FIELD OF THE INVENTION
The present invention provides novel compounds of Formula A,
The present invention further provides process of preparing compounds of Formula A and use in preparation of Omecamtiv Mecarbil and its pharmaceutically acceptable salts.
The present invention further provides solid forms of Omecamtiv Mecarbil, or its pharmaceutically acceptable salts, and process for the preparation thereof.
BACKGROUND OF THE INVENTION
Omecamtiv Mecarbil (CK-1827452), of Formula I having chemical name 4-[(2-fluoro-3-{[N-(6-methylpyridin-3-yl)carbamoyl]amino}phenyl) methyl]piperazine-l-carboxylate and is represented with structure as follows:

Formula I
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).
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
F
A.- Ar^Ar- >aoA.- ^o A„

o
^AN'
H H
oAi,crA^oA)
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. NBS, (BzO)2
l| AoOH
NO,
Br-
N02"
N02
ii. HPO(OEt)2 toluene

jj 1/2 H20
^CT^N^N 1/2HP042"
NH2

M^ F
C ~) -HCI
N

X
itrile k-/kn^
Acetonitrile
H2N

0AN^^N HCI
H

NH,
NO,
out
i. Toluene/ NaOH (Aq.) II. H2/Pd-C/ toluene/ EtOH
0AN^N
H_
O
,N^ F
C ~) -HCI
N
O
N-^N H H
2-PrOH H20/HCl
i. i-Pr2NEt/THF
ACN
IIH20
iii Heptane
C D -HCI
N (Ar"
O
•AN""-^
N^N
H H
2HC1.H20
Crystalline
U.S. Patent No. 9,988,354 B2 discloses a crystalline form of dihydrochloride monohydrate salt of Omecamtiv Mecarbil and process of preparation thereof. It also discloses anhydrous Omecamtiv Mecarbil dihydrochloride and crystalline form thereof.
WO 2020/037164 Al discloses several crystalline forms of free base, and solvates of Omecamtiv Mecarbil. WO'164, also discloses amorphous form of Omecamtiv Mecarbil hydrochloride and various crystalline acid salts of Omecamtiv Mecarbil .

Although there are certain processes known in the published references for the preparation of Omecamtiv Mecarbil and various solid forms thereof, however, there is always a need to provide a process for preparing pure Omecamtiv Mecarbil and other solid forms of Omecamtiv Mecarbil , which are economical and commercially viable and are stable enough to be formulated for final use.
OBJECT OF THE INVENTION
An object of the present invention is to provide novel compounds of Formula A,
pharmaceutically acceptable salts and process of preparation thereof,
F
^3
Formula A
Another object of the present invention is to provide novel compounds of Formula A that can be used as intermediates for the preparation of Omecamtiv Mecarbil of Formula I and its pharmaceutically acceptable salts.
Another object of the present invention is to provide solid forms of Omecamtiv Mecarbil, or its pharmaceutically acceptable salts, and process for the preparation thereof, wherein said solid forms are stable for atleast six months at 25°C to 40°C and 60% to 75% RH.
SUMMARY OF THE INVENTION
The main aspect of the present invention is to provide novel compounds of Formula A and pharmaceutically acceptable salts thereof;
F

wherein, Ri is selected from halogen, OR2, substituted and unsubstituted heterocyclic ring;
wherein R2 is selected from hydrogen or suitable protecting group;
Y is either -CH2 or -CO;
R3 is selected from hydrogen, halogen, cyano, nitro, substituted and unsubstituted amine,
hydrazine, azide, -COR4, -NHCONRs, -N=C=0, and -Q; wherein group Q is represented as:

wherein R4 is selected from azide, -NR6R7, -OR9, wherein R6 and R7 are independently
selected from hydrogen, C1-C6 alkyl, and C1-C6 alkoxy group, substituted and unsubstituted
heteroaryl, hydrazine, substituted and unsubstituted amine;
R5 is hydrogen, halogen, -C=0, -NHOH;
R8 is selected from substituted and unsubstituted heteroaryl; and
R9 is selected from hydrogen, C1-C6 alkyl; and
wherein, when Rs is substituted heteroaryl, then Ri is either halogen, or is represented as OR2.

In another aspect, the present invention provides novel compounds as represented by formulae below:
/ F O F O ' "
o o
Formula IV Formula VI Formula VIII
"j j F> NHOH
*y-0 KJ J^ /OyN^ IJ ± H0^NA



N3 Br
Formula IX
HO

Formula XIII

Formula XIV

Formula XV Formula XX

R90

Formula XXI

RoO
O F
Formula XXII Formula XXIII

R90

Formula XXV

and

Formula XXIX

wherein R2 is as defined above.
In another aspect, the present invention provides process for the preparation of Omecamtiv Mecarbil by using compounds of Formula A as intermediates.
In another aspect, the present invention provides a stable amorphous form of Omecamtiv Mecarbil or pharmaceutical acceptable salt thereof.
In another aspect, the present invention provides a process for the preparation of an amorphous solid dispersion of Omecamtiv Mecarbil or pharmaceutically acceptable salt thereof, comprises the steps of:
a) adding Omecamtiv Mecarbil or pharmaceutically acceptable salt thereof in a suitable solvent to get a mixture;
b) adding atleast one pharmaceutically acceptable carrier to the mixture obtained in step a); and
c) isolating to get amorphous solid dispersion of Omecamtiv Mecarbil or pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION
Definitions:
"Pharmaceutical acceptable salts" as used in the context of the present invention refers to inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid salt; organic acids such as formic acids, acetic acid, diphenyl acetic acid, triphenylacetic acid, caprylic acid, dichloroacetic acid, trifluoro acetic acid, propionic acid, butyric acid, lactic

acid, citric acid, gluconic acid, mandelic acid, oxalic acid, salicylic acid, tartaric acid, malic acid, adipic acid, aspartic acid, fumaric acid, glutamic acid, maleic acid, malonic acid, succinic acid, benzoic acid, /?-chlorobenzoic acid, nicotinic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, l-hydroxy-naphthalene-2-carboxylic acid, hydroxynaphthalene-2-carboxylic acid, ethanesulfonic acid, ethane-1,2-disulfonic acid, 2-hydroxyethane sulfonic acid, methanesulfonic acid, (+)-camphor-10-sulfonic acid, benzenesulfonic acid, naphthalene-2-sulfonic acid, naphthalenedisulfonic acid, p-toluenesulfonic acid; and the like.
The term "protecting group" as used herein means temporary modifications of a potentially reactive functional group which protect it from undesired chemical transformations. The term "suitable protecting group" as used in the context of the present invention refers to carbon or silyl containing moieties selected from, but not limited to, acetyl, benzoyl, benzyl, trimethyl silyl, tetrahydropyran, methyl, ethyl, tertbutyl, allyl, t-butyl dimethyl silyl, t-butyl diphenylsilyl, pivaloyl, and the like.
"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, hydrocarbons, halogenated solvents, esters, ethers, ketones, sulfoxides, formamide, amides, nitriles, pyrrolidines, carbonates, water and the like. Specifically, the suitable solvent as used in the present invention is selected from, but not limited to, tetrahydrofuran, toluene, o/m/p-xylene, 1,4-dioxane, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, dichlorobenzene, chlorobenzene, methanol, ethanol, isopropyl alcohol, butanol, t-butanol, acetonitrile, ethyl acetate, acetone, methyl ethyl ketone, 2-methyl tetrahydrofuran, butyl acetate, isobutyl acetate, t-butyl acetate, propyl acetate, propylene acetate, acetic acid, methyl t-butyl ketone, dimethyl sulfoxide, N-methyl pyrrolidine, dimethyl acetamide, dimethyl formamide, N-methyl acetamide, acetamide, methyl isobutyl ketone, propionitrile, methyl ethyl ether, methyl tert-butyl ether, dimethyl ether, diethyl ether, cyclohexane, hexane, n-heptane, propylene carbonate, water and mixture thereof.
The term "substantially free" or "substantially pure" used in the context of the present invention means Omecamtiv Mecarbil having each impurity less than about 0.2% by area percentage of HPLC. In particular, less than about 0.15% by area percentage of HPLC. More particular, not in detectable amount by area percentage of HPLC.

In one embodiment, the present invention provides novel compounds of Formula A, and pharmaceutical^ acceptable salts thereof,

wherein, Ri, Y and R3 are as defined above.
In another embodiment, the present invention provides use of novel compounds of Formula A in the preparation of Omecamtiv Mecarbil or its pharmaceutical^ acceptable salts.
In another embodiment, the present invention provides a process for the preparation of Omecamtiv Mecarbil or pharmaceutical^ acceptable salt thereof, comprising the steps of:
a) converting compound of Formula VIII to methyl 4-(2-fluoro-3-(iodo((6-methylpyridin-3-
yl)imino)methyl)benzyl)piperazine-l-carboxylate of Formula DC in presence of suitable
solvent;
F o rr"Y I 1
O 0 L^N
Formula Vin Formula IX | anf|
b) converting compound of Formula IX to Omecamtiv Mecarbil or its pharmaceutical^
acceptable salt.
In one another embodiment, the present invention provides a process of preparation of Omecamtiv Mecarbil by employing novel compounds of Formula IV, VI, VIII, IX and X, wherein said process comprises reaction steps as mentioned in the Scheme-3 below:
Scheme-3:



'V' "0'
Formula
Br
Formula III

F 0 Formula IV

O
r^NAo"
F O
-o
F 0

sQ-^H^) KJ
r^N
V^ r^N-^YS^^0H formula vn
,0 N^
Formula VI
O Formula VIII

^XV™
I
0

N F H
HN

Formula XI

0
i y rVx

*JT&X
Y
0

In another embodiment, the present invention provides a process for the preparation of Omecamtiv Mecarbil or pharmaceutical^ acceptable salts thereof, comprising the steps of:
a) converting 2-fluoro-3-(hydroxymethyl)benzoylazide of Formula XV to 2-fluoro-3-(hydroxymethyl)benzyl isocyanate of Formula XVI;
b) converting compound of Formula XVI to Omecamtiv Mecarbil; and
c) optionally converting Omecamtiv Mecarbil to its pharmaceutical^ acceptable salts.
In one another embodiment, the present invention provides a process of preparation of Omecamtiv Mecarbil by employing novel compounds of Formula XIII, XIV, XV, XVI, XVII and XVIII, wherein said process comprises reaction steps as mentioned in the scheme-4 below:
Scheme-4:
F O
-^ HO
F O Formula XIII
Formula XV
Formula XII
Formula XIV

■ocrVS
Formula XV1H
wherein Rj is halogen or OR2, R2 is hydroxyl protecting group

R20

F H2N
NYNY^ -
Formula XVII
wherein R2 is Hydrogen

C^

HO'

Formula XVI

o
H H O

Omecamtiv Mecarbil

In another embodiment, the present invention provides a process of preparation of Omecamtiv Mecarbil or pharmaceutically acceptable salts thereof, comprising the steps of:
a) reacting 3-(bromomethyl)-2-fluorobenzonitrile of Formula XX with methyl piperazine-1-carboxylate in presence of suitable solvent to give methyl 4-(3-cyano-2-fluorobenzyl)piperazine-l-carboxylate of formula XXI;
b) converting compound of Formula XXI to Omecamtiv Mecarbil ; and
c) optionally converting Omecamtiv Mecarbil to its pharmaceutically acceptable salts.
In one another embodiment, the present invention provides a process of preparation of Omecamtiv Mecarbil by employing novel compounds of Formula XX, XXI, and X, wherein said process comprises the reaction steps as mentioned in the Scheme-5 below: Scheme-5:




Br
"N'
0

Formula XIX

Formula XX

O Formula XXI

O Formula X N-~

o=s=o
(
N02
o
x
HN N H

In another embodiment, the present invention provides a process for the preparation of Omecamtiv Mecarbil or its pharmaceutically acceptable salts; comprising the steps of: a) converting compound of Formula XXIII to compound of Formula XVII by reacting with phenyl (6-methylpyridin-3-yl)carbamate of Formula XXIV;
o
CAN
H

F HNM;
V,f
>=( HN
HN

HN

o

R,0
R2 is mesyl or tosyl

Formula I

Formula XVn

In one another embodiment, the present invention provides a process of preparation of Omecamtiv Mecarbil of Formula I by employing novel compounds of Formula XXV and XVII, wherein said process comprises the reaction steps as mentioned in the scheme-7 below: Scheme-7:

out
F HN—NO,
NO,
HO
NH,
Formula XXTV

O F
Formula XXII

O F
Formula XXVII

O F
Formula XXIII'

■0^N^^N V_V ~ /=r\j
Formula XXV

i °Y°

^N

NH

H H
V
o
Formula 1

F N

Formula V

R,0
Formula XVU
R2=H

In one another embodiment, the present invention provides process for the preparation of Omecamtiv Mecarbil or its pharmaceutically acceptable salt, comprises the steps of: a) converting compound of Formula XXIX to compound of Formula XXV in presence of suitable solvent;
H
y
F HNM ^NH2


^4
r%J
>=< HN
R20
Formula XXV
wherein R2 is selected from hydrogen or suitable protecting group;
b) converting compound of Formula XXV to Omecamtiv Mecarbil; and
c) optionally converting the Omecamtiv Mecarbil to its pharmaceutically acceptable salts.
Formula XXIX
In one another embodiment, the present invention provides a process of preparation of Omecamtiv Mecarbil by employing novel compounds of Formula XXIX, XXV and XVIII, wherein said process comprises the reaction steps as mentioned in the scheme-8 below: Scheme-8:




SA5
NH,
HO'
Formula XXIX
H HN
P F
N02
Formula XXII

Formula XXITI
R = H, hydroxyl protecting group

R2.,
1 °Y°
0

O
HN^I

R20
NH2
MsO

F. HN—f
\_J
Formula XXV
F. HN—f
' HN^x ,f
\ // N

Formula XVIII
In another embodiment, the process for purification of Omecamtiv Mecarbil or pharmaceutically acceptable salt thereof or its intermediates or pharmaceutically acceptable salt thereof may optionally include acid-base treatment.
In another embodiment, the process for the preparation of Omecamtiv Mecarbil or pharmaceutically acceptable salt thereof includes preparation of intermediates wherein said intermediates may optionally be purified before proceeding to the next step.
In another embodiment, the intermediates used in the preparation of Omecamtiv Mecarbil may also be converted into their pharmaceutically acceptable salts.

In another embodiment, the present invention provides process for the preparation of Omecamtiv Mecarbil or pharmaceutically acceptable salt thereof, wherein said process involves in-situ reaction steps wherein intermediates are not isolated and are used as such in the next reaction step.
In another embodiment, the present invention provides stable amorphous form of Omecamtiv Mecarbil or pharmaceutically acceptable salt thereof, wherein said amorphous form is stable for atleast six months at 25°C to 40°C and 60% to 75% RH.
In another embodiment, the present invention provides a stable amorphous form of Omecamtiv Mecarbil or pharmaceutical acceptable salt thereof.
In another embodiment, the present invention provides a process for the preparation of amorphous form of Omecamtiv Mecarbil or a pharmaceutically acceptable salt thereof, comprises the steps of:
a) providing a solution of Omecamtiv Mecarbil or a pharmaceutically acceptable salt thereof in one or more suitable solvent; and
b) isolating the amorphous form of Omecamtiv Mecarbil or a pharmaceutically acceptable salt thereof.
In further embodiment, the present invention provides substantially pure Omecamtiv Mecarbil, wherein said Omecamtiv Mecarbil is substantially free of impurities and wherein each impurity is less than about 0.3% w/w or total impurity less than about 1% w/w, more specifically less than about 0.15% w/w of any impurity.
In another embodiment, the present invention provides pure Omecamtiv Mecarbil, wherein said Omecamtiv Mecarbil is characterized by purity of 99.0% and above.
In another embodiment, the present invention provides an amorphous solid dispersion of Omecamtiv Mecarbil or pharmaceutically acceptable salt thereof, with atleast one pharmaceutically acceptable carrier.

In further embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of Omecamtiv Mecarbil or pharmaceutically acceptable salt thereof, comprises the steps of:
a) adding Omecamtiv Mecarbil or pharmaceutically acceptable salt thereof in a suitable solvent to get a mixture;
b) adding atleast one pharmaceutically acceptable carrier to the mixture obtained in step a); and
c) isolating to get amorphous solid dispersion of Omecamtiv Mecarbil or pharmaceutically acceptable salt thereof.
In another embodiment, the Omecamtiv Mecarbil or pharmaceutically acceptable salt thereof, is characterized by particle size distribution of less than about 300um, preferably less than about 200um and most preferably about lOOum.
In another embodiment, the pharmaceutically acceptable carrier used for preparing solid dispersion is selected from the group comprising of polyvinyl pyrrolidine, povidone K-30, povidone K-60, Povidone K-90, polyvinylpyrrolidone vinylacetate, co-povidone NF, polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene-polyoxypropylene copolymers (Poloxamer®188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit), hydroxypropylmethyl cellulose (UPMC), hydroxypropylmethyl cellulose phthalate (UPMC phthalate), hydroxypropylmethyl cellulose acetate succinate (UPMC AS), hydroxypropyl cellulose SL (HPC), hydroxy ethyl cellulose (HEC) and ethyl cellulose (EC).
In preferred embodiments, removal of solvent at any stage of preparation of Omecamtiv Mecarbil or pharmaceutically acceptable salt and its intermediates, include, but not limited to, methods selected from solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Biichi® Rotavapor®, flash evaporation, rotational dying, agitated nutsche filter drying, spray drying, freeze drying, thin film drying, agitated thin film drying, rotary vacuum paddle dryer (RVPD), lyophilisation, and the like. In preferred embodiment, the solvent may be removed under reduced pressures and at a temperature of less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C.

In another preferred embodiment, the Omecamtiv Mecarbil or salt thereof as isolated by the process of the present invention is amorphous in nature, wherein said amorphous Omecamtiv Mecarbil or salt thereof is substantially free of crystalline peaks.
In one another embodiment, the present invention further provides a composition comprising Omecamtiv Mecarbil or its pharmaceutically acceptable salt in combination with one or more pharmaceutical acceptable excipients, wherein said Omecamtiv Mecarbil or its pharmaceutically acceptable salt is prepared as per the process of the present invention.
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 methyl 3-(bromomethyl)-2-fluorobenzoate of Formula IV
To stirred solution of 3-methyl-2 fluoro-3-methyl benzoate of Formula III (20g; l.Oeq) in CHCb/ CCU (50ml) 10-15°C and N-bromosucinimide (25.42g; 1.2eq) and benzoyl peroxide (0.288g, O.Oleq) were added. Reaction mixture was stirred for 3-4 hr at 55-65°C. After completion of reaction, reaction mixture was concentrated in vacuum to get desired crude compound which was taken in ethyl acetate and washed with DM water. Organic layer was dried over sodium sulfate and concentrated to get methyl 3-(bromomethyl)-2-fluorobenzoate ofFormulaIV(21.6g).
Example-2: Synthesis of 2-fluoro-3-((4-(methoxycarbonyl)piperazin-l-yl)methyl)benzoic acid of Formula VI
To stirred solution of methyl 3-(bromomethyl)-2-fluorobenzoate of Formula IV (21.6g, leq) in toluene (85 ml) 0-5°C DIPEA (17.99g, 1.3eq) was added, after 10 minute compound of Formula V (17.24g; 1.12eq) was added slowly. Reaction mixture was stirred for 8-10hr at 80-90°C. After completion, reaction mixture was concentrated in vacuum to get desired crude. Crude compound was taken in ethyl acetate and washed with DM water. Organic layer was dried over sodium sulfate and concentrated to get desired crude (30g). This Crude compound

was taken in THF and cool to 0-5°C and lithium hydroxide monohydrate (20.32g, 5eq), in 20ml water was added to this crude solution and stirred for 3-4 hr at 20-30°C. After completion of reaction, distilled THF, crude compound was neutralised with 2N HC1. This mixture was extracted with ethyl acetate. Organic layer was dried over sodium sulfate and concentrated to get 2-fluoro-3-((4-(methoxycarbonyl)piperazin-l-yl)methyl)benzoic acid of Formula VI (28g).
Example-3: Synthesis of step-3: Methyl 4-(2-fluoro-3-(N-hydroxy-N'-(6-methylpyridin-3-yl)carbamimidoyl)benzyl)piperazine-l-carboxylate of Formula X
To a solution of iodine (34.59 g, 3eq) and triphenylphosphine (71.5g, 3eq) in dry
dichlorom ethane (200 mL) was added in one portion of 2-fluoro-3-((4-
(methoxycarbonyl)piperazin-l-yl)methyl)benzoic acid of Formula VI (26.9g, leq), and 3-
amino-6-methyl pyridine of Formula VII (11.59g, 1.2eq), followed by triethylamine (59.66g)
at 0°C. The resulting mixture was continuously stirred at room temperature for 1 h.
Hydroxylamine hydrochloride (9.47g) was then added and the reaction mixture was allowed
to stirring 2-4 hr at 25°C -30°C. After completion of reaction distilled off the solvent, and
purified the crude mixture by column chromatography using ethyl acetate -hexane, obtained
methyl 4-(2-fluoro-3-(N-hydroxy-N'-(6-methylpyridin-3-yl)carbamimidoyl)benzyl)
piperazine-1-carboxylate of Formula X (31g).
Example-4: Synthesis of methyl 4-(2-fluoro-3-((6-methylpyridin-3-
yl)carbamoyl)benzyl)piperazine-l-carboxylate of Formula VIII
To stirred solution of 2-fluoro-3-((4-(methoxycarbonyl)piperazin-l-yl)methyl)benzoic acid of Formula VI (lg;leq) in dichloromethane (20ml) 0°C HOBT (0.68g ;1.5eq) and ethylene dichloride (0.97g;1.5eq) were added and stirred 20 minute, then 3- amino-6-methyl pyridine of Formula VII (0.438g ;1.2eq), was added slowly and reaction was stirred for 4-6 hr at 20-30°C. Reaction mixture was concentrated and taken in ethyl acetate and washed with DM water. Organic layer was dried over sodium sulfate and concentrated to get 4-(2-fluoro-3-((6-methylpyridin-3-yl)carbamoyl)benzyl)piperazine-l-carboxylate of Formula VIII (1.17g).
Example-5: Synthesis of methyl 4-(2-fluoro-3-(N-hydroxy-N'-(6-methylpyridin-3-yl)carbamimidoyl)benzyl)piperazine-l-carboxylate of Formula X
To a stirred solution of iodine (1.15g, 3eq) and triphenylphosphine (2.38g, 3eq) in dry
dichloromethane (50 mL) methyl 4-(2-fluoro-3-((6-methylpyridin-3-

yl)carbamoyl)benzyl)piperazine-l-carboxylate of Formula VIII (1.17g; leq).was added and stirred for lhr. Added hydroxylamine hydrochloride (0.315 gm, 1.5 eq) to the reaction mass at 25°C -30°C. Stirred the reaction mixture for 2-3hrs.After completion of reaction, distilled off solvent and obtained crude was purified by column chromatography using ethyl acetate -hexane, obtained the desire compound (l.lg).
Example-6: Synthesis of methyl 4-(2-fluoro-3-(3-(6-methylpyridin-3-
yl)ureido)benzyl)piperazine-l-carboxylate (OmecamtivMecarbil) of Formula I
To a stirred solution of 4-(2-fluoro-3-(N-hydroxy-N'-(6-methylpyridin-3-yl) carbamimidoyl)benzyl)piperazine-l-carboxylate of Formula X (31g, l.Oeq) in 150 ml acetonitrile, cooled reaction mixture to 0°C, added DIPEA(11.98g, 1.2eq) was added drop wise and stirred for 15 minutes. Now 4-nitrobenzenesulfonylchloride (20.55g; 1.2eq) was added at 5°C -10°C and then stirred for 8-10 hr at 60-70°C. After completion of reaction organic layer was concentrated and taken in 200 ml ethyl acetate and washed with DM water. Ethyl acetate layer was concentrated to get Omecamtiv Mecarbil of Formula I (27g).
Example-7: Synthesis of 2-fluoro-3-(hydroxymethyl)-N-methoxy-N-methylbenzamide of Formula XIII
To a stirred solution of 2-fluoro-3-(hydroxymethyl)benzoic acid of Formula XII (20.Og, l.Oeq) in Dichloromethane, added DMAP (43.02g, 3.0eq) , EDC.HC1 (28.16g , 1.25eq), and N,0-dimethylhydroxylamine (I8.91g,1.65eq). Stirred the reaction mixture for 8-10 hrs at RT. After completion of reaction quenched the reaction mass over water and extracted with dichloromethane, Combined Organic layer was washed with 1M aq. Solution of citric acid. Concentrated the organic layer to get 2-fluoro-3-(hydroxymethyl)-N-methoxy-N-methylbenzamide of Formula XIII (22.2g).
Example-8: Synthesis of 2-fluoro-3-(hydroxymethyl)benzohydrazide of Formula XIV
To stirred solution of 2-fluoro-3-(hydroxymethyl)-N-methoxy-N-methylbenzamide of Formula XIII (22.2g, l.Oeq) in methanol (112.5ml, 5vol) added hydrazine hydrate (112.5ml, 5vol) and stirred the reaction mixture for 4-6 hrs at 50°C. After completion of reaction cooled the reaction mass to RT, distilled the reaction mass and obtained 2-fluoro-3-(hydroxymethyl)benzohydrazide of Formula XIV (17.2g).
Example-9: Synthesis of 2-fluoro-3-(hydroxymethyl)benzoylazide of Formula XV

Added NaNCte (6.08g, l.Oeq), dissolved in 30ml water, drop wise to stirred solution of 2-fluoro-3-(hydroxymethyl)benzohydrazide of Formula XIV (17.2g, l.Oeq) and cone. HC1 (170ml) at 0°C. Stirred the reaction mass for lhr at 0°C. After completion of reaction added hexane, extracted hexane layer, distilled to obtain the crude 2-fluoro-3-(hydroxymethyl)benzoylazide of Formula XV (17.Og).
Example-10: Synthesis of (2-fluoro-3-isocyanatophenyl) methanol of Formula XVI
To a stirred solution of 2-fluoro-3-(hydroxymethyl)benzoylazide of Formula XV (17.Og, l.Oeq) in toluene (150.2ml) and refluxed the solution for 1-2 hrs under nitrogen atmosphere. After completion of reaction, solvent was removed under nitrogen and obtained the crude (2-fluoro-3-isocyanatophenyl) methanol of Formula XVI (12.81g).
Example-11: Synthesis of l-(2-fluoro-3-(hydroxymethyl) phenyl)-3-(6-methylpyridin-3-yl) urea of Formula XVII
Solution of (2-fluoro-3-isocyanatophenyl) methanol of Formula XVI (12.81g, l.Oeq) and 6-methylpyridin-3-amine (8.28g, l.Oeq) in acetonitrile (60ml) was refluxed under Argon atmosphere. After completion of reaction, distilled the reaction mass, and subjected the residue for crystallization in acetonitrile and afforded l-(2-fluoro-3-(hydroxymethyl) phenyl)-3-(6-methylpyridin-3-yl) urea of Formula XVII (12g).
Example-12: Synthesis of 2-fluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl methanesulfonate of Formula XVIII
To a stirred solution of l-(2-fluoro-3-(hydroxymethyl) phenyl)-3-(6-methylpyridin-3-yl) urea of Formula XVII (6.0g, l.Oeq) in Dichloromethane (150ml) added TEA (2.64g, 1.2eq). Stirred the reaction mixture for 5-10 min. Added Methylsulfonyl chloride (2.74g, l.leq) dropwise at 5-10°C. Stirred the reaction mass for 2-3 hrs at RT. After completion of reaction quenched the reaction over water and extracted the organic layer. Distilled the organic layer to get the crude 2-fluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl methanesulfonate of Formula XVIII (7.5g).
Example-13: Synthesis of l-(3-(chloromethyl)-2-fluorophenyl)-3-(6-methylpyridin-3-yl)urea of Formula XVIII'
To a stirred solution of l-(2-fluoro-3-(hydroxymethyl) phenyl)-3-(6-methylpyridin-3-yl) urea of Formula XVII (6g, l.Oeq) in Dichloromethane (30ml) added thionyl chloride (3.1 lg,

1.2eq) at RT. Refluxed the reaction mixture for 3-4hrs under stirring. After completion of reaction, cooled to RT, quench the reaction mass over water and separated the DCM layer. Distilled the DCM layer to get the crude l-(3-(chloromethyl)-2-fluorophenyl)-3-(6-methylpyridin-3-yl)urea of Formula XVIII' (6.1g).
Example-14: Synthesis of Omecamtiv Mecarbil
To a stirred solution of 2-fluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl methanesulfonate of Formula XVIII (7.5g, l.Oeq) in acetonitrile (50ml), added triethyl amine (2.14g, l.Oeq ). Stirred the reaction mixture for 10-15minutes. Now added methyl piperazine-1-carboxylate of Formula V (3.05g, l.Oeq) slowly at 10-15oC. After addition, stirred the reaction mass for 5-6hrs at 90oC. After completion of reaction cooled the reaction mass at RT and distilled off the solvent. Now the residue was dissolved in ethyl acetate and washed with water. Distilled off the ethyl acetate and obtained OmecamtivMecarbil (7.82g).
Example-15: Synthesis of Omecamtiv Mecarbil
To a stirred solution of l-(3-(chloromethyl)-2-fluorophenyl)-3-(6-methylpyridin-3-yl) urea of Formula XVIII' (6.1g, l.Oeq) in acetonitrile (50ml), added triethyl amine (2.09g, l.Oeq). Stirred the reaction mixture for 10-15minutes. Now added methyl piperazine-1-carboxylate of Formula V (2.99g, l.Oeq) slowly at 10-15°C. After addition, stirred the reaction mass for 5-6 hrs at 90°C. After completion of reaction, reaction mixture was cooled at RT and distilled off the solvent. Now the residue was dissolved in EtOAc and washed with water. Distilled off the ethyl acetate and obtained Omecamtiv Mecarbil (7.2g).
Example-16: Synthesis of 3-(bromomethyl)-2-fluorobenzonitrile of Formula XX
Charged 2-fluoro-3-methyl benzonitrile of Formula XIX (100 g), N-bromo succinimide (223.9 g) and acetic acid (500 ml) in a RBF at room temperature. Reaction mixture was heated for 12-15 hrs at 80-85°C. Added phosphorus acid (8 ml) and heated for 2-3 hrs. To this added water (500 ml) and (800 ml) toluene, stirred and layers were separated. pH was adjusted with NaOH solution. The reaction mass was stirred and layers were separated. Added DIPEA (44 g) and methanol (10 ml). Reaction mixture was heated at 40°C and added 41 g of diethylphosphite in 4-5 hrs. Heated the reaction for 5-6 hrs and used as such in next step.

Example-17: Synthesis of methyl piperazine-1-carboxylate of Formula V
Charged Piperazine (200 g) and water (800 ml) into RBF. Reaction mixture was heated at 35-40°C and stirred for 15-20 mins. Cooled the reaction at 15-25°C. Added slowly methylchloroformate (241 g) in 5-6 hrs. Charged dichloromethane (MDC) into reaction mass, stirred and layer was separated. pH of aqueous layer was adjusted by NaOH solution. Charged sodium chloride (200 g) in to reaction mass and stirred. Aqueous layer was extracted with MDC. MDC was distilled out under vacuum. Charged MTBE into distilled mass. Reaction mass was stirred and filtered. Take FML into RBF and added aq. phosphoric acid solution with MTBE in 3-4 hrs. Reaction mass was heated at 40-45°C for 3 hrs followed by cooling at 20-25°C and further stirred for 1 hour. Reaction mass was filtered and dried to get methyl piperazine-1-carboxylate of Formula V (140g).
Example-18: Synthesis of methyl 4-(3-cyano-2-fluorobenzyl)piperazine-l-carboxylate of Formula XXI
Charged methyl piperazine-1-carboxylate of Formula V (113g) and methanol (150 ml) in to RBF and heated 40°C. Slowly added 3-(bromomethyl)-2-fluorobenzonitrile of Formula XX in DIPEA (220.9 gm) in 1 hour under nitrogen. Reaction mixture was stirred for 6-7 hrs. Added water (500 ml), stirred and layer was separated. Ammonium chloride solution (550 ml) was charged into organic layer, stirred and layer was separated. Charged aq. sodium bicarbonate sol into organic layer, stirred and layer was separated. Solvent was distilled out completely under vacuum at 40-45°C to get methyl 4-(3-cyano-2-fluorobenzyl)piperazine-l-carboxylate of Formula XXI (95 g).
Example-19: Synthesis of methyl 4-(2-fluoro-3-(N-hydroxy-N'-(6-methylpyridin-3-yl)carbamimidoyl)benzyl)piperazine-l-carboxylate of Formula X
Charged methyl 4-(3-cyano-2-fluorobenzyl)piperazine-1-carboxylate of Formula XXI (90 g), 6-methyl pyridine-3-amine (36.85 gm), dry benzene 450 ml, Sodium (7.46 gm), into RBF. Heated the reaction for 27 hrs at 80°C. After completion of reaction, adjusted the pH by aq. NaOH sol. Then collected the material in dilute aq. HCl. Added the reaction mass into a solution of hydroxylamine hydrochloride (33.83 g) in water. Heated for 15 minutes at 80°C. Adjusted the pH by aq ammonia and heated for 30 minutes. Filtered and dried to get methyl 4-(2-fluoro-3-(N-hydroxy-N'-(6-methylpyridin-3-yl)carbamimidoyl)benzyl)piperazine-l-carboxylate of Formula X (105 g).

Example-20: Synthesis of Omecamtiv Mecarbil of Formula I
Charged methyl 4-(2-fluoro-3-(N-hydroxy-N'-(6-methylpyridin-3-yl)carbamimidoyl)benzyl) piperazine-1-carboxylate (105 gm) of Formula X and 505 ml of acetonitrile into RBF. Added 40.56 g of DIPEA into reaction mass and stirred at room temperature. Cooled the reaction to 0-5°C. Added 4-nitro benzensulfonyl chloride (69.56 g) into reaction mass. Stirred the reaction and heated the reaction at 60-70°C for 8-10 hr. After completion of reaction distilled out the reaction mass. Charged ethyl acetate and water, and separated the layers. Distilled out the organic solvent completely to get Omecamtiv Mecarbil of Formula I (95 g).
Example-21: Synthesis of 2-fluoro-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)aniline of Formula XXIII (R2 is tetrahydropyran)
Charged 2-fluoro-3-nitrobenzoic acid (100 gm) of Formula XXII and THF 500 ml into RBF. Reaction mass was cooled to 0°C. Slowly added the solution of BH3 in THF (1000 ml) into the reaction mixture. On completion of the addition, the ice bath was removed and stirring was continued for 24 hrs. The reaction mixture was cooled to 0 °C and methanol was slowly added. Distilled out the solvent completely and the residue was diluted with ethyl acetate, washed with brine, and dried over sodium sulphate. Distilled out the solvent completely to give (3-nitro-2-fluorophenyl) methanol. Charged (3-nitro-2-fluorophenyl) methanol, p-toluenesulfonic acid (18.61 g), 3,4-dihydro-2H-pyran (170 g), and 1-4, dioxan (500 ml) into RBF. Stirred the reaction mixture at room temperature till completion of reaction. After the completion of reaction, it was basified using aq. sodium bicarbonate. Distil out the solvents completely. Residue was extracted with MDC and collected solvent was distilled out completely under vacuum. Charged methanol (500 ml) into distilled mass and transferred into hydrogenator. Charged lOg of 10% Pd/C under hydrogen. Reaction mixture was stirred for 6-7 hrs and filtered through celite and solvent was distilled to get 2-fluoro-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)aniline of Formula XXIII (106 g ).
Example-22: Synthesis of phenyl (6-methylpyridin-3-yl)carbamate of Formula XXIV:
Charged 6-methyl-3-pyridinamine (100 g) and acetonitrile (1500 ml) in to RBF. Added slowly phenyl chloroformate (152 g) in 3-4 hrs at 20-25°C. Reaction mixture was stirred for 3-4 hrs. After the completion of the reaction the reaction mixture was filtered and dried to get phenyl (6-methylpyridin-3-yl)carbamate of Formula XXIV (130g).

Example-23: Synthesis of l-(2-fluoro-3-(((tetrahydro-2H-pyran-2-
yl)oxy)methyl)phenyl)-3-(6-methylpyridin-3-yl)urea of Formula XXV
Charged 2-fluoro-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)aniline (105g) of Formula XXIII, phenyl (6-methylpyridin-3-yl)carbamate (117 g), acetonitrile (260 ml), TUF (260 ml) and 73 g diisopropylethylamine in RBF. Reaction mixture was heated at 55-60°C for 20-25 hrs. Water was added in to reaction at 55-60°C. Reaction mixture was cooled at 20-25°C, filtered and dried to get l-(2-fluoro-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)-3-(6-methylpyridin-3-yl)urea of Formula XXV (132 g).
Example-24: Synthesis of l-(2-fluoro-3-(methoxymethyl)phenyl)-3-(6-methylpyridin-3-yl)urea of Formula XVII (R2 is methyl)
Charged l-(2-fluoro-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)-3-(6-methylpyridin-3-yl)urea of Formula XXV (130 g), methanol (650 mL) and p-toluenesulfonic acid monohydrate (12.45 g). Reaction mixture was stirred at 25-30°C for 16 hours. Added ethyl acetate into reaction and washed with saturated aqueous NaHCCb. The organic layer was separated and dried over Na2S04 and concentrated under vacuum. To this mass, charged dry MDC (650 ml) into another RBF and stirred. Added triethyl amine (73 g) under nitrogen atmosphere. Methanesulfonyl chloride (45.57 g) was added to the above reaction mixture at 0°C, and stirring was continued for another 3 hours. Water was added to the reaction mixture and the mixture was extracted with dichloromethane. The combined organic layers were washed with water and brine. The reaction mixture was dried over Na2S04, filtered and concentrated under vacuum to give l-(2-fluoro-3-(methoxymethyl)phenyl)-3-(6-methylpyridin-3-yl)urea of Formula XVII (117g).
Example 25: Synthesis of Omecamtiv Mecarbil of Formula I
Charged l-(2-fluoro-3-(methoxymethyl)phenyl)-3-(6-methylpyridin-3-yl)urea of Formula XXVI (115 g), dimethyl formamide (345 ml), methyl piperazine-1-carboxylate of Formula V (77g ) and K2CO3 (176.6 g). Reaction mixture was heated at 50°C for 16 hours. After the completion of reaction the reaction mixture was cooled at RT. Added ethyl acetate and water and layers were separated. Organic layer was washed with sat. NaCl solution (200 ml). The solvent was distilled out under vacuum to get Omecamtiv Mecarbil of Formula I (102 g).

Example-26: Synthesis of methyl 2-fluoro-3-nitrobenzoate of Formula XXVII
Charged 2-fluoro-3-nitrobenzoic acid of Formula XXII (100 gm) and methanol (500 ml) into RBF. Reaction mixture was cooled at 10-15°C. Slowly added 10 ml of Sulfuric acid into the reaction. Stirred the reaction mass for 3-4 hrs. Distilled out the solvent completely under vacuum. Added toluene and water, stirred and separated the layers. Organic layer again washed with sodium bicarbonate solution (500 ml) and proceeded as such for the next step.
Example-27: Synthesis of methyl 2-fluoro-3-aminoenzoate of Formula XXIII'
Charged toluene layer of methyl 2-fluoro-3-nitrobenzoate of Formula XXVII, methanol (100 ml) and 10%Pd/C (10 g) into hydrogenator. Applied hydrogen pressure and stirred for 6-8 hrs at RT. After completion of reaction mass was filtered through celite and solvent was evaporated under vacuum at 50°C to get 2-fluoro-3-aminoenzoate of Formula XXIII' (65 g)
Example-28: Synthesis of methyl 2-fluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzoate of Formula XXV
Charged methyl 2-fluoro-3-aminoenzoate of Formula XXIII' (65 g), phenyl (6-methylpyridin-3-yl)carbamate of Formula XXIV (96.51 g), acetonitrile 160 ml, THF 160 ml and 59.6 gm diisopropylethylamine in RBF. Reaction mixture was heated at 55-60°C for 20-25 hrs. After the completion of the reaction added water (975ml) water in to reaction mixture at 55-60°C and cooled the reaction at 20-25°C.reaction mixture was filtered and dried to get 2-fluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzoate of Formula XXV 102 g.
Example-29: Synthesis of l-(2-fluoro-3-(hydroxymethyl)phenyl)-3-(6-methylpyridin-3-yl)urea of Formula XVII (R2 is Hydrogen)
Charge 2-fluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzoate of Formula XXV (100 g) and tetrahydrofuran (500 ml) into RBF. Reaction mixture was cooled at 0°C. Slowly added IM Diisobutyl aluminium hydride in THF (825 ml) under nitrogen. After the completion of reaction slowly added saturated ammonium chloride solution and ethyl acetate into reaction. Reaction mixture was stirred and layer was separated. The solvent was distilled out to get 1-(2-fluoro-3-(hydroxymethyl)phenyl)-3-(6-methylpyridin-3-yl)urea of Formula XVII (77 g).

Example-30: Synthesis of 2-fluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl methanesulfonate of Formula XVII' (R2 is Ms)
Charged l-(2-fluoro-3-(hydroxymethyl)phenyl)-3-(6-methylpyridin-3-yl)urea of Formula
XVII (75 g), and dry dichloromethane (375 ml) into RBF and stirred. Added triethyl amine
(55 g) under nitrogen atmosphere. Methanesulfonyl chloride (34.32 g) was added to the
above reaction mixture at 0°C, and stirred the reaction mixture for 3 hours. Water was added
to the reaction mixture and the mixture was extracted with dichloromethane. The combined
organic layers were washed with water and brine. The reaction mixture was dried over
Na2S04, filtered and concentrated to give 2-fluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl
methanesulfonate of Formula XVII' (83 g)
Example-31: Synthesis of Omecamtiv Mecarbil of Formula I
Charged 2-fluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl methanesulfonate of Formula
XVIII (80g), dimethyl formamide 240 ml, and methyl piperazine-1-carboxylate (53.39 g) and
K2CO3 (125 g) into RBF. Reaction mixture was heated at 50°C for 16 hours. After the
completion, the reaction mixture was cooled at RT. Added Ethyl acetate (2400) ml and water
(800 ml), stirred and layer was separated. Organic layer was washed with sat. NaCl solution.
Distilled out solvent completely under vacuum to get Omecamtiv Mecarbil of Formula I (75
g).
Example-32: Synthesis of phenyl (2-fluoro-3-(((tetrahydro-2H-pyran-2-
yl)oxy)methyl)phenyl)carbamate of Formula XXFX
Charge 2-fluoro-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)aniline of Formula XXIII (105 g) and acetonitrile (1575 ml) in to RBF. Added slowly phenyl chloroformate (77 g) in 3-4 hrs at 20-25°C. Reaction mixture was stirred for 3-4 hrs, filtered and dried to get phenyl (2-fluoro-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)carbamate of Formula XXIX (140 g).
Example-33: Synthesis of l-(2-fluoro-3-(((tetrahydro-2H-pyran-2-
yl)oxy)methyl)phenyl)-3-(6-methylpyridin-3-yl)urea of Formula XXV
Charged phenyl (2-fluoro-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)carbamate (140 g) of Formula XXIX, 6-methyl-3-pyridinamine (46.02 g), acetonitrile 350 ml, TUF 350 ml and Diisopropylethylamine ( 62.87 g) in RBF. Reaction mixture was heated at 55-60°C for 20-25 hrs. Added water in to reaction at 55-60°C. Reaction mixture was cooled at 20-25°C,

filtered and dried to get l-(2-fluoro-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)-3-(6-methylpyridin-3-yl)urea (119 g).

WE CLAIM

1. Compound of Formula A and pharmaceutical^ acceptable salts thereof;
F
Formula A
wherein, Ri is selected from halogen, OR2, substituted and unsubstituted heterocyclic ring; wherein R2 is selected from hydrogen or suitable protecting group; Y is either -CH2 or -CO;
R3 is selected from hydrogen, halogen, cyano, nitro, substituted and unsubstituted amine, hydrazine, azide, -COR4, -NHCONRs, -N=C=0, and -Q; wherein group Q is represented as:
R5
wherein R4 is selected from azide, -NR6R7, -OR9, wherein R6 and R7 are independently
selected from hydrogen, C1-C6 alkyl, and C1-C6 alkoxy group, substituted and unsubstituted
heteroaryl, hydrazine, substituted and unsubstituted amine;
R5 is hydrogen, halogen, -C=0, -NHOH;
R8 is selected from substituted and unsubstituted heteroaryl; and
R9 is selected from hydrogen, C1-C6 alkyl; and
wherein, when Rs is substituted heteroaryl, then Ri is either halogen, or is represented as OR2.
2. The compound as claimed in claim 1, wherein said compound of Formula A comprising
the formulae represented as:


F 0'

F O
^N^A)H ^N
O O

Formula VIII
Formula IV Formula VI
F I
i i i NHOH
^NVY^N r^N^j^V^N F O
O U^N O U^N \[^) I

Formula IX

N3 Br
HO
Formula XIII

Formula XIV

Formula XV Formula XX

R90
Formula XXI

Formula XXII Formula XXIII

R,0
O

o
Fx HN^( Formula XXV

N

and

H
V
o
Formula XXIX

wherein R2 is as defined in claim 1.

3. A process for the preparation of Omecamtiv Mecarbil or pharmaceutically acceptable salt
thereof, comprising the steps of:
a) converting compound of Formula VIII to methyl 4-(2-fluoro-3-(iodo((6-methylpyridin-3-
F I
O K^N
yl)imino)methyl)benzyl)piperazine-l-carboxylate of Formula IX in presence of suitable
solvent;
o
Formula IX
and
Formula VIII

b) converting compound of Formula IX to Omecamtiv Mecarbil or its pharmaceutically acceptable salt.
4. A process for the preparation of Omecamtiv Mecarbil or pharmaceutically acceptable salts
thereof, comprising the steps of:
a) converting 2-fluoro-3-(hydroxymethyl)benzoyl azide of Formula XV to 2-fluoro-3-(hydroxymethyl)benzyl isocyanate of Formula XVI;
b) converting compound of Formula XVI to Omecamtiv Mecarbil; and
c) optionally converting Omecamtiv Mecarbil to its pharmaceutically acceptable salts.
5. A process of preparation of Omecamtiv Mecarbil or pharmaceutically acceptable salts
thereof, comprising the steps of:
a) reacting 3-(bromomethyl)-2-fluorobenzonitrile of Formula XX with methyl piperazine-1-carboxylate in presence of suitable solvent to give methyl 4-(3-cyano-2-fluorobenzyl)piperazine-l-carboxylate of formula XXI;
b) converting compound of Formula XXI to Omecamtiv Mecarbil; and
c) optionally converting Omecamtiv Mecarbil to its pharmaceutically acceptable salts.
6. A process for the preparation of Omecamtiv Mecarbil or its pharmaceutically acceptable
salts; comprising the steps of:
a) converting compound of Formula XXIII to compound of Formula XVII by reacting
with phenyl (6-methylpyridin-3-yl)carbamate of Formula XXIV;
H O

F\_T^ /=V_
Formula XXIV /"A HN^W/
' R2cf^
Formula XXIH
Formula XXV
wherein R2 is selected from suitable protecting group except methyl sulfonyloxy group;
b) converting compound of formula XXV to Omecamtiv Mecarbil; and
c) optionally converting the Omecamtiv Mecarbil to its pharmaceutically acceptable salt.
7. A process for the preparation of Omecamtiv Mecarbil or its pharmaceutically acceptable salt, comprising the steps of:

a) converting compound of Formula XXIX to compound of Formula XXV in presence
of suitable solvent;
F\ H LI F\ H/N v
Formula XXIX Formula XXV
wherein R2 is selected from suitable protecting group;
b) converting compound of Formula XXV to Omecamtiv Mecarbil; and
c) optionally converting the Omecamtiv Mecarbil to its pharmaceutically acceptable salts.

8. The process as claimed in any of the preceding claim, wherein said suitable protecting group is selected from acetyl, benzoyl, benzyl, trimethyl silyl, tetrahydropyran, methyl, ethyl, tertbutyl, allyl, t-butyl dimethyl silyl, t-butyl diphenylsilyl, and pivaloyl.
9. The process as claimed in any of the preceding claim, wherein said suitable solvent is selected from chloroform, carbon tetrachloride, dichloromethane, tetrahydrofuran, toluene, methanol, ethanol, isopropyl alcohol, butanol, t-butanol, acetonitrile, ethyl acetate, acetone, methyl ethyl ketone, dimethyl sulfoxide, N-methyl pyrrolidine, dimethyl acetamide, dimethyl formamide, N-methyl acetamide, acetic acid, and water.
10. The process as claimed in any of the preceding claim, wherein said Omecamtiv Mecarbil
is isolated with purity of purity of 99.0% and above, and wherein said Omecamtiv Mecarbil
is substantially free of impurities with each impurity less than about 0.3% w/w.