CRYSTALLINE FORMS OF (6S, 7S)-6-FLUORO-7-(2-FLUORO-5-METHYLPHENYL)-3-(TETRAHYDRO-2h-PYRAN-4-YL)-5, 6, 7, 8-TETRAHYDROPYRIDO [2, 3-d] PYRIMIDIN-2, 4 (1H, 3H)-DIONE

Abstract

The present invention provides a crystalline form of (6S, 7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5, 6, 7, 8-tetrahydropyrido [2, 3-d] pyrimidine-2, 4 (1H, 3H)-dione ("Compound I"). Related pharmaceutical compositions, methods of preparation, and methods of treatment of hypertrophic cardiomyopathy (HCM), ejection fraction retention heart failure (HFpEF), diastolic dysfunction, left ventricular hypertrophy, and other heart diseases are also provided.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the priority of PCT application number PCT / CN2022 / 109030 filed on July 29, 2022, and the entire contents of the PCT application number are incorporated herein by reference. Technical Field

[0003] Provided herein are crystalline forms of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione ("Compound I") and related pharmaceutical compositions, preparation methods, and methods of treatment. Compound I can be used to treat cardiac disorders, such as hypertrophic cardiomyopathy (HCM), heart failure, diastolic dysfunction, and left ventricular hypertrophy. Background of the Invention

[0005] Hypertrophic cardiomyopathy (HCM) is a disease in which the heart muscle thickens (hypertrophies), which can make it more difficult for the heart to pump blood. HCM is most often transmitted as an autosomal dominant trait, caused by mutations in genes encoding cardiac sarcomeric proteins. U.S. Patent Application Publication No. 2020 / 0165247A1 discloses compounds designed to treat potential disruptions in normal sarcomeric function, which can be used to treat certain cardiac conditions, such as hypertrophic cardiomyopathy (HCM), heart failure, conditions associated with left ventricular hypertrophy, conditions associated with diastolic dysfunction, and / or their symptoms. One such compound is (6S, 7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. US2020 / 0165247 A1 discloses a crystalline form of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, and is referred to therein as Form 1 polymorph.

[0006] There is a need in the art for pharmaceutically useful forms of such compounds, including forms having properties suitable for processing, manufacturing, storage stability and / or use as a drug. Therefore, finding a form having some or all of these desired properties is critical to drug development. Summary of the invention

[0007] The present invention provides a crystalline form of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione ("Compound I").

[0008]

[0009] Disclosed herein are polymorphs of Form A, Form B, Form C, Form D, Form E, and Form F. In one aspect, disclosed herein are Compound I in Form B, Form C, Form D, Form E, or Form F. In another aspect, disclosed herein are mixtures of two or more of Form A, Form B, Form C, Form D, Form E, and Form F.

[0010] In another aspect, provided herein are pharmaceutical compositions comprising one or more crystalline forms as described herein and a pharmaceutically acceptable excipient.

[0011] In another aspect, provided herein are methods of making a crystalline form as described herein.

[0012] In another aspect, provided herein are methods for treating diastolic dysfunction, left ventricular hypertrophy, hypertrophic cardiomyopathy, heart failure with preserved ejection fraction, and other diseases. The methods comprise administering to a subject in need thereof an effective amount of a crystalline form or pharmaceutical composition as described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 Provided is an X-ray powder diffraction (XRPD) pattern of Form A of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (ie, "Compound I").

[0014] Figure 2 An XRPD pattern of Compound 1 Form B is provided.

[0015] Figure 3 A differential scanning calorimetry (DSC) thermogram of Compound 1 Form B is provided.

[0016] Figure 4 A thermogravimetric analysis (TGA) thermogram of Compound 1 Form B is provided.

[0017] Figure 5 A vapor sorption isotherm of Compound 1 Form B is provided.

[0018] Figure 6 An XRPD pattern of Compound 1 Form C is provided.

[0019] Figure 7 A DSC thermogram of Compound 1 Form C is provided.

[0020] Figure 8 A TGA thermogram of Compound 1 Form C is provided.

[0021] Fig. 9 An XRPD pattern of Compound 1 Form D is provided.

[0022] Fig.10 A TGA thermogram of Compound 1 Form D is provided.

[0023] Fig.11 An XRPD pattern of Compound 1 Form E is provided.

[0024] Fig.12 A DSC thermogram of Compound 1 Form E is provided.

[0025] Fig.13 A TGA thermogram of Compound 1 Form E is provided.

[0026] Fig.14 An XRPD pattern of Compound 1 Form F is provided. DETAILED DESCRIPTION

[0027] I. Definitions

[0028] As used herein, the terms "a", "an", or "the" include not only aspects having one member, but also aspects having more than one member. For example, embodiments comprising "an active agent and a pharmaceutically acceptable excipient" should be understood to present certain aspects having at least a second active agent, at least a second pharmaceutically acceptable excipient, or both. Embodiments comprising "an active agent" should be understood to present certain aspects having at least a second active agent, which may be of a different class.

[0029] As used herein, the term "about" for modifying a numerical value indicates a limited range near the value. If "X" is a value, "about X" will generally indicate a value from 0.95X to 1.05X. Any reference to "about X" specifically indicates at least values ​​X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, and 1.05X. Therefore, "about X" is intended to teach and provide written description support for claim limitations such as "0.98X". When the amount "X" only includes integer values ​​(such as "X carbons"), "about X" indicates (X-1) to (X+1). In this case, "about X" as used herein specifically indicates at least values ​​X, X-1, and X+1.

[0030] When "about" is applied to the beginning of a numerical range, it applies to both ends of the range. Thus, "about 5% to 20%" is equivalent to "about 5% to about 20%". When "about" is applied to the first value of a group of values, it applies to all values ​​in that group. Thus, "about 7, 9, or 11%" is equivalent to "about 7%, about 9%, or about 11%".

[0031] As used herein, "agent" indicates a compound or mixture of compounds that, when added to a pharmaceutical composition, tends to produce a particular effect on the properties of the composition. For example, a composition comprising a thickening agent may be more viscous than an otherwise identical comparative composition lacking the thickening agent.

[0032] As used herein, the phrase "effective amount" or "effective dose" means an amount sufficient to achieve the desired result, and therefore will depend on the ingredient and its desired result. Nevertheless, once the desired effect is known, determining the effective amount is within the skill of those skilled in the art.

[0033] As used herein, the term "excipient" refers to a substance that aids in administering an active agent to a subject. Pharmaceutical excipients that can be used in the present invention include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavoring agents, and coloring agents. Those skilled in the art will appreciate that other excipients can be used in the present invention.

[0034] The term "pharmaceutical composition" as used herein refers to a product comprising a compound of the invention, excipients as defined herein, and other optional ingredients in specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0035] The term "pharmaceutically acceptable" means compatible with the treatment of animals, and particularly humans.

[0036] The term "pharmaceutically acceptable salt" means a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable base addition salt. The formation of the desired compound salt is achieved using standard techniques. For example, a neutral compound is treated with an acid or a base in a suitable solvent, and the salt formed is separated by filtration, extraction or any other suitable method. Pharmaceutically acceptable salts can be derived from, for example, mineral acids (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), organic acids (acetic acid, propionic acid, glutamic acid, citric acid, etc.) and quaternary ammonium ions. It should be understood that pharmaceutically acceptable salts are non-toxic. Additional information about suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0037] As used herein, the term "subject" or "patient" includes all members of the animal kingdom, preferably mammals, and most preferably humans.

[0038] The term "substantially" as applied to a composition or substance indicates at least 80% (w / w) identical to the specified substance, and preferably higher levels, for example at least 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0039] As used herein, the terms "treat," "treating," and "treatment" refer to any marker of success in treating or ameliorating a pathology, injury, condition, or symptom associated with a disease or disorder (e.g., a cardiac disorder with pathophysiological features of HCM), including any objective or subjective parameter, such as attenuation; remission; alleviation of symptoms; making the patient more tolerant to the pathology, injury, condition, or symptom; or reducing the frequency or duration of the pathology, injury, condition, or symptom. Treatment or improvement can be based on any objective or subjective parameter; including, for example, the results of a physical examination.

[0040] The prefix "micro" as used herein may alternatively be abbreviated as "μ" or "u." For example, microgram is often abbreviated as μg, but may alternatively be abbreviated as "ug."

[0041] The term "polymorph" or "polycrystalline form" refers to a crystalline form of a compound (or its salt, hydrate or solvate) in a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, melting points, density, hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature and other factors may lead to one crystalline form dominating. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0042] The term "crystalline" refers to a solid phase in which the material has a regular, ordered internal structure at the molecular level and gives a unique X-ray diffraction pattern with defined peaks. Such materials will also exhibit the properties of a liquid when fully heated, but the change from solid to liquid is characterized by a phase transition, typically a first order phase transition (melting point). The term "crystalline" or "crystalline form" refers to a solid form that substantially exhibits three-dimensional order. In certain embodiments, the crystalline form of a solid is a solid form that is substantially not amorphous. In certain embodiments, the X-ray powder diffraction (XRPD) pattern of the crystalline form includes one or more clearly defined peaks.

[0043] The term "amorphous" or "amorphous form" refers to a solid form that substantially lacks three-dimensional order. In certain embodiments, an amorphous form of a solid is a solid form that is substantially not crystalline.

[0044] II. Crystalline Form

[0045] Disclosed herein is a crystalline form of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione ("Compound I") depicted below. Compound I can be synthesized as disclosed in U.S. Patent Application Publication No. 2020 / 0165247A1.

[0046]

[0047] Described herein are Form A, Form B, Form C, Form D, Form E, and Form F polymorphs of Compound 1. In another aspect, provided herein are mixtures of two or more of Form A, Form B, Form C, Form D, Form E, and Form F.

[0048] Form B

[0049] In one aspect, provided herein is the Form B polymorph of Compound 1. Form B is the anhydrate form of the free base of Compound 1. In another aspect, provided herein are compositions comprising Form B.

[0050] Form B is the most thermodynamically stable anhydrous form of Compound I under relevant conditions. Form B is stable at typical temperatures and conditions (e.g., 10°C-60°C) of pharmaceutical processes, resists conversion to other forms in certain solvents (including certain aqueous solvents and organic solvents), and can be crystallized from solvents at reasonable temperatures (e.g., 10°C-60°C). In competitive pulping under certain conditions, Form B is the most thermodynamically stable anhydrous form. Compared with other forms of Compound I that can be transformed between multiple polymorphic forms and mixtures thereof (this behavior may lead to inconsistent drug products), the stability of Form B is advantageous. The ability to produce Form B by direct crystallization is advantageous in manufacturing to avoid additional processing steps and improve scalability, and also allows control of physical properties. Form B has good manufacturability to produce an ordered crystal structure of suitable purity. Form B is non-hygroscopic. The non-hygroscopic nature of Form B is advantageous in that it avoids water absorption, which can lead to stability problems and problems in providing accurate dosages due to the uncertainty of water % in the pharmaceutical composition. The non-hygroscopic nature of Form B also benefits the manufacturability and processability of the drug substance and drug product. Form B has a high melting point and relatively good solid-state thermal stability, as demonstrated by the DSC thermogram of Form B. Form B has minimal weight loss before melting and no desolvation or dehydration issues, as demonstrated by the TGA thermogram of Form B. These properties also contribute to the stability of Form B and the resulting consistency of drug products containing Form B.

[0051] In some embodiments, Form B is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising at least three peaks or at least four peaks selected from the group consisting of 5.5, 7.1, 9.3, 16.5, and 19.0° 2θ ± 0.2° 2θ.

[0052] In some embodiments, Form B is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 5.5, 9.3, and 19.0° 2θ ± 0.2° 2θ.

[0053] In some embodiments, Form B is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 9.3, 16.5, and 19.0° 2θ ± 0.2° 2θ.

[0054] In some embodiments, Form B is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 5.5, 9.3, 16.5, and 19.0° 2θ ± 0.2° 2θ.

[0055] In some embodiments, Form B is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 5.5, 7.1, 9.3, and 19.0° 2θ ± 0.2° 2θ.

[0056] In some embodiments, Form B is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 5.5, 7.1, 9.3, 16.5, 19.0, and 22.3° 2θ ± 0.2° 2θ.

[0057] In some embodiments, Form B is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 5.5, 7.1, 9.3, 16.5, 19.0, and 22.3 °2θ±0.1 °2θ.

[0058] In some embodiments, Form B is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising a peak at 5.5°2θ±0.2°2θ and at least four peaks, at least five peaks, at least six peaks, at least seven peaks, or at least eight peaks selected from the group consisting of 7.1, 8.7, 9.3, 13.8, 16.2, 16.5, 17.2, 19.0, and 22.3°2θ±0.2°2θ.

[0059] In some embodiments, Form B is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 5.5, 7.1, 8.7, 9.3, 13.8, 16.2, 16.5, 17.2, 19.0, and 22.3 °2θ ± 0.2 °2θ.

[0060] In some embodiments, Form B is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 5.5, 7.1, 8.7, 9.3, 13.8, 16.2, 16.5, 17.2, 19.0, and 22.3 °2θ±0.1 °2θ.

[0061] In some embodiments, Form B is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 5.5, 7.1, 8.7, 9.3, 13.8, 15.8, 16.2, 16.5, 17.2, 18.5, 19.0, 19.3, 22.3, 23.1, 23.4, 23.7, 26.2, 27.3, 27.9, and 30.1 °2θ±0.2 °2θ.

[0062] In some embodiments, Form B is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα at room temperature, the pattern comprising a peak at 5.5° 2θ±0.2° 2θ and at least two peaks or at least three peaks selected from the group consisting of 7.1, 9.3, 16.5, and 19.0° 2θ±0.2° 2θ.

[0063] In some embodiments, Form B is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα at room temperature that is substantially as described above. Figure 2 is shown in .

[0064] Table 1 lists the Figure 2 X-ray powder diffraction peaks observed.

[0065]

[0066]

[0067] In some embodiments, Form B is characterized by a DSC thermogram comprising an endotherm with an onset at about 307 °C.

[0068] In some embodiments, Form B is characterized by (i) an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα at room temperature, the pattern comprising peaks at 5.5, 9.3, and 19.0° 2θ ± 0.2° 2θ, and (ii) a DSC thermogram comprising an endotherm with an onset of about 307°C.

[0069] In some embodiments, Form B is characterized by being substantially as follows Figure 3 DSC temperature record diagram shown in .

[0070] In some embodiments, Form B is characterized by exhibiting negligible weight loss prior to decomposition as measured by TGA.

[0071] In some embodiments, Form B is characterized by being substantially as follows Figure 4 TGA temperature record diagram shown in .

[0072] In some embodiments, Form B is characterized by a percent weight gain of less than 0.05% up to 95% RH as measured by a vapor sorption analyzer (eg, TA Instrument VTI-SA+). Vapor sorption analysis shows that Form B is non-hygroscopic.

[0073] In some embodiments, Form B is characterized by a triclinic crystal system with a P1 space group.

[0074] In some embodiments, Form B is characterized by (i) an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα at room temperature, the pattern comprising peaks at 5.5, 9.3, and 19.0° 2θ±0.2° 2θ, and (ii) a triclinic system with a P1 space group.

[0075] In some embodiments, Form B is characterized by (i) an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα at room temperature, the pattern comprising peaks at 5.5, 9.3, and 19.0° 2θ ± 0.2° 2θ; (ii) a triclinic system with a P1 space group; and (iii) a DSC thermogram comprising an endotherm with an onset of about 307°C.

[0076] In some embodiments, Form B is characterized by a unit cell size of α=83.9±1.0°, β=80.0±1.0°, and γ=75.1±1.0°.

[0077] Table 2 provides single crystal x-ray analysis data for Form B.

[0078]

[0079] In some embodiments, Form B is substantially pure, i.e., substantially free of other solid forms of Compound 1 (including amorphous Compound 1 and other polymorphs of Compound 1).

[0080] In some embodiments, provided herein are compositions comprising Compound 1 Form B, wherein the composition is at least 90% by weight Form B. In some embodiments, the composition is at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% by weight Form B. In some embodiments, the ratio of Form B to other solid forms of Compound 1 in the composition (by weight) is at least 90:10, at least 95:5, at least 98:2, at least 99:1, or at least 99.5:0.5.

[0081] Form C

[0082] In one aspect, provided herein is the Form C polymorph of Compound 1. Form C is the anhydrate form of the free base of Compound 1. In another aspect, provided herein are compositions comprising Form C.

[0083] Form C has a high melting point and relatively good solid-state thermal stability, as demonstrated by the DSC thermogram of Form C. Form C has minimal weight loss before melting and no desolvation or dehydration issues, as demonstrated by the TGA thermogram of Form C. These properties may contribute to the consistency of drug products containing Form C. Form C can be crystallized from solvents at reasonable temperatures. The ability to produce Form C by direct crystallization is beneficial in manufacturing to avoid additional processing steps and improve scalability, and also allows control of physical properties.

[0084] In some embodiments, Form C is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising at least three peaks, at least four peaks, or at least five peaks selected from the group consisting of 7.5, 13.8, 16.4, 17.4, 20.1, and 27.7 °2θ±0.2 °2θ.

[0085] In some embodiments, Form C is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 7.5, 13.8, and 16.4° 2θ ± 0.2° 2θ.

[0086] In some embodiments, Form C is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 7.5, 16.4, and 20.1 °2Θ±0.2 °2Θ.

[0087] In some embodiments, Form C is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 7.5, 16.4, and 27.7° 2θ ± 0.2° 2θ.

[0088] In some embodiments, Form C is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 7.5, 13.8, 16.4, 17.4, 20.1, and 27.7° 2θ ± 0.2° 2θ.

[0089] In some embodiments, Form C is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 7.5, 13.8, 16.4, 17.4, 20.1, and 27.7 °2θ±0.1 °2θ.

[0090] In some embodiments, Form C is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising at least four peaks, at least five peaks, at least six peaks, at least seven peaks, at least eight peaks, or at least nine peaks selected from the group consisting of 7.5, 8.2, 13.8, 15.2, 15.6, 16.4, 17.4, 20.1, 22.3, and 27.7 °2θ±0.2 °2θ.

[0091] In some embodiments, Form C is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 7.5, 8.2, 13.8, 15.2, 15.6, 16.4, 17.4, 20.1, 22.3, and 27.7 °2θ ± 0.2 °2θ.

[0092] In some embodiments, Form C is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 7.5, 8.2, 13.8, 15.2, 15.6, 16.4, 17.4, 20.1, 22.3, and 27.7 °2θ±0.1 °2θ.

[0093] In some embodiments, Form C is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature comprising peaks at 7.5, 8.2, 13.8, 14.7, 15.2, 15.6, 16.4, 17.4, 17.8, 20.1, 20.5, 20.9, 21.2, 21.7, 22.3, 22.6, 23.0, 23.5, 24.5, 25.0, 25.6, 26.7, 27.7, 28.2, 28.5, 29.4, 29.9, 30.8, and 31.7 °2θ ± 0.2 °2θ.

[0094] In some embodiments, Form C is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα at room temperature that is substantially as described above. Figure 6 is shown in .

[0095] Table 3 lists the Figure 6 X-ray powder diffraction peaks observed.

[0096]

[0097]

[0098] In some embodiments, Form C is characterized by comprising a DSC thermogram with an endotherm onset at about 306°C. In some embodiments, Form C is characterized by being substantially as Figure 7 DSC temperature record diagram shown in .

[0099] In some embodiments, Form C is characterized by exhibiting negligible weight loss prior to decomposition, as measured by TGA. In some embodiments, Form C is characterized by being substantially Figure 8 TGA temperature record diagram shown in .

[0100] In some embodiments, Form C is substantially pure, ie, substantially free of other solid forms of Compound 1.

[0101] In some embodiments, provided herein are compositions comprising Compound 1 Form C, wherein the composition is at least 90% by weight Form C. In some embodiments, the composition is at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% by weight Form C. In some embodiments, the ratio of Form C to other solid forms of Compound 1 in the composition (by weight) is at least 90:10, at least 95:5, at least 98:2, at least 99:1, or at least 99.5:0.5.

[0102] Form D

[0103] In one aspect, provided herein is the Form D polymorph of Compound 1. Form D is the anhydrate form of the free base of Compound 1. In another aspect, provided herein are compositions comprising Form D.

[0104] Form D has minimal weight loss prior to melting and no desolvation or dehydration issues as evidenced by the TGA thermogram of Form D. These properties may contribute to the consistency of drug products containing Form D.

[0105] In some embodiments, Form D is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising at least three peaks, at least four peaks, at least five peaks, or at least six peaks selected from the group consisting of 11.1, 15.0, 18.3, 19.8, 20.2, 22.5, and 25.9 °2θ±0.2 °2θ.

[0106] In some embodiments, Form D is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 11.1, 15.0, and 25.9° 2θ ± 0.2° 2θ.

[0107] In some embodiments, Form D is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 11.1, 15.0, 19.8, and 25.9° 2θ ± 0.2° 2θ.

[0108] In some embodiments, Form D is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 11.1, 15.0, 18.3, 19.8, 20.2, 22.5, and 25.9 °2θ±0.2 °2θ.

[0109] In some embodiments, Form D is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 11.1, 15.0, 18.3, 19.8, 20.2, 22.5, and 25.9 °2θ±0.1 °2θ.

[0110] In some embodiments, Form D is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising at least four peaks, at least five peaks, at least six peaks, at least seven peaks, at least eight peaks, or at least nine peaks selected from the group consisting of 11.1, 15.0, 18.3, 19.8, 20.2, 22.5, 23.0, 25.0, 25.9, and 28.2 °2θ±0.2 °2θ.

[0111] In some embodiments, Form D is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 11.1, 15.0, 18.3, 19.8, 20.2, 22.5, 23.0, 25.0, 25.9, and 28.2° 2θ ± 0.2° 2θ.

[0112] In some embodiments, Form D is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 11.1, 15.0, 18.3, 19.8, 20.2, 22.5, 23.0, 25.0, 25.9, and 28.2 °2θ±0.1 °2θ.

[0113] In some embodiments, Form D is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 11.1, 14.0, 15.0, 15.4, 18.3, 19.3, 19.8, 20.2, 20.7, 22.5, 23.0, 25.0, 25.9, 26.7, 27.4, 28.2, 30.1, and 31.8 °2θ ± 0.2 °2θ.

[0114] In some embodiments, Form D is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα at room temperature that is substantially as described above. Fig. 9 is shown in .

[0115] Table 4 lists the Fig. 9 X-ray powder diffraction peaks observed.

[0116]

[0117]

[0118] In some embodiments, Form D is characterized by exhibiting negligible weight loss prior to decomposition as measured by TGA. In some embodiments, Form D is characterized by being substantially Fig.10 TGA temperature record diagram shown in .

[0119] In some embodiments, Form D is substantially pure, ie, substantially free of other solid forms of Compound 1.

[0120] In some embodiments, provided herein are compositions comprising Compound 1 Form D, wherein the composition is at least 90% by weight Form D. In some embodiments, the composition is at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% by weight Form D. In some embodiments, the ratio of Form D to other solid forms of Compound 1 in the composition (by weight) is at least 90:10, at least 95:5, at least 98:2, at least 99:1, or at least 99.5:0.5.

[0121] Form E

[0122] In one aspect, provided herein is the Form E polymorph of Compound 1. Form E is the anhydrate form of the free base of Compound 1. In another aspect, provided herein are compositions comprising Form E.

[0123] Form E can be crystallized from solvents at reasonable temperatures (e.g., 10° C.-60° C.). The ability to produce Form E by direct crystallization is advantageous in manufacturing to avoid additional processing steps and improve scalability, and also allows for control of physical properties. Form E has minimal weight loss before melting and no desolvation or dehydration issues, as demonstrated by the TGA thermogram of Form E. Form E has a high melting point and relatively good solid-state thermal stability, as demonstrated by the DSC thermogram of Form E. These properties may contribute to the consistency of drug products containing Form E.

[0124] In some embodiments, Form E is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising at least three peaks or at least four peaks selected from the group consisting of 4.1, 8.6, 16.5, 17.7, and 23.2° 2θ ± 0.2° 2θ.

[0125] In some embodiments, Form E is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 8.6, 17.7, and 23.2° 2θ ± 0.2° 2θ.

[0126] In some embodiments, Form E is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 4.1, 8.6, and 16.5° 2θ ± 0.2° 2θ.

[0127] In some embodiments, Form E is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 4.1, 8.6, and 17.7° 2θ ± 0.2° 2θ.

[0128] In some embodiments, Form E is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 8.6, 16.5, 17.7, and 23.2° 2θ ± 0.2° 2θ.

[0129] In some embodiments, Form E is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 8.6, 17.7, 22.3, and 23.2° 2θ ± 0.2° 2θ.

[0130] In some embodiments, Form E is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 4.1, 8.6, 16.5, 17.7, 22.3, and 23.2° 2θ ± 0.2° 2θ.

[0131] In some embodiments, Form E is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 4.1, 8.6, 16.5, 17.7, 22.3, and 23.2 °2θ±0.1 °2θ.

[0132] In some embodiments, Form E is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising at least four peaks, at least five peaks, at least six peaks, at least seven peaks, at least eight peaks, or at least nine peaks selected from the group consisting of 4.1, 7.2, 8.6, 13.6, 15.7, 16.5, 17.7, 19.3, 22.3, and 23.2 °2θ±0.2 °2θ.

[0133] In some embodiments, Form E is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 4.1, 7.2, 8.6, 13.6, 15.7, 16.5, 17.7, 19.3, 22.3, and 23.2° 2θ ± 0.2° 2θ.

[0134] In some embodiments, Form E is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 4.1, 7.2, 8.6, 13.6, 15.7, 16.5, 17.7, 19.3, 22.3, and 23.2 °2θ ± 0.1 °2θ.

[0135] In some embodiments, Form E is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature comprising peaks at 4.1, 7.2, 7.9, 8.6, 13.6, 14.3, 15.3, 15.7, 16.1, 16.5, 17.3, 17.7, 18.3, 18.7, 19.3, 21.1, 21.7, 22.3, 23.2, 26.4, 27.6, 28.5, 28.8, and 30.2° 2θ ± 0.2° 2θ.

[0136] In some embodiments, Form E is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα at room temperature, the pattern comprising a peak at 4.1° 2θ±0.2° 2θ and at least two peaks or at least three peaks selected from the group consisting of 8.6, 16.5, 17.7, and 23.2° 2θ±0.2° 2θ.

[0137] In some embodiments, Form E is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα at room temperature that is substantially as described above. Fig.11 is shown in .

[0138] Table 5 lists the Fig.11 X-ray powder diffraction peaks observed.

[0139]

[0140] In some embodiments, Form E is characterized by comprising a DSC thermogram with an endotherm onset at about 304°C. In some embodiments, Form E is characterized by being substantially as Fig.12 DSC temperature record diagram shown in .

[0141] In some embodiments, Form E is characterized by exhibiting negligible weight loss prior to decomposition as measured by TGA. In some embodiments, Form E is characterized by being substantially Fig.13 TGA temperature record diagram shown in .

[0142] In some embodiments, Form E is characterized by (i) an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα at room temperature, the pattern comprising peaks at 8.6, 17.7, and 23.2° 2θ ± 0.2° 2θ, and (ii) a DSC thermogram comprising an endotherm with an onset of about 304°C.

[0143] In some embodiments, Form E is characterized by (i) an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα at room temperature, the pattern comprising peaks at 8.6, 17.7, and 23.2° 2θ ± 0.2° 2θ, and (ii) a monoclinic system with a C2 space group.

[0144] In some embodiments, Form E is characterized by (i) an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα at room temperature, the pattern comprising peaks at 8.6, 17.7, and 23.2° 2θ ± 0.2° 2θ, (ii) a monoclinic system with a C2 space group, and (iii) a DSC thermogram comprising an endotherm with an onset of about 304°C.

[0145] In some embodiments, Form E is characterized by a monoclinic crystal system with a C2 space group. In some embodiments, Form E is characterized by a unit cell size of α=90.0±1.0°, β=95.7±1.0°, and γ=90.0±1.0°.

[0146] Table 6 shows the single crystal x-ray analysis data for Form E.

[0147]

[0148] In some embodiments, Form E is substantially pure, ie, substantially free of other solid forms of Compound 1.

[0149] In some embodiments, provided herein are compositions comprising Compound 1 Form E, wherein the composition is at least 90% by weight Form E. In some embodiments, the composition is at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% by weight Form E. In some embodiments, the ratio of Form E to other solid forms of Compound 1 in the composition (by weight) is at least 90:10, at least 95:5, at least 98:2, at least 99:1, or at least 99.5:0.5.

[0150] Form F

[0151] In one aspect, provided herein is a Form F polymorph of Compound 1. Form F is a solvated form of the free base of Compound 1. Form F can be produced from a variety of organic solvents, including certain ethers (e.g., THF), acetates (e.g., isopropyl acetate), alcohols (e.g., methanol), aromatic solvents (e.g., toluene), ketones (e.g., acetone). In another aspect, provided herein is a composition comprising Form F.

[0152] Form F is a crystalline form and can be used for purification. Form F can be used to make various forms, including anhydrous forms, and thus can be used for manufacturing purposes.

[0153] In some embodiments, Form F is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising at least three peaks or at least four peaks selected from the group consisting of 6.8, 9.0, 13.7, 14.2, and 20.3° 2θ ± 0.2° 2θ.

[0154] In some embodiments, Form F is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 6.8, 9.0, and 14.2° 2θ ± 0.2° 2θ.

[0155] In some embodiments, Form F is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 6.8, 9.0, and 20.3° 2θ ± 0.2° 2θ.

[0156] In some embodiments, Form F is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 6.8, 9.0, 13.7, and 14.2° 2θ ± 0.2° 2θ.

[0157] In some embodiments, Form F is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 6.8, 9.0, 14.2, and 20.3° 2θ ± 0.2° 2θ.

[0158] In some embodiments, Form F is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 9.0, 13.7, 14.2, and 20.3° 2θ ± 0.2° 2θ.

[0159] In some embodiments, Form F is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 6.8, 9.0, 13.7, 14.2, 20.3, and 22.9° 2θ ± 0.2° 2θ.

[0160] In some embodiments, Form F is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 6.8, 9.0, 13.7, 14.2, 20.3, and 22.9 °2θ±0.1 °2θ.

[0161] In some embodiments, Form F is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising at least four peaks, at least five peaks, at least six peaks, at least seven peaks, at least eight peaks, or at least nine peaks selected from the group consisting of 6.8, 9.0, 13.7, 14.2, 15.7, 17.4, 17.8, 18.8, 20.3, and 22.9 °2θ±0.2 °2θ.

[0162] In some embodiments, Form F is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 6.8, 9.0, 13.7, 14.2, 15.7, 17.4, 17.8, 18.8, 20.3, and 22.9 °2θ ± 0.2 °2θ.

[0163] In some embodiments, Form F is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 6.8, 9.0, 13.7, 14.2, 15.7, 17.4, 17.8, 18.8, 20.3, and 22.9 °2θ±0.1 °2θ.

[0164] In some embodiments, Form F is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature comprising peaks at 6.8, 7.5, 9.0, 11.2, 13.7, 14.2, 15.2, 15.7, 16.9, 17.4, 17.8, 18.1, 18.8, 19.5, 19.9, 20.3, 20.6, 22.4, 22.9, 23.6, 24.1, 25.1, 27.4, 28.1, 28.5, 29.2, 30.1, and 30.7 °2θ ± 0.2 °2θ.

[0165] In some embodiments, Form F is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα at room temperature that is substantially as described above. Fig.14 is shown in .

[0166] Table 7 lists the Fig.14 X-ray powder diffraction peaks observed.

[0167]

[0168]

[0169] In some embodiments, Form F is substantially pure, ie, substantially free of other solid forms of Compound 1.

[0170] In some embodiments, provided herein are compositions comprising Compound 1 Form F, wherein the composition is at least 90% by weight Form F. In some embodiments, the composition is at least 91% by weight, at least 92% by weight, at least 93% by weight, at least 94% by weight, at least 95% by weight, at least 96% by weight, at least 97% by weight, at least 98% by weight, at least 99% by weight, or at least 99.5% by weight Form F. In some embodiments, the ratio of Form F to other solid forms of Compound 1 in the composition (by weight) is at least 90:10, at least 95:5, at least 98:2, at least 99:1, or at least 99.5:0.5.

[0171] III. Preparation Method

[0172] In one aspect, provided herein is a method of making Form B polymorph of Compound 1, comprising dissolving Compound 1 in tetrahydrofuran (THF), removing THF by rotary evaporation, slurrying the resulting solid in ethanol, thermally cycling the resulting slurry, filtering the slurry, and drying to isolate the Form B solid.

[0173] In another aspect, provided herein is a method of making Form B polymorph of Compound 1, comprising slurrying Form A of Compound 1 in ethanol, thermally cycling the resulting slurry, filtering the slurry and drying, and then slurrying the resulting solid in ethanol at an elevated temperature, filtering the slurry and drying to isolate the Form B solid.

[0174] In another aspect, provided herein are methods of making Form B polymorph of Compound 1, the methods comprising slurrying Compound 1 Form A in anhydrous ethanol at elevated temperature.

[0175] In another aspect, provided herein is a method of making Form B polymorph of Compound 1, the method comprising dissolving Compound 1 in ethanol and water, and crystallizing by adding water as an anti-solvent.

[0176] In another aspect, provided herein is a method of making Form C polymorph of Compound 1, comprising dissolving Compound 1 in a solvent mixture of THF and methanol, evaporating the solvent mixture, suspending the resulting solid in a solvent mixture of ethanol and water, and heating and then cooling the suspension.

[0177] In another aspect, provided herein is a method of making the Form C polymorph of Compound 1, comprising slurrying Compound 1 Form A in ethanol and then in THF, heating and then cooling the slurry, filtering the slurry and drying to isolate Form C.

[0178] In another aspect, provided herein is a method of making Form C polymorph of Compound I, the method comprising drying Compound I Form F in an oven at about 40°C for at least about 24 hours to produce Form C.

[0179] In another aspect, provided herein is a method of making the Form C polymorph of Compound 1, the method comprising suspending Compound 1 Form F in a mixture of ethanol and water, and drying the solid to isolate Form C.

[0180] In another aspect, provided herein is a method of making Form C polymorph of Compound 1, comprising dissolving Compound 1 in a mixture of ethanol and water at elevated temperature, cooling the solution to about room temperature, and then adding water.

[0181] In another aspect, provided herein is a method of making Form C polymorph of Compound 1, comprising dissolving Compound 1 in THF, removing the THF by rotary evaporation, slurrying the resulting material in ethanol and heptane, and thermally cycling the resulting slurry.

[0182] In another aspect, provided herein are methods of making Form D polymorph of Compound I, the methods comprising heating Compound I Form A to about 250 °C and cooling to about 30 °C.

[0183] In another aspect, provided herein is a method of making Form E polymorph of Compound 1, the method comprising slurrying Compound 1 Form A in anhydrous ethanol and thermally cycling the slurry.

[0184] In another aspect, provided herein is a method of making Form E polymorph of Compound 1, comprising slurrying Compound 1 Form A in anhydrous ethanol and stirring the resulting suspension, filtering the slurry and drying.

[0185] In another aspect, provided herein is a method of making Form E polymorph of Compound 1, the method comprising suspending Compound 1 Form F in ethanol.

[0186] In another aspect, provided herein is a method of making Form E polymorph of Compound 1, comprising suspending Compound 1 Form A in ethanol and shaking the resulting suspension, filtering the slurry and drying.

[0187] In another aspect, provided herein is a method for making the Form E polymorph of Compound 1, comprising suspending Compound 1 Form A in ethanol, stirring the resulting suspension, decanting the mother liquor, drying the solid, adding ethanol and stirring the compound in ethanol, filtering and drying to isolate the Form E solid.

[0188] In another aspect, provided herein is a method of making Form F polymorph of Compound 1, comprising dissolving Compound 1 in a solvent mixture of THF and methanol, evaporating the solvent mixture, suspending the resulting solid in a mixture of isopropanol and water, heating the suspension and then cooling the solution.

[0189] In another aspect, provided herein is a method of making Form F polymorph of Compound 1, comprising dissolving Compound 1 in a solvent mixture of THF and methanol, evaporating the solvent mixture, suspending the resulting solid in a mixture of THF and water, heating the suspension and then cooling the solution, and then evaporating the solvent.

[0190] In another aspect, provided herein is a method of making Form F polymorph of Compound 1, comprising dissolving Compound 1 in THF, removing THF by rotary evaporation, slurrying the resulting solid in isopropyl acetate, and thermally cycling the resulting slurry, followed by filtering the slurry and drying.

[0191] In another aspect, provided herein is a method of making Form F polymorph of Compound 1, comprising dissolving Compound 1 in a mixture of THF and water at elevated temperature, polish filtering the solution, partially removing THF by distillation, cooling the slurry, adding 1-butanol to the slurry and further cooling the slurry.

[0192] In some embodiments of various aspects of the preparation methods, the produced crystalline form is substantially pure, ie, substantially free of other forms of Compound I.

[0193] IV. Pharmaceutical Compositions

[0194] In one aspect, provided herein is a pharmaceutical composition comprising a crystalline form disclosed herein (or a combination thereof) and a pharmaceutically acceptable excipient. In another aspect, provided herein is a method for preparing a pharmaceutical composition, the method comprising providing a crystalline form disclosed herein and one or more pharmaceutically acceptable excipients, and forming a pharmaceutical composition from the crystalline form and the excipient.

[0195] In one aspect, the pharmaceutical composition can be used to treat hypertrophic cardiomyopathy (HCM), heart failure with preserved ejection fraction (HFpEF), and other diastolic dysfunction in humans and other subjects. The active agent is generally included in an amount sufficient to produce the desired effect on myocardial contractility (e.g., to reduce the systolic contractility that is usually abnormal in HCM) and to improve diastolic left ventricular relaxation. Such improved relaxation can alleviate the symptoms of hypertrophic cardiomyopathy and other causes of diastolic dysfunction.

[0196] The pharmaceutical composition for administering the compounds provided herein can be conveniently presented in unit dosage form and can be prepared by any method known in pharmaceutical and drug delivery technology. All methods include the step of associating the active ingredient with a carrier containing one or more auxiliary ingredients. In general, the pharmaceutical composition is prepared by uniformly and fully associating the crystalline form of the active ingredient with a fine solid carrier, and then (if necessary) molding the product into the desired formulation.

[0197] Pharmaceutical compositions containing the crystalline form may be in a form suitable for oral use, for example, in the form of tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, hard or soft capsules, buccal patches, chewing gums or chewable tablets. Compositions intended for oral use may be prepared according to any method known in the art of manufacturing pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, antioxidants and preservatives to provide pharmaceutically elegant and palatable preparations.

[0198] Tablets contain active ingredients mixed with non-toxic pharmaceutically acceptable excipients suitable for making tablets. These excipients may be, for example, inert diluents such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate or sodium phosphate; granulating and disintegrants such as corn starch or alginic acid; binders such as PVP, cellulose, PEG, starch, gelatin or gum arabic (acacia), and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated, or they may be enteric coated or otherwise coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide sustained action over a longer period of time. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate may be used. They may also be coated to form osmotic therapeutic tablets for controlled release.

[0199] Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with a liquid or oil medium, such as peanut oil, liquid paraffin or olive oil. In addition, emulsions may be prepared with non-water miscible ingredients, such as oils, and stabilized with surfactants, such as mono-diglycerides, PEG esters, etc.

[0200] Aqueous suspensions contain active materials mixed with excipients suitable for making aqueous suspensions. Such excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic; dispersing or wetting agents may be naturally occurring phospholipids (e.g., lecithin), or condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), or condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexanols (e.g., polyoxyethylene sorbitan monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexanol anhydrides (e.g., polyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives (e.g., ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate), one or more coloring agents, one or more flavoring agents, and one or more sweeteners (e.g., sucrose or saccharin).

[0201] Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil (e.g., peanut oil, olive oil, sesame oil, or coconut oil) or a mineral oil (e.g., liquid paraffin). Oily suspensions may contain thickeners, such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners (e.g., those described above) and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant (e.g., ascorbic acid).

[0202] Dispersible powders and granules suitable for preparing an aqueous suspension by adding water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Other excipients may also be present, such as sweeteners, flavoring agents and coloring agents.

[0203] The pharmaceutical compositions provided herein may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil (e.g., olive oil or peanut oil) or a mineral oil (e.g., liquid paraffin) or a mixture of these oils. Suitable emulsifiers may be naturally occurring gums, such as gum arabic or tragacanth; naturally occurring phospholipids, such as soybeans, lecithin, and esters or partial esters derived from fatty acids and hexanoic anhydride, such as sorbitan monooleate and condensation products of the partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents.

[0204] Syrups and elixirs can be formulated with sweeteners such as glycerol, propylene glycol, sorbitol or sucrose. Such preparations may also contain analgesics, preservatives, and flavoring and coloring agents. Oral solutions can be prepared in combination with, for example, cyclodextrins, PEGs, and surfactants.

[0205] The pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension. Such suspensions may be prepared according to known techniques using those suitable dispersing or wetting agents and suspending agents mentioned above. Sterile injectable preparations may also be sterile injectable solutions or suspensions in nontoxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that may be used are especially water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as suspending media. For this purpose, any mild fixed oil may be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids (e.g., oleic acid) may be used to prepare injectables.

[0206] The compounds provided herein can also be used in the form of suppositories for rectal administration of drugs. These compositions can be prepared by mixing drugs with suitable non-irritating excipients, which are solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycol. In addition, the compound can be administered by eye delivery through a solution or ointment. In addition, the transdermal delivery of the subject compound can be completed by iontophoresis patches and other modes. For topical use, creams, ointments, gels, solutions or suspensions containing the compounds provided herein are used.

[0207] The compound of the present invention can also be coupled to a carrier, which is a polymer suitable for a targeted drug carrier. Such polymers can include polyvinyl pyrrolidone, pyran copolymers, polyhydroxypropyl-methacrylamide-phenol, polyhydroxyethyl-asparagine-phenol or polyethylene oxide-polylysine substituted with palmitoyl residues. In addition, the compound provided herein can be coupled to a carrier, which is a biodegradable polymer that can be used to achieve controlled release of drugs, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, crosslinked or amphiphilic block copolymers of polylactic acid, polyglycolic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and hydrogels. Polymers and semipermeable polymer matrices can form molded products, such as valves, stents, tubing, prostheses, etc.

[0208] V. Methods of treating heart disease

[0209] Provided herein is a method for treating hypertrophic cardiomyopathy (HCM). The method comprises administering an effective amount of a crystalline form as provided herein (or a pharmaceutical composition as provided herein) to a subject in need thereof. In some embodiments, HCM is obstructive HCM. In some embodiments, HCM is non-obstructive HCM.

[0210] Also provided herein are methods for treating heart failure with preserved ejection fraction (HFpEF). The methods include administering an effective amount of a crystalline form as provided herein (or a pharmaceutical composition as provided herein) to a subject in need thereof.

[0211] Also provided herein are methods for treating diastolic dysfunction. The methods include administering an effective amount of a crystalline form as provided herein (or a pharmaceutical composition as provided herein) to a subject in need thereof.

[0212] Also provided herein are methods of treating left ventricular hypertrophy (LVH). The methods comprise administering an effective amount of a crystalline form as provided herein (or a pharmaceutical composition as provided herein) to a subject in need thereof.

[0213] The mutations that cause HCM cause significant disturbances in myosin mechanics. These mutations work by different mechanisms according to their positions in the myosin gene. The well-studied HCM mutations R403Q and R453C are located in different parts of the field of motion and cause different mechanical disturbances, resulting in a common result of increased force generation. Without wishing to be bound by any particular theory, it is believed that the compounds provided herein can be directly bound to mutant sarcomere proteins and correct their abnormal functions in cis (by affecting the same specific function) or trans (by changing the complementary function). Therefore, they can provide therapeutic benefits for HCM patients by counteracting the excessive contraction and / or relaxation associated with the disease.

[0214] Thus, provided herein are methods for treating hypertrophic cardiomyopathy (HCM) or a cardiac disorder having one or more pathophysiological features associated with HCM. The method comprises administering to a subject in need thereof an effective amount of a compound provided herein or a pharmaceutical composition thereof.

[0215] Diastolic dysfunction is present or is an important feature of a range of diseases, including but not limited to hypertrophic cardiomyopathy (HCM), heart failure with preserved ejection fraction (HFpEF, including active achalasia and ventricular stiffness (diabetic HFpEF)); dilated cardiomyopathy (DCM), ischemic cardiomyopathy, cardiac transplant allograft vasculopathy, restrictive cardiomyopathies, including inflammatory subgroups (e.g., Loefllers and EMF), infiltrative subgroups (e.g., amyloid subgroups, sarcoid subgroups, and XRT), storage subgroups (e.g., hemochromatosis, Fabry disease, and glycogen storage disease), idiopathic / inherited subgroups (e.g., Trop I (β-myosin HC), Trop T (α-cardiac actin), and desmin-related subgroups (usually including skeletal muscle)), congenital heart disease subgroups (including pressure-overload RV, Tetralogy of Fallot, and Tetralogy of Fallot). ofFallot, preoperative and early postoperative diastolic dysfunction, postoperative diastolic dysfunction) and pulmonary artery stenosis) and valvular heart disease (e.g., aortic stenosis, including elderly post-AVR / TAVR and congenital forms).

[0216] Other determinants of diastolic dysfunction using echocardiography are described in J Am Soc Echocardiogr. 29(4):277-314 (2016), the contents of which are incorporated herein for all purposes.

[0217] Subjects in need of treatment for diastolic dysfunction include subjects from a patient population characterized by non-obstructive hypertrophic cardiomyopathy, or subjects characterized by heart failure with preserved ejection fraction (HFpEF). Subjects in need of treatment for diastolic dysfunction include subjects exhibiting left ventricular stiffness as measured by echocardiography or left ventricular stiffness as measured by cardiac magnetic resonance. In some embodiments, the subject in need is from a patient population characterized by HFpEF.

[0218] Also provided herein is a method for treating a disease or condition selected from the group consisting of diastolic heart failure (e.g., diastolic heart failure with preserved ejection fraction), ischemic heart disease, angina pectoris, and restrictive cardiomyopathy, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein or a pharmaceutical composition thereof.

[0219] Also provided herein are methods of treating a disease or condition characterized by left ventricular hypertrophy (e.g., due to volume or pressure overload) selected from the group consisting of chronic mitral regurgitation, chronic aortic stenosis, and chronic systemic hypertension, optionally in combination with a therapy directed to correcting or alleviating the primary cause of volume or pressure overload, including valve repair / replacement or effective antihypertensive therapy, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

[0220] Also provided herein are methods of treating hypertrophic cardiomyopathy (HCM) or a cardiac disorder (e.g., a cardiac disorder with pathophysiological features associated with HCM), the methods comprising administering to a subject in need thereof an effective amount of a compound disclosed herein, or a pharmaceutical composition thereof, in combination with: a therapy that slows the progression of heart failure and attempts to prevent cardiac remodeling by downregulating neurohormonal stimulation of the heart (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, aldosterone receptor antagonists, or neuroendopeptidase inhibitors); a therapy that improves cardiac function by stimulating cardiac contractility (e.g., a positive inotropic agent, such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or a therapy that reduces cardiac preload (e.g., a diuretic, such as furosemide) or a therapy that reduces cardiac afterload (any class of vasodilators, including, but not limited to, calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin modulators).

[0221] Also provided herein is a crystalline form as disclosed herein, or a pharmaceutical composition thereof, for use as a medicament.

[0222] Also provided herein are crystalline forms disclosed herein, or pharmaceutical compositions thereof, for use in treating a disease or condition as disclosed herein, such as hypertrophic cardiomyopathy or other cardiac disorders.

[0223] Also provided herein is the use of a crystalline form as disclosed herein, or a pharmaceutical composition thereof, for the manufacture of a medicament for treating a disease or condition as disclosed herein, such as hypertrophic cardiomyopathy or other cardiac conditions.

[0224] The compounds disclosed herein can change the natural course of HCM and other diseases, rather than just alleviating symptoms. The mechanism of clinical benefit conferred to HCM patients can be extended to patients with other forms of heart disease sharing similar pathophysiology, with or without obvious genetic influences. For example, effectively treating HCM by improving ventricular relaxation during diastole can also be effective in a wider group characterized by diastolic dysfunction. The compound can specifically target the root cause of the disease or act on other downstream pathways. Therefore, the compound can also confer benefits to patients with diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris or restrictive cardiomyopathy. The compound can also promote beneficial ventricular remodeling due to left ventricular hypertrophy of volume or pressure overload; the left ventricular hypertrophy is, for example, chronic mitral regurgitation, chronic aortic stenosis or chronic systemic hypertension; combined with therapies (valve repair / replacement, effective antihypertensive therapy) intended to correct or alleviate the main causes of volume or pressure overload. By reducing left ventricular filling pressure, the compound can reduce the risk of pulmonary edema and respiratory failure. Reducing or eliminating functional mitral regurgitation and / or reducing left atrial pressure may reduce the risk of paroxysmal or permanent atrial fibrillation and, in turn, the attendant risk of arterial thromboembolic complications, including but not limited to cerebral arterial embolic stroke. Reducing or eliminating dynamic and / or static left ventricular outflow tract obstruction may reduce the likelihood of requiring septal reduction therapy, either surgical or percutaneous, and the risks of their attendant short-term and long-term complications.

[0225] Depending on the disease to be treated and the condition of the subject, the compounds provided herein can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection or implantation), implantation (e.g., when the compound is coupled to a stent device), inhalation spray, nasal, vaginal, rectal, sublingual or topical administration, and can be formulated separately or together into appropriate dosage unit preparations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles suitable for each administration route.

[0226] In the treatment or prevention of conditions requiring improved ventricular relaxation during diastole, an appropriate dosage level of Compound I is generally about 0.001 mg / kg patient weight / day to 100 mg / kg patient weight / day, which can be administered in a single or multiple doses. Preferably, the dosage level will be about 0.01 mg / kg / day to about 25 mg / kg / day; more preferably about 0.05 mg / kg / day to about 10 mg / kg / day. Suitable dosage levels may be about 0.01 mg / kg / day to 25 mg / kg / day, about 0.05 mg / kg / day to 10 mg / kg / day, or about 0.1 mg / kg / day to 5 mg / kg / day. Within this range, the dosage may be 0.005 mg / kg / day to 0.05 mg / kg / day, 0.05 mg / kg / day to 0.5 mg / kg / day, or 0.5 mg / kg / day to 5.0 mg / kg / day. The pharmaceutical composition preferably contains 1.0 mg to 1000 mg of Compound I, in particular 1.0 mg, 5.0 mg, 10.0 mg, 15.0 mg, 20.0 mg, 25.0 mg, 50.0 mg, 75.0 mg, 100.0 mg, 150.0 mg, 200.0 mg, 250.0 mg, 300.0 mg, 400.0 mg, 500.0 mg, 600.0 mg, 750.0 mg, 800.0 mg, 900.0 mg and 1000.0 mg, for symptomatic adjustment of the dosage of the intended patient. Such compositions can be used for oral administration, for example, in the form of tablets or capsules.

[0227] The compound or pharmaceutical composition thereof may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

[0228] It should be understood that the specific dosage level and dosage frequency for any particular patient may vary and will depend on a variety of factors, including the activity of the specific compound or pharmaceutically acceptable salt used, the metabolic stability and duration of action of the compound or its pharmaceutically acceptable salt, the age, weight, genetic characteristics, general health, sex and diet of the subject, as well as the mode and time of administration, rate of excretion, drug combination and the severity of the particular condition of the subject undergoing therapy.

[0229] The compounds and / or pharmaceutical compositions provided herein can be used in combination with other drugs for treating, preventing, suppressing or improving diseases or illnesses, and the compounds and compositions provided herein are useful for the diseases or illnesses. Such other drugs can be administered simultaneously or successively with the compounds or compositions provided herein by common routes and dosages. When the compounds or compositions provided herein are used simultaneously with one or more other drugs, pharmaceutical compositions containing such other drugs are preferred in addition to the compounds or compositions provided herein. Therefore, in addition to the compounds or compositions provided herein, the pharmaceutical compositions provided herein include those pharmaceutical compositions that also contain one or more other active ingredients or therapeutic agents. The weight ratio of the compound provided herein to the second active ingredient can vary and depends on the effective dose of each ingredient. Generally, the respective effective doses will be used. When the compound of the present invention is administered in combination with another therapeutic agent, the other therapeutic agent can be administered simultaneously, separately or successively with the compound of the present invention. The precise dosage regimen is commensurate with the properties of the therapeutic agent.

[0230] VI. Examples

[0231] Example 1: Characterization of form

[0232] X-ray Powder Diffraction (XRPD):

[0233] The XRPD data of Form B, Form E and Form F are obtained using a Bruker D8 Discover DaVinci with an XYZ stage. A 1 μS X-ray generator is operated using a Cu target (CuKα radiation) at 50 kV and 1 mA. The incident beam optical system includes a Montel mirror with a 0.3 mm collimator. Photon counting is performed using an Eiger2 R 500K detector in 2D, 2θ optimization mode. The sample to detector distance is 137.7 mm. Each sample is loaded into a glass capillary (1 mm in diameter). An exposure time of 1000 s and an approximate step length of 0.01 ° are used in the 2θ range of about 2-32 ° and data are collected at room temperature.

[0234] The XRPD data of Form C and Form D were obtained using a PANalytical X'pert Pro with a Cu target (CuKα radiation). The X-ray generator was operated at 40 kV and 40 mA and the Cu target (CuKα radiation) was run in transmission mode. Each sample was gently ground and loaded onto a porous plate with a Kapton or Mylar polymer film. An approximate step size of 0.01 ° was used in the 2θ range of about 3-35 ° and data were collected at room temperature.

[0235] Differential Scanning Calorimetry (DSC) :

[0236] Differential scanning calorimetry (DSC) experiments of Form B were performed using a TA Instruments-Discovery DSC 2500 with RCS90. Each sample was placed in a TZero aluminum DSC pan with a TZero cover, and the weight was accurately recorded. Data were collected between room temperature and a maximum temperature of about 350°C at a heating rate of 10°C / min.

[0237] Differential scanning calorimetry (DSC) experiments of Form C and Form E were performed using a Seiko DSC6200. Each sample was placed in a hermetically sealed aluminum DSC pan with a perforated lid, and the weight was accurately recorded. Data were collected between 20°C and a maximum temperature of about 330°C at a heating rate of 10°C / min.

[0238] Form D and Form F can be analyzed by DSC by any of the methods described above.

[0239] Thermogravimetric analysis (TGA) :

[0240] Thermogravimetric analysis (TGA) experiments of Form B were performed using a TA Instruments-Discovery TGA model 5500. The sample (approximately 10 mg) was placed in a pre-cleaned and tarred platinum pan and then loaded into the instrument furnace. The furnace was heated under nitrogen. Data were collected between room temperature and about 350° C. at a heating rate of 10° C. / min.

[0241] Simultaneous thermogravimetric / differential thermal analysis (TG / DTA) experiments of Form C, Form D and Form E were performed using a Seiko TG / DTA 7200. Each sample (about 5 mg) was placed in an open aluminum pan and then loaded into the instrument furnace. The furnace was heated under nitrogen. Data were collected between 20°C and about 400°C at a heating rate of 10°C / min.

[0242] Form F can be analyzed by TGA by any of the methods described above.

[0243] Vapor adsorption:

[0244] The vapor sorption experiment of Form B was carried out using a TA Instrument VTI-SA+ vapor sorption analyzer. The sample (about 10 mg) was placed in a pre-cleaned and tarred platinum pan and then loaded into the instrument chamber. The sample was dried at 60°C for 10 minutes until a loss rate of 0.005wt% / min was obtained. The sample was then isothermally maintained at 25°C while the %RH of the system was progressively changed between 4, 5, 15, 25, 35, 45, 55, 65, 75, 85, 95, 85, 75, 65, 55, 45, 35, 25, 15, 5, 4%RH. The equilibrium criterion was + / -0.01wt% for 35min, and the maximum equilibrium time for each step was 600min.

[0245] Form C, Form D, Form E and Form F can be analyzed by vapor sorption by the method described above. In particular, the procedure is well suited for the anhydrate Form C, Form D and Form E.

[0246] Single crystal X-ray analysis :

[0247] Single crystal X-ray data of form B were collected using a Bruker D8-Venture diffractometer equipped with a Photon III detector and monochromatic Cu Kα radiation. During data collection, the single crystal was kept at 100K. The measured intensity data were indexed and processed using the APEX3 program suite (BrukerAXS, Inc., 5465 East Cheryl Parkway, Madison, WI 53711 USA). The final unit cell parameters were determined using a complete data set. The structure was solved by the intrinsic phasing method and refined using the SHELXTL software package (GMSheldrick, SHELXTLv2018 / 3, Bruker AXS, Madison, WI USA) by full matrix least squares. Structural refinement involves minimizing the function defined by ∑w(|Fo|-|Fc|), where w is an appropriate weighting factor based on observed intensity errors, Fo is a structure factor based on measured reflections, and Fc is a structure factor based on calculated reflections. The consistency between the refined crystal structure model and the experimental X-ray diffraction data was evaluated by using the residual factors R = ∑||Fo|-|Fc|| / ∑|Fo| and wR = [∑w(|Fo|-|Fc|)2 / ∑w|Fo|]1 / 2. The difference Fourier map was checked at all stages of refinement. All non-hydrogen atoms were refined using anisotropic thermal shift parameters. Hydrogen atoms on carbon atoms were introduced using an idealized geometry with isotropic temperature factors and included in the structure factor calculation with fixed parameters. Hydrogen atoms on heteroatoms were positioned by residual electron density and were freely refined.

[0248] Single crystal X-ray data of Form E were collected using a Bruker D8-Venture diffractometer equipped with a Photon II detector and monochromatic Mo Kα radiation. During data collection, the single crystal was kept at 302K. The measured intensity data were indexed and processed using the APEX3 program suite (BrukerAXS, Inc., 5465 East Cheryl Parkway, Madison, WI 53711 USA). The final unit cell parameters were determined using a complete data set. The structure was solved by the intrinsic phasing method and refined using the SHELXTL software package (GMSheldrick, SHELXTL v2016 / 6, Bruker AXS, Madison, WI USA.) by full matrix least squares. Structural refinement involves minimizing the function defined by ∑w(|Fo|-|Fc|), where w is an appropriate weighting factor based on observed intensity errors, Fo is a structure factor based on measured reflections, and Fc is a structure factor based on calculated reflections. The consistency between the refined crystal structure model and the experimental X-ray diffraction data was evaluated by using the residual factors R = ∑||Fo|-|Fc|| / ∑|Fo| and wR = [∑w(|Fo|-|Fc|)2 / / ∑w|Fo|]1 / 2. The difference Fourier map was checked at all stages of refinement. All non-hydrogen atoms were refined using anisotropic thermal shift parameters. Hydrogen atoms on all atoms were introduced using an idealized geometry with isotropic temperature factors and included in the structure factor calculation with fixed parameters.

[0249] Example 2. Preparation of Form B

[0250] Example 2A:

[0251] Compound I was dissolved in tetrahydrofuran (THF) and the solvent was removed by rotary evaporation. 400 mg of the resulting solid was slurried in 12 mL of ethanol. The slurry was thermally cycled between ambient and 40 ° C with agitation for 96 hours in a 4 hour cycle. The slurry was filtered and dried at ambient for 1 hour. The solid consists of Form B.

[0252] Example 2B:

[0253] 2.3g of Form A was slurried in 20mL of ethanol. The slurry was divided into 2 bottles and 10mL of ethanol was added to each bottle. The slurry was thermally cycled between the environment and 40°C with a 4-hour cycle under agitation. The samples were filtered together and dried under vacuum at 40°C for 90 minutes. 20mL of ethanol was added to the material and the slurry was stirred at 60°C for 72 hours. The slurry was filtered and dried at 40°C for 2 hours. The solid consists of Form B.

[0254] Example 2C:

[0255] 3 g of Form A was slurried in 90 mL of anhydrous ethanol at 60° C. for 24 hours. The solid consisted of Form B. The conversion of Form A to Form B demonstrates the superior thermodynamic stability of Form B compared to Form A.

[0256] Example 2D:

[0257] A direct crystallization (using seed) process was performed to produce Form B. Ethanol (504.30 kg), water (197.70 kg) and Compound I Form F (31.76 kg) were charged to a 2000 L reactor. The charging port was rinsed with ethanol (141.15 kg). The reaction mass was warmed to 75 ± 5 ° C. The reaction mass was stirred at 75 ± 5 ° C for 0.5 hours (clear solution). The reaction mass was cooled to 60 ± 2 ° C. At 60 ± 2 ° C, Form B seeds (0.5% w / w in 175.5 g in ethanol) in an ethanol suspension were charged to the reaction mass. The slurry was stirred at 60 ± 2 ° C for 1 hour. The slurry was cooled to 58 ± 4 ° C. The slurry was stirred at 58 ± 4 ° C for 2 hours. At 58 ± 4 ° C within 1 hour, water (64.05 kg) was charged to the slurry. The slurry was stirred at 58 ± 4 ° C for 3 hours. At 58 ± 4 ° C, within 1 hour, water (51.00 kg) was loaded into the slurry. At 58 ± 4 ° C, within 2.5 hours, water (160.50 kg) was continued to be loaded into the slurry. At 58 ± 4 ° C, within 3 hours, water (319.70 kg) was continued to be loaded into the slurry. The slurry was stirred at 58 ± 4 ° C for 3 hours. Within 5 hours, the slurry was cooled to 10 ± 5 ° C. The slurry was stirred at 10 ± 5 ° C for 4 hours. The slurry was filtered by centrifugation. The filter cake was rinsed with an ethanol-water mixture (1: 1, 51.00 kg + 63.95 kg). The filter cake was dried at 50 ± 10 ° C for 10 hours. 28.95 kg of Compound I Form B was obtained.

[0258] Example 3. Preparation of Form C

[0259] Example 3A:

[0260] 8mg of Compound I was dissolved in 1mL of 80:20THF:MeOH. The solvent was evaporated at 40°C under a stream of nitrogen. The resulting solid was suspended in 800uL of 50:50 ethanol:water at room temperature under magnetic stirring. The suspension was heated to 80°C, which resulted in the dissolution of the solid. The solution was cooled to 10°C at a cooling rate of 0.1°C / min, resulting in a suspension. The solid consists of Form C.

[0261] Example 3B:

[0262] 500 mg of Form A was slurried in 20 mL of ethanol at ambient for 16 h. The slurry was filtered and re-slurried in 10 mL of tetrahydrofuran, heated to 40 °C for 1 hour and cooled to ambient. The slurry was filtered and dried at 40 °C for 16 hours. The solid consisted of Form C.

[0263] Example 3C:

[0264] 500 mg of Form F material was dried in an oven at 40°C under vacuum for 24 hours. The solid consisted of Form C.

[0265] Example 3D:

[0266] 100 mg of Form F was suspended in ethanol (0.25 mL) and water (3.75 mL) at room temperature overnight. The solid was dried at 50° C. for 2 days. The solid consisted of Form C.

[0267] Example 3E:

[0268] 200 mg of Compound I was dissolved in 5 mL of ethanol and 1.24 mL of water at 80°C. The solution was cooled to room temperature. 3.72 mL of water was added in less than 1 minute, which immediately produced a slurry. The solid consisted of Form C.

[0269] Example 3F:

[0270] Compound I was dissolved in tetrahydrofuran (THF) and the solvent removed by rotary evaporation. 50 mg of the resulting material was slurried in 50:50 ethanol:heptane and then thermocycled between ambient and 40° C. in 4 hour cycles for 24 hours. The solid consisted of Form C.

[0271] Example 4. Preparation of Form D

[0272] Form A was heated to 250° C. and immediately cooled to 30° C. The solid consisted of Form D.

[0273] Example 5. Preparation of Form E

[0274] Example 5A:

[0275] 6 g of Form A was slurried in 180 mL of absolute ethanol. The slurry was thermally cycled between 20°C and 40°C with agitation for 96 hours in 4 hour cycles. The solid consisted of Form E.

[0276] Example 5B:

[0277] 3 g of Form A was slurried in 90 mL of anhydrous ethanol. The suspension was stirred at 25° C. for 24 hours. The solid was collected by filtration and dried at 35° C. overnight. The solid consisted of Form E.

[0278] Example 5C:

[0279] 100 mg of Form F was suspended in 3 mL of ethanol at room temperature overnight. The resulting solid was Form E.

[0280] Example 5D:

[0281] 200 mg of Form A was suspended in 3 mL of ethanol and shaken at ambient temperature for 72 hours. The material was then dried at ambient for 21 hours. The solid consisted of Form E.

[0282] Example 5E:

[0283] 500mg of Form A batch was suspended in 7.5mL of ethanol. The slurry was stirred at ambient temperature for 20 hours. The mother liquor was decanted and the solid was dried in an oven at 40°C under vacuum for 24 hours. 50mg of material was retained and 7.5mL of ethanol was added to the remaining material. The slurry was stirred at ambient temperature for 96 hours. The material was then dried in an oven at 40°C under vacuum for 24 hours. The solid consists of Form E.

[0284] Example 6. Preparation of Form F

[0285] Example 6A:

[0286] 8 mg of Compound I was dissolved in 1 mL of 80:20 THF:MeOH. The solvent was evaporated at 40 ° C under a stream of N2. The resulting solid was suspended in 400 uL of 50:50 isopropanol (IPA): water under magnetic stirring. The suspension was heated to 80 ° C, which resulted in the dissolution of the solid. The solution was cooled to 10 ° C at a cooling rate of 0.1 ° C / min to produce a suspension. The solid consists of Form F.

[0287] Example 6B:

[0288] 8 mg of Compound I was dissolved in 1 mL of 80:20 THF:MeOH. The solvent was evaporated at 40°C under a stream of N2. The resulting solid was suspended in 400 uL of 19:174 water:THF under magnetic stirring. The suspension was heated to 60°C, which resulted in the solid dissolving. The solution was cooled to 10°C and the solvent was evaporated under nitrogen. The solid consisted of Form F.

[0289] Example 6C:

[0290] Compound I was dissolved in THF and the solvent was removed by rotary evaporation. 400 mg of the resulting solid was slurried in 12 mL of isopropyl acetate. The slurry was then thermally cycled between ambient and 40 ° C with a 4 hour cycle for 24 hours under agitation. The slurry was then filtered and dried at ambient for 1 hour. The solid consisted of Form F.

[0291] Example 6D:

[0292] 70 g of Compound I was dissolved in 890 mL of 90:10 THF:water at 65 °C in a reactor under agitation. The solution was removed from the reactor and polished and filtered. The solution was transferred back to the reactor. The slurry was observed at 45 °C. THF was removed by distillation at 85 °C until the volume of the slurry reached 300 mL. The slurry was cooled to 60 °C and 555 mL of 1-butanol was added. The batch was cooled to 20 °C and solidified overnight. The solid consisted of Form F.

[0293] Example 7. Preparation of Form A

[0294] U.S. Patent Application Publication No. 2020 / 0165247A1 discloses Form A of Compound 1, referred to therein as Form 1 polymorph, the entirety of which is incorporated herein by reference. The X-ray powder diffraction pattern of Form A (i.e., Form 1 polymorph) is provided as a Figure 1 Form A can also be prepared according to the following method:

[0295] Under N2, methanol (MeOH) (154.70kg) was loaded into a 300L reactor. The solution was cooled to -10 ± 5°C. Compound I Form F (7.8kg) was loaded into the reactor. The feed port was rinsed with MeOH (12.0kg). The slurry was stirred for 2 hours at -10 ± 5°C. The sample was taken out for XRPD. The pattern of Form F disappeared completely. The slurry was filtered by centrifugation. The filter cake was rinsed with MeOH (12.1kg) and 3.69kg of wet material was obtained. The turbid mother liquor was filtered by vacuum filtration. The filter cake was rinsed with MeOH (24.70kg*2) and 7.77kg of wet material was obtained. The material was dried by gradually increasing the oven temperature to 65 ± 10°C within 38 hours, and finally dried at 65 ± 10°C for 24 hours until the MeOH content was less than 0.3% by 1H NMR. 6.0kg of Compound I material was obtained, which was characterized as Form A.

[0296] Example 8. Stability study

[0297] The relative stability of four anhydrate forms, Form A, Form B, Form C, and Form E, was evaluated. Form B was identified as a pharmaceutically useful form of particular interest, as demonstrated by its thermodynamic stability in competitive slurry assays. Further testing of Form B demonstrated that Form B remained unchanged after 24 hours of shaking in certain biologically relevant media, and that Form B remained stable when subjected to heat and humidity treatments.

[0298] Competitive slurry

[0299] Competitive slurry experiments between Form B and Form E in ethanol showed that Form B was more stable than Form E at 22.5°C and 60°C. Competitive slurry experiments between Form B and Form C in ethanol showed that Form B was more stable than Form C at 10°C and 60°C. Competitive slurry experiments between Form B and Form A in ethanol showed that Form B was more stable than Form A at 10°C and 60°C. The results have shown that Form B is the most thermodynamically stable anhydrous form compared to Form A, Form C, and Form E over the temperature range covered by these experiments.

[0300] Solid-state stability in biorelevant media

[0301] Form B was added to biorelevant media (pH 1 HCl 0.1 M; pH 3.05 Citrate 50 mM; pH 7.4 Phosphate 50 mM; Fassif pH 6.5; Fessif pH 5.0) and the solid state stability in the media was determined. The procedure is described in more detail as follows:

[0302] Preparation of biorelevant media

[0303] pH 1 HCl 0.1M: Dilute 8.33 mL HCl to 100 mL with water. pH 1.02.

[0304] pH 3.05 Citrate 50 mM: Mix 82 mL 0.1 M citric acid and 18 mL 0.1 M sodium citrate together. pH = 3.07.

[0305] pH 7.4 Phosphate 50 mM: Dissolve 50 mL 0.2 M KH2PO4 and 39.1 mL 0.2 M NaOH in water and dilute to 200 mL. pH 7.39.

[0306] Fassif pH 6.5: Dissolve 23.4 mg NaOH, 224.7 mg NaH2PO4·2H2O and 304.3 mg NaCl in water and dilute to 50 mL. Dissolve 33.6 mg SIF powder in 15 mL FaSSIF buffer solution. Keep the solution stirred and equilibrate for 2 hours under ambient conditions away from light. pH = 6.37.

[0307] Fessif pH 5.0: Dissolve 202.6 mg NaOH, 432.7 mg acetic acid and 591.3 mg NaCl in water and dilute to 50 mL. The pH of the solution is 4.99. Dissolve 168 mg SIF powder in 15 mL FeSSIF buffer solution. Keep the solution stirred and equilibrated for 2 hours under ambient conditions protected from light. pH = 4.94.

[0308] Preparation of test solutions

[0309] 30-50 mg of Form B were weighed into a 12 mL sample vial, and then 3 mL of the test medium was added respectively. The suspension was kept shaking at 200 rpm at 37° C. for 24 hours. After 24 hours, the suspension was filtered and the filter cake was characterized by XRPD.

[0310] The results show that Form B is stable in biologically relevant media under the conditions tested and remains Form B by XRPD after 24 hours in media.

[0311] Stability study of Form B

[0312] The stability study of Form B (before grinding) was conducted at 80°C for two weeks and at 40°C / 75%RH for one month. Purity was determined by HPLC and stability was determined by XRPD. Purity (99.9% by HPLC) and crystalline form (by XRPD) remained unchanged after testing, indicating that Form B is stable under those conditions. The stability of the ground Form B was also conducted under the same conditions. The ground Form B did not show any degradation after being placed at 40°C / 75%RH for four weeks. After treatment at 80°C for four weeks, a decrease of 0.8% in the purity of the ground Form B was detected. Based on XRPD, Form B remained unchanged after heat and humidity treatment.

[0313] Other Implementations

[0314] Although the foregoing invention has been described in detail by way of illustration and example for the purpose of clear understanding, it will be appreciated by those skilled in the art that certain changes and modifications may be implemented within the scope of the appended claims. In addition, the full text of each reference provided herein is incorporated by reference to the same extent as if each reference were individually incorporated by reference. In the event of a conflict between the present application and the reference provided herein, the present application shall prevail.

Claims

1. A Form B polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

2. The polymorph of claim 1, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα at room temperature, the pattern comprising at least three peaks selected from the group consisting of 5.5, 7.1, 9.3, 16.5 and 19.0° 2θ ± 0.2° 2θ.

3. The polymorph of claim 1, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα at room temperature, the pattern comprising peaks at 5.5, 9.3 and 19.0° 2θ ± 0.2° 2θ.

4. The polymorph of claim 1, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα at room temperature, the pattern comprising peaks at 9.3, 16.5 and 19.0° 2θ ± 0.2° 2θ.

5. The polymorph of claim 1, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα at room temperature, the pattern comprising peaks at 5.5, 9.3, 16.5 and 19.0° 2θ ± 0.2° 2θ.

6. The polymorph of claim 1, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα at room temperature, the pattern comprising peaks at 5.5, 7.1, 9.3 and 19.0° 2θ ± 0.2° 2θ.

7. The polymorph of claim 1, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 5.5, 7.1, 9.3, 16.5, 19.0 and 22.3° 2θ ± 0.2° 2θ.

8. The polymorph of claim 1 , characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα at room temperature, the pattern comprising a peak at 5.5°2θ±0.2°2θ and at least four peaks selected from the group consisting of 7.1, 8.7, 9.3, 13.8, 16.2, 16.5, 17.2, 19.0 and 22.3°2θ±0.2°2θ.

9. The polymorph of claim 1, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 5.5, 7.1, 8.7, 9.3, 13.8, 16.2, 16.5, 17.2, 19.0 and 22.3° 2θ ± 0.2° 2θ.

10. The polymorph of claim 1, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 5.5, 7.1, 8.7, 9.3, 13.8, 15.8, 16.2, 16.5, 17.2, 18.5, 19.0, 19.3, 22.3, 23.1, 23.4, 23.7, 26.2, 27.3, 27.9, and 30.1 °2θ±0.2 °2θ.

11. The polymorph of claim 1 , characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα at room temperature, the pattern comprising a peak at 5.5°2θ±0.2°2θ and at least two peaks selected from the group consisting of 7.1, 8.7, 9.3, 13.8, 16.2, 16.5, 17.2, 19.0, and 22.3°2θ±0.2°2θ.

12. The polymorph of claim 1, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα at room temperature, the pattern comprising a peak at 5.5°2θ±0.2°2θ and at least two peaks selected from the group consisting of 7.1, 9.3, 16.5 and 19.0°2θ±0.2°2θ.

13. The polymorph of claim 1, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα at room temperature, the pattern comprising a peak at 5.5°2θ±0.2°2θ and at least three peaks selected from the group consisting of 7.1, 8.7, 9.3, 13.8, 16.2, 16.5, 17.2, 19.0 and 22.3°2θ±0.2°2θ.

14. The polymorph of claim 1 characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, said pattern being substantially as shown in FIG.

2.

15. The polymorph of any one of claims 1 to 14, characterized by a DSC thermogram comprising an endotherm with an onset of about 307°C.

16. The polymorph of claim 1, characterized by (i) an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα at room temperature, the pattern comprising peaks at 5.5, 9.3, and 19.0° 2θ ± 0.2° 2θ, and (ii) a DSC thermogram comprising an endotherm with an onset of about 307°C.

17. The polymorph of claim 15, characterized by a DSC thermogram substantially as shown in Figure 3.

18. The polymorph of any one of claims 1 to 17, characterized in that it exhibits negligible weight loss prior to decomposition as measured by TGA.

19. The polymorph of claim 18, characterized by a TGA thermogram substantially as shown in Figure 4.

20. The polymorph of any one of claims 1 to 19, characterized by a percent weight gain of less than 0.05% up to 95% RH as measured by a vapor sorption analyzer.

21. The polymorph of any one of claims 1 to 20, characterized by a triclinic system having a P1 space group.

22. The polymorph of claim 1, characterized by (i) an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα at room temperature, the pattern comprising peaks at 5.5, 9.3 and 19.0° 2θ ± 0.2° 2θ, and (ii) a triclinic system with a P1 space group.

23. The polymorph of claim 1, characterized by (i) an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα at room temperature, the pattern comprising peaks at 5.5, 9.3 and 19.0°2θ±0.2°2θ; (ii) a triclinic system with a P1 space group; and (iii) a DSC thermogram comprising an endotherm with an onset of about 307°C.

24. The polymorph of claim 21, characterized in that at a temperature of 100 Kelvin, the unit cell size is α=83.9±1.0°, β=80.0±1.0°, and γ=75.1±1.0°.

25. The polymorph of any one of claims 1 to 24, wherein the polymorph is substantially free of other solid forms of Compound 1.

26. A composition comprising the Form B polymorph of any one of claims 1 to 25, wherein the composition is at least 90% Form B by weight.

27. The composition of claim 26, wherein the composition is at least 99% by weight Form B.

28. A composition comprising the Form B polymorph of any one of claims 1 to 25, wherein the weight ratio of the Form B polymorph to other solid forms of Compound 1 in the composition is at least 90:

10.

29. The composition of claim 28, wherein the weight ratio of the Form B polymorph to other solid forms of Compound 1 in the composition is at least 99:

1.

30. A Form C polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

31. The polymorph of claim 30, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising at least three peaks selected from the group consisting of 7.5, 13.8, 16.4, 17.4, 20.1 and 27.7° 2θ ± 0.2° 2θ.

32. The polymorph of claim 30, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 7.5, 16.4 and 20.1° 2θ ± 0.2° 2θ.

33. The polymorph of claim 30, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 7.5, 13.8, 16.4 and 20.1° 2θ ± 0.2° 2θ.

34. The polymorph of claim 30, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 7.5, 16.4, 20.1 and 27.7° 2θ ± 0.2° 2θ.

35. The polymorph of claim 30, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 7.5, 13.8, 16.4, 17.4, 20.1 and 27.7° 2θ ± 0.2° 2θ.

36. The polymorph of claim 30, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising at least five peaks selected from the group consisting of 7.5, 8.2, 13.8, 15.2, 15.6, 16.4, 17.4, 20.1, 22.3 and 27.7° 2θ ± 0.2° 2θ.

37. The polymorph of claim 30, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 7.5, 8.2, 13.8, 15.2, 15.6, 16.4, 17.4, 20.1, 22.3 and 27.7° 2θ ± 0.2° 2θ.

38. The polymorph of claim 30, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 7.5, 8.2, 13.8, 14.7, 15.2, 15.6, 16.4, 17.4, 17.8, 20.1, 20.5, 20.9, 21.2, 21.7, 22.3, 22.6, 23.0, 23.5, 24.5, 25.0, 25.6, 26.7, 27.7, 28.2, 28.5, 29.4, 29.9, 30.8, and 31.7 °2θ ± 0.2 °2θ.

39. The polymorph of claim 30, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, said pattern being substantially as shown in Figure 6.

40. The polymorph of any one of claims 30 to 39, characterized by a DSC thermogram comprising an endotherm with an onset of about 306°C.

41. The polymorph of claim 40, characterized by a DSC thermogram substantially as shown in Figure 7.

42. The polymorph of any one of claims 30 to 41 , characterized in that it exhibits negligible weight loss prior to decomposition as measured by TGA.

43. The polymorph of claim 42, characterized by a TGA thermogram substantially as shown in Figure 8.

44. The polymorph of any one of claims 30 to 43, wherein the polymorph is substantially free of other solid forms of Compound 1.

45. A composition comprising the Form C polymorph of any one of claims 30 to 44, wherein the composition is at least 90% Form C by weight.

46. ​​The composition of claim 45, wherein the composition is at least 99% by weight Form C.

47. A composition comprising the Form C polymorph of any one of claims 30 to 44, wherein the weight ratio of the Form C polymorph to other solid forms of Compound 1 in the composition is at least 90:

10.

48. The composition of claim 47, wherein the weight ratio of the Form C polymorph to other solid forms of Compound 1 in the composition is at least 99:

1.

49. A Form D polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

50. The polymorph of claim 49, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising at least three peaks selected from the group consisting of 11.1, 15.0, 18.3, 19.8, 20.2, 22.5 and 25.9° 2θ ± 0.2° 2θ.

51. The polymorph of claim 49, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 11.1, 15.0, and 25.9° 2θ ± 0.2° 2θ.

52. The polymorph of claim 49, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 11.1, 15.0, 19.8 and 25.9° 2θ ± 0.2° 2θ.

53. The polymorph of claim 49, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 11.1, 15.0, 18.3, 19.8, 20.2, 22.5 and 25.9° 2θ ± 0.2° 2θ.

54. The polymorph of claim 49, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising at least five peaks selected from the group consisting of 11.1, 15.0, 18.3, 19.8, 20.2, 22.5, 23.0, 25.0, 25.9 and 28.2° 2θ ± 0.2° 2θ.

55. The polymorph of claim 49, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 11.1, 15.0, 18.3, 19.8, 20.2, 22.5, 23.0, 25.0, 25.9 and 28.2° 2θ ± 0.2° 2θ.

56. The polymorph of claim 49, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 11.1, 14.0, 15.0, 15.4, 18.3, 19.3, 19.8, 20.2, 20.7, 22.5, 23.0, 25.0, 25.9, 26.7, 27.4, 28.2, 30.1, and 31.8 °2θ ± 0.2 °2θ.

57. The polymorph of claim 49, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, said pattern being substantially as shown in FIG.

9.

58. The polymorph of any one of claims 49 to 57, characterized in that it exhibits negligible weight loss prior to decomposition as measured by TGA.

59. The polymorph of claim 58, characterized by a TGA thermogram substantially as shown in Figure 10.

60. The polymorph of any one of claims 49 to 59, wherein the polymorph is substantially free of other solid forms of Compound 1.

61. A composition comprising the Form D polymorph of any one of claims 49 to 60, wherein the composition is at least 90% Form D by weight.

62. The composition of claim 61, wherein the composition is at least 99% by weight Form D.

63. A composition comprising the Form D polymorph of any one of claims 49 to 60, wherein the weight ratio of the Form D polymorph to other solid forms of Compound 1 in the composition is at least 90:

10.

64. The composition of claim 63, wherein the weight ratio of the Form D polymorph to other solid forms of Compound 1 in the composition is at least 99:

1.

65. A Form E polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

66. The polymorph of claim 65, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising at least three peaks selected from the group consisting of 4.1, 8.6, 16.5, 17.7 and 23.2° 2θ ± 0.2° 2θ.

67. The polymorph of claim 65, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 8.6, 17.7 and 23.2° 2θ ± 0.2° 2θ.

68. The polymorph of claim 65, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 4.1, 8.6, and 16.5° 2θ ± 0.2° 2θ.

69. The polymorph of claim 65, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 4.1, 8.6, and 17.7° 2θ ± 0.2° 2θ.

70. The polymorph of claim 65, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 8.6, 16.5, 17.7 and 23.2° 2θ ± 0.2° 2θ.

71. The polymorph of claim 65, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 8.6, 17.7, 22.3 and 23.2° 2θ ± 0.2° 2θ.

72. The polymorph of claim 65, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 4.1, 8.6, 16.5, 17.7, 22.3 and 23.2° 2θ ± 0.2° 2θ.

73. The polymorph of claim 65, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising at least five peaks selected from the group consisting of 4.1, 7.2, 8.6, 13.6, 15.7, 16.5, 17.7, 19.3, 22.3 and 23.2° 2θ ± 0.2° 2θ.

74. The polymorph of claim 65, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 4.1, 7.2, 8.6, 13.6, 15.7, 16.5, 17.7, 19.3, 22.3 and 23.2° 2θ ± 0.2° 2θ.

75. The polymorph of claim 65, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 4.1, 7.2, 7.9, 8.6, 13.6, 14.3, 15.3, 15.7, 16.1, 16.5, 17.3, 17.7, 18.3, 18.7, 19.3, 21.1, 21.7, 22.3, 23.2, 26.4, 27.6, 28.5, 28.8, and 30.2° 2θ ± 0.2° 2θ.

76. The polymorph of claim 65, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising a peak at 4.1°2θ±0.2°2θ and at least two peaks selected from the group consisting of 8.6, 16.5, 17.7, and 23.2°2θ±0.2°2θ.

77. The polymorph of claim 65, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, said pattern being substantially as shown in Figure 11.

78. The polymorph of any one of claims 65 to 77, characterized by a DSC thermogram comprising an endotherm with an onset of about 304°C.

79. The polymorph of claim 65, characterized by (i) an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 8.6, 17.7, and 23.2° 2θ ± 0.2° 2θ, and (ii) a DSC thermogram comprising an endotherm with an onset of about 304°C.

80. The polymorph of claim 78, characterized by a DSC thermogram substantially as shown in Figure 12.

81. The polymorph of any one of claims 65 to 80, characterized in that it exhibits negligible weight loss prior to decomposition as measured by TGA.

82. The polymorph of claim 81 , characterized by a TGA thermogram substantially as shown in FIG.

13.

83. The polymorph of any one of claims 65 to 82, characterized by a monoclinic system having a C2 space group.

84. The polymorph of claim 65, characterized by (i) an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα at room temperature, the pattern comprising peaks at 8.6, 17.7 and 23.2° 2θ ± 0.2° 2θ, and (ii) a monoclinic system with a C2 space group.

85. The polymorph of claim 65, characterized by (i) an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα at room temperature, the pattern comprising peaks at 8.6, 17.7, and 23.2° 2θ ± 0.2° 2θ, (ii) a monoclinic system with a C2 space group, and (iii) a DSC thermogram comprising an endotherm with an onset of about 304°C.

86. The polymorph of claim 83, characterized in that at a temperature of 302 Kelvin, the unit cell size is α=90.0±1.0°, β=95.7±1.0°, and γ=90.0±1.0°.

87. The polymorph of any one of claims 65 to 86, wherein the polymorph is substantially free of other solid forms of Compound 1.

88. A composition comprising the Form E polymorph of any one of claims 65 to 87, wherein the composition is at least 90% Form E by weight.

89. The composition of claim 88, wherein the composition is at least 99% by weight Form E.

90. A composition comprising the Form E polymorph of any one of claims 65 to 87, wherein the weight ratio of the Form E polymorph to other solid forms of Compound 1 in the composition is at least 90:

10.

91. The composition of claim 90, wherein the weight ratio of the Form E polymorph to other solid forms of Compound 1 in the composition is at least 99:

1.

92. A Form F polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

93. The polymorph of claim 92, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising at least three peaks selected from the group consisting of 6.8, 9.0, 13.7, 14.2 and 20.3° 2θ ± 0.2° 2θ.

94. The polymorph of claim 92, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 6.8, 9.0, and 14.2° 2θ ± 0.2° 2θ.

95. The polymorph of claim 92, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 6.8, 9.0, and 20.3° 2θ ± 0.2° 2θ.

96. The polymorph of claim 92, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 6.8, 9.0, 13.7 and 14.2° 2θ ± 0.2° 2θ.

97. The polymorph of claim 92, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 6.8, 9.0, 14.2 and 20.3° 2θ ± 0.2° 2θ.

98. The polymorph of claim 92, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 9.0, 13.7, 14.2, and 20.3° 2θ ± 0.2° 2θ.

99. The polymorph of claim 92, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 6.8, 9.0, 13.7, 14.2, 20.3 and 22.9° 2θ ± 0.2° 2θ.

100. The polymorph of claim 92, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising at least five peaks selected from the group consisting of 6.8, 9.0, 13.7, 14.2, 15.7, 17.4, 17.8, 18.8, 20.3 and 22.9 °2θ±0.2 °2θ.

101. The polymorph of claim 92, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 6.8, 9.0, 13.7, 14.2, 15.7, 17.4, 17.8, 18.8, 20.3 and 22.9° 2θ ± 0.2° 2θ.

102. The polymorph of claim 92, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, the pattern comprising peaks at 6.8, 7.5, 9.0, 11.2, 13.7, 14.2, 15.2, 15.7, 16.9, 17.4, 17.8, 18.1, 18.8, 19.5, 19.9, 20.3, 20.6, 22.4, 22.9, 23.6, 24.1, 25.1, 27.4, 28.1, 28.5, 29.2, 30.1, and 30.7 °2θ ± 0.2 °2θ.

103. The polymorph of claim 92, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Ka at room temperature, said pattern being substantially as shown in Figure 14.

104. The polymorph of any one of claims 92 to 103, wherein the polymorph is substantially free of other solid forms of Compound 1.

105. A composition comprising the Form F polymorph of any one of claims 92 to 104, wherein the composition is at least 90% Form F by weight.

106. The composition of claim 105, wherein the composition is at least 99% by weight Form F.

107. A composition comprising the Form F polymorph of any one of claims 92 to 104, wherein the weight ratio of the Form F polymorph to other solid forms of Compound 1 in the composition is at least 90:

10.

108. The composition of claim 107, wherein the weight ratio of the Form F polymorph to other solid forms of Compound 1 in the composition is at least 99:

1.

109. A pharmaceutical composition comprising a polymorph of Form B, Form C, Form D, Form E or Form F according to any one of the preceding claims, or any combination thereof, and a pharmaceutically acceptable excipient.

110. The pharmaceutical composition of claim 109, comprising the Form B polymorph of any one of claims 1 to 25 or the composition of any one of claims 26 to 29.

111. A method of treating a cardiac disease or disorder, the method comprising administering to a subject in need thereof an effective amount of the polymorph, composition or pharmaceutical composition of any one of the preceding claims.

112. The method of claim 111, wherein the cardiac disease or disorder is hypertrophic cardiomyopathy (HCM).

113. The method of claim 111, wherein the cardiac disease or condition is heart failure with preserved ejection fraction (HFpEF).

114. The method of claim 111, wherein the cardiac disease or disorder is diastolic dysfunction.

115. The method of claim 111, wherein the cardiac disease or condition is left ventricular hypertrophy.

116. The method of any one of claims 111 to 115, wherein the polymorph or composition is the Form B polymorph of any one of claims 1 to 25 or the composition of any one of claims 26 to 29.

117. A method of preparing a pharmaceutical composition, the method comprising providing a polymorph or composition as described in any one of the preceding claims and one or more pharmaceutically acceptable excipients, and forming a pharmaceutical composition from the polymorph and the one or more pharmaceutically acceptable excipients.

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