TW202513557A - Solid forms of n-(methoxycarbonyl)-3-methyl-l-valyl-(4r)-n-{(1s)-1-cyano-2-[(3s)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-l-prolinamide and solvates thereof - Google Patents

Abstract

The present disclosure is directed to solid forms of N-(Methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, I, such as anhydrous forms thereof, an amorphous form thereof, a cyclopentyl methyl ether solvate thereof, an isopropyl acetate solvate thereof, and an ethyl acetate solvate thereof and to pharmaceutical compositions comprising the solid forms and methods of treatment employing the solid forms.

Description

Solid forms of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide and its solvent complex

The present invention relates to solid forms of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide and solvents thereof, pharmaceutical compositions containing the solid forms, and methods for preparing and using the solid forms and pharmaceutical compositions.

For the preparation of N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide (also known by its synonym {( 2S )-1-[( 2S , 4R )-2-({( 1S )-1-cyano-2-[( 3S The synthetic route to the compound of Formula I is described in U.S. Patent Nos. 11,351,149 and 11,452,711 and International Application No. PCT/IB2021/057281, all of which are incorporated herein by reference in their entirety for all purposes, and have the structure shown below. The compounds of formula I inhibit viral proteases, such as the coronavirus major protease and thus inhibit the viral replication process. The compounds of formula I are useful for treating coronavirus infections, such as SARS-CoV-2 infections (COVID-19).

Solid forms are of concern to the pharmaceutical industry and particularly to those involved in developing suitable dosage forms. If the solid form does not remain constant during clinical or stability studies, the exact dosage form used or studied may not be comparable from one batch to another. It is also desirable to have a process for producing a compound in high purity when the compound has a selected solid form for use in clinical studies or in a commercial product, since the presence of impurities may produce undesirable toxicological effects. Certain solid forms may also exhibit enhanced stability or may be easier to manufacture in large quantities at high purity, and therefore be more suitable for inclusion in pharmaceutical formulations. Certain solid forms may exhibit other advantageous physical properties, such as lack of tendency to absorb moisture, filterability, improved solubility, and enhanced dissolution rate due to different lattice energies.

The discussion of the prior art to the present invention herein is included to explain the context of the present invention. This should not be regarded as an admission that any of the material cited was published, known or part of the common general knowledge in any country as of the priority date of the present invention.

Disclosed herein are solid forms of compounds of formula I I and certain solvates thereof, wherein each solid form can be uniquely identified by several different analytical parameters, either independently or in combination, such as, but not limited to, powder X-ray diffraction pattern peaks or a combination of two or more peaks; single crystal X-ray diffraction pattern; solid state NMR ¹³ C chemical shift or a combination of two or more chemical shifts; solid state NMR ¹⁹ F chemical shift; thermogravimetric infrared analysis (TGA-IR); and modulated differential scanning calorimetry (mDSC).

Based on the disclosure provided herein, it will be apparent to one of ordinary skill in the art that various solid forms of the compound of Formula I or a specific solvent thereof (referred to herein as "Form 1", "Form 5", "Form 8", "Form 9", "Form 10", "Form 11", "Form 12", and "Form 14" and "Form 22") and spray-dried dispersions prepared therefrom can be uniquely identified in different combinations by a number of different spectral peaks, patterns or techniques. Any exemplary combination of characteristic peaks that can be used to identify a solid form of the compound of Formula I should in no way be considered to limit other peak combinations disclosed herein.

The present invention describes forms of anhydrous crystalline forms of N- (methoxycarbonyl)-3-methyl-L-hydroxycarbamidyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, which are designated herein as Form 1 and Form 5, respectively. Form 1 is a particularly advantageous form of anhydrous crystalline form of N- (methoxycarbonyl)-3-methyl-L-hydroxycarbamidyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, which exhibits good stability and lacks hygroscopicity and is therefore suitable for use in pharmaceutical compositions. Form 22 is also a particularly advantageous form of anhydrous crystalline form of N- (methoxycarbonyl)-3-methyl-L-hydroxyprolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-hydroxyprolinamide, which exhibits good stability and lacks hygroscopicity and is therefore suitable for use in pharmaceutical compositions. Form 1 and Form 22 are both non-solvated (non-solvate) forms of the compound. The present invention also describes amorphous N- (methoxycarbonyl)-3-methyl-L-hydroxy-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide and N-(methoxycarbonyl)-3-methyl-L-hydroxy-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide ring in pentyl methyl ether solvent, N- ( methoxycarbonyl)-3-methyl-L-hydroxy-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide ring in pentyl methyl ether solvent. Solid forms of an isopropyl acetate solvent complex of N-(methoxycarbonyl)-3-methyl-L-carboxamidoyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide and an ethyl acetate solvent complex of N- (methoxycarbonyl)-3-methyl-L-carboxamidoyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide. The amyl methyl ether solvent of the N- (methoxycarbonyl)-3-methyl-L-vinylamino-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide ring, the isopropyl acetate solvent of N-(methoxycarbonyl)-3-methyl-L-vinylamino-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, and the N- ( methoxycarbonyl)-3-methyl-L-vinylamino-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide -(methoxycarbonyl)-3-methyl-L-carboxamidoyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide in ethyl acetate solvent can be advantageously used as an intermediate to prepare Form 1 solid form. Also disclosed is a spray-dried dispersion of N- (methoxycarbonyl)-3-methyl-L-carboxamidoyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide. The following examples of the present invention are designated as E1 to E.

E1 is a compound which is an anhydrous crystalline form of N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide.

E2 is a compound as E1, which is anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1, characterized by ^{a 13} C solid state NMR peak at 50.8 ppm ± 0.2 ppm.

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

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

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

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

E7 is a compound as E1, which is an anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1, characterized by ¹³ C solid state NMR peaks at 50.8 ppm and 58.3 ppm, each of which is ± 0.2 ppm, and ^{a 19} F solid state NMR peak at -70.7 ppm ± 0.2 ppm.

E8 is a compound as E1 which is an anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1, characterized by ¹³ C solid state NMR peaks at 50.8 ppm and 43.5 ppm, each of which is ± 0.2 ppm, and ^{a 19} F solid state NMR peak at -70.7 ppm ± 0.2 ppm.

E9 is a compound as E1 which is an anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1, characterized by ¹³ C solid state NMR peaks at 50.8 ppm, 58.3 ppm and 43.5 ppm, each of which is ± 0.2 ppm, and ^{a 19} F solid state NMR peak at -70.7 ppm ± 0.2 ppm.

E10 is a compound as E1 which is an anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1, characterized by ^{a 13} C solid state NMR peak at 50.8 ppm ± 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° 2θ, wherein each peak is ± 0.2° 2θ.

E11 is a compound as E1, which is anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1, characterized by ¹³ C solid state NMR peaks at 50.8 ppm and 58.3 ppm, each of which 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° 2θ, each of which is ± 0.2° 2θ.

E12 is a compound as E1, which is an anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1, characterized by ¹³ C solid state NMR peaks at 50.8 ppm and 43.5 ppm, each of which 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° 2θ, each of which is ± 0.2° 2θ.

E13 is a compound as E1, which is an anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1, characterized by ¹³ C solid state NMR peaks at 50.8 ppm, 58.3 ppm and 43.5 ppm, each of which 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° 2θ, each of which is ± 0.2° 2θ.

E14 is a compound as E1, which is an anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1, characterized by ^{a 13} C solid state NMR peak at 50.8 ppm ± 0.2 ppm; ^{a 19} F solid state NMR peak at -70.7 ppm ± 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° 2θ, wherein each peak is ± 0.2° 2θ.

E15 is a compound as E1, which is an anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1, characterized by ¹³ C solid state NMR peaks at 50.8 ppm and 58.3 ppm, each of which is ± 0.2 ppm; ¹⁹ F solid state NMR peak at -70.7 ppm ± 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° 2θ, each of which is ± 0.2° 2θ.

E16 is a compound as E1, which is an anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1, characterized by ¹³ C solid state NMR peaks at 50.8 ppm and 43.5 ppm, each of which is ± 0.2 ppm, ^{a 19} F solid state NMR peak at -70.7 ppm ± 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° 2θ, each of which is ± 0.2° 2θ.

E17 is a compound as E1, which is an anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-hydroxyproline-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-hydroxyproline amide, Form 1, characterized by ¹³ C solid state NMR peaks at 50.8 ppm, 58.3 ppm and 43.5 ppm, each of which is ± 0.2 ppm, ¹⁹ F solid state NMR peak at -70.7 ppm ± 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° 2θ, each of which is ± 0.2° 2θ.

E18 is N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1, which is substantially pure.

E19 is a compound as E1, which is anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1, characterized by an X-ray powder diffraction pattern substantially identical to that in FIG. 1 .

E20 is a compound according to technical solution 1, which is anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-hydroxy-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-hydroxy-prolinamide, form 1, characterized by a single crystal X-ray diffraction pattern (SXRD), wherein the crystal system is orthorhombic, the space group is C222 ₁ , the unit cell dimensions are a = 9.6317(4) Å, α = 90°, b = 19.6368(8) Å, β = 90° and c = 28.2776(11) Å, γ = 90°, and the volume is 5348.3(4) Å3, Z is 8, the calculated density is 1.216 Mg/m ³ , the goodness of fit F ² is 1.061, the final R index [I＞2Σ(I)] is R ₁ = 0.0754, wR ₂ = 0.2246 and the R index (all data) is R ₁ = 0.0907, wR ₂ = 0.2392.

E21 is the compound as E1, which is anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1, characterized by an ORTEP plot of the asymmetric unit of Form 1 plotted at a displacement parameter of 50% that is substantially the same as that in FIG. 7 .

E22 is a solid form of N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, comprising Form 1 of any one of E2 to E21 and wherein the solid form comprises less than 95 wt%, less than 90 wt%, less than 80 wt%, less than 70 wt%, less than 60 wt%, less than 50 wt%, less than 40 wt%, less than 30 wt%, less than 20 wt%, less than 10 wt%, less than 5 wt%, less than 3 wt%, or less than 1 wt% of the compound N -(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide or any other solid forms thereof.

E23 is a solid form of E22, wherein the solid form comprises less than 10% by weight of one or more other solid forms of N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide.

E24 is a solid form of E22 comprising less than 5 wt % of one or more of any other solid forms of N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide.

E25 is a solid form of E22, comprising less than 2 wt % of one or more of any other solid forms of N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide.

E26 is a solid form of E22, comprising less than 1% by weight of one or more of any other solid forms of N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide.

E27 is the solid form of any one of E22 to E26, wherein the one or more other solid forms are selected from Form 5, Form 10, and Form 5 and Form 10.

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

E29 is a pharmaceutical composition as E28, comprising 100 mg to 1000 mg of Form 1.

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

E31 is a pharmaceutical composition as E29, comprising 300 mg to 600 mg of Form 1.

E32 is a method for treating coronavirus infection in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-proline-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide, Form 1, or a solid form as described in any one of E22 to E26 as described in any one of Technical Schemes 2 to 21.

E33 is a method for treating a coronavirus infection in a patient, the method comprising administering a pharmaceutical composition as described in any one of E28 to E31.

E34 is a method as described in E32 or E33, wherein the coronavirus infection is a SARS-CoV-2 infection.

E35 is an anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1 of any one of E2 to E21, which is used for treating coronavirus infection.

E36 is a pharmaceutical composition as described in any one of E28 to E31, which is used for treating coronavirus infection.

E37 is the use of E35 or E36, wherein the coronavirus infection is SARS-CoV-2 infection.

E38 is the compound as E1 which is anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 5, characterized by ¹⁹ F solid state NMR peaks at -72.6 ppm and -73.8 ppm, with each peak being ± 0.2 ppm.

E39 is a compound as in E1, which is an anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 5, characterized by ¹⁹ F solid state NMR peaks at -72.6 ppm and -73.8 ppm, each of which is ± 0.2 ppm, and ^{a 13} C solid state NMR peak at 182.6 ppm ± 0.2 ppm.

E40 is a compound as in E1, which is an anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 5, characterized by ¹⁹ F solid state NMR peaks at -72.6 ppm and -73.8 ppm, each of which is ± 0.2 ppm, and ^{a 13} C solid state NMR peak at 156.1 ppm ± 0.2 ppm.

E41 is a compound as E1, which is anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 5, characterized by ¹⁹ F solid state NMR peaks at -72.6 ppm and -73.8 ppm, each of which is ± 0.2 ppm, and ^{a 13} C solid state NMR peak at 52.6 ppm ± 0.2 ppm.

E42 is a compound as in E1, which is anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 5, characterized by ¹⁹ F solid state NMR peaks at -72.6 ppm and -73.8 ppm, each of which is ± 0.2 ppm, and ¹³ C solid state NMR peaks at 182.6 ppm and 156.1 ppm, each of which is ± 0.2 ppm.

E43 is a compound as in E1, which is anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 5, characterized by ¹⁹ F solid state NMR peaks at -72.6 ppm and -73.8 ppm, each of which is ± 0.2 ppm, and ¹³ C solid state NMR peaks at 182.6 ppm and 52.6 ppm, each of which is ± 0.2 ppm.

E44 is a compound as E1, which is anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 5, characterized by ¹⁹ F solid state NMR peaks at -72.6 ppm and -73.8 ppm, each of which is ± 0.2 ppm; and ¹³ C solid state NMR peaks at 156.1 ppm and 52.6 ppm, each of which is ± 0.2 ppm.

E45 is a compound as in E1, which is anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 5, characterized by ¹⁹ F solid state NMR peaks at -72.6 ppm and -73.8 ppm, each of which is ± 0.2 ppm, and ¹³ C solid state NMR peaks at 182.6 ppm, 156.1 ppm and 52.6 ppm, each of which is ± 0.2 ppm.

E46 is the compound as E1, which is anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 5, characterized by ¹⁹ F solid state NMR peaks at -72.6 ppm ± 0.2 ppm and -73.8 ppm ± 0.2 ppm and one to four powder X-ray diffraction peaks (Cu Kα radiation) selected from a group consisting of peaks at 3.6, 7.1, 10.7 and 17.1° 2θ, each peak being ± 0.2° 2θ.

E47 is a compound as in E1, which is an anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-hydroxyprolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-hydroxyprolinamide, Form 5, characterized by ¹⁹ F solid state NMR peaks at -72.6 ppm ± 0.2 ppm and -73.8 ppm ± 0.2 ppm; one to three ¹³ C solid state NMR peaks selected from the group consisting of peaks at 182.6 ppm, 156.1 ppm and 52.6 ppm, each of which is ± 0.2 ppm; and one to four peaks selected from the group consisting of peaks at 3.6, 7.1, 10.7 and 17.1°. Powder X-ray diffraction peaks (Cu Kα radiation) consisting of a group of peaks at 2θ, where each peak is ± 0.2° 2θ.

E48 is a compound as in E1, which is anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-hydroxyprolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-hydroxyprolinamide, Form 5, characterized by a single crystal X-ray diffraction pattern (SXRD), wherein the crystal system is monoclinic, the space group is _P21 , the unit cell has dimensions a = 17.8885(16) Å, α = 90°, b = 9.2624(8) Å, β = 106.851(4)° and c = 25.291(2) Å, γ = 90°, and a volume of 4.010.5(6) Å3, Z is 6, the calculated density is 1.216 Mg/m ³ , the goodness of fit F ² is 1.138, the final R index [I＞2Σ(I)] is R ₁ = 0.0881, wR ₂ = 0.2492 and the R index (all data) is R ₁ = 0.1088, wR ₂ = 0.2779.

E49 is the compound as E1, which is anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 5, characterized by an ORTEP plot of the asymmetric unit of Form 5 substantially identical to that in FIG. 9 , plotted at a displacement parameter of 50%.

E50 is N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 5, which is substantially pure.

E51 is a solid form of N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide comprising Form 5 and 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 of the compound N Any other solid form of -(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide.

E52 is a solid form as E51, wherein the one or more other solid forms are selected from Form 1, Form 10, and Form 1 and Form 10.

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

E54 is a method for treating a coronavirus infection in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 5, as described in any one of E38 to E50.

E55 is a method of treating a coronavirus infection in a patient, the method comprising administering a pharmaceutical composition such as E53.

E56 is the method of E54 or E55, wherein the coronavirus infection is a SARS-CoV-2 infection.

E57 is an anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 5 of any one of E38 to E50, which is used to treat coronavirus infection.

E58 is a pharmaceutical composition like E53, which is used for treating coronavirus infection.

E59 is the use of E57 or E58, wherein the coronavirus infection is SARS-CoV-2 infection.

E60 is a crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide ring in pentyl methyl ether solvent.

E61 is a compound as in E60, which is a crystalline N- (methoxycarbonyl)-3-methyl-L-hydroxy-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-hydroxy-prolinamide cyclopentyl methyl ether solvent complex, Form 8, characterized by a single crystal X-ray diffraction pattern (SXRD), wherein the crystal system is orthorhombic, the space group is P2 ₁ 2 ₁ 2, the 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°, volume 5979.6(6) Å ³ , Z 8, calculated density 1.199 g/cm ³ , goodness of fit F ² 1.049, final R index [I＞=2σ (I)] R ₁ = 0.0858, wR ₂ = 0.2270, final R index [all data] R ₁ = 0.0892, wR ₂ = 0.2340.

E62 is a compound like E60, which is a crystalline N- (methoxycarbonyl)-3-methyl-L-hydroxypropylamino-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-hydroxypropylamino ring in amyl methyl ether solvent complex, Form 8, characterized by an ORTEP plot of the asymmetric unit of Form 8 plotted at a displacement parameter of 50% that is substantially the same as that in FIG. 11 .

E63 is a compound as E60, which is a crystalline N- (methoxycarbonyl)-3-methyl-L-hydroxyproline-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-hydroxyproline amide ring in amyl methyl ether solvent, Form 9, characterized by ¹⁹ F solid state NMR peaks at -70.2 ppm and -70.5 ppm, each of which is ± 0.2 ppm; and one to three ¹³ C solid state NMR peaks selected from the group consisting of peaks at 32.7 ppm, 24.2 ppm and 56.0 ppm, each of which is ± 0.2 ppm.

E64 is a compound as E60, which is a crystalline N- (methoxycarbonyl)-3-methyl-L-hydroxyproline-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-hydroxyproline amide ring in amyl methyl ether solvent, Form 9, characterized by ¹⁹ F solid state NMR peaks at -70.2 ppm and -70.5 ppm, each of which is ± 0.2 ppm; and one to three powder X-ray diffraction peaks (Cu Kα radiation) selected from peaks at 7.1, 7.9 and 19.8° 2θ, each of which is ± 0.2° 2θ.

E65 is a compound as E60, which is a crystalline N- (methoxycarbonyl)-3-methyl-L-hydroxyproline-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-hydroxyproline amide ring amyl methyl ether solvent complex, Form 9, which is characterized by one to three ¹³ C solid state NMR peaks selected from the group of peaks at 32.7 ppm, 24.2 ppm and 56.0 ppm, wherein each peak is ± 0.2 ppm; and one to three powder X-ray diffraction peaks (Cu Kα radiation) selected from the peaks at 7.1, 7.9 and 19.8° 2θ, wherein each peak is ± 0.2° 2θ.

E66 is a compound as E60, which is a crystalline N- (methoxycarbonyl)-3-methyl-L-hydroxypropylamino-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-hydroxypropylamino ring in amyl methyl ether solvent complex, Form 9, characterized by ¹⁹ F solid state NMR peaks at -70.2 ppm and -70.5 ppm, each of which is ± 0.2 ppm; one to three ¹³ C solid state NMR peaks selected from the group consisting of peaks at 32.7 ppm, 24.2 ppm, and 56.0 ppm, each of which is ± 0.2 ppm; and one to three peaks selected from the group consisting of peaks at 7.1, 7.9, and 19.8°. Powder X-ray diffraction peaks (Cu Kα radiation) at 2θ, where each peak is ± 0.2° 2θ.

E67 is a compound like E60 which is a crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide ring in amyl methyl ether solvent, Form 9, characterized by ¹⁹ F solid state NMR peaks at -70.2 ppm and -70.5 ppm, with each peak being ± 0.2 ppm.

E68 is a compound as E60 which is a crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide ring in amyl methyl ether solvent complex, Form 9, characterized by one to three ¹³ C solid state NMR peaks selected from the group consisting of peaks at 32.7 ppm, 24.2 ppm and 56.0 ppm, wherein each peak is ± 0.2 ppm.

E69 is a crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide in isopropyl acetate solvent, Form 11.

E70 is a compound like E69 characterized by ^a13C solid state NMR peak at 20.9 ppm ± 0.2 ppm.

E71 is a compound like E69 characterized ^by19F solid state NMR peaks at -69.8 ppm, -71.9 ppm and -72.4 ppm, wherein each peak is ± 0.2 ppm.

E72 is a compound like E69 characterized ^by13C solid state NMR peaks at 20.9 ppm ± 0.2 ppm, 38.7 ppm ± 0.2 ppm, and 52.0 ppm ± 0.2 ppm.

E73 is the compound like E69 characterized ^by19F solid state NMR peaks at -69.8 ppm, -71.9 ppm and -72.4 ppm, each of which is ± 0.2 ppm, and ^a13C solid state NMR peak at 20.9 ppm ± 0.2 ppm.

E74 is the compound as E69 characterized ^by19F solid state NMR peaks at -69.8 ppm, -71.9 ppm and -72.4 ppm, wherein each peak is ± 0.2 ppm; and one to ^three13C solid state NMR peaks selected from the group consisting of peaks at 20.9 ppm ± 0.2 ppm, 38.7 ppm ± 0.2 ppm and 52.0 ppm ± 0.2 ppm.

E75 is a compound like E69 characterized ^by19F solid state NMR peaks at -69.8 ppm, -71.9 ppm and -72.4 ppm, each of which is ± 0.2 ppm; and one to four powder X-ray diffraction peaks (Cu Ka radiation) selected from the group consisting of peaks at 8.5, 6.3, 10.7 and 19.1° 2θ, each of which is ± 0.2° 2θ.

E76 is a compound like E69 characterized ^by19F solid state NMR peaks at -69.8 ppm, -71.9 ppm and -72.4 ppm, each of which is ± 0.2 ppm, ^a13C solid state NMR peak at 20.9 ppm ± 0.2 ppm, and one to four powder X-ray diffraction peaks (Cu Ka radiation) selected from the group consisting of peaks at 8.5, 6.3, 10.7, and 19.1° 2θ, each of which is ± 0.2° 2θ.

E77 is the compound as E69 characterized ^by19F solid state NMR peaks at -69.8 ppm, -71.9 ppm and -72.4 ppm, wherein each peak is ± 0.2 ppm; one to ^three13C solid state NMR peaks selected from the group consisting of peaks at 20.9 ppm ± 0.2 ppm, 38.7 ppm ± 0.2 ppm and 52.0 ppm ± 0.2 ppm and one to four powder X-ray diffraction peaks (Cu Ka radiation) selected from the group consisting of peaks at 8.5, 6.3, 10.7 and 19.1° 2θ, wherein each peak is ± 0.2° 2θ.

E78 is the compound as E69 characterized by ^a13C solid state NMR peak at 20.9 ppm ± 0.2 ppm; and one to four powder X-ray diffraction peaks (Cu Ka radiation) selected from the group consisting of peaks at 8.5, 6.3, 10.7 and 19.1° 2θ, wherein each peak is ± 0.2° 2θ.

E79 is the compound as E69 characterized ^by13C solid state NMR peaks at 20.9 ppm ± 0.2 ppm, 38.7 ppm ± 0.2 ppm and 52.0 ppm ± 0.2 ppm and one to four powder X-ray diffraction peaks (Cu Ka radiation) selected from the group consisting of peaks at 8.5, 6.3, 10.7 and 19.1° 2θ, wherein each peak is ± 0.2° 2θ.

E80 is a spray-drying dispersion comprising N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide and a pharmaceutically acceptable excipient.

E81 is a spray-dried dispersion as E80 comprising amorphous N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide.

E82 is a spray-dried dispersion as E81 containing hydroxypropylmethylcellulose acetate succinate - M grade.

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

E84 is a pharmaceutical composition comprising a spray-dried dispersion as described in any one of E80 to E83.

E85 is a method for treating a coronavirus infection in a patient, comprising administering a therapeutically effective amount of a pharmaceutical composition such as E84 to a patient in need thereof.

E86 is a method as in E85, wherein the coronavirus infection is a SARS-CoV-2 infection.

E87 is a crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide in ethyl acetate solvent, Form 14.

E88 is the compound as E87, which is a crystalline N- (methoxycarbonyl)-3-methyl-L-hydroxyprolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-hydroxyprolinamide in ethyl acetate solvent, Form 14, characterized by a single crystal X-ray diffraction pattern (SXRD), wherein the crystal system is orthorhombic, the space group is P2 ₁ 2 ₁ 2, the unit cell has 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 , Z is 8, the calculated density is 1.187 g/cm ³ , the goodness of fit F ² is 1.077, 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 = 0.2666.

E89 is the compound as E87 which is a crystalline N- (methoxycarbonyl)-3-methyl-L-hydroxyprolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-hydroxyprolinamide in ethyl acetate solvent, Form 14, characterized by an ORTEP plot of the asymmetric unit of Form 14 substantially identical to that in FIG. 35 , plotted at a displacement parameter of 50%.

E90 is a crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 22.

E91 is a compound like E90 characterized ^by19F solid state NMR peaks at -71.0 and -71.5 ppm, each ± 0.2 ppm.

E92 is a compound like E90 characterized by one to ^three13C solid state NMR peaks selected from the group consisting of peaks at 53.3 ppm, 39.8 ppm, and 169.1 ppm, wherein each peak is ± 0.2 ppm.

E93 is the compound as E90 characterized ^by19F solid state NMR peaks at -71.0 and -71.5 ppm, each ± 0.2 ppm; and one to ^four13C solid state NMR peaks selected from the group consisting of peaks at 53.3 ppm, 39.8 ppm, 169.1 ppm, and 40.8 ppm, each ± 0.2 ppm.

E94 is a compound like E90 characterized ^by19F solid state NMR peaks at -71.0 ppm and -71.5 ppm, each ± 0.2 ppm; and one to two powder X-ray diffraction peaks (Cu Ka radiation) selected from peaks at 11.6 and 14.6° 2θ, each ± 0.2° 2θ.

E95 is a compound like E90 characterized by one to ^three13C solid state NMR peaks selected from the group consisting of peaks at 53.3 ppm, 39.8 ppm and 169.1 ppm, each of which is ± 0.2 ppm; and one to two powder X-ray diffraction peaks (Cu Ka radiation) selected from peaks at 11.6 and 14.6° 2θ, each of which is ± 0.2° 2θ.

E96 is a compound like E90 characterized ^by19F solid state NMR peaks at -71.0 ppm and -71.5 ppm, wherein each peak is ± 0.2 ppm; one to ^four13C solid state NMR peaks selected from the group consisting of peaks at 53.3 ppm, 39.8 ppm, 169.1 ppm and 40.8 ppm, wherein each peak is ± 0.2 ppm; and one to two powder X-ray diffraction peaks (Cu Ka radiation) selected from peaks at 11.6 and 14.6° 2θ, wherein each peak is ± 0.2° 2θ.

In another aspect, the present invention contemplates 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 of the solid forms described herein (e.g., Form 5, 8, 9, 10, 11, 12, 14, or 22) or a mixture thereof.

In another aspect, the present invention contemplates that Form 1 may exist in the presence of any other of the solid forms (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, wherein Form 1 exists as a solid form comprising 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 of any other physical form of the compound of Formula I. For example, in one embodiment, a solid form of a compound of Formula I in Form 1 having any of the above-described powder X-ray diffraction patterns, NMR spectra, wherein the solid form contains 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 of any other physical form of the compound of Formula I.

In certain embodiments, the present invention relates to Form 1, wherein the form is a substantially pure crystalline form.

In another aspect, the present invention contemplates that Form 22 may exist in the presence of any other of the solid forms (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, wherein Form 1 exists as a solid form comprising 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 of any other physical form of the compound of Formula I. For example, in one embodiment, a solid form of a compound of Formula I in Form 1 having any of the above-described powder X-ray diffraction patterns, NMR spectra, wherein the solid form contains 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 of any other physical form of the compound of Formula I.

In certain embodiments, the present invention relates to Form 22, wherein the form is a substantially pure crystalline form.

In another aspect, the present invention contemplates that one of Forms 5, 8, 9, 10, 11, 12 or 14 may exist in the presence of any other solid form of a 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 as a solid form comprising 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 of any other physical form of a compound of Formula I. For example, in one embodiment, a solid form of a compound of Formula I comprising Form 12 has any of the above-described powder X-ray diffraction patterns, NMR spectra, wherein the solid form contains less than 95% by weight, less than 90% by weight, less than 80% by weight, less than 70% by weight, less than 60% by weight, less than 50% by weight, less than 40% by weight, less than 30% by weight, less than 20% by weight, less than 10% by weight, less than 5% by weight, less than 3% by weight, or less than 1% by weight of any other physical form of the compound of Formula I.

In certain embodiments, the invention relates to any one of Forms 5, 8, 9, 10, 11, 12, and 14, wherein the form is in substantially pure form. Pharmaceutical Compositions

In another embodiment, the present invention comprises a pharmaceutical composition. For the purpose of the pharmaceutical composition, the solid form (Form 1, 5, 8, 9, 10, 11, 12 or 14) of N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide or cyclopentyl methyl ether solvent, isopropyl acetate solvent or ethyl acetate solvent as described herein is referred to as a compound of the present invention.

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

The term "excipient" is used herein to describe any ingredient other than a compound of the invention. The choice of excipient will to a large extent depend on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

As used herein, "excipients" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, carriers, diluents, and the like that are physiologically compatible. Examples of excipients include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, and combinations thereof, and isotonic agents such as sugars, sodium chloride, or polyols such as mannitol or sorbitol may be included in the composition. Examples of excipients also include various organic solvents (such as hydrates and solvates). The pharmaceutical composition may contain additional excipients, if desired, such as taste enhancers, binders/binding agents, lubricants, disintegrants, sweetening or taste enhancers, colorants or dyes, and the like. For example, for oral administration, tablets containing various excipients, such as citric acid, may be used together with various disintegrants, such as starch, alginic acid, and certain complex silicates, and together with binders, such as sucrose, gelatin, and acacia. Examples of excipients, without limitation, include calcium carbonate, calcium phosphate, various sugars and starch types, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often used for tableting purposes. Similar types of solid compositions can also be used in soft and hard-filled gelatin capsules. Therefore, non-limiting examples of excipients also include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are required for oral administration, the active compounds therein can be combined with various sweeteners or flavoring agents, coloring substances or dyes and, if necessary, with emulsifiers or suspending agents and additional excipients such as water, ethanol, propylene glycol, glycerol or a combination thereof.

Examples of excipients also include pharmaceutically acceptable substances such as wetting agents or small amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers which enhance the shelf life or effectiveness of the compound.

The compositions of the invention may be in a variety of forms. These include, for example, liquid, semisolid and solid dosage forms, such as liquid solutions (e.g., injectable solutions and infusible solutions), dispersions or suspensions, tablets, capsules, pills, powders, liposomes and suppositories. The form depends on the desired mode of administration and therapeutic application.

Typical compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with antibodies. One mode 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.

Solid dosage forms for oral administration may be presented, for example, as discrete units such as hard or soft capsules, pills, cachets, buccal tablets or troches, each containing a predetermined amount of at least one compound of the invention. In another embodiment, the oral administration may be in the form of a powder or granules. In another embodiment, the oral dosage form is sublingual, such as, for example, a buccal tablet. In such solid dosage forms, the compounds of the invention are typically combined with one or more adjuvants. Such capsules or troches may contain a controlled release formulation. For capsules, troches and pills, the dosage forms may also contain a buffer or may be prepared with an enteric coating.

In another embodiment, oral administration may be in liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in this technology (e.g., water). Such compositions may also contain adjuvants such as wetting agents, emulsifiers, suspending agents, flavoring agents (e.g., sweeteners) and/or aromatic agents.

In another embodiment, the present invention includes parenteral dosage forms. "Parenteral 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 prepared using appropriate dispersants, wetting agents and/or suspending agents according to known techniques.

In another embodiment, the present invention comprises topical dosage forms. "Topical administration" includes, for example, transdermal administration, such as via a transdermal patch or iontophoresis device, intraocular administration, or intranasal or inhaled 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 active ingredients through the skin or other affected areas. When the compounds of the present invention are administered by a transdermal device, a patch of a reservoir and porous membrane type or a solid matrix item is used to achieve administration. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, rice paper capsules, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Typical excipients include alcohol, water, mineral oil, liquid paraffin, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers may be incorporated—see, e.g., B. C. Finnin and T. M. Morgan, J. Pharm. Sci., Vol. 88, pp. 955-958, 1999.

Formulations suitable for topical administration to the eye include, for example, eye drops in which the compounds of the invention are dissolved or suspended in a suitable excipient. Typical formulations suitable for ocular or otic administration may be in the form of drops of a micronized suspension or a solution in isotonic, pH-adjusted sterile saline. Other formulations suitable for ocular and otic administration include ointments, biodegradable (i.e., absorbable gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, wafer capsules, lenses, and microparticle or vesicular systems such as lipid vesicles (niosomes) or liposomes. Polymers such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose or methylcellulose, or isopolysaccharide polymers such as gelan gum may be incorporated together with preservatives such as ammonium phthalide chloride. Such formulations may also be delivered by ion diffusion.

For intranasal administration or administration by inhalation, the compounds of the invention are conveniently delivered in the form of solutions or suspensions from pump spray containers which are squeezed or pumped by the patient or presented as an aerosol spray from a pressurized container or nebulizer using a suitable propellant. Formulations suitable for intranasal administration are usually administered as dry powders (alone, as a mixture, for example, as a dry blend with lactose, or as mixed component granules, for example, mixed with phospholipids (such as phospholipid acylcholine)) 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). For intranasal use, the powder may contain a bioadhesive, such as chitosan or cyclodextrin.

In another embodiment, the present invention comprises a rectal dosage form. Such a rectal dosage form may be in the form of a suppository, for example. Cocoa butter is a traditional suppository base, but various substitutes may be appropriately used.

Other formulations and modes of administration known in the pharmaceutical art may also be used. The pharmaceutical compositions of the present invention may be prepared by any well-known pharmaceutical technique, 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 formulations of drugs are discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman et al., ed., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe et al., ed., Handbook of Pharmaceutical Excipients (3rd edition), American Pharmaceutical Association, Washington, 1999.

Acceptable formulations are nontoxic to recipients at the dosages and concentrations employed and may contain buffers such as phosphates, citrates and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine; preservatives such as octadecyldimethylbenzylammonium chloride; hexamethonium chloride; chloride); ammonium chloride, chlorpheniramine; phenol, butyl or benzyl alcohol; alkyl esters such as methyl or propyl benzoate; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin or Igs; hydrophilic polymers such as polyvinylpyrrolidone; amino Acids such as glycine, glutamine, aspartic acid, histidine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannose, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants such as TWEEN ^™ , PLURONICS ^™ or polyethylene glycol (PEG). For oral administration, the compositions can 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 mg of active ingredient for symptomatic adjustment of patient dosage. The medicament generally contains about 0.01 mg to about 500 mg of active ingredient, or in another embodiment about 1 mg to about 100 mg of active ingredient or 50 to 500 mg. Intravenously, dosages may range from about 0.01 to about 10 mg/kg/minute during a constant rate infusion.

Liposomes containing the compounds of the invention can be prepared by methods known in the art, such as described in U.S. Pat. Nos. 4,485,045 and 4,544,545. Liposomes with enhanced circulation time are disclosed in U.S. Pat. No. 5,013,556. Particularly useful liposomes can be produced by reverse evaporation of a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE). The liposomes are extruded through a filter of defined pore size to produce liposomes of the desired diameter.

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

Sustained-release preparations may be used. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the compounds of the present invention, which are in the form of shaped 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-glutamine and 7 ethyl L-glutamine esters, non-degradable ethylene-ethyl 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-hydroxybutyric acid.

Formulations for intravenous administration must be sterile. This is readily accomplished, for example, by filtering through a sterile filter membrane. The compounds of the invention are generally placed in a container having a sterile access port, such as an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.

Suitable emulsions can be prepared using commercially available fat emulsions such as Intralipid ^™ , Liposyn ^™ , Infonutrol ^™ , Lipofundin ^™ and Lipiphysan ^™ . The active ingredient may be dissolved in a premixed emulsion composition or it may be dissolved in an oil such as soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil and in an emulsion formed after mixing with a phospholipid such as egg phospholipids, soybean phospholipids or soybean lecithin and water. It will be appreciated that other ingredients such as glycerol or glucose may be added to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, for example between 5% and 20%. The fat emulsion may contain fat droplets between 0.1 μm and 1.0 μm, in particular 0.1 μm and 0.5 μm, and have a pH in the range of 5.5 to 8.0.

The emulsion compositions may be those prepared by mixing the compound of the present invention with Intralipid ^™ or its components (soybean oil, egg lecithin, glycerol and water).

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Such liquid or solid compositions may contain a suitable pharmaceutically acceptable excipient as described above. In some embodiments, the compositions are administered by the oral or nasal respiratory route to achieve a local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulized by the use of a gas. Nebulized solutions may be breathed directly from a nebulizing device, or the nebulizing device may be connected to a mask, tent, or intermittent positive pressure ventilator. Solution, suspension, or powder compositions may be administered preferably orally or nasally from a device that delivers the formulation in an appropriate manner. Administration and administration

The terms "treating", "treat" or "treatment" as used herein encompass preventative, i.e., prophylactic, and palliative treatment, i.e., relieving, alleviating or slowing the progression of a patient's disease (or condition) or any tissue damage associated with the disease.

As used herein, the terms "subject," "individual," or "patient" are used interchangeably and refer to any animal, including mammals. Mammals according to the present invention include canines, felines, bovines, goats, equines, sheep, swine, rodents, lagomorphs, primates, humans, and the like, and encompass mammals in utero. In one embodiment, humans are suitable subjects. Human subjects can be of any sex and at any stage of development.

As used herein, the phrase "therapeutically effective amount" means the amount of an active compound or agent that induces the biological or medical response in a tissue, system, animal, individual or human that a researcher, veterinarian, hospitalist or other clinician is seeking, which may include one or more of the following: (1) preventing the disease; for example, preventing the disease, condition or disorder in an individual who may be susceptible to the disease, condition or disorder but has not yet experienced or displayed 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 displaying the pathology or symptoms of the disease, condition or disorder (i.e., preventing or slowing the further development of the pathology and/or symptoms); and (3) ameliorating the disease; for example, ameliorating the disease, condition or disorder in a subject who is experiencing or exhibiting the pathology or symptoms of the disease, condition or disorder (i.e., reversing the pathology and/or symptoms).

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 may be administered as the compound itself, or as a solvate thereof. For the purpose of administration and dosing, the compound itself or its solvate will be referred to simply as the compounds of the present invention.

The compounds of the invention are administered by any appropriate route in the form of a pharmaceutical composition suitable for such route and in an amount effective for the desired treatment. The compounds of the invention may be administered orally, rectally, vaginally, parenterally, topically, intranasally or by inhalation.

The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or may employ buccal or sublingual administration, whereby the compound enters the bloodstream directly from the mouth.

In another embodiment, the compounds of the invention may also be administered parenterally, for example directly into the bloodstream, muscle or internal organs. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

In another embodiment, the compounds of the present invention may also be administered topically to the skin or mucous membranes, i.e., transdermally or transdermally. In another embodiment, the compounds of the present invention may also 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 also be administered directly to the eyes or ears.

The dosage regimen of the compounds of the present invention and/or compositions containing such compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the specific compound employed. Therefore, the dosage regimen can vary widely. In one embodiment, for the treatment of the indicated conditions discussed herein, the total daily dose of the compounds of the present invention is generally about 0.01 to about 100 mg/kg (i.e., mg of the compounds of the present invention/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 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 (usually no more than 4 times) in a day. Multiple daily doses can usually be used to increase the total daily dose if necessary.

The compounds of the present invention inhibit viral proteases, specifically coronavirus proteases, such as the 3CL (Mpro) protease of SARS-CoV-2, the causative virus of COVID-19. The compounds of the present invention can inhibit the activity of major viral proteases and can be used to treat, prevent, inhibit and improve viral infections, including coronavirus infections, such as SARS-CoV-2 infections and COVID-19. The compounds of the present invention can also be used to treat or improve the sequelae of coronavirus infections, such as the use or treatment of long COVID. Co-administration

The compounds of the invention may be used alone or in combination with one or more other therapeutic agents. The invention provides any use, method or composition as defined herein, wherein the compounds of the invention are used in combination with one or more other therapeutic agents discussed herein.

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 alpha or pegylated interferon, such as PEG-Intron or Pegasus) to a patient infected with the SARS-CoV-2 coronavirus (i.e., a patient suffering from COVID-19) may provide greater clinical benefit than administering an interferon, pegylated interferon, or SARS-CoV-2 coronavirus inhibitor alone. Other additional agents that can be used in the methods of the present invention include dexamethasone, azithromycin, and remdesivir. Examples of greater clinical benefit may include a greater reduction in patients' COVID-19 symptoms, more rapid time to symptom relief, reduced lung pathology, a greater reduction in the amount of SARS-CoV-2 coronavirus (viral load), and reduced mortality.

SARS-CoV-2 coronavirus infected cells express P-glycoprotein. Certain SARS-CoV-2 coronavirus 3CL protease inhibitors of the present invention may be substrates for P-glycoprotein. Compounds that inhibit SARS-CoV-2 coronavirus that are also substrates for P-glycoprotein may be administered with a P-glycoprotein inhibitor. Examples of P-glycoprotein inhibitors are verapamil, vinblastine, ketoconazole, nelfinavir, ritonavir, or cyclosporine. P-glycoprotein inhibitors act by inhibiting the SARS-CoV-2 coronavirus inhibitors of the present invention from escaping cells. The inhibition of the P-glycoprotein-based efflux will prevent the intracellular concentration of the SARS-CoV-2 coronavirus inhibitor from being reduced due to the P-glycoprotein efflux. The inhibition of the P-glycoprotein efflux will result in a greater intracellular concentration of the SARS-CoV-2 coronavirus inhibitor. Administration of the SARS-CoV-2 coronavirus 3CL protease inhibitor and the P-glycoprotein inhibitor of the present invention to patients infected with the SARS-CoV-2 coronavirus can reduce the amount of the SARS-CoV-2 coronavirus 3CL protease inhibitor required to achieve an effective dose by increasing the intracellular concentration of the SARS-CoV-2 coronavirus 3CL protease inhibitor.

Among the agents useful for increasing mammalian exposure to the compounds of the invention are those that can act as inhibitors of at least one isoform of the cytochrome P450 (CYP450) enzyme. Isoforms of CYP450 that can be beneficially inhibited include, but are not limited to, CYP1A2, CYP2D6, CYP2C9, CYP2C19, and CYP3A4. Compounds used in the methods of the invention include compounds that can be substrates for CYP3A4 and are metabolized by CYP3A4. Administration of SARS-CoV-2 coronavirus inhibitors (which are CYP3A4 substrates, such as SARS-CoV-2 coronavirus 3CL protease inhibitors, and CYP3A4 inhibitors, such as ritonavir, nelfinavir, or delavirdine) to patients infected with the SARS-CoV-2 coronavirus will reduce the CYP3A4 metabolism of the SARS-CoV-2 coronavirus inhibitor. This will result in reduced clearance of the SARS-CoV-2 coronavirus inhibitor and increased plasma concentrations of the SARS-CoV-2 coronavirus inhibitor. Reduced clearance and higher plasma concentrations may result in lower effective doses of the SARS-CoV-2 coronavirus inhibitor.

Additional therapeutic agents that can be used in combination with SARS-CoV-2 inhibitors in the methods of the present invention include the following: PLpro inhibitors, Apilomod, EIDD-2801, Ribavirin, Valganciclovir, β -thymidine, Aspartame, Oxprenolol, Doxycycline, Acetophenazine, Iopromide, Riboflavin, Reproterol, 2,2′-cyclocytidine, Chloramphenicol, Chlorphenesin carbamate, levodropropizine, cefamandole, floxuridine, tigecycline, pemetrexed, L(+)-ascorbic acid, glutathione, hesperetin, ademetionine, masoprocol, isotretinoin, dantrolene olene), Sulfasalazine antibacterial agent, Silybin, Nicardipine, Sildenafil, Platycodin, Chrysin, Neohesperidin, Baicalin, Sugetriol-3,9-diacetate, (–)-epigallocatechin gallate, Phaitanthrin 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-tetraol, 2,2-di(3-indolyl)-3-indolone, ( S )-( 1S , 2R , 4aS , 5R , 8aS )-1-carboxamido-1,4a-dimethyl-6-methylene-5-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)decahydronaphthalen-2-yl-2-amino-3-phenylpropionate, Piceatannol, Rosmarinic acid and Magnolol.

3CLpro inhibitors, Lymecycline, Chlorhexidine, Alfuzosin, Cilastatin, Famotidine, Almitrine, Progabide, Nepafenac, Carvedilol, Amprenavir, Cyclomycin, Montelukast, Carminic acid, Mimosine, Flavin, Lutein, Cefpiramide, Phenethicillin, Candoxatril, Nicardipine, Estradiol valerate valerate), Pioglitazone, Conivaptan, Telmisartan, Doxycycline, Oxytetracycline, (1 S , 2 R , 4a S , 5 R , 8a S )-1-carboxamido-1,4a-dimethyl-6-methylene-5-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)decahydronaphthalen-2-yl 5-(( R )-1,2-dithiocyclopentane-3-yl) valerate, Betulonal, Aureoside-7- O -β -glucuronide, Andrographiside, 2-nitrobenzoic acid (1 S , 2 R , 4a S , 5 R ,8a S )-1-carboxamido-1,4a-dimethyl-6-methylene-5-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)decahydronaphthalen-2-yl ester, 2 β -hydroxy-3,4-cyclo-schizofuran-27-oleic acid ( S )-(1 S ,2 R ,4a S ,5 R ,8a S )-1-carboxamido-1,4a-dimethyl-6-methylene-5-(( E ) -2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)decahydronaphthalen-2-yl ester, )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)decahydronaphthalen-2-yl-2-amino-3-phenylpropionate, Isodecortinol, Cerevisterol, Hesperidin, Neohesperidin, Andrograpanin, Benzoic acid 2-((1 R ,5 R ,6 R ,8a S )-6-hydroxy-5-(hydroxymethyl)-5,8a-dimethyl-2-methylenedecahydronaphthalen-1-yl)ethyl ester, Cosmosiin, Cleistocaltone A A), 2,2-di(3-indolyl)-3-indolone, Biorobin, Gnidicin, Phyllaemblinol, Theaflavin 3,3′-di- O -gallate, Rosmarinic acid, Kouitchenside I, Oleanolic acid, Stigmaster-5-en-3-ol, Deacetylcentapicrin and Berchemol.

RdRp inhibitors, Valganciclovir, Chlorhexidine, Ceftibuten, Fenoterol, Fludarabine, Itraconazole, Cefuroxime, Atovaquone, Chenodeoxycholic acid, Cromolyn, Pancuronium bromide, Cortisone, Tibolone, Novobiocin, Silybin, Idarubicin Bromocriptine, Diphenoxylate, Benzylpenicilloyl G, Dabigatran etexilate), birchaldehyde, genidin, 2 β ,30 β -dihydroxy-3,4-opened-schizolin-27-lactone, 14-deoxy-11,12-dihydroandrographolide, geniditrin, theaflavin 3,3′-di- O -gallate, 2-amino-3-phenylpropionic acid ( R )-((1 R ,5a S ,6 R ,9a S )-1,5a-dimethyl-7-methylene-3-oxo-6-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)decahydro-1 H -benzo[ c ]azepin-1-yl)methyl ester, 2 β -Hydroxy-3,4-opened-schizane-27-oleic acid, 2-(3,4-dihydroxyphenyl)-2-[[2-(3,4-dihydroxyphenyl)-3,4-dihydro-5,7-dihydroxy-2 H -1-benzopyran-3-yl]oxy]-3,4-dihydro-2 H -1-benzopyran-3,4,5,7-tetraol, Phyllaemblicin B, 14-hydroxycyperotundone, andrographolide, 2-((1 R ,5 R ,6 R ,8a S ) benzoic acid )-6-hydroxy-5-(hydroxymethyl)-5,8a-dimethyl-2-methylenedecahydronaphthalen-1-yl)ethyl ester, andrographolide, sucrotrialine-3,9-diacetate, baicalin, 5-(( R )-1,2-dithiocyclopentane-3-yl)pentanoic acid (1 S , 2 R , 4a S , 5 R , 8a S )-1-carboxamido-1,4a-dimethyl-6-methylene-5-(( E )-2-(2-oxo-2,5-dihydrofuran-3-yl)vinyl)decahydronaphthalen-2-yl ester, 1,7-dihydroxy-3-methoxyxanthenone, 1,2,6-trimethoxy-8-[(6- O - β -D-xylopyranosyl- The compounds include 1,8-dihydroxy-6-methoxy-2-[(6- O - β -D-xylopyranosyl- β -D-glucopyranosyl)oxy]-9H-oxath- 9 -one and 8- ( β - D-glucopyranosyl)oxy)-1,3,5-trihydroxy- 9H -oxath-9-one.

Additional therapeutic agents that can be used in the methods of the invention include diosmin, hesperidin, MK-3207, venetoclax, dihydroergocristine, bolazine, R428, ditercalinium, etoposide, teniposide, UK-432097, irinotecan, lumacaftor, velpatasvir, eluxadoline, ledipasvir, lopinavir/ritonavir + ribavirin, alferon, and prednisone. Other additional agents suitable for use in the methods of the invention include dexamethasone, azithromycin, and remdesivir, as well as boceprevir, umifenovir, and favipiravir.

Other additional agents that can be used in the methods of the present invention include α-ketoamide compounds designated as 11r, 13a, and 13b as 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 .

Additional agents that may be used in the methods of the invention include RIG 1 pathway activators, such as those described in U.S. Patent No. 9,884,876.

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, including compounds such as the compound shown below and the compound named DC402234 .

Another embodiment of the present invention is a method of treating a patient with COVID-19, wherein in addition to administering a compound 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 and the additional agent is selected from antiviral agents such as nirmatrelvir, remdesivir, galidesivir, favilavir/avifavir, molnupiravir (MK-4482/EIDD 2801), AT-527, AT-301, BLD-2660, favipiravir, camostat, SLV213 emtrictabine/tenofivir, clevudine, dalcetrapib, boceprevir, PBI-0451, EDP-235 and ABX464, glucocorticoids (such as dexamethasone and hydrocortisone), convalescent plasma, recombinant human plasma (such as gelsolin (Rhu-p65N)), monoclonal antibodies (such as regdanvimab (Regkirova), ravulizumab) (Ultomiris), VIR-7831/VIR-7832, BRII-196/BRII-198, COVI-AMG/COVI DROPS (STI-2020), bamlanivimab (LY-CoV555), mavrilimab, leronlimab (PRO140), AZD7442, lenzilumab, infliximab, adalimumab, JS 016, STI-1499 (COVIGUARD), lanadelumab (Takhzyro), canakinumab (Ilaris), gimsilumab, and otilimab), antibody cocktails such as casirivimab/imdevimab (REGN-Cov2), recombinant fusion proteins such as MK-7110 (CD24Fc/SACCOVID), anticoagulants such as heparin and apixaban, IL-6 receptor agonists such as tocilizumab (Actemra) and sarilumab (Kevzara), PIKfyve inhibitors such as apilimod dimesylate ( dimesylate), RIPK1 inhibitors (such as DNL758, DC402234), VIP receptor agonists (such as PB1046), SGLT2 inhibitors (such as dapaglifozin), TYK inhibitors (such as abivertinib), kinase inhibitors (such as ATR-002, bemcentinib ), acalabrutinib, losmapimod, baricitinib, and tofacitinib), H2 blockers (such as phentermine), anthelmintics (such as niclosamide), and furin inhibitors (such as diminazene).

The term "SARS-CoV-2 inhibitor" refers to any SARS-CoV-2 related coronavirus 3C-like protease inhibitor compound described herein, which inhibits the replication of SARS-CoV-2 in any way.

The term "interfering with or preventing" SARS-CoV-2 related coronavirus ("SARS-CoV-2") viral replication in cells means that the SARS-CoV-2 replication or production necessary for progeny viruses is reduced in cells treated with the compounds of the invention compared to cells not treated with the compounds of the invention. Simple and convenient assays to determine whether SARS-CoV-2 viral replication has been reduced include ELISA assays for the presence, absence, or reduced presence of anti-SARS-CoV-2 antibodies in an individual's blood (Nasoff et al., PNAS 88:5462-5466, 1991), 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 of ordinary skill. Alternatively, total RNA from transduced and infected "control" cells can be isolated and analyzed by dot blotting or Northern blot and probed with SARS-CoV-2 specific DNA to determine whether SARS-CoV-2 replication is reduced. Alternatively, a reduction in SARS-CoV-2 protein expression can also be used as an indicator of inhibition of SARS-CoV-2 replication. A reduction of SARS-CoV-2 replication of greater than 50 percent compared to control cells is generally quantified as prevention of SARS-CoV-2 replication.

Administration of two or more compounds in a "combination" means that all of the compounds are administered closely enough in time to achieve treatment of the individual. The two or more compounds may be administered simultaneously or sequentially, via the same or different routes of administration, based on the same or different administration schedules, and with or without specific time limits, depending on the treatment regimen. In addition, simultaneous administration may be performed by mixing the compounds prior to administration or by administering the compounds at the same time point but in separate dosage forms at the same or different administration sites.

The phrases "concurrent administration", "co-administration", "simultaneous administration", "sequential administration" and "administered simultaneously" mean that the compounds are administered in combination.

The compound of the invention and the one or more other therapeutic agents may be administered in a fixed or non-fixed combination of the active ingredients. The term "fixed combination" means that the compound of the invention or a pharmaceutically acceptable salt thereof and the one or more therapeutic agents are all administered to a subject simultaneously in a single composition or dosage. The term "non-fixed combination" means that the compound of the invention or a pharmaceutically acceptable salt thereof and the one or more therapeutic agents are formulated as separate compositions or dosages so that they can be administered to a subject in need thereof simultaneously or sequentially with variable intervention time limits, wherein such administration provides an effective level of two or more compounds in the subject's body.

In one embodiment, the compounds of the invention are administered in combination with additional therapeutic agents useful for treating viral infections, including pharmaceutically acceptable salts of specifically named agents and pharmaceutically acceptable solvent combinations of such agents and salts.

These agents and compounds of the invention may be combined with a pharmaceutically acceptable vehicle such as saline, Ringer's solution, dextrose solution , and the like. The specific dosing regimen (i.e., dose, timing, and replication) will depend on the particular individual and the individual's medical history.

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

In yet another embodiment, the invention comprises a kit suitable for performing the treatment methods described herein. In one embodiment, the kit contains a first dosage form comprising one or more of the compounds of the invention in an amount sufficient to perform the method of the invention. In another embodiment, the kit comprises one or more compounds of the invention in an amount sufficient to perform the method of the invention and a container for the dosage. General Experimental Methods Powder X-ray Diffraction (PXRD) Method

The powder X-ray diffraction (PXRD) of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide or its solvent complex (Forms 1, 5, 9, 10, 11 and 750 mg/g SDD) was determined according to the following method.

Powder X-ray diffraction analysis was performed using a Bruker AXS D8 Endeavor diffraction instrument equipped with a Cu radiation source (CuKᾱ λ = 1.5418 Å). The divergence slit was set to 15 mm continuous illumination. Diffraction radiation was detected by a PSD-Lynx Eye detector with the detector PSD opening set to 4.11 degrees. The X-ray tube voltage and amperage were set to 40 kV and 40 mA, respectively. In addition, an energy dispersive detector (a nickel filter) was used to filter out undesired wavelengths. Data were collected in a θ-θ goniometer at Cu wavelengths from 3.0 to 40.0° 2-θ using a step size of 0.01 degrees and a step time of 1.0 seconds. The backscatter screen was set to a fixed distance of 1.5 mm. The samples were rotated at 15/min during collection. Samples were prepared by placing them in a silicon low background sample holder and rotating them during collection. Data were collected using Bruker DIFFRAC Plus software and analyzed by EVA diffract plus software.

The PXRD data files were not processed prior to peak searching. Preliminary peak assignments were made using the peak search algorithm in the EVA software, using peaks selected with a threshold of 1. Adjustments were made manually to ensure validity; the output of the automated assignments was visually inspected and the peak positions were adjusted to the peak maximum. Peaks with a relative intensity of ≥ 3% were generally selected. Peaks that were unresolved or consistent with noise were not selected. Typical errors associated with PXRD peak positions as specified in the USP are as high as +/- 0.2° 2-θ (USP-941). Single Crystal X-Ray Diffraction (SXRD) Method Single Crystal X-Ray Diffraction (SXRD): Forms 1, 5, 8, 12, and 14

Samples of Forms 1, 5, 8, 12 and 14 single crystals were examined by SXRD. SXRD was performed on a Bruker D8 Quest diffractometer at 298 K for Forms 1, 5 and 12. SXRD for Forms 8 and 14 was performed on a Bruker D8 Venture diffractometer at 100 K. Data collection consisted of ω and φ scans. The structures of Forms 1, ₅ , ₈ , ₁₂ and 14 were solved by intrinsic phasing using the SHELX software suite in space groups C222 ₁ , P2 1 , P2 ₁ 2 1 2, P2 1 2 ₁ 2 and P2 ₁ 2 ₁ 2, respectively. The structures were subsequently refined by the full matrix least squares method. All non-hydrogen atoms were found and refined using anisotropic displacement parameters. Final R ₁ values for Forms 1, 5, 8, 12, and 14 were 7.5%, 8.8%, 8.6%, 4.1%, and 8.8%, respectively. ¹³ C and ¹⁹ F solid-state nuclear magnetic resonance (ssNMR) methods Solid-state nuclear magnetic resonance (ssNMR): Forms 1, 5, 9, 10, 11, and 750 mg/g SDD

Solid state NMR (ssNMR) analysis was performed on a CPMAS probe positioned in a Bruker-BioSpin Avance III 600 MHz ( ¹ H frequency) NMR spectrometer. The material was packed into a ZrO ₂ rotor. A magic angle spinning rate of 15 kHz was used. Spectra were collected at ambient temperature (probe temperature of 25°C).

^13C ssNMR spectra were collected using proton decoupled cross-linked polarization magic angle spinning (CPMAS) experiments. A phase-modulated proton decoupling field of 80 to 100 kHz was applied during spectrum acquisition. The cross-polarization contact time was set to 2 ms and the recycle delay was set to 3.5 seconds for Form 1, Form 5, Form 9, Form 10, Form 11, and 750 mg/g SDD. The number of scans was adjusted to achieve adequate signal-to-noise ratio. The upfield resonance was set to 29.5 ppm using an external standard reference ^13C chemical shift table based on crystalline adamantane for ^13C CPMAS experiments.

¹⁹ F ssNMR spectra were collected using proton decoupled magic angle spinning (MAS) experiments. A phase-modulated proton decoupling field of 80 to 100 kHz was applied during spectral acquisition. Spectra were collected with a recycle delay of 3.5 seconds for Form 1, Form 5, Form 9, Form 10, Form 11, and 750 mg/g SDD. The number of scans was adjusted to achieve adequate signal-to-noise ratio. The resonance was set to -76.54 ppm using a ¹⁹ F MAS experiment based on an external standard reference to a ¹⁹ F chemical shift scale of trifluoroacetic acid (50%/50% v/v in H ₂ O).

Automatic peak picking was performed using Bruker-BioSpin TopSpin version 3.6 software. In general, a threshold of 5% relative intensity was used for preliminary peak selection. The output of the automated peak picking was visually inspected to ensure validity and manually adjusted if necessary. Although specific solid-state NMR peaks are reported herein, there does exist a range in these peaks due to differences in instrumentation, samples, and sample preparation. This is common practice in the art of solid-state NMR because of the inherent variation in peak position. The typical variability in the chemical shift x-axis values is approximately plus or minus 0.2 ppm for crystalline solids and plus or minus 0.5 ppm for amorphous solids. The solid-state NMR peak heights reported herein are relative intensities. Solid-state NMR intensity can vary depending on the actual set of experimental parameters and the thermal history of the sample. Thermogravimetric Infrared Analysis (TGA-IR) Methods Thermogravimetric Infrared Analysis (TGA-IR): Forms 9 and 11

A TA Instruments TGA 5500 was used for the thermal analysis portion of the instrument. Approximately 5 mg to 10 mg of sample was weighed into an aluminum pan and heated from ambient temperature to 275°C (for Form 9) or 200°C (for Form 11) at a heating rate of 10°C/min (10 mL/min for equilibrium and 25 mL/min for the sample chamber) under nitrogen purge.

A Thermo Nicolet IS20 FT-IR spectrometer equipped with a KBr spectroscope and a DTGS KBr detector was used for TGA-IR analysis. The collection range was 4000 to 400 cm ^-1 and Happ-Genzel apodization was used for data collection. Background spectra were collected with 64 co-added scans at 8 cm ^-1 resolution. The IR background was collected with the TGA furnace turned off and purged for 2 to 3 minutes. The sampling method was set up for fast spectrum collection because the escaping gas will quickly sweep through the gas cell. Each sample spectral data point is a co-added spectrum of five spectra collected at 8 cm ^-1 resolution. The total IR collection time was adjusted based on the run length of the TGA. Modulated Differential Scanning Calorimetry (mDSC) Modulated Differential Scanning Calorimetry: Form 10 and 750 mg/g SDD

Modulated differential scanning calorimetry measurements were performed using a Discovery DSC 2500 (TA instruments) equipped with a refrigerated cooling accessory. All experiments were performed in standard/Tzero aluminum pans. Indium was used to determine the unit cell constants and indium and tin were used as standards for temperature calibration. All measurements were performed under continuous dry nitrogen purge (50 mL/min). Approximately 1 to 5 mg of solid sample was weighed into a Tzero aluminum pan, non-hermetically sealed and heated using a heat-cool-heat program. The heating-cooling-heating program used a modulation temperature range of ± 1.0°C, a modulation period of 100 s, and a heating rate of 2°C/min to heat from -50 to 120°C, then a heating rate of 10°C/min to -50°C, followed by a second heating from -50 to 200°C using a modulation temperature range of ± 1.0°C, a modulation time of 100 s, and a heating rate of 2°C/min. The experimental data were analyzed using commercially available software (TA Universal Analysis 2000/Trios software, TA Instruments). Example Example 1 N- (Methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide Form 1 (anhydrous free form) Step 1: Preparation of methyl ((S)-1-((2S,4R)-2-(((S)-1-amino-1-oxo-3-((S)-2-oxo-pyrrolidin-3-yl)propan-2-yl)aminocarbonyl)-4-(trifluoromethyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutyl-2-yl)carbamate, compound II (in an organic solution)

The compound of formula IV, (2S,4R)-1-((S)-2-((methoxycarbonyl)amino)-3,3-dimethylbutyryl)-4-(trifluoromethyl)pyrrolidine-2-carboxylic acid (25.4 g, 69.7 mmol, 1.0 equiv) and methyl ethyl ketone (200 mL, 8 L/kg compound IV) were combined and stirred at 25° C. 2-Hydroxypyridine N-oxide (7.91 g, 69.7 mmol, 1.0 equiv) and triethylamine (17.6 g, 24.3 mL, 0.174 mol, 2.50 equiv) were added and the resulting solution was stirred for 5 minutes. The compound of formula III (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)acrylamide hydrochloride (17.2 g, 80.2 mmol, 1.15 equiv) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC, 20.1 g, 0.105 mol, 1.50 equiv) were loaded, rinsed with methyl ethyl ketone (50 mL, 2 L/kg IV) and stirred at 25°C for 16 hours. The reaction was sampled for completion (no more than 0.5% target of compound IV). [Note: If the reaction was not complete, the mixture was stirred for an additional time]. The reaction was quenched by adding an aqueous NaCl solution (100 mL 14 wt % aqueous saline solution, 4.0 L/kg Compound IV), stirred for 15 to 30 minutes and the phases were separated. The organic phase was washed with a second aqueous NaCl solution (100 mL 14 wt % aqueous saline solution). The two aqueous phases were combined and extracted twice with methyl ethyl ketone (125 mL, 5 L/kg Compound IV). All organic phases were combined and then concentrated to a concentration of about 5 L/kg product by vacuum distillation at 0.3 bar (internal temperature of the reaction mixture was about 30° C.). Isopropyl acetate (200 mL, 8 L/kg Compound IV) was then added to the mixture and distillation was continued to reach a reaction volume of about 5 L/kg product Compound II. A second addition of isopropyl acetate (200 mL, 8 L/kg Compound IV) was added and the distillation process was repeated following the same protocol, ending the distillation at a concentration of 5 L/kg product Compound II. Isopropyl acetate (125 mL, 5 L/kg Compound IV) was added and stirred at 25°C. Samples were analyzed for water content (Karl-Fischer) with a target of no more than 0.2 wt% water. The obtained ((S)-1-((2S,4R)-2-(((S)-1-amino-1-oxo-3-((S)-2-oxo-pyrrolidin-3-yl)propan-2-yl)aminocarbonyl)-4-(trifluoromethyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutyl-2-yl)carbamate solution of compound II in organic isopropyl acetate can be used in the next step without further purification.

Step 2: A solution of ((S)-1-((2S,4R)-2-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)aminocarbonyl)-4-(trifluoromethyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutyl-2-yl)carbamate, Compound II (assuming quantitative conversion, 69.7 mmol, 1.0 equiv) in isopropyl acetate was combined with N-methylmorpholine (36.7 g, 40 mL, 0.36 mol, 5.2 equiv) and stirred at 10 °C. Trifluoroacetic anhydride (38.1 g, 25.5 mL, 0.18 mol, 2.6 equiv) was loaded dropwise over 30 to 60 minutes, maintaining the reaction temperature at no more than 15°C. The resulting mixture was stirred at 10°C for 1 hour. The reaction was complete for the analytical sample (no more than 0.5% Compound II present). [Note: If the reaction was not complete, stirring was maintained for another 60 minutes, and additional N-methylmorpholine and trifluoroacetic anhydride were loaded if necessary (maintaining a 2:1 ratio). The reaction was quenched by adding an aqueous solution of ammonium hydroxide (28 wt %) (10.7 mL, 76 mmol, 1.1 equiv) in water (74.1 mL water, 3.0 L/kg of Compound IV from the previous step). The mixture was stirred for 15 to 30 min, then stopped and the layers were allowed to settle. The aqueous phase was removed and the organic phase was sampled for internal process control (target was no more than 0.1% ((S)-1-((2S,4R)-2-(((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)carbamyl)-4-(trifluoromethyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutyl-2-yl)(2,2,2-trifluoroacetyl)carbamate, also known as {( 2S )-1-[( 2S , 4R )-2-({( 1S )-1-cyano-2-[( 3S [Note: If the internal process control target is not achieved, a second alkaline wash is required (mixing 1.1 equivalents of NH ₄ OH 28 wt % with 74.1 mL of water (3.0 L/kg)) following the same protocol]. The organic phase is washed with water (74.1 mL, 3.0 L/kg of compound IV from the previous step). The organic phase is then concentrated by vacuum distillation (0.3 bar and (internal temperature about 30°C)) to a volume of 200 mL (8 L/kg of compound IV from the previous step). Cyclopentyl methyl ether (CPME, 375 mL, 15.0 L/kg of compound IV from the previous step) was added and the solution was concentrated by vacuum distillation to a volume of 200 mL (8 L/kg of compound IV from the previous step). The sample was analyzed for water content (Karl Fischer), with a target of no more than 0.2 wt% water and isopropyl acetate content (no more than 1%). [Note: If the target is not achieved, the distillation process is continued following the same protocol]. This solution/slurry was stirred at 40°C for 30 to 60 minutes and cooled to 10°C at a rate of 0.1 K/min and then 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 provide 21.1 g of Compound I, CPME solvent complex.

Step 3: Compound I, CPME solvent (30.09 g, 51.03 mmol, 100 mass%) and heptane (300 mL, 2047.9 mmol, 100 mass%) were added to a 1000 mL two-piece OptiMax reactor with overhead stirring at 350 rpm 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 the mixture was cooled to 25°C within 5 hours and stirred overnight. The resulting slurry was filtered and washed with heptane (60 mL, 409.58 mmol, 100 mass%). The solids were dried at 50 °C under vacuum overnight to provide the anhydrous free form of N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1.

The PXRD of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1 was determined and the PXRD patterns are provided in FIGS. 1 and 2 .

Table 1-1. PXRD peak list and relative intensity of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1. PXRD peaks are in °2Ɵ (each ± 0.2 Ɵ). Angle (°2) ± 0.2 °2 Relative strength (%) Angle (°2) ± 0.2 °2 Relative strength (%) 6.3 3 22.3 6 9.1 11 22.8 8 9.6 100 23.8 7 10.3 88 24.3 8 10.7 60 24.7 twenty one 12.0 8 25.1 13 12.6 9 26.2 15 13.1 7 26.7 12 13.9 11 27.3 5 15.5 4 27.6 7 16.2 43 28.0 6 16.7 51 28.9 6 17.6 11 29.8 4 18.1 93 30.2 5 18.4 30 30.4 5 18.9 76 31.1 3 19.2 70 32.4 6 20.4 9 33.3 4 20.8 10 33.7 5 21.5 twenty two 34.2 3

Single crystal X-ray diffraction (SXRD) of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1 was determined and the data are provided in Tables 1-2.

Table 1-2. Crystal structure data of crystalline N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1. Empirical C ₂₁ H ₃₀ F ₃ N ₅ O ₅ Molecular weight 489.50 temperature 298 K Wavelength 1.54178 Å Crystal system Orthorhombic Space Group C222 ₁ Unit cell size a = 9.6317 (4) Å α = 90° b = 19.6368 (8) Å β = 90° c = 28.2776 (11) Å γ = 90° Volume 5348.3 (4) Å ³ Z 8 Density (calculation) 1.216 Mg/m ³ About the goodness of fit of ^F2 1.061 Final R index [I ＞ 2Σ(I)] R ₁ = 0.0754, wR ₂ = 0.2246 R Index (all data) _R1 = 0.0907, _wR2 = 0.2392

13 C solid state NMR of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form ¹ .

Table 1-3. 13 C solid state NMR peak list of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl} ^-4- (trifluoromethyl)-L-prolinamide, Form 1. Each peak is ± 0.2 ppm. ¹³ C chemical shift (ppm) Relative strength (%) 180.6 29 173.4 28 170.6 28 156.8 27 126.7 5 119.7 9 59.1 30 58.3 twenty four 50.8 34 47.8 12 43.5 twenty one 41.6 twenty two 38.7 33 37.6 27 36.7 34 29.5 13 28.0 20 26.5 100

19 F solid state NMR of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form ¹ .

Table 1-4. 19 F solid state NMR peak list for determination of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form ¹ . ¹⁹ F chemical shift (ppm) Relative strength (%) -70.7 100

Table 1-5. Examples of identifiers for characterizing N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1 using a single method or a combination of instrumental methods. Form 1 ^19F ssNMR (ppm) ± 0.2 ppm ^13C ssNMR (ppm) ± 0.2 ppm PXRD (° 2 *) ± 0.2 °2Ɵ Single 50.8 Single 50.8, 58.3, 43.5 Combination -70.7 50.8 Combination -70.7 50.8, 58.3, 43.5 Combination 50.8 At least one of the following: 9.1, 9.6, 10.3, 16.2 Combination 50.8, 58.3, 43.5 At least one of the following: 9.1, 9.6, 10.3, 16.2 Combination -70.7 50.8 At least one of the following: 9.1, 9.6, 10.3, 16.2 Combination -70.7 50.8, 58.3, 43.5 At least one of the following: 9.1, 9.6, 10.3, 16.2 Example 2 Alternative Preparation of N-(Methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1 (Anhydrous Free Form)

Weigh 150.7 mg of amorphous N-(methoxycarbonyl)-3-methyl-L-hydroxyprolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-hydroxyprolinamide into a one-dram vial with a small stir bar. Add 0.5 mL of ethyl acetate (EtOAc) and heat the mixture at about 60° C. for about 5 minutes to completely dissolve it. Slowly add 0.5 mL of heptane to the clear solution. Heat the mixture at about 60° C. for about 10 minutes and it is a clear solution. Cool the mixture back to room temperature (RT) and stir 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 white solid was collected and transferred to a 1 dram glass bottle with a small stirring bar. 1.09 mL of heptane was added to the vial. The mixture was slurried at about 70° C. overnight. The mixture was then vacuum filtered and the resulting white solid was air dried for about 30 minutes. 87.1 mg of white solid was collected and analyzed by PXRD and solution ¹ H NMR. The results of the analysis were consistent with N-(methoxycarbonyl)-3-methyl-L-hydroxyproline-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-proline amide, Form 1 (anhydrous free form). Example 3 Preparation of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 5 Anhydrous Free Form

Crystals are grown from a solution of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1, dissolved in 1-chlorobutane and slowly evaporated at room temperature. Alternative preparation of Form 5

N-(Methoxycarbonyl)-3-methyl-L-carbazyl-(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 about 15 hours. During this time, the mixture became very thick and was not stirred well. Additional 1-chlorobutane (1.5 mL) was added and the mixture was stirred for an additional 6 days. The solid was then collected using vacuum filtration and dried in ambient air.

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

PXRD of the anhydrous free form of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 5 was measured.

Table 3-1. PXRD peak list of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 5 anhydrous free form. PXRD peaks are in °2Ɵ units, each ± 0.2 Ɵ. Angle (°2) ± 0.2 °2 Relative strength (%) Angle (°2) ± 0.2 °2 Relative strength (%) 3.6 9 20.3 44 5.1 11 21.0 6 7.1 42 21.6 15 7.6 7 22.1 12 9.9 twenty one 22.6 12 10.1 48 22.9 19 10.7 100 23.2 19 11.9 15 23.4 twenty two 12.1 15 24.0 7 13.7 twenty one 25.6 8 14.3 20 25.8 9 14.6 18 26.9 3 15.2 15 27.9 7 15.5 33 29.0 7 15.8 8 29.5 7 16.2 19 30.6 10 16.4 16 31.4 6 17.1 95 32.3 7 17.4 twenty three 33.5 4 17.8 50 34.7 4 18.2 64 35.3 5 18.8 11 36.2 4 19.3 36

Table 3-2. SXRD crystal structure data of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 5 Empirical C ₂₁ H ₃₀ F ₃ N ₅ O ₅ Molecular weight 489.50 temperature 298 K Wavelength 1.54178 Å Crystal system Monoclinic Space Group P 2 ₁ Unit cell size a = 17.8885(16) Å α = 90° b = 9.2624(8) Å β = 106.851(4)° c = 25.291(2) Å γ = 90° Volume 4010.5(6) Å ³ Z 6 Density (calculated) 1.216 Mg/m ³ About the goodness of fit of ^F2 1.138 Final R index [I＞2Σ(I)] _R1 = 0.0881, _wR2 = 0.2492 R Index (all data) _R1 = 0.1088, _wR2 = 0.2779

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

Table 3-3. 13 C solid state NMR peak list of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form ⁵ . ¹³ C chemical shift (ppm) Relative strength (%) 182.6 15 180.5 14 179.9 17 172.3 32 171.8 25 170.5 13 158.9 11 156.1 18 127.6 6 125.9 9 120.4 6 60.4 30 59.4 29 58.4 27 52.6 28 51.4 20 47.5 20 42.8 27 42.1 31 41.4 30 38.7 47 38.2 50 36.2 32 35.1 11 34.3 twenty two 29.6 20 29.0 twenty two 27.7 66 27.0 100 25.9 11 24.7 9

The 19 F solid state NMR spectrum of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form ⁵ was measured. The peaks (in ppm) were each ± 0.2 ppm.

Table 3-4. 19 F solid state NMR peak list of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form ⁵ . ¹⁹ F chemical shift (ppm) Relative strength (%) -72.6 100 -73.8 96

Table 3-5. Examples of characteristic identifiers for N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 5 using a single instrumental method or a combination of instrumental methods. NMR peaks are each ± 0.2 ppm and PXRD peaks are each ± 0.2 °2Ɵ. Form 5 ^19F ssNMR (ppm) ^13C ssNMR (ppm) PXRD (°2Ɵ) Single -72.6, -73.8 Combination -72.6, -73.8 At least one of the following: 182.6, 156.1, 52.6 Combination -72.6, -73.8 At least one of the following: 3.6, 7.1, 10.7, 17.1 Combination -72.6, -73.8 At least one of the following: 182.6, 156.1, 52.6 At least one of the following: 3.6, 7.1, 10.7, 17.1 Example 4 Preparation of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide ring pentyl methyl ether (CPME) solvent complex, Form 8

5.0 mL of cyclopentyl methyl ether (CPME) was added to a 20 mL vial containing approximately 30 to 40 mg of N-(methoxycarbonyl)-3-methyl-L-carbamidyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide Form 1. The resulting solution was filtered into a clean 20 mL vial for slow evaporation at 5°C with a needle inserted through the vial cap. A single crystal was obtained and data was collected on a Bruker D8 Venture diffractometer at 100K SXRD (see Figure 11). The resulting crystalline form was named Form 8, N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide ring in pentyl methyl ether (CPME) solvent complex.

SXRD analysis of the solvent complex Form 8 of the pentyl methyl ether of N-(methoxycarbonyl)-3-methyl-L-hydroxyproline-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-hydroxyproline amide ring showed that the structure contained 771.6 Å ³ of residual voids, which accounted for 12.9% of the unit cell volume. The solvent mask was calculated and 142 electrons were found in 2 voids per unit cell in a volume of 836 Å ^3. This is consistent with the presence of 0.6 CPME molecules per asymmetric unit, which accounted for 134 electrons/unit cell.

Table 4-1. Crystal structure data of crystalline form 8. Empirical C ₂₄ H ₃₆ F ₃ N ₅ O _5.5 Molecular weight 539.58 temperature 100K Crystal system Orthorhombic Space Group P2 ₁ 2 ₁ 2 Unit cell size a = 24.8092(16) Å α = 90° b = 25.1091(13) Å β = 90° c = 9.5991(6) Å γ = 90° Volume 5979.6(6) Å ³ Z 8 Density (calculated) 1.199 g/cm ³ About the goodness of fit of ^F2 1.049 Final R index [I ＞ = 2σ (I)] _R1 = 0.0858, _wR2 = 0.2270 Final R Index [All Data] _R1 = 0.0892, _wR2 = 0.2340 Example 5 Preparation of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide ring pentyl methyl ether (CPME) solvent complex, Form 9

259.4 mg of N-(methoxycarbonyl)-3-methyl-L-carbamidyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide Form 1 was added to a 20 mL vial with a stir bar. 10 mL of cyclopentyl methyl ether (CPME) was added thereto and the mixture was heated at about 60° C. for about 2 hours. The resulting solution was cooled down to room temperature and then allowed to evaporate slowly from the loosely capped vial. After 1 week, the resulting solid was collected by vacuum filtration and air dried at room temperature for about 3 hours. About 160.9 mg of a white solid was collected. The obtained solid was analyzed by PXRD (Figure 3), ssNMR (Figures 19 to 20), and TGA-IR (Figures 27 to 29).

Table 5-1. PXRD peak list of Form 9 of N-(methoxycarbonyl)-3-methyl-L-proline-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-proline amide ring in amyl methyl ether (CPME) solvent. The PXRD peaks are °2Ɵ ± 0.2 °2Ɵ. Angle (°2) ± 0.2 °2 Relative strength (%) Angle (°2) ± 0.2 °2 Relative strength (%) 5.0 12 19.8 32 7.1 100 20.5 39 7.9 77 21.1 46 9.8 40 21.9 9 10.4 12 22.5 12 11.1 8 23.2 twenty two 13.5 13 24.1 7 14.0 38 25.4 7 14.4 43 25.7 7 15.7 twenty three 26.6 9 17.2 twenty one 26.9 18 17.5 14 31.8 3 18.2 34 33.0 4 18.9 78 33.9 5

Table 5-2. 13 C solid state NMR peak list of Form 9 of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide ring in amyl methyl ether ^{(CPME) solvent. 13 C} solid state NMR peaks are ± 0.2 ppm each. ¹³ C chemical shift (ppm) Relative strength (%) 180.2 35 173.0 28 170.8 28 157.0 28 128.1 6 127.2 7 119.8 9 83.4 42 59.4 40 56.0 55 52.3 30 51.6 28 47.7 16 43.2 19 41.5 39 38.1 53 36.5 33 36.1 30 32.7 100 27.5 96 26.8 97 24.2 77

Table 5-3. 19 F solid state NMR peak list of Form 9 of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide ring in amyl methyl ether ^{(CPME) solvent. 19 F} solid state NMR peaks are ± 0.2 ppm each. ¹⁹ F chemical shift (ppm) Relative strength (%) -70.2 100 -70.5 100

Thermogravimetric infrared analysis (TGA-IR): TGA-IR data of N-(methoxycarbonyl)-3-methyl-L-hydroxypropyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide cyclopentyl methyl ether (CPME) solvent complex, Form 9 are shown in Figures 27 to 29. The observed weight loss of 10.8% is consistent with the theoretical weight loss of 10.9% for Form 9 (0.6 equivalents of CPME solvent complex). Analysis of infrared spectra indicated the presence of cyclopentyl methyl ether.

For CPME solvent compositions, it has been found that the amount of CPME can vary from batch to batch, ranging from about 8 wt% (about 0.4 molar equivalent) to 14 wt% (about 0.8 molar equivalent). The PXRD pattern of the CPME solvent composition can vary slightly due to the different amounts of CPME in the crystal lattice of different batches of this form. Reference Example 6 Preparation of N-(methoxycarbonyl)-3-methyl-L-hydroxyproline-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-hydroxyproline amide amorphous free form, Form 10

About 2 g of N-(methoxycarbonyl)-3-methyl-L-hydroxyproline-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-hydroxyproline amide, 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 min. 100 mL of water was then added to the RBF. The mixture was then sonicated for 5 min to ensure that no crystals were present. The mixture was then frozen by cooling it in a dry ice/acetone bath and the resulting frozen mixture was freeze dried. The resulting solid was analyzed by PXRD, ssNMR, and mDSC.

Table 6-1. 13 C solid state NMR peak list of amorphous free form of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin- ^{3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 10. 13 C} solid state NMR peaks are each ± 0.2 ppm. ¹³ C chemical shift (ppm) Relative strength (%) 180.0 16 171.9 35 157.7 twenty two 127.6 14 119.7 9 59.8 60 52.4 35 47.7 twenty four 42.4 51 40.5 56 37.9 67 35.1 35 26.7 100

Table 6-2. List of 19 F solid state NMR peaks of amorphous free form of N-(methoxycarbonyl)-3-methyl- ^{L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 10. 19 F} solid state NMR peaks are ± 0.2 ppm. ¹⁹ F chemical shift (ppm) Relative strength (%) -71.2 100

Modulated differential scanning calorimetry (mDSC): The glass transition temperature of the amorphous free form of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 10, is about 95°C, as determined by mDSC analysis (see Figure 33). Example 7 Preparation method of N-(methoxycarbonyl)-3-methyl-L-proline-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-proline-amide in isopropyl acetate solvent, Form 11

565.0 mg of N-(methoxycarbonyl)-3-methyl-L-carbamidyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1 was weighed into a 2-dram vial equipped with a stir bar and 2.5 mL of isopropyl acetate was pipetted into the vial. The mixture was stirred in a heating block at about 25° C. for about 2 days. The mixture was vacuum filtered and the solids were allowed to stand in ambient air for 3 days. 280.7 mg of a white solid N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide in isopropyl acetate solvent, Form 11, was collected. The solids were analyzed by PXRD, solid state ¹³ C and ¹⁹ F NMR, and thermogravimetric infrared analysis (TGA-IR).

Table 7-1. PXRD peak list of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide in isopropyl acetate solvent, Form 11. Each PXRD peak is °2Ɵ ± 0.2 °2Ɵ. Angle (°2) ± 0.2 °2 Relative strength (%) Angle (°2) ± 0.2 °2 Relative strength (%) 4.4 3 19.8 twenty four 5.2 9 20.7 45 6.3 39 21.2 30 7.5 5 21.6 32 8.5 32 22.9 59 10.0 20 23.6 25 10.4 62 24.3 6 10.7 92 24.7 10 11.3 17 25.2 6 11.7 twenty two 25.9 5 12.0 12 26.7 10 13.0 7 27.1 8 14.0 50 27.8 6 14.3 37 28.2 4 14.9 15 28.8 5 15.5 20 29.4 5 15.9 26 30.3 10 16.6 36 31.4 8 17.0 35 32.2 5 17.6 79 32.7 5 18.2 67 33.6 3 18.5 68 35.3 5 19.1 100 37.2 4

Table 7-2. 13 C solid state NMR peak list of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin ^{-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide in isopropyl acetate solvent, Form 11. 13 C} solid state NMR peaks are each ± 0.2 ppm. ¹³ C chemical shift (ppm) Relative strength (%) 182.4 11 180.5 14 179.7 13 173.5 13 172.9 16 172.0 15 171.4 15 170.8 twenty four 170.1 5 158.4 8 156.9 11 156.7 11 156.3 12 128.4 8 126.6 8 120.0 8 67.1 15 59.9 twenty four 59.5 twenty two 58.6 18 52.0 41 48.0 14 42.6 29 42.0 28 38.7 33 38.0 42 36.2 34 34.2 18 27.8 100 26.6 52 22.1 14 20.9 19

Table 7-3. 19 F solid state NMR peak list of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin ^{-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide in isopropyl acetate solvent, Form 11. 19 F} solid state NMR peaks are each ± 0.2 ppm. ¹⁹ F chemical shift (ppm) Relative strength (%) -69.8 73 -71.9 88 -72.4 100

Thermogravimetric infrared analysis (TGA-IR): TGA-IR data of N-(methoxycarbonyl)-3-methyl-L-vinylamino-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide in isopropyl acetate solvent, Form 11 are shown in Figures 30 to 32. The observed weight loss of 5.8% is consistent with the theoretical weight loss of 5.9% for 0.3 equivalents of isopropyl acetate solvent. Analysis of the infrared spectrum indicates the presence of isopropyl acetate. Example 8 Preparation method of N-(methoxycarbonyl)-3-methyl-L-proline-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-proline-amide in isopropyl acetate solvent, Form 12

About 0.5 mL to 1.0 mL of isopropyl acetate/heptane (1:1, v:v) was added to a 1 dram glass vial containing 5 mg to 10 mg of N-(methoxycarbonyl)-3-methyl-L-carbazyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1. It was completely dissolved and the resulting solution was filtered into a clean 20 mL vial for slow evaporation at room temperature using a loosely capped vial. Single crystals of the resulting N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 12 were obtained and single crystal structure determination and data collection were performed on a Bruker D8 Quest diffractometer at 298 K.

SXRD analysis of the isopropyl acetate solvent complex of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 12, showed that the structure contained 1666 Å ³ of residual voids, which accounted for 26.9% of the unit cell volume. The solvent mask was calculated, and 420 electrons were found in 1 void per unit cell in a volume of 1772 Å 3. This is consistent with the presence of 1 [C5H10O2] per asymmetric unit, which accounts for 448 electrons/unit cell.

Table 8-1. Crystal structure data of crystalline N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide in isopropyl acetate solvent, Form 12. Empirical C ₂₁ H ₃₀ F ₃ N ₅ O ₅ Molecular weight 489.50 temperature 298 K Wavelength 1.54178 Å Crystal system Orthorhombic Space Group P 2 ₁ 2 ₁ 2 Unit cell size a = 25.199(4) Å α = 90° b = 25.381(4) Å β = 90° c = 9.6798(14) Å γ = 90° Volume 6191.0(15) Å ³ Z 8 Density (calculated) 1.050 Mg/m ³ About the goodness of fit of ^F2 1.049 Final R index [I＞2Σ(I)] _R1 = 0.0405, _wR2 = 0.1108 R Index (all data) _R1 = 0.0462, _wR2 = 0.1156 Example 9 Preparation of N-(methoxycarbonyl)-3-methyl-L-proline-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolineamide/ HPMAS-MG 750 mg/g spray dried dispersion (SDD)

The active pharmaceutical ingredient (API) N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide and HPMCAS-MG polymer [75/25 N-(Methoxycarbonyl)-3-methyl-L-carboxamidoyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide/hydroxypropylmethylcellulose acetate succinate-M grade] was dissolved in acetone to prepare a 750 mg/g spray dried dispersion (SDD) of N-(Methoxycarbonyl)-3-methyl-L-carboxamidoyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide. The resulting solution having a weight percentage of API/polymer/acetone of 7.5/2.5/90 was atomized into a co-current 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 (according to guidelines, the acceptable level is < 5000 ppm (acetone), typically less than 0.05% according to the USBD-334 test).

^N- (Methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S) ^-1- cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide/HPMCAS-MG SDD was characterized by PXRD ( FIG. 6 ), 13 C and 19 F solid state NMR ( FIGS. 25 to 26 ), and modulated differential scanning calorimetry (mDSC) ( FIG. 34 ). Example 10 Preparation of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide in ethyl acetate solvent, Form 14

210.4 mg of N-(methoxycarbonyl)-3-methyl-L-hydroxyprolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1 was weighed into a double dram equipped with a stirring bar and 4.0 mL of ethyl acetate/heptane (3/2, v/v) was added to the vial. The mixture was stirred at room temperature for about 4 hours.

SXRD analysis of the ethyl acetate solvent complex of N-(methoxycarbonyl)-3-methyl-L-carbamidyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 14, showed that the asymmetric unit contained two N-(methoxycarbonyl)-3-methyl-L-carbamidyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide molecules identified using a solvent mask (Z'=2), one ordered ethyl acetate molecule, and one additional disordered ethyl acetate molecule. This gave an overall API:solvent ratio of 1:1. Table 10. Crystal structure data of crystalline form 14 of PF-07817883-00. Empirical C ₂₃ H ₃₄ F ₃ N ₅ O ₆ Molecular weight 533.55 temperature 100K Wavelength 1.54178 Å Crystal system Orthorhombic Space Group P 2 ₁ 2 ₁ 2 Unit cell size a = 24.7926(16) Å α = 90° b = 25.0341(15) Å β = 90° c = 9.6240(6) Å γ = 90° Volume 5973.2(6) Å ³ Z 8 Density (calculated) 1.187 Mg/m ³ About the goodness of fit of ^F2 1.077 Final R index [I＞2Σ(I)] _R1 = 0.0880, _wR2 = 0.2433 R Index (all data) _R1 = 0.1056, _wR2 = 0.2666 Example 11 Preparation of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 22

98.9 mg of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide Form 1 and 1 mL of isopropyl alcohol (IPA) were slurried at room temperature (RT) for about 1 hour (98.9 mg/mL). The mixture was a clear solution. 0.5 mL of the mixture was pipetted and filtered by syringe with an Acrodisc 0.2 μm syringe filter into a double dram vial. 2.83 mL of heptane was slowly loaded into the vial by syringe over about 7.5 minutes. The mixture was heated up to 60°C overnight, then cooled down to RT and slurried at RT for about 3 hours. The solid was then collected by vacuum filtration and analyzed by PXRD and solution ¹ H NMR. 26.4 mg of white solid was collected (yield: about 53.4%). Instrumental Powder X-ray Diffraction (PXRD):

Powder X-ray diffraction analysis was performed using a Bruker AXS D8 Endeavor diffraction instrument equipped with a Cu radiation source (K-alpha average). The divergence slit was set to 15 mm continuous illumination. Diffraction radiation was detected by a PSD-Lynx Eye detector with the detector PSD opening set to 4.10 degrees. The X-ray tube voltage and amperage were set to 40 kV and 40 mA, respectively. Data were collected in a theta-theta goniometer at Cu wavelengths from 3.0 to 40.0° 2-theta using a step size of 0.01 degree and a step time of 1.0 second. The backscatter screen was set to a fixed distance of 3.0 mm. The sample was rotated at 15/min during the collection period. Samples were prepared by placing them in a silicon low background sample holder and rotating during collection. Data were collected using Bruker DIFFRAC Plus software and analyzed by EVA diffract plus software.

The PXRD data files were not processed prior to peak searching. Preliminary peak assignments were made using the peak search algorithm in the EVA software, using peaks selected with a threshold of 1. Adjustments were made manually to ensure validity; the output of the automated assignments was visually inspected and the peak positions were adjusted to the peak maximum. Peaks with a relative intensity of ≥ 3% were generally selected. Peaks that were unresolved or consistent with noise were not selected. Typical errors associated with PXRD peak positions as specified in the USP are up to +/- 0.2° 2-θ (USP-941). Single Crystal X-Ray Diffraction (SXRD):

A sample of Form 22 single crystal was examined by SXRD. SXRD was performed on a Bruker D8 Venture diffractometer at 298 K. Data collection consisted of ω and φ scans. The structure was solved by internal intrinsic phasing using the SHELX software suite in monoclinic space group P2 _1. The structure was subsequently refined by the full matrix least squares method. All non-hydrogen atoms were found and refinement was performed using anisotropic displacement parameters. The final R index was 4.8%.

Table 2 contains structural data from SXRD analysis of Form 22. The ORTEP plot of the asymmetric unit of Form 22 is presented in Figure 3, with the shift parameters at 50% probability. Solid-state nuclear magnetic resonance (ssNMR):

¹³ C solid state NMR (ssNMR) analysis was performed on a CPMAS probe positioned in a Bruker-BioSpin Avance NEO 500 MHz ( ¹ H frequency) NMR spectrometer. ¹⁹ F solid state NMR (ssNMR) analysis was performed on a CPMAS probe positioned in a Bruker-BioSpin Avance III 600 MHz ( ¹ H frequency) NMR spectrometer. The materials were packaged in a ZrO ₂ rotor. A magic angle spinning rate of 15 kHz was used. Spectra were collected at ambient temperature (probe temperature of 25°C).

^13C ssNMR spectra were collected using proton decoupled cross-linked polarization magic angle spinning (CPMAS) experiments. A phase-modulated proton decoupling field of 80 to 100 kHz was applied during spectrum acquisition. The cross-polarization contact time was set to 2 ms and the recycle delay was set to 3.5 seconds. The number of scans was adjusted to achieve adequate signal-to-noise ratio. The ^13C chemical shift scale was referenced to an external standard of crystalline adamantane using ^13C CPMAS experiments, with the upfield resonance set to 29.5 ppm.

¹⁹ F ssNMR spectra were collected using proton decoupled magic angle spinning (MAS) experiments. A phase-modulated proton decoupling field of 80 to 100 kHz was applied during spectrum acquisition. Spectra were collected with a recycle delay of 3.5 seconds. The number of scans was adjusted to achieve adequate signal-to-noise ratio. The ¹⁹ F chemical shift scale was referenced to an external standard of trifluoroacetic acid (50%/50% v/v in H2O) using ¹⁹ F MAS experiments, with the resonance set to -76.54 ppm.

Automatic peak picking was performed using Bruker-BioSpin TopSpin version 4.1 software. In general, a cutoff of 5% relative intensity was used for preliminary peak selection. The output of the automated peak picking was visually inspected to ensure validity and manually adjusted if necessary. Although specific solid-state NMR peaks are reported herein, there does exist a range in these peaks due to differences in instrumentation, samples, and sample preparation. This is common practice in the art of solid-state NMR because of the inherent variability in peak positions. The typical variability of the x-axis values of chemical shifts for crystalline solids is approximately plus or minus 0.2 ppm. The solid-state NMR peak heights reported herein are relative intensities. Solid-state NMR intensities may vary depending on the actual setup of the experimental parameters and the thermal history of the sample.

Table 11-1. PXRD peak list of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 22 Angle (°2) ± 0.2 °2 Relative strength Angle (°2) ± 0.2 °2 Relative strength 3.5 8% 22.9 15% 8.2 9% 23.3 twenty four% 9.7 75% 23.9 twenty four% 10.4 14% 24.2 17% 10.9 46% 24.6 twenty four% 11.6 98% 25.3 32% 12.2 twenty one% 26.0 twenty three% 12.7 38% 26.2 11% 13.8 twenty one% 26.6 twenty two% 14.3 18% 27.0 8% 14.6 98% 27.4 5% 15.4 8% 27.7 5% 15.6 10% 28.1 7% 16.1 7% 28.6 10% 16.5 37% 29.0 18% 16.6 42% 29.4 26% 16.8 twenty two% 29.6 25% 17.4 73% 30.2 twenty two% 18.2 35% 31.2 17% 18.5 93% 32.2 8% 18.7 67% 32.5 11% 19.3 88% 33.2 5% 19.5 100% 33.7 7% 19.7 95% 34.3 9% 20.6 26% 34.6 11% 20.8 26% 35.4 9% 21.0 27% 36.0 8% 21.2 36% 36.6 6% 21.5 twenty two% 36.9 6% 21.6 twenty one% 37.2 7% 22.0 47% 37.8 11% 22.2 35% 38.2 6% 22.7 twenty one% 39.0 7% Single Crystal X-Ray Diffraction (SXRD)

Table 11-2 contains structural data from the SXRD analysis of Form 22. The ORTEP plot of the asymmetric unit of Form 22 is presented in Figure 39, where the displacement parameters are at 50% probability.

Table 11-2. Crystal structure data of the crystalline form 22 of N-(methoxycarbonyl)-3-methyl-L-proline-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-proline Empirical C ₂₁ H ₃₀ F ₃ N ₅ O ₅ Molecular weight 489.50 temperature 298 K Wavelength 1.54178 Å Crystal system Monoclinic Space Group P 2 ₁ Unit cell size a = 15.461(3) Å α = 90° b = 9.7458(13) Å β = 100.122(7)° c = 25.786(4) Å γ = 90° Volume 3824.9(11) Å ³ Z 6 Density (calculated) 1.275 Mg/m ³ About the goodness of fit of ^F2 0.951 Final R index [I＞2Σ(I)] _R1 = 0.0480, _wR2 = 0.0987 R Index (all data) _R1 = 0.0874, _wR2 = 0.1148 Solid-state nuclear magnetic resonance (ssNMR):

The 13 C and 19 F ssNMR spectra of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl} ^-4- ( ^{trifluoromethyl} )-L-prolinamide Form 22 are shown in Figures 41 and 42, and the corresponding peak lists (in ppm) are shown in Tables 11-3 and 11-4, where each peak is ± 0.2 ppm. Selected characteristic peaks of Form 22 are shown in Table 11-5.

Table 11-3. 13 C solid state NMR peak list of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide Form ²² (unit: ppm ± 0.2 ppm). ¹³ C chemical shift (ppm) Relative strength (%) ¹³ C chemical shift (ppm) Relative strength (%) 181.3 18 43.1 29 180.8 25 42.2 29 172.8 17 41.7 19 170.5 26 40.8 29 169.1 12 39.8 twenty three 158.9 8 39.0 41 157.0 9 38.5 20 156.0 9 37.9 30 127.4 5 36.4 31 120.5 5 35.4 twenty two 119.4 8 34.5 17 119.1 6 30.6 14 60.1 16 29.9 17 59.3 twenty four 29.0 31 58.6 30 28.7 20 53.3 27 27.5 100 52.5 twenty three 26.7 10 48.5 13 25.5 17 47.7 19

Table 11-4. 19 F solid state NMR peak list of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide Form ²² (unit: ppm ± 0.2 ppm). ¹⁹ F chemical shift (ppm) Relative strength (%) -71.0 100 -71.5 62

Table 11-5. Characteristic peaks of Form 22. Asterisks indicate peaks characteristic of Form 22 in combination with ¹⁹ F peaks at -71.0 and -71.5 ppm and/or ¹³ C peaks at 53.3 and/or 39.8 and/or 169.1 ppm. ¹³ C chemical shift (ppm) ¹⁹ F chemical shift (ppm) 53.3 -71.0 and -71.5 39.8 169.1 40.8*

Table 11-6. Examples of key characterization identifiers of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide Form 22 using a single instrumental method or a combination of instrumental methods. Form 22 ^19F ssNMR (ppm) ^13C ssNMR (ppm) PXRD (°2Ɵ) ± 0.2 °2Ɵ Single -71.0 and -71.5 Single At least one of the following: 53.3, 39.8, 169.1 Combination -71.0 and -71.5 At least one of the following: 53.3, 39.8, 169.1, 40.8 Combination -71.0 and -71.5 At least one of the following: 11.6, 14.6 Combination At least one of the following: 53.3, 39.8, 169.1 At least one of the following: 11.6, 14.6 Combination -71.0 and -71.5 At least one of the following: 53.3, 39.8, 169.1, 40.8 At least one of the following: 11.6, 14.6

Figure 1 is the PXRD pattern of Form 1.

FIG. 2 is the PXRD pattern of Form 5.

FIG. 3 is a PXRD pattern of cyclopentyl methyl ether (CPME) solvent complex, Form 9.

FIG. 4 is a PXRD pattern of the amorphous free form, Form 10.

FIG. 5 is the PXRD of isopropyl acetate solvent complex, Form 11.

Figure 6 is the PXRD pattern of the 750 mg/g spray dried dispersion (SDD).

Figure 7 is an ORTEP diagram of the asymmetric unit of form 1 drawn when the displacement parameter is 50%.

Figure 8 shows the calculated Form 1 PXRD pattern derived from single crystal (SXRD) data.

Figure 9 is an ORTEP diagram of the asymmetric unit of form 5 drawn when the displacement parameter is 50%.

FIG. 10 is the calculated PXRD pattern of Form 5 in anhydrous form.

FIG. 11 is an ORTEP diagram of a CPME solvent complex, form 8 asymmetric unit, plotted when the displacement parameter is 50%.

FIG. 12 is the calculated PXRD pattern of the CPME solvent compound, Form 8.

FIG. 13 is an ORTEP diagram of the asymmetric unit of the isopropyl acetate solvent complex, Form 12, plotted at a displacement parameter of 50%.

FIG. 14 is the calculated PXRD pattern of the isopropyl acetate solvent complex, Form 12.

FIG. 15 is a ¹³ C solid-state NMR spectrum of Form 1 and the peaks marked with pound signs are rotational sidebands.

FIG. 16 is a ¹⁹ F solid-state NMR spectrum of Form 1 and the peaks marked with pound signs are rotational sidebands.

FIG. 17 is a ¹³ C solid-state NMR spectrum of Form 5 and the peaks marked with pound signs are rotational sidebands.

FIG. 18 is a ¹⁹ F solid-state NMR spectrum of Form 5 and the peaks marked with pound signs are rotational sidebands.

FIG. 19 is ^{the 13} C solid-state NMR spectrum of CPME solvent complex Form 9 and the peaks marked by pound signs are rotational side bands.

FIG. 20 is ^{the 19} F solid-state NMR spectrum of CPME solvent complex Form 9 and the peaks marked by pound signs are rotational side bands.

FIG. 21 is a ¹³ C solid-state NMR spectrum of the amorphous free form, Form 10, and the peaks marked with pound marks are rotational side bands.

FIG. 22 is a ¹⁹ F solid-state NMR spectrum of the amorphous free form, Form 10, and the peaks marked with pound marks are rotational side bands.

FIG. 23 is the ¹³ C solid-state NMR spectrum of isopropyl acetate solvent complex Form 11 and the peaks marked by pound signs are rotational side bands.

FIG. 24 is a ¹⁹ F solid state NMR spectrum of isopropyl acetate solvent complex Form 11 and the peaks marked by pound signs are rotational side bands.

Figure 25 is the ¹³ C solid state NMR spectrum of the 750 mg/g spray dried dispersion (SDD).

FIG. 26 is the ¹⁹ F solid-state NMR spectrum of 750 mg/g SDD and the peaks marked with pound signs are rotational sidebands.

FIG. 27 is a thermogravimetric infrared analysis (TGA-IR) temperature record of CPME solvent complex Form 9.

Figure 28 shows the Gram-Schmidt and IR of the CPME solvent complex, Form 9 (TGA-IR) at 9.056 min.

Figure 29 is an overlay of the IR spectra of the CPME solvent complex, Form 9 (top) and cyclopentyl methyl ether solvent (bottom).

FIG. 30 is a thermogram of the thermogravimetric infrared analysis (TGA-IR) of the isopropyl acetate solvent complex, Form 11.

Figure 31 is the Gram-Schmidt and IR of isopropyl acetate solvent complex, Form 11 (TGA-IR) at 10.321 min.

FIG. 32 is an overlay of the IR spectra of the isopropyl acetate solvent complex, Form 11 (top) and isopropyl acetate solvent (bottom).

FIG. 33 is a modulated differential scanning calorimetry (DSC) data of Form 10 amorphous free form showing a glass transition temperature (Tg) of about 95°C.

Figure 34 is the prepared DSC data of the 750 mg/g spray dried dispersion (SDD), which shows a Tg of about 92°C.

FIG. 35 is a representative labeling scheme for Form 14 and a partial asymmetric unit plot of the anisotropic displacement parameter plotted at 50% probability.

Figure 36 is the calculated powder pattern of Form 14, a complex of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide in ethyl acetate solvent.

Figure 37 is the PXRD pattern of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 22.

Figure 38 is a PXRD pattern of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 22, wherein peak picking is for peaks with a relative intensity exceeding 3%.

Figure 39 is an ORTEP diagram (color) of the asymmetric unit of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 22, plotted at a displacement parameter of 50%.

Figure 40 is an overlay of the powder pattern obtained for N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 22 (bottom) and the calculated powder pattern from single crystal data (top).

Figure 41 is the 13 C solid state NMR spectrum of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form ²² - the peaks marked by the hash marks are rotational side bands.

Figure 42 is a 19 F solid state NMR spectrum of N-(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl} ^-4- (trifluoromethyl)-L-prolinamide Form 22. The peaks marked by the hash mark are rotational side bands.

Claims (41)

A compound which is an anhydrous crystalline form of N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide. The compound of claim 1, which is anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1, characterized by ¹³ C solid state NMR peaks at 50.8 ppm, 58.3 ppm and 43.5 ppm, wherein each peak is ± 0.2 ppm. The compound of claim 1, which is anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1, characterized by ¹³ C solid state NMR peaks at 50.8 ppm and 58.3 ppm, each of which is ± 0.2 ppm; and ¹⁹ F solid state NMR peak at -70.7 ppm ± 0.2 ppm. The compound of claim 1, which is anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1, characterized by ¹³ C solid state NMR peaks at 50.8 ppm and 43.5 ppm, each of which is ± 0.2 ppm; and ¹⁹ F solid state NMR peak at -70.7 ppm ± 0.2 ppm. The compound of claim 1, which is anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1, characterized by ¹³ C solid state NMR peaks at 50.8 ppm, 58.3 ppm and 43.5 ppm, each of which is ± 0.2 ppm; and ¹⁹ F solid state NMR peak at -70.7 ppm ± 0.2 ppm. The compound of claim 1, which is anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1, characterized by ¹³ C solid state NMR peaks at 50.8 ppm and 58.3 ppm, each of which 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° 2θ, each of which is ± 0.2° 2θ. The compound of claim 1, which is anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1, characterized by ¹³ C solid state NMR peaks at 50.8 ppm and 43.5 ppm, each of which 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° 2θ, each of which is ± 0.2° 2θ. The compound of claim 1, which is anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1, characterized by ¹³ C solid state NMR peaks at 50.8 ppm, 58.3 ppm and 43.5 ppm, each of which 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° 2θ, each of which is ± 0.2° 2θ. The compound of claim 1, which is anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1, characterized by ¹³ C solid state NMR peaks at 50.8 ppm and 58.3 ppm, each of which is ± 0.2 ppm; ¹⁹ F solid state NMR peak at -70.7 ppm ± 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° 2θ, each of which is ± 0.2° 2θ. The compound of claim 1, which is anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1, characterized by ¹³ C solid state NMR peaks at 50.8 ppm and 43.5 ppm, each of which is ± 0.2 ppm; ¹⁹ F solid state NMR peak at -70.7 ppm ± 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° 2θ, each of which is ± 0.2° 2θ. The compound of claim 1, which is anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1, characterized by ¹³ C solid state NMR peaks at 50.8 ppm, 58.3 ppm and 43.5 ppm, each of which is ± 0.2 ppm; ¹⁹ F solid state NMR peak at -70.7 ppm ± 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° 2θ, each of which is ± 0.2° 2θ. N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 1, as claimed in any one of claims 2 to 11, which is substantially pure. A solid form of N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, comprising Form 1 of any one of claims 2 to 11 and wherein the solid form comprises less than 95% by weight, less than 90% by weight, less than 80% by weight, less than 70% by weight, less than 60% by weight, less than 50% by weight, less than 40% by weight, less than 30% by weight, less than 20% by weight, less than 10% by weight, less than 5% by weight, less than 3% by weight, or less than 1% by weight of the compound N -(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide or any other solid forms thereof. A pharmaceutical composition comprising a therapeutically effective amount of the form 1 of any one of claims 2 to 12 or the solid form of claim 13 and a pharmaceutically acceptable carrier. The compound of claim 1, which is anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-hydroxyprolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-hydroxyprolinamide, Form 5, characterized by ¹⁹ F solid state NMR peaks at -72.6 ppm and -73.8 ppm, each of which is ± 0.2 ppm; and ¹³ C solid state NMR peaks at 182.6 ppm, 156.1 ppm and 52.6 ppm, each of which is ± 0.2 ppm. The compound of claim 1, which is anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 5, characterized by ¹⁹ F solid state NMR peaks at -72.6 ppm ± 0.2 ppm and -73.8 ppm ± 0.2 ppm and one to four powder X-ray diffraction peaks (Cu Kα radiation) selected from the group consisting of peaks at 3.6, 7.1, 10.7 and 17.1° 2θ, each peak being ± 0.2° 2θ. The compound of claim 1, which is anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-hydroxyproline-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-hydroxyproline amide, Form 5, characterized by ¹⁹ F solid state NMR peaks at -72.6 ppm ± 0.2 ppm and -73.8 ppm ± 0.2 ppm; one to three ¹³ C solid state NMR peaks selected from the group consisting of peaks at 182.6 ppm, 156.1 ppm and 52.6 ppm, each of which is ± 0.2 ppm; and one to four peaks selected from the group consisting of peaks at 3.6, 7.1, 10.7 and 17.1° Powder X-ray diffraction peaks (Cu Kα radiation) consisting of a group of peaks at 2θ, where each peak is ± 0.2° 2θ. N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 5, which is substantially pure. A solid form of N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide comprising Form 5 and wherein the solid form comprises less than 95 wt%, less than 90 wt%, less than 80 wt%, less than 70 wt%, less than 60 wt%, less than 50 wt%, less than 40 wt%, less than 30 wt%, less than 20 wt%, less than 10 wt%, less than 5 wt%, less than 3 wt%, or less than 1 wt% of the compound N Any other solid form of -(methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide. A pharmaceutical composition comprising a therapeutically effective amount of anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 5 as claimed in any one of claims 15 to 19 and a pharmaceutically acceptable carrier. A crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide ring in an amyl methyl ether solvent. The compound of claim 21, which is a crystalline N- (methoxycarbonyl)-3-methyl-L-hydroxypropyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-hydroxypropylamine cyclopentyl methyl ether solvent complex, Form 9, characterized by ¹⁹ F solid state NMR peaks at -70.2 ppm and -70.5 ppm, each of which is ± 0.2 ppm; and one to three ¹³ C solid state NMR peaks selected from the group consisting of peaks at 32.7 ppm, 24.2 ppm and 56.0 ppm, each of which is ± 0.2 ppm. The compound of claim 21, which is a crystalline N- (methoxycarbonyl)-3-methyl-L-hydroxypropylamino-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-hydroxypropylamino ring in pentyl methyl ether solvent complex, Form 9, characterized by ¹⁹ F solid state NMR peaks at -70.2 ppm and -70.5 ppm, each of which is ± 0.2 ppm; and one to three powder X-ray diffraction peaks (Cu Kα radiation) selected from peaks at 7.1, 7.9 and 19.8° 2θ, each of which is ± 0.2° 2θ. The compound of claim 21, which is a crystalline N- (methoxycarbonyl)-3-methyl-L-hydroxypropyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-hydroxypropylamine cyclopentyl methyl ether solvent complex, Form 9, characterized by ¹⁹ F solid state NMR peaks at -70.2 ppm and -70.5 ppm, each of which is ± 0.2 ppm; one to three ¹³ C solid state NMR peaks selected from the group of peaks at 32.7 ppm, 24.2 ppm and 56.0 ppm, each of which is ± 0.2 ppm; and one to three peaks selected from the group of peaks at 7.1, 7.9 and 19.8°. Powder X-ray diffraction peaks (Cu Kα radiation) at 2θ, where each peak is ± 0.2° 2θ. A crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide in isopropyl acetate solvent, Form 11. The compound of claim 25, characterized by ¹⁹ F solid state NMR peaks at -69.8 ppm, -71.9 ppm and -72.4 ppm, each of which is ± 0.2 ppm; and one to three ¹³ C solid state NMR peaks selected from the group consisting of peaks at 20.9 ppm ± 0.2 ppm, 38.7 ppm ± 0.2 ppm and 52.0 ppm ± 0.2 ppm. The compound of claim 25, characterized by ¹⁹ F solid state NMR peaks at -69.8 ppm, -71.9 ppm and -72.4 ppm, each of which is ± 0.2 ppm; and one to four powder X-ray diffraction peaks (Cu Kα radiation) selected from the group consisting of peaks at 8.5, 6.3, 10.7 and 19.1° 2θ, each of which is ± 0.2° 2θ. The compound of claim 25, characterized by ¹⁹ F solid state NMR peaks at -69.8 ppm, -71.9 ppm and -72.4 ppm, each of which is ± 0.2 ppm; one to three ¹³ C solid state NMR 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 and one to four powder X-ray diffraction peaks (Cu Kα radiation) selected from the group of peaks at 8.5, 6.3, 10.7 and 19.1° 2θ, each of which is ± 0.2° 2θ. A spray-drying dispersion comprising N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide and a pharmaceutically acceptable excipient. A spray dried dispersion as claimed in claim 29 comprising hydroxypropylmethylcellulose acetate succinate - M grade. A spray-dried dispersion as claimed in claim 30, consisting of 750 mg/g of amorphous N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide and 250 mg/g of hydroxypropylmethylcellulose acetate succinate - M grade. A pharmaceutical composition comprising the spray-dried dispersion of any one of claims 29 to 31. A crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide in ethyl acetate solvent. The compound of claim 33, which is a crystalline N- (methoxycarbonyl)-3-methyl-L-hydroxypropyl-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-hydroxypropylamine in ethyl acetate solvent, Form 14, characterized by a single crystal X-ray diffraction pattern (SXRD), wherein the crystal system is orthorhombic, the space group is P2 ₁ 2 ₁ 2, the unit cell has 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 , Z is 8, the calculated density is 1.187 g/cm ³ , the goodness of fit F ² is 1.077, 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 = 0.2666. The compound of claim 1, which is anhydrous crystalline N- (methoxycarbonyl)-3-methyl-L-prolinamide-(4R)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-4-(trifluoromethyl)-L-prolinamide, Form 22. The compound of claim 35 is characterized by ¹⁹ F solid state NMR peaks at -71.0 and -71.5 ppm, each being ± 0.2 ppm. The compound of claim 35, characterized by one to ^three13C solid state NMR peaks selected from the group consisting of peaks at 53.3 ppm, 39.8 ppm, and 169.1 ppm, wherein each peak is ± 0.2 ppm. The compound of claim 35, characterized by ¹⁹ F solid state NMR peaks at -71.0 and -71.5 ppm, each ± 0.2 ppm; and one to four ¹³ C solid state NMR peaks selected from the group consisting of peaks at 53.3 ppm, 39.8 ppm, 169.1 ppm and 40.8 ppm, each ± 0.2 ppm. The compound of claim 35, characterized by ¹⁹ F solid state NMR peaks at -71.0 ppm and -71.5 ppm, each of which is ± 0.2 ppm; and one to two powder X-ray diffraction peaks (Cu Kα radiation) selected from peaks at 11.6 and 14.6° 2θ, each of which is ± 0.2° 2θ. The compound of claim 35, characterized by one to three ¹³ C solid state NMR peaks selected from the group consisting of peaks at 53.3 ppm, 39.8 ppm and 169.1 ppm, each of which is ± 0.2 ppm; and one to two powder X-ray diffraction peaks (Cu Kα radiation) selected from the group consisting of peaks at 11.6 and 14.6° 2θ, each of which is ± 0.2° 2θ. The compound of claim 35, characterized by ¹⁹ F solid state NMR peaks at -71.0 ppm and -71.5 ppm, each of which is ± 0.2 ppm; one to four ¹³ C solid state NMR peaks selected from the group of peaks at 53.3 ppm, 39.8 ppm, 169.1 ppm and 40.8 ppm, each of which is ± 0.2 ppm; and one to two powder X-ray diffraction peaks (Cu Kα radiation) selected from the group of peaks at 11.6 and 14.6° 2θ, each of which is ± 0.2° 2θ.