were expressly written herein. Every minimum numerical limitation given throughout this specification includes every higher numerical limitation, as if such higher numerical limitations were expressly written herein. Values given for optimized parameters are understood to be approximate, as it is not possible to test every availability of every vendor and every lot of every vendor.

[0057] Examples

[0058] In this section, the contents of the present application will be detailed via the following examples. These examples are for illustration only and one skilled in the art can readily devise variations and modifications. Thus, various embodiments of the present application will be described in detail hereinafter, while it is to be understood that the application is not limited to this preferred embodiments, but includes all possible embodiments which are equivalent within the spirit and technical scope of the present application.

[0059] Methods and Materials

[0060] X-ray powder diffraction (XPRD): XPRD data shown below were collected according to the following measurement parameters:

[0061] Instrument: X-ray diffractometer D2 Phaser, Bruker;

[0062] Anode: Cu;

[0063] Generator voltage: 30 kV;

[0064] Generator current: 10 mA;

[0065] Scan type: Coupled 2theta / theta;

[0066] Divergence slit: 0.2 mm;

[0067] Anti-scatter screen: 0.5 mm;

[0068] Start angle: 3.5 degrees;

[0069] End angle: 40 degrees;

[0070] Step size: 0.03 degrees / step;

[0071] Time: 1.0 seconds / step;

[0072] Differential scanning calorimetry (DSC): DSC measurements in the present invention were performed using a TA Q20, thermal analyzer. 3.0-15.0 mg sample weight was placed in a hermetically sealed aluminum pan. The sample was equilibrated to 100 °C, and then ramped to 200 °C at a scan rate of 5 °C / min. Dry nitrogen gas was used as the purge gas.

[0073] Example 1: Preparation of a crystalline form of ABT-101 free base

[0074] The ABT-101 compound was obtained via the following procedure: A mixture of S-2-[5-(3-nitro-phenyl)-6-phenyl-furo[2,3-d]pyrimidin-4-ylamino]-2-phenyl-ethanol (1 g, 0.002 mmol) and 5% Pd / C (10 mg) in MeOH (10 mL) was hydrogenated at 3 atmospheres for 8 h. The reaction mixture was filtered through celite, the solvent was removed under vacuum to give S-2-[5-(3-amino-phenyl)-6-phenyl-furo[2,3-d]pyrimidin-4-ylamino]-2-phenyl-ethanol. To a mixture of the above compound in DCM (5 mL) was added 4-bromocrotonic acid (422 mg, 2.55 mmol), EDCI (490 mg, 2.55 mmol), and the reaction mixture was stirred for 8 h. Subsequently, N,N-dimethylamine (1.18 ml, 23.2 mmol) was added and stirring was continued at room temperature for 8 h. Water was added to the reaction mixture and extracted with dichloromethane (3 x 20 mL). The combined organics were dried over MgS04, concentrated under vacuum, and the residue was purified by silica gel flash column chromatography using dichloromethane:methanol (20:1) to give the ABT-101 compound. The following purification was performed by recrystallization with hot acetone at 53-58 °C. After the mixture was allowed to cool to 0-5 °C to produce ABT-101 crystals, the solvent was then centrifuged, followed by washing the ABT-101 crystals with acetone to produce ABT-101.

[0075] In addition, the obtained ABT-101 compound was crystallized using different solvents. The corresponding samples and their descriptions are described in Table 1. In addition, the DSC curve of the crystallization of ABT-101 free base is shown in Figure 1 .

[0076] Table 1

[0077]

[0078] Example 2

[0079] Physical characterization of the crystalline forms of ABT-101 free base

[0080] Crystalline forms of ABT-101 free base were obtained and further tested for physical characterization. First, the DSC thermograms of samples of crystalline forms of ABT-101 free base prepared using different solvents are shown in Figure 2a and 2b Second, the XRPD pattern of one of the crystalline forms of ABT-101 free base (01BP-063-184) is shown in Figure 3 , wherein the corresponding tabled data is shown in Table 2.

[0081] Table 2

[0082]

[0083]

[0084] In addition, the XRPD patterns of crystalline forms of ABT-101 free base prepared using different solvents were compared and compared in Figure 4

[0085] Example 3: Comparison of different solid crystalline forms of ABT-101

[0086] In this section, different solid crystalline forms of ABT-101 were compared as shown in Table 3.

[0087] Table 3

[0088]

[0089]

[0090] In Table 3, “FaSSIF” means “fasted state simulated intestinal fluid”; “FeSSIF” means “fed state simulated intestinal fluid”; “SGF” means “simulated gastric fluid”.

[0091] From Table 3, it can be concluded that the free base form of ABT-101 exhibits better “pre-melt weight loss”, “hygroscopicity”, “DVS post-crystalline form change”, “solubility” and “stability” compared to the glycolate form, the succinate form and the hydrochloride form.

[0092] In addition, the results of the comparison between the amorphous free form of ABT-101 (ABT-101 S0) and the crystalline free form (ABT-101 S0*) are shown in Figure 5

[0093] Example 4: Pharmacokinetic study​​

[0094] In this section, the test and comparison of the pharmacokinetics of the crystalline form of ABT-101 (ABT-101 S0*) and the amorphous form of ABT-101 (ABT-101 S0) are shown in Table 4.

[0095] Table 4

[0096]

[0097] According to Table 4, the Cmax, AUC and F (%) of the crystalline form of ABT-101 (ABT-101 S0*) are increased by about 1.9-3 times compared to the amorphous form of ABT-101 (ABT-101 S0).

[0098] Example 5: Stability Study

[0099] In this section, the stability of the crystalline form of ABT-101 free base as an active pharmaceutical ingredient (API) is tested according to various aspects.

[0100] First, the long-term stability of the crystalline form of ABT-101 free base tested is shown in Table 5.

[0101] Table 5

[0102]

[0103]

[0104] Second, the pharmaceutical compositions currently manufactured, more specifically, capsules containing different amounts (25 mg and 100 mg, respectively) of the crystalline form of ABT-101 free base as an API (ABT-101 free base), and the composition thereof is shown in Table 6.

[0105] Table 6

[0106]

[0107] In addition, the above-mentioned ABT-101 capsules are tested according to the procedures shown in Table 7; wherein: "S" means stability test; "M" means microbial limit test (MLT); "(-)" means optional, samples are taken for testing only when necessary.

[0108] Table 7

[0109]

[0110]

[0111] Thus, the stability data for the 25 mg capsules and 100 mg capsules described above under long-term storage conditions (25 °C, 60% RH) are shown in Tables 8 and 9, respectively; and the comparison results therebetween are shown in Table 10.

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118] Table 10

[0119]

[0120] In summary, the crystalline forms of ABT-101 free base can exhibit unexpected stability and improved pharmacokinetic properties compared to other forms or salts thereof, thereby allowing the compound to be more suitable for pharmaceutical development and to meet the requirements for bioavailability and drug efficacy. Particular embodiments of the present application have been disclosed, but they are not intended to limit the present application. Those skilled in the art can understand. And various changes and modifications can be made without departing from the principles and spirit of the present application, therefore the protection scope of the present application should be based on the protection scope of the present application defined in the scope of the attached patent application.

Claims

1. A crystalline form of (S,E)-4-(dimethylamino)-N-(3-(4-(2-hydroxy-l- phenylethylamino)-6-phenylfuro[2,3-d]pyrimidin-5-yl)phenyl)but-2-enamide (ABT-101) free base characterized by an X-ray powder diffraction pattern further comprising a peak at a 2Θ value of 8.7°±0.2°.

2. The crystalline form of claim 1, characterized by an X-ray powder diffraction pattern further comprising a peak at a 2Θ value of 19.4°±0.2°.

3. The crystalline form of claim 1, characterized by an X-ray powder diffraction pattern further comprising a peak at a 2Θ value of 23.1°±0.2°.

4. The crystalline form of claim 1, characterized by an X-ray powder diffraction pattern further comprising a peak at a 2Θ value of 23.1°±0.2°.

5. The crystalline form of claim 1, having a melting point temperature of 170 °C to 195 °C.

6. The crystalline form of claim 1, having a melting enthalpy of 75 °C to 85 °C.

7. A pharmaceutical composition comprising the crystalline form of claim 1, and a pharmaceutically acceptable carrier or excipient.

8. The pharmaceutical composition of claim 7, which is an EGFR inhibitor, a HER2 inhibitor, or a tumor-agnostic inhibitor.

9. The pharmaceutical composition of claim 7, which is in the form of a capsule.

10. The pharmaceutical composition of claim 9, comprising 0.1 mg to 200 mg of the crystalline form of claim 1.

11. The pharmaceutical composition of claim 9, comprising 25 mg to 100 mg of the crystalline form of claim 1.

12. The pharmaceutical composition of claim 9, comprising 50 mg to 100 mg of the crystalline form of claim 1.

13. The pharmaceutical composition of claim 9, wherein the pharmaceutically acceptable carrier or excipient comprises a filler.

14. The pharmaceutical composition of claim 9, wherein the pharmaceutically acceptable carrier or excipient comprises a disintegrant.

15. The pharmaceutical composition of claim 9, wherein the pharmaceutically acceptable carrier or excipient comprises a lubricant.

16. Use of a crystalline form of (S,E)-4-(dimethylamino)-N-(3-(4-(2-hydroxy-1- phenylethylamino)-6-phenylfuro[2,3-d]pyrimidin-5-yl)phenyl)but-2-enamide (ABT-101) free base for the manufacture of a medicament for treating cancer, wherein the crystalline form is the crystalline form of any one of claims 1 to 6.

17. The use of claim 16, wherein the crystalline form of any one of claims 1 to 6 is an EGFR inhibitor, a HER2 inhibitor, or a tumor-agnostic inhibitor.

18. The use of claim 16, wherein the cancer is peritoneal cancer, small intestine cancer, non-small cell lung cancer (NSCLC), neuroendocrine cancer, bladder cancer, breast cancer, cervical cancer, cholangiocarcinoma, esophageal cancer, stomach cancer, colorectal cancer, prostate cancer, ovarian cancer, head and neck cancer, endometrial cancer, renal cancer, melanoma cancer, sarcoma cancer, pancreatic cancer, small cell lung cancer (SCLC), leukemia cancer, or brain cancer.

19. The use of claim 16, wherein the cancer is salivary gland cancer or thyroid cancer.

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