The present invention relates to solid forms of Omecamtiv Mecarbil (methyl 4-[(2-fluoro-3-{[N-(6-methylpyridin-3-yl)carbamoyl]amino}phenyl) methyl] piperazine -1-carboxylate) of Formula I or salts thereof, methods for preparation and pharmaceutical compositions thereof.

The present invention further relates to a composition comprising solid forms of Omecamtiv Mecarbil of Formula I along with at least one pharmaceutical acceptable excipients thereof.
BACKGROUND OF THE INVENTION
Omecamtiv Mecarbil (CK-1827452) of Formula I having chemical name methyl 4-[(2-fluoro-3-{[N-(6-methylpyridin-3-yl)carbamoyl]amino}phenyl) methyljpiperazine- 1-carboxylate and represented with structure as follows:

Omecamtiv Mecarbil is a cardiac-specific myosin activator. Omecamtiv Mecarbil is being studied for the treatment of chronic heart failure with reduced ejection fraction (GALACTIC-HF).
US7507735B2 (herein after referred as US'735) describes Omecamtiv Mecarbil, its preparative process, pharmaceutical composition and its use in treating heart failure.

WO 2014152270 Al (herein after referred as WO'270 application) describes the crystalline Form A of Omecamtiv Mecarbil dihydrochloride hydrate and anhydrous dihydrochloride forms B and C, which are metastable.
WO 2020037164 Al (herein after referred as WO'164 application) discloses the crystalline Form III, Form IV, Form V, Form VI, Form VII, amorphous hydrochloride salt and different crystalline acid salts of Omecamtiv mecarbil.
WO 2020014406 Al (the WO '406 application) discloses crystalline forms of Omecamtiv Mecarbil as well as dihydrochloride and other acid salts including glycolic acid, citric acid, malic acid and malonic acid.
Further, Org. Process Res. Dev. 2015, 19, 12, 1842-1848 discloses PXRD patterns of anhydrous and hemihydrate forms of Omecamtiv Mecarbil free base.
Although there are certain known polymorphic forms of Omecamtiv Mecarbil in the prior publications, however the development of new solid forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the range of materials that a formulation scientist can use for designing pharmaceutical formulation having desired characteristics.
The solid forms of the present invention have advantages in the preparation of pharmaceutical compositions of the Omecamtiv Mecarbil, such as ease of processing, handling, and dosing. In particular, they exhibit improved physicochemical properties, such as solubility, stability to stress, and rate of dissolution, rendering them particularly suitable for the manufacture of various pharmaceutical dosage forms.

Based on aforesaid, the present invention is focussed towards the development of new solid forms of Omecamtiv Mecarbil by employing simple, low cost and less time consuming processes.
OBJECT OF THE INVENTION
The main object of the present invention is to provide novel solid forms of Omecamtiv Mecarbil of Formula I, that possesses good stability, good processability and other favourable properties.
Another object of the present invention is to provide crystalline Form M of Omecamtiv Mecarbil of Formula I and its process for preparation thereof.
Another object of the present invention is to provide amorphous form of Omecamtiv Mecarbil salts.
Another object of the present invention is to provide process for the preparation of amorphous form of Omecamtiv Mecarbil salts.
SUMMARY OF THE INVENTION
In the main aspect, the present invention provides novel solid forms of Omecamtiv Mecarbil of Formula I or salts thereof, which possesses good stability, good processability and other favourable properties.
In another aspect, the present invention provides a crystalline form M of Omecamtiv Mecarbil of formula I, characterized by XRPD having peaks expressed invaluesofdegrees20at4.6°, 12.1° and 17.5°±0.1.
In another aspect, the present invention provides a crystalline form M of Omecamtiv Mecarbil of formula I, characterized by DSC thermogram with a first

endotherm having an onset temperature at about 85°C and second endotherm having an onset temperature at about 184°C.
In another aspect, the present invention provides a process for preparation of crystalline Form M of Omecamtiv Mecarbil of Formula I, wherein said process comprising the steps of:
i. treating Omecamtiv Mecarbil with one or more solvent; and
ii. isolating crystalline Omecamtiv Mecarbil Form M.
In another aspect, the present invention provides amorphous form of Omecamtiv Mecarbil salts and process for preparation thereof.
In another aspect, the present invention provides amorphous form of Omecamtiv Mecarbil salts wherein said salts are selected from Oxalate salt, Malonate salt, Succinate salt, Salicylate salt, Citrate salt, DL-Tartarate, DL-Malate salt, L-Malate salt, Nicotinate salt, and S-(+)-Mandelate salt.
In another aspect, the present invention provides process for preparing amorphous form of Omecamtiv Mecarbil salts, wherein said salts are selected from Oxalate salt, Malonate salt, Succinate salt, Salicylate salt, Citrate salt, DL-Tartrate, DL-Malate salt, L-Malate salt, Nicotinate salt, and S-(+)-Mandelate salt, wherein said process comprises the steps of:
i. providing a mixture of Omecamtiv Mecarbil and the suitable acid in one or
more solvent; and ii. isolating the amorphous Omecamtiv Mecarbil salt.
DETAILED DESCRIPTION
Brief description of drawings:
Fig. 1, represents the X-ray (powder) diffraction (XRPD) pattern of the crystalline
Form M of Omecamtiv Mecarbil.

Fig. 2, represents the Differential Scanning calorimetry (DSC) of the crystalline
Form M of Omecamtiv Mecarbil.
Fig. 3, represents the Thermogravimetric analysis (TGA) of the crystalline Form M
of Omecamtiv Mecarbil.
Fig. 4, represents the X-ray (powder) diffraction (XRPD) pattern of the amorphous
Form of Oxalate salt of Omecamtiv Mecarbil.
Fig. 5, represents the X-ray (powder) diffraction (XRPD) pattern of the amorphous
Form of Malonate salt of Omecamtiv Mecarbil.
Fig. 6, represents the X-ray (powder) diffraction (XRPD) pattern of the amorphous
Form of Succinate salt of Omecamtiv Mecarbil.
Fig. 7, represents the X-ray (powder) diffraction (XRPD) pattern of the amorphous
Form of Salicylate salt of Omecamtiv Mecarbil.
Fig. 8, represents the X-ray (powder) diffraction (XRPD) pattern of the amorphous
Form of Citrate salt of Omecamtiv Mecarbil.
Fig. 9, represents the X-ray (powder) diffraction (XRPD) pattern of the amorphous
Form of DL- tartrate salt of Omecamtiv mecarbil.
Fig. 10, represents the X-ray (powder) diffraction (XRPD) pattern of the amorphous
Form of DL- malate salt of Omecamtiv Mecarbil.
Fig. 11, represents the X-ray (powder) diffraction (XRPD) pattern of the amorphous
Form of L-malate salt of Omecamtiv Mecarbil.
Fig. 12, represents the X-ray (powder) diffraction (XRPD) pattern of the amorphous
Form of Nicotinate salt of Omecamtiv Mecarbil.
Fig. 13, represents the X-ray (powder) diffraction (XRPD) pattern of the amorphous
Form of S-(+)-Mandelate salt of Omecamtiv Mecarbil.
Definitions:
The names used herein to characterize a specific form, e.g. "Form M", should not be considered limiting with respect to any other substance possessing similar or identical physical and/or chemical characteristics, but rather it should be understood that these designations are mere identifiers.

"Salts" as used in the context of the present invention includes organic or inorganic acid addition salts, but are not limited to, hydrochloride salt, dihydrochloride salt, oxalate salt, malonate salt, succinate salt, salicylate salt, citrate salt, DL- tartrate salt, DL- malate salt, L- malate salt, nicotinate salt, and S-(+) mandelate salt.
The crystalline forms may be prepared by a variety of methods, including methods other than the methods disclosed in the present invention, for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid state transformation from another phase, crystallization from a supercritical fluid, and jet spraying. Techniques for crystallization or recrystallization of crystalline forms from a solvent mixture include, for example, evaporation of the solvent, decreasing the temperature of the solvent mixture, crystal seeding a supersaturated solvent mixture of the molecule and/or salt, freeze drying the solvent mixture, and addition of anti-solvents (counter solvents) to the solvent mixture.
"Solvent" as used in the context of the present invention refers to polar or non-polar solvents selected from, but not limited to, the group comprising of alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxy ethanol, diethylene glycol, 1 -, 2-, or 3- pentanol, neo-pentyl alcohol, t-pentyl alcohol, cyclohexanol, aliphatic hydrocarbons such as hexane, heptanes and petroleum ether, aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene , halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, esters such as methyl acetate, ethyl acetate, methyl propionate and ethyl propionate, ethers, ketones, sulfoxides, formamide, amides, nitriles such as acetonitrile; amides such as N,N-dimethylformamide and N,N-dimethylacetamide, sulfoxides such as dimethyl sulfoxide and mixtures thereof, pyrrolidines, carbonates, water and mixture thereof.

"Solid forms" as used herein refers to polymorphs, crystalline or amorphous, solvates, hydrates and co-crystals, premix, solid dispersion, solid solution, or mixture thereof in any proportion.
Before the present invention is described, it is to be understood that unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Further, it is to be understood that the present invention is not limited to the methodologies and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described, as these may vary within the specification indicated. Unless stated to the contrary, any use of the words such as "including," "containing," "comprising," "having" and the like, means "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims. Further the terms disclosed embodiments are merely exemplary methods of the invention, which may be embodied in various forms.
In an embodiment, the present invention provides solid forms of Omecamtiv Mecarbil of Formula I or salts thereof.
In another embodiment, the present invention provides crystalline Form M of Omecamtiv Mecarbil of Formula I.
In another embodiment, the present invention provides a crystalline Form M of Omecamtiv Mecarbil of Formula I, characterized by X-ray (powder) diffraction (XRPD) having peaks (20 values) at 3.9°, 4.6°,7.8°, 11.7°, 12.1°, 13.0°, 14.0°, 14.8°, 15.7°, 16.0°, 16.4°, 17.5°,21.4°, 21.8°, 22.8°,23.2°, 23.6°,24.3°, 24.5°, 25.1°,

26.0°, 27.0°, 28.0°, 29.1°, 31.4° and 36.2° ±0.1. In other embodiment, the present invention provides a crystalline Form M of Omecamtiv Mecarbil of Formula I, characterized by X-ray (powder) diffraction (XRPD) pattern as depicted in Fig. 1.
In particular embodiment, the present invention provides a crystalline Form M of Omecamtiv Mecarbil of Formula I, characterized by X-ray (powder) diffraction (XRPD) having peaks (20 values) at 4.6°, 12.1° and 17.5°±0.1.
In another embodiment, the present invention provides a crystalline Form M of Omecamtiv Mecarbil of Formula I, characterized by DSC thermogram with a first endotherm having an onset temperature at about 85°C and second endotherm having an onset temperature at about 184°C.
In other embodiment, the present invention provides a crystalline Form M of Omecamtiv Mecarbil of Formula 1, characterized by Differential Scanning calorimetry (DSC) as depicted in Fig. 2.
In other embodiment, the present invention provides a crystalline Form M of Omecamtiv Mecarbil of Formula 1, characterized by Thermogravimetric analysis (TGA) as depicted in Fig. 3.
In another embodiment, the present invention provides a process for preparation of crystalline form M of Omecamtiv Mecarbil of Formula I, wherein said process comprising the steps of:
i. treating Omecamtiv Mecarbil with one or more solvent; and ii. isolating crystalline Omecamtiv Mecarbil Form M.
In particular embodiment, the solvent used for preparing crystalline form M of Omecamtiv Mecarbil is a mixture of acetonitrile and water.

In other embodiment, the process of preparing crystalline form M of Omecamtiv Mecarbil is carried out at a temperature below -70°C followed by lyophilisation for 24 hrs resulting into complete crystallization.
In another embodiment, the present invention provides a stable amorphous form of Omecamtiv Mecarbil salts.
In another embodiment, the present invention provides a process for preparing amorphous form of Omecamtiv Mecarbil salts, wherein said salts are selected from Oxalate salt, Malonate salt, Succinate salt, Salicylate salt, Citrate salt, DL-Tartrate, DL-Malate salt, L-Malate salt, Nicotinate salt, and S-(+) Mandelate salt, and wherein said process comprising the steps of:
i. providing a mixture comprising Omecamtiv Mecarbil and suitable acid in one or more solvent; and
ii. isolating the amorphous Omecamtiv Mecarbil salt.
In another embodiment, said isolation to get amorphous Omecamtiv Mecarbil salt, is carried out at a temperature below -70°C followed by lyophilisation for 16-24 hrs, specifically overnight lyophilisation.
In another embodiment, present invention provides a solid pharmaceutical composition of amorphous Omecamtiv Mecarbil or salts and one or more pharmaceutically acceptable carrier.
The present invention is explained below by way of examples. However, the examples are provided as one of the possible way to practice the invention and should not be considered as limitation of the scope of the invention.
While the present invention has been particularly described, persons skilled in the art will appreciate that many variations and modifications can be made. Therefore, the invention is not to be construed as restricted to the particularly described

embodiments, examples and the scope and concept of the invention will be more readily understood by reference to the claims, which follow.
EXAMPLES Example-1: Synthesis of crystalline Form M of Omecamtiv Mecarbil of Formula I:
Omecamtiv Mecarbil (0.6 g) was dissolved in a mixture of acetonitrile: water (80:20) (150ml) at room temperature. Reaction mixture was filtered through 0.45 micron filter paper. Obtained filtrate was cooled at temperature below -70°C and lyophilized for 24hrs to get crystalline Omecamtiv Mecarbil (0.5 g).
Example-2: Synthesis of Oxalate salt of Omecamtiv Mecarbil:
Omecamtiv mecarbil (0.5g) and oxalic acid dihydrate (0.157 g) was dissolved in a mixture of acetonitrile: water (15ml: 15ml) at room temperature. Reaction mixture was filtered through 0.45 micron filter paper. Obtained filtrate was cooled at temperature below -70°C and lyophilized for overnight to get amorphous oxalate salt of Omecamtiv Mecarbil (0.64 g).
Example-3: Synthesis of Malonate salt of Omecamtiv Mecarbil:
Omecamtiv mecarbil (0.5g) and malonic acid (0.129 g) was dissolved in a mixture of acetonitrile: water (20 ml: 20 ml) at room temperature. Reaction mixture was filtered through 0.45 micron filter paper. Obtained filtrate was cooled at temperature below -70°C and lyophilized for overnight to get amorphous malonate salt of Omecamtiv Mecarbil (0.610 g).
Example-4: Synthesis of Succinate salt of Omecamtiv Mecarbil:
Omecamtiv mecarbil (0.5g) and succinic acid (0.147 g) was dissolved in a mixture of acetonitrile: water (9 ml: 9 ml) at room temperature. Reaction mixture was filtered through 0.45 micron filter paper. Obtained filtrate was cooled at temperature below -70°C and lyophilized for overnight to get amorphous Succinate salt of Omecamtiv Mecarbil (0.610 g).

Example-5: Synthesis of Salicylate salt of Omecamtiv Mecarbil:
Omecamtiv mecarbil (0.5g) and salicylic Acid (0.172 g) was dissolved in a mixture of acetonitrile: water (18 ml: 18 ml) at room temperature. Reaction mixture was filtered through 0.45 micron filter paper. Obtained filtrate was cooled at temperature below -70°C and lyophilized for overnight to get amorphous salicylate salt of Omecamtiv Mecarbil (0.635 g).
Example-6: Synthesis of Citrate salt of Omecamtiv Mecarbil:
Omecamtiv mecarbil (0.5g) and citric acid anhydrous (0.239 g) was dissolved in a mixture of acetonitrile: water (18 ml: 18 ml) at room temperature. Reaction mixture was filtered through 0.45 micron filter paper. Obtained filtrate was cooled at temperature below -70°C and lyophilized for overnight to get amorphous citrate salt of Omecamtiv Mecarbil (0.635 g).
Example-7: Synthesis of DL- tartrate salt of Omecamtiv mecarbil:
Omecamtiv mecarbil (0.5g) and D, L-tartaric acid (0.187 g) was dissolved in a mixture of acetonitrile: water (20 ml: 20 ml) at room temperature. Reaction mixture was filtered through 0.45 micron filter paper. Obtained filtrate was cooled at temperature below -70°C and lyophilized for overnight to get amorphous DL-tartrate salt of omecamtiv mecarbil (0.670 g).
Example-8: Synthesis of DL- malate salt of Omecamtiv Mecarbil:
Omecamtiv mecarbil (0.5g) and DL-Malic Acid (0.100 g) was dissolved in a mixture of acetonitrile: water (18 ml: 18 ml) at room temperature. Reaction mixture was filtered through 0.45 micron filter paper. Obtained filtrate was cooled at temperature below -70°C and lyophilized for overnight to get amorphous DL-Malate salt of Omecamtiv Mecarbil (0.385 g).
Example-9: Synthesis of L-malate salt of Omecamtiv Mecarbil:

Omecamtiv Mecarbil (0.5 g) and L-malic Acid (0.167 g) was dissolved in isopropanol at 80°C till clear solution. Reaction mixture was cooled and distilled out under vacuum at 50°C. Charged methanol (25 ml) and water (10 ml) and heated to 50-55°C. Solvent was distilled out at same temperature and chased out with methanol (25 ml). Obtained solid was degassed under vacuum to get amorphous L-malate salt of Omecamtiv Mecarbil (0.480 g)
Example-10: Synthesis of Nicotinate salt of Omecamtiv Mecarbil:
Omecamtiv mecarbil (0.5g) and nicotinic Acid (0.153 g) was dissolved in methanol (40 ml) at room temperature. Solvent was distilled out at 50°C under vacuum and degassed at same temperature to get amorphous nicotinate salt of Omecamtiv Mecarbil (0.645 g).
Example-11: Synthesis of S-(+)-Mandelate salt of Omecamtiv Mecarbil:
Omecamtiv mecarbil (0.5g) and S-(+)-Mandalic Acid (0.303 g) was dissolved in isopropanol at 80°C till clear solution. Solvent was distilled out at 60°C under vacuum and degassed at same temperature to get amorphous S-(+)-mandelate salt of Omecamtiv Mecarbil (0.8 g).
Example 12: Synthesis of crude Omecamtiv Mecarbil of Formula I:
Charged toluene (160ml) to methyl 4-[3-(azidocarbonyl)-2-flurorobenzyl] piperazine-1-carboxylate (4.32g). Added 3-amino-6-methyl pyridine (1.64g) under inert atmosphere at 20-25°C. Raised the temperature to 85-95°C and stirred for 4-5hours. After completion of reaction, reaction mixture was concentrated and added acetonitrile (20ml) and stirred for 30min. Filtered the mass to get desired crude Omecamtiv Mecarbil.


We Claim

1. A crystalline Form M of Omecamtiv Mecarbil of formula I,
wherein said form is characterized by
i. an X-ray powder diffraction (XRPD) pattern with characteristic
peaks at 4.6°, 12.1° and 17.5°±0.1 20; or ii. a DSC thermogram with a first endotherm having an onset temperature at about 85°C and second endotherm having an onset temperature at about 184°C.
2. A process for preparing crystalline Form M as claimed in claim 1, wherein
said process comprising the steps of:
i. treating Omecamtiv Mecarbil with one or more solvent; and ii. isolating crystalline Omecamtiv Mecarbil Form M.
3. The process as claimed in claim 2, wherein said solvent is a mixture of acetonitrile and water.
4. An amorphous form of Omecamtiv Mecarbil salts.
5. The amorphous form as claimed in claim 4, wherein said salts of Omecamtiv Mecarbil are selected from Oxalate salt, Malonate salt, Succinate salt, Salicylate salt, Citrate salt, D, L-Tartarate, D, L-Malate salt, L-Malate salt, Nicotinate salt, and S-(+) Mandelate salt.
6. A process for preparing amorphous form of Omecamtiv Mecarbil salts, wherein said salts are selected from Oxalate salt, Malonate salt, Succinate

salt, Salicylate salt, Citrate salt, D, L-Tartarate, D, L-Malate salt, L-Malate salt, Nicotinate salt, and S-(+) Mandelate salt, and wherein said process comprising the steps of:
i. providing a mixture of Omecamtiv Mecarbil and suitable acid in one or more solvent; and
ii. isolating the amorphous Omecamtiv Mecarbil salt.
7. The process as claimed in claim 6, wherein said suitable acid used in step i) is selected from the group comprising of Oxalic acid, Malonic acid, Succinic acid, Salicylic acid, Citric acid, D, L-Tartaric acid, D, L-Malic acid, L-Malic acid, Nicotinic acid, and S-(+) Mandelic acid.
8. The process as claimed in claim 6, wherein the said solvent is a mixture of acetonitrile and water.
9. The process as claimed in claim 6, wherein said isolation is carried out by a technique selected from filtration, rotational distillation device such as a Buchi® Rotavapor®, spray drying, agitated thin film drying, freeze drying (lyophilization), atmospheric distillation, and vacuum distillation.
10. The process as claimed in claim 9, wherein said isolation is carried out at a temperature below -70°C followed by lyophilisation for 16-24 hrs.