WO2022189599A1

WO2022189599A1 - Crystalline forms of mavacamten for the treatment of hcm

Info

Publication number: WO2022189599A1
Application number: PCT/EP2022/056267
Authority: WO
Inventors: Doris Braun; Ulrich Griesser; Marijan STEFINOVIC
Original assignee: Sandoz Ag
Priority date: 2021-03-12
Filing date: 2022-03-10
Publication date: 2022-09-15

Abstract

The present invention relates to anhydrous crystalline forms of mavacamten and processes for their preparation. Furthermore, the invention relates to a pharmaceutical composition comprising an anhydrous crystalline form of the present invention and at least one pharmaceutically acceptable excipient. The pharmaceutical composition of the present invention can be used as a medicament, in particular for the treatment of hypertrophic cardiomyopathy (HCM).

Description

WO 2022/189599 _ j _ PCT/EP2022/056267

CRYSTALLINE FORMS OF MAVACAMTEN FOR THE TREATMENT OF HCM

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION Mavacamten is an oral cardiac myosin inhibitor investigated for the treatment of symptomatic obstructive hypertrophic cardiomyopathy (HCM), non-obstructive HCM and precision diastolic disease. The chemical name of macacamten is fV)-3-isopropyl-6-((l - phenylethyl)amino)pyrimidine-2,4( l//,3//)-dione. Mavacamten can be represented by the following chemical structure according to Formula (A)

Formula (A).

Mavacamten and its preparation are disclosed in WO 2014/205223 Al. In example 1 mavacamten is obtained as white solid after precipitation from ethyl acetate and further stirring in a solvent mixture of ethyl acetate/ «-hexane. The same process is disclosed in example 1 of WO 2019/028360 Al. Both documents are silent about the nature of the solid-state form obtained though.

Different solid-state forms of an active pharmaceutical ingredient (API) often possess different properties. Differences in physicochemical properties of solid-state forms can play a crucial role for the improvement of pharmaceutical compositions, for example, pharmaceutical formulations with improved dissolution profile and bioavailability or with improved stability or shelf-life can become accessible due to an improved solid-state form of an active pharmaceutical ingredient. Also processing or handling of the active pharmaceutical ingredient during the formulation process may be improved. New solid-state forms of an active pharmaceutical ingredient can thus have desirable processing properties. They can be easier to handle, better suited for storage, and/or allow for better purification, compared to previously known solid-state forms.

For example, the sudden appearance or disappearance of a metastable polymorph can present a problem in pharmaceutical development. Similarly, serious pharmaceutical consequences may arise if transformation occurs in a dosage form, e.g. upon storage.

There is thus a need for the provision of solid-state forms of mavacamten having improved physicochemical properties. In particular, there is a strong need for the provision of a solid form of mavacamten which is stable and does not undergo phase transformation during pharmaceutical processing or storage. There is also a strong need for the provision of a pharmaceutical composition comprising a solid-state form of mavacamten, which is stable at the conditions typically encountered during pharmaceutical processing and storage.

SUMMARY OF THE INVENTION

The present invention provides anhydrous crystalline forms of mavacamten, hereinafter also designated as “Form I”, “Form II”, “Form III”, “Form IV”, “Form V” and “Form VI”.

The crystalline forms of the present invention possess one or more advantageous properties selected from the group consisting of chemical stability, physical stability, melting point, hygroscopicity, solubility, dissolution, morphology, crystallinity, flowability, bulk density, compactibility and wettability.

In particular, the crystalline forms of the present invention are stable against temperature stress e.g. they don’t show any thermal events during DSC up to a temperature of about 170°C.

In addition, mavacamten Form I of the present invention was found to be the most stable form at room temperature. The usage of a stable API form is of great importance since polymorphic conversions, which may occur during the manufacturing process and/or during storage of a drug substance or drug product containing the drug substance can be excluded when a stable form is used. This ensures reliable bioavailability and therefore consistent efficacy and safety of the drug product containing the stable form throughout shelf-life.

Abbreviations

PXRD powder X-ray diffractogram

FTIR Fourier transform infrared

DSC differential scanning calorimetry

TGA thermogravimetric analysis

GMS gravimetric moisture sorption

NMP /V-methyl -2-pyrrol i done

HCM hypertrophic cardiomyopathy w-% weight percent

RH relative humidity

Definitions

In the context of the present invention the following definitions have the indicated meaning, unless explicitly stated otherwise:

As used herein, the term “measured at a temperature in the range of from 20 to 30°C” refers to a measurement under standard conditions. Typically, standard conditions mean a temperature in the range of from 20 to 30°C, i.e. at room temperature. Standard conditions can mean a temperature of about 22°C. Typically, standard conditions can additionally mean a measurement at 20-60% RH, preferably at 30-50% RH, more preferably at 40% RH.

As used herein the term “room temperature” refers to a temperature in the range of from 20 to 30°C.

The term “reflection” with regard to powder X-ray diffraction as used herein, means peaks in an X-ray diffractogram, which are caused at certain diffraction angles (Bragg angles) by constructive interference from X-rays scattered by parallel planes of atoms in solid material, which are distributed in an ordered and repetitive pattern in a long-range positional order. Such a solid material is classified as crystalline material, whereas amorphous material is defined as solid material, which lacks long-range order and only displays short-range order, thus resulting in broad scattering. According to literature, long-range order e.g. extends over approximately 100 to 1000 atoms, whereas short-range order is over a few atoms only (see “Fundamentals of Powder Diffraction and Structural Characterization of Materials ” by Vitalij K. Pecharsky and Peter Y. Zavalij, Kluwer Academic Publishers, 2003, page 3).

The term “essentially the same” with reference to powder X-ray diffraction means that variabilities in reflection positions and relative intensities of the reflections are to be taken into account. For example, a typical precision of the 2-Theta values is in the range of ± 0.1° 2-Theta. Thus, a reflection that usually appears at 10.1° 2-Theta for example can appear between 10.0° and 10.2° 2-Theta on most X-ray diffractometers under standard conditions. Furthermore, one skilled in the art will appreciate that relative reflection intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, particle size, sample preparation and other factors known to those skilled in the art and should be taken as qualitative measure only.

A crystalline form of mavacamten of the present invention may be referred to herein as being characterized by graphical data "as shown in" a figure. Such data include, for example, powder X-ray diffraction. The person skilled in the art understands that factors such as variations in instrument type, response and variations in sample directionality, sample concentration and sample purity may lead to small variations for such data when presented in graphical form, for example variations relating to the exact reflection positions and intensities. However, a comparison of the graphical data in the figures herein with the graphical data generated for another or an unknown solid form and the confirmation that two sets of graphical data relate to the same crystal form is well within the knowledge of a person skilled in the art.

The term “solid-state form” as used herein refers to any crystalline and/or amorphous phase of a compound.

As used herein, the term “amorphous” refers to a solid-state form of a compound that is not crystalline. An amorphous compound possesses no long-range order and does not display a definitive X-ray diffraction pattern with reflections.

The terms “anhydrous form” or “anhydrate” as used herein refer to a crystalline solid where no water is cooperated in or accommodated by the crystal structure. Anhydrous forms may still contain residual water, which is not part of the crystal structure but may be adsorbed on the surface or absorbed in disordered regions of the crystal. The term “non-solvated” as used herein, when talking about a crystalline solid indicates that no organic solvent is cooperated in or accommodated by the crystal structure. Non-solvated forms may still contain residual organic solvents, which are not part of the crystal structure but may be adsorbed on the surface or absorbed in disordered regions of the crystal.

A “predetermined amount” as used herein with regard to a crystalline form of mavacamten refers to the initial amount of the crystalline form used for the preparation of a pharmaceutical composition having a desired dosage strength of mavacamten.

The term “effective amount” as used herein with regard to a crystalline form of mavacamten encompasses an amount of the crystalline form which causes the desired therapeutic and/or prophylactic effect.

As used herein, the term “about” means within a statistically meaningful range of a value. Such a range can be within an order of magnitude, typically within 10%, more typically within 5%, even more typically within 1% and most typically within 0.1% of the indicated value or range. Sometimes, such a range can lie within the experimental error, typical of standard methods used for the measurement and/or determination of a given value or range.

The term “pharmaceutically acceptable excipient” as used herein refers to substances, which do not show a significant pharmacological activity at the given dose and that are added to a pharmaceutical composition in addition to the active pharmaceutical ingredient. Excipients may take the function of vehicle, diluent, release agent, disintegrating agent, dissolution modifying agent, absorption enhancer, stabilizer or a manufacturing aid among others. Excipients may include fillers (diluents), binders, disintegrants, lubricants and glidants.

The terms “filler” or “diluent” as used herein refer to substances that are used to dilute the active pharmaceutical ingredient prior to delivery. Diluents and fillers can also serve as stabilizers.

As used herein the term “binder” refers to substances which bind the active pharmaceutical ingredient and pharmaceutically acceptable excipient together to maintain cohesive and discrete portions.

The terms “disintegrant” or “disintegrating agent” as used herein refers to substances which, upon addition to a solid pharmaceutical composition, facilitate its break-up or disintegration after administration and permits the release of the active pharmaceutical ingredient as efficiently as possible to allow for its rapid dissolution.

The term “lubricant” as used herein refers to substances which are added to a powder blend to prevent the compacted powder mass from sticking to the equipment during tableting or encapsulation process. They aid the ejection of the tablet from the dies and can improve powder flow.

The term “glidant” as used herein refers to substances which are used for tablet and capsule formulations in order to improve flow properties during tablet compression and to produce an anti -caking effect.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1: illustrates a representative PXRD of mavacamten Form I according to the present invention. The x-axis shows the scattering angle in °2-Theta, the y-axis shows the intensity of the scattered X-ray beam in counts of detected photons.

Figure 2: illustrates a representative PXRD of mavacamten Form II according to the present invention. The x-axis shows the scattering angle in °2-Theta, the y-axis shows the intensity of the scattered X-ray beam in counts of detected photons.

Figure 3: illustrates a representative PXRD of mavacamten Form III according to the present invention. The x-axis shows the scattering angle in °2-Theta, the y-axis shows the intensity of the scattered X-ray beam in counts of detected photons.

Figure 4: illustrates a representative PXRD of mavacamten Form IV according to the present invention. The x-axis shows the scattering angle in °2-Theta, the y-axis shows the intensity of the scattered X-ray beam in counts of detected photons.

Figure 5: illustrates a representative PXRD of mavacamten Form V according to the present invention. The x-axis shows the scattering angle in °2-Theta, the y-axis shows the intensity of the scattered X-ray beam in counts of detected photons.

Figure 6: illustrates a comparison of PXRDs of mavacamten Form I, Form II, Form III, Form IV and Form V (from top to bottom). The x-axis shows the scattering angle in °2-Theta. The PXRDs were shifted along the y-axis to separate the diffractograms for clarity.

Figure 7: illustrates a representative DSC curve of mavacamten Form I according to the present invention. The x-axis shows the temperature in degree Celsius (°C), the y-axis shows the heat flow rate in milliwatt (mW) with endothermic peaks going up. Figure 8: illustrates a representative DSC curve of mavacamten Form II according to the present invention. The x-axis shows the temperature in degree Celsius (°C), the y-axis shows the heat flow rate in milliwatt (mW) with endothermic peaks going up.

Figure 9: illustrates a representative DSC curve of mavacamten Form III according to the present invention. The x-axis shows the temperature in degree Celsius (°C), the y-axis shows the heat flow rate in milliwatt (mW) with endothermic peaks going up.

Figure 10: illustrates a representative DSC curve of mavacamten Form IV according to the present invention. The x-axis shows the temperature in degree Celsius (°C), the y-axis shows the heat flow rate in milliwatt (mW) with endothermic peaks going up.

Figure 11: illustrates a representative DSC curve of mavacamten Form V according to the present invention. The x-axis shows the temperature in degree Celsius (°C), the y-axis shows the heat flow rate in milliwatt (mW) with endothermic peaks going up.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a crystalline form of mavacamten according to the chemical structure as depicted in Formula (A)

Formula (A), characterized in being anhydrous.

In particular the invention provides anhydrous crystalline forms of mavacamten, hereinafter also designated as “Form I”, “Form II”, “Form III”, “Form IV”, “Form V” and “Form VI”.

The crystalline forms of mavacamten of the present invention may be characterized by analytical methods well known in the field of the pharmaceutical industry for characterizing solids. Such methods comprise but are not limited to powder X-ray diffraction, single X-ray diffraction, FTIR spectroscopy, DSC, TGA and GMS. The crystalline forms of the present invention may be characterized by one of the aforementioned analytical methods or by combining two or more of them. In particular, the crystalline forms of mavacamten of the present invention may be characterized by any one of the following embodiments or by combining two or more of the following embodiments.

Crystalline Form I of mavacamten

In one embodiment the invention relates to a crystalline form (Form I) of mavacamten characterized by having a PXRD comprising reflections at 2-Theta angles of:

(10.1 ± 0.1)°, (11.7 ± 0.1)° and (18.8 ± 0.1)°; or

(10.1 ± 0.1)°, (11.7 ± 0.1)°, (14.7 ± 0.1)° and (18.8 ± 0.1)°; or

(10.1 ± 0.1)°, (11.7 ± 0.1)°, (14.7 ± 0.1)°, (17.4 ± 0.1)° and (18.8 ± 0.1)°; or

(10.1 ± 0.1)°, (11.7 ± 0.1)°, (14.7 ± 0.1)°, (15.8 ± 0.1)°, (17.4 ± 0.1)° and (18.8 ± 0.1)°; or

(10.1 ± 0.1)°, (11.7 ± 0.1)°, (14.7 ± 0.1)°, (15.8 ± 0.1)°, (16.3 ± 0.1)°, (17.4 ± 0.1)° and (18.8 ±

0.1)°; or

(10.1 ± 0.1)°, (11.7 ± 0.1)°, (14.7 ± 0.1)°, (15.8 ± 0.1)°, (16.3 ± 0.1)°, (17.4 ± 0.1)°, (18.8 ± 0.1)° and (22.4 ± 0.1)°; or

(10.1 ± 0.1)°, (11.7 ± 0.1)°, (14.7 ± 0.1)°, (15.8 ± 0.1)°, (16.3 ± 0.1)°, (17.4 ± 0.1)°, (18.8 ± 0.1)°, (20.0 ± 0.1)° and (22.4 ± 0.1)°; or

(10.1 ± 0.1)°, (11.7 ± 0.1)°, (14.7 ± 0.1)°, (15.8 ± 0.1)°, (16.3 ± 0.1)°, (17.4 ± 0.1)°, (18.8 ± 0.1)°, (20.0 ± 0.1)°, (22.4 ± 0.1)° and (25.7 ± 0.1)°; when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

In a particular preferred embodiment, the invention relates to a crystalline form of mavacamten (Form I) as defined in any one of the above described embodiments characterized by having a PXRD comprising no reflections at or below (9.8 ± 0.1)° 2-Theta, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

In yet another embodiment, the present invention relates to a crystalline form of mavacamten (Form I) characterized by having a PXRD essentially the same as shown in Figure 1 of the present invention, when measured at a temperature in the range of from 20 to 30°C with Cu- Kalphai,2 radiation having a wavelength of 0.15419 nm.

In a further embodiment, the present invention relates to a crystalline form of mavacamten (Form I) characterized by exhibiting an orthorhombic unit cell having space group 2i2i2i. Preferably, the unit cell has the following parameters (at 25°C): a = 9.45 Angstrom b = 12.07 Angstrom c = 2.66 Angstrom alpha = 90° beta = 90° gamma = 90°

In another embodiment, the present invention relates to a crystalline form (Form I) of mavacamten, characterized by having a melting point onset at a temperature of about 224.5°C, when measured with DSC at a heating rate of 10 K/min.

In one embodiment, the present invention relates to a crystalline form (Form I) of mavacamten characterized in being anhydrous.

In another embodiment, the present invention relates to a crystalline form (Form I) of mavacamten characterized in being non-solvated.

Crystalline Form II of mavacamten

In another embodiment the invention relates to a crystalline form (Form II) of mavacamten characterized by having a PXRD comprising reflections at 2-Theta angles of:

(8.5 ± 0.1)°, (11.9 ± 0.1)° and (13.4 ± 0.1)°; or

(8.5 ± 0.1)°, (11.9 ± 0.1)°, (13.4 ± 0.1)° and (18.7 ± 0.1)°; or

(8.5 ± 0.1)°, (11.9 ± 0.1)°, (13.4 ± 0.1)°, (15.8 ± 0.1)° and (18.7 ± 0.1)°; or

(8.5 ± 0.1)°, (11.9 ± 0.1)°, (13.4 ± 0.1)°, (14.8 ± 0.1)°, (15.8 ± 0.1)° and (18.7 ± 0.1)°; or

(8.5 ± 0.1)°, (11.9 ± 0.1)°, (13.4 ± 0.1)°, (14.8 ± 0.1)°, (15.8 ± 0.1)°, (18.7 ± 0.1)° and (23.8 ±

0.1)°; or

(8.5 ± 0.1)°, (11.9 ± 0.1)°, (13.4 ± 0.1)°, (14.8 ± 0.1)°, (15.8 ± 0.1)°, (18.7 ± 0.1)°, (21.4 ± 0.1)° and (23.8 ± 0.1)°; or

(8.5 ± 0.1)°, (11.9 ± 0.1)°, (13.4 ± 0.1)°, (14.8 ± 0.1)°, (15.8 ± 0.1)°, (18.7 ± 0.1)°, (20.1 ± 0.1)°, (21.4 ± 0.1)° and (23.8 ± 0.1)°; or

(8.5 ± 0.1)°, (11.9 ± 0.1)°, (13.4 ± 0.1)°, (14.8 ± 0.1)°, (15.8 ± 0.1)°, (16.6 ± 0.1)°, (18.7 ± 0.1)°, (20.1 ± 0.1)°, (21.4 ± 0.1)° and (23.8 ± 0.1)°; when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm. In yet another embodiment, the present invention relates to a crystalline form of mavacamten (Form II) characterized by having a PXRD essentially the same as shown in Figure 2 of the present invention, when measured at a temperature in the range of from 20 to 30°C with Cu- Kalphai,2 radiation having a wavelength of 0.15419 nm.

In a further embodiment, the present invention relates to a crystalline form of mavacamten

(Form II) characterized by exhibiting an orthorhombic unit cell having space group P2_\.

Preferably, the unit cell has the following parameters (at 25°C): a = 6.66 Angstrom b = 10.65 Angstrom c = 10.56 Angstrom alpha = 90° beta = 98.11° gamma = 90°

In another embodiment, the present invention relates to a crystalline form (Form II) of mavacamten, characterized by having a melting point onset at a temperature of about 238°C, when measured with DSC at a heating rate of 10 K/min.

In one embodiment, the present invention relates to a crystalline form (Form II) of mavacamten characterized in being anhydrous.

In another embodiment, the present invention relates to a crystalline form (Form II) of mavacamten characterized in being non-solvated.

Crystalline Form III of mavacamten

In another embodiment the invention relates to a crystalline form (Form III) of mavacamten characterized by having a PXRD comprising reflections at 2-Theta angles of:

(7.8 ± 0.1)°, (8.5 ± 0.1)° and (11.2 ± 0.1)°; or

(7.8 ± 0.1)°, (8.5 ± 0.1)°, (11.2 ± 0.1)° and (17.0 ± 0.1)°; or

(7.8 ± 0.1)°, (8.5 ± 0.1)°, (11.2 ± 0.1)°, (14.6 ± 0.1)° and (17.0 ± 0.1)°; or

(7.8 ± 0.1)°, (8.5 ± 0.1)°, (11.2 ± 0.1)°, (14.6 ± 0.1)°, (15.6 ± 0.1)° and (17.0 ± 0.1)°; or

(7.8 ± 0.1)°, (8.5 ± 0.1)°, (11.2 ± 0.1)°, (14.6 ± 0.1)°, (15.6 ± 0.1)°, (17.0 ± 0.1)° and (19.0 ±

0.1)°; or (7.8 ± 0.1)°, (8.5 ± 0.1)°, (11.2 ± 0.1)°, (14.6 ± 0.1)°, (15.6 ± 0.1)°, (17.0 ± 0.1)°, (19.0 ± 0.1)° and (21.5 ± 0.1)°; or

(7.8 ± 0.1)°, (8.5 ± 0.1)°, (11.2 ± 0.1)°, (11.9 ± 0.1)°, (14.6 ± 0.1)°, (15.6 ± 0.1)°, (17.0 ± 0.1)°, (19.0 ± 0.1)° and (21.5 ± 0.1)°; or

(7.8 ± 0.1)°, (8.5 ± 0.1)°, (11.2 ± 0.1)°, (11.9 ± 0.1)°, (14.6 ± 0.1)°, (15.6 ± 0.1)°, (17.0 ± 0.1)°, (18.1 ± 0.1)°, (19.0 ± 0.1)° and (21.5 ± 0.1)°; when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

In yet another embodiment, the present invention relates to a crystalline form of mavacamten (Form III) characterized by having a PXRD essentially the same as shown in Figure 3 of the present invention, when measured at a temperature in the range of from 20 to 30°C with Cu- Kalphai,2 radiation having a wavelength of 0.15419 nm.

(Form III) characterized by exhibiting a monoclinic unit cell having space group 12 Preferably, the unit cell has the following parameters (at 25 °C): a = 14.94 Angstrom b = 6.65 Angstrom c = 15.89 Angstrom alpha = 90° beta = 94.81° gamma = 90°

In another embodiment, the present invention relates to a crystalline form (Form III) of mavacamten, characterized by having a melting point onset at a temperature of about 249.5°C, when measured with DSC at a heating rate of 10 K/min.

In one embodiment, the present invention relates to a crystalline form (Form III) of mavacamten characterized in being anhydrous.

In another embodiment, the present invention relates to a crystalline form (Form III) of mavacamten characterized in being non-solvated. Crystalline Form IV of mavacamten

In another embodiment the invention relates to a crystalline form (Form IV) of mavacamten characterized by having a PXRD comprising reflections at 2-Theta angles of:

(7.3 ± 0.1)°, (11.4 ± 0.1)° and (18.2 ± 0.1)°; or

(7.3 ± 0.1)°, (11.4 ± 0.1)°, (13.0 ± 0.1)° and (18.2 ± 0.1)°; or

(7.3 ± 0.1)°, (11.4 ± 0.1)°, (12.0 ± 0.1)°, (13.0 ± 0.1)° and (18.2 ± 0.1)°; or

(7.3 ± 0.1)°, (11.4 ± 0.1)°, (12.0 ± 0.1)°, (13.0 ± 0.1)°, (14.6 ± 0.1)° and (18.2 ± 0.1)°; or

(7.3 ± 0.1)°, (11.4 ± 0.1)°, (12.0 ± 0.1)°, (13.0 ± 0.1)°, (13.5 ± 0.1)°, (14.6 ± 0.1)° and (18.2 ±

0.1)°; or

(7.3 ± 0.1)°, (11.4 ± 0.1)°, (12.0 ± 0.1)°, (13.0 ± 0.1)°, (13.5 ± 0.1)°, (14.6 ± 0.1)°, (15.8 ± 0.1)° and (18.2 ± 0.1)°; or

(7.3 ± 0.1)°, (11.4 ± 0.1)°, (12.0 ± 0.1)°, (13.0 ± 0.1)°, (13.5 ± 0.1)°, (14.6 ± 0.1)°, (15.8 ± 0.1)°, (18.2 ± 0.1)° and (23.2 ± 0.1)°; or

(7.3 ± 0.1)°, (11.4 ± 0.1)°, (12.0 ± 0.1)°, (13.0 ± 0.1)°, (13.5 ± 0.1)°, (14.6 ± 0.1)°, (15.8 ± 0.1)°, (18.2 ± 0.1)°, (19.3 ± 0.1)° and (23.2 ± 0.1)°; when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

In yet another embodiment, the present invention relates to a crystalline form of mavacamten (Form IV) characterized by having a PXRD essentially the same as shown in Figure 4 of the present invention, when measured at a temperature in the range of from 20 to 30°C with Cu- Kalphai,2 radiation having a wavelength of 0.15419 nm.

(Form IV) characterized by exhibiting an orthorhombic unit cell having space group 2i2i2i.

Preferably, the unit cell has the following parameters (at 25°C): a = 9.85 Angstrom b = 12.60 Angstrom c = 24.24 Angstrom alpha = 90° beta = 90° gamma = 90° In another embodiment, the present invention relates to a crystalline form (Form IV) of mavacamten, characterized by having a melting point onset at a temperature of about 236°C, when measured with DSC at a heating rate of 10 K/min.

In one embodiment, the present invention relates to a crystalline form (Form IV) of mavacamten characterized in being anhydrous.

In another embodiment, the present invention relates to a crystalline form (Form IV) of mavacamten characterized in being non-solvated.

Crystalline Form V of mavacamten

In another embodiment the invention relates to a crystalline form (Form V) of mavacamten characterized by having a PXRD comprising reflections at 2-Theta angles of:

(9.3 ± 0.1)°, (11.7 ± 0.1)° and (13.3 ± 0.1)°; or

(9.3 ± 0.1)°, (11.7 ± 0.1)°, (13.3 ± 0.1)° and (13.9 ± 0.1)°; or

(9.3 ± 0.1)°, (11.7 ± 0.1)°, (13.3 ± 0.1)°, (13.9 ± 0.1)° and (18.7 ± 0.1)°; or

(9.3 ± 0.1)°, (11.7 ± 0.1)°, (13.3 ± 0.1)°, (13.9 ± 0.1)°, (18.7 ± 0.1)° and (20.8 ± 0.1)°; or

(9.3 ± 0.1)°, (11.7 ± 0.1)°, (13.3 ± 0.1)°, (13.9 ± 0.1)°, (17.7 ± 0.1)°, (18.7 ± 0.1)° and (20.8 ±

0.1)°; or

(9.3 ± 0.1)°, (11.7 ± 0.1)°, (13.3 ± 0.1)°, (13.9 ± 0.1)°, (15.7 ± 0.1)°, (17.7 ± 0.1)°, (18.7 ± 0.1)° and (20.8 ± 0.1)°; or

(9.3 ± 0.1)°, (11.7 ± 0.1)°, (13.3 ± 0.1)°, (13.9 ± 0.1)°, (15.7 ± 0.1)°, (16.3 ± 0.1)°, (17.7 ± 0.1)°, (18.7 ± 0.1)° and (20.8 ± 0.1)°; or

(9.3 ± 0.1)°, (11.7 ± 0.1)°, (13.3 ± 0.1)°, (13.9 ± 0.1)°, (15.7 ± 0.1)°, (16.3 ± 0.1)°, (16.8 ± 0.1)°, (17.7 ± 0.1)°, (18.7 ± 0.1)° and (20.8 ± 0.1)°; when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

In yet another embodiment, the present invention relates to a crystalline form of mavacamten (Form V) characterized by having a PXRD essentially the same as shown in Figure 5 of the present invention, when measured at a temperature in the range of from 20 to 30°C with Cu- Kalphai,2 radiation having a wavelength of 0.15419 nm.

In a further embodiment, the present invention relates to a crystalline form of mavacamten (Form V) characterized by exhibiting an orthorhombic unit cell having space group 2i2i2. Preferably, the unit cell has the following parameters (at 25°C): a = 10.52 Angstrom b = 21.79 Angstrom c = 6.66 Angstrom alpha = 90° beta = 90° gamma = 90°

In another embodiment, the present invention relates to a crystalline form (Form V) of mavacamten, characterized by having a melting point onset at a temperature of about 240°C, when measured with DSC at a heating rate of 10 K/min.

In one embodiment, the present invention relates to a crystalline form (Form V) of mavacamten characterized in being anhydrous.

In another embodiment, the present invention relates to a crystalline form (Form V) of mavacamten characterized in being non-solvated.

Crystalline Form VI of mavacamten

In another embodiment the invention relates to a crystalline form (Form VI) of mavacamten characterized by having a PXRD comprising reflections at 2-Theta angles of:

(5.9 ± 0.1)°, (9.7 ± 0.1)° and (17.8 ± 0.1)°; or

(5.9 ± 0.1)°, (8.3 ± 0.1)°, (9.7 ± 0.1)° and (17.8 ± 0.1)°; or

(5.9 ± 0.1)°, (8.3 ± 0.1)°, (9.7 ± 0.1)°, (11.8 ± 0.1)° and (17.8 ± 0.1)°; or

(5.9 ± 0.1)°, (8.3 ± 0.1)°, (9.7 ± 0.1)°, (11.8 ± 0.1)°, (14.1 ± 0.1)° and (17.8 ± 0.1)°; or

(5.9 ± 0.1)°, (8.3 ± 0.1)°, (9.7 ± 0.1)°, (11.8 ± 0.1)°, (14.1 ± 0.1)°, (17.8 ± 0.1)° and (18.5 ±

0.1)°; or

(5.9 ± 0.1)°, (8.3 ± 0.1)°, (9.7 ± 0.1)°, (11.8 ± 0.1)°, (14.1 ± 0.1)°, (17.8 ± 0.1)°, (18.3 ± 0.1)° and (18.5 ± 0.1)°; or

(5.9 ± 0.1)°, (8.3 ± 0.1)°, (9.7 ± 0.1)°, (11.8 ± 0.1)°, (14.1 ± 0.1)°, (17.8 ± 0.1)°, (18.3 ± 0.1)°, (18.5 ± 0.1)° and (18.8 ± 0.1)°; or

(5.9 ± 0.1)°, (8.3 ± 0.1)°, (9.7 ± 0.1)°, (11.8 ± 0.1)°, (13.9 ± 0.1)°, (14.1 ± 0.1)°, (17.8 ± 0.1)°, (18.3 ± 0.1)°, (18.5 ± 0.1)° and (18.8 ± 0.1)°; when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphal,2 radiation having a wavelength of 0.15419 nm. In one embodiment, the present invention relates to a crystalline form (Form VI) of mavacamten characterized in being anhydrous.

In another embodiment, the present invention relates to a crystalline form (Form VI) of mavacamten characterized in being non-solvated.

Pharmaceutical compositions and medical use

In a further aspect, the present invention relates to the use of crystalline mavacamten ( e.g . Form

I, II, III, IV, V or VI as defined herein) of the present invention as defined in any one of the above described aspects and their corresponding embodiments for the preparation of a pharmaceutical composition.

Furthermore, the present invention relates to a pharmaceutical composition comprising crystalline mavacamten (e.g. Form I, II, III, IV, V or VI as defined herein) of the present invention as defined in any one of the above described aspects and their corresponding embodiments, preferably in an effective and/or predetermined amount, and at least one pharmaceutically acceptable excipient.

Preferably, the effective and/or predetermined amount of crystalline mavacamten (e.g. Form I,

II, III, IV, V or VI as defined herein) of the present invention is in the range of from about 1 to 50 mg, preferably of from about 2 to 30 mg and most preferably of from about 2.5 to 15 mg calculated as mavacamten (water free). For example, the effective and/or predetermined amount is selected from the group consisting of 1 mg, 2 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg and 50 mg calculated as mavacamten (water free). Preferably, the effective and/or predetermined amount is selected from the group consisting of 2 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg and 15 mg calculated as mavacamten (water free).

The at least one pharmaceutically acceptable excipient, which is comprised in the pharmaceutical composition of the present invention, is preferably selected from the group consisting of fillers, disintegrants, binders, lubricants, glidants and combinations thereof. Preferably, the at least one pharmaceutically acceptable excipient, which is comprised in the pharmaceutical composition of the present invention is selected from the group consisting of fillers, glidants and combinations thereof. In one embodiment, the filler is selected from the group consisting of dibasic calcium phosphate, kaolin, lactose, dextrose, magnesium carbonate, sucrose, mannitol, glucose or other monosaccharides, dextrin or other polysaccharides, microcrystalline cellulose, powdered cellulose, cellulose derivatives, precipitated calcium carbonate, calcium sulfate, sorbitol, inositol and starch, and combinations thereof.

In one embodiment, the glidant is selected from the group consisting of coloidal silica, colloidal silicon dioxide, fumed silica, silicon dioxide, com starch, talc, calcium silicate, magnesium silicate, tribasic calcium phosphate, silicon hydrogel, and combinations thereof.

Preferably, the pharmaceutical composition of the present invention as defined in any one of the above described embodiments is an oral solid dosage form, more preferably a tablet or a capsule. In a particular preferred embodiment, the pharmaceutical composition of the present invention as described above is a capsule, preferably a hard gelatin capsule.

The pharmaceutical compositions of the present invention as defined in any one of the above described embodiments may be produced by standard manufacturing processes, which are well- known to the skilled person e.g. selected from the group consisting of micronization, blending, milling, granulation (wet or dry granulation), capsule filling, tabletting, film-coating and any combinations thereof.

In a further aspect, the present invention relates to crystalline mavacamten (e.g. Form I, II, III, IV, V or VI as defined herein) or a pharmaceutical composition comprising a crystalline form of mavacamten as defined in any one of the above described aspects and their corresponding embodiments for use as a medicament.

In still a further aspect, the present invention relates to crystalline mavacamten (e.g. Form I, II, III, IV, V or VI as defined herein) or a pharmaceutical composition comprising a crystalline form of mavacamten as defined in any one of the above described aspects and their corresponding embodiments for use in the treatment of cardiac disorder.

In another aspect, the present invention relates to a method of treating a cardiac disorder said method comprising administering an effective amount of crystalline mavacamten (e.g. Form I, II, III, IV, V or VI as defined herein) or a pharmaceutical composition comprising a crystalline form of mavacamten as defined in any one of the above described aspects and their corresponding embodiments to a patient in need of such a treatment. In a preferred embodiment, the cardiac disorder is selected from the group consisting of hypertrophic cardiomyopathy (HCM), such as obstructive HCM and non-obstructive HCM, and precision diastolic disease. In a particular preferred embodiment, the cardiac disorder is ostructive HCM.

Use as intermediates for salt preparation

In another aspect the invention relates to crystalline mavacamten (e.g. Form I, II, III, IV, V or VI as defined herein) for use in the preparation of a pharmaceutically acceptable salt of mavacamten.

In one embodiment the pharmaceutically acceptable salt is an acid addition salt or a base addition salt, preferably an acid addition salt. Pharmaceutically acceptable salts may be derived by reacting crystalline mavacamten (e.g. Form I, II, III, IV, V or VI as defined herein) with an acid or a base in a suitable solvent or solvent mixture. The acid may be selected from the group consisting of acetic acid, adipic acid, alginic acid, aminosalicylic acid, /.-ascorpic acid, L- aspartic acid, aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphor-10-sulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, galactaric acid, //-glucaric acid, //-gluconic acid, //-glucuronic acid, /.-gluta ic acid, glutaric acid, hippuric acid, hydrochloric acid, hydrobromic acid, lactic acid, lactobionic acid, lauric acid, malic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, naphtalene-l,5-disulfonic acid, naphtelene-2- sulfonic acid, nitric acid, oxalic acid, pamoic acid, phosphoric acid, salicylic acid, stearic acid, succinic acid, sulfonic acid, tartaric acid and /i-toluene sulfonic acid. The base may be selected from the group consisting of aluminum, ammonia, /.-arginine, benethamine, benzathine, tert- butylamine, calcium hydroxide, chloroprocaine, choline hydroxide, diethanolamine, diethylamine, ethanolamine, ethylenediamine, lithium, /.-lysine, magnesium hydroxide, meglumine, piperazine, potassium hydroxide, procaine, sodium hydroxide, tromethamine and zinc hydroxide.

EXAMPLES

The following non-limiting examples are illustrative for the disclosure and are not to be construed as to be in any way limiting for the scope of the invention. The mavacamten starting material was obtained by following the procedure disclosed in example 1 of WO 2014/205223 Al. Example 1: Preparation of mavacamten Form I

Mavacamten (45 mg) was dissolved in ethanol (1.8 mL) upon heating. The resulting clear solution was filtrated and allowed to naturally cool to room temperature, whereat crystals formed within 24 hours. Subsequently, the mixture was cooled to -20°C for about 16 hours before the crystals were collected by filtration and air-dried to obtain crystalline Form I of mavacamten.

Example 2: Preparation of mavacamten Form II

Mavacamten (15 mg) was dissolved in methanol (2.3 mL) at room temperature. The obtained clear solution was filtrated and transferred to a watch glass for solvent evaporation at room temperature to obtain crystalline Form II of mavacamten

Example 3: Preparation of mavacamten Form III

Mavacamten (Form I, Form II, Form IV or Form V prepared according to the procedures disclosed herein) was annealed at 240°C for 5 minutes and at 210°C for 10 minutes. The sample was then cooled to room temperature to obtain crystalline Form III of mavacamten.

Example 4: Preparation of mavacamten Form IV

Mavacamten (130 mg) was dissolved in isopropanol (20 mL) upon heating to reflux temperature. The resulting clear solution was filtrated and the solvent removed on a rotavapor (40°C, 50-100 mbar) under reduced pressure to obtain crystalline Form IV of mavacamten.

Example 5: Preparation of mavacamten Form V

Mavacamten (80 mg) was dissolved in chloroform (12 mL) upon heating. The resulting clear solution was filtrated and the solvent removed on a rotavapor (40°C, 250-350 mbar) under reduced pressure to obtain crystalline Form V of mavacamten.

Example 6: Preparation of mavacamten Form VI

Mavacamten (15 mg) was dissolved in pyridine (1 mL). The resulting clear solution was filtered and transferred to a watch glass for solvent evaporation at room temperature. Within one day needle shaped crystals of form VI were obtained.

Example 7: Preparation of mavacamten pyridine /lew/solvate

Mavacamten (92 mg) was dissolved in pyridine (2.7 mL) upon heating. The resulting clear solution was filtrated and the solvent removed on a rotavapor (40°C, 10-100 mbar) to obtain the mavacamten pyridine /lew/solvate. Example 8: Preparation of mavacamten chloroform /wi/zosolvate

Mavacamten (85 mg) was dissolved in chloroform (11 mL) upon heating. The resulting clear solution was filtrated and the solvent removed on a rotavapor (25 °C, 100 mbar) to obtain the mavacamten chloroform /wwosolvate.

Example 9: Preparation of mavacamten NMP

solvate

Mavacamten (20 mg) was dissolved in A -m ethyl -2-pyrrol i done (1 mL). The resulting clear solution was filtrated and transferred to a watch glass for solvent evaporation at room temperature. After approximately 2 weeks needle shaped NMP solvate crystals and blocks (Form I) were obtained.

Example 10: Powder X-ray diffraction

The powder X-ray diffraction patterns were recorded (at 25°C) with a X’Pert PRO diffractometer (PANalytical, Almelo, The Netherlands), equipped with a Theta/Theta coupled goniometer in transmission geometry, programmable XYZ stage with well plate holder, Cu- Kalphai,2 radiation source with a focussing mirror, a 0.5° divergence slit, a 0.02° sober slit collimator and a 1° anti -scattering slit on the incident beam side, a 2 mm anti -scattering slit, a 0.04° sober slit collimator, a Ni-filter, and a solid state PIXcel detector on the diffracted beam side. The patterns were recorded at a tube voltage of 40 kV, tube current of 40 mA, applying a step-size of 0.007° 2-Theta with 400 s per step in the angular range of 2° to 70° 2-Theta.

A representative diffractogram of mavacamten Form I is displayed in Figure 1 hereinafter. The corresponding reflection list in the range of from 2 to 30° 2-Theta is provided in Table 1 below.

Table 1: Reflection positions of crystalline Form I of mavacamten in the range of from 2 to 30° 2-Theta; a typical precision of the 2-Theta values is in the range of ± 0.1° 2-Theta.

A representative diffractogram of mavacamten Form II is displayed in Figure 2 hereinafter. The corresponding reflection list in the range of from 2 to 30° 2-Theta is provided in Table 2 below.

Table 2: Reflection positions of crystalline Form II of mavacamten in the range of from 2 to 30° 2- Theta; a typical precision of the 2-Theta values is in the range of ± 0.1° 2-Theta.

A representative diffractogram of mavacamten Form III is displayed in Figure 3 hereinafter. The corresponding reflection list in the range of from 2 to 30° 2-Theta is provided in Table 3 below.

Table 3: Reflection positions of crystalline Form III of mavacamten in the range of from 2 to 30° 2- Theta; a typical precision of the 2-Theta values is in the range of ± 0.1° 2-Theta.

A representative diffractogram of mavacamten Form IV is displayed in Figure 4 hereinafter. The corresponding reflection list in the range of from 2 to 30° 2-Theta is provided in Table 4 below.

Table 4: Reflection positions of crystalline Form IV of mavacamten in the range of from 2 to 30° 2- Theta; a typical precision of the 2-Theta values is in the range of ± 0.1° 2-Theta. A representative diffractogram of mavacamten Form V is displayed in Figure 5 hereinafter. The corresponding reflection list in the range of from 2 to 30° 2-Theta is provided in Table 5 below.

Table 5: Reflection positions of crystalline Form V of mavacamten in the range of from 2 to 30° 2- Theta; a typical precision of the 2-Theta values is in the range of ± 0.1° 2-Theta. The reflection list of mavacamten Form VI in the range of from 2 to 30° 2-Theta is provided in

Table 6 below.

Table 6: Reflection positions of crystalline form VI of mavacamten in the range of from 2 to 30° 2- Theta; a typical precision of the 2-Theta values is in the range of ± 0.1° 2-Theta.

The reflection list of mavacamten pyridine hemi solvate in the range of from 2 to 30° 2-Theta is provided in Table 7 below.

Table 7: Reflection positions of crystalline mavacamten pyridine hera/solvate in the range of from 2 to 30° 2-Theta; a typical precision of the 2-Theta values is in the range of ± 0.1° 2-Theta.

The reflection list of mavacamten chloroform /ww solvate in the range of from 2 to 30° 2- Theta is provided in Table 8 below.

Table 8: Reflection positions of crystalline mavacamten chloroform monosolvate in the range of from 2 to 30° 2-Theta; a typical precision of the 2-Theta values is in the range of ± 0.1° 2-Theta.

The reflection list of mavacamten NMP hemi solvate in the range of from 2 to 30° 2-Theta is provided in Table 9 below.

Table 9: Reflection positions of crystalline mavacamten NMP hemisolvatc in the range of from 2 to 30° 2-Theta; a typical precision of the 2-Theta values is in the range of ± 0.1° 2-Theta.

Example 11: Crystal structures

Mavacamten Forms I to V were indexed and the space groups were determined based on a statistical assessment of systematic absences using DicvoKM¹ as implemented in HighScore Plus 3.0.5 (PANalytical, Almelo, The Netherlands). Pawley fits and Rietveld refinements were performed with Topas v.4.1 (Bruker AXS Inc., Madison, Wisconsin, USA).

Table 10: Crystallographic information for mavacamten forms I to V Example 12: Differential Scanning Calorimetry

Differential Scanning Calorimetry (DSC) thermograms were recorded on a DSC 7 (Perkin- Elmer, Norwalk, Connecticut, USA) controlled by the Pyris software. Using a UM3 ultra microbalance (Mettler, Greifensee, CH), samples of approximately 2 - 3 mg were weighed into perforated aluminum pans, then heated at a rate of 10 K/min with dry nitrogen as the purge gas (purge: 20 mL/min). The instrument was calibrated for temperature with pure benzophenone (mp 48.0°C) and caffeine (236.2°C), and the energy calibration was performed with indium (mp 156.6°C, heat of fusion 28.45 J/g).

Representative DSC curves of mavacamten Forms I to V are displayed in Figures 7 to 11 hereinafter and the results are sumarized in Table 11 below.

Table 11: Melting points of various anhydrous mavacamten forms

Claims

1) A crystalline form of mavacamten according to the chemical structure as depicted in Formula (A)

Formula (A), characterized in being anhydrous.

2) The crystalline form of claim 1 in crystalline Form I, characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (10.1 ± 0.1)°, (11.7 ± 0.1)° and (18.8 ± 0.1)° and comprising no reflection at or below (9.8 ± 0.1)° 2-Theta, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

3) The crystalline form of claim 1 in crystalline Form II, characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (8.5 ± 0.1)°, (11.9 ± 0.1)° and (13.4 ± 0.1)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

4) The crystalline form of claim 1 in crystalline Form III, characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (7.8 ± 0.1)°, (8.5 ± 0.1)° and (11.2 ± 0.1)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

5) The crystalline form of claim 1 in crystalline Form IV, characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (7.3 ± 0.1)°, (11.4 ± 0.1)° and (18.2 ± 0.1)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm.

6) The crystalline form of claim 1 in crystalline Form V, characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (9.3 ± 0.1)°, (11.7 ± 0.1)° and (13.3 ± 0.1)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm. 7) The crystalline form of claim 1 in crystalline Form VI, characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (5.9 ± 0.1)°, (9.7 ± 0.1)° and (17.8 ± 0.1)°, when measured at a temperature in the range of from 20 to 30°C with Cu-Kalphai,2 radiation having a wavelength of 0.15419 nm. 8) The crystalline form according to any one of the preceding claims characterized in being non-solvated.

9) Use of the crystalline form as defined in any one of the preceding claims for the preparation of a pharmaceutical composition.

10) A pharmaceutical composition comprising a predetermined and/or effective amount of the crystalline form as defined in any one of claims 1 to 8 and at least one pharmaceutically acceptable excipient.

11) The pharmaceutical composition according to claim 10 which is an oral solid dosage form.

12) The pharmaceutical composition according to claim 11 which is a tablet or a capsule. 13) The crystalline form as defined in any one of claims 1 to 8 or the pharmaceutical composition as defined in any one of claims 10 to 12 for use as a medicament.

14) The crystalline form as defined in any one of claims 1 to 8 or the pharmaceutical composition as defined in any one of claims 10 to 12 for use in the treatment of a cardiovascular disease. 15) The use according to claim 14, wherein the cardiovascular disease is hypertrophic cardiomyopathy (HCM).