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Novel Compounds And Its Use In The Preparation Of Omecamtiv Mecarbil And Pharmaceutically Acceptable Salts Thereof

Abstract: Present invention relates to novel compounds of Formula II, its pharmaceutically acceptable salts, and polymorphs thereof. Formula II Present invention further relates to process of preparing compounds of Formula II and use in preparation of Omecamtiv Mecarbil and its pharmaceutically acceptable salts.

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Patent Information

Application #
Filing Date
09 August 2021
Publication Number
09/2023
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
amit.bansal@mankindpharma.com
Parent Application

Applicants

Mankind Pharma Ltd.
208, Okhla Industrial Estate Phase III, New Delhi India

Inventors

1. AHMAD, Ghufran
Mankind Research Centre 191-E, Sector 4-II, IMT Manesar Gurugram, Haryana India Pin No.- 122050
2. AHMAD, Pervez
Mankind Research Centre 191-E, Sector 4-II, IMT Manesar Gurugram, Haryana India Pin No.- 122050
3. SINGH, Avtar
Mankind Research Centre 191-E, Sector 4-II, IMT Manesar Gurugram, Haryana India Pin No.- 122050
4. BHASHKAR, Bhuwan
Mankind Research Centre 191-E, Sector 4-II, IMT Manesar Gurugram, Haryana India Pin No.- 122050
5. KUMAR, Anil
Mankind Research Centre 191-E, Sector 4-II, IMT Manesar Gurugram, Haryana India Pin No.- 122050

Specification

The present invention provides novel compounds of Formula II or its pharmaceutically acceptable salts, polymorphs, process of preparation and its use in preparation of methyl 4-[[2-fluoro-3-[(6-methylpyridin-3-yl)carbamoylamino]phenyl]methyl]piperazine-l-carboxylate of Formula I or pharmaceutically acceptable salts thereof, ^^KXD kAAJkA H F F Formula n o wherein Ri is selected from (CO)N3 or (CO)OR2, and wherein R2 is selected from hydrogen, substituted and unsubstituted C1-C10 alkyl, or substituted and unsubstituted C1-C10 aryl. BACKGROUND OF THE INVENTION Omecamtiv Mecarbil (CK-1827452), chemically known as methyl 4-[[2-fluoro-3-[(6-methylpyridin-3-yl)carbamoylamino]phenyl]methyl]piperazine-l-carboxylate represented by structure of Formula I as follows: o ^O-^N-^i 1^1 HN F H Formula I Omecamtiv Mecarbil is a selective cardiac myosin activator that specifically binds the catalytic SI domain of cardiac myosin but without any significant effect over other types of myosin (smooth or skeletal muscle). Omecamtiv Mecarbil is described in U.S. Patent No. 7,507,735 B2. US'735 further discloses the process for preparation of Omecamtiv Mecarbil as mentioned in the Scheme-1 below: Scheme-1 NO, 1 1 OHC ^^NO; ^N-^N02 OJJL F H H 0 ON H H H Omecamtiv mecarbil Formula I WO 2019006231 Al discloses a process for the preparation of Omecamtiv Mecarbil, as shown in the Scheme-2 below: Scheme-2 I 1/2H2° r n "V0''^N-^vl 1/2HP042- k " NO, Br- N02 n ° (AN H ll AcOH N02 i. NBS, (BzO)2 HPO(OEt>2 r toluene H2N a O ,N. F C D HCI N (Ay" HCI OU ™ NH, O VCAN' N02 i. Toluene/ NaOH (Aq.) II. H2/Pd-C/ toluene/ EtOH iii Heptane N. F N. F y-1 cAo- ti , HCI .HCI i. i-Pr2NEt/THF ACN IIH20 ' O Y Y o^ M-J 9 n N Formula VI R2 Formula XIX wherein R2 and R3 are as defined above; and e) converting compound of Formula VI or its salt to compound of Formula X and/or salt thereof, ffF ^0 HO Formula VI o M ' / I—N / C) F >=° Formula X The reaction of step a) is carried by reacting 2-fluoro-3-methylbenzoic acid with suitable reagent which is capable of forming a leaving group optionally in presence of radical initiator. In another embodiment, the reagent used in step a) is leaving agent which are selected from halogenating agents like Liq. bromine, Iodine, chlorine (gas), HBr, N-bromosuccinimide, N-chlorosuccinimide, N-Iodosuccinimide, p-toluenesulfonic acid, p-toluenesulfonyl chloride, methanesulphonic acid, methanesulphonyl chloride, phosphorus pentachloride, phosphorus trichloride, and the like. In another embodiment, reaction of step a) may be carried out in presence of suitable radical initiator selected from AIBN, ABCN, hydrogen peroxide, benzoyl peroxide and the like. In another embodiment, the solvent used in step a) is selected from group comprising of non-polar or polar solvent or its mixture thereof. In another embodiment optional esterification at step b) is carried out by the known methods of esterification using suitable solvent such as non-polar or polar solvents. In another embodiment the reaction of step c) involves reaction of compound of Formula XVII or XVIII with compound of formula XV to give compound of Formula XIX or VI. In another embodiment, the reaction of compound of Formula XVII or XVIII with compound of formula XV to give compound of Formula XIX or VI at step c) is carried out in presence of suitable base. In another embodiment, base used for the reaction between compound of Formula XVII or XVIII with compound of formula XV at step c) to give compound of Formula XIX or VI is selected from organic base or inorganic base. In another embodiment, deprotection in step d) is carried out in presence of acid or base. Preferably acid is selected from HC1, H2SO4, acetic acid or the like and base such as lithium diisopropylamide, Sodium bis(trimethylsilyl)amide to potassium hydroxide, sodium hydroxide, potassium tert-butoxide, lithium hydroxide and other strong bases known in art. In another embodiment, deprotection in step d) is carried out in absence of acid or base and heating the reactant in solvent for deprotection. In another embodiment, step d) is carried out in presence of suitable solvent such as non-polar and polar solvents or its mixtures thereof. In a preferred another embodiment, the conversion of compound of Formula VI to compound of Formula X at step e) is carried out by reacting compound of Formula VI with diphenylphosphoryl azide in presence of suitable solvent selected from non-polar solvent or polar solvent or its mixture thereof. The conversion of compound of Formula VI to compound of Formula X is carried at a temperature ranging from -10°C to boiling point of solvent, and most preferably at 0 °C to 10°C. In preferred embodiment, solvent used at step e) is selected from but not limited to non-polar solvent or polar solvents or its mixtures thereof. In a preferred another embodiment, the conversion of compound of Formula VI to compound of Formula X at step e) is carried out in presence of base. Preferably organic base. In another embodiment, the salts of compound of Formulae XI, XII XIV, XV, XVI, XI, X, XIII XVII, XVIII, and VI is selected from, but not limited to, hydrochloride salt, hydrobromide salt, sulphate salt, phosphate salt, succinate salt, formate salt, acetate salt, diphenyl acetate salt triphenylacetate salt, dichloroacetate salt, trifluoro acetate salt, propionate salt, butyrate salt, lactate salt, citrate salt, gluconic acid salt, mandelate salt, tartarate salt, maleate salt, adipic acid salt, aspartate salt, fumarate salt, glutamate salt, malic acid salt, malonate salt, benzoate salt, ^-chlorobenzoate salt, dibenzoyl tartarate sat, oxalate salt, nicotinic acid salt, o-hydroxybenzoate salt, ^-hydroxybenzoate salt, 1-hydroxy-naphthalene-2-carboxylate salt, hydroxynaphthalene-2-carboxylate salt, ethanesulfonate salt, ethane-1,2-disulfonate salt, 2-hydroxyethane sulfonate salt, methanesulfonate salt, (+)-camphor- 10-sulfonate salt, benzenesulfonate salt, naphthalene-2-sulfonate salt, p-toluenesulfonate salt, dicyclohexylamine salt, morpholine, pyridine, trimethyl amine salt, diisopropyl amine salt, sodium salt, potassium salt, calcium salt, barium salt, magnesium salt, diisopropyl ethyl amine, and the like. Preferably, salt of compound of Formula IV is selected from hydrochloride salt, hydrobromide salt, sulphate salt, phosphate salt, succinate salt, formate salt, acetate salt, dicyclohexylamine salt, trimethyl amine salt, diisopropyl amine salt, sodium salt, potassium salt, calcium salt, barium salt, magnesium salt, and diisopropyl ethyl amine. In another embodiment the present invention provides a process for the preparation of methyl 4-[[2-fluoro-3-[(6-methylpyridin-3-yl)carbamoylamino]phenyl]methyl]piperazine-l-carboxylate (Omecamtiv Mecarbil) of Formula I or pharmaceutically acceptable salts thereof, comprising the steps of: a) reacting compound of Formula XI or its salt with compound of Formula XII or its salt to give methyl 4-[[2-fluoro-3-[(6-methylpyridin-3-yl)carbamoylamino]phenyl]methyl] piperazine-1-carboxylate of Formula I or its pharmaceutically acceptable salt, o ^CT^N^ p^fi Formula XII ° [j^^f Formula XI I H Formula I • nrn A b) optionally purifying compound of Formula I or its pharmaceutically acceptable salt. In another embodiment, the reaction of compound of Formula XI and XII is carried out in presence of suitable solvent selected from, but not limited to, non-polar solvent, polar aprotic solvent, polar protic solvent or mixture thereof. In another embodiment, the present invention provides a process for the preparation of compound of Formula XI or salt thereof, wherein said process comprising the steps of: a) converting 2-fluoro-l-methyl-3-nitrobenzene of Formula XX to compound of Formula XIV; -Q - cQ F N02 F N02 Formula XX Formula XIV i wherein R3 is Halogen, hydroxy, alkylsulfonyl having 1-12 carbon atoms, formyl, methanesulfonyl (mesyl), trifluoroacetyl, p-toluenesulfonyl (tosyl), p-bromobenzenesulfonyl (brosyl) and p-nitrobenzenesulfonyl (nosyl); b) reacting compound of Formula XIV with compound of Formula XV or its salt to give compound of Formula XVI or salt thereof; NH N- / \_/ Formula XV ^N )—R3 / \ •"( \ F NO, F N02 N. Formula XIV ^ Formula XVI wherein R3 is as defined above; c) reducing compound of Formula XVI or its salt to give compound of Formula XI; %-/ /~\J N / \ /~~N /—F N02 ► ( \ F NH2 rN—' M / Formula XVI I Formula XI , °~- °^ ; and o d) optionally converting compound of Formula XI to its salt. The reaction of step a) is carried by reacting the compound of Formula XX with a suitable reagent which is capable of forming a leaving group optionally in presence of radical initiator. In another embodiment, the reagent used in step a) is leaving agent which are selected from halogenating agents like Liq. Bromine, Iodine, chlorine (gas), HBr, N-Bromosuccinimide, N-Chlorosuccinimide, N-Iodosuccinimide, p-toluenesulfonic acid, p-toluenesulfonyl chloride, methanesulphonic acid, methanesulphonyl chloride, phosphorus pentachloride, phosphorus trichloride, and the like. In another embodiment, reaction of step a) may be carried out in presence of suitable radical initiator selected from AIBN, ABCN, hydrogen peroxide, benzoyl peroxide and the like. In another embodiment, the solvent used in step a) is selected from suitable solvent such as non-polar or polar solvent or its mixtures thereof. The reaction of step b) is carried by reacting the compound of Formula XIV with compound of Formula XV or its salt in presence of suitable solvent and suitable base to give compound of Formula XVI or its salt. In another embodiment, suitable base used at step b) is selected from organic or inorganic base. In another embodiment, the reduction of compound of Formula XVI or its salt in step c) is carried out in presence of suitable solvent, suitable metal catalyst and hydrogen source. In another embodiment, suitable metal catalyst used for reduction of compound of Formula XVI in step c) is selected from but not limited to palladium, zinc or raney nickel, most preferred metal catalyst is zinc / Iron. In another embodiment, the suitable solvent used in step c) is selected from, but not limited to, non-polar solvent, polar aprotic solvent, polar protic solvent or its mixture thereof. In another embodiment, the conversion of 2-fluoro-l-methyl-3-nitrobenzene of Formula XX to compound of Formula XI or its salt is optionally carried out in presence of suitable base selected from inorganic and organic base. In another embodiment compounds obtained in any of the steps a), b) or c) is purified or processed directly without the purification to next step. In another aspect the present provides a novel compound of Formula XXI or its pharmaceutically acceptable salts, and polymorphs thereof, F R4 Formula XXI wherein R3 is Halogen, hydroxy, alkylsulfonyl having 1-12 carbon atoms, formyl, methanesulfonyl (mesyl), trifluoroacetyl, p-toluenesulfonyl (tosyl), p-bromobenzenesulfonyl (brosyl) and p-nitrobenzenesulfonyl (nosyl); and R4 is selected from NO2, (CO)OR2, wherein R2 is selected from hydrogen, substituted and unsubstituted C1-C10 alkyl, or substituted and unsubstituted C1-C10 aryl. In another embodiment the present invention provides compound of Formula XXI, wherein said compound is selected from the Formulae: / \o2 Forumtl* JCVH Fotmul* Will Formula XIV wherein, R3 is halogen, hydroxy, alkylsulfonyl having 1-12 carbon atoms, formyl, methanesulfonyl (mesyl), trifluoroacetyl, p-toluenesulfonyl (tosyl), p-bromobenzenesulfonyl (brosyl) and p-nitrobenzenesulfonyl (nosyl). In another embodiment, the process for the preparation of Omecamtiv Mecarbil includes preparation of intermediates wherein said intermediates may optionally be not isolated, and may be proceeded as such to next step. In another embodiment, the intermediates are not isolated and reaction may be carried out in one-pot. In another embodiment, the process for the preparation of Omecamtiv Mecarbil includes preparation of intermediates wherein said intermediates may optionally be isolated as its pharmaceutically acceptable salts. In another embodiment, intermediate prepared in any of the steps of the present invention may purified before using it for the next step of synthesis. In another embodiment, present invention also involves converting Omecamtiv Mecarbil obtained to its Omecamtiv Mecarbil salts or its hydrates or solvates thereof. In yet another embodiment, the present invention relates to preparing Omecamtiv Mecarbil and its intermediates having a purity of greater than 99.9%. In yet another embodiment, the present invention relates to preparing Omecamtiv Mecarbil having a required particle size suitable for formulation. In yet another embodiment, the present invention relates to one-pot / in-situ process for preparing Omecamtiv Mecarbil and its intermediates with a purity of greater than 99.9%. In another embodiment, the present invention provides a process for the purification of Omecamtiv Mecarbil or its pharmaceutically acceptable salt, wherein said process comprising the steps of: a) treating Omecamtiv Mecarbil or its pharmaceutically acceptable salt in a suitable solvent; b) optionally heating at a temperature ranging from 30°C to reflux temperature of the solvent; c) optionally adding anti-solvent for precipitation; and d) isolating the pure Omecamtiv Mecarbil or its pharmaceutically acceptable salt. In another embodiment, the process for purification of Omecamtiv Mecarbil or pharmaceutically acceptable salt thereof; may optionally include acid-base treatment. In a preferred embodiment, the Omecamtiv Mecarbil of Formula I may be isolated from the reaction mixture by purification, centrifugation, crystallization, filtration, extraction, evaporation and lyophilization. In another embodiment, the Omecamtiv Mecarbil of Formula I is further treated with HCl in presence of solvent, optionally further treatment with anti-solvent to give novel crystalline form of Omecamtiv Mecarbil diHCl. Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application. EXAMPLES Example-1: Synthesis of Omecamtiv Mecarbil Step-1 (a): Synthesis of 3-(bromomethyl)-2-fluorobenzoic acid: To a stirred solution of 2-fiuoro-3-methylbenzoic acid (lOmmol; leq) in acetonitrile (50ml) at 10-15°C was added N-bromosucinimide (1.02 mmol; 1.2eq) and AIBN (O.lmmol O.Oleq). Reaction mixture was stirred for 6-7 hr at 75-80°C and concentrated to get desired crude, which was taken in ethyl acetate (100ml) and washed with DM water (2x100ml). Organic layer was dried over sodium sulphate and concentrated to get 3-(bromomethyl)-2-fluorobenzoic acid. Step-1 (b): Synthesis of methyl 3-(bromomethyl)-2-fluorobenzoate: To stirred solution of methyl 2-fluoro-3-methylbenzoate (lOmmol; leq) in acetonitrile (50ml) atl0-15°C was added N-bromosucinimide (10.2 mmol; 1.2eq) and AIBN (O.lmmol; O.Oleq). Reaction mixture was stirred for 6-7 hr at 75-80°C and concentrated to get desired crude, which was taken in ethyl acetate (110ml) and washed with DM water (2x100ml). Organic layer was dried over sodium sulphate and concentrated to get methyl 3-(bromomethyl)-2-fluorobenzoate. Step-1 (c): Synthesis of methyl 3-(chloromethyl)-2-fluorobenzoate/3-(chloromethyl)-2-fluorobenzoate benzoic acid: To stirred solution of methyl 2-fluoro-3-methylbenzoate/ 2-fluoro-3-methylbenzoic acid (lOmmol; leq) in acetonitrile (50ml) at 10-15°C was added N-chlorosucinimide (10.2 mmol; 1.2eq) and AIBN (O.lmmol; O.Oleq). Reaction mixture was stirred for 6-7 hr at 75-80°C and concentrated in vacuum to get desired crude, which was taken in ethyl acetate (110ml) and washed with DM water (2x100ml). Organic layer was dried over sodium sulphate and concentrated to get desired compound. Step-2: Synthesis of 2-fluoro-3-((4-(methoxvcarbonvl)piperazin-l-vl)methyl)benzoic acid) of Formula VI (a) To a stirred solution of methyl 3-(bromomethyl)-2-fluorobenzoate (21.4mmol; leq) or methyl 3-(chloromethyl)-2-fluorobenzoate (21.4mmol; leq) in acetonitrile (50 ml) was added potassium carbonate (75.1mmol; 3.5eq) at 20-25°C and after 10 minute was added Methyl piperazine-1-carboxylate of Formula XV (27.8mmol; 1.3eq). Reaction mixture was stirred for 4-5hr at 60-70°C. After completion reaction, added 100 ml of DM water and extracted with ethylacetate. Aqueous layer was acidified with 2NHC1. Aqueous layer was then extracted again with n-Butanol and concentrated to give compound of Formula VI. (b) To a stirred solution of 3-(bromomethyl)-2-fluorobenzoic acid or 3-(chloromethyl)-2-fluorobenzoic acid (22mmol; leq) in acetonitrile (60 ml) was added potassium carbonate (75.1mmol; 3.5eq) at 20-25°C and after 20 minute was added Methyl piperazine-1-carboxylate of Formula XV (27.8mmol; 1.3eq). Reaction mixture was stirred for 5-6 hr at 60-70°C. After completion reaction, added 110 ml of DM water and extracted with ethylacetate. Aqueous layer was acidified with 2N HC1. Aqueous layer was then extracted again with n-butanol and concentrated to give compound of Formula VI. (c) To stirred solution of compound obtained from either example 1(a), (b) or (c) (5.0g; 21.4mmol: leq) in acetonitrile (50 ml) at 20-25°C followed by addition of K2CO3 (10.3gm; 75.1mmol 3.5eq) and Methyl piperazine-1-carboxylate (9.48g; 27.8mmol; 1.3eq). Reaction mixture was stirred for 4-5hr at 60-70°C. After completion reaction, added 100 ml of DM water and adjusted pH of mass 4-5 with 2 N HC1 at RT. Added ethyl acetate (100ml) and extracted aq. layer with ethyl acetate. Distilled out aq. layer and charged acetone (50ml) into it and stirred at 15 -200C for 30 min. Filtered the salt and washed the salt with 10ml of acetone. Distilled out acetone at 400C and charged TIFF (100ml) at RT and stirred the oily mass at 35-400C for 1 hr. Cooled the mass to 10-150C for 30 min and filtered. Distilled the mother liquor at 400C and degassed the solid mass so obtained to get desired compound. Step-3: Synthesis of methyl 4-(3-(azidocarbonyl)-2-fluorobenzyl)piperazine-l-carboxylate of Formula X: Added compound of Formula VI (13.5 mmol; l.Oeq) in 40ml DMF and cooled to 0-50°C under stirring. Added TEA (14.8mmol; l.leq) and diphenylphosphorylazide (DPPA; 14.8mmol; l.leq) dropwise and reaction mixture was stirred for 1-2 hr at 0-100°C. After completion of reaction, reaction mixture was quenched with ice water (100ml) and extracted with toluene (2x100ml) which is proceeded in-situ to the next step. Step-4: Synthesis of Omecamtiv Mecarbil: To stirred solution of toluene obtained from previous step was added 3-amino-6-methyl pyridine (16.2mmol; l.leq) in acetone (40ml) under inert atmosphere at 20-25°C and reaction was then heated at 85-95°C for 2-3 hr. After completion of reaction, reaction mixture was concentrated and added acetonitrile. Stirred the reaction mass and then filtered to get pure Omecamtiv Mecarbil. Example-2: Synthesis of Omecamtiv Mecarbil Step-1: Synthesis of l-(bromomethyl)-2-fluoro-3-nitrobenzene: To a stirred solution of 2-fluoro-l-methyl-3-nitrobenzene(64mmol; leq) in acetic acid (100ml) at 20-25°C was added N-bromosuccinimide (103mmol; 1.6eq) and AIBN (9mmol; 0.15eq) and reaction mixture was stirred for 3-4hr at 75-85°C. After completion of reaction, reaction mixture was concentrated to get desired crude compound of Formula XIV. Compound of Formula XIV so obtained was taken in ethyl acetate (100ml) and washed with DM water (2x100ml). Organic layer was dried over sodium sulphate and concentrated to get l-(bromomethyl)-2-fluoro-3-nitrobenzene. Step-2: Synthesis of methyl 4-(2-fluoro-3-nitrobenzyl)piperazine-l-carboxylate of Formula XVI: To a stirred solution of l-(bromomethyl)-2-fluoro-3-nitrobenzene (40mmol; leq) in toluene (100 ml) at 0-5°C was added DIPEA (0.1 eq) and methyl piperazine-1-carboxylate of Formula XV (44.8mmol; 1.12eq). Reaction mixture was stirred for 8-10hr at 80-90°C. After completion of reaction, reaction mixture was concentrated to get desired crude compound of Formula XVI. Compound of Formula XVI obtained was taken in ethyl acetate (100ml) and washed with DM water (2x100ml), dried over sodium sulphate and concentrated to get desired compound of Formula XVI. Step-3: Synthesis of methyl 4-(3-amino-2-fluorobenzyl)piperazine-l-carboxylate compound of Formula XI: Compound of Formula XVI (40mmol, l.Oeq) was charged in 30ml ethanol and cooled to 0-5°C and added ammonium chloride (160mmol; 4.0eq) in 10 ml water followed by addition of Zn powder (160mmol; 4.0eq). After addition, reaction was stirred at 20-30°C for 2-3hr. After completion of reaction, filtered through Hyflow and concentrated to get crude compound of Formula XI which was directly used in next step. Step 4: Synthesis of Omecamtiv Mecarbil: To a stirred solution of compound of Formula XII (6-methylnicotinoyl azide) (30mmol; leq) in toluene (200 ml) added solution of compound of Formula XI (33mmol; l.leq) dissolved in acetone under inert atmosphere at 20-25°C. Reaction mixture was stirred at 85-95°C for 2-3 hr. After completion of reaction, reaction mixture was concentrated to get crude compound which was then purified by crystallization to get desired Omecamtiv Mecarbil. Example-3: Synthesis of compound of Formula XII (6-methylnicotinoyl azide): 6- methylnicotinic acid (30 mmol; l.Oeq) was taken in 60ml DMF and cooled to 0-5°C under stirring. Added TEA (30mmol; l.leq) and Diphenylphosphorylazide (DPPA; 33mmol; l.leq). Reaction mixture was stirred for 1-2 hr at 0-10°C. After completion of reaction, reaction mixture was quenched with ice water (100ml) and extracted with Toluene (2x100ml) to get desired compound of formula XII. We Claim 1. Compounds of Formula II or pharmaceutically acceptable salts, and polymorphs thereof, o Formula II wherein Ri is selected from (CO)N3 or (CO)OR2, and wherein R2 is selected from hydrogen, substituted and unsubstituted C1-C10 alkyl, or substituted and unsubstituted C1-C10 aryl. 2. The compounds as claimed in claim 1, wherein said compounds of Formula II are selected from the Formulae: F O Formula III o 1 A ^O F O Formula IV O ON Formula V F O O ON F O Formula VI O o OH ^N^WX^oJ/- k^,N F O Formula VIT F O ^^ Formula Vm NH2 O o F O V^-Formula IX O O F O O O Formula XI 3. A process for the preparation of methyl 4-[[2-fluoro-3-[(6-methylpyridin-3- yl)carbamoylamino]phenyl]methyl]piperazine-l-carboxylate (Omecamtiv Mecarbil) of Formula I or pharmaceutically acceptable salts thereof, comprising the steps of: a) reacting compound of Formula XI or its salt with compound of Formula XII or its salt to give methyl 4-[[2-fluoro-3-[(6-methylpyridin-3- yl)carbamoylamino]phenyl]methyl]piperazine-l-carboxylate of Formula I or its pharmaceutically acceptable salt, °YN3 ^CT^N^ r*^ Formula XII ° (T ^f G JvAN„ ► W», ^ HN^N Formula XI I H Formula I • an(J b) optionally purifying compound of Formula I or its pharmaceutical^ acceptable salt. 4. The process as claimed in claim 3, wherein said step a) is carried out in presence of solvent selected from polar solvent, polar aprotic solvent, polar protic solvent or mixture thereof. 5. The process as claimed in claim 3, wherein said compound of Formula XI is prepared by process comprising the steps of: a) converting 2-fluoro-l-methyl-3-nitrobenzene of Formula XX to compound of Formula XIV; // \ -J R F N02 F NOz Formula XX Formula XIV wherein R3 is halogen; hydroxy, alkylsulfonyl having 1-12 carbon atoms, formyl, methanesulfonyl (mesyl), trifluoroacetyl, p-toluenesulfonyl (tosyl), p-bromobenzenesulfonyl (brosyl), and p-nitrobenzenesulfonyl (nosyl), b) reacting compound of Formula XIV with compound of Formula XV or its salt to give compound of Formula XVI or salt thereof; /—NH < ) Formula XV N / R3 7 \ "( \ F NO, F N02 ^ Formula XIV 1 wherein R3 is as defined above; c) reducing compound of Formula XVI or its salt to give compound of Formula XI; - /ft r^t F N02 ( \ F NH2 I Formula XVI 1 Formula XI , U^ °^ ; and d) optionally converting compound of Formula XI to its salt. 6. Compounds of Formula XXI or its pharmaceutically acceptable salts, and polymorphs thereof, F R4 Formula XXI 1 wherein R3 is halogen; hydroxy, alkylsulfonyl having 1-12 carbon atoms, formyl, methanesulfonyl (mesyl), trifluoroacetyl, p-toluenesulfonyl (tosyl), p-bromobenzenesulfonyl (brosyl) and p-nitrobenzenesulfonyl (nosyl); and R4 is selected from NO2, (CO)OR2, wherein R2 is selected from hydrogen, substituted and unsubstituted C1-C10 alkyl, or substituted and unsubstituted C1-C10 aryl. 7. The compounds as claimed in claim 6, wherein said compounds are selected from the Formulae: e9- ^ F >=0 FN02 KnrmulaXVtl Furmul* Will Formula XIV wherein, R3 is as defined above. 8. A process for the preparation of methyl 4-[[2-fluoro-3-[(6-methylpyridin-3-yl)carbamoylamino]phenyl]methyl] piperazine-1-carboxylate of Formula I or pharmaceutically acceptable salt thereof, wherein said process comprising the steps of: a) reacting compound of Formula X or its salt with compound of Formula XIII or its salt to give methyl 4-[[2-fluoro-3-[(6-methylpyridin-3-yl)carbamoylamino]phenyl]methyl] piperazine-1-carboxylate of Formula I or its pharmaceutically acceptable salt, NH, O L M -L II M Formula xm \„^.,—^ ^^ ....^^N ^N^kJLAn k^^kA^N, FormulaX1H ^ >AN^ F O ^■"^^^N^O F H Formula X Formula I • ^rj(J b) optionally purifying compound of Formula I or its pharmaceutically acceptable salt. 9. The process as claimed in claim 8, wherein said compound X is prepared by a process comprising the steps of: a) converting 2-fluoro-3-methylbenzoic acid to compound of Formula XVII or its salt; 2-fluoro-3-methylbenzoic acid Formula XVII wherein R3 is as defined above; b) optionally converting compound of Formula XVII or its salt to compound of Formula XVIII; — R F O 1 R2 Formula XVIII wherein R2 is selected from substituted and unsubstituted alkyl, or substituted and unsubstituted aryl; and R3 is as defined above; c) reacting compound of Formula XVII or XVIII with compound of Formula XV or its salt to give compound of Formula VI or XIX; // \ Jv -J n N' I R2 Formula XIX °^r / &. O^.N-- HO T Formula VI Y F )=° HO Formula XVII Formula XV wherein R2 and R3 are as defined above; d) optionally deprotecting compound of Formula XIX to give compound of Formula VI or its salt; F ;=o HO o>> ■ o J^" N—' O n. N—' I Formula XIX wherein R2 and R3 are as defined above; and e) converting compound of Formula VI or its salt to compound of Formula X and/or salt thereof, o F y=o HO F" f=0 N3 o M ' J^" I /■ /* 10. A process for the purification of Omecamtiv Mecarbil or its pharmaceutically acceptable salt, wherein said process comprising the steps of: a) treating Omecamtiv Mecarbil or its pharmaceutically acceptable salt in a suitable solvent; b) optionally heating at a temperature ranging from 30°C to reflux temperature of the solvent; c) optionally adding anti-solvent for precipitation; and d) isolating the pure Omecamtiv Mecarbil or its pharmaceutically acceptable salt.

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# Name Date
1 202111035890-STATEMENT OF UNDERTAKING (FORM 3) [09-08-2021(online)].pdf 2021-08-09
2 202111035890-PROVISIONAL SPECIFICATION [09-08-2021(online)].pdf 2021-08-09
3 202111035890-POWER OF AUTHORITY [09-08-2021(online)].pdf 2021-08-09
4 202111035890-FORM 1 [09-08-2021(online)].pdf 2021-08-09
5 202111035890-DECLARATION OF INVENTORSHIP (FORM 5) [09-08-2021(online)].pdf 2021-08-09
6 202111035890-Proof of Right [20-08-2021(online)].pdf 2021-08-20
7 202111035890-OTHERS-090921.pdf 2021-10-19
8 202111035890-Correspondence-090921.pdf 2021-10-19
9 202111035890-FORM 3 [29-07-2022(online)].pdf 2022-07-29
10 202111035890-CORRESPONDENCE-OTHERS [29-07-2022(online)].pdf 2022-07-29
11 202111035890-COMPLETE SPECIFICATION [29-07-2022(online)].pdf 2022-07-29