Methods of synthesis and crystalline forms of heteroaryl derivatives of triazolyl acrylamide

Abstract

The present invention relates to a method for preparing a compound represented by structural formula (VII), comprising reacting a compound represented by structural formula (II) with a compound represented by structural formula (III) in a solvent in the presence of a Pd catalyst and one or more inorganic bases under conditions suitable for preparing a compound represented by structural formula (VII). Values ​​and example values ​​of the variables in structural formulas (VII), (II), and (III) are defined herein. The present invention also relates to crystalline forms I and II of the compound represented by structural formula (VII), the use of the crystalline forms in treating diseases or disorders associated with CRM1, and methods for preparing the crystalline forms.

Description

[Technical field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 190,987, filed May 20, 2021, the entire disclosure of which is incorporated herein by reference. [Background technology]

[0002] Certain triazolyl acrylamides, especially phenyl triazolyl acrylamides, are useful as selective inhibitors of nuclear export (SINEs), particularly as anticancer drugs. Such phenyl triazolyl acrylamides act by binding to exportin 1 (XPO1 or CRM1) and thus blocking the transport of several proteins involved in cancer-cell growth from the cell nucleus to the cytoplasm, ultimately arresting the cell cycle and leading to apoptosis. The synthetic methods utilized to produce these SINEs are multi-step schemes that require strict control of conditions to ensure acceptable yields and stereoselectivity. There is a need for robust, high-yielding synthetic methods for the production of such SINEs on an industrial scale.

[0003] In addition to the need for high-yielding synthetic methods, there is also a need for crystalline forms of SINE compounds, as such forms can be important in the formulation of pharmaceutical compositions. Summary of the Invention [Means for solving the problem]

[0004] The present invention relates to crystalline Forms I and II of the compound represented by structural formula (VII), compositions comprising crystalline Forms I and II, methods of treatment comprising administering crystalline Form I or crystalline Form II, or compositions comprising crystalline Form I or crystalline Form II for the treatment of a CRM-1 related disease or disorder, and methods of preparing the compound represented by structural formula (VII) and crystalline forms of the compound (e.g., crystalline Forms I and II).

[0005] In an example embodiment, the present invention provides a compound represented by structural formula (VII): [ka] The present invention relates to a method for preparing a

[0006] The method comprises the steps of: [ka] with a compound represented by structural formula (III): [ka] with a first solvent in the presence of a Pd catalyst and one or more inorganic bases under conditions suitable for preparing a compound represented by structural formula (VII), wherein each R is hydrogen, C1-C4 alkyl, or two groups R together with the oxygen atom to which they are attached form a 5-7 membered cyclic acetal moiety, thereby obtaining a compound represented by structural formula (VII).

[0007] In another exemplary embodiment, the present invention provides a compound represented by structural formula (V): [ka] or a salt thereof.

[0008] In another exemplary embodiment, the present invention provides a compound represented by structural formula (VII): [ka] wherein the crystalline form is Form I characterized by X-ray powder diffraction peaks at 2θ angles of 4.6°, 22.8°, 23.2°, and 24.4°.

[0009] In yet another exemplary embodiment, the present invention provides a compound represented by structural formula (VII): [ka] wherein the crystalline form is Form II characterized by X-ray powder diffraction peaks at 2θ angles of 9.9°, 19.2°, 22.4°, and 24.4°.

[0010] In another embodiment, the present invention relates to a pharmaceutical composition comprising a crystalline form of the compound represented by structural formula (VII) (e.g., crystalline Form I or crystalline Form II) and a pharma- ceutically acceptable carrier.

[0011] In another embodiment, the present invention relates to a method for treating or preventing a CRM1-related disease or disorder, comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of a crystalline form (e.g., crystalline Form I or crystalline Form II) of a compound represented by structural formula (VII) described herein.

[0012] In another embodiment, the present invention relates to the use of crystalline Form I or crystalline Form II described herein for treating a CRM-1 related disease or disorder described herein in a subject in need thereof.

[0013] In yet another embodiment, the present invention relates to the use of crystalline Form 1 or crystalline Form II as described herein for the manufacture of a medicament for treating a CRM-1 related disease or disorder as described herein in a subject in need thereof.

[0014] The foregoing will be apparent from the following more detailed description of example embodiments of the invention, as illustrated in the accompanying drawings, in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating embodiments of the invention. [Brief description of the drawings]

[0015] [Figure 1] 1 depicts an overall synthetic scheme according to one aspect of an example embodiment. [Diagram 2] 1 shows a table summarizing the results of initial Pd catalyst evaluation. [Diagram 3] This table summarizes the results of screening reaction solvents for Pd-catalyzed reactions. [Figure 4] 1 is a table summarizing the results of screening inorganic bases. [Diagram 5] 1 is a table summarizing the results of screening reaction conditions for catalytic reactions. [Figure 6] 1 is a table summarizing the results of catalyst screening. [Figure 7] 1 is a table summarizing the results of experiments conducted to investigate the effect of catalyst stoichiometry on chemistry performance. [Figure 8] 1 is a table summarizing the results of experiments conducted to investigate the lower limit of MB7 equivalents. [Figure 9] 1 is a table summarizing the results of solvent screening for Suzuki coupling. [Figure 10] 1 is a table summarizing the results of experiments testing ratios of dioxane:water solvent systems. [Figure 11] 1 is a table summarizing the results of testing the effect of total solvent volume on Suzuki coupling reactions. [Figure 12] 1 is a table summarizing the results of evaluation of the reaction temperature of Suzuki coupling. [Figure 13] 1 is a table comparing the results of degassed and non-degassed Suzuki coupling reactions. [Figure 14] 1 is a table summarizing experiments evaluating the effect of pH on Suzuki coupling reactions. [Figure 15A-15B] Collectively, they represent a summary of significant changes and improvements of the synthetic methods disclosed herein over conventional procedures. [Figure 16] 4 shows the HPLC analysis of the products of step 1 of the overall reaction. [Figure 17] 1 shows the proton NMR in DMSO of a batch of the product of step 2 of the overall reaction. [Figure 18] The 1H NMR spectrum of compound MB3 is shown (see Figure 1). [Figure 19] The 1H NMR of compound MB6(5) is shown (see Figure 1). [Figure 20] 1 is an X-ray powder diffraction (XRPD) pattern of crystalline Form I of compound MB6 (5). [Figure 21] 1 is a graph depicting a differential scanning calorimetry (DSC) thermogram of crystalline Form I of compound MB6 (5). [Figure 22] 1 is a graph depicting a thermogravimetric analysis (TGA) thermogram of compound MB6(5). [Diagram 23] 1 is a dynamic vapor sorption (DVS) pattern of crystalline Form I of compound MB6 (5). [Figure 24] 1 is an XRPD pattern of crystalline Form II of compound MB6 (5). [Diagram 25] 1 is a graph depicting a DSC thermogram of crystalline Form II of compound MB6(5). [Figure 26] 1 is a graph depicting the TGA thermogram of crystalline Form II of compound MB6(5). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] A description of example embodiments of the invention follows.

[0017] process In a first exemplary embodiment, the present invention provides a compound represented by structural formula (VII): [ka] The present invention relates to a method for preparing a

[0018] In a first aspect of the first embodiment, the method comprises: [ka] with a compound represented by structural formula (III): [ka] in a first solvent, in the presence of a Pd catalyst and one or more inorganic bases under conditions suitable for preparing a compound represented by structural formula (VII), where each R is hydrogen, C1-C4 alkyl, or two groups R together with the oxygen atom to which they are attached form a 5-7 membered cyclic acetal moiety, thereby obtaining a compound represented by structural formula (VII).

[0019] In a second aspect, the one or more inorganic bases are selected from carbonate, bicarbonate, acetate, or quaternary ammonium, sodium, potassium, or cesium hydroxide. The remainder of the first example embodiment values ​​and example values ​​are as defined above for the first aspect.

[0020] In a third aspect, the Pd catalyst is selected from chloro{[4-(N,N-dimethylamino)phenyl]di-t-butylphosphino}(2'-amino-1,1'-biphenyl-2-yl)palladium(II) or chloro(crotyl)[di-tert-butyl(4-dimethylaminophenyl)phosphine]palladium(II). The values ​​of the first example embodiment and the remainder of the example values ​​are as defined above for their respective first to second aspects.

[0021] In a fourth embodiment, the compound represented by structural formula (III) is a compound represented by structural formula (IIIB): [ka] The values ​​of the first example embodiment and the remainder of the example values ​​are as defined above with respect to their respective first to third aspects.

[0022] In a fifth aspect, the inorganic base is Cs2CO3 or CsOH, e.g., Cs2CO3. The remainder of the first example embodiment values ​​and example values ​​are as defined above for their respective first to fourth aspects.

[0023] In a sixth aspect, the Pd catalyst is chloro(crotyl)[di-tert-butyl(4-dimethylaminophenyl)phosphine]palladium(II). The values ​​of the first example embodiment and the remainder of the example values ​​are as defined above for their respective first to fifth aspects.

[0024] In a seventh aspect, the first solvent is an ether solvent, a C1-C4 alcohol, or a combination thereof. For example, the first solvent is selected from MTBE, CPME, THF, dioxane, MeTHF, methanol, alone or in combination with water or ethanol. The remainder of the values ​​of the first example embodiment and example values ​​are as defined above with respect to their respective first to sixth aspects.

[0025] In an eighth aspect, the Pd catalyst load is 0.5 mol% to 10 mol%. The remainder of the first example embodiment values ​​and example values ​​are as defined above for their respective first to seventh aspects.

[0026] In a ninth aspect, the amount of inorganic base is 0.5 to 2 molar equivalents of base relative to the compound represented by structural formula (II). The values ​​of the first example embodiment and the remainder of the example values ​​are as defined above for their respective first to eighth aspects.

[0027] In a tenth embodiment, suitable conditions for preparing a compound represented by structural formula (VII) are -Pd catalyst loading from 0.5 mol% to 3 mol%; - 1.0 to 2.2 molar equivalents of the compound represented by structural formula (III) relative to the compound represented by structural formula (II); an amount of inorganic base of 0.8 to 1.2 total molar equivalents of base relative to the compound represented by structural formula (II); - the first solvent comprises 16 to 21 parts dioxane and 2 to 3 parts water; A reaction temperature of about 55°C to about 60°C; and -Reaction time of about 7 to 8 hours The values ​​of the first example embodiment and the remainder of the example values ​​are as defined above with respect to their respective first to ninth aspects.

[0028] In an eleventh aspect, the method comprises the step of: [ka] A process for preparing a compound represented by structural formula (IV): [ka] in a second solvent in the presence of an organic base under conditions suitable to produce a compound represented by structural formula (II). The remainder of the first example embodiment values ​​and example values ​​are as defined above with respect to their respective first through tenth aspects.

[0029] In a twelfth aspect, the organic base is triethylamine or diisopropylethylamine (DIPEA). The remainder of the first example embodiment values ​​and example values ​​are as defined above with respect to their respective first through eleventh aspects.

[0030] In a thirteenth aspect, the second solvent comprises acetonitrile (ACN). The remainder of the first example embodiment values ​​and example values ​​are as defined above with respect to their respective first to twelfth aspects.

[0031] In a fourteenth aspect, the second solvent is 80% ACN / 20% water. The remainder of the first example embodiment values ​​and example values ​​are as defined above for their respective first to thirteenth aspects.

[0032] In a fifteenth embodiment, the method comprises the step of: [ka] A process for preparing a compound represented by structural formula (V): [ka] with bromine (Br2) in a third solvent in the presence of a bromide salt under conditions suitable to prepare a compound represented by structural formula (IV). The values ​​of the first example embodiment and the remainder of the example values ​​are as defined above with respect to their respective first through fourteenth aspects.

[0033] In a sixteenth aspect, the third solvent comprises water and the bromide salt is sodium bromide. The values ​​of the first example embodiment and the remainder of the example values ​​are as defined above with respect to their respective first to fifteenth aspects.

[0034] In a seventeenth embodiment, the second solvent comprises about 11 parts ACN and about 4 parts HO relative to the compound represented by structural formula (IV), the organic base is DIPEA, and suitable conditions for preparing the compound represented by structural formula (II) are: - about 1 molar equivalent of DIPEA relative to the compound represented by formula (IV); A reaction temperature of -20°C to 25°C; and - 2-3 hour reaction time The first example embodiment values ​​and the remainder of the example values ​​are as defined above with respect to their respective first to sixteenth aspects.

[0035] In an eighteenth aspect, the third solvent is acetic acid. The remainder of the first example embodiment values ​​and example values ​​are as defined above for their respective first through seventeenth aspects.

[0036] In a nineteenth aspect, reacting the compound represented by structural formula (V) with Br2 is carried out at a temperature between 20° C. and 30° C. for a time period between 12 hours and 16 hours. The remainder of the first example embodiment values ​​and example values ​​are as defined above with respect to their respective first through eighteenth aspects.

[0037] In a twentieth embodiment, the method comprises administering to a subject a compound represented by structural formula (V): [ka] A process for preparing a compound represented by structural formula (VI): [ka] in a fourth solvent with an amidating agent in the presence of a tertiary amine organic base and a chloroformate ester under conditions suitable to produce a compound represented by Structural Formula (V). The remainder of the first example embodiment values ​​and example values ​​are as defined above with respect to their respective first through nineteenth aspects.

[0038] In a twenty-first embodiment, the amidating agent is ammonium hydroxide, the tertiary amine organic base is N-methylmorpholine (NMM), and the chloroformate has the following structural formula: [ka] The remainder of the values ​​of the first example embodiment and example values ​​are as defined above with respect to their respective first to twentieth aspects.

[0039] In a twenty-second aspect, the fourth solvent is tetrahydrofuran (THF) or 2-methyltetrahydrofuran (MeTHF). The remainder of the first example embodiment values ​​and example values ​​are as defined above for their respective first to twenty-first aspects.

[0040] In a twenty-third aspect, the fourth solvent is MeTHF, and the amidating of the compound represented by structural formula (VI) is carried out at a temperature between 0° C. and 5° C. for a time period between 3 hours and 4 hours. The remainder of the first example embodiment values ​​and example values ​​are as defined above with respect to their respective first through twenty-second aspects.

[0041] In a second exemplary embodiment, the present invention provides a compound represented by the following structural formula: [ka] or a salt thereof.

[0042] Crystalline Forms I and II of the compound represented by structural formula (VII) and a recrystallization method: When the term "about" refers to a numerical value of a temperature, it should be understood to mean that the numerical value has a range of ±5° C. of the recited numerical value, unless otherwise specified. For example, if a described embodiment or claim recites a temperature of "about 20° C.," this shall be understood to mean 20° C. ±5° C., i.e., a temperature between 15° C. and 25° C.

[0043] When the term "about" refers to a numerical value of time, it should be understood to mean that the numerical value has a range of ±5 minutes of the recited numerical value, unless otherwise specified. For example, if a described embodiment or claim recites a period of "about 60 minutes," this shall be understood to mean 60 minutes ±5 minutes, i.e., a period of 55 minutes to 65 minutes.

[0044] When the term "about" refers to a numerical value of an alcohol-to-water volume ratio, it should be understood to mean that the numerical value of x has a range of ±5% of the recited numerical value, unless otherwise specified. For example, if a described embodiment or claim recites an alcohol-to-water volume ratio of "about 70 / 30," this shall be understood to mean an alcohol-to-water volume ratio of 75 / 25 to 65 / 35.

[0045] Provided herein are crystalline forms of the compound of structural formula (VII), designated as crystalline Form I and crystalline Form II.

[0046] As used herein, "crystalline" or "crystal" refers to a homogeneous solid formed by a repeating three-dimensional pattern of atoms, ions, or molecules (e.g., anhydrous molecules or salts thereof, solvates thereof, or combinations of the above) with consistent distances between the constituent parts. The unit cell is the simplest repeating unit in this pattern.

[0047] The crystalline forms provided herein can be identified based on characteristic peaks in an X-ray powder diffraction (XRPD) analysis. XRPD is a scientific technique that measures X-rays, neutrons, or electrons scattered by a powder or microcrystalline material as a function of scattering angle. XRPD can be used to identify and characterize crystalline solids, since the diffraction pattern produced by a particular solid is typically unique to that solid and can be used as a "fingerprint" to identify that solid. For example, an XRPD pattern or diffractogram (e.g., a pattern or diffractogram produced by a sample, such as an unknown sample) that substantially matches a reference XRPD pattern or diffractogram can be used to determine identity between the sample material and the reference material. Both the position and relative intensity of the peaks in the XRPD diffractogram indicate the particular phase and identity of the material.

[0048] The crystalline forms provided herein may be a single crystalline form or may comprise a mixture of two or more different crystalline forms. For example, in some embodiments, crystalline Form I of the compound represented by Structural Formula (VII) is provided as a single crystalline form. Alternatively, in other embodiments, the crystalline form may comprise a mixture of two or more crystalline forms of the compound represented by Structural Formula (VII).

[0049] As used herein, a "single crystalline form" refers to a single crystal of a crystalline solid or multiple crystals of a crystalline solid, each of which has the same crystalline morphology.

[0050] Figures 20 and 24 show the XRPD patterns of crystalline Forms I and II described herein, respectively. An XRPD pattern that is "substantially consistent" with one or more figures herein showing XRPD patterns or diffractograms is an XRPD pattern that would be considered by a person skilled in the art to represent the same crystalline form of the compound represented by Structural Formula (VII) as the sample of the compound represented by Structural Formula (VII) that gave rise to the XRPD pattern in one or more figures provided herein. Thus, a substantially consistent XRPD pattern may be identical to one of the figures, or perhaps may differ somewhat from one or more of the figures. An XRPD pattern that differs somewhat from one or more of the figures may not necessarily show each of the lines of the diffraction patterns presented herein, and / or may show slight changes in the appearance or intensity of the lines or shifts in the position of the lines. These differences typically result from differences in the conditions involved in obtaining the data or differences in the purity of the samples used to obtain the data. One of ordinary skill in the art can determine whether a sample of a crystalline compound is in the same or a different form than those disclosed herein by comparing the XRPD pattern of the sample of the crystalline compound to the corresponding XRPD pattern disclosed herein.

[0051] Any 2θ angle specified herein should be understood to mean the specified value ±0.2°. For example, if a described embodiment or claim specifies a 2θ of 4.4°, this shall be understood to mean 4.4°±0.2°, i.e., a 2θ angle of 4.2° to 4.6°.

[0052] Crystalline Form I and Crystalline Form II provided herein can also be identified based on differential scanning calorimetry (DSC) and / or thermogravimetric analysis (TGA). DSC is a thermal analysis technique in which the difference in the amount of heat required to increase the temperature of a sample is measured as a function of temperature. DSC can be used to detect physical transformations, such as phase transitions, of a sample. For example, DSC can be used to detect the temperature at which a sample undergoes crystallization, melting, or glass transition.

[0053] TGA is a method of thermogravimetric analysis in which the changes in the physical and chemical properties of a material are measured as a function of increasing temperature (with a constant heating rate) or time (with a constant temperature and / or constant mass loss). TGA can provide information about physical phenomena such as second order phase transitions, or chemical phenomena such as desolvation and / or decomposition.

[0054] Figures 21 and 25 show DSC thermograms for crystalline Forms I and II, respectively, described herein. A DSC or TGA thermogram that is "substantially in accordance with" one or more figures herein showing DSC or TGA thermograms is a DSC or TGA thermogram that would be considered by one of ordinary skill in the art to represent the same crystalline form of the compound represented by Structural Formula (VII) as the sample of the compound represented by Structural Formula (VII) that gave rise to the DSC or TGA thermogram in one or more figures provided herein.

[0055] Any temperatures associated with DSC or TGA specified herein should be understood to mean ±5° C. or less of the specified value. For example, if an embodiment or claim specifies an endothermic peak at about 184° C., this shall be understood to mean a temperature of 184° C. ±5° C. or less, i.e., 179° C. to 189° C. In preferred embodiments, the DSC or TGA temperature is ±3° C. of the specified value, and in more preferred embodiments, ±2° C.

[0056] The provided crystalline Form I can be additionally characterized by dynamic water vapor sorption (DVS), where a sample is exposed to various conditions of humidity and temperature and the sample response is measured gravimetrically. The results of a DVS analysis can be specifically a double curve giving the sample weight percent as a function of relative humidity (RH) over time, a double curve giving the sample water content as a function of RH over time, a curve giving the weight percent relative to RH, or a curve giving the water content relative to RH. Devices useful for measuring such data are known in the art, and any such device can be used to measure compounds according to the present disclosure. In certain embodiments, the DVS analysis can be performed by scanning at a series of specific RH values. Thus, a particular polymorph according to the present disclosure can be identified and described in relation to a representative graph and / or approximate peaks obtained in a DVS analysis, specifically scanning from 0% to 95% RH at 5% or 10% RH step intervals.

[0057] Figure 23 shows the DVS pattern of crystalline Form I described herein. A DVS pattern that is "substantially in accordance with" one or more figures herein showing a DVS pattern is a DVS pattern that would be considered by one of ordinary skill in the art to represent the same crystalline form of the compound represented by Structural Formula (VII) as the sample of the compound represented by Structural Formula (VII) that gave rise to the DVS pattern in one or more figures provided herein.

[0058] In some embodiments, the crystalline forms provided herein may be crystalline forms of a compound represented by the compound represented by Structural Formula (VII), in which the compound is in the form of a solvate. As used herein, "solvate" refers to a chemical compound formed by the interaction of a solute (e.g., a compound of Structural Formula (VII)) with one or more solvents (e.g., methanol, ethanol, water). Thus, "solvate" includes solvates containing one type of solvent molecule and solvates containing two or more solvent molecules (mixed solvates or co-solvates). Typically, the one or more solvents in the solvates described herein are organic solvents or combinations of organic solvents, although water may also form solvates, referred to as hydrates.

[0059] Form I In a third example embodiment, the present invention is a crystalline form of the compound represented by Structural Formula (VII), the crystalline form is Form I and is characterized by X-ray powder diffraction peaks at 2θ angles of 4.6°, 22.8°, 23.2°, and 24.4°; at least four X-ray powder diffraction peaks at 2θ angles selected from 4.6°, 20.0°, 22.8°, 23.2°, and 24.4°; or at least five X-ray powder diffraction peaks at 2θ angles selected from 4.6°, 19.0°, 20.0°, 22.8°, 23.2°, 23.7°, 24.4°, and 27.9°. In some aspects of the third example embodiment, the crystalline Form I is characterized by an X-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 20.

[0060] Crystalline Form I may be further characterized by a differential scanning calorimetry thermogram comprising a sharp endothermic peak at about 225° C. consistent with melting. In some aspects of the third embodiment, the DSC thermogram is substantially in accordance with that of FIG. 21. In some aspects of the third embodiment, the TGA thermogram is substantially in accordance with that of FIG.

[0061] Crystalline Form I may additionally be characterized by a dynamic water vapor sorption pattern exhibiting a reversible 0.12% w / w water sorption from 0 to 90% RH. In some aspects of the third embodiment, the DVS pattern is substantially in accordance with that shown in FIG.

[0062] Form II In a fourth example embodiment, the invention is a crystalline form of the compound represented by Structural Formula (VII), wherein the crystalline form is Form II and is characterized by X-ray powder diffraction peaks at 2θ angles of 9.9°, 19.2°, 22.4°, and 24.4°; at least four X-ray powder diffraction peaks at 2θ angles selected from 9.9°, 19.2°, 22.4°, 23.5°, and 24.4°; or at least five X-ray powder diffraction peaks at 2θ angles selected from 9.9°, 19.2°, 21.3°, 21.9°, 22.4°, 23.5°, 24.4°, and 29.2°. In some aspects of the fourth embodiment, the crystalline Form VI is characterized by an X-ray powder diffraction pattern substantially in accordance with that depicted in FIG.

[0063] Crystalline Form II may be further characterized by a differential scanning calorimetry thermogram comprising a broad endothermic peak at about 112° C. consistent with desolvation and a sharp endothermic peak at about 225° C. consistent with melting. In some aspects of the fourth embodiment, the DSC thermogram is substantially in accordance with that of Figure 25. In some aspects of the fourth embodiment, the TGA thermogram is substantially in accordance with that of Figure 26.

[0064] Crystalline Form II can be a crystalline form of the compound represented by structural formula (VII) in which the compound is in the form of a solvate, for example, the compound of structural formula (VII) is a methanol solvate.

[0065] Recrystallization Procedure to Isolate Form I: In a fifth exemplary embodiment, the present invention provides a compound represented by structural formula (VII): [ka] 1. A method for preparing crystalline Form I of The method includes: (a) contacting crystalline Form II of the compound represented by structural formula (VII) with about 18 volumes of 4-methyl-2-pentanone (MIBK) to form a mixture; (b) heating the mixture of step (a) to about 80-85° C. to form a heated mixture; (c) optionally adding SiDMT to the heated mixture of step (b); (d) maintaining the heated mixture at a temperature of about 80-85° C. for about 4.5 hours; (e) filtering the heated mixture to obtain a filtrate; (f) adding MIBK at a temperature of about 80-85° C. to the filtrate; (g) inducing nucleation of Form I in the filtrate by cooling the filtrate to about 20-25° C.; (h) crystallizing Form I by controlled cooling crystallization of the filtrate with a final temperature of 0-5° C.; and (i) isolating crystalline Form I from the filtrate. In one embodiment, isolating crystalline Form I from the filtrate is performed by filtration.

[0066] definition Compounds of the invention include those generally described above and are further represented by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise specified. For purposes of the present invention, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics 75 th In addition, the general principles of organic chemistry are specified in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999 and “March's Advanced Organic Chemistry”, 5 th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0067] Unless otherwise specified herein, the nomenclature used herein generally follows the examples and rules set forth in Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F, and H, Pergamon Press, Oxford, 1979, which is incorporated herein by reference for its exemplary chemical structure names and rules for naming chemical structures. Optionally, names of compounds may be generated using a chemical naming program: ACD / ChemSketch, Version 5.09 / September 2001, Advanced Chemistry Development, Inc., Toronto, Canada.

[0068] The compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (e.g., as described in E.L. Eliel and S.H. Wilen, Stereo-chemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190) and may occur as racemates, racemic mixtures, and as individual diastereomers or enantiomers, with all possible isomers and mixtures thereof, including optical isomers, being included in the present invention.

[0069] As used herein, "ether solvent" refers to an organic solvent that contains a COC moiety. Examples include tert-amyl ethyl ether, cyclopentyl methyl ether (CPME), di-tert-butyl ether, di(propylene glycol) methyl ether, dibutyl ether, diethyl ether, diisopropyl ether, dimethoxyethane, dimethoxymethane, 1,4-dioxane (dioxane), ethyl tert-butyl ether, methoxyethane, 2-(2-methoxyethoxy)ethanol, methyl tert-butyl ether (MBTE), morpholine, polyethylene glycol, propylene glycol methyl ether, tetrahydrofuran (THF), 2-methyl-THF (MeTHF), tetrahydrofurfuryl alcohol, tetrahydropyran, and 2,2,5,5-tetramethyltetrahydrofuran.

[0070] As used herein, the term "alkyl" means, unless otherwise specified, typically C1 to C 12 , preferably C1 to C6 linear or branched saturated monovalent hydrocarbon radical. Thus, "C1 to C6 alkyl" means a linear or branched saturated monovalent hydrocarbon radical having 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, and t-butyl.

[0071] The term "alkoxy" as used herein means an "alkyl-O-" group, where alkyl is defined above. Examples of alkoxy include methoxy and ethoxy.

[0072] As used herein, the term "alkenyl" refers to a saturated straight or branched chain acyclic hydrocarbon having 2 to 12 carbon atoms and at least one carbon-carbon double bond. An alkenyl group may be optionally substituted with one or more substituents. Any of the terms "alkenyl" or structural depictions thereof include radicals having carbon-carbon double bonds in the "cis" and "trans" or, alternatively, "E" and "Z" configurations. When an alkenyl group contains more than one carbon-carbon double bond, each carbon-carbon double bond is independently a cis or trans double bond, or a mixture thereof.

[0073] As used herein, the term "amino" includes mono- and dialkylamino groups and refers to a chemical moiety having the formula -N(R)2, where each R is independently selected from hydrogen and C1-C4 alkyl.

[0074] The term "aryl" as used herein, alone or in combination, refers to a carbocyclic aromatic system containing one or more rings that may be pendantly attached together or fused. In certain embodiments, an aryl is 1, 2, or 3 rings. In one aspect, an aryl has 6 to 12 ring atoms. The term "aryl" encompasses aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl, and acenaphthyl. An aryl group may be optionally substituted as defined and described herein.

[0075] The term "halo" or "halogen" as used herein means halogen, including, for example, but not limited to, fluoro, chloro, bromo, iodo, etc. in both radioactive and non-radioactive forms. In preferred embodiments, halo is selected from the group consisting of fluoro, chloro and bromo.

[0076] The term "haloalkyl," as used herein, includes alkyl substituted with one or more F, Cl, Br, or I, where alkyl is defined above.

[0077] The term "heteroaryl" as used herein refers to an aromatic group containing one or more heteroatoms (e.g., one or more heteroatoms independently selected from O, S, and N). Heteroaryl groups can be monocyclic or polycyclic, for example, monocyclic heteroaryl rings fused to one or more carbocyclic aromatic groups or other monocyclic heteroaryl groups. Heteroaryl groups of the invention can also include ring systems substituted with one or more oxo moieties. In one embodiment, heteroaryl has 5 to 15 ring atoms, preferably 5 or 6 ring atoms. Examples of heteroaryl groups include pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pristine, and the like. Heteroaryl groups include, but are not limited to, aryl, oxadiazolyl, thiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridinyl, pyrrolopyrimidinyl, and azaindolyl. The heteroaryl groups may be C- or N-attached (where such is possible). For example, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).

[0078] "Hydroxyl" means --OH.

[0079] "Oxo" means =O.

[0080] "Sulfhydryl" means -SH.

[0081] "Cyano" means -CN.

[0082] "Thioalkoxy" and "thioalkyl" mean, respectively, --S-alkoxy and --S-alkyl, where alokoxy and alkyl are defined above.

[0083] "Pyrimidinyl" is a radical derived from a pyrimidine ring, whether substituted or unsubstituted. [ka]

[0084] "Dioxane" is a compound represented by the following structural formula: [ka]

[0085] As used herein, the term "acetal" refers to a moiety represented by the following structural formula: [ka] In the formula, "atom" means any atom, such as carbon or boron, that can form a covalent bond with two oxygen atoms, and the wavy lines represent the points of attachment to other atoms. A cyclic acetal moiety is an acetal in which "atom" forms a cyclic group with the two oxygen atoms to which it is attached. An example of a cyclic acetal moiety is a group represented by the following structural formula: [ka] It is.

[0086] As used herein, "inorganic base" refers to a base that does not contain an organic moiety. Examples include metals (NH +Examples of inorganic bases include hydroxides, phosphates, acetates, carbonates, and bicarbonates of cations such as Li, K, Na, K, Rb, Cs, Mg, Ca, Ba, Sr, etc. Additional examples include Na, K, or Cs carbonates or bicarbonates, phosphates, acetates, and hydroxides. Further examples of inorganic bases are quaternary ammonium salts. In some example embodiments, the inorganic base is CsOH or Cs2CO3.

[0087] An "organic base" is an organic base that acts as a base according to any one of the accepted definitions of a base (Arrhenius, Bronsted, or Lewis).

[0088] As used herein, "Pd catalyst" refers to any Pd-containing material, whether preformed or formed in situ by the addition of a Pd-containing material and another ligand, capable of facilitating the reaction between a compound represented by structural formula (II) and a compound represented by structural formula (III) to produce a compound represented by structural formula (VII). An example of such a catalyst is a Pd catalyst selected from chloro{[4-(N,N-dimethylamino)phenyl]di-t-butylphosphino}(2'-amino-1,1'-biphenyl-2-yl)palladium(II) or chloro(crotyl)[di-tert-butyl(4-dimethylaminophenyl)phosphine]palladium(II).

[0089] It is understood that the substituents and substitution patterns on the compounds of the present invention can be selected by those skilled in the art to provide compounds that are chemically stable and can be easily synthesized by techniques known in the art as well as by the methods described below. In general, the term "substituted", whether preceded by the term "optionally", means that one or more hydrogens of the specified moiety are replaced with a suitable substituent. Unless otherwise specified, an "optionally substituted group" can have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituents can be the same or different at all positions. Alternatively, an "optionally substituted group" can be unsubstitued.

[0090] Exemplary substituents on any alkyl, aryl or heteroaryl are -OH, -SH, nitro (-NO2), halogen, amino, cyano, C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C1-C 12 Alkoxy, C1-C 12 Haloalkyl, C1-C 12 Haloalkoxy and C1-C 12 thioalkoxy. Exemplary substituents on alkyl include the above substituents and oxo. In one embodiment, the substituents are amino groups having the formula -N(R)2, where each R is independently selected from hydrogen and C1-C4 alkyl.

[0091] Pharmaceutical Compositions In a sixth example embodiment, the present disclosure relates to a pharmaceutical composition comprising crystalline Form I of the compound represented by structural formula (VII) according to any one of the aspects of the third embodiment and a pharma- ceutically acceptable carrier. For example, the pharmaceutical composition comprises crystalline Form I of the compound represented by structural formula (VII), characterized by X-ray powder diffraction peaks at 2θ angles of 4.6°, 22.8°, 23.2°, and 24.4°, and a pharma- ceutically acceptable carrier.

[0092] The term "pharmaceutically acceptable carrier" refers to a non-toxic solvent, dispersant, excipient, adjuvant or other material that is mixed with an active ingredient to allow the formation of a pharmaceutical composition, i.e., a dosage form that can be administered to a subject. A "pharmaceutically acceptable carrier" should not destroy the activity of the compound with which it is formulated. Pharmaceutically acceptable carriers are well known in the art.

[0093] Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the pharmaceutical compositions of the present disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, protamine sulfate, disodium hydrogen phosphate, sodium hydrogen phosphate, sodium chloride, salts or electrolytes such as zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0094] The pharmaceutical compositions of the present disclosure can be administered orally, parenterally (including subcutaneously, intramuscularly, intravenously and intradermally), by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. In some embodiments, provided pharmaceutical compositions are administered orally.

[0095] The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraocular, intravitreal, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intraperitoneal, intralesional and intracranial injection or infusion techniques. In certain embodiments, the pharmaceutical composition is administered orally, subcutaneously, intraperitoneally or intravenously. The pharmaceutical composition of the present disclosure in sterile injectable form may be an aqueous or oily suspension. These suspensions may be formulated using suitable dispersing or wetting agents and suspending agents by techniques known in the art. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as solvents or suspending media.

[0096] The pharmaceutical compositions of the present disclosure may be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring, or coloring agents may also be added. In some embodiments, the oral formulations provided are formulated for immediate release or sustained / delayed release. In some embodiments, the compositions are suitable for buccal or sublingual administration, including tablets, lozenges, and pastilles. The compounds provided may be in microencapsulated form.

[0097] Specific pharma- ceutically acceptable carriers suitable for use in oral formulations such as tablets or capsules include, but are not limited to, microcrystalline cellulose (Avicel PH101), croscarmellose sodium (Ac-Di-Sol), Kollidon 30 powder (polyvinylpyrrolidone, povidone), colloidal silicon dioxide M5-P, magnesium stearate, microcrystalline cellulose (Avicel PH102), sodium lauryl sulfate (Kolliphor SLS Fine), and colloidal silicon dioxide M5-P. Each of the above listed carriers can be used alone or in any combination in the oral formulation.

[0098] Additional pharma- ceutically acceptable carriers suitable for use in oral formulations such as tablets or capsules include, but are not limited to, microcrystalline cellulose (Avicel PH112), crospovidone (polyplasdone XL-10), colloidal silicone dioxide (Cab-O-Sil M-5P), talc, starch, and calcium stearate.

[0099] The pharmaceutical compositions of this disclosure may also be administered by intranasal aerosol or inhalation.

[0100] The amount of crystalline Form I of the compound represented by structural formula (VII) in the pharmaceutical compositions of the present disclosure is such that it is effective to measurably treat or prevent a disorder associated with CRM1 activity in a subject. As used herein, the term "subject" can be a human subject or an animal.

[0101] The amount of crystalline Form I that can be combined with pharma- ceutically acceptable carrier materials to produce a pharmaceutical composition in a single dosage form will vary depending on the host treated and / or the particular mode of administration. In one embodiment, the pharmaceutical compositions should be formulated so that a dose of 0.01 to 200 mg of crystalline Form I of the compound represented by structural formula (VII) can be administered to a patient receiving these compositions. In another embodiment, the dose is about 0.5 to about 100 mg. Doses can be administered once a day or multiple times per day, once a week or multiple times per week (e.g., on days 1, 3, and 5) over a given treatment cycle.

[0102] It should also be understood that the specific dosage and treatment regimen for any particular subject (e.g., patient) will depend on a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician, as well as the severity of the particular disease being treated.

[0103] Upon improvement of the subject's condition, a maintenance dose of the pharmaceutical composition of the present disclosure may be administered if necessary. Thereafter, the dose or frequency of administration, or both, may be reduced as a function of symptoms to a level that maintains the improved condition when symptoms are alleviated to a desired level. However, the subject may require intermittent treatment on a long-term basis upon recurrence of disease symptoms.

[0104] Methods of Treatment and Use of Crystalline Form I and Pharmaceutical Compositions Containing Same Crystalline Form I of the compound represented by structural formula (VII) disclosed herein and pharmaceutical compositions comprising same are generally useful for inhibiting CRM1 and thus for treating one or more disorders associated with CRM1 activity. Thus, in a seventh embodiment, the present disclosure provides a method for treating a disorder associated with CRM1 activity, comprising administering to a subject in need thereof a therapeutically effective amount of crystalline Form I or a pharmaceutical composition comprising crystalline Form I and a pharma- ceutically acceptable carrier as described herein. Crystalline Form I and pharmaceutical compositions comprising same can be administered, for example, to cells in culture in vitro or ex vivo, or administered, for example, to a subject in vivo, to treat, prevent, and / or diagnose various disorders, including those described herein below.

[0105] The activity of crystalline Form I and pharmaceutical compositions containing it as inhibitors of CRM1 can be assayed in vitro, in vivo, or in a cell line. Detailed conditions for assaying inhibitors of CRM1, such as crystalline Form I of the compound represented by structural formula I, are described in WO 14 / 205389.

[0106] The term "treat" or "treating" means to alleviate the symptoms, remove the cause of the symptoms either temporarily or permanently, or prevent or slow the appearance of the symptoms of the named disorder or condition.

[0107] As used herein, the term "CRM1-mediated" disorder or condition or "disorder associated with CRM1 activity" refers to any disease or other deleterious condition in which CRM1 is known to play a role. Accordingly, another embodiment of the present disclosure relates to treating or reducing the severity of one or more diseases in which CRM1 is known to play a role. In some embodiments, the present disclosure provides a method of treating a disease associated with p53, p73, p21, pRB, p27, INB, NFNB, c-Abl, FOXO proteins, COX-2, or HDAC (histone deacetylase) expression or activity in a subject, comprising administering to the subject a therapeutically effective amount of crystalline Form I described herein. In another embodiment, the present disclosure relates to a method of treating or lessening the severity of a disease or condition selected from a proliferative disease (e.g., cancer), an inflammatory disease, an autoimmune disease, a viral infection, an ophthalmological disease, or a neurodegenerative disease, comprising administering to a patient in need thereof a pharmaceutical composition comprising crystalline Form I of a compound represented by structural formula (VII) or Form I and a pharma- ceutically acceptable carrier. In a more specific embodiment, the present disclosure relates to a method of treating or lessening the severity of cancer. Specific examples of the above disorders are described in detail below.

[0108] The term "therapeutically effective amount" refers to an amount of crystalline Form I of the compound represented by structural formula (VII) that is effective in treating or reducing the severity of one or more symptoms of a disorder or condition. In the case of promoting wound healing, a therapeutically effective amount is an amount that promotes wound healing.

[0109] As used herein, the term "prevention" or "prophylactic" refers to measures taken prior to the onset of a disease to prevent or increase resistance to a disease, as well as measures that ameliorate symptoms of a disease when taken prior to the onset of a disease. Prevention also includes measures taken to prevent the recurrence of a disease.

[0110] The term "prophylactically effective amount" means an amount of crystalline Form I of the compound represented by structural formula (VII) that is effective in preventing a condition treatable by the compound represented by structural formula (VII).

[0111] As used herein, "promoting wound healing" refers to treating a subject with a wound to achieve partial or complete wound healing. Promoting wound healing can mean, for example, one or more of the following: promoting epidermal closure; promoting dermal migration; promoting skin closure in the dermis; reducing wound healing complications such as epidermal hyperplasia and adhesion; reducing wound dehiscence; and promoting proper scab formation.

[0112] In some embodiments, the present disclosure relates to a method of promoting wound healing in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of crystalline Form I of the compound represented by Structural Formula (VII) or a pharmaceutical composition described herein.

[0113] Cancers treatable by the crystalline Form I of the compound represented by structural formula VII or pharmaceutical compositions described herein include, but are not limited to, hematological malignancies (leukemia, lymphoma, myeloma including multiple myeloma, myelodysplastic syndromes and myeloproliferative disorders) and solid tumors (carcinomas of the prostate, breast, lung, colon, pancreas, kidney, ovary, etc., as well as soft tissue and bone sarcomas, and stromal tumors). Breast cancer (BC) may include basal-like breast cancer (BLBC), triple-negative breast cancer (TNBC), and breast cancer that is both BLBC and TNBC. In addition, breast cancer may include invasive or non-invasive ductal or lobular carcinoma, ductal, medullary, mucinous, papillary, cribriform carcinoma of the breast, male breast cancer, recurrent or metastatic breast cancer, phyllodes tumor of the breast, and Paget's disease of the nipple. In one embodiment, the cancer is multiple myeloma.

[0114] Inflammatory diseases treatable by crystalline Form I of the compound represented by structural formula (VII) or pharmaceutical compositions described herein include, but are not limited to, multiple sclerosis, rheumatoid arthritis, degenerative joint disease, systemic lupus, systemic sclerosis, vasculitis syndromes (small, medium, and large vessels), atherosclerosis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, mucous colitis, ulcerative colitis, gastritis, sepsis, psoriasis and other inflammatory diseases of the skin (such as eczema, atopic dermatitis, contact dermatitis, urticaria, scleroderma, and skin diseases with an acute inflammatory component, pemphigus, pemphigoid, allergic dermatitis, etc.), and urticaria syndromes.

[0115] Viral diseases treatable with the crystalline Form I or pharmaceutical compositions of the compound represented by structural formula (VII) described herein include acute febrile pharyngitis, pharyngoconjunctival fever, epidemic keratoconjunctivitis, pediatric gastroenteritis, Coxsackie infections, infectious mononucleosis, Burkitt's lymphoma, acute hepatitis, chronic hepatitis, liver cirrhosis, hepatocellular carcinoma, primary HSV-1 infection (e.g., gingivostomatitis in children, tonsillitis and pharyngitis, keratoconjunctivitis in adults), subclinical HSV-1 infection (e.g., herpes labialis and herpes simplex), primary HSV-2 infection, subclinical HSV-2 infection, aseptic The diseases that can be treated with the compounds of the present disclosure include, but are not limited to, meningitis, infectious mononucleosis, giant cell inclusion disease, Kaposi's sarcoma, multicentric Castleman's disease, primary effusion lymphoma, AIDS, influenza, Reye's syndrome, measles, post-infectious encephalomyelitis, mumps, atypical proliferative lesions (e.g., common, flat, plantar and anogenital warts, laryngeal papillomas, epidermodysplasia verruciformis), cervical cancer, squamous cell carcinoma, croup, pneumonia, bronchiolitis, common cold, polio, rabies, influenza-like syndrome, severe bronchiolitis with pneumonia, rubella, congenital rubella, chickenpox, and shingles. Viral diseases that can be treated with the compounds of the present disclosure also include chronic viral infections, including hepatitis B and hepatitis C. Additionally, viral diseases treatable by the compounds of the present disclosure include infections caused by coronaviruses, such as SARS, MERS, and SARS-CoV-2.

[0116] Exemplary ophthalmic disorders treatable with crystalline Form I of the compound represented by structural formula (VII) or pharmaceutical compositions described herein include macular edema (diabetic and non-diabetic macular edema), wet and atrophic forms of age-related macular degeneration, aged disciform macular degeneration, cystoid macular edema, eyelid edema, retinal edema, diabetic retinopathy, chorioretinitis, neovascular maculopathy, neovascular glaucoma, uveitis, iritis, retinal vasculitis, endophthalmitis, panophthalmitis, metastatic ophthalmitis, choroiditis, retinal pigment epitheliitis, conjunctivitis, cyclitis, scleritis, episcleritis, optic neuritis, retrobulbar optic neuritis, keratoconjunctiv ... These include, but are not limited to, uveitis, blepharitis, exudative retinal detachment, corneal ulcer, conjunctival ulcer, chronic nummular keratitis, eye disease associated with hypoxia or ischemia, retinopathy of prematurity, proliferative diabetic retinopathy, polypoidal choroidal vasculopathy, retinal angiomatous proliferation, retinal artery occlusion, retinal vein occlusion, Coats' disease, familial exudative vitreoretinopathy, pulseless disease (Takayasu's disease), Eales' disease, antiphospholipid syndrome, leukemic retinopathy, blood hyperviscosity syndrome, macroglobulinemia, interferon-associated retinopathy, hypertensive retinopathy, radiation retinopathy, corneal epithelial stem cell deficiency, or cataract.

[0117] Neurodegenerative diseases treatable by crystalline Form I of the compound represented by structural formula (VII) or pharmaceutical compositions described herein include, but are not limited to, Parkinson's disease, Alzheimer's disease, and Huntington's disease, and amyotrophic lateral sclerosis (ALS / Lou Gehrig's disease).

[0118] Crystalline Form I of the compound represented by structural formula (VII) or pharmaceutical compositions described herein may also be used to treat disorders of abnormal tissue proliferation and fibrosis, including dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, pulmonary fibrosis, hepatic fibrosis, glomerulonephritis, polycystic kidney disease (PKD), and other renal disorders.

[0119] Crystalline Form I of the compound represented by structural formula (VII) or pharmaceutical compositions described herein may also be used to treat eating-related disorders, such as obesity and hyperphagia.

[0120] In another embodiment, the crystalline Form I of the compound represented by structural formula (VII) or pharmaceutical compositions described herein can be used to treat or prevent allergies and respiratory diseases, including asthma, bronchitis, pulmonary fibrosis, allergic rhinitis, oxygen toxicity, emphysema, chronic bronchitis, acute respiratory distress syndrome, and any chronic obstructive pulmonary disease (COPD).

[0121] In some embodiments, the disorder or condition associated with CRM1 activity and treatable by crystalline Form I of the compound represented by structural formula (VII) is β-thalassemia, muscular dystrophy, arthritis, e.g., osteoarthritis and rheumatoid arthritis, ankylosing spondilitis, traumatic brain injury, spinal cord injury, sepsis, rheumatic diseases, cancer. Atherosclerosis, type 1 diabetes, type 2 diabetes, leptospirosis, kidney disease, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, ischemia / reperfusion, stroke, cerebral aneurysm, angina, lung disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, asthma, chronic obstructive pulmonary disease, Sjogren's syndrome, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, intestinal disease, peritoneal endometriosis, skin disease, nasal sinusitis, mesothelioma, anhidrotic ecodermal dysplasia dysplasia-ID, Behcet's disease, incontinentia pigmenti, tuberculosis, asthma, Crohn's disease, colitis, eye allergies, appendicitis, Paget's disease, pancreatitis, periodontitis, endometriosis, inflammatory bowel disease, inflammatory lung disease, silica-induced disease, sleep apnea, AIDS, HIV-1, autoimmune diseases, antiphospholipid syndrome, lupus, lupus nephritis, familial Mediterranean fever, hereditary periodic fever syndromes, psychosocial stress disorders, neuropathological disorders, familial amyloid polyneuropathy, inflammatory neuropathy, Parkinson's disease, multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, cataracts, or hearing loss.

[0122] In other embodiments, the disorder or condition associated with CRM1 activity is head injury, uveitis, inflammatory pain, allergen-induced asthma, non-allergen-induced asthma, glomerulonephritis, ulcerative colitis, necrotizing enterocolitis, hyperimmunoglobulin D syndrome with recurrent fever (HIDS), TNF receptor-associated periodic syndrome (TRAPS), cryopyrin-associated periodic syndrome, Muckle-Wells syndrome (urticaria deafness amyloidosis), familial cold urticaria, neonatal-onset multisystem inflammatory disease (NOMID), periodic fever, aphthous stomatitis, pharyngitis and adenitis (P FAPA syndrome), Blau syndrome, suppurative sterile arthritis, pyoderma acne gangrenosum (PAPA), interleukin-1-receptor antagonist deficiency (DIRA), subarachnoid hemorrhage, polycystic kidney disease, transplant, organ transplant, tissue transplant, myelodysplastic syndrome, irritant-induced inflammation, plant irritant-induced inflammation, poison ivy / urushiol oil-induced inflammation, chemical irritant-induced inflammation, bee sting-induced inflammation, insect bite-induced inflammation, sunburn, thermal injury, dermatitis, endotoxemia, lung injury, acute respiratory distress syndrome, alcoholic hepatitis, or kidney damage caused by parasitic infection.

[0123] In a further aspect, the disclosure relates to the use of crystalline Form I or a pharmaceutical composition of the compound represented by structural formula (VII) described herein for the manufacture of a medicament for the treatment of a disorder associated with CRM1 activity. The disclosure also relates to crystalline Form I or a pharmaceutical composition described herein for use in the treatment of a disorder associated with CRM1 activity. Specific examples of disorders associated with CRM1 activity are described in detail herein.

[0124] In yet a further aspect, the disclosure relates to the use of crystalline Form I or a pharmaceutical composition of the compound represented by structural formula (VII) described herein for the manufacture of a medicament for the treatment of a disease associated with expression or activity of p53, p73, p21, pRB, p27, INB, NFNB, c-Abl, FOXO proteins, COX-2 or HDAC in a subject. In some embodiments, the disclosure relates to the use of crystalline Form I or a pharmaceutical composition described herein in the manufacture of a medicament for the treatment of any of cancer and / or neoplastic diseases, angiogenesis, autoimmune diseases, inflammatory disorders and / or diseases, epigenetics, hormonal disorders and / or diseases, viral diseases, neurodegenerative disorders and / or diseases, wounds, and ophthalmological disorders.

[0125] In some embodiments, the present disclosure relates to a method of inhibiting CRM1 in a biological sample, comprising contacting the biological sample with crystalline Form I of the compound represented by Structural Formula (VII) or a pharmaceutical composition described herein, or administering to a patient crystalline Form I of the compound represented by Structural Formula (VII) or a pharmaceutical composition described herein.

[0126] Neoplastic diseases The crystalline Form I or pharmaceutical composition of the compound represented by structural formula (VII) described herein can be used to treat neoplastic disease. A "neoplastic disease" is a disease or disorder characterized by cells having the capacity for autonomous growth or replication, e.g., an abnormal state or condition characterized by proliferative cell growth. Exemplary neoplastic diseases include carcinomas, sarcomas, metastatic disorders, e.g., tumors arising from prostate, brain, bone, colon, lung, breast, ovary, and liver origin, hematopoietic neoplastic disorders, e.g., leukemia, lymphoma, myeloma, and other malignant plasma cell disorders, and metastatic tumors. Common cancers include breast cancer, prostate cancer, colon cancer, lung cancer, liver cancer, and pancreatic cancer. Treatment with the compound can be in an amount effective to improve at least one symptom of the neoplastic disorder, e.g., reduce cell proliferation, reduce tumor burden, etc.

[0127] The crystalline Form I or pharmaceutical compositions of the compound represented by structural formula (VII) described herein are useful, for example, in the prevention and treatment of cancer, including solid tumors, soft tissue tumors, and metastases thereof, and in familial cancer syndromes, such as Li-Fraumeni syndrome, familial breast-ovarian cancer (BRCA1 or BRAC2 mutation) syndrome. The crystalline Form I or pharmaceutical compositions described herein are also useful in the treatment of non-solid cancers. Exemplary solid tumors include malignant tumors (e.g., sarcomas, adenocarcinomas, and carcinomas) of various organ systems, such as those of the lung, breast, lymphatic, gastrointestinal (e.g., colon), and genitourinary (e.g., renal, urothelial, or testicular) tract, pharynx, prostate, and ovary. Exemplary adenocarcinomas include colorectal cancer, renal cell carcinoma, liver cancer, non-small cell carcinoma of the lung, and cancer of the small intestine.

[0128] Exemplary cancers as described by the National Cancer Institute include acute lymphoblastic leukemia, adult; acute lymphoblastic leukemia, childhood; acute myeloid leukemia, adult; adrenal cortical carcinoma; adrenal cortical carcinoma, childhood; AIDS-related lymphoma; AIDS-related malignancies; anal cancer; astrocytoma, childhood cerebellar; astrocytoma, childhood cerebral; cholangiocarcinoma, extrahepatic; bladder cancer; bladder cancer, childhood; bone cancer, osteosarcoma / malignant fibrous histiocytoma; brain stem glioma, childhood; brain tumor, adult; brain tumor, brain stem glioma, childhood; brain tumor, cerebellar astrocytoma, childhood; brain tumor, cerebral astrocytoma / malignant glioma, childhood;brain tumor, ependymoma, childhood;brain tumor, medulloblastoma, childhood;brain tumor, supratentorial primitive neuroectodermal tumor, childhood;brain tumor, visual pathway and hypothalamic glioma, childhood;brain tumor, childhood (other);breast cancer;breast cancer and pregnancy;breast cancer, childhood;breast cancer, male;bronchial adenoma / carcinoid, childhood;carcinoid tumor, childhood;carcinoid tumor, gastrointestinal;carcinoma, adrenal cortex;carcinoma, islet cell;cancer of unknown primary;central nervous system lymphoma, primary;cerebellar astrocytoma, childhood;cerebral astrocytoma / malignant glioma, childhood;cervical cancer;childhood cancer;chronic lymphocytic leukemia;chronic myeloid Leukemia;Chronic myeloproliferative disorders;Clear cell sarcoma of tendon sheath;Colon cancer;Colorectal cancer, childhood;Cutaneous T-cell (T-ceIl) lymphoma;Endometrial cancer;Ependymoma, childhood;Epithelial carcinoma, ovary;Esophageal cancer;Esophageal cancer, childhood;Ewing family tumors;Extracranial germ cell tumors, childhood;Extragonadal germ cell tumors;Extrahepatic bile duct carcinoma;Eye cancer, intraocular melanoma;Eye cancer, retinoblastoma;Gallbladder cancer;Gastric (stomach) cancer;Gastric (stomach) cancer, childhood;Gastrointestinal carcinoid tumors;Germ cell tumors, extracranial, childhood;Germ cell tumors, extragonadal;Embryonic Cell tumors, ovarian;Gestational trophoblastic tumor;Glioma, childhood brain stem;Glioma, childhood visual pathway and hypothalamus;Hairy cell leukemia;Head and neck cancer;Hepatocellular (liver) carcinoma, adult (primary);Hepatocellular (liver) carcinoma, childhood (primary);Hodgkin's lymphoma, adult;Hodgkin's lymphoma, childhood;Hodgkin's lymphoma during pregnancy;Hypopharyngeal carcinoma;Hypothalamic and visual pathway glioma, childhood;Intraocular melanoma;Islet cell carcinoma (endocrine pancreas);Kaposi's sarcoma;Kidney cancer;Laryngeal cancer;Laryngeal cancer, childhood;Leukemia, acute lymphoblastic, adult;Leukemia, acute lymphoblastic, childhood;Leukemia, acute myeloid, adult;Leukemia, acute myeloid, childhood;Leukemia, chronic lymphocytic;Leukemia, chronic myeloid;Leukemia, hairy cell;Oral and labial cancer;Liver cancer, adult (primary);Liver cancer, childhood (primary);Lung cancer, non-small cell;Lung cancer, small cell;Lymphoblastic leukemia, adult acute;Lymphoblastic leukemia, childhood acute;Lymphocytic leukemia, chronic;Lymphoma, AIDS-related;Lymphoma, central nervous system (primary);Lymphoma, cutaneous T-cell;Lymphoma, Hodgkin, adult;Lymphoma, Hodgkin, childhood;Lymphoma, Hodgkin during pregnancy;Lymphoma, non-Hodgkin, adult;Lymphoma, non-Hodgkin, childhood;Lymphoma, pregnancy Non-Hodgkin's during pregnancy;Lymphoma, primary central nervous system;Macroglobulinemia, Waldenstrom;Male breast cancer;Malignant mesothelioma, adult;Malignant mesothelioma, childhood;Malignant thymoma;Medulloblastoma, childhood;Melanoma;Melanoma, intraocular;Merkel cell carcinoma;Mesothelioma, malignant;Metastatic squamous neck cancer of unknown primary;Multiple endocrine neoplasia syndrome, childhood;Multiple myeloma / plasma cell neoplasm;Mycosis fungoides;Myelodysplastic syndrome;Myeloid leukemia, chronic;Myeloid leukemia, acute childhood;Myeloma, multiple;Myeloproliferative disorders, chronic;Cancer of the nasal cavity and paranasal sinuses;Nasopharyngeal carcinoma;Nasopharyngeal carcinoma, childhood;Neuroblastoma; Non-Hodgkin's lymphoma, adult;Non-Hodgkin's lymphoma, childhood;Non-Hodgkin's lymphoma during pregnancy;Non-small cell lung cancer;Oral cavity cancer, childhood;Cancer of the oral cavity and lip;Oropharyngeal cancer;Osteosarcoma / malignant fibrous histiocytoma of bone;Ovarian cancer, childhood;Ovarian epithelial cancer;Ovarian germ cell tumor;Ovarian low malignant potential tumor;Pancreatic cancer;Pancreatic cancer, childhood;Pancreatic islet cell cancer;Sino-nasal and nasal cancer;Parathyroid cancer;Penile cancer;Pheochromocytoma;Pineal and supratentorial primitive neuroectodermal tumors, childhood;Pituitary tumors;Plasma cell neoplasms / multiple myeloma;Pleuropulmonary blastoma;Pregnancy and breast cancer;Pregnancy and Hodgkin's lymphoma;Pregnancy and non-Hodgkin's lymphoma;Primary Central nervous system lymphoma;Primary liver cancer, adult;Primary liver cancer, childhood;Prostate cancer;Rectal cancer;Renal cell (kidney) cancer;Renal cell carcinoma, childhood;Renal pelvis and ureter, transitional cell carcinoma;Retinoblastoma;Rhabdomyosarcoma, childhood;Salivary gland cancer;Salivary gland cancer, childhood;Sarcoma, Ewing family tumor;Sarcoma, Kaposi;Sarcoma (osteosarcoma) / malignant fibrous histiocytoma of bone;Sarcoma, rhabdomyosarcoma, childhood;Sarcoma, soft tissue, adult;Sarcoma, soft tissue, childhood;Sezary syndrome;Skin cancer;Skin cancer, childhood;Skin cancer (melanoma);Skin cancer, Merkel cell;Small cell lung cancer;Small intestine cancer;Soft tissue sarcoma, adult;Soft tissue sarcoma, childhood;Squamous cell neck cancer of unknown primary site, metastatic;gastric (stomach) cancer;gastric (stomach) cancer, childhood;supratentorial primitive neuroectodermal tumor, childhood;T-cell lymphoma, skin;testicular cancer;thymoma, childhood;thymoma, malignant;thyroid cancer;thyroid cancer, childhood;transitional cell carcinoma of the renal pelvis and ureter;trophoblastic tumor, gestational;cancer of unknown primary site, childhood;rare cancers of childhood;ureter and renal pelvis, transitional cell carcinoma;urethral cancer;uterine sarcoma;vaginal cancer;optic pathway and hypothalamic glioma, childhood;vulvar cancer;Waldenstrom macroglobulinemia;and Wilms' tumor.

[0129] Further exemplary cancers include diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL).Still further exemplary cancers include cervical cancer, B-cell ALL, T-cell ALL, B or T cell lymphoma, mast cell carcinoma, glioblastoma, neuroblastoma, follicular lymphoma, and Richter's syndrome.

[0130] Exemplary sarcomas include fibrosarcoma, alveolar soft part sarcoma (ASPS), liposarcoma, leiomyosarcoma, chondrosarcoma, synovial sarcoma, chordoma, spindle cell sarcoma, histiocytoma, rhabdomyosarcoma, Ewing's sarcoma, neuroectodermal sarcoma, phyllodes / osteogenic sarcoma, and chondroblastic osteosarcoma.

[0131] Metastasis of the above-mentioned cancers can also be treated or prevented according to the methods described herein.

[0132] In various example embodiments, the crystalline Form I of the compound represented by structural formula (VII) described herein, or the pharmaceutical composition, can be used to treat a disorder selected from colorectal cancer, prostate cancer, myelodysplastic syndrome, inflammatory bowel disease, nasopharyngeal carcinoma, and penile cancer.

[0133] Combination therapy In some embodiments, the crystalline Form I or pharmaceutical composition of the compound represented by structural formula (VII) described herein is administered with an additional "second" therapeutic agent or treatment. The selection of the second therapeutic agent can be made from any agent typically used in monotherapy to treat the indicated disease or condition. As used herein, the term "co-administered" and related terms refer to the simultaneous or sequential administration of a therapeutic agent to a subject in need thereof to treat one or more indications described herein. For example, the crystalline Form I or pharmaceutical composition described herein can be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms, or in a single unit dosage form. Thus, the present disclosure relates to a single unit dosage form comprising the crystalline Form I or pharmaceutical composition described herein, an additional therapeutic agent, and a pharmaceutically acceptable carrier.

[0134] In one embodiment of the present disclosure, when a second therapeutic agent is administered to a subject, the effective amount of crystalline Form I of the compound represented by structural formula (VII) is less than its effective amount when the second therapeutic agent is not administered. In another embodiment, the effective amount of the second therapeutic agent is less than its effective amount when crystalline Form I of the compound represented by structural formula (VII) is not administered. In this manner, undesirable side effects associated with high dosages of either agent can be minimized. Other potential advantages (including, but not limited to, improved dosing regimens and / or reduced drug costs) will be apparent to those skilled in the art. The additional agents can be administered as part of a multiple dose regimen, separately from crystalline Form I of the compound represented by structural formula (VII) or pharmaceutical compositions described herein. Alternatively, the agents can be mixed with crystalline Form I or pharmaceutical compositions described herein to be part of a single dosage form.

[0135] In certain embodiments, the crystalline Form I of the compound represented by structural formula (VII) or pharmaceutical compositions described herein may be administered alone or in combination with other compounds useful for treating or preventing inflammation. Exemplary anti-inflammatory agents include, for example, steroids (e.g., cortisol, cortisone, fludrocortisone, prednisone, 6α-methylprednisone, triamcinolone, betamethasone, or dexamethasone), nonsteroidal anti-inflammatory drugs (NSAIDS (e.g., aspirin, acetaminophen, tolmetin, ibuprofen, mefenamic acid, piroxicam, nabumetone, rofecoxib, celecoxib, etodolac, or nimesulide). In another embodiment, the other therapeutic agent is an antibiotic (e.g., vancomycin, penicillin, amoxicillin, ampicillin, cefotaxime, ceftriaxone, cefixime, rifampin, metronidazole, doxycycline, or streptomycin). In another embodiment, In one embodiment, the other therapeutic agent is a PDE4 inhibitor (e.g., roflumilast or rolipram). In another embodiment, the other therapeutic agent is an antihistamine (e.g., cyclizine, hydroxyzine, promethazine, or diphenhydramine). In another embodiment, the other therapeutic agent is an antimalarial (e.g., artemisinin, artemether, artsunate, chloroquine phosphate, mefloquine hydrochloride, doxycycline hyclate, proguanil hydrochloride, atovaquone, or halofantrine). In one embodiment, the other compound is drotrecogin alpha. In a specific embodiment, the crystalline Form I or pharmaceutical composition of the compound represented by structural formula (VII) described herein is administered in combination with dexamethasone.

[0136] Further examples of anti-inflammatory agents include, for example, aceclofenac, acemetacin, e-acetamidocaproic acid, acetaminophen, acetaminosalol, acetanilide, acetylsalicylic acid, S-adenosylmethionine, alclofenac, alclometasone, alfentanil, algestone, allylprozin, aluminoprofen, aloxypurine, alphaprozin, aluminum bis(acetylsalicylate), amcinonide, amfenac, aminochlorthenoxazine, 3-amino-4-hydroxybutyric acid, 2-amino-4-picoline, amine, Nopropyrone, aminopyrine, amixetrine, ammonium salicylate, ampiroxicam, amtolmetin guacil, anileridine, antipyrine, anthraphenine, apazone, beclomethasone, bendazac, benolylate, benoxaprofen, benzpiperylon, benzydamine, benzylmorphine, bermoprofen, betamethasone, betamethasone-17-valerate, bezitramide, α-bisabolol, bromfenac, p-bromoacetanilide, 5-bromosalicylic acid acetate, bromosaligenin, bucetin, bucloxic acid, buclofenac ... Bucolome, budesonide, bufexamac, bumadizone, buprenorphine, butacetin, butibufen, butorphanol, carbamazepine, carbifen, caiprofen, carsalam, chlorobutanol, chloroprednisone, chlortenoxazine, choline salicylate, cinchophen, cinmetacin, ciramadol, clidanac, clobetasol, clocortolone, clometacin, clonitazene, clonixin, clopirac, cloprednol, clove, codeine, codeine methyl bromide, codeine phosphate, codeine sulfate , cortisone, cortivazol, clopropamide, clottethamide, cyclazocine, deflazacort, dehydrotestosterone, desomorphine, desonide, desoximetasone, dexamethasone, dexamethasone-21-isonicotinate, dexoxadrol, dextromoramide, dextropropoxyphene, deoxycorticosterone, dezocine, diampromide, diamorphone, diclofenac, difenamizole, difenpyramide, diflorasone, diflucortolone, diflunisal, difluprednate,Dihydrocodeine, dihydrocodeinone enol acetate, dihydromorphine, dihydroxyaluminum acetylsalicylate, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, diprocetyl, dipyrone, ditazol, droxicam, emorfazone, enfenamic acid, enoxolone, epirizole, eptazocine, etersalate, ethenzamide, ethoheptadine, ethoxazene, ethylmethylthiambutene, ethylmorphine, etodolac, etofenamate , etonitazene, eugenol, felbinac, fenbufen, fenclozate, fendosal, fenoprofen, fentanyl, fentiazac, feprazinol, feprazone, floctafenine, fluazacort, flucloronide, flufenamic acid, flumethasone, flunisolide, flunixin, flunoxaprofen, fluocinolone acetonide, fluocinonide, fluocinolone acetonide, fluocortin butyl, fluocoitolone, fluorescein, fluorometholone, fluperolone, flupirtine , fluprednidene, fluprednisolone, fluproquazone, flurandrenolide, flurbiprofen, fluticasone, formocortal, fosfosal, gentisic acid, glafenine, glucamethacin, glycol salicylate, guaiazulene, halcinonide, halobetasol, halometasone, haloprednone, heroin, hydrocodone, hydrocortamate, hydrocortisone, hydrocortisone acetate, hydrocortisone succinate, hydrocortisone hemisuccinate, hydrocortisone 21 -lysinate, hydrocortisone cypionate, hydromorphone, hydroxypethidine, ibufenac, ibuprofen, ibuproxam, imidazole salicylate, indomethacin, indoprofen, isofezolac, isoflupredone, isoflupredone acetate, isoladol, isomethadone, isonixin, isoxepac, isoxicam, ketobemidone, ketoprofen, ketorolac, p-lactophenetide, lefetamine, levallorphan, levorphanol, levophenacylmorphan, lofentanil,lonazolac, lornoxicam, loxoprofen, lysine acetylsalicylate, mazipredone, meclofenamic acid, medrysone, mefenamic acid, meloxicam, meperidine, meprednisone, meptazinol, mesalamine, metazosine, methadone, methotrimeprazine, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, methylprednisolone suleptnate, metiazinic acid, metofolin, metopon, mofebutazone, mofezolac, mometasone, morazone, mo rufin, morphine hydrochloride, morphine sulfate, morpholine salicylate, myrofin, nabumetone, nalbuphine, nalorphine, 1-naphthyl salicylate, naproxen, narceine, nefopam, nicomorphine, nifenazone, niflumic acid, nimesulide, 5'-nitro-2'-propoxyacetanilide, norlevorphanol, normethadone, normorphine, norpipanone, olsalazine, opium, oxaceprol, oxamethacin, oxaprozin, oxycodone, oxymorphone, oxyphenbutazone, papaveretam, paramethasone, paranyline, Parsalmid, pentazocine, perisoxal, phenacetin, phenadoxone, phenazocine, phenazopyridine hydrochloride, fenocol, phenoperidine, phenopyrazone, phenomorphan, phenyl acetylsalicylate, phenylbutazone, phenyl salicylate, phenylamidol, piketoprofen, piminodine, pipebuzone, piperylone, pyrazolac, piritramide, piroxicam, pirprofen, pranoprofen, prednicarbate, prednisolone, prednisone, prednibal, prednylidene, proglumetacin, prohept Tadine, Promedol, Propacetamol, Properidine, Propiram, Propoxyphene, Propyphenazone, Proquazone, Protizinic acid, Proxazole, Ramifenazone, Remifentanil, Rimazolium methylsulfate, Salacetamide, Salicin, Salicylamide, Salicylamide o-acetate, Salicylic acid, Salicylsulfate, Salsalate, Salverine, Simetride, Sufentanil, Sulfasalazine, Sulindac, Superoxide dismutase, Suprofen, Suxibuzone, Talniflumate, Tenidap, Tenoxicam, Terofenamate,Tetrandrine, thiazolinobutazone, tiaprofenic acid, tiaramide, tilidine, tinoridine, tixocortol, tolfenamic acid, tolmetin, tramadol, triamcinolone, triamcinolone acetonide, tropesin, viminol, xenbucin, xymoprofen, zaltoprofen, and zomepirac.

[0137] In one embodiment, the crystalline Form I or pharmaceutical composition of the compound represented by structural formula (VII) described herein may be administered with a selective COX-2 inhibitor to treat or prevent inflammation. Exemplary selective COX-2 inhibitors include, for example, deracoxib, parecoxib, celecoxib, valdecoxib, rofecoxib, etoricoxib, and lumiracoxib.

[0138] In some embodiments, the crystalline Form I or pharmaceutical composition of the compound represented by structural formula VII described herein is administered in combination with an anthracycline or a Topo II inhibitor. In certain embodiments, the crystalline Form I or pharmaceutical composition of the compound represented by structural formula (VII) described herein is administered in combination with doxorubicin (Dox). In certain embodiments, the crystalline Form I or pharmaceutical composition of the compound represented by structural formula (VII) described herein is administered with bortezomib (and more broadly including carfilzomib).

[0139] Cancer Combination Therapy In some embodiments, the crystalline Form I of the compound represented by structural formula (VII) described herein or pharmaceutical compositions (e.g., in pharmaceutical compositions described herein) are administered together with an additional cancer treatment. Exemplary additional cancer treatments include, for example, chemotherapy, targeted therapy such as antibody therapy, kinase inhibitors, immunotherapy, and hormonal therapy, epigenetic therapy, proteosome inhibitors, and antiangiogenic therapy. Examples of each of these treatments are provided below. As used herein, the terms "combination," "concomitant," and related terms refer to simultaneous or sequential administration of therapeutic agents according to the present disclosure. For example, the crystalline Form I of the compound represented by structural formula (VII) can be administered together with another therapeutic agent in separate unit dosage forms, simultaneously or sequentially, or together in a single unit dosage form. Thus, the present disclosure provides a single unit dosage form comprising the crystalline Form I of the compound represented by structural formula (VII), an additional therapeutic agent, and a pharmaceutically acceptable carrier.

[0140] The amount of both crystalline Form I of the compound of structural formula (VII) and additional therapeutic agent (in pharmaceutical compositions containing additional therapeutic agents as described above) that can be combined with carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. Preferably, the pharmaceutical compositions of the present disclosure should be formulated to allow administration of a dose of 0.01 to 200 of crystalline Form I of the compound of structural formula (VII).

[0141] chemotherapy In some embodiments, the crystalline Form I of the compound represented by structural formula (VII) or pharmaceutical compositions described herein can be co-administered with chemotherapy. Chemotherapy is the treatment of cancer with drugs capable of destroying cancer cells. "Chemotherapy" generally refers to cytotoxic agents that affect rapidly dividing cells in general, as opposed to targeted therapy. Chemotherapy drugs potentially interfere with cell division, such as with DNA replication or the separation of newly formed chromosomes, in a variety of ways. Most forms of chemotherapy target all rapidly dividing cells and are not specific to cancer cells, although some specificity may arise from the fact that many cancer cells are unable to repair DNA damage, while normal cells are able to repair DNA damage.

[0142] Examples of chemotherapeutic agents used in cancer therapy include, for example, antimetabolites (e.g., folic acid, purine, and pyrimidine derivatives) and alkylating agents (e.g., nitrogen mustards, nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes, aziridines, spindle inhibitors, cytotoxic agents, topoisomerase inhibitors, and others). Exemplary agents include aclarubicin, actinomycin, alitretinoin, altretamine, aminopterin, aminolevulinic acid, amrubicin, amsacrine, anagrelide, arsenic trioxide, asparaginase, atrasentan, belotecan, bexarotene, bendamustine, bleomycin, bortezomib, busulfan, camptothecin, capecitabine, carboplatin, carboquone, carfilzomib, carmofur, carmustine, celecoxib, cetuximab, chlorambucil, chlormethine, CHOEP-21, CHOP, cisplatin, cladribine, clofarabine, crisantaspase, cyclophosphamide, cytarabine or ara-C, dacarbazine, dactinomycin, DAEPOCH, daratumumab, daunorubicin, decitabine, demecolcine, dexamethasone, docetaxel, doxorubicin, efaproxiral, elesclomol, elsamitrucin, enocitabine, epirubicin, eribulin, estramustine, etoglucide, etoposide, FLAG (Flu+Cyt), floxuridine, fludarabine, fluorouracil (5FU), FOLFOX, fotemustine, gemcitabine, gemcitabine-oxaliplatin (GemOx), Gliadel implant, hydroxycarbamide, hydroxyurea, ibrutinib, idarubicin, ifosfamide, irinotecan, irofulven, ixabepilone, ixazomib, larotaxel, lenalidomide, leucovorin, liposomal doxorubicin, liposomal daunorubicin Rubicin, lonidamine, lomustine, lucantone, mannosulfan, masoprocol, melphalan, mercaptopurine, mesna, methotrexate, methyl aminolevulinate, mitobronitol, mitoguazone, mitotane, mitomycin, mitoxantrone, nab-paclitaxel, nedaplatin, nimustine, oblimersen, omacetaxine, ortataxel, oxaliplatin, paclitaxel, pegaspargase, pemetrexed, pentostatin, pirarubicin, pixantrone, PLD (pegylated liposomal doxorubicin), plicamycin, pomalidomide, porfimer sodium, prednimustine, procarbazine, raltitrexed, ranimustine, R-CHOP, r-dhaox, r-dhap, rituximab, romidepsinRubitecan, Sapacitabine, Semustine, Citigene Seradenovec, Sorafonib, Strataplatin, Streptozocin, Talaporfin, Tegafur-uracil, Temoporfin, Temozolomide, Teniposide, Tesetaxel, Testolactone, Tetranitrate, Thiotepa, Tiazofurin, Thioguanine, Tipifarnib, Topotecan, Trabectedin, Triaziquone, Triethylenemelamine, Triplatin, Tretinoin, Treosulfan, Trofosfamide, Uramustine, Valrubicin, Verteporfin, Vinblastine, Vincristine, Vindesine, Vinflunine, Vinorelbine, Vorinostat, Zorubicin, and other cytostatic or cytotoxic agents described herein.

[0143] Targeted therapy The crystalline form I or pharmaceutical composition of the compound represented by structural formula (VII) described herein may be used in combination with or as part of targeted therapy. Targeted therapy constitutes the use of drugs that are specific to a target of interest (e.g., a deregulated protein) in cancer cells. Small molecule targeted therapy drugs are generally inhibitors of enzyme domains on proteins that are mutated, overexpressed, or otherwise critical in cancer cells. Prominent examples are tyrosine kinase inhibitors such as axitinib, bosutinib, cediranib, desatinib, erolotinib, imatinib, gefitinib, lapatinib, lestaurtinib, nilotinib, semaxanib, sorafenib, sunitinib, and vandetanib, and cyclin-dependent kinase inhibitors such as alvocidib and seliciclib. Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody that specifically binds to a protein on the surface of cancer cells. Examples include the anti-HER2 / neu antibody trastuzumab (Herceptin®), typically used in breast cancer, and the anti-CD20 antibodies rituximab and tositumomab, typically used in various B-cell malignancies. Other exemplary antibodies include cetuximab, panitumumab, trastuzumab, alemtuzumab, bevacizumab, edrecolomab, and gemtuzumab. Exemplary fusion proteins include aflibercept and denileukin diftitox. In some embodiments, targeted therapies, such as Gleevec (Vignari and Wang 2001), can be used in combination with the pharmaceutical compositions described herein.

[0144] Targeted therapies may also include small peptides as "homing devices" that can bind to cell surface receptors around tumors or to the affected extracellular matrix. Radionuclides attached to these peptides (e.g., RGD) ultimately kill cancer cells when the nuclides decay near the cells. An example of such a therapy is BEXXAR®.

[0145] A process for preparing a compound represented by structural formula (VII) (compound 5): Referring to Figure 1, a general reaction scheme of one embodiment of the present invention is shown. In step 1, compound 1 is amidated. In step 2, two telescoping reactions convert compound 2 to dibrominated compound 3, followed by dehydrobromination of 3 to compound 4. In step 3, Suzuki coupling between compound 4 and a compound represented by structural formula (IIIB) produces compound 5.

[0146] Crystalline form of the compound represented by structural formula (VII) (Compound 5): 20-26, characterization data for crystalline Forms I and II of the compound represented by structural formula (VII) (also referred to herein as Compound 5 or Compound MB6, and also referred to in the art as Ertanexor or KPT-8602) are shown. Such data include X-ray powder diffraction (XRPD) patterns, differential scanning calorimetry (DSC) thermograms, thermogravimetric analysis (TGA) thermograms, and dynamic vapor sorption (DVS) patterns. A description of how each form was isolated and the techniques used to generate the characterization data is provided below.

[0147] General Materials and Methods for Characterization of Crystalline Morphology XRPD According to USP guidelines, variable hydrates and solvates may exhibit peak dispersions greater than 0.2 degrees 2θ, and therefore the peak dispersion of 0.2 degrees 2θ does not apply to these materials.

[0148] "Significant peaks" are a subset of the entire list of observed peaks. Significant peaks are preferably selected from the observed peaks by identifying non-overlapping low angle peaks that have high intensity.

[0149] When multiple diffraction patterns are available, evaluation of particle statistics (PS) and / or preferred orientation (PO) is possible. Reproducibility between XRPD patterns of multiple samples analyzed with one diffractometer indicates sufficient particle statistics. Agreement of relative intensities between XRPD patterns from multiple diffractometers indicates good orientation statistics. Alternatively, observed XRPD patterns can be compared to calculated XRPD patterns based on crystal structures, if available. Two-dimensional scattering patterns using an area detector can also be used to evaluate PS / PO. If both PS and PO contributions are determined to be negligible, the XRPD pattern can be representative of the powder average intensity of the sample, and prominent peaks can be identified as "representative peaks". In general, the more data collected to determine representative peaks, the more confidence can be placed in the classification of those peaks.

[0150] "Characteristic peaks", to the extent they exist, are a subset of the representative peaks that are used to distinguish one crystalline polymorph from another (polymorphs that are crystalline forms having the same chemical composition). Characteristic peaks are determined by assessing which representative peaks, if any, are present in a crystalline polymorph of a compound relative to all other known crystalline polymorphs of the compound within ±0.2° 2θ. Not all crystalline polymorphs of a compound necessarily have at least one characteristic peak.

[0151] X-ray powder diffraction patterns were collected on a Bruker AXS C2 GADDS diffractometer using Cu Kα radiation (40 kV, 40 mA), an automated XYZ stage, a laser video microscope for automated sample positioning, and a HiStar 2D area detector. The X-ray optics consisted of a single Goebel multilayer mirror coupled with a 0.3 mm pinhole collimator. Weekly performance checks were performed using certified standard NIST 1976 corundum (flat plates).

[0152] The beam divergence, i.e. the effective size of the X-ray beam on the sample, was approximately 4 mm. A θ-θ continuous scan mode was utilized with a sample-detector distance of 20 cm, which gave an effective 2θ range of 3.2° to 29.7°. Typically, the sample was exposed to the X-ray beam for 120 seconds. The software used for data collection was GADDS for XP / 2000 4.1.43, and the data were analyzed and presented using Diffrac Plus EVA v15.0.0.0.

[0153] Ambient conditions: Samples were prepared as flat specimens using the powder as received without grinding. Approximately 1-2 mg of sample was lightly pressed onto a glass slide to obtain a flat surface.

[0154] Non-ambient conditions: Samples to be run in non-ambient conditions were mounted on a silicon wafer with a thermally conductive compound. The samples were then heated to the appropriate temperature at 20°C / min and then kept isothermal for 1 min before data collection began.

[0155] Additionally, X-ray powder diffraction patterns were collected on a Bruker D8 diffractometer using Cu Kα radiation (40 kV, 40 mA), a θ-2θ goniometer, and V4 divergent and receiving slits, a Ge monochromator, and a Lynxeye detector. The instrument was performance checked using a certified corundum standard (NIST 1976). The software used for data collection was Diffrac Plus XRD Commander v2.6.1, and the data was analyzed and presented using Diffrac Plus EVA v15.0.0.0.

[0156] The samples were run as flat specimens using the as-received powder under ambient conditions. The samples were gently packed into cavities cut into polished zero background (510) silicon wafers. The samples were rotated in their own plane during the analysis. Data collection details are as follows: Angle range: 2~42°2θ; Step size: 0.05° 2θ; Acquisition time: 0.5 sec / step.

[0157] TGA TGA data were collected on a TA Instruments Q500 TGA equipped with a 16-position autosampler. The instrument was temperature calibrated using certified alumel and nickel. Typically, 5-10 mg of each sample was loaded into a pre-tared aluminum DSC pan and heated from ambient to 350 °C at 10 °C / min. A nitrogen purge at 60 ml / min was maintained over the sample.

[0158] The instrument control software was Advantage for Q Series v2.5.0.256 and Thermal Advantage v5.5.3 and data were analyzed using Universal Analysis v4.5A.

[0159] DSC DSC data were collected on a TA Instruments Q2000 equipped with a 50-position autosampler. Heat capacity calibration was performed using sapphire, and energy and temperature calibrations were performed using certified indium. Typically, 0.5-3 mg of each sample in an aluminum pan with a pinhole was heated from 25 to 280 °C at 10 °C / min. A purge of dry nitrogen at 50 ml / min was maintained over the samples.

[0160] The instrument control software was Advantage for Q Series v2.8.0.394 and Thermal Advantage v5.5.3 and data were analyzed using Universal Analysis v4.5A.

[0161] DVS Sorption isotherms were obtained using an SMS DVS Intrinsic moisture sorption analyzer controlled by DVS Intrinsic Control software v1.0.1.2 (or v1.0.1.3). Sample temperature was maintained at 25°C by the instrument control. Humidity was controlled by mixing dry and humid nitrogen streams, with a total flow rate of 200 ml / min. Relative humidity (RH) was measured by a calibrated Rotronic probe (dynamic range 1.0-100% RH) placed close to the sample. Sample weight change (mass relaxation) as a function of RH% was constantly monitored by a microbalance (accuracy ±0.005 mg).

[0162] Typically, 5-20 mg of sample was placed into a tared mesh stainless steel basket under ambient conditions. Samples were loaded and unloaded at 40% RH and 25°C (typical room conditions). Moisture sorption isotherms were performed as outlined below (two scans give one complete cycle). Standard isotherms were performed at 25°C over the range 0-90% RH at 10% RH intervals. Data analysis was performed using Microsoft Excel using DVS Analysis Suite v6.2 (or 6.1 or 6.0).

[0163] [Table 1]

[0164] Samples were withdrawn after completion of the isotherm and reanalyzed by XRPD.

[0165] 1 H NMR NMR spectra were collected on a Bruker 400MHz instrument equipped with an autosampler and controlled by a DRX400 console. Automated experiments were acquired using standard Bruker on-board experiments using ICON-NMR v4.0.7 running on Topspin v1.3. For atypical spectroscopy, data were acquired using Topspin alone. Samples were prepared in DMSO-d6 unless otherwise stated. Offline analysis was performed using an ACD Spectrus Processor 2012. EXAMPLES

[0166] process Process 1 Step 1 involves the preparation of an acrylamide, represented by the chemical structure designated KPT-9508 / MB3 in Figure 1. Isobutyl chloroformate is used to generate the mixed anhydride, which is then quenched in ammonium hydroxide to yield MB3 / KPT-9508. The detailed reaction scheme is as follows: [ka]

[0167] Ammonium hydroxide (29.653 kg 26% w / w aqueous solution) was charged to a 558 L glass-lined conical bottom vessel equipped with a sulfuric acid scrubber and inerted under nitrogen and the solution temperature was adjusted to 0-5°C (internal temperature 8.4°C-3.0°C 11 hours 36 minutes).

[0168] Another 206 L glass-lined vessel, inerted under nitrogen, was charged with 2-MeTHF (24.0 kg) and heated to reflux for 30 minutes to dry the glass vessel and condenser assembly. The vessel and contents were conditioned to below 30° C., then the 2-MeTHF was sampled for IPC (the initial sample showed residual water of 0.2% w / v versus a target of 0.1% w / v, so reflux was repeated with additional 2-MeTHF). The vessel was emptied and then dried under vacuum.

[0169] A 206 L vessel was charged with KG1 (KPT-454, 15.5 kg) and 2-MeTHF (77.1 kg), then the batch was stirred and adjusted to 0-5° C. (internal temperature 15.5° C. to 0.7° C. over 15 minutes) to form a solution. Subsequent additions of isobutyl chloroformate and N-methylmorpholine followed by quenching in ammonium hydroxide took up to 4 hours to complete (actual time 3 hours 5 minutes). While maintaining the temperature at 0-5° C., isobutyl chloroformate (12.1 kg) was charged (25 minutes, temperature range 0.0° C. to 1.0° C.) and the addition apparatus was forward rinsed with 2-MeTHF (8.1 kg). While maintaining the temperature at 0-5° C. (temperature range 0.4° C. to 5.6° C. over 25 min), N-methylmorpholine (8.9 kg, pre-cooled to 4-8° C.) was charged and the addition apparatus was rinsed forward with 2-MeTHF (5.4 kg). The batch was stirred for a period of 30-45 min (35 min, internal temperature 1.8° C. to 0.5° C.).

[0170] While maintaining a temperature of 0-5°C, the batch was transferred with vigorous agitation to the first vessel containing ammonium hydroxide while maintaining the temperature of the receiving vessel at 0-10°C (temperature range of 0.1°C to 9.1°C over a 40 minute span). The reaction mixture from the second vessel was rinsed into the first vessel with 2-MeTHF (13.1 kg) and agitated at 4.3°C for 30 minutes, then sampled for IPC (residual KG1+KG5 for MB3+MC8 was 2% a / a vs. target of 2% a / a or less). The batch was then adjusted to a temperature of 20-25°C (53 minutes, internal temperature 1.7°C to 20.4°C). Agitation was stopped for 49 minutes to allow for phase separation, and the lower aqueous phase was drained and discarded (separation time 58 minutes, interface with organic layer, 140 L upper organic phase, 20 L lower aqueous phase). Water (77.5 kg) was charged and stirred for 20 minutes while maintaining a temperature of 20-25°C (temperature range 22.2°C-24.3°C for 40 minutes). Agitation was then stopped for 45 minutes to allow for phase separation and the lower aqueous phase was drained and discarded (separation time 35 minutes, at interface with aqueous layer, 144 L upper organic phase, 86 L lower aqueous phase).

[0171] The batch was cooled to 0-5°C (22.5°C to 3.3°C in 65 minutes), placed under vacuum, then gradually warmed to a temperature of 17.3°C and distilled over 3 hours 10 minutes to a target volume of 57-62 L (visual volume 61 L, dip volume measured at 57 L). N-heptane (10.5 kg) was charged over 30 minutes at a temperature of 20.7°C to 21.7°C and then stirred for 1 hour to allow the product to crystallize. The presence of solids was confirmed visually, then additional n-heptane (94.9 kg) was charged over 1 hour at a temperature range of 22.2°C to 22.5°C.

[0172] The batch was isolated by filtration through a 20 cfm polyester filter cloth with a cotton lining (2 hour 20 minute filtration time held at 22.5°C on the SRF filter), then the filtrate was returned to the vessel and filtered again over 1 hour 24 minutes at 22.2°C, rinsing remaining solids forward. The filter cake was washed with n-heptane (2 l.2 kg in two portions - 15 and 17 minute filtration times), then de-liquored (2 hours) and dried under a stream of nitrogen (58 hours, ambient temperature). IPC analysis showed a detection limit of 1.4% w / w at 58 hours, with a limit of 5% w / w or less, and the product was packaged to give 12.4 kg, an 80% yield of KPT-9508. The isolated product matched HPLC standards for this compound. HPLC of the product is shown in Figure 16.

[0173] The HPLC conditions were as follows:

[0174] [Table 2]

[0175] The final product (KPT-9508 / MB3) 1 The H NMR spectrum is shown in Figure 18.

[0176] Process 2 Step 2 consists of two telescopic conversions to form a dibrominated mixture of isomers ME2 / KPT-9515+ME3 / KPT-9506 (Step 2a in FIG. 1), followed by dehydrobromination to form an intermediate mixture of isomers MB5 / KPT-7538+MB9 / KPT-9507 (Step 2b in FIG. 1).

[0177] Step 2a scheme [ka]

[0178] In a 2 L, 3-neck round bottom flask equipped with an overhead stirrer, thermometer, addition funnel, and nitrogen bubbler, 14.69 g of NaBr and 110 mL of acetic acid were added. The contents of the batch were stirred at ambient temperature. To the batch, 45.6 g of bromine was added. The addition funnel was rinsed forward with 110 mL of acetic acid. In a separate 500 mL, 3-neck flask, 55 g of MB3 and 220 mL of acetic acid were added. The contents of the 500 mL flask were stirred at ambient temperature to form a solution.

[0179] The contents of the 500 mL vessel were transferred via the addition funnel to the 2 L vessel over 1 hour while maintaining the internal temperature in the range of 20-30° C. The addition funnel was rinsed forward with 110 mL of acetic acid. The batch was further stirred at 20-30° C. for a minimum period of 16 hours.

[0180] The batch was charged with 275 mL of 10% w / v sodium bisulfite solution over a minimum period of 30 minutes while maintaining an internal temperature of 20-30° C. The batch was charged with 275 mL of water over a period of 5 minutes while maintaining an internal temperature of 20-30° C. The batch was further stirred at 20-30° C. for a minimum period of 60 minutes. An aliquot of the batch was removed and observed for the presence of residual bromine. Complete reduction of bromine was observed by the presence of a white to off-white suspension.

[0181] The batch contents were then filtered through Whatmann paper (70 mm) in a Buchner funnel under vacuum. The filter cake was washed with 220 mL of water divided into two approximately equal portions. The collected cake was held at 20-30° C. under vacuum for a minimum period of 15 minutes. The intermediate ME2 product was obtained with a crude mass of 102.13 g and HPLC purity against developed standards of ME2: 86.0% a / a and ME3: 9.5% a / a.

[0182] Step 2b scheme [ka]

[0183] The reaction procedure described for step 2b provides an improvement over earlier development work that presented challenges with sampling the reaction mixture during in-process control (IPC) testing. The challenges with IPC testing were largely a result of the overly rich reaction mixture of step 2b. The challenges were addressed by using diisopropylethylamine rather than trimethylamine as the base, increasing the volume of the mixture by approximately three-fold, and using a mixture of water and acetonitrile rather than acetonitrile alone. The final procedure discovered to address the challenges stated is described below.

[0184] A 500 mL three-neck round bottom flask was fitted with a thermometer, overhead stirrer and nitrogen inlet. The flask was charged with 25 g of ME2 (49 mmol; 1.0 equiv.), 140 mL of ACN (8 parts per MB3) and 70 mL of water (4 parts per MB3). A separate 100 mL round bottom flask was charged with 8.6 mL of DIPEA (49 mmol, 1.0 equiv. per MB3) and 52 mL of ACN (3 parts per MB3). The mixture was stirred for 20-30 min. With vigorous stirring, the DIPEA solution was added in portions to the suspension of ME2 over a period of 1.0-1.5 h. The addition assembly was rinsed forward with 9 mL of ACN (0.5 parts per MB3). The batch was stirred for 2-3 h at 20-25°C. An IPC test was performed and the IPC target was met (target: residual ME2 for MB5 is 0.3% a / a or less).

[0185] The resulting suspension was filtered using filter paper. The filter cake was washed with 34 mL of 8:2 ACN / H2O mixture (2 parts to MB3). The filter cake was washed with 34 mL of ACN (2 parts to MB3). The filter cake was dried with nitrogen purge and aspirator for 20 hours. The isolated product was a white solid and purity was assessed by HPLC according to the following protocol.

[0186] [Table 3]

[0187] Duplicate experiments gave isolated yields of 86.0% and 90.7% with 99.2% a / a and 99.2% a / a, respectively. The proton NMR in DMSO of the batch isolated in 86.0% yield is shown in FIG.

[0188] Process 3 [ka]

[0189] In this study, a scalable process for the production of compound 5, (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-(pyrimidin-5-yl)acrylamide (MB6 / KPT-8602), was developed.

[0190] The following HPLC protocol can be used.

[0191] [Table 4]

[0192] The final product, compound KPT-8602 / MB6 / 5 1 The H NMR is shown in Figure 19.

[0193] Having noticed the poor selectivity of the utilized palladium tetrakistriphenylphosphine, a more robust and selective Pd catalyst (i.e., Strem amphos palladacycle gen 2 (cat. no. 46-0342)) was found by screening several catalysts for the Suzuki coupling of this step. Based on the new catalyst system, the process was further evaluated by studying some key process parameters, namely, stoichiometry of Strem amphos palladacycle gen 2 (cat. no. 46-0342) and boronic acid (compound represented by structural formula (IIIB), MB7), reaction solvent and solvent ratio, solvent volume, reaction temperature, and different bases. Other issues such as MB7 decomposition, simplifying the process operation, conditions for crude product isolation (MB6 methanol solvate, crystalline form II described herein) and recrystallization of MB6 in MIBK to produce crystalline form I described herein, and finally, Pd and MB7 residual levels, respectively, in the isolated product were also studied. It was found that removal of palladium from the crude product by treatment with Si-DMT silica scavenger is not necessary (but is acceptable) in the improved process since palladium levels in the crude product were always below current limits (400 ppm or less).

[0194] Surprisingly, the new reaction system was found to be very robust and well-performing without vigorous degassing. The new process was carried out in a proof-of-concept experiment on a 15.5 g scale, successfully resulting in 81-86% overall yields of compound 5 (MB6 (KPT-8602) represented by structural formula (VII)) as crystalline Form I. The 81-86% yield is a significant improvement over the reported yields of 26-49% for the previous process. The purity of the product was very good (HPLC purity was 100% a / a) with acceptable levels of Pd and boronic acid MB7.

[0195] General Reaction Conditions Step 3: Based on experiments evaluating various process parameters for step 3 (discussed in detail below), the following reaction conditions were utilized: about 1.0 equivalent MB5, about 2.0 equivalent MB7, about 0.5 equivalent Cs2CO3, about 24 parts degassed dioxane:H2O 7:1 v / v, 2 mol% Strem amphos palladacycle 2nd generation (catalog no. 46-0342), 7-7.5 hours at 55-60°C. All equivalents are relative to MB5.

[0196] Isolation of the Methanolate (Form II) - General Procedure 1: A typical isolation procedure for Form II (methanolate precursor to final Form I) is as follows: After 7-7.5 hours reaction time at 55-60°C (see general reaction conditions above), the reaction mixture is adjusted to about 40-45°C, followed by slurrying Celite (about 0.5 parts per MB5) and about 7:1 v / v dioxane:water (about 2.5 parts per MB5). The resulting suspension is stirred at about 40-45°C for about 15-20 minutes. The reaction mixture is filtered and the filter cake is washed with about 7:1 v / v dioxane:water (about 40-45°C, about 3 parts per MB5). The resulting filtrate is subjected to vacuum distillation to a target volume of about 4.5-5.5 parts per MB5. The resulting suspension is adjusted to an internal temperature of about 50-55°C. The reaction mixture is then charged in small portions with MeOH (about 20 parts per MB5). The suspension is then stirred at about 50-55° C. for about 60-70 minutes. The reaction mixture is then cooled to about 20-25° C. and then further cooled to about 0-5° C. over about 2-2.5 hours and maintained at that temperature for a period of about 2-2.5 hours. The resulting suspension is then filtered and the filter cake is washed with MeOH (about 10 parts per MB5). The cake is then dried.

[0197] Isolation of Form I - General Procedure 2: The dried filter cake from General Procedure 1 is then transferred to a flask equipped with an overhead stirrer, thermometer, and nitrogen inlet, and Si DMT (about 5 equivalents relative to MB5) is charged to the flask. MIBK is then charged to the flask (about 25 parts relative to MB5). The reaction mixture is then heated to an internal temperature of about 65-70°C and maintained at that temperature for about 1-1.5 hours if no scavenger is used, or about 4-5 hours if a scavenger is used. The reaction mixture is then filtered while still hot at about 65-70°C into a clean flask equipped with an overhead stirrer, thermometer, and nitrogen inlet. The filter is washed with MIBK (about 1.0 part relative to MB5 at about 65-70°C). With stirring, the filtrate is slowly cooled to about 20-30°C over about 3-3.5 hours, and then distilled under vacuum to a target volume of about 3-4 parts relative to MB5. The batch temperature is adjusted to about 55-60° C. and the reaction mixture is stirred at 55-60° C. for about 2-2.5 hours. The suspension is then cooled to about 0-5° C. over about 2-2.5 hours and stirred at this temperature for a minimum of about 1 hour. The reaction mixture is then filtered and the resulting cake is washed with MIBK (about 1.0 part per MB5 at about 0-5° C.).

[0198] The general procedure above was followed on a 15.5 g scale. Procedural variations (amounts used, temperature, time, etc.) can occur, but still give good yields and purity. Additional examples of isolation (General Procedure 1) and recrystallization conditions (General Procedure 2) are also provided below.

[0199] General Procedures 1 and 2 for 15.5g Scale A 500 mL four-neck round bottom flask was fitted with an overhead stirrer, thermometer, reflux condenser and N2 bubbler. The flask was flushed with nitrogen for a minimum of 30 minutes. Under N2 flow, the flask was charged with 15.5 g of compound 4 (MB5) (36.1 mmol, 1.0 equiv.), 8.95 g of MB7 (72.2 mmol, 2.0 equiv. relative to MB5), 5.88 g of Cs2CO3 (18.0 mmol, 0.5 equiv. relative to MB5) and 0.415 g of Pd catalyst PT4 (Strem Amphos palladacycle 2nd generation, catalogue no. 46-0342, 0.72 mmol, 0.02 equiv. relative to MB5), followed by 326 mL of degassed 1,4-dioxane (21 parts relative to MB5) and 47 mL of degassed water (3 parts relative to MB5).

[0200] With moderate stirring, the reaction mixture was then further degassed by bubbling nitrogen through it for a period of 60-70 minutes. The reaction mixture was then heated to an internal temperature of 55-60°C and maintained at that temperature for a period of 7-7.5 hours. The reaction temperature was adjusted to 40-45°C and an IPC sample was taken. Upon completion, the reaction mixture was adjusted to 40-45°C followed by a slurry of 7.75 g of Celite (0.5 parts per MB5) and 39 mL of dioxane:water 7:1 v / v (2.5 parts per MB5). The resulting suspension was stirred at 40-45°C for 15-20 minutes. The reaction mixture was filtered and the filter cake was washed with 46.5 mL of pre-warmed dioxane:water 7:1 v / v (40-45°C, 3 parts per MB5). The resulting filtrate was subjected to vacuum distillation to a target volume of 70-85 mL (4.5-5.5 parts with respect to MB5). The resulting thick suspension was adjusted to an internal temperature of 50-55°C. 310 mL of MeOH (20 parts with respect to MB5) was then charged in small portions to the reaction mixture at 50-55°C. The suspension was then stirred at 50-55°C for a period of 60-70 minutes. The reaction mixture was then cooled to 20-25°C and then further cooled to 0-5°C over a period of 2-2.5 hours and maintained at that temperature for a period of 2-2.5 hours. The resulting suspension was then filtered through a Buchner funnel using Whatmann filter paper and the filter cake was washed with 155 mL of MeOH (10 parts with respect to MB5). The cake was then dried under vacuum at 45-50°C for about 4.5 hours. Crystalline Form II (methanolate) was obtained in 89% yield. The purity of the product was very good (HPLC purity was 99.3%-99.4 area %, and Pd and boronic acid were at acceptable levels.

[0201] The dried filter cake was then transferred to a 500 mL three-neck round bottom flask equipped with an overhead stirrer, thermometer, and nitrogen inlet, followed by 0.25 g of SiDMT (5 equivalents relative to MB5 (230 ppm residual Pd). [The following calculation can be used to determine how much DMT silica should be loaded based on the residual palladium level. To calculate mm Pd in ​​the product: Mmol Pd = ppm Pd x g of product / 106.42 x 100 and scavenger loading = mmol Pd×4 equivalents / scavenger loading (mmol / g).] The solid was then charged with 390 mL of 4-methyl-2-pentanone, also referred to herein as MIBK (25 parts per MB5). The reaction mixture was then heated to an internal temperature of 65-70° C. and maintained at that temperature for a period of 4-5 hours if scavenger treatment is performed (1-1.5 hours is sufficient if no scavenger treatment is performed). The reaction mixture was then filtered (using Whatmann filter paper) through a Buchner funnel while still hot at 65-70° C. into a new 500 mL three-neck round bottom flask equipped with an overhead stirrer, thermometer and nitrogen inlet. The filter paper was then washed with 15 mL of pre-warmed MIBK (65-70° C., 1 part per MB5). The filtrate was then heated to an internal temperature of 65-70° C., 20-30° C., 1 part per MB5 ... Cooled slowly over 3-3.5 hours and then distilled under vacuum to a target volume of 50-55 mL (3-4 parts relative to MB5). The bath temperature was adjusted to 55-60°C and the reaction mixture was stirred at 55-60°C for 3-3.5 hours. The suspension was cooled to 0-5°C over 2-2.5 hours and stirred at that temperature for a minimum of 1.0 hour. The reaction mixture was then filtered through a Buchner funnel using Whatmann filter paper. The cake was then washed with 15.5 mL of pre-chilled 0-5°C MIBK (1.0 part relative to MB5). The filter cake was then dried in a vacuum oven at 48-53°C for 1-2 hours to give the product (crystalline Form I) as a solid. The overall yield was 81-86%, the HPLC purity was 100.0% a / a, and Pd and boronic acid were at acceptable levels.

[0202] Isolation of Form I - General Procedure 2A: Crude MB6 methanolate Form II is charged to the reactor, followed by about 18 volumes of MIBK. The slurry is heated to about 80-85°C to produce a solution. At this point, about 1 volume of SiliaMetS® DMT (also referred to herein as SiDMT, which is a silica-bound 2,4,6-trimercaptotriazine (trithiocyanuric acid, TMT) scavenger) in MIBK can be charged to the reactor for removal of Pd. Use of this scavenger is optional. The solution (without scavenger) or slurry (with scavenger) is then mixed for a period of time. At the completion of that time, the solution / slurry is polish filtered hot into a clean reactor while maintaining a temperature of about 80-85°C. 2 volumes of MIBK are then charged to the original reactor and heated to about 80-85°C. Once at temperature, the solvent is transferred to the batch via a polish filter as a rinse for the reactor / filtration system. The solution is then cooled slightly to induce nucleation during the holding period. After nucleation is confirmed, the solids are crystallized by controlled cooling crystallization with a final temperature of 0-5°C. The slurry is held at this temperature for a suitable time to complete the crystallization and then the solids are isolated by filtration. Approximately 2 volumes of MIBK are polished and filtered into the reactor and cooled to approximately 0-5°C. Once at temperature, the wash liquor is poured into the cake in two portions and drawn off the cake by suction. After washing is complete, the solids are dried and packaged.

[0203] General Procedure 2A for 17g scale: 17 g of crude MB6 (methanol solvate form II) was weighed into a 400 ml Easy max vessel. Approximately 306 mL of 4-methyl-2-pentanone (MIBK; 18V vs. MB6 methanolate form II) was added. The mixture was stirred moderately and warmed to approximately 80-85°C to dissolve the solids. Approximately 0.51 g of Si DMT (3% vs. MB6 (methanolate form II)) was added to the vessel. Approximately 18 mL of MIBK (2V X 0.51 g + 1V rinse) was added to the vessel. The mixture was stirred moderately at approximately 80-85°C for approximately 4.5 hours. The reaction mixture was then filtered hot at approximately 80-85°C through a Buchner funnel (using Whatmann filter paper) into a 500 mL Erlenmeyer flask. The filter paper / SiDMT / Cs2CO3 was then washed with about 34 mL of pre-warmed 4-methyl-2-pentanone / MIBK (about 80-85°C; about 2V for MB6 as methanolate form II). The easy max vessel was washed and the contents of the Erlenmeyer flask including the filtrate and washings were warmed to about 80-85°C and transferred back to the easy max vessel. The batch temperature was adjusted to about 80-85°C and the reaction mixture was stirred for about 30 minutes to reach dissolution. The solution was then cooled to about 20-25°C over a minimum of 3 hours. The suspension was then cooled to about 0-5°C over about 2-2.5 hours and stirred at this temperature for a minimum of about 1.0 hour. The reaction mixture was then filtered through a Büchner funnel using Whatmann filter paper.

[0204] The cake was then washed with about 34 mL of pre-chilled 4-methyl-2-pentanone / MIBK (about 2 volumes relative to MB6 methanolate Form II; about 0-5° C.). The filter cake was then dried in a vacuum oven at about 25-30° C. for about 3 hours to give the product as a white solid (yield %75%, purity=99.98% a / a).

[0205] Pd-catalyzed Suzuki coupling reaction - Catalyst evaluation The results of the initial Pd catalyst evaluation are summarized in the table presented in Figure 2. A baseline experiment was performed using Pd(dppf)Cl2·DCM (Figure 2; entry 1). As previously observed, the baseline experiment showed incomplete conversion (71.1% a / a) and significant levels of debromination (15.8% a / a).

[0206] Screening with a series of crotyl-based precatalyst systems showed improved results, especially when bulky electron-rich ligands such as Amphos and P(tBu)3 were used (Figure 2; entries 3 and 4). P(tBu)3 was found to perform slightly better than Amphos, giving higher levels of conversion (93.5 vs. 81.3% after 24 h). P(tBu)3 was repeated and found to give similar performance (97.2% a / a conversion), demonstrating reproducibility (Figure 2; entry 11). It is also noteworthy that the debromination pathway was significantly reduced (3.8-5.7% a / a). Interestingly, a previously uncharacterized impurity with m / z=699 (ESI) was identified in the screening study. A tentative structure (PF9) was assigned based on the observed mass. This impurity is hypothesized to arise from a side reaction involving a Heck-type coupling of MC8 with MB5. Based on the above results, tBu3PPd(crotyl)Cl was identified as a desirable catalyst for further process development.

[0207] The three impurities shown below were the major by-products in this Suzuki coupling, and their levels after the reaction were major factors in assessing the performance of the coupling. [ka]

[0208] Reaction solvents were also screened for Pd-catalyzed reactions, and the results are summarized in Figure 3.

[0209] Reactions carried out in dioxane / H2O, THF / H2O, and EtOH / MeTHF / H2O gave 100% conversion with good product purity. However, there was still a significant amount of impurity formation. Reactions in both MeTHF / H2O and toluene / MeTHF / H2O were observed to stall. Thus, the THF / H2O solvent system represented a possibility for further evaluation. Suzuki couplings were attempted using different types of bases. The results are summarized in Figure 4 below. Cs2CO3 was found to give the best performance out of these four bases.

[0210] Further process investigations For this work, a single lot of MB5 with high HPLC purity (99.5% a / a) was used unless otherwise stated.

[0211] First, the catalytic system tBu3PPd(crotyl)Cl) identified above as the preferred catalyst was tested in a 4.3 g scale reaction. The reaction conditions were chosen as 1.0 eq MB5, 2.0 eq boronic acid MB7, 0.5 eq cesium carbonate, and 3% tBu3PPd(crotyl)Cl in 16 parts degassed THF / H2O 15:2 v / v at reflux (63 °C) (the reaction mixture as a suspension was degassed for 20-30 min before heating). After 4 h at reflux, IPC showed that a significant amount of MC8 (21% a / a relative to MB6) had been formed, while the remaining MB5 relative to MB6 was 115% a / a (the reaction had stalled after 1 h). The coupling could be reactivated after additional Pd catalyst (another 2 mol%) was introduced. However, the reaction was observed to stall again at 55% a / a of remaining MB5 relative to MB6. The reaction was carried out again under similar conditions and the results are summarized in FIG.

[0212] These results indicated that these reaction conditions did not give reproducible results. Additional catalysts were evaluated and the results are summarized in Figure 6.

[0213] Both JM Amphos Pd(crotyl)Cl (Pd-161) and Strem Amphos palladacycle 2nd generation (catalog no. 46-0342) were found to give the same excellent results when dioxane:HO was used as the solvent system for the reaction (Figure 6; entries 5, 6 and 7) and had much lower levels of impurities. When Strem Amphos palladacycle 2nd generation was used with THF:HO as the solvent system (Table 6; entries 3 and 4), there was an increase in impurities produced. Both JM Amphos Pd(crotyl)Cl (Pd-161) and Strem Amphos palladacycle 2nd generation (catalog no. 46-0342) as Suzuki coupling catalysts showed better selectivity and robustness than tBu3PPd(crotyl)Cl. [ka]

[0214] Strem Amphos palladacycle 2nd generation (catalog number 46-0342) and JM Amphos catalyst are preferred as active catalyst systems.

[0215] Figure 7 summarizes the results of experiments performed to investigate the effect of catalyst stoichiometry on the performance of the chemistry. These results show that while there is comparable performance between 2 mol% and 3 mol% Pd catalysts, reaction stalling was observed when the catalyst was reduced below 2 mol%. It may be possible to further reduce the catalyst loading.

[0216] The amount of boronic acid MB7 should be minimized to avoid undesired effects. Experiments were carried out to explore the lower limit of MB7 equivalents. Figure 8 summarizes these studies.

[0217] The reaction was observed to stall when the boronic acid was reduced to 1.5 equiv, even when 3 mol% Pd catalyst was used. When the boronic acid was at 1.8 equiv, the residual MB5 after reaction completion was marginal (less than 1% a / a). To ensure that the Suzuki coupling was robust, a slightly higher level (2.0 equiv) of MB7 was set in the final step of this process. It is noteworthy that the excess residual MB7 was successfully removed during the product isolation step.

[0218] Several solvent systems were investigated to optimize the Suzuki coupling, and the experimental results are listed in Figure 9.

[0219] Dioxane:water was identified as a beneficial system since it gave a cleaner reaction, while other solvent systems resulted in either stalls or higher levels of impurities. Although dioxane is a Class 2 solvent and has lower ICH limits than other solvents, the dioxane:water solvent system was still selected for the final process because it gave superior performance and could be reduced to meet the required limits in the final API after product isolation / recrystallization operations, which was demonstrated in previous GMP manufacturing.

[0220] The ratio of the dioxane:water solvent system was further evaluated and the results are summarized in Figure 10. Reducing the water (14:1 v / v dioxane:water; Figure 10, entry 1) slowed the reaction, while higher water (2:1 v / v dioxane:water; Figure 10, entry 3) resulted in higher levels of impurities. 7:1 v / v dioxane:water gave the best results and was therefore set as the final solvent ratio for this process.

[0221] The total solvent volume for this coupling was also evaluated. Figure 11 summarizes the results of these experiments.

[0222] There was comparable performance between 24 and 34 parts (Figure 11; entries 1 and 2). 18 parts was also deemed acceptable, but with reduced performance. Coupling stalled when 12 parts was utilized (presumably due to biphasic reaction conditions that occurred). Therefore, this coupling volume was selected to be 24 parts for the final process.

[0223] The reaction temperature for this Suzuki coupling was also investigated, and the summarized results of this study are tabulated in FIG.

[0224] Elevated temperature (71-72°C; entry 4 in Figure 12) gave increased levels of MC0 (Z isomer). The 50-55°C reaction (entry 1 in Figure 12) was slightly cleaner but slower. Reactions at 55-60°C or 60-65°C gave comparable performance. The final process was set at 55-60°C.

[0225] FIG. 13 is a comparison of the results of degassed and non-degassed Suzuki coupling reactions (after reagent / solvent combination).

[0226] The Suzuki coupling has been found to work well without vigorous degassing after reagent / solvent combination. Degassing the reaction mixture before heating can be performed if desired to ensure robustness.

[0227] Several bases were evaluated in parallel with the boronic acid decomposition studies discussed below. These different base tests can be considered to evaluate pH as a factor that can affect the performance of the reaction. The relevant results are summarized in Figure 14.

[0228] When K3PO4 was used in place of Cs2CO3 (Figure 14, entry 2), the reaction stalled. When a 1:1 mixture of 0.25 equivalents Cs2CO3 / 0.25 equivalents CsHCO3 was used (Figure 14, entry 3), the reaction also stalled but could be restarted by charging additional CsHCO3 (0.25 equivalents), which increased the base charge to a level equal to that of the baseline condition (Figure 14, entry 1). The reaction using a mixture of 0.25 equivalents Cs2CO3 / 0.50 equivalents CsOH (Figure 14, entry 4) performed comparable to the use of Cs2CO3 alone. These results indicate that variations in CO2 off-gas rate are unlikely to affect process performance upon scale-up.

[0229] General Reaction Conditions As mentioned in step 3, upon completion of the above set of experiments, the following reaction conditions were recommended: 1.0 eq MB5, 2.0 eq MB7, 0.5 eq Cs2CO3, 24 parts degassed dioxane:H2O 7:1 v / v, 2 mol% Strem amphos palladacycle 2nd generation, 7-7.5 hours at 55-60 °C. Notable changes and improvements over the previous procedure are summarized in Figure 15A and Figure 15B.

[0230] The disclosures of all patents, published applications, and references cited herein are incorporated by reference in their entirety.

[0231] Although the present invention has been shown and described in detail with reference to example embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention as encompassed by the appended claims.

Claims

1. A compound represented by the following structural formula (VII): 【Chemistry 1】 wherein the crystalline form is Form I characterized by X-ray powder diffraction peaks at 2θ angles of 4.6°, 22.8°, 23.2°, and 24.4°.

2. 2. The crystalline form of claim 1, characterized by at least four X-ray powder diffraction peaks at 2θ angles selected from 4.6°, 20.0°, 22.8°, 23.2°, and 24.4°.

3. 3. The crystalline form of claim 1 or 2, characterized by at least five X-ray powder diffraction peaks at 2θ angles selected from 4.6°, 19.0°, 20.0°, 22.8°, 23.2°, 23.7°, 24.4°, and 27.9°.

4. 3. The crystalline form of any one of claims 1 to 2, characterized by an X-ray powder diffraction pattern substantially in accordance with that depicted in Figure 20.

5. The crystalline form of any one of claims 1 to 2, characterized by a DSC thermogram having an endothermic event at about 226°C.

6. 3. The crystalline form of any one of claims 1 to 2, characterized by a DSC thermogram substantially in accordance with that depicted in Figure 21.

7. Compounds represented by structural formula (VII): 【Chemistry 2】 wherein the crystalline form is Form II characterized by X-ray powder diffraction peaks at 2θ angles of 9.9°, 19.2°, 22.4°, and 24.4°.

8. 8. The crystalline form of claim 7, characterized by at least four X-ray powder diffraction peaks at 2θ angles selected from 9.9°, 19.2°, 22.4°, 23.5°, and 24.4°.

9. 9. The crystalline form of claim 7 or 8, characterized by at least five X-ray powder diffraction peaks at 2θ angles selected from 9.9°, 19.2°, 21.3°, 21.9°, 22.4°, 23.5°, 24.4°, and 29.2°.

10. 9. The crystalline form of any one of claims 7 to 8, characterized by an X-ray powder diffraction pattern substantially in accordance with that depicted in Figure 24.

11. The crystalline form of any one of claims 7 to 8, characterized by a DSC thermogram having two endothermic events at about 112°C and about 225°C.

12. 9. The crystalline form of any one of claims 7 to 8, characterized by a DSC thermogram substantially in accordance with that depicted in Figure 25.

13. The crystalline form of any one of claims 7 to 8, wherein the compound of formula (VII) is in the form of a solvate.

14. The crystalline form of any one of claims 7 to 8, wherein said form is a methanol solvate.

15. Compounds represented by structural formula (VII) 【Chemistry 3】 A method for preparing Compounds represented by structural formula (II) 【Chemistry 4】 with a compound represented by structural formula (III): 【Chemistry 5】 in a first solvent in the presence of a Pd catalyst and one or more inorganic bases under conditions suitable for preparing a compound represented by structural formula (VII), wherein the first solvent comprises dioxane and water, the Pd catalyst is selected from chloro{[4-(N,N-dimethylamino)phenyl]di-t-butylphosphino}(2′-amino-1,1′-biphenyl-2-yl)palladium(II) or chloro(crotyl)[di-tert-butyl(4-dimethylaminophenyl)phosphine]palladium(II), and each R is hydrogen, C １ ~C ４ alkyl, or the two groups R together with the oxygen atom to which they are attached form a 5- to 7-membered cyclic acetal moiety; and thereby obtaining the compound represented by structural formula (VII). The method includes:

16. 16. The method of claim 15, wherein the one or more inorganic bases are selected from carbonate, bicarbonate, acetate, or quaternary ammonium, sodium, potassium, or cesium hydroxide.

17. The compound represented by structural formula (III) is a compound represented by structural formula (IIIB): 【Chemistry 6】 The method according to any one of claims 15 to 16, wherein

18. The inorganic base is Cs ２ CO ３ The method according to any one of claims 15 to 16, wherein the cation is CsOH or CsOH.

19. The inorganic base is Cs ２ CO ３ The method according to any one of claims 15 to 16, wherein

20. The method according to any one of claims 15 to 16, wherein the Pd catalyst is chloro{[4-(N,N-dimethylamino)phenyl]di-t-butylphosphino}(2'-amino-1,1'-biphenyl-2-yl)palladium(II).

21. The process according to any one of claims 15 to 16, wherein the Pd catalyst loading is between 0.5% mol% and 10 mol%.

22. The method of any one of claims 15 to 16, wherein the amount of the inorganic base is 0.5 to 2 molar equivalents of base relative to the compound represented by structural formula (II).

23. The conditions suitable for preparing the compound represented by structural formula (VII) are - the Pd catalyst loading between 0.5 mol% and 3 mol%; - 1.0 to 2.2 molar equivalents of the compound represented by structural formula (III) relative to the compound represented by structural formula (II); an amount of said inorganic base of 0.8 to 1.2 total molar equivalents of base relative to said compound represented by structural formula (II); the first solvent comprises 16 to 21 parts of dioxane and 2 to 3 parts of water; A reaction temperature of about 55° C. to about 60° C.; and - Reaction time of about 7 to 8 hours The method according to any one of claims 15 to 16, comprising:

24. The compound represented by structural formula (II) 【Chemistry 7】 wherein said preparing step comprises preparing a compound represented by structural formula (IV): 【Chemistry 8】 in a second solvent in the presence of an organic base under conditions suitable to produce the compound represented by structural formula (II); The method of any one of claims 15 to 16, further comprising:

25. 25. The method of claim 24, wherein the organic base is triethylamine or diisopropylethylamine (DIPEA).

26. 25. The method of claim 24, wherein the second solvent comprises acetonitrile (ACN).

27. 25. The method of claim 24, wherein the second solvent is 80% ACN / 20% water.

28. The second solvent comprises about 11 parts ACN and about 4 parts H2O relative to the compound represented by structural formula (IV), the organic base is DIPEA, and the conditions suitable for preparing the compound represented by structural formula (II) are - about 1 molar equivalent of DIPEA relative to the compound represented by structural formula (IV); a reaction temperature of 20° C. to 25° C.; and - 2-3 hour reaction time 25. The method of claim 24, comprising:

29. The compound represented by structural formula (IV): 【Chemistry 9】 wherein said preparing step comprises preparing a compound represented by structural formula (V) 【Chemistry 10】 Bromine (Br ２ ) in a third solvent in the presence of a bromide salt under conditions suitable for preparing the compound represented by structural formula (IV). The method of any one of claims 15 to 16, further comprising:

30. 30. The method of claim 29, wherein the third solvent comprises water and the bromide salt is sodium bromide.

31. 30. The method of claim 29, wherein the third solvent is acetic acid.

32. The compound represented by structural formula (V) is ２ 30. The method of claim 29, wherein reacting with is carried out at a temperature of 20° C. to 30° C. for a period of 12 to 16 hours.

33. Compounds represented by structural formula (V) 【Chemistry 11】 wherein said preparing step comprises preparing a compound represented by structural formula (VI): 【Chemistry 12】 with an amidating agent in a fourth solvent, in the presence of a tertiary amine organic base and a chloroformate ester, under conditions suitable to produce the compound represented by structural formula (V). The method of any one of claims 15 to 16, further comprising:

34. The amidating agent is ammonium hydroxide, the tertiary amine organic base is N-methylmorpholine (NMM), and the chloroformate has the following structural formula: 【Chemistry 13】 The method of claim 33, wherein the isobutyl chloroformate is represented by

35. 34. The method of claim 33, wherein the fourth solvent is tetrahydrofuran (THF) or 2-methyltetrahydrofuran (MeTHF).

36. 34. The method of claim 33, wherein the fourth solvent is MeTHF, and the amidating of the compound represented by structural formula (VI) is carried out at a temperature between 0° C. and 5° C. for a period between 3 hours and 4 hours.

37. Compound represented by structural formula (V) 【Chemistry 14】 Or its salt.

38. The compound represented by structural formula (VII) 【Chemistry 15】 1. A method for preparing crystalline Form I of (a) contacting crystalline Form II of the compound represented by Structural Formula (VII) with about 18 volumes of 4-methyl-2-pentanone (MIBK) to form a mixture; (b) heating the mixture of step (a) to about 80-85° C. to form a heated mixture; (c) optionally adding SiDMT to the heated mixture of step (b); (d) maintaining the heated mixture at a temperature of about 80-85° C. for about 4.5 hours; (e) filtering the heated mixture to obtain a filtrate; (f) adding MIBK to the filtrate at a temperature of about 80-85°C; (g) inducing nucleation of Form I in said filtrate by cooling said filtrate to about 20-25° C.; (h) crystallizing Form I by controlled cooling crystallization of the filtrate with a final temperature of 0-5° C.; and (i) isolating crystalline Form I from the filtrate. The method includes:

39. A compound according to claim 19, comprising a compound of formula VII: 【Chemistry 16】 wherein the crystalline form is Form I, characterized by X-ray powder diffraction peaks at 2θ angles of 4.6°, 22.8°, 23.2°, and 24.4°.

40. A pharmaceutical composition comprising crystalline Form I of the compound represented by structural formula (VII) and a pharma- ceutically acceptable carrier.

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