Crystalline forms of anti-SARS-CoV-2 agents

Abstract

The present invention provides compounds of Compound I, including polymorphs and pseudopolymorphs, which are useful in the preparation of pharmaceutical compositions. [Formula 1] JPEG2025533641000051.jpg4366 It is characterized by the crystalline form of

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 413,850, filed October 6, 2022, the entire teachings of which are incorporated herein by reference.

[0002] The present invention relates to novel crystalline polymorphic forms of Compound I, methods for their preparation, pharmaceutical compositions comprising said polymorphic forms, methods of using said polymorphic forms for preparing pharmaceutical compositions, and methods of using said polymorphic forms for treating or preventing coronavirus infections. [Background technology]

[0003] Coronaviruses are enveloped, positive-sense, single-stranded RNA viruses. The genomic RNA of CoVs contains a 5' cap structure and a 3' poly(A) tail and at least six open reading frames (ORFs). The first ORF (ORF 1a / b) directly translates two polyproteins: pp1a and pp1ab. These polyproteins are then processed into 16 nonstructural proteins by a 3C-like protease (3CL), also known as the main protease (Mpro). These nonstructural proteins are involved in the production of subgenomic RNAs that encode four structural proteins: envelope, membrane, spike, and nucleocapsid proteins, as well as accessory proteins. Consequently, it is understood that 3C-like proteases play a critical role in the coronavirus life cycle.

[0004] 3CLpro is a cysteine ​​protease responsible for most cleavage events within the precursor polyprotein. Active 3CLpro is a homodimer containing two protomers and characterized by a Cys-His dyad located between domains I and II. 3CLpro is conserved among coronaviruses, and several common features are shared among 3CLpro substrates in various coronaviruses. Because there is no human homolog of 3CLpro, 3CLpro is an ideal antiviral target. Although several compounds have been reported to inhibit 3CLpro activity, none have been approved as coronavirus therapies. (International Publication No. 2004101742(A2), U.S. Patent Application Publication No. 2005 / 0143320(A1), U.S. Patent Application Publication No. 2006 / 0014821(A1), U.S. Patent Application Publication No. 2009 / 0137818(A1), International Publication No. 2013049382(A2), International Publication No. 2013166319(A1), International Publication No. 2018042343, International Publication No. See WO 2018023054, WO 2022013684, WO 2021252644, WO 2022020711, WO 2022020242, U.S. Pat. No. 11,174231(B1), U.S. Pat. No. 11,124497(B1), WO 2005113580, and WO 2006061714).

[0005] Novel therapeutic agents are needed to treat, ameliorate, or prevent SARS-CoV-2 infection. Summary of the Invention

[0006] The present invention provides polymorphic and pseudopolymorphic forms of Compound I, chemical name: N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidin]-1'-yl)-4-methyl-1-oxopentan-2-yl)-4,6,7-trifluoro-N-methyl-1H-indole-2-carboxamide, having the following structure: [ka]

[0007] In certain embodiments, the present invention provides Compound I in a polymorphic or pseudopolymorphic form as disclosed herein.

[0008] In certain embodiments, the present invention provides methods for producing the polymorphs and pseudopolymorphs of Compound I disclosed herein.

[0009] In certain embodiments, the present invention provides compositions comprising a polymorph or pseudopolymorph of Compound I disclosed herein. In certain embodiments, the composition is a pharmaceutical composition comprising at least one polymorph or pseudopolymorph of Compound I and a pharmaceutically acceptable carrier or excipient. In certain embodiments, the composition is substantially free of other polymorphs or pseudopolymorphs of Compound I.

[0010] In certain embodiments, the present invention provides a method for treating or preventing a coronavirus infection in a subject in need thereof, comprising administering to the subject (a) a therapeutically effective amount of a polymorph or pseudopolymorph of Compound I, (b) a therapeutically effective amount of two or more polymorphic or pseudopolymorphic forms of Compound I, or (c) a therapeutically effective amount of one or more polymorphs and / or pseudopolymorphs of Compound I and an amorphous form of Compound I. [Brief explanation of the drawings]

[0011] The foregoing and other objects, features, and advantages of the present invention will become apparent from the following more particular description of preferred 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 the principles of the invention. [Figure 1] FIG. 1 is an X-ray powder diffraction (XRPD) pattern of the amorphous form of Compound I. [Figure 2]FIG. 2 is a differential scanning calorimetry (DSC) thermogram of the amorphous form of Compound I. [Figure 3] FIG. 3 is an XRPD pattern of Form 1 of Compound I. [Figure 4] FIG. 4 is a DSC thermogram of Compound I Form 1. [Figure 5] FIG. 5 is a Fourier transform infrared (FT-IR) spectrum of Form 1 of Compound I. [Figure 6] FIG. 6 is an ORTEP plot of the single crystal X-ray structure of Form 1. [Figure 7] FIG. 7 is an XRPD pattern of Form 2 of Compound I. [Figure 8] FIG. 8 is a DSC thermogram of Compound I Form 2. [Figure 9] FIG. 9 is an XRPD pattern of Form 3 of Compound I. [Figure 10] FIG. 10 is a DSC thermogram of Compound I Form 3. [Figure 11] FIG. 11 is an FT-IR spectrum of Form 3 of Compound I. [Figure 12] FIG. 12 is an XRPD pattern of Form 4 of Compound I. [Figure 13] FIG. 13 is an XRPD pattern for a mixture of Forms 2 and 4 of Compound I. [Figure 14] FIG. 14 is a DSC thermogram for a mixture of Forms 2 and 4 of Compound I. [Figure 15] FIG. 15 is an XRPD pattern of Compound I Form A. [Figure 16] FIG. 16 is a DSC thermogram of Compound I Form A. [Figure 17] FIG. 17 is an XRPD pattern of Form B of Compound I. [Figure 18] FIG. 18 is a DSC thermogram of Form B of Compound I. [Figure 19] FIG. 19 is an XRPD pattern of Form C of Compound I. [Figure 20]FIG. 20 is an XRPD pattern of Form D of Compound I. [Figure 21] FIG. 21 is a DSC thermogram of Compound I Form D. [Figure 22] FIG. 22 is an FT-IR spectrum of Form D of Compound I. [Figure 23] FIG. 23 is an XRPD pattern of Form E of Compound I. [Figure 24] FIG. 24 is a DSC thermogram of Form E of Compound I. [Figure 25] FIG. 25 is an XRPD pattern of Form F of Compound I. [Figure 26] FIG. 26 is an XRPD pattern of Form G of Compound I. [Figure 27] FIG. 27 is a DSC thermogram of Form G of Compound I. [Figure 28] FIG. 28 is an XRPD pattern of Form H of Compound I. [Figure 29] FIG. 29 is a DSC thermogram of Form H of Compound I. [Figure 30] FIG. 30 is an XRPD pattern of Form H1 of Compound I. [Figure 31] FIG. 31 is an FT-IR spectrum of Form H1 of Compound I. [Figure 32] FIG. 32 is an XRPD pattern of Form J of Compound I. [Figure 33] FIG. 33 is a DSC thermogram of Form J of Compound I. [Figure 34] FIG. 34 is an FT-IR spectrum of Form J of Compound I. DETAILED DESCRIPTION OF THE INVENTION

[0012] Compound I is a potent 3CL protease inhibitor and is described in patent application WO 2022 / 109363, the contents of which are incorporated herein by reference in their entirety. Compound I is a single enantiomer with three chiral centers. The methods for preparing Compound I disclosed in WO 2022 / 109363 yield amorphous forms of Compound I, which are disclosed herein. Table 1 outlines the procedures for producing four polymorphs (Forms 1, 2, 3, and 4), a mixture of Forms 2 and 4, and ten pseudopolymorphic forms (Forms A, B, C, D, E, F, G, H, H1, and J). [Table 1]

[0013] Proton Nuclear Magnetic Resources ( 1 All polymorphs and pseudopolymorphs were proven to be identical in solution, as evidenced by H NMR. Solid-state techniques such as differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), and powder X-ray diffraction (XRD) revealed differences between the forms. The current synthetic process produces the drug substance as an anhydrous, nonsolvated, amorphous solid that is stable under the storage conditions described in this application.

[0014] In one embodiment, the present invention provides four polymorphic forms (Forms 1, 2, 3, 4), a mixture of Forms 2 and 4, and ten pseudopolymorphs (Forms A, B, C, D, E, F, G, H, H1, J) characterized by differential scanning calorimetry (DSC). The DSC thermal properties of these polymorphic and pseudopolymorphic forms are set forth in Figures 4, 8, 10, 14, 16, 18, 21, 24, 27, 29, 33, and Tables 2 and 3. [Table 2] [Table 3]

[0015] In one embodiment, the present invention provides four polymorphs (Forms 1, 2, 3, and 4), a mixture of Forms 2 and 4, and ten pseudopolymorphs (Forms A, B, C, D, E, F, G, H, H1, and J), which are further characterized by X-ray powder diffraction (XRPD). Characteristic powder diffraction peaks are expressed in degrees 2θ. The peak positions (2θ) for all forms are different from each other. The positions of the intense peaks of the polymorphic and pseudopolymorphic forms are shown in Tables 4 and 5. The relative intensities and positions of the intense peaks in Figures 3, 7, 9, 12, 13, 15, 17, 19, 20, 23, 25, 26, 28, 30, and 32 may change or shift under certain conditions, but the crystalline form remains the same. One skilled in the art can readily determine whether a given polymorphic form is the same polymorphic form as that depicted in one of Figures 3, 7, 9, 12, 13, 15, 17, 19, 20, 23, 25, 26, 28, 30, 32, Table 4 or Table 5 by comparing their peak positions and intensities in the XRPD data.

[0016] The powder X-ray diffraction data of the crystalline polymorphic and pseudopolymorphic forms and mixtures were found to be different from each other. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 5-1]

Table 5-2

Table 5-3

Table 5-4

Table 5-6

Table 5-7

Table 5-8

Table 5-9

Table 5-10

Table 5-11

Table 5-12

Table 5-13

Table 5-14

Table 5-16

[0017] In one embodiment, the present invention provides Form 1, Form 3, Form D, Form H1, and Form J, which are further characterized by Fourier transform infrared spectroscopy (FT-IR). Characteristic peaks are identified at wavenumbers (cm -1 ) The positions of characteristic peaks for each form are unique to that form. The positions of the intense peaks of polymorphs and pseudopolymorphs are shown in Table 6. The relative intensities and positions of the intense peaks in Figure 5, Figure 11, Figure 22, Figure 31, or Figure 34 may change or shift under certain conditions, but the crystalline form will remain the same. One skilled in the art should be able to readily determine whether a given polymorphic form is the same polymorphic form as that described in one of Figures 5, Figure 11, Figure 22, Figure 31, Figure 34, or Table 6 by comparing their peak positions and intensities in the IR data.

[0018] The FT-IR spectra of Form 1, Form 3, Form D, Form H1 and Form J were found to be different from each other. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5]

[0019] Form 1 of Compound I provides improved or modified physicochemical properties of the compound, including, but not limited to, solid-state properties (e.g., crystallinity, hygroscopicity, melting point), pharmaceutical properties (e.g., stability or compatibility), and crystallization characteristics (e.g., purity, yield, or morphology).

[0020] Crystalline Form 1 was further characterized by single crystal X-ray diffraction. The crystalline parameters obtained from this analysis are shown in Table 7. [Table 7]

[0021] Crystalline Form 1 was further characterized by single crystal X-ray diffraction analysis.

[0022] The results of single crystal X-ray diffraction analysis, which list the atomic positions and other structural parameters determining the structure of Form 1, are shown in Tables 8 and 9, and the bond distances and bond angles for Form 1 are listed in Table 10. Distances are expressed in angstroms and bond angles are expressed in degrees. Estimated standard deviations of bond distances and bond angles to the least significant figure are shown in parentheses. The molecular structure from single crystal X-ray diffraction analysis for Form 1 is shown as an Oak Ridge Thermal Ellipsoid Plot (ORTEP) in Figure 6. [Table 8-1] [Table 8-2] [Table 9] [Table 10-1] [Table 10-2]

[0023] The DSC thermogram of crystalline form 1 is shown in Figure 4. The DSC thermogram of crystalline form 1 has an onset temperature of 250°C and a characteristic endotherm at 251°C.

[0024] The characteristic peaks (2θ) in the X-ray powder diffraction pattern of crystalline Form 1 are shown in Figure 3. The characteristic peaks are 6.88, 8.32, 10.82, 11.90, 13.15, 13.74, 14.54, 15.41, 16.09, 18.19, 19.19, 20.04, 20.56, 21.69, 22.29, 23.87, 24.83, 25.19, 25.31, 26.13, and 26.6. at two-theta (2θ) values ​​of 6, 27.63, 27.92, 28.90, 29.29, 30.14, 31.32, 31.32, 31.74, 32.48, 32.86, 34.66, 34.95, 35.75, 36.11, 36.79, 37.12, 37.79, 38.76 and 39.74. Alternatively, the characteristic peaks can be expressed as (2θ) 6.9, 8.3, 10.8, 11.9, 13.2, 13.7, 14.5, 15.4, 16.1, 18.2, 19.2, 20.0, 20.6, 21.7, 22.3, 23.9, 24.8, 25.2, 25.3, 26.1, 26.7, 27.6, 27.9, 28.9, 29.3, 30.1, 31.3, 31.3, 31.7, 32.5, 32.9, 34.7, 35.0, 35.8, 36.1, 36.8, 37.1, 37.8, 38.8 and 39.7.

[0025] The FT-IR spectrum of crystalline Form 1 is shown in Figure 5. Form 1 exhibits the following peaks (wavenumbers (cm)): 549, 572, 592, 602, 649, 676, 706, 726, 751, 762, 803, 884, 897, 934, 967, 1016, 1050, 1087, 1111, 1128, 1161, 1185, 1201, 1227, 1243, 1320, 1392, 1447, 1470, 1485, 1528, 1546, 1599, 1673, 1694, 1712, 2868, 2960, and 3199. -1 ) has a characteristic peak at ).

[0026] Methods for preparing the polymorphs and pseudopolymorphs of the present invention are described below. For each volume / weight ratio given herein, volumes are in milliliters (mL) and weights are in grams (g).

[0027] The present invention provides a method for preparing Form 1 of Compound I by crystallization. In one embodiment, the method comprises: 1. Preparing a solution of Compound I by dehydrating (3R,5'S)-1'-(N-methyl-N-(4,6,7-trifluoro-1H-indole-2-carbonyl)-L-leucyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (Compound N) in the presence of an appropriate dehydrating reagent or reagents, a suitable base, and a suitable solvent. 2. Concentrating the solution of Compound I from Step 1 at a temperature of about 20°C to about 80°C, preferably about 45°C to about 55°C, more preferably about 50°C, to a solvent / Compound N volume (milliliters) / weight (grams) ratio of about 2:1 to about 6:1, preferably about 3.5:1 to about 4.5:1, more preferably about 4:1. 3. Optionally, adding Form 1 of Compound I as a crystal seed to the concentrated solution from Step 2 in an amount ranging from about 0.0001X (where X=weight of Compound N in Step 1) to about 0.1X, more preferably 0.001X, by weight to induce crystallization of Form 1 of Compound I. 4. Exchange the solvent for a suitable solvent at a temperature of about 20°C to about 80°C, preferably about 45°C to about 55°C, more preferably about 50°C, to a solvent / compound N ratio of about 6:1 to about 10:1, preferably about 7.5:1 to about 8.5:1, more preferably about 8:1, in terms of volume (milliliters) / weight (grams). Suitable solvents include, but are not limited to, anisole, toluene, xylene, ethyl acetate, isopropyl acetate, and mixtures of two or more thereof. Preferably, the suitable solvent is a mixture of toluene and ethyl acetate. 5. Cooling to a temperature of about 0°C to about 50°C, preferably about 20°C to about 30°C, more preferably about 25°C; and 6. Filtering the resulting suspension to provide Compound I Form 1. Includes.

[0028] In one embodiment, step 1 is carried out at a suitable temperature, such as, for example, about −10° C. to about 10° C., preferably about −5° C. to about 5° C., and more preferably about 0° C. In one embodiment, preparing the solution of Compound I is carried out over a period of about 30 minutes to about 2 hours, preferably about 1 hour.

[0029] In one embodiment of Step 1, suitable solvents include, but are not limited to, acetonitrile, acetone, dichloromethane, dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, dioxane, ethyl acetate, heptane, hexane, methyl t-butyl ether, tetrahydrofuran, toluene, and mixtures of two or more thereof. A preferred solvent is ethyl acetate. Suitable dehydrating reagents include, but are not limited to, n-propylphosphonic anhydride (T3P), trifluoroacetic anhydride (TFAA), methyl N-(triethylammonium sulfonyl)carbamate (Burgess reagent), and phosphorus oxide (PO5). A preferred dehydrating reagent is trifluoroacetic anhydride (TFAA). Suitable bases include, but are not limited to, triethylamine, diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), imidazole, pyridine, 2,6-lutidine, ethyl nicotinate, N-methylpiperazine, or 1-methylimidazole. A preferred base is triethylamine.

[0030] In certain embodiments, the present invention provides a method for preparing Form 1 of Compound I by precipitation, said method comprising: i. adding Compound I to a first solvent, such as, but not limited to, ethanol, isopropyl alcohol, ethyl acetate, isopropyl acetate, or methyl tert-butyl ether, to form a solution; Compound I used to form the solution can be a solid form of the compound or a mixture of two or more solid forms; ii. removing a portion of the first solvent from the solution, for example by distillation, and then adding more of the first solvent; iii. Repeating the process of removing a portion of the first solvent from the solution and adding more of the first solvent until a solution of Compound I is produced in which the residual solvent is adjusted to a predetermined value or less, for example, 0.1% (w / w) or less; iv. adding a second solvent, such as, but not limited to, water or n-heptane, to the solution to precipitate Form 1 of Compound I; and v. Isolating Form 1 of Compound I by filtration Includes.

[0031] The DSC thermogram of Form 2 is shown in Figure 8. The DSC thermogram has a characteristic exotherm at 175°C with an onset temperature of 175°C and an endotherm at 251°C with an onset temperature of 250°C.

[0032] In one embodiment, the characteristic peaks (2θ) in the X-ray powder diffraction pattern of Form 2 are shown in Figure 7. The characteristic peaks are at two-theta (2θ) values ​​of 6.88, 10.82, 11.90, 13.74, 14.54, 16.08, 18.10, 20.04, 20.56, 21.68, 22.29, 23.87, 24.80, 25.18, 26.12, 26.67, 27.93, 28.77, 29.23, 30.13, 31.25, 32.84, 34.28, 34.66, 35.71, 36.07, 37.10 and 39.66. Alternatively, the characteristic peaks can be expressed as (2θ) 6.9, 10.8, 11.9, 13.7, 14.5, 16.1, 18.1, 20.0, 20.6, 21.7, 22.3, 23.9, 24.8, 25.2, 26.1, 26.7, 27.9, 28.8, 29.2, 30.1, 31.3, 32.8, 34.3, 34.7, 35.77, 36.1, 37.1 and 39.9.

[0033] In one embodiment, the present invention provides a process for preparing Form 2 of Compound I. The process includes heating Form J of Compound I to a temperature of about 140° C. to about 170° C., preferably about 150° C. to about 160° C., more preferably about 155° C., to provide Form 2 of Compound I.

[0034] The DSC thermogram for Form 3 is shown in Figure 10. The DSC thermogram for Form 3 has a characteristic endotherm at 150°C with an onset temperature of 142°C. The DSC thermogram for Form 3 also has a characteristic exotherm at 176°C with an onset temperature of 171°C, followed by an endotherm at 252°C with an onset temperature of 251°C.

[0035] The characteristic peaks (2θ) in the X-ray powder diffraction pattern of Form 3 are shown in Figure 9. The characteristic peaks are 7.10, 8.71, 8.92, 11.03, 11.70, 13.07, 14.06, 15.23, 15.55, 16.17, 17.14, 17.45, 17.96, 19.16, 19.56, 20.43, 20.68, 21.89, 22.56, 23.45, 23.83, 24.06, 25.06, 26.06, 27.06, 28.06, 29.06, 30.06, 31.06, 32.06, 33.06, 34.06, 35.06, 36.06, 37.06, 38.06, 39.06, 40.06, 41.06, 42.06, 43.06, 44.06, 45.06, 46.06, 47.06, 48.06, 49.06, 50.06, 51.06, 52.06, 53.06, 54.06, 55.06, 56.06, 57.06, 58.06, 59.06, 60.06, 61.06, 62.06, 63.06, 64.06, 65.06, 66.06, 67.06, 68.06, 69.06, 70.06, 71.06 at two-theta (2θ) values ​​of .74, 25.79, 26.26, 26.95, 28.12, 28.64, 29.68, 30.44, 31.28, 31.76, 32.34, 32.79, 33.30, 34.67, 35.56, 36.11, 36.47, 37.07, 37.85, and 38.22. Alternatively, the characteristic peaks can be expressed as (2θ) 7.1, 8.7, 8.9, 11.0, 11.7, 13.1, 14.1, 15.2, 15.6, 16.2, 17.1, 17.5, 18.0, 19.2, 19.6, 20.4, 20.7, 21.9, 22.6, 23.5, 23.8, 24.7, 25.8, 26.3, 27.0, 28.1, 28.6, 29.7, 30.4, 31.3, 31.8, 32.3, 32.8, 33.3, 34.7, 35.6, 36.1, 36.5, 37.1, 37.9 and 38.2.

[0036] The characteristic peaks in the Fourier transform infrared (FT-IR) spectrum of crystalline form 3 are shown in Figure 11. -1) characteristic peaks are at 563, 589, 623, 646, 674, 706, 725, 740, 754, 802, 815, 966, 1023, 1049, 1079, 1096, 1119, 1130, 1158, 1186, 1215, 1254, 1283, 1310, 1352, 1376, 1385, 1394, 1439, 1469, 1484, 1519, 1549, 1598, 1656, 1727, 2878, 2957, 3422 and 3464.

[0037] In one embodiment, the present invention provides a process for preparing Form 3 of Compound I. The process comprises heating Form J of Compound I to a temperature of about 70° C. to about 100° C., preferably about 75° C. to about 85° C., more preferably about 80° C., to provide Form 3 of Compound I.

[0038] The characteristic peaks (2θ) in the X-ray powder diffraction pattern of Form 4 are shown in Figure 12. Form 4 has the following peaks in the X-ray powder diffraction (XRPD) pattern: 4.39, 5.14, 7.06, 7.50, 8.47, 8.92, 9.75, 10.08, 10.33, 11.03, 11.71, 12.45, 13.09, 13.83, 14.06, 14.62, 14.84, 15.38, 15.78, 15.95, 16.06. It has characteristic peaks at two-theta (2θ) values ​​of 91, 17.45, 17.93, 18.54, 19.23, 19.66, 20.07, 20.96, 21.84, 22.50, 23.42, 24.19, 24.91, 25.13, 26.18, 26.54, 27.81, 28.54, 29.41 and 30.99. Alternatively, the characteristic peaks can be expressed as (2θ) 4.4, 5.1, 7.1, 7.5, 8.5, 8.9, 9.8, 10.1, 10.3, 11.0, 11.7, 12.5, 13.1, 13.8, 14.1, 14.6, 14.8, 15.4, 15.8, 16.0, 16.9, 17.5, 17.9, 18.5, 19.2, 19.7, 20.1, 21.0, 21.8, 22.5, 23.4, 24.2, 24.9, 25.1, 26.2, 26.5, 27.8, 28.5, 29.4 and 31.0.

[0039] In one embodiment, the present invention provides a method for preparing Form 4 of Compound I. The method includes heating Form J of Compound I to a temperature of about 40° C. to about 70° C., preferably about 55° C. to about 65° C., more preferably about 60° C., to provide Form 4 of Compound I.

[0040] The DSC thermogram of a mixture of Forms 2 and 4 is shown in Figure 14. The DSC thermogram has both a characteristic melting endotherm at 175°C with an onset temperature of 166°C and an endotherm at 139°C with an onset temperature of 132°C. The DSC thermogram also has a characteristic exotherm at 151°C with an onset temperature of 147°C, followed by an endotherm at 251°C with an onset temperature of 250°C.

[0041] The characteristic peaks (2θ) in the X-ray powder diffraction pattern of a mixture of Form 2 and Form 4 are shown in FIG. Characteristic peaks (2θ) are at 4.36, 6.87, 7.06, 8.46, 8.71, 8.92, 9.77, 10.80, 11.04, 11.72, 11.89, 12.43, 12.58, 13.73, 14.06, 14.53, 15.81, 16.07, 18.08, 18.55, 20.03, 20.56, 21.06, 21.68, 21.87, 22.30, 22.58, 23.44, 23.86, 24.21, 24.79, 25.18, 26.11, 26.66, 27.90, 30.11, 31.25, 31.72, 32.88, and 35.72. Alternatively, the characteristic peaks can be expressed as (2θ) 4.4, 6.9, 7.1, 8.5, 8.7, 8.9, 9.8, 10.8, 11.0, 11.7, 11.9, 12.4, 12.6, 13.7, 14.1, 14.5, 15.8, 16.1, 18.1, 18.6, 20.0, 20.6, 21.1, 21.7, 21.9, 22.3, 22.6, 23.4, 23.9, 24.2, 24.8, 25.2, 26.1, 26.7, 27.9, 30.1, 31.3, 31.7, 32.9 and 35.7.

[0042] In one embodiment, the present invention provides a method for preparing a mixture of Forms 2 and 4 of Compound I. The method includes heating Form J of Compound I to a temperature of about 100° C. to about 140° C., preferably about 120° C. to about 130° C., and more preferably about 125° C., to provide a mixture of Forms 2 and 4 of Compound I.

[0043] The DSC thermogram of Form A of Compound I is shown in Figure 16. The DSC of Form A has an onset temperature of 107°C and a characteristic endotherm at 109°C.

[0044] The characteristic peaks (2θ) in the X-ray powder diffraction pattern of Form A are shown in Figure 15. The characteristic peaks are at two-theta (2θ) values ​​of 6.96, 8.05, 13.00, 13.97, and 21.03. Alternatively, the characteristic peaks can be expressed as (2θ) 7.0, 8.1, 13.0, 14.0, and 21.0.

[0045] In one embodiment, the present invention provides a method for preparing Form A of Compound I, the method comprising: i. preparing a suspension of an amorphous form of Compound I in a mixture of benzyl alcohol and toluene in a volume ratio of about 1:1 to about 4:1; ii. heating and then cooling the suspension at about 5°C to 50°C in multiple cycles for about 1 to 20 days, preferably about 12 days, to obtain a suspension of Form A of Compound I; and iii. filtering the suspension of Compound I Form A from step ii at a temperature of about 10°C to about 30°C, preferably about 15°C to about 25°C, more preferably about 22°C, to provide Compound I Form A. Includes.

[0046] The DSC thermogram of Form B of Compound I is shown in Figure 18. The DSC thermogram of Form B has an onset temperature of 93°C and a characteristic endotherm at 108°C.

[0047] The characteristic peaks (2θ) in the X-ray powder diffraction pattern of Form B are shown in Figure 17. The characteristic peaks are at two-theta (2θ) values ​​of 7.17, 14.33, and 21.55. Alternatively, the characteristic peaks can be designated as (2θ) 7.2, 14.3, and 21.6.

[0048] In one embodiment, the present invention provides a method for preparing Form B of Compound I, the method comprising: i. preparing a suspension of an amorphous form of Compound I in anisole; ii. repeatedly heating and cooling the suspension at about 5°C to 50°C for about 1 to 10 days, preferably about 5 days, to obtain a suspension of Form B of Compound I; and iii. filtering the suspension at a temperature of about 10°C to about 30°C, preferably about 15°C to about 25°C, more preferably about 22°C, to provide Form B of Compound I. Includes.

[0049] Characteristic peaks (2θ) in the X-ray powder diffraction pattern of Form C are shown in Figure 19. Characteristic peaks are at two-theta (2θ) values ​​of 4.99, 6.01, 6.72, 7.83, 8.70, 9.33, 10.68, 10.98, 11.66, 11.90, 12.96, 13.43, 13.71, 14.01, 14.92, 15.19, 15.53, 16.28, 17.73, 18.22, 18.96, 20.44, 21.11, 21.99, 23.09, 24.06, 25.33, 25.86, 27.91 and 28.52. Alternatively, the characteristic peaks can be expressed as (2θ) 5.0, 6.0, 6.7, 7.8, 8.7, 9.3, 10.7, 11.0, 11.7, 11.9, 13.0, 13.4, 13.7, 14.0, 14.9, 15.2, 15.5, 16.3, 17.7, 18.2, 19.0, 20.4, 21.1, 22.0, 23.1, 24.1, 25.3, 25.9, 27.9 and 28.5.

[0050] In one embodiment, the present invention provides a method for preparing Form C of Compound I, the method comprising: i. Preparing a clear solution of the amorphous form of Compound I in anisole (approximately 6 times by volume); ii. removing the anisole by slow evaporation at about 10°C to 30°C, preferably about 15°C to about 25°C, more preferably about 22°C for about 1 to 10 days, preferably about 6 days, to obtain a suspension; and iii. filtering the suspension to obtain Form C of Compound I. Includes.

[0051] The DSC thermogram of Form D of Compound I is shown in Figure 21. The DSC thermogram of Form D has an onset temperature of 117°C and a characteristic endotherm at 118°C.

[0052] In one embodiment, the characteristic peaks (2θ) in the X-ray powder diffraction pattern of Form D are shown in Figure 20. The characteristic peaks are at two-theta (2θ) values ​​of 7.10, 7.99, 8.27, 8.98, 9.89, 11.88, 13,14, 13.27, 14.16, 16.21, 17.55, 18.45, 18.77, 20.97, 21.32, 21.79, 23.11, 24.72, 26.71, and 27.72. Alternatively, the characteristic peaks can be expressed as (2θ) 7.1, 8.0, 8.3, 9.0, 9.9, 11.9, 13.1, 13.3, 14.2, 16.2, 17.6, 18.5, 18.8, 21.0, 21.3, 21.8, 23.1, 24.7, 26.7 and 27.7.

[0053] In one embodiment, the Fourier transform infrared (FT-IR) spectrum of Form D is shown in Figure 22. The FT-IR spectrum of Form D contains peaks at wavenumbers (cm) 591, 626, 671, 696, 707, 731, 752, 810, 968, 1050, 1079, 1094, 1114, 1130, 1161, 1202, 1329, 1376, 1387, 1431, 1469, 1485, 1524, 1546, 1595, 1649, 1727, 2958, and 3231. -1 ) has a characteristic peak.

[0054] In one embodiment, the present invention comprises and provides a method for preparing Form D of Compound I, the method comprising: i. preparing a suspension of Form A of Compound I in a mixed solvent comprising acetone and water; ii. stirring the suspension at a temperature of about 10°C to about 40°C, preferably about 20°C to about 30°C, more preferably about 25°C; and iii. filtering the suspension to provide Form D of Compound I. Includes.

[0055] The DSC thermogram of Form E is shown in Figure 24. The DSC thermogram of Form E has an onset temperature of 138°C and a characteristic endotherm at 142°C.

[0056] The characteristic peaks (2θ) in the X-ray powder diffraction pattern of Form E are shown in FIG. Characteristic peaks are at two-theta (2θ) values ​​of 5.85, 8.52, 9.26, 11.08, 12.69, 12.95, 13.22, 14.71, 15.01, 16.01, 16.83, 17.04, 17.56, 18.54, 18.83, 19.18, 19.73, 20.19, 20.83, 21.09, 21.38, 21.99, 22.67, 23.19, 23.77, 24.67, 25.10, 25.84, 26.68, 27.40, 27.69, 28.41, 28.97, 29.60, 30.51, 30.83, 31.99, 32.56, and 33.52. Alternatively, the characteristic peaks can be expressed as two-theta (2θ) values ​​of 5.9, 8.5, 9.3, 11.1, 12.7, 13.0, 13.2, 14.7, 15.0, 16.0, 16.8, 17.0, 17.6, 18.5, 18.8, 19.2, 19.7, 20.2, 20.8, 21.1, 21.4, 22.0, 22.7, 23.2, 23.8, 24.7, 25.1, 25.8, 26.7, 27.4, 27.7, 28.4, 29.0, 29.6, 30.5, 30.8, 32.0, 32.6 and 33.5.

[0057] In one embodiment, the present invention provides a method for preparing Form E of Compound I, the method comprising: i. preparing a suspension of Form D of Compound I in a solvent mixture comprising dimethyl sulfoxide (about a 1 / 1 ratio of dimethyl sulfoxide volume to Compound I weight) and water (about a 1 / 1 ratio of water volume to Compound I weight); ii. Seeding Compound I Form E in an amount preferably from about 0.0001X (where X=weight of Compound I in Step 1) to about 0.1X, more preferably 0.001X by weight; iii. Repeatedly heating and cooling the suspension, preferably at about 5°C to 50°C, preferably about 15 to 25 times, more preferably about 20 times; and iv. filtering the resulting suspension to provide Form E of Compound I. Includes.

[0058] The characteristic peaks (2θ) in the X-ray powder diffraction pattern of Form F are shown in Figure 25. The characteristic peaks are at two-theta (2θ) values ​​of 6.87, 13.07, and 20.63. Alternatively, the characteristic peaks can be expressed as (2θ) 6.9, 13.1, and 20.6.

[0059] In one embodiment, the present invention provides a method for preparing Form F of Compound I, the method comprising: i. preparing a suspension of Form D of Compound I in a solvent mixture comprising polyethylene glycol (about a 1 / 1 ratio of polyethylene glycol volume / Compound I weight) and water (about a 1 / 1 ratio of water volume / Compound I weight); ii. repeatedly heating and cooling the suspension, preferably at about 5°C to 50°C, preferably about 5 to 15 times, more preferably about 10 times; and iii. filtering the suspension to provide Form F of Compound I. Includes.

[0060] The DSC thermogram of Form G of Compound I is shown in Figure 27. The DSC thermogram has an onset temperature of 109°C and a characteristic endotherm at 130°C.

[0061] The characteristic peaks (2θ) in the X-ray powder diffraction pattern of Form G are shown in Figure 26. The characteristic peaks are 4, 18, 6.86, 8.35, 9.03, 9.44, 10.34, 11.08, 11.39, 12.53, 12.86, 13.28, 13.52, 14.31, 14.75, 15.14, 15.73, 16.22, 16.72, 16.96, 17.48, 17.62, 17.97, 18.75, 19.08, 19.10, 19.13, 19.14, 19.15, 19.16, 19.17, 19.18, 19.19, 19.19, 19.20, 19.21, 19.22, 19.23, 19.24, 19.26, 19.27, 19.28, 19.29, 19.30, 19.31, 19.32, 19.33, 19.34, 19.36, 19.37, 19.38, 19.40, 19.41, 19.42, 19.43, 19.46, 19.47, 19.48, 19.49, 19.50, 19.51, 19.52, 19.53, 19.54, 19.56, 19.57, 19.59, 19.66, 19.67, 19.68, at two-theta (2θ) values ​​of 68, 20.16, 20.60, 20.90, 21.13, 22.02, 22.39, 23.01, 23.38, 23.57, 23.98, 24.31, 24.64, 25.07, 25.38, 25.84, 26.63, 27.21, 28.29, 28.72, 29.01, 29.91 and 31.30. Alternatively, the characteristic peaks can be expressed as (2θ) 4, 2, 6.9, 8.4, 9.0, 9.4, 10.3, 11.1, 11.4, 12.5, 12.9, 13.3, 13.6, 14.3, 14.8, 15.1, 15.7, 16.2, 16.7, 17.0, 17.5, 17.6, 18.0, 18.8, 19.1, 19.7, 20.2, 20.6, 20.9, 21.1, 22.0, 22.4, 23.0, 23.4, 23.6, 24.0, 24.3, 24.6, 25.1, 25.4, 25.8, 26.6, 27.2, 28.3, 28.7, 29.0, 29.9 and 31.3.

[0062] In one embodiment, the present invention provides a method for preparing Form G of Compound I, the method comprising: i. preparing a suspension of Form D of Compound I in a solvent mixture comprising methyl ethyl ketone (about a 1 / 1 ratio of methyl ethyl ketone volume / Compound I weight) and heptane (about a 1 / 1 ratio of heptane volume / Compound I weight); ii. Seeding Compound I Form G in an amount preferably from about 0.0001X (where X=weight of Compound I in step 1) to about 0.1X, more preferably 0.001X, by weight; iii. Repeatedly heating and cooling the suspension, preferably at a temperature of about 5°C to 50°C; the heating and cooling cycle is preferably performed about 5 to 15 times, more preferably about 10 times; and iv. filtering the suspension to provide Form G of Compound I. Includes.

[0063] The DSC thermogram of Form H of Compound I is shown in Figure 29. The DSC thermogram of Form H has a characteristic endotherm at 74°C with an onset temperature of 60°C, followed by an endotherm at 157°C with an onset temperature of 151°C.

[0064] The characteristic peaks (2θ) in the X-ray powder diffraction pattern of Form H are shown in Figure 28. The characteristic peaks are 3.83, 7.04, 7.61, 7.79, 8.94, 9.37, 11.46, 11.68, 12.32, 12.81, 13.21, 13.74, 14.06, 14.56, 14.80, 15.14, 15.47, 15.93, 16.15, 16.63, 17.17, at two-theta (2θ) values ​​of 17.44, 18.01, 18.64, 19.03, 19.13, 19.59, 20.46, 20.82, 21.21, 22.20, 23.02, 23.22, 3.56, 23.80, 24.14, 25.85, 26.76, 26.96 and 27.56. Alternatively, the characteristic peaks can be expressed as (2θ) 3.8, 7.0, 7.6, 7.8, 8.9, 9.4, 11.5, 11.7, 12.3, 12.8, 13.2, 13.7, 14.1, 14.6, 14.8, 15.1, 15.5, 15.9, 16.2, 16.6, 17.2, 17.4, 18.0, 18.6, 19.0, 19.1, 19.6, 20.5, 20.8, 21.2, 22.2, 23.0, 23.2, 23.6, 23.8, 24.1, 25.9, 26.8, 27.0 and 27.6.

[0065] In one embodiment, the present invention provides a method for preparing Form H of Compound I, comprising: i. preparing a suspension of Form D of Compound I in a solvent mixture comprising isopropyl alcohol (about a 1 / 1 ratio of isopropyl alcohol volume to Compound I weight) and water (about a 1 / 1 ratio of water volume to Compound I weight); ii. Seeding Compound I Form H in an amount preferably from about 0.0001X (where X=weight of Compound I in Step 1) to about 0.1X, more preferably 0.001X, by weight; iii. stirring the suspension at preferably about 10°C to 40°C, preferably about 20°C to 30°C, more preferably 25°C, for preferably about 5 days to about 15 days, more preferably about 10 days; and iv. filtering the suspension to provide Form H of Compound I. Includes.

[0066] In one embodiment, the characteristic peaks (2θ) in the X-ray powder diffraction pattern of Form H1 are shown in Figure 30. The characteristic peaks are 3.91, 6.45, 7.08, 7.58, 7.90, 8.14, 9.28, 9.76, 10.32, 10.68, 11.63, 12.51, 12.95, 13.27, 14.15, 14.78, 15.12, 15.86, 16.57, 17.56, 17.98, 18.43, 18.67, 19.4 at two-theta (2θ) values ​​of 1, 20.25, 20.79, 21.25, 21.42, 21.74, 22.93, 23.36, 23.86, 24.09, 24.69, 25.40, 26.24, 26.94, 27.24, 28.16, 28.67, 29.67, 30.48, 31.12, 31.75 and 33.71. Alternatively, the characteristic peaks can be expressed as (2θ) 3.9, 6.5, 7.1, 7.6, 7.9, 8.1, 9.3, 9.8, 10.3, 10.7, 11.6, 12.5, 13.0, 13.3, 14.2, 14.8, 15.1, 15.9, 16.6, 17.6, 18.0, 18.4, 18.7, 19.4, 20.3, 20.8, 21.3, 21.4, 21.7, 22.9, 23.4, 23.9, 24.1, 24.7, 25.4, 26.2, 26.9, 27.2, 28.2, 28.7, 29.7, 30.5, 31.1, 31.8 and 33.7.

[0067] In one embodiment, the Fourier transform infrared (FT-IR) spectrum of crystalline form H1 is shown in Figure 31. The FT-IR spectrum is -1) It has characteristic peaks at 537, 590, 627, 674, 708, 732, 744, 755, 791, 811, 969, 1053, 1084, 1110, 1132, 1161, 1203, 1234, 1284, 1325, 1388, 1445, 1470, 1525, 1598, 1638, 1658, 1711 and 3245.

[0068] The present invention provides a method for preparing Form H1 of Compound I. The method comprises storing Form H of Compound I at about −15° C. to 20° C., preferably about 0° C. to 10° C., more preferably about 25° C., preferably for about 1 month to 12 months, more preferably about 6 months, to provide Form H1 of Compound I.

[0069] The DSC thermogram of Form J of Compound I is shown in Figure 33. The DSC thermogram has a characteristic endotherm at 110°C with an onset temperature of 83°C and an endotherm at 140°C with an onset temperature of 133°C. The DSC thermogram also has a characteristic exotherm at 179°C with an onset temperature of 133°C, followed by an endotherm at 251°C with an onset temperature of 250°C.

[0070] The characteristic peaks (2θ) in the X-ray powder diffraction pattern of Form J are shown in Figure 32. The characteristic peaks are 4.36, 6.92, 7.05, 7.44, 8.21, 8.45, 9.47, 9.76, 10.22, 10.80, 11.26, 11.49, 12.02, 12.41, 12.90, 13.48, 13.74, 14.09, 14.53, 14.82, 15.24, 15.63, 15.78, 16.07, 16.41, 16.61, 17.60, 17.95, 18.20, 18.64, 19.13, 19.43, 19.72, 20.03, 20.26, 20.36, 20.51, 21.1 at two-theta (2θ) values ​​of 1, 21.87, 22.32, 22.97, 23.07, 23.35, 23.80, 24.14, 24.75, 24.99, 25.16, 25.42, 26.11, 26.69, 27.12, 27.42, 27.89, 28.51, 28.74, 29.16, 29.89, 30.06, 30.51, 31.07, 31.42, 31.98, 32.33, 32.88, 33.67, 34.13, 34.38, 35.03, 35.73, 36.53, 37.47, and 38.84. Alternatively, the characteristic peaks are (2θ) 4.4, 6.9, 7.1, 7.4, 8.2, 8.5, 9.5, 9.8, 10.2, 10.8, 11.3, 11.5, 12.0, 12.4, 12.9, 13.5, 13.7, 14.1, 14.5, 14.8, 15.2, 15.6, 15.8, 16.1, 16.4, 16.6, 17.6, 18.0, 18.2, 18.6, 19.1, 19.4, 19.7, 20.0, 20.3, 20.4, 20.5 , 21.1, 21.9, 22.3, 23.0, 23.1, 23.4, 23.8, 24.1, 24.8, 25.0, 25.2, 25.4, 26.1, 26.7, 27.1, 27.4, 27.9, 28.5, 28.7, 29.2, 29.9, 30.1, 30.5, 31.1, 31.4, 32.0, 32.3, 32.9, 33.7, 34.1, 34.4, 35.0, 35.7, 36.5, 37.5 and 38.8.

[0071] The Fourier transform infrared (FT-IR) spectrum of Form J is shown in Figure 34. The FT-IR spectrum shows characteristic wavenumbers (cm) at 564, 598, 620, 648, 676, 706, 737, 749, 813, 910, 968, 1005, 1019, 1065, 1089, 1120, 1133, 1156, 1209, 1249, 1267, 1306, 1326, 1353, 1377, 1394, 1426, 1439, 1471, 1484, 1522, 1546, 1598, 1657, 1723, 2870, 2957, 3196, and 3335. -1 ) has a characteristic peak.

[0072] In one embodiment, the present invention provides a method for preparing Form J of Compound I, the method comprising: i. preparing a solution of Compound I in about 2.3X by volume (X=weight of Compound I) tetrahydrofuran, preferably at about 10°C to 40°C, more preferably at about 22°C to 25°C; ii. preferably adding about 0.001X to about 0.1X of Form J of Compound I as a seed and about 3X by volume of heptane to provide a suspension of Compound Form J; and iii. filtering the suspension to provide Form J of Compound I. Includes.

[0073] In another aspect, the present invention features a substantially pure crystalline (polymorphic or pseudopolymorphic) form of Compound I having characteristic peaks in an X-ray powder diffraction (XRPD) pattern as shown in Figures 3, 7, 9, 12, 13, 15, 17, 19, 20, 23, 25, 26, 28, 30, and 32. As used herein, the term "substantially pure," when used with respect to a given crystalline form, refers to a crystalline form that is at least about 90% pure. This means that the crystalline form contains no more than about 10% of any other form of Compound I. Preferably, the term "substantially pure" refers to a crystalline form of Compound I that is at least about 95% pure. This means that the crystalline form of Compound I contains no more than about 5% of any other form of Compound I. More preferably, the term "substantially pure" refers to a crystalline form of Compound I that is at least about 97% pure. This means that the crystalline form of Compound I contains no more than about 3% of any other form of Compound I.

[0074] Each polymorph and pseudopolymorph disclosed herein 1 The 1 H NMR spectrum is largely consistent with compound I.

[0075] The instruments and associated methods used to characterize the polymorphs and pseudopolymorphs of Compound I are listed in Table 11. The results of these studies are shown in Figures 1-34. As is known in the art, the relative intensities of the peaks in Figures 1-34 may change or shift under certain conditions, but the polymorphs and pseudopolymorphs are the same. One of ordinary skill in the art can readily determine whether a given polymorphic form or pseudopolymorphic form is the same polymorphic form or pseudopolymorphic form described herein by comparing its XRPD pattern with Figures 3, 7, 9, 12, 13, 15, 17, 19, 20, 23, 25, 26, 28, 30, and 32, its DSC thermogram with Figures 4, 8, 10, 14, 16, 18, 21, 24, 27, 29, and 33 for DSC, and its FTIR spectrum with Figures 5, 11, 22, 31, and 34. [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4]

[0076] In one embodiment, a process or composition of the invention described herein (including any process or composition described in any aspect, embodiment, example, or preference) uses or comprises substantially pure crystalline Form 1 of Compound I. For example, crystalline Form 1 can be at least 90% pure, preferably at least 95% pure, or more preferably at least 97% pure.

[0077] In one embodiment, a process or composition of the invention described herein (including any process or composition described in any aspect, embodiment, example, or preference) uses or includes substantially pure Form 2 of Compound I. For example, Form 2 can be at least 90% pure, preferably at least 95% pure, or more preferably at least 97% pure.

[0078] In one embodiment, a process or composition of the invention described herein (including any process or composition described in any aspect, embodiment, example, or preference) uses or comprises substantially pure Form 3 of Compound I. For example, Form 3 can be at least 90% pure, preferably at least 95% pure, or more preferably at least 97% pure.

[0079] In one embodiment, the processes or compositions of the invention described above (including any process or composition described in any aspect, embodiment, example, or preference) use substantially pure Form 4 of Compound I. For example, Form 4 can be at least 90% pure, preferably at least 95% pure, or more preferably at least 97% pure.

[0080] In one embodiment, the processes of the invention described above (including any process described in any aspect, embodiment, example, or preference) use substantially pure Form A of Compound I. For example, Form A can be at least 90% pure, preferably at least 95% pure, or more preferably at least 97% pure.

[0081] In one embodiment, the processes of the invention described above (including any process described in any aspect, embodiment, example, or preference) use substantially pure Form B of Compound I. For example, Form B can be at least 90% pure, preferably at least 95% pure, or more preferably at least 97% pure.

[0082] In one embodiment, the processes of the invention described above (including any process described in any aspect, embodiment, example, or preference) use substantially pure Form C of Compound I. For example, Form C can be at least 90% pure, preferably at least 95% pure, or more preferably at least 97% pure.

[0083] In one embodiment, the processes of the invention described above (including any process described in any aspect, embodiment, example, or preference) use substantially pure Form D of Compound I. For example, Form D can be at least 90% pure, preferably at least 95% pure, or more preferably at least 97% pure.

[0084] In one embodiment, the processes of the invention described above (including any process described in any aspect, embodiment, example, or preference) use substantially pure Form E of Compound I. For example, Form E can be at least 90% pure, preferably at least 95% pure, or more preferably at least 97% pure.

[0085] In one embodiment, the processes of the invention described above (including any process described in any aspect, embodiment, example, or preference) use substantially pure Form F of Compound I. For example, Form F can be at least 90% pure, preferably at least 95% pure, or more preferably at least 97% pure.

[0086] In one embodiment, the processes of the invention described above (including any process described in any aspect, embodiment, example, or preference) use substantially pure Form G of Compound I. For example, Form G may be at least 90% pure, preferably at least 95% pure, or more preferably at least 97% pure.

[0087] In one embodiment, the processes of the invention described above (including any process described in any aspect, embodiment, example, or preference) use substantially pure Form H of Compound I. For example, Form H can be at least 90% pure, preferably at least 95% pure, or more preferably at least 97% pure.

[0088] In one embodiment, the processes of the invention described above (including any process described in any aspect, embodiment, example, or preference) use substantially pure Form H1 of Compound I. For example, Form H1 can be at least 90% pure, preferably at least 95% pure, or more preferably at least 97% pure.

[0089] In one embodiment, the processes of the invention described above (including any process described in any aspect, embodiment, example, or preference) use substantially pure Form J of Compound I. For example, Form J can be at least 90% pure, preferably at least 95% pure, or more preferably at least 97% pure.

[0090] Unless otherwise defined, all technical and scientific terms used herein are consistent with the meaning commonly known to those skilled in the art. All references cited herein, whether in print, electronic, computer-readable storage media, or other form, are expressly incorporated by reference in their entirety, including, but not limited to, abstracts, articles, magazines, publications, texts, papers, Internet websites, databases, patents, and patent publications.

[0091] Pharmaceutical Compositions The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a polymorph or pseudopolymorph of Compound I of the present invention, or a combination of two or more such polymorphs or pseudopolymorphs of Compound I, formulated together with one or more pharmaceutically acceptable carriers or excipients.

[0092] As used herein, the term "pharmaceutically acceptable carrier or excipient" means a non-toxic, inert solid, semi-solid, or liquid filler, diluent, encapsulating material, or formulation auxiliary of any type. Some examples of materials which may serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer, and other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening agents, flavorings and perfuming agents, preservatives, and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0093] The pharmaceutical compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir, preferably by oral administration or injection.The pharmaceutical compositions of the present invention can contain any conventional non-toxic pharmaceutically acceptable carrier, adjuvant, or vehicle.In some cases, the pH of the formulation can be adjusted with pharmaceutically acceptable acids, bases, or buffers to enhance the stability of the formulated compound or its delivery form.The term parenteral as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0094] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to active compounds, liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions can also contain auxiliary agents such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings and fragrances.

[0095] Injectable preparations, for example, sterile injectable aqueous or oily suspensions, can be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0096] Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0097] To prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of a drug depends on its dissolution rate, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. The drug release rate can be controlled depending on the ratio of drug to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations have also been prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0098] Compositions for rectal or vaginal administration are preferably suppositories, which may be prepared by mixing a compound of the invention with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity to release the active compound.

[0099] The solid dosage form for oral administration includes capsules, tablets, pills, powders and granules.In such solid dosage form, active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) filler or extender, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binder, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose and acacia, c) humectant, such as glycerol, d) disintegrant, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retardant. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0100] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0101] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation field.They may optionally contain opacifying agents and can also be of a composition that releases the active ingredient only or preferentially in a certain part of the intestinal tract, optionally in a delayed manner.Examples of embedding compositions that can be used include polymeric substances and waxes.

[0102] The dosage forms for topical or transdermal administration of the compound of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and, if necessary, with any necessary preservatives or buffers.Ophthalmic preparations, ear drops, eye ointments, powders and solutions are also considered to be within the scope of the present invention.

[0103] The ointments, pastes, creams and gels may contain, in addition to the active compounds of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0104] Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain conventional propellants such as chlorofluorohydrocarbons.

[0105] Transdermal patch has the additional advantage of providing controlled delivery of compound to the body.Such dosage forms can be prepared by dissolving or dispensing compound in suitable medium.Absorption enhancers can also be used to increase the flux of compound across the skin.The rate can be controlled by providing a rate-controlling membrane or by dispersing compound in a polymer matrix or gel.

[0106] For pulmonary delivery, the therapeutic compositions of the present invention are formulated and administered to patients / animals in solid or liquid particulate form by direct administration, for example, inhalation into the respiratory system.The solid or liquid particulate form of the active compound prepared for carrying out the present invention includes particles of respirable size, i.e., particles small enough to pass through the mouth and larynx upon inhalation and enter the bronchi and alveoli of the lungs.The delivery of aerosolized therapeutic agents, particularly aerosolized antibiotics, is known in the art (see, for example, U.S. Patent No. 5,767,068 to Van Devanter et al., U.S. Patent No. 5,508,269 to Smith et al., and International Publication No. WO 98 / 43650 to Montgomery, all of which are incorporated herein by reference).

[0107] Antiviral activity The present invention provides a treatment for preventing a viral infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a polymorph or pseudopolymorph of Compound I described herein, or a combination of two or more thereof. The viral infection is preferably a coronavirus infection. In certain embodiments, the coronavirus is SARS-CoV-1, SARS-CoV-2, or MERS-CoV. Preferably, the coronavirus is SARS-CoV-2.

[0108] A viral suppressive amount or dose of Compound I of the present invention can range from about 0.01 mg / kg to about 500 mg / kg, or from about 1 to about 50 mg / kg. The suppressive amount or dose will also vary depending on the route of administration and the possibility of co-administration with other drugs.

[0109] According to the treatment methods of the present invention, viral infections are treated or prevented in a patient / subject, such as a human or another animal, by administering to the patient / subject a therapeutically effective amount of a compound of the present invention in an amount and for a time necessary to achieve the desired result.

[0110] A "therapeutically effective amount" of a compound of the present invention refers to that amount of compound that confers a therapeutic effect on the treated subject at a reasonable benefit / risk ratio applicable to any medical treatment. The therapeutic effect can be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject shows an indication of or feels an effect). A therapeutically effective amount of the compound described above can range, for example, from about 0.1 mg / kg to about 500 mg / kg, preferably from about 1 to about 50 mg / kg. The effective dose will also vary depending on the route of administration and the possibility of coadministration with other drugs. It will be understood, however, that the total daily dose of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend on a variety of factors, including the disorder being treated and the severity of the disorder, the activity of the particular compound used, the particular composition used, the age, weight, general health, sex and diet of the patient, the time of administration, route of administration and rate of excretion of the particular compound used, the duration of treatment, drugs used in combination or concomitantly with the particular compound used, and similar factors well known in the medical arts.

[0111] The total daily dose of the compounds of this invention administered to a human or other animal in single or divided doses can be, for example, 0.01 to 50 mg / kg body weight or more, usually 0.1 to 25 mg / kg body weight. Single dose compositions may contain such amounts, or fractions thereof, to make up the daily dose. In general, treatment regimens according to the present invention comprise administering to a patient in need of such treatment from about 10 mg to about 1000 mg of the compounds of this invention per day, in single or multiple doses.

[0112] The compounds of the present invention described herein can be administered, for example, by intravenous, intraarterial, subdermal, intraperitoneal, intramuscular, or subcutaneous injection, or orally, buccally, nasally, transmucosally, topically, in ophthalmic preparations, or by inhalation, at doses ranging from about 0.1 to about 500 mg / kg body weight, or at doses of 1 mg to 1000 mg / dose, every 4 to 120 hours, or according to the requirements of the particular drug. The methods herein contemplate administering an effective amount of a compound or compound composition to achieve the desired or described effect. Typically, pharmaceutical compositions of the present invention are administered about 1 to about 6 times per day, or alternatively as a continuous infusion. Such administration can be used for chronic or acute treatment. The amount of active ingredient that can be combined with pharmaceutical excipients or carriers to produce a single dosage form will vary depending on the host treated and the particular mode of administration. Typical preparations contain about 5% to about 95% active compound (w / w). Alternatively, such preparations may contain from about 20% to about 80% active compound. Lower or higher doses than those recited above may be required. The specific dosage and treatment regimen for any particular patient / animal will depend on a variety of factors, including the activity of the specific compound used, the patient's age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition, or symptom, the patient's predisposition to the disease, condition, or symptom, and the judgment of the treating physician.

[0113] Once the patient's / animal's condition improves, a maintenance dose of the compound, composition or combination of the present invention can be administered as needed.Then, the dosage or frequency of administration, or both, can be reduced as a function of symptoms, to a level at which the improved condition is maintained when the symptoms are alleviated to a desired level.However, the patient / animal may require intermittent treatment on a long-term basis in response to any recurrence of disease symptoms.

[0114] Combination and Alternative Therapies The compounds of the present invention may be used in combination with one or more antiviral or anti-inflammatory therapeutic agents useful in the prevention or treatment of viral diseases or associated pathophysiology. Thus, the compounds of the present invention and their salts, solvates, or other pharmaceutically acceptable derivatives may be used alone or in combination with other antiviral or anti-inflammatory therapeutic agents.The compounds herein and pharmaceutically acceptable salts thereof may be used in combination with one or more other agents that may be useful in the prevention or treatment of respiratory diseases, inflammatory diseases, autoimmune diseases, such as antihistamines, corticosteroids (e.g., fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, ciclesonide, mometasone furoate, triamcinolone, flunisolide), NSAIDs, leukotriene modulators (e.g., montelukast, zafirlukast, pranlukast), tryptophan, benzodiazepines (e.g., benzodiazepines), and the like. and / or steroids such as steroid hormone receptor antagonists, IKK2 inhibitors, p38 inhibitors, Syk inhibitors, protease inhibitors such as elastase inhibitors, integrin antagonists (e.g. beta-2 integrin antagonists), adenosine A2a agonists, mediator release inhibitors such as sodium cromoglycate, 5-lipoxygenase inhibitors (zyflo), DP1 antagonists, DP2 antagonists, PI3K delta inhibitors, ITK inhibitors, LP (lysophosphatidic acid) inhibitors or FLAP (5-lipoxygenase activating protein) inhibitors (e.g. naphthostat thorium 3-(3-(tert-butylthio)-1-(4-(6-ethoxypyridin-3-yl)benzyl)-5-((5-ethylpyridin-2-yl)methoxy)-1H-indol-2-yl)-2,2-dimethylpropanoate), bronchodilators (e.g., muscarinic antagonists, beta-2 agonists), methotrexate, and similar agents, monoclonal antibody therapy, e.g., anti-lgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1, and similar agents, cytokine receptor therapy, e.g., Etanercept and similar agents may be used in combination with appropriate anti-infective agents, including antigen-nonspecific immunotherapy (e.g., interferons or other cytokines / chemokines, chemokine receptor modulators such as CCR3, CCR4 or CXCR2 antagonists, other cytokine / chemokine agonists or antagonists, TLR agonists and similar agents), antibiotics, including those listed at https: / / www.drugs.com / drug-class / anti-infectives.html, antifungals, anthemintic agents, antimalarials, antiprotozoans, antituberculous agents, and antivirals.In general, combination therapy is typically preferred over alternation therapy because it induces multiple simultaneous stresses on the virus.

[0115] When a composition of the invention comprises one or more polymorphs or pseudopolymorphs of Compound I described herein and one or more additional therapeutic or prophylactic agents, both the compound and the additional agents should be present at dosage levels that are about 1-100%, more preferably about 5-95%, of the dosage normally administered in a monotherapy regimen. The additional agents may be administered separately from the compound of the invention as part of a multiple dose regimen.

[0116] Alternatively, those agents may be part of a single dosage form, combined with the compounds of this invention in a single composition.

[0117] "Additional therapeutic or prophylactic agents" include, but are not limited to, immunotherapy (e.g., interferon), therapeutic vaccines, antifibrotic agents, anti-inflammatory agents such as corticosteroids or NSAIDs, bronchodilators such as beta-2 adrenergic agonists and xanthines (e.g., theophylline), mucolytic agents, antimuscarinics, anti-leukotrienes, cell adhesion inhibitors (e.g., ICAM antagonists), antioxidants (e.g., N-acetylcysteine), cytokine agonists, cytokine antagonists, pulmonary surfactants, and / or antibacterial and antiviral agents (e.g., ribavirin and amantidine). The compositions according to the invention may also be used in combination with gene replacement therapy. [Example]

[0118] The compounds and methods of the present invention will be better understood in connection with the following examples, which are intended as illustrative only and not to limit the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art, and such changes and modifications, including but not limited to with respect to the chemical structures, substituents, derivatives, formulations and / or methods of the invention, may be made without departing from the spirit of the invention and the scope of the appended claims.

[0119] Example 1: Preparation of Form 1 of Compound I Procedure 1A: Ethyl acetate (700 mL, 10 V (volume), 1 volume means 1 g of solid in 1 mL of solvent) was added to a reactor (R1), followed by the compound (3R,5'S)-1'-(N-methyl-N-(4,6,7-trifluoro-1H-indole-2-carbonyl)-L-leucyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (70 g). The reaction mixture was cooled to 0°C (-5 to +5°C), and then triethylamine (89.6 g) was added, followed by trifluoroacetic anhydride (92.4 g) at 0°C (-5 to +5°C). The reaction mixture was stirred at 0°C (-5 to +5°C) for 1 hour (0.5 to 2 hours). Upon completion of the reaction, the reaction mixture was slowly added to 0.2 N aqueous HCl (700 g) over 1 h at 0 °C (-5 to 5 °C). The resulting solution was stirred at 0 °C (-5 to 5 °C) for 10 to 30 min, and the organic layer was separated. The organic layer was separated and washed five times with 10% brine. The organic layer was then separated and distilled to 280 mL (Note: 280 mL is the total volume of the solution). Form 1 crystal seeds were added to induce crystallization at 50 °C. A toluene-EtOAc exchange was then performed to adjust the EtOAc level to 1 to 5% wt / wt (weight of EtOAc / weight of toluene by gas chromatography) by repeating the cycle by adding approximately 10 V of toluene, followed by distillation to 8 V, then adding 8 V of toluene, followed by distillation to 8 V (Note: volume of solution). The suspension was slowly cooled from 50 °C to 25 °C over 1 h and stirred at 25 °C (20 to 30 °C) for 5 h (3 to 8 h). The suspension was filtered and the wet cake was rinsed with toluene (2 V). The wet cake was dried at 50 °C (45-55 °C) for 48 h to give Form 1 of Compound I as a white solid in 80-85% yield.

number

[0120] Procedure 1B: Ethyl acetate (300 mL, 10 volumes, where 1 volume represents 1 g of solid in 1 mL of solvent) was added to the reactor (R1), followed by the compound (3R,5'S)-1'-(N-methyl-N-(4,6,7-trifluoro-1H-indole-2-carbonyl)-L-leucyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (30 g) to form a clear solution. The reaction was cooled to 0°C (-5 to 5°C), and then triethylamine (38.3 g) was added, followed by trifluoroacetic anhydride (39.7 g) at 0°C (-5 to 5°C). The reaction was stirred at 0°C (-5 to 5°C) for 20 minutes, after which a sample was taken for purity analysis. Upon completion of the reaction, the reaction mixture was slowly added to 0.2 N aqueous HCl (300 g) in reactor R2 over 1 h at 0 °C (-5 to 5 °C). The resulting solution was stirred at 0 °C (-5 to 5 °C) for 20 min, and the organic layer was separated and washed five times with 10% brine (300 mL). The organic layer was then separated and distilled under vacuum below 50 °C to 60 mL (Note: 60 mL is the volume of the solution). Toluene (300 mL) was then added, and the mixture was concentrated to 120 mL. Additional toluene (300 mL) was added, and the resulting mixture was concentrated to a final volume of 240 mL. The temperature of the mixture was adjusted to 75 °C (70 to 80 °C) and stirred at 75 °C (70 to 80 °C) for 1 h. The mixture was then slowly cooled to 20 °C (15 to 25 °C) over 1 h, and the resulting suspension was stirred at 20 °C (15 to 25 °C) for 1 h (0.5 to 2 h). The suspension was filtered and the wet cake was rinsed with toluene (60 mL). The wet cake was dried at 50 °C (45-55 °C) for 16 h to give Form 1 of Compound I as a white solid in 80-85% yield.

number

[0121] Procedure 2: To further purify Compound I Form 1, such as Form 1 prepared as described in Procedure 1(a) or 1(b) above, the following procedure is used: 20 g of Compound I and ethanol (300 mL, 15V) were added to a reactor at 20-30°C. The mixture was stirred at 70-80°C to completely dissolve Compound I Form 1. The solution was slowly cooled to 60°C over 1 hour. Compound I Form 1 seeds were added to induce crystallization, and the resulting suspension was stirred at 60°C for 0.5-1.5 hours. The suspension was then slowly cooled to 20-30°C over 1 hour. Water (300 mL, 15V) was slowly added to the suspension over 5 hours. The resulting suspension was stirred at 20-30°C for 0.5-2 hours. The slurry was filtered, and the wet cake was rinsed with EtOH / HO (30 mL / 30 mL). The wet cake was dried at 50°C (45-55°C) for 48 hours to give Compound I Form 1 as a solid in 95-100% yield.

number

[0122] Example 2: Preparation of Form 2 of Compound I Approximately 15 mg of Compound I Form J was heated to 155° C. at a rate of 10° C. / min and held at 155° C. for 3 minutes to obtain Compound I Form 2.

[0123] Example 3: Preparation of Form 3 of Compound I During a variable temperature powder X-ray diffraction (VT-XRPD) experiment, approximately 15 mg of Compound I Form J was heated to 80° C. and then cooled at ambient conditions for approximately 3 hours to yield Compound I Form 3.

[0124] Example 4: Preparation of Form 4 of Compound I During a variable temperature powder X-ray diffraction (VT-XRPD) experiment, approximately 15 mg of Compound I Form J was heated to 60° C. to give Compound I Form 4.

[0125] Example 5: Preparation of Form A of Compound I 100 mg of amorphous Compound I was stirred in a mixture of benzyl alcohol (BnOH) and toluene (20:80, v / v) and temperature cycled between 5°C and 50°C using a heating / cooling rate of 0.1°C / min. After approximately 4 to 15 cycles, the wet cake was collected by filtration to obtain Compound I Form A. The wet cake was 1 By H-NMR it contains approximately 23.1% by weight of BnOH (1.5 equivalents) and 0.5% by weight of toluene (0.04 equivalents).

[0126] Example 6: Preparation of Form B of Compound I 100 mg of amorphous Compound I was stirred in anisole and temperature cycled between 5°C and 50°C using a heating / cooling rate of 0.1°C / min. After approximately 4 to 15 cycles, the wet cake was collected by filtration to obtain Compound I Form B. The wet cake was 1 By H-NMR it contains 13.4% anisole by weight (0.8 equivalents).

[0127] Example 7: Preparation of Form C of Compound I Approximately 30 mg of amorphous Compound I was dissolved in anisole. The resulting solution was filtered through a 0.45 μm membrane filter. The resulting clear solution was slowly evaporated under ambient conditions to obtain Compound I Form C. The wet cake was 1 Contains approximately 60.7% anisole by weight (7.7 equivalents) by 1 H NMR.

[0128] Example 8: Preparation of Form D of Compound I 10 g of amorphous Compound I was dissolved in 100 ml of EtOAc. A solvent exchange was performed under vacuum to replace the EtOAc with toluene to a final volume of approximately 30-40 ml at or below 50°C. Additional toluene (50 mL) was added and the slurry was stirred at 50°C for 2 hours. The suspension was cooled to 20°C over 1-2 hours and then stirred at 20°C (15-25°C) for 10 hours. The suspension was filtered, rinsed with toluene (20 mL), and then dried to obtain Compound I Form D.

[0129] Example 9: Preparation of Form E of Compound I Approximately 200 mg of Compound I Form D was added to a 2 mL glass vial. 1.2 mL of DMSO / water (1:1, v / v) was added to the vial. The mixture was stirred at 25°C for approximately 5 minutes to obtain a suspension. Approximately 10 mg of crystal seeds of Form E were added to the suspension. The suspension was stirred by temperature cycling between 5°C and 50°C using a heating / cooling rate of 0.1°C / min for 20 cycles. The resulting suspension was filtered through a 0.45 μm membrane filter by centrifugation. The wet cake was collected to obtain Compound I Form E.

[0130] Example 10: Preparation of Form F of Compound I Approximately 50 mg of Compound I Form D was stirred in 0.1-0.2 mL of PEG / water (1:1, v / v) at a temperature cycle between 5°C and 50°C using a heating / cooling rate of 0.1°C / min for at least 10 cycles. The resulting suspension was filtered through a 0.45 μm membrane filter by centrifugation at 14,000 rpm. The wet cake was collected to obtain Compound I Form F.

[0131] Example 11: Preparation of Form G of Compound I Approximately 200 mg of Compound I Form D was added to a 2 mL glass vial. 0.4 mL of MEK / heptane (1:1, v / v) was added to the vial. The mixture was stirred at 25°C for approximately 5 minutes to obtain a suspension. Approximately 10 mg of crystal seeds of Form G were added to the suspension. The suspension was stirred at a temperature cycle between 5°C and 50°C using a heating / cooling rate of 0.1°C / min for 10 cycles. The resulting suspension was filtered through a 0.45 μm membrane filter by centrifugation at 14,000 rpm. The wet cake was collected to obtain Compound I Form G.

[0132] Example 12: Preparation of Form H of Compound I Approximately 200 mg of Compound I Form D was added to a 2 mL glass vial. 0.4 mL of IPA / water (1:1, v / v) was added to the vial. The resulting mixture was stirred at 25° C. for approximately 5 minutes to obtain a suspension. Approximately 10 mg of crystal seeds of Form H were added to the above suspension. The suspension was stirred at 25° C. for approximately 10 days. The solid was collected by centrifugation and then dried under vacuum at 50° C. for approximately 1 hour. Approximately 180 mg of Compound I Form H was obtained as an off-white solid in 90% yield.

[0133] Example 13: Preparation of Form H1 of Compound I Approximately 10 mg of Compound I Form H was stored at 4° C. for 6 months to obtain Compound I Form H1.

[0134] Example 14: Preparation of Form J of Compound I Approximately 130 mg of Compound I Form 1 was dissolved in 0.3 mL of THF at approximately 22-25°C. The resulting solution was filtered through a 0.45 μm membrane filter. Form J seeds were added to the resulting clear solution, followed by the slow addition of 0.4 mL of heptane to form a suspension. The solid was collected by centrifugal filtration through a 0.45 μm membrane filter at 14,000 rpm to obtain Compound I Form J.

[0135] Abbreviation DSC: Differential scanning calorimetry DVS: Dynamic Vapor Sorption FT-IR: Fourier transform infrared RH: Relative humidity PEG: polyethylene glycol XRPD: X-ray powder diffraction 1 H-NMR: proton nuclear magnetic resonance T3P: Propanephosphonic anhydride TFAA: Trifluoroacetic anhydride P2O5: Phosphorus pentoxide MEK: Methyl ethyl ketone EtOH: ethanol H2O: Water DMSO: dimethyl sulfoxide EtOAc: ethyl acetate HCl: Hydrogen chloride ACN: acetonitrile

[0136] While the present invention has been particularly shown and described with reference to preferred 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. Crystalline Form 1 of Compound I, 【Chemical 1】 3. Crystalline Form 1 of Compound I, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having characteristic peaks at values ​​of two-theta (°2θ) of 6.9, 8.3, 10.8, 11.9, 13.2, 13.7, 14.5, 15.4, 16.1, 18.2, 19.2, 20.0, 20.6, 21.7, 22.3, 23.9, 24.8, 25.2, 25.3, 26.1, 26.7, 27.6, 27.9, 28.9, 29.3, 30.1, 31.3, 31.3, 31.7, 32.5, 32.9, 34.7, 35.0, 35.8, 36.1, 36.8, 37.1, 37.8, 38.8, and 39.

7.

2. 10. The crystalline form of claim 1, further characterized by a differential scanning calorimeter thermogram having an endotherm at 251°C with an onset temperature of 250°C.

3. 3. The crystalline form of claim 1 or claim 2, characterized by the X-ray powder diffraction powder pattern of FIG.

4. 4. The crystalline form of any one of claims 1 to 3, wherein the crystalline form is characterized by a differential scanning calorimeter thermogram having an endotherm at 175°C with an onset temperature of 175°C and an endotherm at 251°C with an onset temperature of 250°C.

5. Crystalline Form 2 of Compound I, 【Chemistry 2】 Crystalline Form 2 of Compound I, wherein the crystalline form is characterized by an X-ray powder diffraction pattern with characteristic peaks at 6.9, 10.8, 11.9, 13.7, 14.5, 16.1, 18.1, 20.0, 20.6, 21.7, 22.3, 23.9, 24.8, 25.2, 26.1, 26.7, 27.9, 28.8, 29.2, 30.1, 31.3, 32.8, 34.3, 34.7, 35.77, 36.1, 37.1, and 39.9 two-theta (°2θ).

6. 5. The crystalline form of claim 4, wherein the crystalline form is further characterized by a differential scanning calorimeter thermogram having an endotherm at 175°C with an onset temperature of 175°C and an endotherm at 251°C with an onset temperature of 250°C.

7. 7. The crystalline form of claim 5 or claim 6, wherein the crystalline form is characterized by the XRPD pattern shown in Figure 7.

8. Crystalline Form 3 of Compound I, 【Chemistry 3】 The crystalline form has (i) a differential scanning calorimeter thermogram with an endotherm at 150°C with an onset temperature of 142°C, an exotherm at 176°C with an onset temperature of 171°C, and an endotherm at 252°C with an onset temperature of 251°C; (ii) the following peaks: 7.10, 8.71, 8.92, 11.03, 11.70, 13.07, 14.06, 15.23, 15.55, 16.17, 17.14, 17.45, 17.96, 19.16, 19.56, 20.43, 20. Crystalline Form 3 of Compound I, characterized by an X-ray powder diffraction pattern with major peaks (2θ) at: 68, 21.89, 22.56, 23.45, 23.83, 24.74, 25.79, 26.26, 26.95, 28.12, 28.64, 29.68, 30.44, 31.28, 31.76, 32.34, 32.79, 33.30, 34.67, 35.56, 36.11, 36.47, 37.07, 37.85, and 38.

22.

9. Crystalline Form 3 of Compound I, 【Chemistry 4】 crystalline Form 3 of Compound I, wherein the crystalline form is characterized by an XRPD pattern having characteristic peaks at two-theta (°2θ) values ​​of 7.1, 8.7, 8.9, 11.0, 11.7, 13.1, 14.1, 15.2, 15.6, 16.2, 17.1, 17.5, 18.0, 19.2, 19.6, 20.4, 20.7, 21.9, 22.6, 23.5, 23.8, 24.7, 25.8, 26.3, 27.0, 28.1, 28.6, 29.7, 30.4, 31.3, 31.8, 32.3, 32.8, 33.3, 34.7, 35.6, 36.1, 36.5, 37.1, 37.9, and 38.

2.

10. 9. The crystalline form of claim 8, wherein the crystalline form is characterized by the XRPD pattern of FIG.

11. Crystalline Form 4 of Compound I, 【Chemistry 5】 The crystalline forms are 4.39, 5.14, 7.06, 7.50, 8.47, 8.92, 9.75, 10.08, 10.33, 11.03, 11.71, 12.45, 13.09, 13.83, 14.06, 14.62, 14.84, 15.38, 15.78, 15.95, 16.91, 17.45, 17.93, 18.54, 19.23, 1 Crystalline Form 4 of Compound I, characterized by an X-ray powder diffraction pattern having characteristic peaks at degrees two-theta (°2θ) values ​​of 9.66, 20.07, 20.96, 21.84, 22.50, 23.42, 24.19, 24.91, 25.13, 26.18, 26.54, 27.81, 28.54, 29.41 and 30.99 (2θ).

12. Crystalline Form 4 of Compound I, 【Chemistry 6】 crystalline Form 4 of Compound I, wherein the crystalline form is characterized by an XRPD pattern having characteristic peaks at two-theta (°2θ) values ​​of 4.4, 5.1, 7.1, 7.5, 8.5, 8.9, 9.8, 10.1, 10.3, 11.0, 11.7, 12.5, 13.1, 13.8, 14.1, 14.6, 14.8, 15.4, 15.8, 16.0, 16.9, 17.5, 17.9, 18.5, 19.2, 19.7, 20.1, 21.0, 21.8, 22.5, 23.4, 24.2, 24.9, 25.1, 26.2, 26.5, 27.8, 28.5, 29.4, and 31.

0.

13. 12. The crystalline Form 4 of claim 1, wherein the XRPD pattern is shown in FIG.

14. A composition comprising the crystalline form of any one of claims 1 to 12.

15. 13. A method for making a pharmaceutical composition comprising Compound I, comprising dissolving the crystalline form of any one of claims 1 to 12 in a solvent.

16. 1. A process for the preparation of Form 1 of Compound I, comprising: 【Chemistry 7】 The method comprises: 1) preparing a solution of Compound I by dehydrating (3R,5'S)-1'-(N-methyl-N-(4,6,7-trifluoro-1H-indole-2-carbonyl)-L-leucyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (Compound n) in the presence of a suitable dehydrating reagent or reagents, a suitable base, and a suitable solvent; 2) concentrating the solution of Compound I from Step 1 at a temperature of about 20° C. to about 80° C. to obtain a solvent / Compound n ratio by volume (milliliters) to weight (grams) of about 2:1 to about 6:1; 3) optionally adding Form 1 of Compound I as a seed to the concentrated solution from Step 2 in an amount ranging from about 0.0001X (where X=weight of Compound n in Step 1) to about 0.1X by weight to induce crystallization of Form 1 of Compound I; 4) exchanging the solvent with a suitable solvent at a temperature of about 20° C. to about 80° C. in a solvent / compound n volume (milliliters) / weight (grams) ratio of about 6:1 to about 10:1, wherein the suitable solvent includes, but is not limited to, anisole, toluene, xylene, ethyl acetate, isopropyl acetate, and mixtures of two or more thereof; 5) cooling to a temperature of about 0°C to about 50°C; and 6) filtering to provide Compound I Form 1 A method comprising:

17. 16. The method of claim 15, wherein the solvent is selected from anisole, toluene, xylene, ethyl acetate, isopropyl acetate, and mixtures of two or more thereof.

18. 1. A process for the preparation of Form 1 of Compound I, comprising: 【Chemistry 8】 I. Adding Compound I to a first solvent to form a solution; the Compound I used to form the solution can be a solid form or a mixture of two or more solid forms of the compound; II. Removing a portion of the first solvent from the solution, for example by distillation, and then adding more first solvent; III. Repeatedly removing a portion of the first solvent from the solution and adding more of the first solvent until a solution of Compound I is produced in which the residual solvent is adjusted to a predetermined value or less, for example, 0.1% (w / w) or less; IV. adding a second solvent to the solution to precipitate Form 1 of Compound I; and V. Isolating Form 1 of Compound I by filtration A method comprising:

19. 19. The method of claim 18, wherein the first solvent is EtOH, isopropanol, acetone, EtOAc, IPAc, or MTBE.

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