N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide and its solvate in solid form

Abstract

This disclosure relates to N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide (I) of formula (I), for example, its anhydrous form, its amorphous form, its cyclopentyl methyl ether solvate, its isopropyl acetate solvate, its ethyl acetate solvate, and pharmaceutical compositions comprising the solid form, as well as treatment methods using the solid form. [Case 1] TIFF2026520022000037.tif4772 [Figure 1] TIFF2026520022000038.tif106152

Description

[Technical Field]

[0001] The present invention relates to a solid form of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide and its solvate, a pharmaceutical composition containing the solid form, and a method for preparing the solid form and the pharmaceutical composition, and a method for using them. [Background technology]

[0002] N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide (also known as methyl{(2S)-1-[(2S,4R)-2-({(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}carbamoyl)-4-(trifluoromethyl)pyrrolidine-1 The synthetic route for preparing the compound of formula I (also known as [-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate) (hereinafter referred to as "the compound of formula I") is described in U.S. Patent Nos. 11,351,149 and 11,452,711, and International Patent Application PCT / IB2021 / 057281 (all of which are incorporated herein by reference in their entirety for all purposes), and has the structure shown below.

[0003] [ka]

[0004] The compound of formula I inhibits viral proteases, including the major protease of coronaviruses, thereby inhibiting the viral replication process. The compound of formula I is intended for use in the treatment of coronavirus infections, such as SARS-CoV-2 infection (COVID-19).

[0005] Solid-state compounds are of interest to the pharmaceutical industry, particularly those involved in the development of suitable dosage forms. If the solid-state compound is not kept constant during clinical or stability studies, it may be impossible to compare the exact dosage form used or studied across lots. Furthermore, when a compound is used in clinical research or a commercial product, present impurities can lead to undesirable toxic effects; therefore, it is desirable to have a process for producing compounds with a selected solid-state compound in high purity. Certain solid-state compounds may exhibit improved stability or be easier to manufacture in high purity and in large quantities, making them more suitable for inclusion in pharmaceutical formulations. Other advantageous physical properties may include lack of hygroscopicity, improved filterability and solubility, and increased dissolution rates due to differences in lattice energy.

[0006] The discussion relating to the background of the invention in this specification is included to explain the context of the invention. This should not be construed as an acknowledgment that the referenced material was publicly available, publicly known, or part of the common general knowledge in any country as of the priority date of the invention. [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] [Means for solving the problem]

[0008] Compound of formula I

[0009] [ka] Solid states of and certain solvates of are disclosed herein, each solid state being described by, but not limited to, the peaks or combinations of two or more peaks of a powder X-ray diffraction pattern, a single crystal X-ray diffraction pattern, or solid-state NMR. 13 ¹¹C chemical shift or a combination of two or more chemical shifts, solid-state NMR 19It can be uniquely identified by multiple different analytical parameters, either individually or in combination, such as F chemical shift, thermogravimetric infrared analysis (TGA-IR), and modulated differential scanning calorimetry (mDSC).

[0010] Based on the disclosures provided herein, those skilled in the art will understand that various solid forms of the compound of formula I or its particular solvates (referred herein to as “Form 1,” “Form 5,” “Form 8,” “Form 9,” “Form 10,” “Form 11,” “Form 12,” and “Form 14,” as well as “Form 22”) and spray-dried dispersions prepared therefrom may be uniquely identified by multiple distinct spectral peaks, patterns, or techniques in various combinations. None of the exemplary combinations of characteristic peak values ​​that may be used to identify the solid forms of the compound of formula I should be considered limiting to other combinations of peak values ​​disclosed herein. [Brief explanation of the drawing]

[0011] [Figure 1] This is the PXRD pattern of form 1. [Figure 2] This is a PXRD pattern of form 5. [Figure 3] This is the PXRD pattern of cyclopentyl methyl ether (CPME) solvate, form 9. [Figure 4] This is the PXRD pattern of the amorphous free form, form 10. [Figure 5] This is the PXRD pattern of isopropyl acetate solvate, form 11. [Figure 6] This is the PXRD pattern of a 750 mg / g spray-dried dispersion (SDD). [Figure 7] This is an ORTEP diagram plotted using a 50% displacement parameter for the asymmetrical unit of form 1. [Figure 8] This is the calculated PXRD pattern of form 1, derived from single crystal (SXRD) data. [Figure 9]This is an ORTEP diagram plotted using a 50% displacement parameter for the asymmetrical unit of form 5. [Figure 10] This is the calculated PXRD pattern of the anhydrous free form of form 5. [Figure 11] This is an ORTEP diagram plotted using the 50% displacement parameter for the asymmetric unit of CPME solvate, form 8. [Figure 12] This is the calculated PXRD pattern of CPME solvate, form 8. [Figure 13] This is an ORTEP diagram plotted using the 50% displacement parameter for the asymmetric unit of isopropyl acetate solvate, form 12. [Figure 14] This is the calculated PXRD pattern of isopropyl acetate solvate, form 12. [Figure 15] This is the 13C solid-state NMR spectrum of Form 1, where the peaks marked with hash marks are spinning sidebands. [Figure 16] This is the 19F solid-state NMR spectrum of Form 1, where the peaks marked with hash marks are spinning sidebands. [Figure 17] This is the 13C solid-state NMR spectrum of form 5, where the peaks marked with hash marks are spinning sidebands. [Figure 18] This is the 19F solid-state NMR spectrum of form 5, where the peaks marked with hash marks are spinning sidebands. [Figure 19] This is the 13C solid-state NMR spectrum of CPME solvate form 9, with peaks marked with hashes being spinning sidebands. [Figure 20] This is the 19F solid-state NMR spectrum of CPME solvate form 9, with peaks marked with hashes being spinning sidebands. [Figure 21] This is the 13C solid-state NMR spectrum of the amorphous free form, form 10, where the peaks marked with hash marks are spinning sidebands. [Figure 22]This is the 19F solid-state NMR spectrum of the amorphous free form, form 10, where the peaks marked with hash marks are spinning sidebands. [Figure 23] This is the 13C solid-state NMR spectrum of isopropyl acetate solvate form 11, with peaks marked with hash marks being spinning sidebands. [Figure 24] This is the 19F solid-state NMR spectrum of isopropyl acetate solvate form 11, with peaks marked with hashes being spinning sidebands. [Figure 25] This is the 13C solid-state NMR spectrum of a 750 mg / g spray-dried dispersion (SDD). [Figure 26] This is the 19F solid-state NMR spectrum of 750 mg / g SDD, with peaks marked with hash marks being spinning sidebands. [Figure 27] This is a thermogravimetric infrared (TGA-IR) thermogram of CPME solvate form 9. [Figure 28] CPME solvate at 9.056 min, Gram-Schmidt and IR (TGA-IR) of form 9. [Figure 29] This is a superposition of the IR spectra of CPME solvate, form 9 (top), and cyclopentyl methyl ether solvent (bottom). [Figure 30] This is a thermogravimetric infrared (TGA-IR) thermogram of isopropyl acetate solvate, form 11. [Figure 31] Isopropyl acetate solvate at 10.321 min, Gram-Schmidt and IR (TGA-IR) of form 11. [Figure 32] This is a superposition of the IR spectra of isopropyl acetate solvate, Form 11 (top), and isopropyl acetate solvent (bottom). [Figure 33] This is modulated differential scanning calorimetry (DSC) data for the amorphous free form of form 10, showing a glass transition temperature (Tg) of approximately 95°C. [Figure 34]This is modulated DSC data for a 750 mg / g spray-dried dispersion (SDD), showing the Tg at approximately 92°C. [Figure 35] This figure shows a representative labeling scheme for morphology 14 and a partially asymmetric unit including anisotropic displacement parameters drawn with a 50% probability. [Figure 36] This is the calculated powder pattern of the ethyl acetate solvate of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 14. [Figure 37] N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, PXRD pattern of form 22. [Figure 38] This is the PXRD pattern of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 22, with peak picking of peaks with relative intensity exceeding 3%. [Figure 39] This is an ORTEP diagram (color) plotted using a 50% displacement parameter for the asymmetric unit of form 22, N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide. [Figure 40] This is a superposition of the powder pattern obtained for form 22, N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide (bottom) and the powder pattern calculated from single crystal data (top). [Figure 41]This is the 13C solid-state NMR spectrum of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 22, where the peaks marked with hashes are spinning sidebands. [Figure 42] This is the 19F solid-state NMR spectrum of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide form 22. Peaks marked with hash marks are spinning sidebands. [Modes for carrying out the invention]

[0012] This disclosure describes several forms of the anhydrous crystalline form of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, designated herein as Form 1 and Form 5, respectively. Form 1 is a particularly advantageous form of the anhydrous crystalline form of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, which exhibits good stability and lack of hygroscopicity, and is therefore suitable for use in pharmaceutical compositions. Form 22 is also a particularly advantageous anhydrous crystalline form of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, which exhibits good stability and lack of hygroscopicity, and is therefore suitable for use in pharmaceutical compositions. Both Form 1 and Form 22 are non-solvated (solvation-free) forms of this compound. The present invention also relates to amorphous N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, and the cyclopentyl methyl ether solvate of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, N The solid forms of the isopropyl acetate solvate of -(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide and the ethyl acetate solvate of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide are described.Cyclopentyl methyl ether solvate of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl} The isopropyl acetate solvate of {(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide and the ethyl acetate solvate of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide can be advantageously used as intermediates for preparing the solid form of Form 1. Also disclosed are spray-dried dispersions of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide. The following embodiments of the present invention are designated E1 to E.

[0013] E1 is a compound that is the anhydrous crystalline form of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide.

[0014] E2 is 50.8 ppm ± 0.2 ppm 13 It is an anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, a compound of form 1, E1, characterized by its 1C solid-state NMR peak.

[0015] E3 contains 50.8 ppm and 58.3 ppm 13The anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, compound E1 in Form 1, which is characterized by C solid-state NMR peaks (each peak is ±0.2 ppm).

[0016] E4 has C solid-state NMR peaks at 50.8 ppm and 43.5 ppm 13 The anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, compound E1 in Form 1, which is characterized by C solid-state NMR peaks (each peak is ±0.2 ppm).

[0017] E5 has C solid-state NMR peaks at 50.8 ppm, 58.3 ppm and 43.5 ppm 13 The anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, compound E1 in Form 1, which is characterized by C solid-state NMR peaks (each peak is ±0.2 ppm).

[0018] E6 has a C solid-state NMR peak at 50.8 ppm ±0.2 ppm 13 and an F solid-state NMR peak at -70.7 ppm ±0.2 ppm 19 The anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, compound E1 in Form 1, which is characterized by C solid-state NMR peaks and F solid-state NMR peaks.

[0019] E7 has C solid-state NMR peaks at 50.8 ppm and 58.3 ppm 13The 13C solid-state NMR peaks (each peak is ±0.2 ppm), as well as the -70.7 ppm ± 0.2 ppm 19 It is an anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, a compound of form 1, E1, characterized by its 1-fluorine solid-state NMR peak.

[0020] E8 contains 50.8 ppm and 43.5 ppm 13 The 13C solid-state NMR peaks (each peak is ±0.2 ppm), as well as the -70.7 ppm ± 0.2 ppm 19 It is an anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, a compound of form 1, E1, characterized by its 1-fluorine solid-state NMR peak.

[0021] E9 contains 50.8 ppm, 58.3 ppm, and 43.5 ppm. 13 ¹¹¹ solid-state NMR peaks (each peak is ±0.2 ppm) and -70.7 ppm ± 0.2 ppm 19 It is an anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, a compound of form 1, E1, characterized by its 1-fluorine solid-state NMR peak.

[0022] E10 is 50.8 ppm ± 0.2 ppm 13This is an anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, a compound of form 1, E1, characterized by a 1C solid-state NMR peak and 1 to 4 powder X-ray diffraction peaks (Cu Kα line) selected from the group consisting of peaks at 9.1, 9.6, 10.3, and 16.2 degrees 2θ (each peak is ±0.2 degrees 2θ).

[0023] E11 contains 50.8 ppm and 58.3 ppm 13 This is an anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 1, compound E1, characterized by 13C solid-state NMR peaks (each peak ±0.2 ppm) and 1 to 4 powder X-ray diffraction peaks (Cu Kα line) selected from the group consisting of peaks at 9.1, 9.6, 10.3, and 16.2 degrees 2θ (each peak ±0.2 degrees 2θ).

[0024] E12 contains 50.8 ppm and 43.5 ppm 13 This is an anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 1, compound E1, characterized by 13C solid-state NMR peaks (each peak ±0.2 ppm) and 1 to 4 powder X-ray diffraction peaks (Cu Kα line) selected from the group consisting of peaks at 9.1, 9.6, 10.3, and 16.2 degrees 2θ (each peak ±0.2 degrees 2θ).

[0025] E13 contains 50.8 ppm, 58.3 ppm, and 43.5 ppm. 13This is an anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 1, compound E1, characterized by 13C solid-state NMR peaks (each peak ±0.2 ppm) and 1 to 4 powder X-ray diffraction peaks (Cu Kα line) selected from the group consisting of peaks at 9.1, 9.6, 10.3, and 16.2 degrees 2θ (each peak ±0.2 degrees 2θ).

[0026] E14 is 50.8 ppm ± 0.2 ppm 13 ¹¹¹ solid-state NMR peak, -70.7 ppm ± 0.2 ppm 19 This is an anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, a compound of form 1, E1, characterized by a solid-state NMR peak and 1 to 4 powder X-ray diffraction peaks (Cu Kα line) selected from the group consisting of peaks at 9.1, 9.6, 10.3, and 16.2 degrees 2θ (each peak is ±0.2 degrees 2θ).

[0027] E15 contains 50.8 ppm and 58.3 ppm 13 ¹¹¹ solid-state NMR peaks (each peak is ±0.2 ppm), -70.7 ppm ± 0.2 ppm 19 This is an anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, a compound of form 1, E1, characterized by a solid-state NMR peak and 1 to 4 powder X-ray diffraction peaks (Cu Kα line) selected from the group consisting of peaks at 9.1, 9.6, 10.3, and 16.2 degrees 2θ (each peak is ±0.2 degrees 2θ).

[0028] E16 contains 50.8 ppm and 43.5 ppm13 ¹¹¹ solid-state NMR peaks (each peak is ±0.2 ppm), -70.7 ppm ± 0.2 ppm 19 This is an anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, a compound of form 1, E1, characterized by a solid-state NMR peak and 1 to 4 powder X-ray diffraction peaks (Cu Kα line) selected from the group consisting of peaks at 9.1, 9.6, 10.3, and 16.2 degrees 2θ (each peak is ±0.2 degrees 2θ).

[0029] E17 contains 50.8 ppm, 58.3 ppm, and 43.5 ppm. 13 ¹¹¹ solid-state NMR peaks (each peak is ±0.2 ppm), -70.7 ppm ± 0.2 ppm 19 This is an anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, a compound of form 1, E1, characterized by a solid-state NMR peak and 1 to 4 powder X-ray diffraction peaks (Cu Kα line) selected from the group consisting of peaks at 9.1, 9.6, 10.3, and 16.2 degrees 2θ (each peak is ±0.2 degrees 2θ).

[0030] E18 is substantially pure, N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 1.

[0031] E19 is a compound of E1, which is form 1 of anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, characterized by an X-ray powder diffraction pattern that is substantially the same as the X-ray powder diffraction pattern in Figure 1.

[0032] E20 is an orthorhombic crystal with a space group of C2221, a unit cell with dimensions a=9.6317(4) Å, α=90°, b=19.6368(8) Å, β=90°, and c=28.2776(11) Å, γ=90°, and a volume of 5348.3(4) Å. 3 Therefore, Z is 8, and the computational density is 1.216 g / m³. 3 And F 2 The compound of claim 1 is form 1 of anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, characterized by a single-crystal X-ray diffraction pattern (SXRD) characterized by a goodness of fit of 1.061, a final R index [I>2 sigma(I)] of R1=0.0754, wR2=0.2246, and an R index (all data) of R1=0.0907, wR2=0.2392.

[0033] E21 is a compound of E1, which is form 1 of anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, characterized by an ORTEP diagram drawn with a 50% displacement parameter for the asymmetric unit of form 1, which is substantially the same as the ORTEP diagram in Figure 7.

[0034] E22 is a solid form of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide containing form 1 of any one of E2 to E21, in an amount of less than 95%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 3%, or less than 1% by weight. The solid form of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide is N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, which comprises one or more solid forms of the compound N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide.

[0035] E23 is a solid form of E22 containing less than 10% by weight of one or more other solid forms of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide.

[0036] E24 is a solid form of E22 containing less than 5% by weight of one or more other solid forms of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide.

[0037] E25 is a solid form of E22 containing less than 2% by weight of one or more other solid forms of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide.

[0038] E26 is a solid form of E22 containing less than 1% by weight of one or more other solid forms of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide.

[0039] E27 is one of the solid forms from E22 to E26, and one or more other solid forms are selected from form 5, form 10, and forms 5 and 10.

[0040] E28 is a pharmaceutical composition comprising a therapeutically effective amount of one of E2 to E21 in Form 1 or one of E22 to E27 in solid form and a pharmaceutically acceptable carrier.

[0041] E29 is a pharmaceutical composition of E28, including Form 1 in doses ranging from 100 mg to 1000 mg.

[0042] E30 is a pharmaceutical composition of E29, comprising Form 1 of 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg.

[0043] E31 is a pharmaceutical composition of E29, including Form 1 in doses of 300 mg to 600 mg.

[0044] E32 is a method for treating coronavirus infection in a patient, comprising the step of administering to a patient in need an effective amount of anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 1, or one solid form of any one of E22 to E26 according to any one of claims 2 to 21.

[0045] E33 is a method for treating coronavirus infection in a patient, comprising the step of administering a pharmaceutical composition according to any one of E28 to E31.

[0046] E34 is the same as E32 or E33, where the coronavirus infection is a SARS-CoV-2 infection.

[0047] E35 is an anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 1, for use in the treatment of coronavirus infections, according to one of E2 to E21.

[0048] E36 is a pharmaceutical composition comprising one of E28 to E31 for use in the treatment of coronavirus infection.

[0049] E37 is used when the coronavirus infection is a SARS-CoV-2 infection, or E35 or E36.

[0050] E38 is -72.6 ppm and -73.8 ppm 19It is an anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, a compound of form 5, E1, characterized by solid-state NMR peaks (each peak is ±0.2 ppm).

[0051] E39 contains -72.6 ppm and -73.8 ppm. 19 The F solid-state NMR peaks (each peak is ±0.2 ppm), as well as 182.6 ppm ± 0.2 ppm 13 It is an anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, a compound of form 5, E1, characterized by its 1C solid-state NMR peak.

[0052] E40 is -72.6 ppm and -73.8 ppm 19 The F solid-state NMR peaks (each peak is ±0.2 ppm), as well as 156.1 ppm ± 0.2 ppm 13 It is an anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, a compound of form 5, E1, characterized by its 1C solid-state NMR peak.

[0053] E41 contains -72.6 ppm and -73.8 ppm 19 The F solid-state NMR peaks (each peak is ±0.2 ppm), as well as 52.6 ppm ± 0.2 ppm 13 It is an anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, a compound of form 5, E1, characterized by its 1C solid-state NMR peak.

[0054] E42 is -72.6 ppm and -73.8 ppm 19 The 1F solid-state NMR peaks (each peak is ±0.2 ppm), as well as the 182.6 ppm and 156.1 ppm peaks. 13 It is an anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 5, E1, characterized by 13C solid-state NMR peaks (each peak is ±0.2 ppm).

[0055] E43 is -72.6 ppm and -73.8 ppm 19 The 1F solid-state NMR peaks (each peak is ±0.2 ppm), as well as the 182.6 ppm and 52.6 ppm peaks. 13 It is an anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 5, E1, characterized by 13C solid-state NMR peaks (each peak is ±0.2 ppm).

[0056] E44 contains -72.6 ppm and -73.8 ppm. 19 The F solid-state NMR peaks (each peak is ±0.2 ppm), as well as 156.1 ppm and 52.6 ppm 13 It is an anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 5, E1, characterized by 13C solid-state NMR peaks (each peak is ±0.2 ppm).

[0057] E45 is -72.6 ppm and -73.8 ppm 19The 1F solid-state NMR peaks (each peak is ±0.2 ppm), as well as the peaks at 182.6 ppm, 156.1 ppm, and 52.6 ppm. 13 It is an anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 5, E1, characterized by 13C solid-state NMR peaks (each peak is ±0.2 ppm).

[0058] E46 has concentrations of -72.6 ppm ± 0.2 ppm and -73.8 ppm ± 0.2 ppm. 19 The compound E1, which is anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, is characterized by a solid-state NMR peak and one to four powder X-ray diffraction peaks (Cu Kα line) selected from the group consisting of peaks at 3.6, 7.1, 10.7, and 17.1 degrees 2θ (each peak is ±0.2 degrees 2θ).

[0059] E47 is -72.6 ppm ± 0.2 ppm and -73.8 ppm ± 0.2 ppm 19 One to three peaks selected from the group consisting of the 1F solid-state NMR peak and peaks at 182.6 ppm, 156.1 ppm, and 52.6 ppm. 13 This is an anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 5, compound E1, characterized by 13C solid-state NMR peaks (each peak ±0.2 ppm) and 1 to 4 powder X-ray diffraction peaks (Cu Kα line) selected from the group consisting of peaks at 3.6, 7.1, 10.7, and 17.1 degrees 2θ (each peak ±0.2 degrees 2θ).

[0060] E48 is a monoclinic crystal with a P21 space group, and its unit cell has dimensions a=17.8885(16) Å, α=90°, b=9.2624(8) Å, β=106.851(4)°, c=25.291(2) Å, and γ=90°, with a volume of 4.010.5(6) Å. 3 Therefore, Z is 6, and the computational density is 1.216 g / m³. 3 And F 2 It is an anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 5, E1, characterized by a single-crystal X-ray diffraction pattern (SXRD) with a goodness of fit of 1.138, a final R index [I>2 sigma(I)] of R1=0.0881, wR2=0.2492, and an R index (all data) of R1=0.1088, wR2=0.2779.

[0061] E49 is an anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, compound E1 which is form 5, characterized by an ORTEP diagram drawn with a 50% displacement parameter for the asymmetric unit of form 5, which is substantially the same as the ORTEP diagram in Figure 9.

[0062] E50 is substantially pure N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 5.

[0063] E51 is a solid form of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide containing form 5, and is available in any other solid form by weight of less than 95%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 3%, or less than 1%. This is the solid form of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, which contains the compound N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide.

[0064] E52 is a solid form of E51, and one or more other solid forms are selected from form 1, form 10, and forms 1 and 10.

[0065] E53 is a pharmaceutical composition comprising an anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, Form 5, and a pharmaceutically acceptable carrier in a therapeutically effective amount of any one of E38 to E50.

[0066] E54 is a method for treating coronavirus infection in a patient, comprising the step of administering anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 5, in a therapeutically effective amount of any one of E38 to E50, to a patient in need.

[0067] E55 is a method for treating a coronavirus infection in a patient, comprising the step of administering a pharmaceutical composition according to E53.

[0068] E56 indicates that the coronavirus infection is a SARS-CoV-2 infection, as in E54 or E55.

[0069] E57 is an anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 5, for use in the treatment of coronavirus infections, according to one of E38 to E50.

[0070] E58 is a pharmaceutical composition containing E53 for use in the treatment of coronavirus infection.

[0071] E59 is used when referring to a coronavirus infection, specifically a SARS-CoV-2 infection, or E57 or E58.

[0072] E60 is the cyclopentyl methyl ether solvate of crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide.

[0073] E61 is an orthorhombic crystal with a space group of P21212, and its unit cell has dimensions a=24.8092(16) Å, α=90°, b=25.1091(13) Å, β=90° and c=9.5991(6) Å, γ=90°, with a volume of 5979.6(6) Å. 3 Therefore, Z is 8, and the computational density is 1.199 g / cm³. 3 And F 2It is a compound of form 8, E60, characterized by a single-crystal X-ray diffraction pattern (SXRD) characterized by a goodness of fit of 1.049, a final R index [I>=2σ(I)] of R1=0.0858, wR2=0.2270, and a final R index [all data] of R1=0.0892, wR2=0.2340. It is a cyclopentyl methyl ether solvate of crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, embodied in form 8.

[0074] E62 is a compound of E60, which is form 8, a cyclopentyl methyl ether solvate of crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, characterized by an ORTEP diagram drawn with a 50% displacement parameter for the asymmetric unit of form 8, which is substantially the same as the ORTEP diagram in Figure 11.

[0075] E63 is -70.2 ppm and -70.5 ppm 19 The 1F solid-state NMR peaks (each peak is ±0.2 ppm), and 1 to 3 peaks selected from the group of peaks at 32.7 ppm, 24.2 ppm, and 56.0 ppm. 13 It is a compound of form 9, E60, characterized by 13C solid-state NMR peaks (each peak being ±0.2 ppm), and is the cyclopentyl methyl ether solvate of crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide.

[0076] E64 is -70.2 ppm and -70.5 ppm 19This compound is E60, form 9, a cyclopentyl methyl ether solvate of crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, characterized by solid-state NMR peaks (each peak ±0.2 ppm) and 1-3 powder X-ray diffraction peaks (Cu Kα line) selected from peaks at 7.1, 7.9, and 19.8 degrees 2θ (each peak ±0.2 degrees 2θ).

[0077] E65 consists of 1 to 3 peaks selected from the groups of 32.7 ppm, 24.2 ppm, and 56.0 ppm. 13 This compound is E60, form 9, and is characterized by 13C solid-state NMR peaks (each peak being ±0.2 ppm) and 1 to 3 powder X-ray diffraction peaks (Cu Kα line) selected from peaks at 7.1, 7.9, and 19.8 degrees 2θ (each peak being ±0.2 degrees 2θ). It is a cyclopentyl methyl ether solvate of crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide.

[0078] E66 is -70.2 ppm and -70.5 ppm 19 1 to 3 peaks selected from the group of 1F solid-state NMR peaks (each peak is ±0.2 ppm), 32.7 ppm, 24.2 ppm, and 56.0 ppm. 13This compound is E60, form 9, and is characterized by 13C solid-state NMR peaks (each peak being ±0.2 ppm) and 1 to 3 powder X-ray diffraction peaks (Cu Kα line) selected from peaks at 7.1, 7.9, and 19.8 degrees 2θ (each peak being ±0.2 degrees 2θ). It is a cyclopentyl methyl ether solvate of crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide.

[0079] E67 is -70.2 ppm and -70.5 ppm 19 This compound is E60, form 9, and is characterized by solid-state NMR peaks (each peak being ±0.2 ppm) of crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide cyclopentyl methyl ether solvate.

[0080] E68 consists of 1 to 3 peaks selected from the groups of 32.7 ppm, 24.2 ppm, and 56.0 ppm. 13 This compound is E60, form 9, and is characterized by 13C solid-state NMR peaks (each peak being ±0.2 ppm), and is the cyclopentyl methyl ether solvate of crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide.

[0081] E69 is the isopropyl acetate solvate of crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 11.

[0082] E70 is 20.9 ppm ± 0.2 ppm 13 This compound is characterized by its E69 NMR peak in the solid state of 1C.

[0083] E71 is -69.8 ppm, -71.9 ppm, and -72.4 ppm. 19 This compound is characterized by its solid-state NMR peaks (each peak being ±0.2 ppm) and is classified as E69.

[0084] E72 is available in concentrations of 20.9 ppm ± 0.2 ppm, 38.7 ppm ± 0.2 ppm, and 52.0 ppm ± 0.2 ppm. 13 This compound is characterized by its E69 NMR peak in the solid state of 1C.

[0085] E73 is -69.8 ppm, -71.9 ppm, and -72.4 ppm 19 The F solid-state NMR peaks (each peak is ±0.2 ppm), as well as 20.9 ppm ± 0.2 ppm 13 This compound is characterized by its E69 NMR peak in the solid state of 1C.

[0086] E74 is -69.8 ppm, -71.9 ppm, and -72.4 ppm. 19 The 1F solid-state NMR peaks (each peak is ±0.2 ppm), and 1 to 3 peaks selected from the group of peaks at 20.9 ppm ± 0.2 ppm, 38.7 ppm ± 0.2 ppm, and 52.0 ppm ± 0.2 ppm. 13 This compound is characterized by its E69 NMR peak in the solid state of 1C.

[0087] E75 is -69.8 ppm, -71.9 ppm, and -72.4 ppm. 19 This compound is characterized by solid-state NMR peaks (each peak being ±0.2 ppm) and 1 to 4 powder X-ray diffraction peaks (Cu Kα line) selected from the group of peaks at 8.5, 6.3, 10.7, and 19.1 degrees 2θ (each peak being ±0.2 degrees 2θ), according to E69.

[0088] E76 is -69.8 ppm, -71.9 ppm, and -72.4 ppm. 19 F solid-state NMR peaks (each peak is ±0.2 ppm), 20.9 ppm ± 0.2 ppm 13 This compound is characterized by a 1C solid-state NMR peak and 1 to 4 powder X-ray diffraction peaks (Cu Kα line) selected from the group of peaks at 8.5, 6.3, 10.7, and 19.1 degrees 2θ (each peak is ±0.2 degrees 2θ), according to E69.

[0089] E77 is -69.8 ppm, -71.9 ppm, and -72.4 ppm. 19 1 to 3 peaks selected from the group of 1F solid-state NMR peaks (each peak is ±0.2 ppm), peaks at 20.9 ppm ± 0.2 ppm, 38.7 ppm ± 0.2 ppm, and 52.0 ppm ± 0.2 ppm. 13 This compound is characterized by a 1C solid-state NMR peak and 1 to 4 powder X-ray diffraction peaks (Cu Kα line) selected from the group of peaks at 8.5, 6.3, 10.7, and 19.1 degrees 2θ (each peak is ±0.2 degrees 2θ), according to E69.

[0090] E78 is 20.9 ppm ± 0.2 ppm 13 This compound is characterized by a 1C solid-state NMR peak and 1 to 4 powder X-ray diffraction peaks (Cu Kα line) selected from the group of peaks at 8.5, 6.3, 10.7, and 19.1 degrees 2θ (each peak is ±0.2 degrees 2θ), according to E69.

[0091] E79 is available in concentrations of 20.9 ppm ± 0.2 ppm, 38.7 ppm ± 0.2 ppm, and 52.0 ppm ± 0.2 ppm. 13 This compound is characterized by a 1C solid-state NMR peak and 1 to 4 powder X-ray diffraction peaks (Cu Kα line) selected from the group of peaks at 8.5, 6.3, 10.7, and 19.1 degrees 2θ (each peak is ±0.2 degrees 2θ), according to E69.

[0092] E80 is a spray-dried dispersion containing N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide and pharmaceutically acceptable excipients.

[0093] E81 is a spray-dried dispersion of E80 containing amorphous N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide.

[0094] E82 is a spray-dried dispersion of E81 containing hydroxypropyl methylcellulose acetate succinate, M grade.

[0095] E83 is a spray-dried dispersion of E82 consisting of 750 mg / g of amorphous N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide and 250 mg / g of hydroxypropyl methylcellulose acetate succinate, M grade.

[0096] E84 is a pharmaceutical composition comprising one of the spray-dried dispersions from E80 to E83.

[0097] E85 is a method for treating coronavirus infection in a patient, comprising the step of administering a therapeutically effective amount of a pharmaceutical composition containing E84 to a patient in need.

[0098] E86 is the method described in E85, which states that the coronavirus infection is a SARS-CoV-2 infection.

[0099] E87 is the ethyl acetate solvate of crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 14.

[0100] E88 has an orthorhombic crystal system, a space group of P21212, and a unit cell with dimensions a=24.7926(16)Å, α=90°, b=25.0341(15)Å, β=90°, and c=9.6240(6)Å, γ=90°, with a volume of 5973.2(6)Å. 3 Therefore, Z is 8, and the computational density is 1.187 g / cm³. 3 And F 2 This compound is E87, form 14, characterized by a single-crystal X-ray diffraction pattern (SXRD) characterized by a goodness of fit of 1.077, a final R index [I>=2σ(I)] of R1=0.0880, wR2=0.2433, and a final R index [all data] of R1=0.1056, wR2=0.2666. It is the ethyl acetate solvate of crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide.

[0101] E89 is a compound of form 14, E87, which is the ethyl acetate solvate of crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, characterized by an ORTEP diagram drawn with a 50% displacement parameter for the asymmetric unit of form 14, which is substantially the same as the ORTEP diagram in Figure 35.

[0102] E90 is crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 22.

[0103] E91 is -71.0 and -71.5 ppm 19 This compound is characterized by its E90 solid-state NMR peaks (each ±0.2 ppm).

[0104] E92 consists of 1 to 3 peaks selected from the group of peaks at 53.3 ppm, 39.8 ppm, and 169.1 ppm. 13 This compound is characterized by its 13C solid-state NMR peaks (each peak being ±0.2 ppm) and is classified as E90.

[0105] E93 is -71.0 and -71.5 ppm 19 1 to 4 peaks selected from the group of 14F solid-state NMR peaks (each ±0.2 ppm) and peaks at 53.3 ppm, 39.8 ppm, 169.1 ppm, and 40.8 ppm. 13 This compound is characterized by its 13C solid-state NMR peaks (each peak being ±0.2 ppm) and is classified as E90.

[0106] E94 is -71.0 ppm and -71.5 ppm 19 This compound is characterized by a solid-state NMR peak (each peak is ±0.2 ppm) and one to two powder X-ray diffraction peaks (Cu Kα line) selected from peaks at 11.6 and 14.6 degrees 2θ (each peak is ±0.2 degrees 2θ), according to E90.

[0107] E95 consists of 1 to 3 peaks selected from the groups of 53.3 ppm, 39.8 ppm, and 169.1 ppm. 13 This compound is characterized by a 1C solid-state NMR peak (each peak is ±0.2 ppm) and one to two powder X-ray diffraction peaks (Cu Kα line) selected from peaks at 11.6 and 14.6 degrees 2θ (each peak is ±0.2 degrees 2θ), according to E90.

[0108] E96 is -71.0 ppm and -71.5 ppm 191 to 4 peaks selected from the group of peaks at 53.3 ppm, 39.8 ppm, 169.1 ppm, and 40.8 ppm, respectively, in solid-state NMR spectrum (each peak is ±0.2 ppm). 13 This compound is characterized by a 1C solid-state NMR peak (each peak is ±0.2 ppm) and one to two powder X-ray diffraction peaks (Cu Kα line) selected from peaks at 11.6 and 14.6 degrees 2θ (each peak is ±0.2 degrees 2θ), according to E90.

[0109] In further embodiments, the present invention intends that individual solid forms of the compounds of the present invention may exist in the presence of other solid forms of the compounds of the present invention. For example, Form 1 may exist in the presence of any other solid form described herein (e.g., Forms 5, 8, 9, 10, 11, 12, 14, or 22) or mixtures thereof.

[0110] In further embodiments, the present invention intends that Form 1 may exist in the presence of any other solid form (e.g., Forms 5, 8, 9, 10, 11, 12, 14, or 22) or mixtures thereof. Thus, in one embodiment, the present invention provides Form 1 in which Form 1 is present in a solid form, the solid form containing any other physical form of the compound of Formula I in an amount of less than 95%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 3%, or less than 1% by weight. For example, one embodiment is a solid form of a compound of formula I comprising form 1 having either the powder X-ray diffraction pattern or the NMR spectrum, wherein the solid form contains any other physical form of the compound of formula I in an amount of less than 95%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 3%, or less than 1% by weight.

[0111] In a particular embodiment, the present invention relates to Embodiment 1, which is substantially a pure crystalline form.

[0112] In a further embodiment, the present invention intends that form 22 may exist in the presence of any other solid form (e.g., forms 5, 8, 9, 10, 11, 12, 14 or 1) or mixtures thereof. Thus, in one embodiment, the present invention provides form 1 in which form 1 is present in a solid form, the solid form containing a compound of formula I in any other physical form in an amount of less than 95%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 3%, or less than 1% by weight. For example, one embodiment is a solid form of a compound of formula I comprising form 1 having either the powder X-ray diffraction pattern or the NMR spectrum, wherein the solid form contains any other physical form of the compound of formula I in an amount of less than 95%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 3%, or less than 1% by weight.

[0113] In a particular embodiment, the present invention relates to embodiment 22, which is substantially a pure crystalline form.

[0114] In further embodiments, the present invention intends that one of forms 5, 8, 9, 10, 11, 12, or 14 may exist in the presence of any other solid form of the compound of formula I or a mixture thereof. Thus, in one embodiment, the present invention provides one of forms 5, 8, 9, 10, 11, 12, or 14, wherein the form exists in a solid form containing any other physical form of the compound of formula I in an amount of less than 95%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 3%, or less than 1% by weight. For example, one embodiment is a solid form of a compound of formula I comprising form 12 having either the powder X-ray diffraction pattern or the NMR spectrum, wherein the solid form contains any other physical form of the compound of formula I in an amount of less than 95%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 3%, or less than 1% by weight.

[0115] In certain embodiments, the present invention relates to any one of embodiments 5, 8, 9, 10, 11, 12, and 14, the said embodiments being substantially pure embodiments.

[0116] Pharmaceutical composition In another embodiment, the present invention includes pharmaceutical compositions. For the purposes of pharmaceutical compositions, the solid forms (forms 1, 5, 8, 9, 10, 11, 12, or 14) of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, or cyclopentyl methyl ether solvate, isopropyl acetate solvate, or ethyl acetate solvate described herein are referred to as the compounds of the present invention.

[0117] "Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention and one or more pharmaceutically acceptable excipients.

[0118] The term "excipient" is used herein to describe any component other than the compounds of the present invention. The choice of excipient largely depends on factors such as the method of administration, the effect of the excipient on solubility and stability, and the properties of the dosage form.

[0119] As used herein, “excipients” include any physiologically compatible solvent, dispersion medium, coating, antimicrobial and antifungal agent, isotonic and absorption retardant, carrier, diluent, and analogues. Examples of excipients include one or more of water, saline, phosphate-buffered saline, glucose, glycerol, ethanol, and analogues, as well as combinations thereof, and the composition may also contain isotonic agents, such as sugars, sodium chloride, or polyhydric alcohols such as mannitol or sorbitol. Examples of excipients also include various organic solvents (such as hydrates and solvates). Pharmaceutical compositions may optionally contain additional excipients such as fragrances, binders / combiners, lubricants, disintegrants, sweeteners or flavorings, colorants or dyes, and analogues. For example, for oral administration, tablets containing various excipients such as citric acid may be used with various disintegrants such as starch, alginic acid, and certain complex silicates, as well as binders such as sucrose, gelatin, and acacia. Examples of excipients, though not limited to them, include calcium carbonate, calcium phosphate, various sugars and several types of starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are often useful for tableting purposes. Similar types of solid compositions can also be used for soft gelatin capsules and hard gelatin capsules. Therefore, non-limiting examples of excipients include lactose and high molecular weight polyethylene glycol. When aqueous suspensions or elixirs are preferred for oral administration, the active compound can be combined with various sweeteners or flavorings, colorants or dyes, and preferably emulsifiers or suspending agents, along with additional excipients such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

[0120] Examples of excipients include pharmaceutically acceptable substances such as humectants, or small amounts of auxiliary substances such as humectants or emulsifiers, preservatives, or buffers that improve the shelf life or effectiveness of a compound.

[0121] The compositions of the present invention may be in various forms. These include, for example, liquid, semi-solid, and solid dosage forms, such as liquid solutions (e.g., injectable and injectable solutions), dispersions or suspensions, tablets, capsules, pills, powders, liposomes, and suppositories. The form is determined according to the intended method of administration and therapeutic use.

[0122] Typical compositions are in the form of injectable and infusionable solutions, such as compositions similar to those commonly used for passive immunization in humans using antibodies. One method of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In another embodiment, the compound is administered by intravenous infusion or injection. In yet another embodiment, the compound is administered by intramuscular or subcutaneous injection.

[0123] Oral administration in solid form can be presented as individual units such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present invention. In another embodiment, oral administration may be in the form of a powder or granules. In yet another embodiment, the oral dosage form is a sublingual dosage form, such as a lozenge. In such solid dosage forms, the compounds of the present invention are typically combined with one or more adjuvants. Such capsules or tablets may contain a controlled-release formulation. In the case of capsules, tablets, and pills, the dosage form may include a buffer or may be prepared using an enteric coating.

[0124] In another embodiment, oral administration may be carried out in liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing an inert diluent commonly used in the art (e.g., water). Such compositions may also contain adjuvants such as wetting agents, emulsifiers, suspending agents, flavorings (e.g., sweeteners), and / or fragrances.

[0125] In another embodiment, the present invention includes parenteral dosage forms. "Pareral administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection, and infusion. Injectable preparations (i.e., sterile, injectable aqueous or oily suspensions) can be formulated according to known techniques using suitable dispersants, wetting agents, and / or suspending agents.

[0126] In another embodiment, the present invention includes topical dosage forms. "Topical administration" includes transdermal administration, such as via a transdermal patch or iontophoresis device, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. Topical formulations may include compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected area. When the compounds of the present invention are administered by a transdermal device, administration is achieved using a reservoir and porous membrane type patch or a solid matrix type patch. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, sprays, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Typical excipients include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers can be incorporated. See, for example, BCFinnin and TMMorgan, J.Pharm.Sci., vol.88, pp.955-958, 1999.

[0127] Formulations suitable for topical administration to the eye include, for example, eye drops in which the compounds of the present invention are dissolved or suspended in a suitable excipient. Typical formulations suitable for administration to the eye or ear may be in the form of eye drops of a micronized suspension or solution in isotonic, pH-adjusted sterile saline. Other formulations suitable for administration to the eye and ear include ointments, biodegradable (i.e., absorbent gel sponge, collagen) and non-biodegradable (i.e., silicone) implants, wafers, lenses, and particulate or vesicular systems such as niosomes or liposomes. Polymers such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulosic polymers, e.g., hydroxypropyl methylcellulose, hydroxyethylcellulose, or methylcellulose, or heteropolysaccharide polymers, e.g., gellan gum, can be incorporated together with preservatives such as benzalkonium chloride. Such formulations can also be delivered by iontophoresis.

[0128] When administered intranasally or by inhalation, the compounds of the present invention are conveniently delivered in the form of a solution or suspension from a pump spray container compressed or pumped by the patient, or as an aerosol spray presentation from a pressurized container or nebulizer using a suitable propellant. Formulations suitable for intranasal administration are typically administered in the form of a dry powder (alone, as a mixture, e.g., a dry blend with lactose, or mixed component particles, e.g., mixed with phospholipids such as phosphatidylcholine) from a dry powder inhaler, or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. When used intranasally, the powder may contain a bioadhesive, e.g., chitosan or cyclodextrin.

[0129] In another embodiment, the present invention includes a rectal dosage form. Such a rectal dosage form may be, for example, a suppository. Cocoa butter is a traditional suppository base, but various substitutes may be used where appropriate.

[0130] Other excipients and administration methods known in the field of pharmaceutical technology may also be used. The pharmaceutical compositions of the present invention can be prepared by any of the well-known pharmaceutical techniques, such as effective formulations and administration procedures. The above considerations regarding effective formulations and administration procedures are well known in the art and are described in standard textbooks. The formulation of drugs is discussed, for example, in Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Kibbe et al., Eds., Handbook of Pharmaceutical Excipients (3rd Ed.), American Pharmaceutical Association, Washington, 1999.

[0131] Acceptable excipients are non-toxic to the recipient at the dosage and concentration used and include buffers such as phosphoric acid, citrate, and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzylammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol, alkylparabens such as methyl or propylparaben, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol), low molecular weight (less than approximately 10 residues) polypeptides, serum alcohol Proteins such as lubumin, gelatin, or Ig; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn protein complexes); and / or nonionic surfactants such as TWEEN®, PLURONICS®, or polyethylene glycol (PEG).

[0132] For oral administration, the composition may be provided in the form of tablets or capsules containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250, 300, 350, 400, 450, 500, 600, 750, or 1000 milligrams of the active ingredient, in order to adjust the dosage to the patient according to their symptoms. The pharmaceutical product typically contains about 0.01 mg to about 500 mg of the active ingredient, or in another embodiment, about 1 mg to about 100 mg or 50 to 500 milligrams of the active ingredient. For intravenous administration, the dose may range from about 0.01 to about 10 mg / kg / min during constant-rate infusion.

[0133] Liposomes containing the compounds of the present invention can be prepared by methods known in the art, such as those described in U.S. Patents 4,485,045 and 4,544,545. Liposomes with extended circulation times are disclosed in U.S. Patent 5,013,556. Particularly useful liposomes can be produced by reverse-phase evaporation using a lipid composition containing phosphatidylcholine, cholesterol, and PEG-derivativeized phosphatidylethanolamine (PEG-PE). The liposomes are extruded through a filter of a specified pore size to obtain liposomes with a desired diameter.

[0134] The compounds of the present invention can also be encapsulated in microcapsules prepared by, for example, coacervation technology or interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, using colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or macroemulsions, respectively. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy, 20th Ed., Mack Publishing (2000).

[0135] Sustained-release preparations may be used. Preferred examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the compounds of the present invention, where these matrices are in the form of molded articles, such as films or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), polylactide (U.S. Patent No. 3,773,919), copolymers of L-glutamic acid and 7-ethyl-L-glutamic acid, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as those used in LUPRON DEPOT (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyrate.

[0136] Preparations used for intravenous administration must be sterile. This can be easily achieved, for example, by filtration through a sterile filtration membrane. The compounds of the present invention are generally placed in containers having a sterile access port, such as intravenous solution bags or vials with a stopper that can be punctured by a subcutaneous injection needle.

[0137] Suitable emulsions can be prepared using commercially available lipid emulsions such as Intralipid®, Liposyn®, Infonutrol®, Lipofandin®, and Lipiphysan®. The active ingredient can be dissolved in a pre-mixed emulsion composition, or alternatively in an oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil, or almond oil), and when mixed with phospholipids (e.g., egg phospholipids, soybean phospholipids, or soybean lecithin) and water, an emulsion is formed. It will be understood that other components, such as glycerol or glucose, may be added to adjust the osmotic pressure of the emulsion. Suitable emulsions typically contain up to 20% oil, for example, between 5% and 20%. The lipid emulsion may contain lipid droplets between 0.1 μm and 1.0 μm, particularly between 0.1 μm and 0.5 μm, and may have a pH in the range of 5.5 to 8.0.

[0138] The emulsion composition may also be prepared by mixing the compound of the present invention with Intralipid® or its components (soybean oil, egg phospholipid, glycerol, and water).

[0139] Compositions for inhalation or inhalation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, compositions are administered orally or via nasal respiratory routes for topical or systemic effects. Compositions in preferably sterile, pharmaceutically acceptable solvents may be sprayed using gas. The sprayed solution may be inhaled directly from the spraying device, or the spraying device may be attached to a face mask, tent, or intermittent positive airway pressure (CPAP) respirator. Solutions, suspensions, or powder compositions may be administered preferably orally or nasally from a device that delivers the formulation in an appropriate manner.

[0140] Dosage and dosage The terms “to treat,” “to treat,” or “treatment,” as used herein, encompass both preventive treatment, i.e., protective treatment, and symptomatic treatment, i.e., treatment that reduces, mitigates, or delays the progression of a patient’s disease (or condition) or any tissue damage associated with the disease.

[0141] As used herein, the terms “subject,” “individual,” or “patient” are interchangeable and refer to any animal, including mammals. Mammals according to the present invention include canids, felids, bovids, goats, equids, sheep, pigs, rodents, rabbits, primates, humans, and similar animals, and also include mammals in utero. In one embodiment, humans are preferred subjects. Human subjects may be of any sex and at any developmental stage.

[0142] As used herein, the term “therapeutic dose” means the amount of an active compound or drug that elicits one or more of the following biological or pharmacokinetic responses in a tissue, system, animal, individual or human, as determined by a researcher, veterinarian, physician, or other clinician: (1) To prevent disease, for example, to prevent disease, condition or disorder in individuals who are susceptible to disease, condition or disorder but have not yet experienced or shown the pathology or symptoms of the disease. (2) Inhibiting the disease, for example, inhibiting the disease, condition, or disorder in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder (i.e., preventing or delaying the further progression of the pathology and / or symptoms), (3) To improve a disease, for example, to improve a disease, condition, or disorder in an individual who is experiencing or exhibiting the pathology or symptoms of a disease, condition, or disorder (i.e., to reverse the pathology and / or symptoms).

[0143] Typically, the compounds of the present invention are administered in an amount effective to treat the conditions described herein. The compounds of the present invention can be administered as the compound itself or, alternatively, as its solvate. For the purposes of administration and dosage, the compound itself or its solvate is simply referred to as the compound of the present invention.

[0144] The compounds of the present invention are administered by any preferred route, in the form of a pharmaceutical composition adapted to such route, in a dose effective for the intended treatment. The compounds of the present invention can be administered orally, rectally, vaginally, parenterally, topically, intranasally, or by inhalation.

[0145] The compounds of the present invention can be administered orally. Oral administration may involve swallowing so that the compounds enter the gastrointestinal tract, or buccal or sublingual administration may be used so that the compounds enter the bloodstream directly from the mouth.

[0146] In another embodiment, the compounds of the present invention may also be administered parenterally, for example, directly into the bloodstream, muscle, or internal organs. Suitable means of parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) syringes, needleless syringes, and injection techniques.

[0147] In another embodiment, the compounds of the present invention may be administered topically to the skin or mucous membrane, i.e., transdermally or transdermally. In another embodiment, the compounds of the present invention may be administered intranasally or by inhalation. In another embodiment, the compounds of the present invention may be administered rectally or vaginally. In another embodiment, the compounds of the present invention may be administered directly to the eyes or ears.

[0148] The dosage regimen for the compounds of the present invention and / or compositions containing such compounds is determined based on various factors, including the patient's type, age, weight, sex, and medical condition, the severity of the condition, the route of administration, and the activity of the specific compound used. Therefore, the dosage regimen can vary considerably. In one embodiment, the total daily dose of the compounds of the present invention for the treatment of the indications discussed herein is typically about 0.01 to about 100 mg / kg (i.e., mg of the compounds of the present invention per kg of body weight). In another embodiment, the total daily dose of the compounds of the present invention is about 0.1 to about 50 mg / kg, and in yet another embodiment, about 0.5 to about 30 mg / kg. It is not uncommon for the administration of the compounds of the present invention to be repeated multiple times a day (typically four times or less). If desired, multiple doses per day can typically be used to increase the total daily dose.

[0149] Treatment methods and use The compounds of the present invention inhibit viral proteases, particularly coronavirus viral proteases such as the 3CL(Mpro) protease of SARS-CoV-2, the virus that causes COVID-19. The compounds of the present invention can inhibit the activity of major viral proteases and may be useful in the treatment, prevention, suppression, and improvement of viral infections, including SARS-CoV-2 infection and coronavirus infections such as COVID-19. The compounds of the present invention may also be useful in the treatment or improvement of post-coronavirus infection complications, such as for long-term use or treatment of COVID.

[0150] Concomitant administration The compounds of the present invention can be used alone or in combination with one or more other therapeutic agents. The present invention provides any of the uses, methods, or compositions defined herein in which the compounds of the present invention are used in combination with one or more other therapeutic agents discussed herein.

[0151] The compounds of the present invention can be used in combination with other drugs in the methods of the present invention. For example, administering the SARS-CoV-2 coronavirus 3CL protease inhibitor of the present invention and an interferon such as interferon alfa, or a pegylated interferon such as PEG-Intron or Pegasus, to a patient infected with SARS-CoV-2 coronavirus (i.e., a patient with COVID-19) can yield greater clinical benefits than administering any of the interferon, pegylated interferon, or SARS-CoV-2 coronavirus inhibitor alone. Other additional drugs that can be used in the methods of the present invention include dexamethasone, azithromycin, and remdesivir. Examples of greater clinical benefits include a significant reduction in COVID-19 symptoms, a shorter time to symptom relief, reduced lung lesions, a significant decrease in the amount of SARS-CoV-2 coronavirus in the patient's body (viral load), and a lower mortality rate.

[0152] SARS-CoV-2 coronavirus infects cells that express P-glycoprotein. Some of the SARS-CoV-2 coronavirus 3CL protease inhibitors of the present invention may be substrates of P-glycoprotein. Compounds that inhibit SARS-CoV-2 coronavirus, which is also a substrate of P-glycoprotein, can be administered together with P-glycoprotein inhibitors. Examples of P-glycoprotein inhibitors include verapamil, vinblastine, ketoconazole, nelfinavir, ritonavir, or cyclosporine. P-glycoprotein inhibitors act by inhibiting the extracellular efflux of the SARS-CoV-2 coronavirus inhibitors of the present invention. Inhibition of P-glycoprotein efflux prevents a decrease in the intracellular concentration of the SARS-CoV-2 coronavirus inhibitor due to P-glycoprotein efflux. Inhibition of P-glycoprotein efflux increases the intracellular concentration of the SARS-CoV-2 coronavirus inhibitor. By administering the SARS-CoV-2 coronavirus 3CL protease inhibitor and P-glycoprotein inhibitor of the present invention to patients infected with SARS-CoV-2 coronavirus, the intracellular concentration of the SARS-CoV-2 coronavirus 3CL protease inhibitor increases, thereby reducing the amount of SARS-CoV-2 coronavirus 3CL protease inhibitor required to achieve an effective dose.

[0153] Agents that can be used to increase the exposure of mammals to the compounds of the present invention include those that can act as inhibitors of at least one isoform of cytochrome P450 (CYP450) enzymes. CYP450 isoforms that can be beneficially inhibited include, but are not limited to, CYP1A2, CYP2D6, CYP2C9, CYP2C19, and CYP3A4. Compounds used in the methods of the present invention include compounds that are substrates of CYP3A4 and are metabolized by CYP3A4. By administering SARS-CoV-2 coronavirus inhibitors that are CYP3A4 substrates, such as SARS-CoV-2 coronavirus 3CL protease inhibitors, and CYP3A4 inhibitors, such as ritonavir, nelfinavir, or delavirdin, to patients infected with SARS-CoV-2 coronavirus, the metabolism of SARS-CoV-2 coronavirus inhibitors by CYP3A4 is reduced. This leads to decreased clearance of SARS-CoV-2 coronavirus inhibitors and increased plasma concentrations of SARS-CoV-2 coronavirus inhibitors. Reduced clearance and higher plasma concentrations may result in a reduction in the effective dose of SARS-CoV-2 coronavirus inhibitors.

[0154] Additional therapeutic agents that can be used in combination with SARS-CoV-2 inhibitors in the method of the present invention include the following:

[0155] PLpro inhibitors, apiromod, EIDD-2801, ribavirin, valganciclovir, β-thymidine, aspartame, oxprenolol, doxycycline, acetophenazine, iopromide, riboflavin, reproterol, 2,2'-cyclocytidine, chloramphenicol, chlorphenesin carbamate, levodropropidine, cephamandol, phloxuridine, tigecycline, pemetrexed, L(+)-ascorbic acid, glutathione, hesperetin, ademethionine, masopropyl alcohol, isotretinoin, dantrolene, sulfasalazine antibacterial agents, silibin, nicardipine, sildenafil platycodin, chrysin, neohesperidin, baicalin, sugetriol-3,9-diacetate Tate, (-)-epigallocatechin gallate, phytanthrin D, 2-(3,4-dihydroxyphenyl)-2-[[2-(3,4-dihydroxyphenyl)-3,4-dihydro-5,7-dihydroxy-2H-1-benzopyran-3-yl]oxy]-3,4-dihydro-2H-1-benzopyran-3,4,5,7-tetrol, 2,2-di(3-indolyl)-3-indorone, (S)-(1S,2R,4aS,5R,8aS)-1-formamide-1,4a-dimethyl-6-methylene-5-((E)-2-(2-oxo-2,5-dihydrofuran-3-yl)ethenyl)decahydronaphthalen-2-yl-2-amino-3-phenylpropanoate, piceatannol, rosmarinic acid, and magnolol.

[0156] 3CLpro inhibitors, rimecycline, chlorhexidine, alfuzosin, cilastatin, famotidine, almitrin, progavid, nepafenac, carvedilol, amprenavir, tigecycline, montelukast, carminic acid, mimosin, flavin, lutein, cefpyramide, pheneticillin, candoxatril, nicardipine, estradiol valerate, pioglitazone, conivaptan, telmisartan, doxycycline, oxytetracycline, (1S,2R,4aS,5R,8aS)-1-form Amido-1,4a-dimethyl-6-methylene-5-((E)-2-(2-oxo-2,5-dihydrofuran-3-yl)ethenyl)decahydronaphthalen-2-yl5-((R)-1,2-dithiolan-3-yl)pentanoate, betulonal, chrysin-7-O-β-glucuronide, andrographicide, (1S,2R,4aS,5R,8aS)-1-formamide-1,4a-dimethyl-6-methylene-5-((E)-2-(2-oxo-2,5-dihydrofuran-3-yl)ethenyl)decahydronaphthalen -2-yl 2-nitrobenzoate, 2β-hydroxy-3,4-seco-freederolactone-27-euic acid (S)-(1S,2R,4aS,5R,8aS)-1-formamide-1,4a-dimethyl-6-methylene-5-((E)-2-(2-oxo-2,5-dihydrofuran-3-yl)ethenyl)decahydronaphthalen-2-yl-2-amino-3-phenylpropanoate, isodecortinol, celevisterol, hesperidin, neohesperidin, andrograpanin, 2-((1R,5R,6R,8 aS)-6-hydroxy-5-(hydroxymethyl)-5,8a-dimethyl-2-methylenedecahydronaphthalene-1-yl)ethylbenzoate, cosmosyin, cristocarton A, 2,2-di(3-indolyl)-3-indorone, biorobin, gunidicine, filamembrinol, theaflavin 3,3'-di-O-gallate, rosmarinic acid, Kouitchenside I, oleanolic acid, stigmasto-5-en-3-ol, deacetylcentapicrin, and berkemol.

[0157] RdRp inhibitors, valganciclovir, chlorhexidine, ceftibutene, fenoterol, fludarabine, itraconazole, cefuroxime, atovaquone, chenodeoxycholic acid, cromolyn, pancuronium bromide, cortisone, tiborone, novobiocin, silibin, idarubicin, bromocriptine, diphenoxylate, benzylpenicilloyl G, dabigatran etexylate, betulonal, gunidicine, 2β,30β-dihydroxy-3,4-seco-freederolactone-27-lactone, 14-deoxy-11,12-dide Hydroandrophagolide, guniditrin, theaflavin 3,3'-di-O-gallate, (R)-((1R,5aS,6R,9aS)-1,5a-dimethyl-7-methylene-3-oxo-6-((E)-2-(2-oxo-2,5-dihydrofuran-3-yl)ethenyl)decahydro-1H-benzo[c]azepine-1-yl)methyl 2-amino-3-phenylpropanoate, 2β-hydroxy-3,4-seco-freederolactone-27-euic acid, 2-(3,4-dihydroxyphenyl)-2-[[2-(3,4-dihydroxy Phenyl)-3,4-dihydro-5,7-dihydroxy-2H-1-benzopyran-3-yl]oxy]-3,4-dihydro-2H-1-benzopyran-3,4,5,7-tetraol, filambricin B, 14-hydroxycyperotundone, andrographicide, 2-((1R,5R,6R,8aS)-6-hydroxy-5-(hydroxymethyl)-5,8a-dimethyl-2-methylenedecahydronaphthalene-1-yl)ethylbenzoate, andrographicide, sugetriol Ru-3,9-diacetate, baicalin, (1S,2R,4aS,5R,8aS)-1-formamido-1,4a-dimethyl-6-methylene-5-((E)-2-(2-oxo-2,5-dihydrofuran-3-yl)ethenyl)decahydronaphthalen-2-yl, 5-((R)-1,2-dithiolan-3-yl)pentanoate, 1,7-dihydroxy-3-methoxyxanthone, 1,2,6-trimethoxy-8-[(6-O-β-D-xylopyranosyl-β-D-glucopyranosyl)oxy]-9H-xanthene-9-one, and 1,8-dihydroxy-6-methoxy-2-[(6-O-β-D-xylopyranosyl-β-D-glucopyranosyl)oxy]-9H-xanthene-9-one, 8-(β-D-glucopyranosyloxy)-1,3,5-trihydroxy-9H-xanthene-9-one.

[0158] Additional therapeutic agents that can be used in the methods of the present invention include diosmin, hesperidin, MK-3207, venetoclax, dihydroergocristine, borazine, R428, ditercalinium, etoposide, teniposide, UK-432097, irinotecan, lumafter, velpatasvir, erxadrine, ledipasvir, lopinavir / ritonavir + ribavirin, alferon, and prednisone. Other additional agents useful in the methods of the present invention include dexamethasone, azithromycin, and remdesivir, as well as boceprevir, umifenovir, and favipiravir.

[0159] Other additional agents that can be used in the method of the present invention include α-ketoamide compounds designated as 11r, 13a, and 13b shown below, as described in Zhang, L.; Lin, D.; Sun, X.; Rox, K.; Hilgenfeld, R.; X-ray Structure of Main Protease of the Novel Coronavirus SARS-CoV-2 Enables Design of α-Ketoamide Inhibitors; bioRxiv preprint doi:https: / / doi.org / 10.1101 / 2020.02.17.952879.

[0160] [ka]

[0161] Additional agents that can be used in the method of the present invention include RIG1 pathway activators, such as those described in U.S. Patent No. 9,884,876.

[0162] Other additional therapeutic agents include protease inhibitors, such as those described in Dai W, Zhang B, Jiang XM et al., Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease. Science. 2020;368(6497):1331~1335, which include the compounds listed below and the compound designated as DC402234.

[0163] [ka]

[0164] Another embodiment of the present invention is a method for treating COVID-19 in a patient, wherein in addition to administering the compounds of the present invention (i.e., Form 1, Form 5, Form 8, Form 9, Form 10, Form 11, Form 12, or Form 14), an additional agent is administered, the additional agent being nilmatrelvir, remdesivir, galidesivir, faviravir / avifavir, mornupiravir (MK-4482 / EIDD2801), AT-527, AT-301, BLD-2660, favipiravir, camostat, SLV213, emtrictabine / tenof Antiviral drugs such as Ivir, Klevudine, dalcetrapib, boceprevir, PBI-0451, EDP-235 and ABX464, glucocorticoids such as dexamethasone and hydrocortisone, convalescent plasma, recombinant human plasma such as gelzolin (Rhu-p65N), regdanvimab (Regkirova), ravulizumab (Ultomiris), VIR-7831 / VIR-7832, BRII-196 / BRII-198, COVI-AMG / COVIDROPS (STI-2020), bamranivimab (LY-CoV555), mabri Monoclonal antibodies such as limab, leronlimab (PRO140), AZD7442, lentilumab, infliximab, adalimumab, JS016, STI-1499 (COVIGUARD), lanadelmab (Takhzyro), canakinumab (Ilaris), gymcirumab and ocilimab; antibody cocktails such as cacilibimab / imdevimab (REGN-Cov2); recombinant fusion proteins such as MK-7110 (CD24Fc / SACCOVID); anticoagulants such as heparin and apixaban; tocilizumab (Actemra) and sa The treatment is selected from IL-6 receptor agonists such as rilumab (Kevzara), PIKfyve inhibitors such as apyrimod dimesylate, RIPK1 inhibitors such as DNL758 and DC402234, VIP receptor agonists such as PB1046, SGLT2 inhibitors such as dapaglifodine, TYK inhibitors such as avivertinib, kinase inhibitors such as ATR-002, vemcentinib, acalabrutinib, rosmapimod, baricitinib, and tofacitinib, H2 blockers such as famotidine, anthelmintics such as niclosamide, and furin inhibitors such as diminazene.

[0165] The term "SARS-CoV-2 inhibitor" means any of the SARS-CoV-2-related coronavirus 3C-like protease inhibitor compounds described herein that inhibit the replication of SARS-CoV-2 in any manner.

[0166] The term “interfering with or preventing” the replication of SARS-CoV-2-related coronavirus ("SARS-CoV-2") virus within cells means that in cells treated with the compound of the present invention, the production of SARS-CoV-2 components necessary for SARS-CoV-2 replication or progeny viruses is reduced compared to cells not treated with the compound of the present invention. Simple and convenient assays for determining whether SARS-CoV-2 virus replication is reduced include ELISA assays for the presence, absence, or reduction of anti-SARS-CoV-2 antibodies in the blood of the subject (Nasoff et al., PNAS 88:5462~5466, 1991) and RT-PCR (Yu et al., Viral Hepatitis and Liver Disease 574~577, Nishioka, Suzuki and Mishiro (Eds.), Springer-Verlag, Tokyo, 1994). Such methods are well known to those skilled in the art. Alternatively, total RNA can be isolated from transduced and infected "control" cells, analyzed by dot blotting or Northern blotting, and probed with SARS-CoV-2 specific DNA to determine whether SARS-CoV-2 replication has decreased. Alternatively, a decrease in SARS-CoV-2 protein expression can also be used as an indicator of SARS-CoV-2 replication inhibition. Typically, a decrease of 50 percent or more in SARS-CoV-2 replication compared to control cells quantifies the prevention of SARS-CoV-2 replication.

[0167] Administering two or more compounds "in combination" means that all compounds are administered at time intervals close enough to affect the treatment in question. Depending on the treatment regimen, two or more compounds may be administered simultaneously or sequentially, via the same or different routes of administration, on the same or different administration schedules, with or without specific time constraints. In addition, simultaneous administration can be achieved by mixing the compounds before administration, or by administering the compounds at the same time, but in different dosage forms, to the same or different administration sites.

[0168] The terms "simultaneous administration," "combined administration," "concurrent administration," "sequential administration," and "administered at the same time" all mean that the compounds are administered in combination.

[0169] The compounds of the present invention and one or more other therapeutic agents can be administered as fixed or unfixed combinations of active ingredients. The term "fixed combination" means that the compounds of the present invention or pharmaceutically acceptable salts thereof and one or more therapeutic agents are administered together to a subject simultaneously in a single composition or dosage form. The term "unfixed combination" means that the compounds of the present invention or pharmaceutically acceptable salts thereof and one or more therapeutic agents can be administered simultaneously or sequentially with variable time limits in between to a subject that requires them, and such administrations are formulated as separate compositions or dosage forms so as to bring effective levels of two or more compounds into the subject's body.

[0170] In one embodiment, the compounds of the present invention are administered in combination with additional therapeutic agents useful for treating viral infections, which include pharmaceutically acceptable salts of a specifically named drug, as well as pharmaceutically acceptable solvates of the drug and salt.

[0171] These agents and compounds of the present invention can be combined with pharmaceutically acceptable media such as saline solution, Ringer's solution, glucose solution, and analogues. Specific dosing regimens, i.e., dose, timely selection, and number of repetitions, are determined according to the specific individual and their medical history.

[0172] kit Another aspect of the present invention provides a kit comprising the compound of the present invention or a pharmaceutical composition comprising the compound of the present invention. The kit may include a diagnostic agent or a therapeutic agent in addition to the compound of the present invention or its pharmaceutical composition. The kit may also include instructions for use in a diagnostic or therapeutic method. In some embodiments, the kit comprises the compound or its pharmaceutical composition and a diagnostic agent. In other embodiments, the kit comprises the compound or its pharmaceutical composition and one or more therapeutic agents, such as another antiviral agent such as nilmatrelvir, remdesivir, or mornupyravir.

[0173] In yet another embodiment, the present invention includes a kit suitable for use in carrying out the treatment method described herein. In one embodiment, the kit contains a first dosage form comprising one or more of the compounds of the present invention in an amount sufficient to carry out the method of the present invention. In another embodiment, the kit includes one or more of the compounds of the present invention in an amount sufficient to carry out the method of the present invention, and a container for the dosage.

[0174] General experimental methods Powder X-ray diffraction (PXRD) method Powder X-ray diffraction (PXRD) was determined for N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide or its solvate (forms 1, 5, 9, 10, 11 and 750 mg / g SDD) according to the following method.

[0175] Powder X-ray diffraction analysis was performed using a Bruker AXS D8 Endeavor diffractometer equipped with a Cu radiation source (CuKαλ = 1.5418 Å). The divergent slit was set to 15 mm continuous irradiation. Diffracted radiation was detected by a PSD-Lynx Eye detector, with the detector's PSD aperture set to 4.11 degrees. The X-ray tube voltage and current were set to 40 kV and 40 mA, respectively. In addition, an energy-dispersive detector was used with a nickel filter to block unwanted wavelengths. Data were acquired using a theta-theta goniometer at 3.0–40.0 degrees 2-theta Cu wavelengths, with a step size of 0.01 degrees and a step time of 1.0 seconds. The anti-scattering screen was set to a fixed distance of 1.5 mm. The sample was rotated at 15 / min during acquisition. The sample was prepared by placing it in a silicon low-background sample holder and rotated during acquisition. Data was collected using Bruker DIFFRAC Plus software and analyzed using EVA diffract plus software.

[0176] The PXRD data files were not processed before peak retrieval. Preliminary peak assignment was performed using the EVA software's peak retrieval algorithm, with peaks selected at threshold 1. Manual adjustments were made to ensure validity. The automated assignment output was visually checked, and peak positions were adjusted to the maximum peak values. Generally, peaks with a relative intensity of 3% or higher were selected. Peaks that were not separated or matched noise were not selected. A typical error associated with PXRD peak position is specified in the USP as + / -0.2° 2-theta (USP-941).

[0177] Single-crystal X-ray diffraction (SXRD) method Single-crystal X-ray diffraction (SXRD): Forms 1, 5, 8, 12 and 14 Single crystal samples of Morphologies 1, 5, 8, 12, and 14 were investigated by SXRD. SXRD was performed at 298 K using a Bruker D8 Quest diffractometer for Morphologies 1, 5, and 12. SXRD for Morphologies 8 and 14 was performed at 100 K using a Bruker D8 Venture diffractometer. Data collection consisted of omega scans and phi scans. The structures of Morphologies 1, 5, 8, 12, and 14 were elucidated by intrinsic phasing analysis using the SHELX software suite to be space groups C2221, P21, P21212, P21212, and P21212, respectively. Subsequently, the structures were refined by the full-matrix least-squares method. All atoms except hydrogen were located and refined using anisotropic displacement parameters. The final R1 values for Morphologies 1, 5, 8, 12, and 14 were 7.5%, 8.8%, 8.6%, 4.1%, and 8.8%, respectively.

[0178] 13 C and 19 F solid-state nuclear magnetic resonance (ssNMR) method Solid-state nuclear magnetic resonance (ssNMR): Morphologies 1, 5, 9, 10, 11, and 750 mg / g of SDD Solid-state NMR (ssNMR) analysis was performed using a CPMAS probe attached to a Bruker-BioSpin Avance III 600 MHz ( 1 H frequency) NMR spectrometer. The material was filled into a ZrO2 rotor. A magic angle rotation speed of 15 kHz was used. Spectra were collected at ambient temperature (probe temperature 25 °C).

[0179] 13 CssNMR spectra were collected using a proton decoupling cross-polarization magic angle rotation (CPMAS) experiment. During spectrum acquisition, a phase-modulated proton decoupling magnetic field of 80 - 100 kHz was applied. For Morphology 1, Morphology 5, Morphology 9, Morphology 10, Morphology 11, and 750 mg / g of SDD, the cross-polarization contact time was set to 2 milliseconds and the recycle delay was set to 3.5 seconds. The number of scans was adjusted to obtain an appropriate signal-to-noise ratio. 13The 1C chemical shift scale is measured using crystalline adamantane as an external standard. 13 The C CPMAS experiment was used as a reference, and its high-field resonance was set to 29.5 ppm.

[0180] 19 F ssNMR spectra were collected using a proton decoupling magic angle rotation (MAS) experiment. A phase-modulated proton decoupling magnetic field of 80–100 kHz was applied during spectrum acquisition. Spectra were collected for forms 1, 5, 9, 10, 11, and 750 mg / g SDD with a 3.5-second recycle delay. The number of scans was adjusted to obtain a suitable signal-to-noise ratio. 19 The F chemical shift scale is based on the external standard substance trifluoroacetic acid (50% / 50% v / v in H2O solution). 19 The F MAS experiment was used as a reference, and its resonance was set to -76.54 ppm.

[0181] Automated peak picking was performed using Bruker-BioSpin TopSpin version 3.6 software. Generally, a 5% relative intensity threshold was used for preliminary peak selection. The output of automated peak picking was visually checked for validity and manually adjusted where necessary. While specific solid-state NMR peak values ​​are reported herein, in reality, these peak values ​​will vary due to differences in instrumentation, sample, and sample preparation. This is common in the field of solid-state NMR due to inherent variability in peak position. Typical variability in chemical shift x-axis values ​​is approximately ±0.2 ppm for crystalline solids and ±0.5 ppm for amorphous solids. The solid-state NMR peak heights reported herein are relative intensities. Solid-state NMR intensities may vary depending on the actual settings of experimental parameters and the thermal history of the sample.

[0182] Thermogravimetric infrared analysis (TGA-IR) method Thermogravimetric infrared analysis (TGA-IR): Forms 9 and 11 The TA Instruments TGA 5500 is used in the thermal analysis section of the apparatus. A sample of approximately 5 mg to 10 mg was weighed and placed in an aluminum pan, and heated from room temperature to 275 °C (for Form 9) or 200 °C (for Form 11) at a heating rate of 10 °C / min under nitrogen purge (10 mL / min on the balance and 25 mL / min in the sample chamber).

[0183] For TGA-IR analysis, a Thermo Nicolet IS20 FT-IR spectrometer equipped with a KBr beam splitter and a DTGS KBr detector was used. The collection range was 4000 - 400 cm -1 and Happ-Genzel apodization was used for data collection. The background spectrum was collected by 64 co-added scans at a resolution of 8 cm -1 The IR background is collected with the TGA furnace closed and purged for 2 - 3 minutes. The sample method is set to match rapid spectrum collection because the generated gas quickly passes through the gas cell. Each sample spectrum data point is the co-added spectrum of 5 spectra collected at a resolution of 8 cm -1 The total IR collection time is adjusted based on the length of the TGA run time.

[0184] Modulated differential scanning calorimetry (mDSC) method Modulated differential scanning calorimetry: Form 10 and 750 mg / g SDD Modulated differential scanning calorimetry was performed using a Discovery DSC 2500 (TA instruments) equipped with refrigerated accessories. All experiments were performed in standard / Tzero aluminum pans. Cell constants were determined using indium, and temperature calibration was performed using indium and tin as standard materials. All measurements were performed under continuous dry nitrogen purging (50 mL / min). Approximately 1–5 mg of solid sample was weighed and placed in a Tzero aluminum pan, closed but not sealed, and heated using a heat-cool-heat program. The heat-cool-heat program heated from -50°C to 120°C using a modulation temperature amplitude of ±1.0°C, a modulation period of 100 seconds, and a ramp rate of 2°C / min, then cooled to -50°C at a ramp rate of 10°C / min, followed by a second heating from -50°C to 200°C using a modulation temperature amplitude of ±1.0°C, a modulation period of 100 seconds, and a ramp rate of 2°C / min. Experimental data were analyzed using commercially available software (TA Universal Analysis 2000 / Trios software, TA Instruments). [Examples]

[0185] (Example 1) N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, Form 1 (anhydrous free form)

[0186] [ka]

[0187] Step 1: Preparation of methyl((S)-1-((2S,4R)-2-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidine-3-yl)propan-2-yl)carbamoyl)-4-(trifluoromethyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate, compound II (as an organic solution). The compound of formula IV, (2S,4R)-1-((S)-2-((methoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-(trifluoromethyl)pyrrolidine-2-carboxylic acid (25.4 g, 69.7 mmol, 1.0 equivalent) and methyl ethyl ketone (200 mL, 8 L per 1 kg of compound IV) were combined and stirred at 25°C. 2-hydroxypyridine N-oxide (7.91 g, 69.7 mmol, 1.0 equivalent) and triethylamine (17.6 g, 24.3 mL, 0.174 mol, 2.50 equivalents) were added, and the resulting solution was stirred for 5 minutes. Compound III, (S)-2-amino-3-((S)-2-oxopyrrolidine-3-yl)propenamide hydrochloride (17.2 g, 80.2 mmol, 1.15 equivalents) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 20.1 g, 0.105 mol, 1.50 equivalents) were added, rinsed with methyl ethyl ketone (50 mL, 2 L per kg of compound IV), and stirred at 25°C for 16 hours. A sample was taken to confirm completion of the reaction (target: less than 0.5% compound IV). [Note: If the reaction was not complete, the mixture was stirred further.] The reaction was quenched by adding aqueous NaCl solution (100 mL of 14 wt% brine solution, 4.0 L per kg of compound IV), stirred for 15-30 minutes, and the phases were separated. The organic phase was washed again with an aqueous NaCl solution (100 mL of 14 wt% brine solution). Both aqueous phases were combined and extracted twice with methyl ethyl ketone (125 mL, 5 L per kg of compound IV). All organic phases were combined and concentrated by vacuum distillation at 0.3 bar (internal temperature of the reaction mixture approximately 30°C) to a product concentration of approximately 5 L / kg. Next, isopropyl acetate (200 mL, 8 L per kg of compound IV) was added to the mixture and distillation was continued until the reaction volume of the product, compound II, reached approximately 5 L / kg. A second dose of isopropyl acetate (200 mL, 8 L per kg of compound IV) was added and the distillation process was repeated according to the same protocol until the concentration of the product, compound II, reached 5 L / kg, at which point distillation was terminated. Isopropyl acetate (125 mL, 5 L per kg of compound IV) was added and the mixture was stirred at 25°C.The sample was analyzed for water content (Karl-Fischer), and the target was defined as water at 0.2 wt% or less. The resulting methyl((S)-1-((2S,4R)-2-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidine-3-yl)propan-2-yl)carbamoyl)-4-(trifluoromethyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate, an organic isopropylacetic acid solution of compound II, was used in the next step without further purification.

[0188] Step 2: The methyl((S)-1-((2S,4R)-2-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidine-3-yl)propan-2-yl)carbamoyl)-4-(trifluoromethyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate and isopropyl acetate solution of compound II (estimated quantitative conversion amount, 69.7 mmol, 1.0 equivalent) were combined with N-methylmorpholine (36.7 g, 40 mL, 0.36 mol, 5.2 equivalents) and stirred at 10°C. Anhydrous trifluoroacetic acid (38.1 g, 25.5 mL, 0.18 mol, 2.6 equivalents) was added dropwise over 30-60 minutes while maintaining the reaction temperature below 15°C. The resulting mixture was stirred at 10°C for 1 hour. The sample was analyzed for completion of the reaction (compound II was present at a concentration of 0.5% or less). [Note: If the reaction is not complete, continue stirring for another 60 minutes and add additional N-methylmorpholine and trifluoroacetic anhydride if necessary (maintaining a 2:1 ratio)]. The reaction was quenched by adding aqueous ammonium hydroxide solution (28 wt%) (10.7 mL, 76 mmol, 1.1 equivalents) in water (74.1 mL of water, 3.0 L of compound IV from the previous step per 1 kg). The mixture was stirred for 15-30 minutes, then stopped and the layer was allowed to settle. The aqueous phase was removed, and the organic phase was sampled for internal process control (the target was less than 0.1% methyl((S)-1-((2S,4R)-2-(((S)-1-cyano-2-((S)-2-oxopyrrolidine-3-yl)ethyl)carbamoyl)-4-(trifluoromethyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)(2,2,2-trifluoroacetyl)carbamate, which is also known as methyl{(2S)-1-[(2S,4R)-2-({(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}carbamoyl)-4-(trifluoromethyl)pyrrolidine-1-yl]-3,3-dimethyl-1-oxobutan-2-yl}(trifluoroacetyl)carbamate).[Note: If the internal process control target was not achieved, a second basic wash was required according to the same protocol (1.1 equivalents of 28 wt% NH4OH mixed with 74.1 mL of water (3.0 L / kg)). The organic phase was washed with water (74.1 mL, 3.0 L per kg of compound IV from the previous step). Next, the organic phase was concentrated by vacuum distillation (0.3 bar and (internal temperature approximately 30°C)) to a volume of 200 mL (8 L per kg of compound IV from the previous step). Cyclopentyl methyl ether (CPME, 375 mL, 15.0 L per kg of compound IV from the previous step) was added, and the solution was concentrated by vacuum distillation to a volume of 200 mL (compound IV from the previous step). (8 L per 1 kg). The sample was analyzed for water content (Karl-Fischer), with the target being a water content of 0.2 wt% or less and an isopropyl acetate content of 1% or less. [Note: If the target is not achieved, continue the distillation process according to the same protocol.] This solution / slurry was stirred at 40°C for 30-60 minutes, cooled to 10°C at a rate of 0.1 K / min, and stirred at 10°C for at least 1 hour. The solid was collected by filtration, rinsed with 2.5 L / kg and 1 L / kg of CPME, and dried in a vacuum oven at 70°C for 12 hours to obtain 21.1 g of CPME solvate of compound I.

[0189] [ka]

[0190] Step 3: The CPME solvate of compound I (30.09 g, 51.03 mmol, 100% by mass) and heptane (300 mL, 2047.9 mmol, 100% by mass) were added to a 1000 mL two-piece OptiMax reactor and stirred at 350 rpm using an overhead stirrer and baffles. The mixture was stirred at 20°C and heated to 70°C. The mixture was stirred at 70°C for 12 hours, then cooled to 25°C over 5 hours and stirred overnight. The resulting slurry was filtered and washed with heptane (60 mL, 409.58 mmol, 100% by mass). The solid was dried overnight under vacuum at 50°C to obtain N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, the anhydrous free form of Form 1.

[0191] The PXRD was determined for form 1 of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, and the PXRD patterns are shown in Figures 1 and 2.

[0192] [Table 1]

[0193] Single-crystal X-ray diffraction (SXRD) was determined for form 1 of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, and the data are shown in Table 1-2.

[0194] [Table 2]

[0195] Regarding N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 1 13 The 13C solid-state NMR spectrum was determined.

[0196] [Table 3]

[0197] Regarding N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 1 19 The 1F solid-state NMR spectrum was determined.

[0198] [Table 4]

[0199] [Table 5]

[0200] (Example 2) Alternative preparation of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, Form 1 (anhydrous free form) 150.7 mg of amorphous N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide was weighed and placed in a 1-drum vial containing a small stirring bar. 0.5 mL of ethyl acetate (Â) was added, and the mixture was heated at approximately 60°C for about 5 minutes until completely dissolved. 0.5 mL of heptane was slowly added to the clear solution. The mixture was heated at approximately 60°C for about 10 minutes until a clear solution was obtained. The mixture was returned to room temperature (RT) and stirred at RT for about 4 days. The resulting white solid was collected by vacuum filtration and air-dried for about 30 minutes. 108.8 mg of the white solid was collected and transferred to a 1-drum vial containing a small stirring bar. 1.09 mL of heptane was added to the vial. The mixture was slurryed overnight at approximately 70°C. The mixture was then vacuum filtered, and the resulting white solid was air-dried for approximately 30 minutes. 87.1 mg of the white solid was collected and analyzed using PXRD and solution analysis. 1 Analysis was performed by 1H NMR. The results were consistent with N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 1 (anhydrous free form).

[0201] (Example 3) Preparation of the anhydrous free form of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 5 Crystals were grown from a solution of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, Form 1, dissolved in 1-chlorobutane, by slowly evaporating the solution at room temperature.

[0202] Alternative preparation of Form 5 N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1 (373.6 mg) was combined with 1-chlorobutane (2.5 mL) and stirred at 50 °C for approximately 15 hours. During this time, the mixture became very viscous and could not be stirred sufficiently. Additional 1-chlorobutane (1.5 mL) was added and the mixture was stirred for an additional 6 days. The solid was then collected by vacuum filtration and dried in ambient air.

[0203] Single crystals were obtained and the single crystal structure was determined. Data collection was carried out at 298 K on a Bruker D8 Quest diffractometer and it was determined to be the anhydrous free form of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 5.

[0204] Powder X-ray diffraction (PXRD) was determined for the anhydrous free form of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 5.

[0205] [Table 6]

[0206] <( [Table 7]

[0207] For the anhydrous free form of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 5 13The 13C solid-state NMR spectrum was determined. The peaks (ppm) are each ±0.2 ppm.

[0208] [Table 8-1]

[0209] [Table 8-2]

[0210] Regarding N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 5 19 The solid-state NMR spectrum of 1F was determined. The peaks (ppm) are each ±0.2 ppm.

[0211] [Table 9]

[0212] [Table 10]

[0213] (Example 4) Preparation of cyclopentyl methyl ether (CPME) solvate of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, Form 8 5.0 mL of cyclopentyl methyl ether (CPME) was added to a 20 mL vial containing about 30 - 40 mg of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1. The resulting solution was filtered and placed into a clean 20 mL vial. A needle was inserted into the vial cap and the solution was slowly evaporated at 5 °C. Single crystals were obtained and X-ray diffraction data collection was performed at 100 K by SXRD using a Bruker D8 Venture diffractometer (see Figure 11). The obtained crystal form was designated as the cyclopentyl methyl ether (CPME) solvate of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 8.

[0214] SXRD analysis of the cyclopentyl methyl ether solvate of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 8, indicates that this structure contains residual voids of 771.6 Å 3 which account for 12.9% of the unit cell volume. A solvent mask was calculated and 142 electrons were found in the volume of 836 Å 3 of two voids per unit cell. This is consistent with the presence of 0.6 CPME molecules per asymmetric unit, which account for 134 electrons per unit cell.

[0215] [Table 11]

[0216] (Example 5) Preparation of cyclopentyl methyl ether (CPME) solvate of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, Form 9 259.4 mg of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, Form 1, was added to a 20 mL vial containing a stirring bar. 10 mL of cyclopentyl methyl ether (CPME) was added, and the mixture was heated at approximately 60°C for approximately 2 hours. The resulting solution was cooled to room temperature and then slowly evaporated from the loosely capped vial. After one week, the resulting solid was collected by vacuum filtration and air-dried at room temperature for approximately 3 hours. Approximately 160.9 mg of white solid was collected. The obtained solid was analyzed by PXRD (Figure 3), ssNMR (Figures 19-20), and TGA-IR (Figures 27-29).

[0217] [Table 12]

[0218] [Table 13]

[0219] [Table 14]

[0220] Thermogravimetric infrared spectroscopy (TGA-IR): TGA-IR data for cyclopentyl methyl ether (CPME) solvate of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 9, are shown in Figures 27-29. The observed weight loss rate of 10.8% is consistent with the theoretical weight loss rate of 10.9% for form 9 (0.6 equivalents of CPME solvate). Infrared spectral analysis indicates the presence of cyclopentyl methyl ether.

[0221] In the case of CPME solvates, the amount of CPME has been found to vary between different lots, ranging from approximately 8 wt% (approximately 0.4 molar equivalents) to 14 wt% (approximately 0.8 molar equivalents). The PXRD pattern of CPME solvates may vary slightly due to the differing amounts of CPME in the crystal lattice of different lots of this morphology.

[0222] (Reference Example 6) Preparation of amorphous free form of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 10. Approximately 2 g of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, Form 1 was added to a 250 mL round-bottom flask (RBF). 30 mL of acetonitrile (ACN) was added to the 250 mL RBF and sonicated for 5 minutes. Next, 100 mL of water was added to the RBF. The mixture was then sonicated for 5 minutes to confirm the absence of crystals. The mixture was then frozen by cooling in a dry ice / acetone bath, and the resulting freeze-dried mixture was lyophilized. The resulting solid was analyzed by PXRD, ssNMR, and mDSC.

[0223] [Table 15]

[0224] [Table 16]

[0225] Modulated differential scanning calorimetry (mDSC): The glass transition temperature of the amorphous free form, form 10, of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide is approximately 95°C, as determined by mDSC analysis (see Figure 33).

[0226] (Example 7) Preparation of Isopropyl Acetate Solvate of N-(Methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, Form 11 565.0 mg of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, Form 1 was weighed and placed in a 2-drum vial equipped with a stirring bar, and 2.5 mL of isopropyl acetate was pipetteed into the vial. The mixture was stirred in a heat block at approximately 25°C for approximately 2 days. The mixture was vacuum filtered, and the solid was left in ambient air for 3 days. 280.7 mg of the isopropyl acetate solvate of the white solid N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, Form 11 was collected. Solid, PXRD, solid 13 C and 19 Analysis was performed using FNMR and thermogravimetric infrared (TGA-IR) analysis.

[0227] [Table 17]

[0228] [Table 18-1]

[0229] [Table 18-2]

[0230] [Table 19]

[0231] Thermogravimetric infrared spectroscopy (TGA-IR): TGA-IR data for isopropyl acetate solvate of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 11, are shown in Figures 30-32. The observed weight loss rate of 5.8% is consistent with the theoretical weight loss rate of 5.9% for 0.3 equivalents of isopropyl acetate solvate. Infrared spectral analysis indicates the presence of isopropyl acetate.

[0232] (Example 8) Preparation of Isopropyl Acetate Solvate of N-(Methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, Form 12 Approximately 0.5 mL to 1.0 mL of isopropyl acetate / heptane (1:1, v:v) was added to a 1-drum vial containing 5 mg to 10 mg of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, Form 1. The solution was completely dissolved, filtered, and placed in a clean 20 mL vial. The vial was then loosely capped and slowly evaporated at room temperature. As a result, a single crystal of the isopropyl acetate solvate of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 12, was obtained, and the single crystal structure was determined and data was collected using a Bruker D8 Quest diffractometer at 298 K.

[0233] SXRD analysis of the isopropyl acetate solvate of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 12, revealed that this structure is 1666 Å. 3 It contains residual voids, which account for 26.9% of the unit cell volume. The solvent mask was calculated, and there is 1772 Å of voids per unit cell. 3 420 electrons were found in the volume. This is consistent with the presence of one [C5H10O2] atom per asymmetric unit, occupying 448 electrons per unit cell.

[0234] [Table 20]

[0235] (Example 9) Preparation of a 750 mg / g spray-dried dispersion (SDD) of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide / HPMAS-MG A 750 mg / g spray-dried dispersion (SDD) of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide is used as the active pharmaceutical ingredient (API) N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl] The solution was prepared by dissolving ethyl-4-(trifluoromethyl)-L-prolineamide and HPMCAS-MG polymer [75 / 25 N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide / hydroxypropyl methylcellulose acetate succinate, M grade] in acetone. The resulting solution, having 7.5 / 2.5 / 90 by weight percent API / polymer / acetone, was sprayed through a parallel stream of heated nitrogen, during which the solvent was removed to form SDD particles. The SDD particles were subjected to a secondary drying step in a vacuum tray dryer to remove residual acetone solvent from the SDD to an acceptable level (the acceptable level is <5000 ppm (acetone) as tested by the guidance USBD-334, and is typically less than 0.05%).

[0236] The SDD of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide / HPMCAS-MG was PXRD (Figure 6). 13 C and 19 The data was characterized by 14-fluorine solid-state NMR (Figures 25-26) and modulated differential scanning calorimetry (mDSC) (Figure 34).

[0237] (Example 10) Preparation of ethyl solvate of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, Form 14 210.4 mg of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, Form 1 was weighed and placed in a 2-drum vial equipped with a stirring bar. 4.0 mL of ethyl acetate / heptane (3 / 2, v / v) was added to the vial. The mixture was stirred at room temperature for approximately 4 hours.

[0238] SXRD analysis of the ethyl acetate solvate of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 14, shows that the asymmetric unit consists of two molecules of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, one molecule of aligned ethyl acetate, and one additional unaligned ethyl acetate molecule identified using a solvent mask (Z'=2). This results in an overall API:solvent ratio of 1:1.

[0239] [Table 21]

[0240] (Example 11) Preparation of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 22 98.9 mg of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, Form 1, and 1 mL of isopropanol (IPA) were slurryed at room temperature (RT) for approximately 1 hour (98.9 mg / mL). The mixture was a clear solution. 0.5 mL of the mixture was pipetted and filtered through a syringe fitted with an Acrodisc 0.2 μm syringe filter into a 2-drum vial. 2.83 mL of heptane was slowly added to the vial by syringe over approximately 7.5 minutes. The mixture was heated to 60°C overnight, then cooled to RT, and slurryed at RT for approximately 3 hours. The solid was then collected by vacuum filtration, and the PXRD and solution were analyzed. 1 Analysis was performed by 1H NMR. 26.4 mg of white solid was collected (yield: approximately 53.4%).

[0241] Measurement by device Powder X-ray diffraction (PXRD): Powder X-ray diffraction analysis was performed using a Bruker AXS D8 Endeavor diffractometer equipped with a Cu radiation source (K-α averaged). The divergent slit was set to 15 mm continuous irradiation. Diffracted radiation was detected by a PSD-Lynx Eye detector, with the PSD aperture of the detector set to 4.10 degrees. The X-ray tube voltage and current were set to 40 kV and 40 mA, respectively. Data were acquired using a theta-theta goniometer at 3.0–40.0 degrees 2-theta Cu wavelengths, with a step size of 0.01 degrees and a step time of 1.0 seconds. The anti-scattering screen was set to a fixed distance of 3.0 mm. The sample was rotated at 15 / min during acquisition. The sample was prepared by placing it in a silicon low-background sample holder and rotated during acquisition. Data were acquired using Bruker DIFFRAC Plus software and analyzed using EVA diffract plus software.

[0242] The PXRD data files were not processed before peak retrieval. Preliminary peak assignment was performed using the EVA software's peak retrieval algorithm, with peaks selected at threshold 1. Manual adjustments were made to ensure validity. The automated assignment output was visually checked, and peak positions were adjusted to the maximum peak values. Generally, peaks with a relative intensity of 3% or higher were selected. Peaks that were not separated or matched noise were not selected. A typical error associated with PXRD peak position is specified in the USP as + / -0.2° 2-theta (USP-941).

[0243] Single-crystal X-ray diffraction (SXRD): A single crystal sample of morphology 22 was investigated by SXRD. SXRD was performed at 298K using a Bruker D8 Venture diffractometer. Data acquisition consisted of omega scans and fiscans. The structure was elucidated using the SHELX software suite in monoclinic space group P21 by intrinsic phase analysis. Subsequently, the structure was refined using the full matrix least squares method. All atoms except hydrogen were identified and refined using anisotropy displacement parameters. The final R index was 4.8%.

[0244] Table 2 contains structural data from the SXRD analysis of morphology 22. The ORTEP diagram of the asymmetric unit of morphology 22 is shown in Figure 3 with a 50% probability displacement parameter.

[0245] Solid state nuclear magnetic resonance (ssNMR) 13 14C solid-state NMR (ssNMR) analysis is performed using the Bruker-BioSpin Avance NEO 500MHz. 1 The procedure was performed using a CPMAS probe attached to a (H-frequency) NMR spectrometer. 19 1F solid-state NMR (ssNMR) analysis is performed using a Bruker-BioSpin Avance III 600MHz instrument. 1 The analysis was performed using a CPMAS probe mounted on a (H-frequency) NMR spectrometer. The material was packed into a ZrO2 rotor. A magic angle rotation speed of 15 kHz was used. Spectra were collected at ambient temperature (probe temperature 25°C).

[0246] 13 CssNMR spectra were collected using a proton decoupling cross-polarization magic angle rotation (CPMAS) experiment. A phase-modulated proton decoupling magnetic field of 80–100 kHz was applied during spectrum acquisition. The cross-polarization contact time was set to 2 milliseconds, and the recycle delay to 3.5 seconds. The number of scans was adjusted to obtain a suitable signal-to-noise ratio. 13 The 1C chemical shift scale is measured using crystalline adamantane as an external standard. 13 The C CPMAS experiment was used as a reference, and its high-field resonance was set to 29.5 ppm.

[0247] 19 F ssNMR spectra were collected using a proton decoupling magic angle rotation (MAS) experiment. A phase-modulated proton decoupling magnetic field of 80–100 kHz was applied during spectrum acquisition. Spectra were collected with a 3.5-second recycle delay. The number of scans was adjusted to obtain a suitable signal-to-noise ratio. 19 The F chemical shift scale is based on the external standard substance trifluoroacetic acid (50% / 50% v / v in H2O solution). 19 The F MAS experiment was used as a reference, and its resonance was set to -76.54 ppm.

[0248] Automated peak picking was performed using Bruker-BioSpin TopSpin version 4.1 software. Generally, a 5% relative intensity threshold was used for preliminary peak selection. The output of automated peak picking was visually checked for validity and manually adjusted where necessary. While specific solid-state NMR peak values ​​are reported herein, in reality, these peak values ​​will vary due to differences in instrumentation, sample, and sample preparation. This is common in the field of solid-state NMR due to inherent variability in peak position. Typical variability in chemical shift x-axis values ​​is approximately plus or minus 0.2 ppm for crystalline solids. The solid-state NMR peak heights reported herein are relative intensities. Solid-state NMR intensities may vary depending on the actual settings of experimental parameters and the thermal history of the sample.

[0249] [Table 22]

[0250] Single-crystal X-ray diffraction (SXRD) Table 11-2 contains structural data from the SXRD analysis of morphology 22. The ORTEP diagram of the asymmetric unit of morphology 22 is shown in Figure 39 with a displacement parameter of 50% probability.

[0251] [Table 23]

[0252] Solid state nuclear magnetic resonance (ssNMR): N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide form 22 13 C and 19 The FssNMR spectra are shown in Figures 41 and 42, and the corresponding peak lists (ppm) are shown in Tables 11-3 and 11-4 (each peak ±0.2 ppm). Selected characteristic peaks for morphology 22 are shown in Table 11-5.

[0253] [Table 24]

[0254] [Table 25]

[0255] [Table 26]

[0256] [Table 27]

Claims

1. A compound that is the anhydrous crystalline form of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide.

2. 50.8 ppm, 58.3 ppm and 43.5 ppm １３ The compound according to claim 1, which is an anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 1, characterized by 13C solid-state NMR peaks (each peak being ±0.2 ppm).

3. 50.8 ppm and 58.3 ppm １３ C solid-state NMR peaks (each peak is ±0.2 ppm), and -70.7 ppm ± 0.2 ppm １９ The compound according to claim 1, which is an anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, characterized by the F solid-state NMR peak.

4. 50.8 ppm and 43.5 ppm １３ C solid-state NMR peaks (each peak is ±0.2 ppm), and -70.7 ppm ± 0.2 ppm １９ The compound according to claim 1, which is an anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, characterized by the F solid-state NMR peak.

5. 50.8 ppm, 58.3 ppm and 43.5 ppm １３ C solid-state NMR peaks (each peak is ±0.2 ppm), and -70.7 ppm ± 0.2 ppm １９ The compound according to claim 1, which is an anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, characterized by the F solid-state NMR peak.

6. 50.8 ppm and 58.3 ppm １３ The compound according to claim 1, which is anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 1, characterized by a 1C solid-state NMR peak (each peak being ±0.2 ppm) and one to four powder X-ray diffraction peaks (Cu Kα line) selected from the group consisting of peaks at 9.1, 9.6, 10.3 and 16.2 degrees 2θ (each peak being ±0.2 degrees 2θ).

7. 50.8 ppm and 43.5 ppm of １３ C solid state NMR peaks (each peak is ±0.2 ppm), and one to four powder X-ray diffraction peaks (Cu Kα radiation) selected from the group consisting of peaks at 9.1, 9.6, 10.3 and 16.2 degrees 2θ (each peak is ±0.2 degrees 2θ), the anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1, of the compound according to claim 1.

8. 50.8 ppm, 58.3 ppm and 43.5 ppm １３ The compound according to claim 1, which is anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 1, characterized by a 1C solid-state NMR peak (each peak being ±0.2 ppm) and one to four powder X-ray diffraction peaks (Cu Kα line) selected from the group consisting of peaks at 9.1, 9.6, 10.3 and 16.2 degrees 2θ (each peak being ±0.2 degrees 2θ).

9. 50.8 ppm and 58.3 ppm １３ C solid-state NMR peaks (each peak is ±0.2 ppm), -70.7 ppm ± 0.2 ppm １９ The compound according to claim 1, which is anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 1, characterized by a solid-state NMR peak and one to four powder X-ray diffraction peaks (Cu Kα line) selected from the group consisting of peaks at 9.1, 9.6, 10.3 and 16.2 degrees 2θ (each peak is ±0.2 degrees 2θ).

10. 50.8 ppm and 43.5 ppm １３ C solid-state NMR peaks (each peak is ±0.2 ppm), -70.7 ppm ± 0.2 ppm １９ The compound according to claim 1, which is anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 1, characterized by a solid-state NMR peak and one to four powder X-ray diffraction peaks (Cu Kα line) selected from the group consisting of peaks at 9.1, 9.6, 10.3 and 16.2 degrees 2θ (each peak is ±0.2 degrees 2θ).

11. 50.8 ppm, 58.3 ppm and 43.5 ppm １３ C solid-state NMR peaks (each peak is ±0.2 ppm), -70.7 ppm ± 0.2 ppm １９ The compound according to claim 1, which is anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 1, characterized by a solid-state NMR peak and one to four powder X-ray diffraction peaks (Cu Kα line) selected from the group consisting of peaks at 9.1, 9.6, 10.3 and 16.2 degrees 2θ (each peak is ±0.2 degrees 2θ).

12. Form 1 of the N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide according to any one of claims 2 to 11, which is substantially pure.

13. A solid form of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide comprising form 1 according to any one of claims 2 to 11, wherein the solid form comprises less than 95%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 3%, or less than 1% by weight. A solid form of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, comprising one or more solid forms of the compound N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide.

14. A pharmaceutical composition comprising a therapeutically effective amount of the solid form described in any one of claims 2 to 12 or claim 13 and a pharmaceutically acceptable carrier.

15. -72.6 ppm and -73.8 ppm １９ F solid-state NMR peaks (each peak is ±0.2 ppm), as well as 182.6 ppm, 156.1 ppm and 52.6 ppm １３ The compound according to claim 1, which is anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 5, characterized by 13C solid-state NMR peaks (each peak being ±0.2 ppm).

16. -72.6 ppm ± 0.2 ppm and -73.8 ppm ± 0.2 ppm １９ The compound according to claim 1, which is anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 5, characterized by a solid-state NMR peak and one to four powder X-ray diffraction peaks (Cu Kα line) selected from the group consisting of peaks at 3.6, 7.1, 10.7 and 17.1 degrees 2θ (each peak is ±0.2 degrees 2θ).

17. -72.6 ppm ± 0.2 ppm and -73.8 ppm ± 0.2 ppm １９ One to three peaks selected from the group consisting of the F solid-state NMR peak, and peaks at 182.6 ppm, 156.1 ppm, and 52.6 ppm. １３ The compound according to claim 1, which is anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 5, characterized by a 13C solid-state NMR peak (each peak being ±0.2 ppm) and one to four powder X-ray diffraction peaks (Cu Kα line) selected from the group consisting of peaks at 3.6, 7.1, 10.7 and 17.1 degrees 2θ (each peak being ±0.2 degrees 2θ).

18. Substantially pure, N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 5.

19. A solid form of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide containing Form 5, in any other solid form by weight of less than 95%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 3%, or less than 1% Solid form of N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, which contains the compound N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide.

20. A pharmaceutical composition comprising an effective therapeutic amount of anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, Form 5, and a pharmaceutically acceptable carrier.

21. Cyclopentyl methyl ether solvate of crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide.

22. -70.2 ppm and -70.5 ppm １９ F solid-state NMR peaks (each peak is ±0.2 ppm), and 1 to 3 peaks selected from the group of peaks at 32.7 ppm, 24.2 ppm, and 56.0 ppm. １３ The compound according to claim 21, which is the cyclopentyl methyl ether solvate of crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, characterized by 14C solid-state NMR peaks (each peak being ±0.2 ppm), the compound according to claim 9.

23. -70.2 ppm and -70.5 ppm １９ The compound according to claim 21, which is a cyclopentyl methyl ether solvate of crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 9, characterized by a solid-state NMR peak (each peak being ±0.2 ppm) and one to three powder X-ray diffraction peaks (Cu Kα line) selected from peaks at 7.1, 7.9 and 19.8 degrees 2θ (each peak being ±0.2 degrees 2θ).

24. -70.2 ppm and -70.5 ppm １９ One to three F solid-state NMR peaks (each peak is ±0.2 ppm), selected from the group of peaks at 32.7 ppm, 24.2 ppm, and 56.0 ppm. １３ The compound according to claim 21, which is a cyclopentyl methyl ether solvate of crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 9, characterized by a 13C solid-state NMR peak (each peak being ±0.2 ppm) and one to three powder X-ray diffraction peaks (Cu Kα line) selected from peaks at 7.1, 7.9 and 19.8 degrees 2θ (each peak being ±0.2 degrees 2θ).

25. Isopropyl acetate solvate of crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 11.

26. -69.8 ppm, -71.9 ppm and -72.4 ppm １９ F solid-state NMR peaks (each peak is ±0.2 ppm), and 1 to 3 peaks selected from the group of peaks at 20.9 ppm ± 0.2 ppm, 38.7 ppm ± 0.2 ppm, and 52.0 ppm ± 0.2 ppm. １３ The compound according to claim 25, characterized by a 1C solid-state NMR peak.

27. -69.8 ppm, -71.9 ppm and -72.4 ppm １９ The compound according to claim 25, characterized by a solid-state NMR peak (each peak being ±0.2 ppm) and one to four powder X-ray diffraction peaks (Cu Kα line) selected from the group of peaks at 8.5, 6.3, 10.7, and 19.1 degrees 2θ (each peak being ±0.2 degrees 2θ).

28. -69.8 ppm, -71.9 ppm and -72.4 ppm １９ F solid-state NMR peaks (each peak is ±0.2 ppm), one to three selected from the group of peaks at 20.9 ppm ± 0.2 ppm, 38.7 ppm ± 0.2 ppm, and 52.0 ppm ± 0.2 ppm. １３ The compound according to claim 25, characterized by a ¹¹¹¹ solid-state NMR peak and one to four powder X-ray diffraction peaks (Cu Kα line) selected from the group of peaks at 8.5, 6.3, 10.7, and 19.1 degrees 2θ (each peak being ±0.2 degrees 2θ).

29. A spray-dried dispersion comprising N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide and pharmaceutically acceptable excipients.

30. A spray-dried dispersion according to claim 29, comprising hydroxypropyl methylcellulose acetate succinate, M grade.

31. The spray-dried dispersion according to claim 30, comprising 750 mg / g of amorphous N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide and 250 mg / g of hydroxypropyl methylcellulose acetate succinate, M grade.

32. A pharmaceutical composition comprising a spray-dried dispersion according to any one of claims 29 to 31.

33. The ethyl acetate solvate of crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide.

34. The crystal system is orthorhombic, and the space group is P2 １ 2 １ The unit cell is 2, with dimensions a = 24.7926 (16) Å, α = 90°, b = 25.0341 (15) Å, β = 90°, and c = 9.6240 (6) Å, γ = 90°, and a volume of 5973.2 (6) Å. ３ Therefore, Z is 8, and the computational density is 1.187 g / cm³. ３ F ２ The goodness of fit is 1.077, and the final R-index [I>=2σ(I)] is R １ =0.0880, wR ２ = 0.2433, and the final R-index [all data] is R １ =0.1056, wR ２ The compound according to claim 33, which is form 14, an ethyl acetate solvate of crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, characterized by a single-crystal X-ray diffraction pattern (SXRD) of 0.2666.

35. The compound according to claim 1, which is anhydrous crystalline N-(methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, form 22.

36. -71.0 and -71.5 ppm １９ The compound according to claim 35, characterized by the F solid-state NMR peaks (each ±0.2 ppm).

37. Select one to three peaks from the groups of 53.3 ppm, 39.8 ppm, and 169.1 ppm. １３ The compound according to claim 35, characterized by 14C solid-state NMR peaks (each peak being ±0.2 ppm).

38. -71.0 ppm and -71.5 ppm １９ F solid-state NMR peaks (each at ±0.2 ppm), and 1 to 4 peaks selected from the group of peaks at 53.3 ppm, 39.8 ppm, 169.1 ppm, and 40.8 ppm. １３ The compound according to claim 35, characterized by 14C solid-state NMR peaks (each peak being ±0.2 ppm).

39. -71.0 ppm and -71.5 ppm １９ The compound according to claim 35, characterized by a solid-state NMR peak (each peak being ±0.2 ppm) and one or two powder X-ray diffraction peaks (Cu Kα line) selected from peaks at 11.6 and 14.6 degrees 2θ (each peak being ±0.2 degrees 2θ).

40. Select one to three peaks from the groups of 53.3 ppm, 39.8 ppm, and 169.1 ppm. １３ The compound according to claim 35, characterized by a 13C solid-state NMR peak (each peak being ±0.2 ppm) and one or two powder X-ray diffraction peaks (Cu Kα line) selected from peaks at 11.6 and 14.6 degrees 2θ (each peak being ±0.2 degrees 2θ).

41. -71.0 ppm and -71.5 ppm １９ F solid-state NMR peaks (each peak is ±0.2 ppm), 1 to 4 peaks selected from the group of peaks at 53.3 ppm, 39.8 ppm, 169.1 ppm, and 40.8 ppm. １３ The compound according to claim 35, characterized by a 13C solid-state NMR peak (each peak being ±0.2 ppm) and one or two powder X-ray diffraction peaks (Cu Kα line) selected from peaks at 11.6 and 14.6 degrees 2θ (each peak being ±0.2 degrees 2θ).

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