EA044681B1 - POLYMORPHS AND CO-CRYSTALS OF CARDIOTROPONIN ACTIVATOR - Google Patents

Description

State of the art

Compound (1R,3R,5R)-N-((R)-cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-(5(methylsulfonyl)nicotinoyl)-2-azabicyclo[3.1. 0]hexane-3-carboxamide is applicable as an activator of cardiotroponin:

There is a need for various new salt and crystalline forms of Compound A with varying chemical and physical stability, as well as formulations and routes for their use.

Brief description of the invention

Provided herein are crystalline forms of Compound A or a salt thereof, including free base crystalline forms, crystalline salts, and crystalline solvates. In some embodiments, provided herein is an anhydrous crystalline Form I of the free base of Compound A. In some embodiments, provided herein is an anhydrous crystalline Form II of the free base of Compound A. In some embodiments, provided herein is a crystalline Form III of the free base of Compound A In some embodiments, provided herein is an anhydrous crystalline form of the free base of Compound A. In some embodiments, provided herein is a crystalline form of the hydrochloride salt of Compound A. In some embodiments, provided herein is a crystalline form of Compound A and dichloromethane. In some embodiments, a crystalline form of Compound A and nitromethane is provided herein. In some embodiments, provided herein is a crystalline form of Compound A and hexafluoro-2-propanol.

Also provided herein are cocrystals containing Compound A and a coformer. In some embodiments, the coformer is propyl gallate. In some embodiments, the coformer is glycerol. In some embodiments, the coformer is propylene glycol. In some embodiments, the coformer is maltol. In some embodiments, the coformer is urea.

Additionally provided are pharmaceutical compositions containing a crystalline form or cocrystal of Compound A or a salt thereof, as disclosed herein, and a pharmaceutically acceptable carrier.

Also provided are methods of treating heart failure in a subject in need thereof, comprising administering to the subject a crystalline form or co-crystal of Compound A or a salt thereof disclosed herein in an amount effective to treat the heart failure.

Brief description of graphic materials

In fig. 1 is an X-ray powder diffractometry (XRPD) diagram of the anhydrous crystalline form I of the free base.

In fig. 2 shows a differential scanning calorimetry (DSC) thermogram of the anhydrous crystalline Form I and Form II free base.

In fig. 3 depicts a thermogravimetric analysis (TGA) curve of the anhydrous crystalline Form I free base.

In fig. 4 is a dynamic vapor sorption (DVS) plot of anhydrous crystalline form I of the free base.

In fig. Figure 5 depicts the XRPD pattern of the anhydrous crystalline form II of the free base.

In fig. 6 is an XRPD diagram of crystalline form III of the free base monohydrate.

In fig. 7 shows a DSC thermogram of crystalline form III of the free base monohydrate.

In fig. 8 shows the TGA curve of crystalline form III of the free base monohydrate.

In fig. 9 is a DVS plot of the crystalline form III of the free base monohydrate.

In fig. 10 depicts the XRPD pattern of the anhydrous crystalline form IV of the free base.

In fig. 11 is a DSC thermogram of the anhydrous crystalline form IV of the free base.

In fig. 12 depicts the TGA curve of the anhydrous crystalline form IV of the free base.

In fig. 13 is a DVS plot of the anhydrous crystalline form IV of the free base.

In fig. Figure 14 shows an overlay of the XRPD pattern of free base forms I (top), II (top middle), III (bottom middle), and IV (bottom).

In fig. 15 shows a general representation of the thermodynamic relationships between free base forms I, II, III and IV.

- 1 044681

In fig. 16 is an XRPD diagram of the crystalline form of the hydrochloride salt.

In fig. 17 shows a DSC thermogram of a crystalline form of hydrochloride salt.

In fig. 18 shows the TGA curve of the crystalline form of the hydrochloride salt.

In fig. 19 is a DVS plot of the crystalline form of the hydrochloride salt.

In fig. 20 shows the XRPD pattern of the crystalline form of Compound A and dichloromethane.

In fig. 21 shows a DSC thermogram of the crystalline form of Compound A and dichloromethane.

In fig. 22 is a TGA curve of the crystalline form of Compound A and dichloromethane.

In fig. 23 shows the XRPD pattern of the crystalline form of Compound A and nitromethane.

In fig. 24 shows a DSC thermogram of the crystalline form of Compound A and nitromethane.

In fig. 25 shows a TGA curve of the crystalline form of Compound A and nitromethane.

In fig. 26 shows the XRPD pattern of the crystalline form of Compound A and hexafluoro-2propanol.

In fig. 27 shows a DSC thermogram of the crystalline form of Compound A and hexafluoro-2propanol.

In fig. 28 is a TGA curve of the crystalline form of Compound A and hexafluoro-2propanol.

In fig. 29 shows the XRPD pattern of a cocrystal of Compound A and propyl gallate.

In fig. 30 shows a DSC thermogram of a cocrystal of Compound A and propyl gallate.

In fig. 31 shows the TGA curve of a cocrystal of Compound A and propyl gallate.

In fig. 32 shows the XRPD pattern of a cocrystal of Compound A and glycerol.

In fig. 33 shows a DSC thermogram of a cocrystal of compound A and glycerol.

In fig. 34 shows the TGA curve of a cocrystal of Compound A and glycerol.

In fig. 35 shows the XRPD pattern of a cocrystal of Compound A and propylene glycol.

In fig. 36 shows a DSC thermogram of a cocrystal of Compound A and propylene glycol.

In fig. 37 shows the TGA curve of a cocrystal of Compound A and propylene glycol.

In fig. 38 shows the XRPD pattern of a cocrystal of compound A and maltol.

In fig. 39 shows a DSC thermogram of a cocrystal of compound A and maltol.

In fig. 40 shows the TGA curve of a cocrystal of Compound A and maltol.

In fig. 41 shows the XRPD pattern of a cocrystal of Compound A and urea.

In fig. 42 shows a DSC thermogram of a cocrystal of Compound A and urea.

In fig. 43 shows the TGA curve of a cocrystal of Compound A and urea.

In fig. Figure 44 shows the XRPD pattern of the amorphous form of compound A.

In fig. 45 shows the TGA curve of the amorphous form of Compound A.

Detailed description of the invention

The present invention provides polymorphs and cocrystals of (1R,3R,5R)-N-((R)cyclopropyl(2,5-difluoro-4-(trifluoromethyl)phenyl)methyl)-2-(5-(methylsulfonyl)nicotinoyl)- 2azabicyclo[3.1.0]hexane-3-carboxamide, referred to herein as compound A and having the structure:

Embodiments of the free base forms, salt forms, solvates, cocrystals, and amorphous forms of Compound A can be characterized by one or more parameters, described in more detail below.

Crystalline forms of the free base of compound A.

Provided herein are crystalline forms of the free base of Compound A. In embodiments, the crystalline forms of the free base of Compound A may be non-ionic forms of Compound A. In embodiments, the crystalline forms of the free base of Compound A may be anhydrous. In embodiments, the free base crystalline forms of Compound A may be a monohydrate.

Anhydrous crystalline form of free base I.

The anhydrous crystalline Form I of the free base of Compound A (Form I) can be characterized by the X-ray powder diffraction pattern obtained as indicated in the Examples with peaks at approximately 9.78, 12.45, 15.70, 16.46 and 16.94 ± 0.2° 2-theta using Cu Ka radiation. Form I may optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at approximately 8.23, 24.40, 25.03, 25.49 and 32.03 ± 0.2° 2-theta using Cu Ka radiation . Form I may optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at approximately 19.56, 20.11, 22.99, 23.97, 29.53, 41.91 and 42.83

- 2 044681 ± 0.2° 2-theta using Cu Ka radiation. Form I may optionally be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 1. 1 given in the examples. In some embodiments, Form I has an X-ray powder diffraction pattern substantially as depicted in FIG. 1, whereby it is essentially meant that said peaks may vary by approximately ±0.2°. It is well known in the XRPD field that while the relative heights of peaks in spectra depend on a number of factors, such as sample preparation and instrument geometry, peak positions are relatively insensitive to experimental details.

Differential scanning calorimetry (DSC) thermograms were obtained as indicated in the examples for Form I. The DSC curve indicates an endothermic transition at approximately 152 ± 3°C. Thus, in some embodiments, Form I may be characterized by a DSC thermograph having a solid-solid transition endotherm with an onset ranging from about 147 to about 157°C. For example, in some embodiments, Form I is characterized by DSC, as depicted in FIG. 2. Form I can also be characterized using thermogravimetric analysis (TGA). Thus, Form I can be characterized by a weight loss ranging from about 0% to about 1% with an initial temperature ranging from about 145 to about 150°C. For example, Form I may be characterized by a weight loss of approximately 0.6% up to approximately 200°C. In some embodiments, Form I has thermogravimetric analysis results substantially as depicted in FIG. 3, which essentially means that the specified TGA characteristics can vary by approximately ± 5°C. In embodiments, Form I has dynamic vapor sorption (DVS), essentially as depicted in FIG. 4.

Anhydrous crystalline form of free base II.

The anhydrous crystalline Form II of the free base of Compound A (Form II) can be characterized by the X-ray powder diffraction pattern obtained as indicated in the Examples with peaks at approximately 7.67, 11.54, 18.27 and 23.28 ± 0.2° 2-theta using Cu Ka radiation. Form II may optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at approximately 15.36, 16.33, 18.58, 21.38, 23.59, 24.61, 27.09, 43.40 and 44 .26 ± 0.2° 2-theta using Cu Ka radiation. Form II may optionally be further characterized by an X-ray powder diffractometry pattern having additional peaks at approximately 18.01, 25.17, 38.15 and 39.26 ± 0.2° 2 theta using Cu Ka radiation. Form II may optionally be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 1. 2 given in the examples. In some embodiments, Form II has an X-ray powder diffraction pattern substantially as depicted in FIG. 5, whereby it is essentially meant that said peaks may vary by approximately ±0.2°. It is well known in the XRPD field that while the relative heights of peaks in spectra depend on a number of factors, such as sample preparation and instrument geometry, peak positions are relatively insensitive to experimental details.

Differential scanning calorimetry (DSC) thermograms were obtained as indicated in the examples for Form II. The DSC curve indicates an endothermic transition at approximately 181 ± 3°C. Thus, in some embodiments, Form II may be characterized by a DSC thermograph having a melting endotherm with an onset in the range of about 175 to about 185°C. For example, in some embodiments, Form II is characterized by DSC, as depicted in FIG. 2. A mixture of Form I and Form II is present in the DSC shown in FIG. 2.

Crystalline form III of the free base monohydrate.

Crystalline Form III of the free base monohydrate of Compound A (Form III) can be characterized by the X-ray powder diffraction pattern obtained as indicated in the Examples, having peaks at approximately 7.31, 10.77 and 13.96 ± 0.2° 2-theta using Cu Ka radiation. Form III may optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at approximately 16.60, 18.56, 18.84, 19.41, 20.57, 21.61, 21.92, 22.28, 23 .34, 24.23, 24.70, 25.69 and 28.87 ± 0.2° 2-theta using Cu Ka radiation. Form III may optionally be further characterized by an X-ray powder diffractometry pattern having additional peaks at approximately 7.94, 20.10, 23.88 and 28.38 ± 0.2° 2-theta using Cu Ka radiation. Form III may optionally be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 1. 3 given in the examples. In some embodiments, Form III has an X-ray powder diffraction pattern substantially as depicted in FIG. 6, whereby it is essentially meant that said peaks may vary by approximately ±0.2°.

Differential scanning calorimetry (DSC) thermograms were obtained as indicated in the examples for Form III. The DSC curve indicates an endothermic transition at approximately 132 ± 3°C. Thus, in some embodiments, Form III may be characterized by a DSC thermograph having a melting endotherm with an onset in the range of about 127 to about 137°C. For example, in some embodiments, Form III is characterized by DSC, as depicted in FIG. 7. Form III can also be characterized using thermogravimetric analysis (TGA). Thus, Form III would be characterized by a weight loss ranging from about 2.5% to about 3.2% with an initial temperature ranging from about 25°C to about 35°C. For example, Form III is characterized by a weight loss of approximately 2.8% up to approximately 200°C. In some embodiments, Form III has thermogravimetric analysis results substantially as depicted in FIG. 8, which essentially means that the specified TGA characteristics can vary by approximately ± 5°C. In embodiments, Form III has dynamic vapor sorption (DVS), essentially as depicted in FIG. 9.

Anhydrous crystalline form of free base IV.

The anhydrous crystalline Form IV of the free base of Compound A (Form IV) can be characterized by the X-ray powder diffraction pattern obtained as indicated in the Examples, having peaks at approximately 8.06, 11.29 and 14.97 ± 0.2° 2-theta using Cu Ka radiation. Form IV may optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at approximately 17.19, 17.63, 18.39, 18.95, 19.17, 20.50, 24.87, 26.03, 26 .62, 27.99 and 29.25 ± 0.2° 2-theta using Cu Ka radiation. Form IV may optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at approximately 12.08, 20.17, 22.37, 22.86, 25.69, 28.26 and 28.73 ± 0.2°2 -theta using Cu Ka radiation. Form IV may optionally be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 1. 4 given in the examples. In some embodiments, Form IV has an X-ray powder diffraction pattern substantially as depicted in FIG. 10, whereby it is essentially meant that said peaks may vary by approximately ±0.2°.

Differential scanning calorimetry (DSC) thermograms were obtained as indicated in the examples for Form IV. The DSC curve indicates an endothermic transition at approximately 167 ± 3°C. Thus, in some embodiments, Form IV may be characterized by a DSC thermograph having a melting endotherm with an onset in the range of about 160 to about 175°C. For example, in some embodiments, Form IV is characterized by DSC, as depicted in FIG. 11. Form IV can also be characterized using thermogravimetric analysis (TGA). Thus, Form IV will be characterized by a weight loss ranging from about 0 to about 0.5% with an initial temperature ranging from about 25 to about 35°C. For example, Form IV would be characterized by a weight loss of approximately 0% up to approximately 200°C. In some embodiments, Form IV has thermogravimetric analysis results substantially as depicted in FIG. 12, which essentially means that the specified TGA characteristics can vary by approximately ± 5°C. In embodiments, Form IV has dynamic vapor sorption (DVS), essentially as depicted in FIG. 13.

An overview of the individual XRPD peaks in crystalline forms I-IV of the free base can be found in Table 1. 5, and an overlay of four different crystal forms is depicted in FIG. 14. A depiction of the thermodynamic relationship between crystalline forms I-IV of the free base is depicted in FIG. 15.

Salts of compound A.

Crystalline hydrochloride salt.

The crystalline form of the hydrochloride salt of compound A (hydrochloride salt) can be characterized by the X-ray powder diffraction pattern obtained as indicated in the examples with peaks of approximately 8.45, 16.93, 23.74, 24.59 and 26.57 ± 0. 2° 2-theta using Cu Ka radiation. The hydrochloride salt may optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at approximately 17.33, 17.76, 18.75, 19.51, 19.81, 20.53, 21.36, 22.95, 25 .28, 25.89, 26.94, 27.44 and 29.41 ± 0.2° 2-theta using Cu Ka radiation. The hydrochloride salt may optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at approximately 8.74, 16.08, 19.81 and 28.58 ± 0.2° 2-theta using Cu Ka radiation. The hydrochloride salt may optionally be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 1. 6 given in the examples. In some embodiments, the hydrochloride salt has an X-ray powder diffractometry pattern substantially as depicted in FIG. 16, whereby it is essentially meant that said peaks may vary by approximately ±0.2°.

Differential scanning calorimetry (DSC) thermograms were obtained as indicated in the examples for the hydrochloride salt. The DSC curve indicates an endothermic transition at approximately 134 ± 3°C. Thus, in some embodiments, the hydrochloride salt

- 4 044681 can be characterized by a DSC thermograph having a decomposition endotherm with an onset in the range of about 125°C to about 140°C. For example, in some embodiments, the hydrochloride salt is characterized by DSC, as depicted in FIG. 17.

The hydrochloride salt can also be characterized using thermogravimetric analysis (TGA). Thus, the hydrochloride salt may have a mass loss ranging from about 6.5 to about 8.5% with an initial temperature ranging from about 25 to about 35°C. For example, the hydrochloride salt may exhibit a mass loss of approximately 7.5% up to approximately 200°C. In some embodiments, the hydrochloride salt has thermogravimetric analysis results substantially as depicted in FIG. 18, which essentially means that the specified TGA characteristics can vary by approximately ± 5°C. In embodiments, the hydrochloride salt has dynamic vapor sorption (DVS), essentially as depicted in FIG. 19.

Solvates of compound A.

Dichloromethane solvate.

The crystalline form of compound A and dichloromethane (dichloromethane solvate) can be characterized by the X-ray powder diffraction pattern obtained as indicated in the examples with peaks at approximately 11.46, 16.91, 23.10 and 24.58 ± 0.2° 2- theta using Cu Ka radiation. The dichloromethane solvate may optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at approximately 8.25, 16.26, 18.82, 19.50, 19.90, 20.52, 20.79, 21.58, 23 .92 and 29.35 ± 0.2° 2-theta using Cu Ka radiation. The dichloromethane solvate may optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at approximately 6.76, 25.18, 26.20, 26.95, 27.18, 27.62 and 28.26 ± 0.2°2 -theta using Cu Ka radiation. The dichloromethane solvate may optionally be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 1. 7 given in the examples. In some embodiments, the dichloromethane solvate has an X-ray powder diffraction pattern substantially as depicted in FIG. 20, whereby it is essentially meant that said peaks may vary by approximately ±0.2°.

Differential scanning calorimetry (DSC) thermograms were obtained as indicated in the examples for dichloromethane solvate. The DSC curve indicates an endothermic transition at approximately 76°C ± 3°C. Thus, in some embodiments, the dichloromethane solvate may be characterized by a DSC thermograph having a desalting endotherm with an onset in the range of about 70 to about 80°C. For example, in some embodiments, the dichloromethane solvate is characterized by DSC, as depicted in FIG. 21. Dichloromethane solvate can also be characterized using thermogravimetric analysis (TGA). Thus, the dichloromethane solvate may exhibit a mass loss ranging from about 10% to about 12% with an initial temperature ranging from about 65 to about 85°C. For example, dichloromethane solvate may exhibit a mass loss of approximately 10.9% up to approximately 200°C. In some embodiments, the dichloromethane solvate has thermogravimetric analysis results substantially as depicted in FIG. 22, which essentially means that the specified TGA characteristics can vary by approximately ± 5°C.

Nitromethane solvate.

The crystalline form of Compound A and nitromethane (nitromethane solvate) can be characterized by the X-ray powder diffraction pattern obtained as indicated in the Examples with peaks at approximately 8.94, 15.86, 17.12, 19.51, 19.83 and 24. 41 ± 0.2° 2-theta using Cu Ka radiation. The nitromethane solvate may optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at approximately 10.18, 18.16, 20.54, 21.93, 23.06, 23.92 and 25.37 ± 0.2°2 -theta using Cu Ka radiation. The nitromethane solvate may optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at approximately 19.01, 22.68, 26.61 and 28.32 ± 0.2° 2-theta using Cu Ka radiation. The nitromethane solvate may optionally be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 1. 8 given in the examples. In some embodiments, the nitromethane solvate has an X-ray powder diffraction pattern substantially as depicted in FIG. 23, whereby it is essentially meant that said peaks may vary by approximately ±0.2°.

Differential scanning calorimetry (DSC) thermograms were obtained as indicated in the examples for nitromethane solvate. The DSC curve indicates an endothermic transition at approximately 89 ± 3°C. Thus, in some embodiments, the nitromethane solvate may be characterized by a DSC thermograph having a desalting endotherm with an onset ranging from about 81°C to about 97°C. For example, in some embodiments, the solvate

- 5 044681 nitromethane is characterized by DSC, as shown in FIG. 24. Nitromethane solvate can also be characterized using thermogravimetric analysis (TGA). Thus, the nitromethane solvate may have a mass loss ranging from about 6% to about 7% with an initial temperature ranging from about 60 to about 80°C. For example, nitromethane solvate may exhibit a mass loss of approximately 6.5% up to approximately 200°C. In some embodiments, the nitromethane solvate has thermogravimetric analysis results substantially as depicted in FIG. 25, which essentially means that the specified TGA characteristics can vary by approximately ± 5°C.

Hexafluoro-2-propanol solvate.

The crystalline form of Compound A and hexafluoro-2-propanol (hexafluoro-2-propanol solvate) can be characterized by the X-ray powder diffraction pattern obtained as indicated in the Examples with peaks at approximately 16,17, 16,70, 18,20 and 23. 03 ± 0.2° 2-theta using Cu Ka radiation. The hexafluoro-2-propanol solvate may optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at approximately 9.49, 11.20, 20.18, 21.39, 23.74, 25.46, 27.00, 29 .24 and 33.76 ± 0.2° 2-theta using Cu Ka radiation. The hexafluoro-2-propanol solvate may optionally be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 1. 9 given in the examples. In some embodiments, the hexafluoro-2-propanol solvate has an X-ray powder diffraction pattern substantially as depicted in FIG. 26, whereby it is essentially meant that said peaks may vary by approximately ±0.2°.

Differential scanning calorimetry (DSC) thermograms were obtained as indicated in the examples for hexafluoro-2-propanol solvate. The DSC curve indicates an endothermic transition at approximately 90 ± 3°C. Thus, in some embodiments, the hexafluoro-2propanol solvate may be characterized by a DSC thermograph having a decomposition endotherm with an onset in the range of about 85 to about 95°C. For example, in some embodiments, the hexafluoro-2-propanol solvate is characterized by DSC, as depicted in FIG. 27.

Hexafluoro-2-propanol solvate can also be characterized using thermogravimetric analysis (TGA). Thus, the hexafluoro-2-propanol solvate may exhibit a weight loss ranging from about 9.4 to about 10.4% with an initial temperature ranging from about 75 to about 85°C. For example, hexafluoro-2-propanol solvate may exhibit a weight loss of approximately 9.9% up to approximately 200°C. In some embodiments, the hexafluoro-2-propanol solvate has thermogravimetric analysis results substantially as depicted in FIG. 28, which essentially means that the specified TGA characteristics can vary by approximately ± 5°C.

Cocrystals of compound A.

Cocrystals with different coformers are presented herein. The cocrystals contain compound A hydrogen bonded to the coformer. In embodiments, the cocrystal may comprise Compound A and the coformer in a molar ratio of 10:1 to 1:10 or 5:1 to 1:5. For example, the cocrystal may contain Compound A and the coformer in a molar ratio of about 2:1, about 1:1, about 1:1.5, about 1:2, about 1:2.5, about 1:3, about 1:3 ,5, approximately 1:4 or approximately 1:5.

In embodiments, the coformer may be benzoic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, glutaric acid, adipic acid, pimelic acid, 3,5-dihydroxybenzoic acid, trifluoroacetic acid, 2,5-dihydroxybenzoic acid , 2,4-dihydroxybenzoic acid, m-nitrobenzoic acid, 5-chlorosalicylic acid, saccharin, citric acid, tartaric acid, 2,3-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid, barbital, 4-hydroxybenzoic acid, 1-hydroxy-2 -naphthoic acid, malic acid, 3-hydroxybenzoic acid, 6-hydroxy2-naphthoic acid, methyl gallate, salicylic acid, 2-hydroxybenzoic acid, formic acid, 3-hydroxy-2-naphthoic acid, sulfacetamide, acetic acid, sulfaproxilin, sulfuric acid , sulfamic acid, ethylenediamine, octadecylamine, glucono-delta-lactone, allisotic acid, sucralose, indole, 1-hydroxyethylden-1,1-diphosphonic acid, skatole, 5-chlorosalicylic acid, urea, 5-nitroisophthalic acid, trimesic acid, gentisic acid, ketoglutaric acid, adamantinetricarboxylic acid, tert-butylhydroquinone, isocitric acid, trifluoroethanol, camphoric acid, 4-aminobenzoic acid, 2,6pyridinedicarboxylic acid, aspirin, butyric acid, formamide, nicotinamide, nitromethane, 1,4benzoquinone, glycolic acid, tereft alanoldehyde, dioxane, N-methylpyrrolidone, dimethyl sulfoxide, dimethylacetamide, acetone, dimethylformamide, furfural, 4,4'-bipyridine or a mixture thereof. In embodiments, the coformer may contain propyl gallate, glycerol, propylene glycol, maltol, urea, or a mixture thereof. In embodiments, the cocrystals may further comprise a cocrystallization solvent. The cocrystallization solvent is a solvent from which

- 6 044681 cocrystallization of the cocrystal occurs. The co-crystallization solvent may include an organic solvent used in the crystallization. Such organic solvents are known to those skilled in the art. In embodiments, the cocrystallization solvent may be ethyl acetate or acetone.

Propyl gallate cocrystal.

A cocrystal of compound A and propyl gallate is proposed herein. The cocrystal of compound A and propyl gallate (propyl gallate cocrystal) can be characterized by the X-ray powder diffraction pattern obtained as indicated in the examples with peaks of approximately 8.66, 15.00, 17.72, 18.82 and 20.32 ± 0.2 ° 2-theta using Cu Ka radiation. The propyl gallate cocrystal may optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at approximately 9.21, 19.36, 20.49 and 22.57 ± 0.2° 2theta using Cu Ka radiation. The propyl gallate cocrystal may optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at approximately 3.05, 11.24, 18.32, 21.73, 22.98, 23.39, 25.01, 25.51, 26 .30, 26.52 and 28.31 ± 0.2° 2-theta using Cu Ka radiation. The propyl gallate cocrystal may optionally be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 1. 10 given in the examples. In some embodiments, the propyl gallate cocrystal has an X-ray powder diffraction pattern substantially as depicted in FIG. 29, whereby it is essentially meant that said peaks may vary by approximately ±0.2°.

Differential scanning calorimetry (DSC) thermograms were obtained as indicated in the examples for the propyl gallate cocrystal. The DSC curve indicates an endothermic transition at approximately 121 ± 3°C. Thus, in some embodiments, the propyl gallate cocrystal may be characterized by a DSC thermograph having a melting endotherm with an onset in the range of about 116 to about 126°C. For example, in some embodiments, the propyl gallate cocrystal is characterized by DSC, as depicted in FIG. thirty.

The propyl gallate cocrystal can also be characterized using thermogravimetric analysis (TGA). Thus, the propyl gallate cocrystal can be characterized by a mass loss ranging from about 25 to about 35% with an initial temperature ranging from about 190 to about 210°C. For example, a propyl gallate cocrystal may exhibit a mass loss of approximately 29.9% up to approximately 260°C. In some embodiments, the propyl gallate cocrystal has thermogravimetric analysis results substantially as depicted in FIG. 31, which essentially means that the specified TGA characteristics can vary by approximately ± 5°C.

Glycerol cocrystal.

This document proposes a cocrystal of compound A and glycerol. A cocrystal of Compound A and glycerol (glycerol cocrystal) can be characterized by the X-ray powder diffraction pattern obtained as indicated in the Examples with peaks at approximately 16.84, 18.48, 19.40 and 21.49 ± 0.2° 2-theta using Cu Ka radiation. The glycerol cocrystal may optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at approximately 9.70, 15.60, 16.39, 18.95, 22.51, 24.53 and 24.92 ± 0.2°2 -theta using Cu Ka radiation. The glycerol cocrystal may optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at approximately 8.17, 12.38, 22.87 and 27.61 ± 0.2° 2-theta using Cu Ka radiation. The glycerol cocrystal may optionally be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 1. 11 given in the examples. In some embodiments, the glycerol cocrystal has an X-ray powder diffraction pattern substantially as depicted in FIG. 32, whereby it is essentially meant that said peaks may vary by approximately ±0.2°.

Differential scanning calorimetry (DSC) thermograms were obtained as indicated in the examples for the glycerol cocrystal. The DSC curve indicates an endothermic transition at approximately 148 ± 3°C and 156 ± 3°C. Thus, in some embodiments, the glycerol cocrystal may be characterized by a DSC thermograph having a decomposition endotherm with an onset ranging from about 140 to about 151°C and from about 152 to 165°C. For example, in some embodiments, the glycerol cocrystal is characterized by DSC, as depicted in FIG. 33.

The glycerol cocrystal can also be characterized using thermogravimetric analysis (TGA). Thus, the glycerol cocrystal may have a mass loss ranging from about 20 to about 35% with an initial temperature ranging from about 25 to about 35°C. For example, a glycerol cocrystal can be characterized

- 7 044681 mass loss of approximately 30.5% up to approximately 250°C. In some embodiments, the glycerol cocrystal has thermogravimetric analysis results substantially as depicted in FIG. 34, which essentially means that the specified TGA characteristics can vary by approximately ± 5°C.

Propylene glycol cocrystal.

This document proposes a cocrystal of compound A and propylene glycol. A cocrystal of compound A and propylene glycol (propylene glycol cocrystal) can be characterized by the X-ray powder diffraction pattern obtained as indicated in the examples with peaks of approximately 16.82, 18.26, 18.93, 19.37 and 21.52 ± 0.2 ° 2-theta using Cu Ka radiation. The propylene glycol cocrystal may optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at approximately 7.87, 15.61, 16.36, 18.39, 20.39, 21.12, 22.47, and 24.46 ± 0 ,2° 2-theta using Cu Ka radiation. The propylene glycol cocrystal may optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at approximately 9.69, 20.02, 21.83, 22.85, 23.84, 25.05 and 27.07 ± 0.2°2 -theta using Cu Ka radiation. The propylene glycol cocrystal may optionally be characterized by an X-ray powder diffraction pattern having the peaks presented in Table 1. 12 given in the examples. In some embodiments, the propylene glycol cocrystal has an X-ray powder diffraction pattern substantially as depicted in FIG. 35, whereby it is essentially meant that said peaks may vary by approximately ±0.2°.

Differential scanning calorimetry (DSC) thermograms were obtained as indicated in the examples for the propylene glycol cocrystal. The DSC curve indicates a broad endothermic transition from approximately 89 ± 3°C to 124 ± 3°C. Thus, in some embodiments, the propylene glycol cocrystal may be characterized by a DSC thermograph having a decomposition endotherm with an onset in the range of about 80 to about 135°C. For example, in some embodiments, the propylene glycol cocrystal is characterized by DSC, as depicted in FIG. 36.

The propylene glycol cocrystal can also be characterized using thermogravimetric analysis (TGA). Thus, the propylene glycol cocrystal may have a mass loss ranging from about 5.5% to about 8% with an initial temperature ranging from about 30 to about 50°C. For example, a propylene glycol propyl gallate cocrystal may exhibit a mass loss of approximately 7.3% up to approximately 200°C. In some embodiments, the propylene glycol cocrystal has thermogravimetric analysis results substantially as depicted in FIG. 37, which essentially means that the specified TGA characteristics can vary by approximately ± 5°C.

Maltol cocrystal.

This document proposes a cocrystal of compound A and maltol. A cocrystal of compound A and maltol (maltol cocrystal) can be characterized by the X-ray powder diffraction pattern obtained as indicated in the examples with peaks at approximately 16.85, 18.18, 19.53 and 23.54 ± 0.2° 2-theta using Cu Ka radiation. The maltol cocrystal may optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at approximately 6.58, 8.86, 13.68, 14.60, 15.25, 21.52, 25.26 and 26.63 ± 0 ,2° 2-theta using Cu Ka radiation. The maltol cocrystal may optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at approximately 4.44, 7.98 and 13.13 ± 0.2° 2-theta using Cu Ka radiation. The maltol cocrystal may optionally be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 1. 13 given in the examples. In some embodiments, the maltol cocrystal has an X-ray powder diffraction pattern substantially as depicted in FIG. 38, whereby it is essentially meant that said peaks may vary by approximately ±0.2°.

Differential scanning calorimetry (DSC) thermograms were obtained as indicated in the examples for the maltol cocrystal. The DSC curve indicates a broad endothermic transition at approximately 130 ± 3°C. Thus, in some embodiments, a maltol cocrystal may be characterized by a DSC thermograph having a decomposition endotherm with an onset in the range of about 125 to about 135°C. For example, in some embodiments, the maltol cocrystal is characterized by DSC, as depicted in FIG. 39. Maltol cocrystal can also be characterized by thermogravimetric analysis (TGA). Thus, the maltol cocrystal may exhibit a mass loss ranging from about 1% to about 2.5% with an initial temperature ranging from about 60 to about 80°C. For example, a maltol cocrystal may exhibit a mass loss of approximately 1.5% up to approximately 200°C. In some embodiments, the maltol cocrystal has the results

- 8 044681 thermogravimetric analysis, essentially as shown in FIG. 40, which essentially means that the specified TGA characteristics can vary by approximately ± 5°C.

Urea cocrystal.

Herein, a cocrystal of Compound A and urea is proposed. A cocrystal of Compound A and urea (urea cocrystal) can be characterized by the X-ray powder diffraction pattern obtained as indicated in the Examples, with peaks at approximately 3.99, 11.24, 17.62, and 18.37 ± 0.2° 2-theta using Cu Κα radiation. The urea cocrystal may optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at approximately 8.θ1, 8.39, 14.96, 17.47, 18.94, 19.13, 20.51, 24.65, 24 .86, 25.70, 25.97 and 26.62 ± 0.2° 2-theta using Cu Κα radiation. The urea cocrystal may optionally be further characterized by an X-ray powder diffraction pattern having additional peaks at approximately 15.21, 16.93, 17.16, 22.37, 26.35, 28.01, 28.26, 28.77 and 29 .25 ± 0.2° 2-theta using Cu Kα radiation. The urea cocrystal may optionally be characterized by an X-ray powder diffraction pattern having the peaks shown in Table 1. 14 given in the examples. In some embodiments, the urea cocrystal has an X-ray powder diffraction pattern substantially as depicted in FIG. 41, whereby it is essentially meant that said peaks may vary by approximately ±0.2°.

Differential scanning calorimetry (DSC) thermograms were obtained as indicated in the examples for urea. The DSC curve indicates a broad endothermic transition at approximately 167 ± 3°C and 174 ± 3°C. Thus, in some embodiments, the urea cocrystal may be characterized by a DSC thermograph having a decomposition endotherm with an onset in the range of about 160 to about 170°C and from about 171°C to about 180°C. For example, in some embodiments, the urea cocrystal is characterized by DSC, as depicted in FIG. 42. The urea cocrystal can also be characterized by thermogravimetric analysis (TGA). Thus, the urea cocrystal can be characterized by a mass loss ranging from about 9.6% to about 11.6% with an initial temperature ranging from about 145 to about 165°C. For example, a urea cocrystal may exhibit a mass loss of approximately 10.6% up to approximately 225°C. In some embodiments, the urea cocrystal has thermogravimetric analysis results substantially as depicted in FIG. 43, which essentially means that the specified TGA characteristics can vary by approximately ± 5°C.

Amorphous form.

Provided herein is an amorphous form of Compound A. In some embodiments, the amorphous form of Compound A has an X-ray powder diffraction pattern substantially as depicted in FIG. 44, whereby it is essentially meant that said peaks may vary by approximately ±0.2°.

The amorphous form of compound A can also be characterized using thermogravimetric analysis (TGA). Thus, the amorphous form of Compound A may exhibit a weight loss ranging from about 2% to about 4% with an onset temperature ranging from about 25 to about 55°C. For example, the amorphous form of Compound A may exhibit a weight loss of approximately 2.9% up to approximately 150°C. In some embodiments, the amorphous form has thermogravimetric analysis results substantially as depicted in FIG. 45, which essentially means that the specified TGA characteristics can vary by approximately ± 5°C.

Pharmaceutical compositions

Also provided herein are pharmaceutical compositions containing a crystalline form and/or cocrystal of Compound A or a salt thereof described herein; and a pharmaceutically acceptable carrier. In embodiments, the carrier may contain filler.

The phrase pharmaceutically acceptable is used herein to designate those ligands, materials, compositions and/or dosage forms that, within the bounds of sound medical judgment, are suitable for use in contact with tissues of humans and animals without undue toxicity, irritation, allergic reaction or other problems. or complications commensurate with a reasonable benefit/risk ratio. The compositions described herein can be formulated for any form of administration. In various cases, the composition is intended for oral administration. In various cases, the composition is in the form of tablets.

The phrase pharmaceutically acceptable carrier as used herein means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid excipient, diluent, excipient, solvent or encapsulating material. As used herein, the phrase pharmaceutically acceptable carrier includes buffers, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents.

- 9 044681 cyclic agents, isotonic agents and absorption retarding agents, etc., compatible with pharmaceutical administration. Each carrier must be acceptable in terms of compatibility with the other ingredients of the drug and not cause harm to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch, potato starch and substituted or unsubstituted p-cyclodextrin; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline solution; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances used in pharmaceutical formulations. In certain embodiments, the pharmaceutical compositions provided herein are pyrogen-free, i.e. do not cause a significant increase in temperature when administered to a patient.

Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavoring agents, preservatives and antioxidants may also be present in the compositions as excipients. Examples of pharmaceutically acceptable antioxidants as excipients include: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like.

The pharmaceutical composition may also contain excipients such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenolsorbic acid, etc. It may also be desirable to include tonicity adjusting agents, such as sugars and the like, in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be caused by the inclusion of absorption delaying agents such as aluminum monostearate and gelatin.

In some cases, to prolong the action of one or more compounds proposed herein, it is desirable to slow down the absorption of the compound by subcutaneous or intramuscular injection. For example, delayed absorption of a compound administered parenterally can be achieved by dissolving or suspending the compound in an oily vehicle.

The composition must be stable under the conditions of manufacture and storage and must be protected from the contaminating action of microorganisms such as bacteria and fungi. Prevention of the action of microorganisms can be achieved using various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases it will be preferable to include isotonic agents in the composition, for example, sugars, polyhydric alcohols such as mannitol, sorbitol and sodium chloride. Prolonged absorption of injectable compositions can be achieved by including an absorption delaying agent in the composition, for example, aluminum monostearate and gelatin. Sterile injection solutions can be prepared by incorporating the active compound in the required amount into an appropriate diluent with one or a combination of the ingredients listed above, if necessary, followed by sterilization by filtration. In general, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains the basic dispersion medium and other necessary ingredients listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preparation methods are freeze-drying (lyophilization), which results in the preparation of a powder of the active ingredient together with any additional active ingredient from its previously sterile-filtered solution. Injectable depot forms can be prepared by forming matrices of microcapsules or nanoencapsules of the compound proposed herein in biodegradable polymers such as polylactide-polyglycolide. Depending on the drug to polymer ratio and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations are also prepared by incorporating the drug into liposomes, microemulsions or nanoemulsions that are compatible with body tissues.

In some embodiments, the polymorphs and salts disclosed herein are

- 10 044681 are rayed with carriers that will protect the therapeutic compounds from rapid elimination from the body, for example, controlled release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid can be used. Such formulations can be prepared using standard techniques or obtained commercially, for example, from Alza Corporation and Nova Pharmaceuticals, Inc. Liposome suspensions (including liposomes targeting selected cells with monoclonal antibodies to cellular antigens) can also be used as pharmaceutically acceptable carriers. They can be prepared by methods known to those skilled in the art, for example, as described in US Pat. No. 4,522,811, which is incorporated herein by reference in its entirety. The pharmaceutical compositions may be included in a container, package or dispenser along with instructions for use.

Methods of application

Forms or co-crystals of Compound A or a salt thereof disclosed herein, or the pharmaceutical compositions described herein, can be used to treat or prevent heart failure, including, but not limited to: acute (or decompensated) congestive heart failure and chronic heart failure. failure; in particular, diseases associated with systolic dysfunction of the heart.

Also provided herein are methods of treating or preventing heart failure in a subject in need thereof, comprising administering to the subject one or more forms or co-crystals of Compound A or a salt thereof disclosed herein, or one or more pharmaceutical compositions described herein, in an amount effective to treat or prevent heart failure. In addition, methods are provided for using the disclosed forms or co-crystals of Compound A or a salt thereof or compositions thereof for the treatment or prevention of heart failure, including, but not limited to: acute (or decompensated) congestive heart failure and chronic congestive heart failure. This document also provides the use of forms or co-crystals of Compound A or a salt thereof disclosed herein, or pharmaceutical compositions described herein, in the manufacture of a medicament for the treatment or prevention of heart failure. In some embodiments, the present invention provides the use of forms or co-crystals of Compound A or a salt thereof disclosed herein, or pharmaceutical compositions described herein, in the manufacture of a medicament for the treatment of acute (or decompensated) congestive heart failure, and chronic congestive heart failure. heart failure. In some embodiments, forms or co-crystals of Compound A or a salt thereof disclosed herein are used for the treatment or prevention of heart failure with reduced ejection fraction (HFrEF) or systolic heart failure, dilated cardiomyopathy, postpartum cardiomyopathy, idiopathic cardiomyopathy, pediatric HFrEF, cardiac chemotherapy-induced failure, heart failure associated with muscular dystrophy, biventricular HFrEF, HFrEF with pulmonary hypertension, heart failure with preserved ejection fraction (HFpEF) with right ventricular dysfunction, pulmonary hypertension with right ventricular dysfunction, scleroderma with pulmonary hypertension, right ventricular dysfunction , Chagas disease or myocarditis. In some embodiments, provided herein are methods of treating or preventing heart failure with reduced ejection fraction (HFrEF) or systolic heart failure, dilated cardiomyopathy, peripartum cardiomyopathy, idiopathic cardiomyopathy, pediatric HFrEF, chemotherapy-induced heart failure, muscle-associated heart failure dystrophy, biventricular HFrEF, HFrEF with pulmonary hypertension, heart failure with preserved ejection fraction (HFpEF) with right ventricular dysfunction, pulmonary hypertension with right ventricular dysfunction, scleroderma with pulmonary hypertension, right ventricular dysfunction, Chagas disease, or myocarditis, which involves administering to a subject, to a person in need thereof, an effective amount of one or more forms or co-crystals of Compound A or a salt thereof disclosed herein. Also provided herein is the use of one or more forms or co-crystals of Compound A or a salt thereof disclosed herein in the manufacture of a medicament for the treatment or prevention of heart failure with reduced ejection fraction or systolic heart failure, dilated cardiomyopathy, peripartum cardiomyopathy, idiopathic cardiomyopathy , pediatric HFrEF, chemotherapy-induced heart failure, heart failure associated with muscular dystrophy, biventricular HFrEF, HFrEF with pulmonary hypertension, heart failure with preserved ejection fraction (HFpEF) with right ventricular dysfunction, pulmonary hypertension with right ventricular dysfunction, scleroderma with pulmonary hypertension, right ventricular dysfunction, Chagas disease or myocarditis.

In some embodiments, dilated cardiomyopathy is selected from the group with

- 11 044681 consisting of genetic dilated cardiomyopathy, perinatal cardiomyopathy (eg, postpartum cardiomyopathy), idiopathic dilated cardiomyopathy, post-infectious dilated cardiomyopathy, toxin-induced dilated cardiomyopathy and malnutrition-related dilated cardiomyopathy. In some embodiments, pediatric HFrEF occurs in pediatric patients with a univentricular or single ventricle heart, or in patients following a Fontan or Fontan-Kreutzer procedure. In some embodiments, childhood HFrEF is childhood heart failure associated with congenital heart disease. In some embodiments, chemotherapy-induced heart failure is selected from the group consisting of chemotherapy-induced left ventricular dysfunction, radiation-induced heart failure, heart failure caused by anthracycline treatment (including, but not limited to, doxorubicin, epirubicin, and daunorubicin), heart failure resulting from treatment with an anti-ERBB2 antibody (including, but not limited to, trastuzumab and lapatinib), heart failure resulting from treatment with a VEGF inhibitor (including, but not limited to, bevacizumab), and heart failure resulting from treatment with a tyrosine kinase inhibitor (including, but not limited to imatinib, dasatinib, nilotinib, sorafenib and sunitinib). In some embodiments, the muscular dystrophy-associated heart failure is selected from the group consisting of Duchenne muscular dystrophy-associated heart failure, Becker muscular dystrophy-associated heart failure, myotonic dystrophy-associated heart failure (eg, Steinert disease), heart failure associated with muscular dystrophy with laminopathies such as Emery-Dreyfus muscular dystrophy (EDMD), including both X-linked EDMD and autosomal dominant EDMD, heart failure associated with facioscapulohumeral muscular dystrophy (FSHMD), heart failure, associated with muscular dystrophy of the lumbar spine, including sarcoglycanopathies and the autosomal dominant form of the disease, as well as heart failure associated with congenital muscular dystrophy. In some embodiments, pulmonary hypertension with right ventricular dysfunction is associated with high (diastolic) left ventricular pressure in HFrEF or high (diastolic) left ventricular pressure in HFpEF.

Treating or administering a treatment includes one or more of the following: a) inhibiting the disease or disorder; b) slowing or stopping the development of clinical symptoms of a disease or disorder; and/or c) alleviation of the disease or disorder, i.e. regression of clinical symptoms. The term covers both complete and partial reduction of a condition or disorder, and complete or partial reduction of clinical symptoms of a disease or disorder. Thus, forms or co-crystals of Compound A or a salt thereof described herein, or pharmaceutical compositions described herein, can prevent the exacerbation of an existing disease or disorder, help treat a disease or disorder, or reduce or eliminate a disease or disorder. Warning, i.e. preventing the development of clinical symptoms of a disease or disorder includes prophylactic administration of a pharmaceutical composition described herein to a subject (ie, an animal, preferably a mammal, most preferably a human) believed to be in need of prophylactic treatment, such as, for example, chronic heart failure.

Example

Ways.

X-ray powder diffractometry (XRPD).

X-ray powder diffractometry (XRPD) data were obtained using a PANalytical X'Pert PRO diffractometer. Samples were scanned at ambient temperature in a continuous mode from 5-30 to 5-45 degrees (2-theta) with a step size of 0.0334 degrees at 45 kV and 40 mA with CuKa radiation (1.54 A). The incident beam path was equipped with a 0.02 rad Soller slit, a 15 mm mask, a fixed 4 degree anti-scatter slit, and a programmable divergence slit. The diffracted beam was equipped with a 0.02 rad Soller slit, a programmable anti-scattering slit, and a 0.02 mm nickel filter.

Samples were prepared on a low-background sample holder and placed on a rotating platform with a rotation time of 2 s.

Optionally, X-ray powder diffraction (XRPD) data were obtained using a PANalytical Empyrean diffractometer. Samples were scanned at ambient temperatures in a continuous mode from 2.5 to 32 degrees (2-theta) with a step size of 0.0131 degrees at 35 kV and 30 mA with CuKa radiation (1.54 A).

Differential scanning calorimetry (DSC).

Differential scanning calorimetry (DSC) analysis was performed on a TA Instruments Discovery Series calorimeter at 10 degrees C/min, from 30 to 250 degrees Celsius in a corrugated aluminum pan under a dry nitrogen atmosphere at 50 ml/min.

- 12 044681

Thermogravimetric analysis (TGA).

Thermogravimetric analysis (TGA) was performed on a TA Instruments Discovery Series analyzer at 10 degrees C/min, from ambient temperature to 250 degrees C in a platinum pan under a dry nitrogen atmosphere at 25 ml/min.

Optional thermogravimetric analysis (TGA) was performed on a TA Instruments thermogravimetric analyzer at 10°C/min from ambient to 350°C in a platinum tray under dry nitrogen at 25 ml/min.

Moisture sorption.

Moisture sorption data were collected using a dynamic vapor sorption (DVS) analyzer. A sample size of approximately 5-10 mg was used in a quartz bowl. Hygroscopicity was assessed from 0 to 95% rel. ow. in steps of 5 or 10% rel. ow. Data were collected for adsorption and desorption cycles. Equilibrium criteria were set at 0.002% mass change over 5 min with a maximum equilibration time of 120 min.

Solubility.

Water: Excess solid was added to water to form a suspension and dispersed for at least 24 hours at room temperature. The suspensions were filtered. The filtrate was analyzed by UPLC-UV and compared with a standard curve to determine the concentration of the crystalline form solution. The solids were analyzed by XRPD to determine the crystalline form.

Toluene and propanol: Excess solid was added to form a suspension and dispersed for at least 24 hours at 25, 35 and 45°C. The suspensions were filtered. The filtrate was analyzed by UPLC-UV and compared with a standard curve to determine the concentration of the crystalline form solution. The solids were analyzed by XRPD to determine the crystalline form.

Co-suspension.

Excess solid Form I, Form III and Form IV were added to water or 80% acetonitrile in water and dispersed for at least 24 hours at 25 or 50°C. The suspensions were filtered. The solids were analyzed by XRPD to determine the crystalline form.

Solid stability.

The drug substance was stored at 25°C/60% rel. h., 40°С/75% rel. h., 40°C/ambient temperature or 60°C/ambient temperature. Chemical stability was determined at each time point by dissolving the drug substance in 50% acetonitrile in water for UPLC analysis. Physical stability was determined by analyzing the solid using XRPD, DSC and TGA.

Crystalline Form I Free Base: Form I was initially prepared by precipitation from 30% hydroxypropyl-β-cyclodextrin in deionized (DI) water during formulation screening. Form I undergoes a solid-solid transition to form II at ~150-152°C. Form I is non-hygroscopic and the solubility of Form I in water is 0.013 mg/ml. Form I was physically and chemically stable for 14 weeks when stored at 25°C/60% RH. h., 40°С/75% rel. h., 40°C/ambient temperature or 60°C/ambient temperature.

The crystalline form I free base was characterized by an XRPD pattern containing the peaks presented in Table 1. 1.

- 13 044681

Table 1

Position [° FWHM [°2-theta] d-spacing [A] Height [cts] Rel. INT. [%] 8.23 0.19 10.74 2514.11 16.09 9.78 0.23 9.05 2824.50 18.07 11.99 0.19 7.38 148.65 0.95 12.45 0.23 7.11 1090.19 6.98 13.24 0.19 6.69 145.27 0.93 15.70 0.19 5.64 1696.06 10.85 16.46 0.23 5.38 9676.43 61.91 16.94 0.23 5.24 15629.64 100.00 17.73 0.19 5.00 589.01 3.77 18.49 0.16 4.80 592.88 3.79 19.29 0.13 4.60 582.51 3.73 19.56 0.16 4.54 975.13 6.24 20.11 0.23 4.41 686.92 4.39 22.12 0.26 4.02 301.03 1.93 22.99 0.19 3.87 864.08 5.53 23.97 0.19 3.71 964.78 6.17 24.40 0.16 3.65 1492.59 9.55 25.03 0.19 3.56 3022.92 19.34 25.49 0.19 3.49 1716.68 10.98 27.23 0.16 3.27 728.39 4.66 29.53 0.19 3.03 994.57 6.36 30.68 0.16 2.91 412.95 2.64 32.03 0.19 2.79 1808.66 11.57 32.71 0.19 2.74 481.52 3.08 33.21 0.19 2.70 538.94 3.45 34.07 0.39 2.63 541.55 3.46 35.25 0.23 2.55 504.85 3.23 35.72 0.23 2.51 529.35 3.39 37.78 0.52 2.38 251.86 1.61 38.99 0.19 2.31 370.56 2.37 39.68 0.26 2.27 328.25 2.10 41.43 0.26 2.18 455.68 2.92 41.91 0.23 2.16 668.58 4.28 42.83 0.19 2.11 620.66 3.97 44.18 0.32 2.05 366.30 2.34

Crystalline Form II of the free base: Form II was prepared by heating Form I to 150-152°C. The melting point of Form II is ~180-182°C (see DSC Form I). Form II reverts to form I at temperatures below 132°C.

Crystalline form II of the free base was characterized by an XRPD pattern containing the peaks presented in Table 1. 2.

- 14 044681

table 2

Position [° FWHM [°2-theta] d-spacing [Ά] Height [cts] Rel. int. [%] 6.80 0.40 13.00 70.17 0.37 7.67 0.12 11.53 1931.78 10.23 8.13 0.10 10.88 2273.22 12.04 8.31 0.08 10.64 1005.25 5.32 9.63 0.12 9.19 1849.18 9.79 10.08 0.13 8.77 178.57 0.95 11.54 0.08 7.67 377.37 2.00 12.21 0.12 7.25 1126.77 5.97 15.36 0.12 5.77 6568.02 34.78 16.03 0.10 5.53 1124.36 5.95 16.33 0.13 5.43 6328.35 33.52 16.70 0.13 5.31 18881.83 100.00 17.48 0.10 5.07 711.33 3.77 18.01 0.10 4.92 2943.21 15.59 18.27 0.15 4.86 7661.64 40.58 18.58 0.15 4.78 8159.62 43.21 18.82 0.05 4.72 2482.36 13.15 19.29 0.12 4.60 2006.87 10.63 19.51 0.12 4.55 2532.32 13.41 19.95 0.15 4.45 2239.77 11.86 20.29 0.12 4.38 2013.11 10.66 21.03 0.10 4.22 1553.42 8.23 21.38 0.17 4.16 4139.64 21.92 21.90 0.17 4.06 1859.08 9.85 22.37 0.13 3.97 2079.53 11.01 23.28 0.17 3.82 9093.31 48.16 23.59 0.15 3.77 4435.41 23.49 24.18 0.12 3.68 1838.59 9.74 24.61 0.12 3.62 5314.89 28.15 25.17 0.15 3.54 2887.39 15.29 25.55 0.13 3.49 1465.85 7.76 25.96 0.20 3.43 1654.51 8.76 26.83 0.15 3.32 3724.07 19.72 27.09 0.17 3.29 6075.01 32.17 27.40 0.08 3.26 2947.73 15.61 27.94 0.10 3.19 1834.95 9.72 29.30 0.17 3.05 2613.79 13.84 29.91 0.13 2.99 1866.59 9.89 30.60 0.17 2.92 1863.53 9.87 31.06 0.17 2.88 1707.07 9.04 31.63 0.08 2.83 2365.90 12.53 33.54 0.13 2.67 2626.06 13.91 34.56 0.13 2.60 2479.73 13.13 35.16 0.13 2.55 2087.81 11.06 35.80 0.17 2.51 2471.92 13.09 36.45 0.13 2.47 2252.74 11.93 36.94 0.13 2.43 2715.72 14.38 38.15 0.13 2.36 2892.52 15.32 39.26 0.20 2.29 3029.55 16.04 41.04 0.40 2.20 2628.09 13.92 41.80 0.20 2.16 2686.52 14.23 43.40 0.23 2.09 4923.31 26.07 44.26 0.37 2.04 6793.09 35.98

Crystalline Form III free base: Form III was prepared by precipitation from acetonitrile (100 mg/ml) with water (1:2) at 25°C during solvent solubility screening. The monohydrate is dehydrated in a vacuum at ambient temperature, at temperatures above 25 °C or at low humidity.

Crystalline form III of the free base was characterized by an XRPD pattern containing the peaks presented in Table 1. 3.

Table 3

Position [° FWHM [°2-theta] d-spacing [Ά] Height [cts] Rel. INT. [%] 7.31 0.16 12.10 813.30 14.92 7.94 0.16 11.13 883.71 16.21 8.32 0.16 10.63 723.35 13.27 10.77 0.16 8.21 3540.32 64.93 13.96 0.16 6.35 5452.58 100.00 15.12 0.13 5.86 326.55 5.99 15.87 0.16 5.59 579.15 10.62 16.60 0.19 5.34 2334.84 42.82 17.50 0.26 5.07 200.86 3.68 18.56 0.16 4.78 3195.21 58.60 18.84 0.10 4.71 2228.08 40.86 19.41 0.19 4.57 2229.23 40.88 20.10 0.13 4.42 858.07 15.74 20.57 0.23 4.32 1604.20 29.42 21.19 0.13 4.19 496.70 9.11 21.61 0.16 4.11 3107.55 56.99 21.92 0.10 4.06 1744.88 32.00 22.28 0.16 3.99 1957.62 35.90 22.74 0.13 3.91 655.06 12.01 23.34 0.19 3.81 1466.83 26.90 23.88 0.13 3.73 1001.74 18.37 24.23 0.16 3.67 2702.38 49.56 24.70 0.26 3.60 3982.07 73.03 25.69 0.36 3.47 1123.49 20.60 27.08 0.19 3.29 338.52 6.21 27.65 0.26 3.23 592.55 10.87 28.07 0.13 3.18 615.00 11.28 28.38 0.13 3.15 823.46 15.10 28.87 0.13 3.09 1770.44 32.47 29.65 0.16 3.01 503.05 9.23

Crystalline Form IV free base: Form IV was originally prepared by dehydrating Form III by passing air through the Form III solids on a filter for 30 minutes. under environmental conditions. The melting point of Form IV is -167°C. Form IV is non-hygroscopic, its solubility in water is 0.010 mg/ml. Form IV was physically and chemically stable for 13 weeks when stored at 25°C/60% RH. h., 40°С/75% rel. h., 40°C/ambient temperature or 60°C/ambient temperature.

Crystalline form IV of the free base was characterized by an XRPD pattern containing the peaks presented in Table 1. 4.

- 16 044681

Table 4

Position [° FWHM [°2-theta] d-spacing [A] Height [cts] Rel. INT. [%] 8.06 0.13 10.97 1567.47 50.56 11.29 0.13 7.84 3040.49 98.08 11.70 0.13 7.57 234.88 7.58 12.08 0.13 7.33 531.63 17.15 13.27 0.13 6.67 312.17 10.07 14.97 0.13 5.92 1660.61 53.57 16.92 0.10 5.24 421.26 13.59 17.19 0.13 5.16 1073.59 34.63 17.63 0.23 5.03 2813.16 90.75 18.39 0.13 4.82 2738.42 88.34 18.95 0.10 4.68 1472.04 47.48 19.17 0.10 4.63 1373.13 44.29 20.17 0.10 4.40 892.21 28.78 20.50 0.13 4.33 3100.01 100.00 22.37 0.13 3.97 831.98 26.84 22.86 0.13 3.89 551.57 17.79 23.88 0.16 3.73 404.57 13.05 24.87 0.13 3.58 1377.52 44.44 25.69 0.16 3.47 669.55 21.60 26.03 0.16 3.42 1045.50 33.73 26.62 0.19 3.35 1281.30 41.33 27.13 0.13 3.29 438.28 14.14 27.99 0.13 3.19 945.91 30.51 28.26 0.13 3.16 715.51 23.08 28.73 0.13 3.11 585.91 18.90 29.25 0.16 3.05 1007.67 32.51 29.74 0.16 3.00 273.29 8.82

The XRPD peaks unique to each of the free base crystalline Forms I-IV disclosed herein are presented in Table 1. 5.

Table 5

Free Peaks unique to each shape (KA1°) Form I 9.78 12.45 15.70 16.46 16.94 Form II 7.67 11.54 18.27 23.28 Form III 7.31 10.77 13.96 Form IV 8.06 11.29 14.97

Hydrochloric salt form: The hydrochloric salt form was initially prepared by precipitation from MTBE using 37 wt.% hydrochloric acid in water. Salt disproportionates to its free form when exposed to water during experiments involving moisture sorption (hygroscopicity) or suspension in water.

The hydrochloride salt form was characterized by an XRPD pattern containing the peaks presented in Table. 6.

Table 6

Position FWHM [°2-theta] d-spacing [A] Height [cts] Rel. INT. 8.45 0.23 10.46 2119.63 49.89 8.74 0.13 10.12 629.01 14.80 9.39 0.19 9.42 106.24 2.50 11.92 0.19 7.43 398.60 9.38 15.13 0.16 5.85 301.79 7.10 16.08 0.19 5.51 492.73 11.60 16.93 0.23 5.24 3630.10 85.44 17.33 0.16 5.12 1772.88 41.73

- 17 044681

17.76 0.19 4.99 | 1464.20 | 34.46 18.75 0.19 4.73 922.62 21.71 19.51 0.19 4.55 1176.47 27.69 19.81 0.10 4.48 616.64 14.51 20.53 0.23 4.33 1279.42 30.11 21.36 0.23 4.16 1297.74 30.54 22.28 0.19 3.99 271.79 6.40 22.95 0.23 3.87 1840.89 43.33 23.74 0.23 3.75 2478.58 58.33 24.59 0.39 3.62 2988.72 70.34 25.28 0.26 3.52 1009.44 23.76 25.89 0.19 3.44 1000.65 23.55 26.57 0.23 3.36 4248.95 100.00 26.94 0.13 3.31 1082.71 25.48 27.44 0.19 3.25 1054.98 24.83 28.58 0.19 3.12 482.67 11.36 29.41 0.19 3.04 1194.59 28.11

Dichloromethane solvate: Form I of dichloromethane solvate was prepared by evaporation from dichloromethane (100 mg/ml) at ambient temperature. The solvate desolvates into free form I at ~75°C.

The dichloromethane solvate was characterized by an XRPD pattern containing the peaks presented in Table. 7.

Table 7

Position [° FWHM [°2-theta] d-spacing [Ά] Height [cts] Rel. INT. [%] 6.76 0.16 13.07 720.61 11.92 8.25 0.16 10.71 861.09 14.24 9.43 0.19 9.38 164.11 2.71 11.46 0.19 7.72 2116.94 35.01 13.47 0.19 6.57 212.57 3.52 14.04 0.10 6.31 377.20 6.24 16.26 0.16 5.45 782.81 12.95 16.91 0.19 5.24 6047.20 100.00 18.82 0.19 4.72 937.49 15.50 19.50 0.13 4.55 936.06 15.48 19.90 0.16 4.46 1609.40 26.61 20.52 0.16 4.33 1974.39 32.65 20.79 0.10 4.27 1332.81 22.04 21.58 0.29 4.12 1516.98 25.09 22.53 0.19 3.95 527.26 8.72 23.10 0.16 3.85 2306.11 38.14 23.92 0.13 3.72 1360.97 22.51 24.58 0.16 3.62 1948.89 32.23 25.18 0.13 3.54 844.76 13.97 26.20 0.16 3.40 1047.32 17.32 26.95 0.13 3.31 844.84 13.97 27.18 0.13 3.28 837.05 13.84 27.62 0.13 3.23 721.27 11.93 28.26 0.13 3.16 766.28 12.67 29.35 0.19 3.04 1496.50 24.75

Nitromethane solvate: Nitromethane solvate Form I was prepared by evaporation from nitromethane (44 mg/ml) under ambient conditions. The solvate desolvates into free form I at ~81-97°C.

The dichloromethane solvate was characterized by an XRPD pattern containing the peaks presented in Table. 8.

- 18 044681

Table 8

Position FWHM [°2-theta] d-spacing [Ά] Height [cts] Rel. INT. [%] 6.61 0.16 13.38 949.30 19.09 7.37 0.19 12.00 219.82 4.42 8.14 0.23 10.87 213.73 4.30 8.94 0.19 9.90 2315.01 46.56 10.18 0.19 8.69 1099.24 22.11 11.33 0.23 7.81 261.74 5.26 11.98 0.19 7.39 143.75 2.89 12.45 0.13 7.11 236.85 4.76 13.31 0.19 6.65 144.03 2.90 13.87 0.16 6.38 428.90 8.63 14.63 0.19 6.06 173.65 3.49 15.86 0.13 5.59 2109.15 42.42 17.12 0.19 5.18 4971.90 100.00 18.16 0.26 4.88 1301.24 26.17 19.01 0.19 4.67 846.61 17.03 19.51 0.16 4.55 2162.56 43.50 19.83 0.19 4.48 1882.29 37.86 20.54 0.23 4.32 1638.55 32.96 21.93 0.19 4.05 1343.45 27.02 22.68 0.10 3.92 764.69 15.38 23.06 0.23 3.86 1834.23 36.89 23.92 0.19 3.72 2273.36 45.72 24.41 0.19 3.65 1858.60 37.38 25.37 0.23 3.51 1052.59 21.17 26.61 0.29 3.35 883.52 17.77 28.32 0.29 3.15 728.80 14.66

Hexafluoro-2-propanol solvate: Form I of hexafluoro-2-propanol solvate was prepared by dropwise crystallization from a solvent (sonication ~5 mg with 50 μL hexafluoro-2-propanol for 60 min). The solvate desolvates into free form I at ~83-100°C.

Hexafluoro-2-propanol solvate was characterized by an XRPD pattern containing the peaks presented in Table. 9.

Table 9

Position [° FWHM [°2-theta] d-spacing [Ά] Height [cts] Rel. INT. [%] 9.49 0.20 9.32 105.76 25.75 11.20 0.20 7.90 110.51 26.90 16.17 0.20 5.48 240.31 58.50 16.70 0.20 5.31 410.77 100.00 18.20 0.20 4.88 172.73 42.05 20.18 0.34 4.40 77.32 18.82 21.39 0.30 4.15 50.73 12.35 23.03 0.20 3.86 127.08 30.94 23.74 0.25 3.75 113.20 27.56 25.46 0.79 3.50 49.71 12.10 27.00 0.30 3.30 50.17 12.21 29.24 0.15 3.05 56.78 13.82 33.76 0.30 2.65 37.09 9.03

Cocrystal of compound A and propyl gallate: The cocrystal of propyl gallate was prepared by grinding liquid of compound A (30 mg) with 1 mol equiv of propyl gallate and 5 μl of solvent (EtOH) in a planetary Fritsch mill with 2 small ball bearings at 500 rpm for 2 h. The sample was then treated with toluene (500 μL) and matured in six 4-hour cycles from RT to 50°C, then kept at 5°C for 48 hours. The isolated solids were identified as a propyl gallate cocrystal.

This cocrystal was also prepared by liquid grinding of compound A (30 mg) with 1 mol equiv of propyl gallate and 5 μl of solvent (EtOAc) in a planetary Fritsch mill with 2 small ball bearings at 500 rpm for 2 h. The isolated solids were identified

- 19 044681 in the form of a propyl gallate cocrystal. 1H NMR confirms the chemical structure and the presence of ~2.0 mol equivalents of propyl gallate and ~0.07 mol equivalents of residual EtOAc. NMR of propyl gallate cocrystal: 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.33-0.41 (m, 2H) 0.42-0.50 (m, 1H) 0.54-0.62 (m , 1H) 0.70-0.82 (m, 1H) 0.91-0.99 (m, 3H) 1.07-1.13 (m, 1H) 1.15-1.27 (m, 1H ) 1.61-1.80 (m, 4H) 1.97-2.00 (m, 1H)

2.53-2.64 (m, 1H) 3.33-3.43 (m, 4H) 3.71-3.77 (m, 1H) 3.99-4.06 (m, 1H) 4, 08-4.15 (m, 2H) 4.48-4.57 (m, 1H)

4.67-4.73 (m, 1H) 4.91-4.99 (m, 1H) 6.92-6.97 (m, 2H) 7.43-7.50 (m, 1H) 7, 55-7.63 (m, 1H) 7.69-7.74 (m, 1H)

7.74-7.81 (m, 1H) 8.29-8.33 (m, 1H) 8.47-8.51 (m, 1H) 8.71-8.80 (m, 1H) 8, 85-8.90 (m, 1H) 9.11-9.16 (m, 1H)

9.18-9.24 (m, 1H).

The propyl gallate cocrystal was characterized by an XRPD pattern containing the peaks presented in Table 10.

Table 10

Position [°2-theta] FWHM [°2theta] d-spacing [A] Height [cts] Rel. INT. [%] 3.05 0.10 28.97 138.41 13.30 6.12 0.10 14.44 88.73 8.52 8.66 0.08 10.21 395.91 38.03 9.21 0.08 9.60 285.10 27.39 10.65 0.08 8.31 52.51 5.04 11.24 0.08 7.87 125.53 12.06 13.23 0.20 6.69 26.54 2.55 15.00 0.06 5.91 1041.03 100.00 17.16 0.15 5.17 50.86 4.89 17.72 0.14 5.01 577.05 55.43 18.32 0.05 4.84 204.49 19.64 18.82 0.09 4.72 405.73 38.97 19.36 0.09 4.58 249.50 23.97 20.32 0.14 4.37 395.72 38.01 20.49 0.12 4.33 339.45 32.61 21.73 0.12 4.09 164.40 15.79 22.57 0.08 3.94 324.89 31.21 22.98 0.15 3.87 107.36 10.31 23.39 0.18 3.80 160.61 15.43 23.86 0.15 3.73 90.48 8.69 25.01 0.13 3.56 126.37 12.14 25.51 0.18 3.49 187.06 17.97 26.30 0.10 3.39 139.71 13.42 26.52 0.10 3.36 167.23 16.06 28.31 0.13 3.15 150.52 14.46 28.66 0.18 3.11 73.65 7.07 29.68 0.15 3.01 28.04 2.69 30.54 0.41 2.93 19.74 1.90

Cocrystal of Compound A and Glycerol: A cocrystal of glycerol was prepared by grinding Compound A liquid (30 mg) with 1 mol equiv of propyl gallate and 5 μL of solvent (EtOAc) in a planetary Fritsch mill with 2 small ball bearings at 500 rpm for 2 h. The sample was then treated with acetone (500 μl) and matured in six 4-hour cycles from RT to 50°C, then kept at 5°C for 48 hours. The isolated solids were identified as glycerol cocrystals. 1H NMR confirms the chemical structure and the presence of ~2.6 mol equivalents of glycerol and ~0.11 mol equivalents of residual acetone. Stable when stored at 40°C/75% rel. ow. when stored for 7 days according to XRPD. NMR of glycerol cocrystal: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.37 (br s, 2H) 0.46 (br t, J=8.72 Hz, 1H) 0.57 (br s, 1H) 0.77 (br d, J=8.84 Hz, 1H) 1.10 (br d, J=2.53 Hz 1H) 1.73 (br s, 1H) 1.74-1.74 (m, 1H) 1.77 (d, J=3.54 Hz,

- 20 044681

1H) 2.07 (s, 1H) 3.23-3.31 (m, 4 H) 3.24-3.31 (m, 1H) 3.27-3.31 (m, 1H) 3.31 -3.46 (m, 23H) 3.35-3.46 (m, 1H) 3.49-3.52 (m, 1H) 3.71 - 3.77 (m, 1H) 4.07 (t , J=8.34 Hz, 1H) 4.40 (t, J=5.68 Hz, 5 H) 4.48 (d, J=4.80 Hz, 3H) 4.52 (t, J=7 .96 Hz, 1H) 4.70 (dd, J=11.24, 2.65 Hz, 1H) 4.95 (dd, J=11.49, 3.66 Hz, 1H) 7.46 (dd, J=10.74, 5.68 Hz, 1H) 7.59 (dd, J=10.99, 5.43 Hz, 1H) 7.72 (dd, J=9.47, 5.94 Hz, 1H ) 7.77 (dd, J=9.35, 5.81 Hz, 1H) 8.31 (t, J=2.15 Hz, 1H) 8.49 (t, J=2.15 Hz, 1H) 8.53 (d, J=7.83 Hz, 1H) 8.75 (d, J=7.58 Hz, 1H) 8.87 (d, J=2.02 Hz, 1H) 9.13 (d , J=2.02 Hz, 1H) 9.21 (d, J=2.27 Hz, 1H).

The cocrystal of Compound A and glycerol was characterized by an XRPD pattern containing the peaks presented in Table 11.

Table 11

Position [°2-theta] FWHM [°2theta] d-spacing [A] Height [cts] Rel. INT. [%] 2.87 0.61 30.77 14.43 0.63 7.90 0.06 11.19 173.39 7.54 8.17 0.06 10.83 126.26 5.49 8.38 0.08 10.55 60.82 2.64 9.70 0.08 9.12 186.10 8.09 11.85 0.08 7.47 50.19 2.18 12.38 0.08 7.15 104.08 4.52 13.13 0.20 6.74 24.53 1.07 15.60 0.08 5.68 202.49 8.80 16.39 0.06 5.41 358.00 15.56 16.84 0.10 5.26 1007.09 43.77 18.25 0.08 4.86 164.46 7.15 18.48 0.10 4.80 1779.04 77.32 18.95 0.10 4.68 411.95 17.91 19.40 0.06 4.58 936.22 40.69 20.03 0.10 4.43 166.63 7.24 21.49 0.05 4.14 2300.74 100.00 22.51 0.13 3.95 196.74 8.55 22.87 0.13 3.89 142.01 6.17 23.87 0.13 3.73 170.06 7.39 24.53 0.13 3.63 224.80 9.77 24.92 0.08 3.57 193.80 8.42 25.44 0.26 3.50 66.39 2.89 27.10 0.13 3.29 170.48 7.41 27.61 0.18 3.23 79.43 3.45 28.88 0.20 3.09 42.07 1.83 30.62 0.20 2.92 29.68 1.29

Cocrystal of compound A and propylene glycol: The cocrystal of propylene glycol was prepared by grinding liquid of compound A (30 mg) with 1 mol equiv of propylene glycol and 5 μl of solvent (EtOAc) in a planetary Fritsch mill with 2 small ball bearings at 500 rpm for 2 h. The sample was then treated with acetone (500 μl) and matured in six 4-hour cycles from RT to 50°C, then kept at 5°C for 48 hours. The isolated solids were identified as a propylene glycol co-crystal.

1H NMR confirms the chemical structure and the presence of ~1.0 mol equivalent of propylene glycol. Stable when stored at 40°C/75% rel. ow. when stored for 7 days according to XRPD.

Propylene glycol NMR: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.37 (br s, 2H) 0.42-0.51 (m, 1H) 0.530.62 (m, 1H) 0.77 ( br d, J=8.84 Hz, 2H) 0.99 (d, J=6.32 Hz, 3H) 1.10 (br d, J=2.53 Hz, 1H) 1.20 (brd, J =8.08 Hz, 1H) 1.67-1.79 (m, 2H) 3.10-3.18 (m, 1H)3.11-3.29 (m, 1H) 3.25 (dt, J=10.74, 5.49 Hz, 1H) 3.35-3.42 (m, 4H) 3.50-3.61 (m, 1H) 3.70-3.78 (m, 1H) 4 .07 (br t, J=8.21 Hz, 1H) 4.41 (d, J=4.29 Hz, 1H) 4.47 (t, J=5.68 Hz, 1H)

- 21 044681

4.52 (t, J=7.83 Hz, 1H) 4.70 (br dd, J=11.37, 2.53 Hz, 1H) 4.95 (dd, J=11.37, 3.54 Hz, 1H) 7.46 (br dd, J=10.99, 5.18 Hz, 1H) 7.59 (dd, J=10.99, 5.43 Hz, 1H) 7.68-7.73 (m, 1H) 7.77 (dd, J=9.47, 5.94 Hz, 1H) 8.28-8.33 (m, 1H) 8.45-8.51 (m, 1H) 8, 51-8.56 (m, 1H) 8.75 (br d, J=7.33 Hz, 1H) 8.87 (d, J=1.77 Hz, 1H) 9.13 (d, J=1 .77 Hz, 1H) 9.21 (d, J=2.02 Hz, 1H). The cocrystal of compound A and propylene glycol was characterized by an XRPD pattern containing the peaks presented in Table. 12.

Table 12

Position [°2-theta] FWHM [°2theta] d-spacing [A] Height [cts] Rel. INT. [%] 7.87 0.06 11.23 160.28 5.25 8.16 0.08 10.84 74.47 2.44 9.69 0.06 9.13 124.64 4.08 11.84 0.08 7.47 41.96 1.37 12.36 0.05 7.16 77.17 2.53 13.08 0.15 6.77 21.61 0.71 15.61 0.08 5.68 176.30 5.77 16.36 0.09 5.42 201.92 6.61 16.82 0.08 5.27 540.59 17.70 18.26 0.06 4.86 321.63 10.53 18.39 0.06 4.82 269.95 8.84 18.93 0.09 4.69 1668.23 54.63 19.37 0.10 4.58 3053.51 100.00 20.02 0.08 4.44 106.48 3.49 20.39 0.04 4.36 246.13 8.06 21.12 0.09 4.21 184.55 6.04 21.52 0.08 4.13 388.81 12.73 21.83 0.08 4.07 113.27 3.71 22.47 0.13 3.96 268.23 8.78 22.85 0.09 3.89 135.31 4.43 23.39 0.15 3.80 44.11 1.44 23.84 0.13 3.73 115.84 3.79 24.46 0.09 3.64 291.01 9.53 25.05 0.08 3.55 97.85 3.20 25.36 0.10 3.51 37.13 1.22 26.66 0.13 3.34 45.55 1.49 27.07 0.13 3.29 107.42 3.52 27.60 0.13 3.23 66.70 2.18 28.85 0.15 3.09 44.28 1.45 30.56 0.10 2.93 46.14 1.51

Cocrystal of compound A and maltol: The cocrystal of maltol was prepared by grinding liquid of compound A (30 mg) with 1 mol equiv of maltol and 5 μl of solvent (EtOAc) in a planetary Fritsch mill with 2 small ball bearings at 500 rpm for 2 h. The sample was then treated with acetone (500 μl) and matured in six 4-hour cycles from RT to 50°C, then kept at 5°C for 48 hours. The isolated solids were identified as a maltol cocrystal. 1H NMR confirms the chemical structure and the presence of ~0.8 mol equivalents of maltol and ~0.14 mol equivalents of residual acetone. Stable when stored at 40°C/75% rel. ow. when stored for 7 days according to XRPD. NMR of maltol cocrystal: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.37 (br s, 2H) 0.42 - 0.50 (m, 1H) 0.53-0.62 (m, 1H ) 0.71-0.81 (m, 2H) 1.07-1.13 (m, 1H) 1.20 (br d, J=8.08 Hz, 1H) 1.67-1.79 (m , 2H) 2.07 (s, 1H) 2.24 (s, 2H) 3.36-3.44 (m, 5H) 3.71 -3.78 (m, 1H) 4.07 (t, J =8.34 Hz, 1H) 4.52 (t, J=7.96 Hz, 1H) 4.70 (dd, J=11.37, 2.78 Hz, 1H) 4.95 (dd, J= 11.37, 3.54 Hz, 1H) 6.33 (d, J=5.56 Hz, 1H) 7.46 (dd, J=11.12, 5.81 Hz, 1H) 7.59 (dd , J=10.86,

- 22 044681

5.56 Hz, 1H) 7.72 (dd, J=9.47, 5.94 Hz, 1H) 7.77 (dd, J=9.35, 5.81 Hz, 1H) 8.03 (d , J=5.56 Hz, 1H) 8.31 (t, J=2.15 Hz, 1H) 8.49 (t, J=2.15 Hz, 1H) 8.53 (d, J=7, 58 Hz, 1H) 8.75 (d, J=7.33 Hz, 1H) 8.84 (s, 1H) 8.87 (d, J=2.02 Hz, 1H) 9.13 (d, J =1.77 Hz, 1H) 9.21 (d, J=2.27 Hz, 1H).

1H NMR confirms the chemical structure and the presence of ~1.0 mol equivalent of propylene glycol. Stable when stored at 40°C/75% rel. ow. when stored for 7 days according to XRPD.

The cocrystal of compound A and maltol was characterized by an XRPD pattern containing the peaks presented in table. 13.

Table 13

Position [°2-theta] FWHM [°2theta] d-spacing [A] Height [cts] Rel. INT. [%] 4.44 0.31 19.90 24.21 11.73 6.58 0.18 13.43 42.00 20.36 7.98 0.41 11.08 26.78 12.98 8.86 0.15 9.99 75.50 36.60 13.13 0.15 6.74 34.27 16.61 13.68 0.10 6.47 48.09 23.31 14.60 0.15 6.07 46.55 22.57 15.25 0.31 5.81 48.15 23.34 16.85 0.13 5.26 154.05 74.67 18.18 0.26 4.88 115.14 55.81 19.53 0.08 4.55 206.30 100.00 21.52 0.31 4.13 50.69 24.57 23.54 0.51 3.78 89.47 43.37 25.26 0.31 3.53 46.38 22.48 26.63 0.31 3.35 56.21 27.25

Cocrystal of compound A and maltol: a cocrystal of urea was prepared by grinding liquid of compound A (30 mg) with 1 mol equiv of urea and 5 μl of solvent (EtOH or EtOAc) in a planetary Fritsch mill with 2 small ball bearings at 500 rpm for 2 h. The isolated solids were identified as a urea cocrystal.

1H NMR confirms the chemical structure and the presence of ~1.0 mol equivalent of urea. Stable when stored at 25° C/97% rel. ow. and 40°C/75% rel. ow. when stored for 7 days according to XRPD.

NMR of urea cocrystal: 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm -0.21 (br dd, J=8.84, 4.55 Hz, 1H) 0.07-0.03 (m, 1H) 0.37 (br s, 1H) 0.46 (br t, J=8.59 Hz, 1H) 0.53-0.61 (m, 1H) 0.77 (td, J=8.97, 4 ,80 Hz, 1H) 1.10 (td, J=5.05, 2.78 Hz, 1H) 1.15-1.26 (m, 1H) 1.58-1.64 (m, 1H) 1 .67-1.79 (m, 2H) 3.35-3.42 (m, 4H) 3.68 3.79 (m, 1H) 4.02-4.11 (m, 1H) 4.52 ( t, J=7.96 Hz, 1H) 4.70 (br dd, J=11.24, 2.65 Hz, 1H) 4.95 (dd, J=11.37, 3.54 Hz, 1H) 5.40 (brs, 3H) 5.35-5.47 (m, 1H) 6.55 (s, 1H) 7.46 (dd, J=11.24, 5.68 Hz, 1H) 7.59 (dd, J=10.99, 5.43 Hz, 1H) 7.69-7.82 (m, 1H) 8.31 (t, J=2.15 Hz, 1H) 8.49 (t, J =2.02 Hz, 1H) 8.53 (d, J=7.58 Hz, 1H) 8.75 (d, J=7.33 Hz, 1H) 8.87 (d, J=2.02 Hz , 1H) 9.13 (d, J=2.02 Hz, 1H) 9.21 (d, J=2.27 Hz, 1H).

The cocrystal of compound A and urea was characterized by an XRPD pattern containing the peaks presented in table. 14.

- 23 044681

Table 14

Position [°2-theta] FWHM [°2theta] d-spacing [A] Height [cts] Rel. INT. [%] 3.99 0.05 22.15 946.23 47.52 8.01 0.06 11.04 673.52 33.82 8.39 0.08 10.54 538.35 27.04 11.24 0.08 7.87 1991.25 100.00 11.63 0.06 7.61 128.89 6.47 12.03 0.06 7.36 182.97 9.19 12.22 0.08 7.24 65.14 3.27 13.24 0.08 6.69 175.95 8.84 14.96 0.10 5.92 701.61 35.23 15.21 0.06 5.83 343.50 17.25 15.98 0.13 5.55 162.31 8.15 16.93 0.05 5.24 240.73 12.09 17.16 0.14 5.17 371.57 18.66 17.47 0.06 5.08 764.91 38.41 17.62 0.09 5.03 1101.50 55.32 18.37 0.12 4.83 1422.78 71.45 18.94 0.10 4.69 461.78 23.19 19.13 0.09 4.64 575.50 28.90 19.75 0.08 4.50 137.57 6.91 20.13 0.09 4.41 198.36 9.96 20.51 0.13 4.33 741.55 37.24 20.86 0.08 4.26 168.67 8.47 21.50 0.10 4.13 136.81 6.87 22.37 0.13 3.97 238.21 11.96 22.62 0.10 3.93 188.58 9.47 22.83 0.08 3.90 190.97 9.59 23.41 0.10 3.80 126.41 6.35 23.80 0.13 3.74 108.28 5.44 24.24 0.13 3.67 135.64 6.81 24.65 0.09 3.61 702.18 35.26 24.86 0.10 3.58 609.98 30.63 25.36 0.13 3.51 155.46 7.81 25.70 0.06 3.47 439.89 22.09 25.97 0.14 3.43 425.91 21.39 26.35 0.08 3.38 214.61 10.78 26.62 0.18 3.35 490.09 24.61 27.12 0.13 3.29 90.14 4.53 28.01 0.13 3.19 352.78 17.72 28.26 0.13 3.16 236.03 11.85 28.77 0.20 3.10 196.12 9.85 29.25 0.15 3.05 318.69 16.00 29.75 0.15 3.00 51.41 2.58

Amorphous form: Compound A (300 mg) was dissolved in tBuOH:H2O (1:1, 30 vol.) at 50°C. The clear solution was filtered to remove any undissolved particles that might act as

Claims (16)

as nucleation points. The filtered solution was immediately frozen in a dry ice/acetone bath and placed in a freeze dryer for lyophilization. The resulting solid was analyzed by XRPD. 1H NMR confirms the structure with ~0.39 mol equivalents of residual tBuOH. TGA indicates 2.9% w/w, ranging from 50 to 96°C, corresponding to ~0.22 mol-eq residual tBuOH. Crystallizes during static storage at 80°C/0% rel. ow. or 40°C/75% rel. ow. within 1 week. NMR of amorphous crystalline form: 1H NMR (400 MHz, DMSO-d6) δ ppm -0.31-0.06 (m, 1H)-0.28 -0.14 (m, 1H)-0.12-0, 04(m, 1H)-0.10-0.04(m, 1H)-0.09-0.04(m, 1H) 0.37 (br s, 3H)0.52-0.67(m , 1H) 0.68-0.84 (m, 2H) 1.07-1.23 (m, 6H) 1.57-1.79 (m, 3H) 2.3 -2.36 (m, 1H ) 2.53-2.79 (m, 2H) 3.68 - 3.79 (m, 1H) 4.20 (s, 1H) 4.15-4.24 (m, 1H) 4.52 (t , J=7.96 Hz, 1H) 4.64-4.78 (m, 1H) 4.95 (dd, J=11.37, 3.54 Hz, 1H) 7.41-7.52 (m , 1H) 7.59 (dd, J=11.12, 5.56 Hz, 1H) 7.77 (dd, J=9.47, 5.94 Hz, 2H) 8.27-8.34 (m , 1H) 8.49 (t, J=2.15 Hz, 2H) 8.76 (d, J=7.33 Hz, 1H) 8.87 (d, J=1.77 Hz, 1H) 9, 10 - 9.17 (m, 1H) 9.21 (d, J=2.27 Hz, 1H). CLAIM 1. Free base crystalline form of compound A where the crystalline form of the free base is anhydrous Form I, characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 9.78, 12.45, 15.70, 16.46 and 16.94 ± 0.2° 2-theta using Cu Ka radiation. 2. The free base crystalline form of claim 1, further characterized by XRPD pattern peaks at 8.23, 24.40, 25.03, 25.49 and 32.03 ± 0.2° 2-theta using Cu Ka radiation . 3. The crystalline form of the free base according to claim 1 or 2, additionally characterized by XRPD pattern peaks at 19.56, 20.11, 22.99, 23.97, 29.53, 41.91 and 42.83 ± 0.2 ° 2-theta using Cu Ka radiation. 4. A crystalline form according to any one of claims 1 to 3, having an XRPD pattern as shown in FIG. 1. 5. A crystalline form according to any one of claims 1 to 4, having an endothermic transition from 147 to 157°C, measured using differential scanning calorimetry. 6. Crystalline form according to claim 5, where the endothermic transition is at 152 ± 3°C. 7. A crystalline form according to any one of claims 1 to 6, having dynamic vapor sorption (DVS) as shown in FIG. 4. 8. The crystalline form according to any one of claims 1 to 7, having a thermogravimetric analysis (TGA) result as shown in FIG. 3. 9. Free base crystalline form of compound A where the crystalline form is anhydrous Form IV characterized by an X-ray powder diffractometry (XRPD) pattern containing peaks at 8.06, 11.29 and 14.97 ± 0.2° 2-theta using Cu Ka radiation. 10. The crystalline form of the free base according to claim 9, further characterized by XRPD pattern peaks at 17.19, 17.63, 18.39, 18.95, 19.17, 20.50, 24.87, 26.03, 26 .62, 27.99 and 29.25 ± 0.2° 2theta using Cu Ka radiation. 11. The crystalline form of the free base according to claim 9 or 10, further characterized by XRPD pattern peaks at 12.08, 20.17, 22.37, 22.86, 25.69, 28.26 and 28.73 ± 0.2 ° 2-theta using Cu Ka radiation. 12. A crystalline form according to any one of claims 9 to 11, having an XRPD pattern as shown in FIG. 10. 13. The crystalline form according to any one of claims 9 to 12, having an endothermic transition from 160 to 175°C, measured using differential scanning calorimetry. 14. Crystal form according to claim 13, where the endothermic transition is at 167 ± 3°C. 15. A crystalline form according to any one of claims 9 to 14, having dynamic vapor sorption (DVS) as shown in FIG. 13. 16. The crystalline form according to any one of claims 9 to 15, having a thermogravimetric analysis (TGA) result as shown in FIG. 12. -