DESC:Field of the Invention:
The present invention relates to a novel process for the preparation of indazole,
compound of formula (I) and to intermediates thereof.

Background of the Invention:
Vascular endothelial growth factor (VEGF) antagonists have been recognized as an important class of pharmaceutical agents for development due to their efficiency in controlling growth and proliferation of cancer cells. Indazole compound, namely 6- [2-(methyl carbamoyl)phenyl sulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]indazole of formula (I) (also referred to as "Compound I")

Formula I
is a VEGF inhibitor for the treatment of solid tumors, including metastatic renal cell carcinoma (RCC).

Compound (I) is a potent and selective inhibitor of vascular endothelial growth factor (VEGF)/platelet-derived growth factor (PDGF) receptor tyrosine kinase (RTK) being developed for use in early to late stage cancers. Protein tyrosine kinases have been identified as crucial targets in the therapeutic treatment of cancer. Growth factor ligands and their respective RTKs are required for tumor angiogenesis and growth. VEGF and PDGF are critical components in the process leading to the branching, extension, and survival of endothelial cells forming new blood vessels during angiogenesis.

By inhibiting tyrosine kinase signal transduction, Compound (I) inhibits unwanted cell proliferation. Compound I can be used to treat cancer and other disease states associated with unwanted cellular proliferation, such as diabetic retinopathy, neovascular glaucoma, rheumatoid arthritis, and psoriasis.

Thio indazole compounds of the general formula (II)

Formula II
wherein R1 is an activated substituent group, a substituted or unsubstituted aryl or heteroaryl, or a group of the formula CH=CH—R3 or CH=N—R3, where R3 is a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and R2 is H, or protecting group, are important intermediates useful in the synthesis of compound (I). Various compounds of Formula II have been disclosed in the patented literature as described below.

Compound (I), as well as pharmaceutically acceptable salts thereof, and its process for manufacture using the intermediate (IIA)

(IIA)
wherein R1 is CH=CH—R3, where R3 is pyridyl and R2 is protecting group;
are first described in U. S. Pat. No. 6531491. The process of particular relevance is depicted in scheme 1.

Scheme 1

In the process, the nitro group of intermediate 6-nitroindazole (VII) is reduced to the 6-amino indazole (VI). The amine undergoes a Sandmeyer reaction to provide 6-iodoindazole (VA). After coupling with 2-mercapto-N-methyl benzamide (III) using Pd(dppf)Cl2 as catalyst, THP protected compound (IIA) is obtained. Deprotection of (IIA) with p-TsOH in methanol affords compound (I).

An alternate route for the preparation of making Compound (I) using intermediate IIB

(IIB)
wherein R1 is iodo and R2 is H,
and IIC

(IIC),
wherein R1 and R2 both H; are described in U. S. Pat. No. 7232910. The process disclosed is as depicted in Scheme 2.

Scheme 2

In the process, 6-iodoindazole (VC) is coupled with 2-mercapto-N-methylbenzamide (III) to offer compound (IIC) which undergoes iodination to yield compound (IIB). Alternatively, 6-iodoindazole (VC) undergoes iodination to offer 3,6-diiodoindazole (VB) which is then is coupled with 2-mercapto-N-methylbenzamide (III) to yield compound (IIB). Heck reaction between compound (IIB) and 2-vinylpyridine (X) affords compound (I).

Thus, the preparation of key intermediate thio indazole (II) involves use of 2-mercapto-N-methylbenzamide (III).

Intermediate 2-mercapto-N-methylbenzamide (III) is produced by the reduction of disulfide linkage of dithio-2,2'-bis(N-methylbenzamide) (IV)

with sodium borohydride in ethanol at low temperature of 0-5ºC. The reduction involves use of hazardous reagent such as sodium borohydride. Further, the tedious process of extraction, separation, concentration and isolation of 2-mercapto-N-methylbenzamide (II) increases number of steps and makes the process cumbersome on industrial scale. Further, 2-mercapto-N-methylbenzamide (II) has tendency to form disulfide on exposure to air. Hence, needs to protect continuously from the light.

All these disadvantages of the prior art are overcome by the process in accordance with the present invention.

Objects of the Invention
The object of the present invention is to provide a novel process for preparing an Indazole compound (I).

Another object of the present invention is to provide an improved cross coupling process to prepare intermediate thio indazole (II) which avoids the handling of air sensitive intermediate 2-mercapto-N-methylbenzamide (III).
Another object of the present invention is to provide a process which avoids the use of hazardous reducing agent sodium borohydride and subsequently simplifies work up procedure.

Yet another object of the present invention is to provide a process for the synthesis of an Indazole compound (I), which is simple, economical and suitable for industrial scale-up.

Statements of Invention
According to a first aspect of the present invention, there is provided a process for preparing compound (I)

or a pharmaceutically acceptable salt or solvate thereof, comprises the steps of: reacting indazole compound (V) with dithio-2,2'-bis(N-methylbenzamide (IV)

in the presence of copper catalyst and a suitable ligand to form compound (II)

Formula II
wherein R1 is an activated substituent group, a substituted or unsubstituted aryl or heteroaryl, or a group of the formula CH=CH—R3 or CH=N—R3, where R3 is a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and R2 is H, or protecting group; wherein X is an activated substituent group; and converting compound (II) into compound (I).

Protecting groups that are suitable for use in the processes of the present invention are well known. The chemical properties of such protecting groups, methods for their introduction and their removal can be found, for example, in T. Greene and P. Wuts, Protective Groups in Organic Synthesis (3rd ed.), John Wiley & Sons, NY (1999}, herein incorporated by reference in its entirety.

In one embodiment R1 is a group of the formula CH=CH—R3, where R3 is pyridyl; R2 is protecting group selected from tetrahydropyran, t-butyloxycarbonyl (Boc), benzyloxycarbonyl (cbz), fluorine-9-methyloxycarbonyl (FMOC), trityl, benzyl, substituted benzyl and the like and the activated substituent group X is chloride, bromide, or iodide, preferably iodide and the process comprises copper catalyzed cross coupling of compound (VA) with dithio-2,2'-bis(N-methylbenzamide) (IV)

in the presence of a ligand to obtain compound (IIA)
;
followed by deprotection of compound (IIA) to obtain compound (I).

In another embodiment R1 is X, R2 is H, and the activated substituent group X is chloride, bromide, or iodide, preferably iodide and the process comprises steps of;
copper catalyzed cross coupling of compound (VB) with dithio-2,2'-bis(N-methylbenzamide) (IV) in the presence of a ligand,

to produce compound (IIB)
,
followed by reaction with vinylpyridine compound (X)

to obtain compound (I).

In yet an alternative embodiment, both R1 and R2 are H, and the activated substituent group X is chloride, bromide, or iodide, preferably iodide and the process comprises steps of;
copper catalyzed cross coupling of compound (VC) with dithio-2,2'-bis(N-methylbenzamide) (IV) in the presence of a ligand,

to produce compound (IIC)
;
iodination to obtain compound (IIB)
;
and
reaction with vinylpyridine compound (X)

to obtain compound (I).

The process of the present invention is advantages over prior art as it avoids handling of intermediate 2-mercapto-N-methylbenzamide (III).

Further, the present invention provides an indazole compound of formula (I), prepared according to the process described above, having a purity of more than about 99% and a chiral purity of more than about 99% by HPLC.

The indazole compound of formula (I) prepared according to the process of the present invention may be formulated with one or more pharmaceutically acceptable excipients to provide a pharmaceutical composition. Such excipients and compositions are well known to those skilled in the art.

Detailed Description of the Invention

In an embodiment of the present invention, there is provided an improved synthesis of an Indazole compound (I), as depicted below in reaction scheme 3.

Scheme 3

In an embodiment compound (VA) undergoes cross coupling reaction with dithio-2,2'-bis(N-methylbenzamide (IV) in the presence of Cu and a ligand to obtain compound (IIA). The Cu catalyzed reactions are robust, can be performed with simple ligands and can be used in the presence of a plethora of functional groups, making them highly attractive to those engaged in the synthesis of complex molecular architectures.

In an embodiment copper source used is CuI, Cu bronze, Cu(OAc)2, CuCl2, Cu(OMe)2 and the like. In a preferred embodiment reaction is performed using CuI which gives the highest yields and has the advantage of being cheap and air stable.

A range of different useful ligands have emerged including phenanthrolines, a-amino acids selected from L-proline, glycine, D-alanine and DL-serine, 1,3-diketones, imines, salicylamides. O,O-type, N,N-type and N,O-type ligands are preferred such as N,N'-Dimethyl-1,2-cyclohexanediamine (DMCyDA), 1,2- cyclohexanediamine (CyDA) and 1,10- phenanthroline are used. Other useful ligands include Ethyl 2-oxocyclohexanecarboxylate, 2,9-Dimethyl -1,10- phenanthroline, N-methyl amino acetic acid, [1,1'-Binaphthalene]-2,2'-diol, D-Proline, N,N'-Dimethylethylenediamine (DMEDA), and Tetramethylethylenediamine (TMEDA or TEMED).

In a preferred embodiment ligand used is diamine based ligand such as ethylenediamine and cyclohexanediamine.

Alternatively, Cu catalyzed cross coupling reactions may be conducted in the “ligand-free” systems.

The Cu catalyzed cross coupling reactions are conducted in the presence of a suitable base and a solvent.

In an embodiment, 0.5 to 2 moles of dithio-2,2'-bis(N-methylbenzamide (IV) may be used per mole of compound (VA).

Example of suitable base includes inorganic base such as K2CO3, K3PO4, KHMDS and the like.

Example of suitable base includes organic base such as TEA, DIPEA and the like.

Example of suitable solvent include polar solvents such as dimetylformamide (DMF), N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO), dioxane, water, MeCN and non polar solvents such as toluene, xylene.

The prior art teaches coupling of intermediate 2-mercapto-N-methylbenzamide (III) with compound (V) in the presence of a palladium catalyst such as Pd(dppf)Cl2 and Xantphos.
Intermediate 2-mercapto-N-methylbenzamide (III) is produced by the reduction of disulfide linkage of dithio-2,2'-bis(N-methylbenzamide) (IV) with sodium borohydride in ethanol at low temperature of 0-5ºC. The reduction involves use of hazardous reagent such as sodium borohydride. Further, the tedious extraction, separation, concentration and isolation of 2-mercapto-N-methylbenzamide (III) increases number of steps and makes the process cumbersome on industrial scale. Further, 2-mercapto-N-methylbenzamide (III) has tendency to form disulfide on exposure to air. Hence, needs to protect continuously from the light.

Disadvantage of the prior art process is overcome by the process of the present invention. In the process of the present invention, dithio-2,2'-bis(N-methylbenzamide) (IV) is insitu converted to 2-mercapto-N-methylbenzamide (III), without using any reduction reagent. Thus, the present process reduces formation of impurities and this forms one aspect of the present invention.

The work up procedure and isolation of 2-mercapto-N-methylbenzamide (III) is avoided, thus reduces number of steps and time, making the process more economical and industrially suitable. This forms another aspect of the present invention.

The insitu generation of 2-mercapto-N-methylbenzamide (III), avoids its handling and exposure to air. This forms another aspect of the present invention.

Further, the insitu generated 2-mercapto-N-methylbenzamide (III) inturn condenses with compound (VA) to produce THP protected compound (IIA). This forms another aspect of the present invention.

Prior art teaches Palladium based cross coupling. These palladium based catalysts are very costly and removal of residual palladium from the final API is an important objective. Such palladium removal can be accomplished using 10% cysteine-silica.
In the process of the present invention, the Copper salt catalysis has advantage over the palladium based catalytic systems due to its low cost and can be used with readily accessible and stable ligands. Preferably, the reaction is conducted in CuI/ EDA. Cu is less toxic and hazardous and removal is easy compare to palladium complexes removal. This forms yet another aspect of the present invention.

The reaction is typically carried out at a temperature in the range of from about 0°C to about reflux temperature of the solvent used. Preferably, the reactions are carried out at a temperature in the range of from about 25°C to about reflux temperature of the solvent used. In still other aspects, they are carried out at a temperature in the range of from about 50°C to about 100°C.

The reaction is typically carried out for a time ranging from 10 minutes to 24 hours, preferably 20 minutes to 15 hours, and most preferably 30 minutes to 10 hours.

In the process of the present invention, the work up procedure may be simplified to give the product in high purity and to minimize the formation of impurities which are formed when one employs the work-up procedure given in the prior art. In the present process, after completion of reaction, the product is easily isolated by quenching the reaction mass in the solvent such as water or ethyl acetate and separated by filtration. In addition, EDTA solution may be used to remove traces of copper impurities.

This improved process also results in the simplified work up procedure, by avoiding extraction using organic solvents such as ethyl acetate, MDC and THF as reported in the prior art and purification of the intermediates by using water as a solvent for isolation. All these advantages form another aspect of the present invention.

In an embodiment compound (VA) may be prepared from compound (VI) by using standard process known in the art, such as Sandmeyer reaction, using potassium iodide as the iodine source.
In yet an alternative embodiment compound (IIA) may be obtained from compound (VI) without isolating intermediate (VA). In an embodiment Sandmeyer reaction and coupling steps may be carried out without isolating the intermediate (VA).

In the context of the present invention, the term “without isolation” means that the product referred is not isolated as a solid, for example it is not isolated from the reaction mass and dried to form a solid. Thus, “without isolation” may mean that the product remains in solution and is then used directly in the next synthetic step, or it may mean that solvent is substantially removed from a solution of the product such that the product is present as a residue, but not as a solid.

Compound (IIA) is then subjected to deprotection to obtain compound (I). The choice of suitable reagents and reaction conditions for deprotecting the N-1 indazole ring nitrogen group, are well known. For example, when protecting group is a tetrahydropyran protecting group, suitable reagents include, but are not limited to, inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, organic acid such as para-toluenesulfonic acid, methanesulfonic acid, or Lewis acids such as boron trifluoride etherate.

These reactions may be conducted in solvents that are compatible with the specific reaction conditions chosen and will not interfere with the desired transformation. Among such suitable solvents include , but are not limited to, for example, esters, such as ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate; ketones such as methyl isobutyl ketone; ethers such as diisopropyl ether, diethyl ether, methyl-t-butyl ether, diphenyl ether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran; alcohols, such as methanol, ethanol, 1-propanol, 2-propanol, t-butanol, n-butanol, 2-butanol; nitriles such as acetionitrile, propionitrile, butyronitrile; halogenated solvents such as dichloromethane, chloroform, 1 ,2-dichloroethane; benzene, toluene, anisole, xylenes, and pyridine,, or mixture thereof.

Without departing from the present invention, the scope of the invention may be further extended to alternate processes to prepare compound(I).

In an alternative approach, the compound (I) may be prepared by a process comprising the steps of:
a) Cu catalyzed cross coupling reaction between iodo indazole compound (VC) and dithio-2,2'-bis(N-methylbenzamide) (IV) to obtain compound (IIC;) and
b) Iodination of compound (IIC) to obtain compound (IIB); or
c) Iodination of compound (VC) to obtain compound (VB);and
d) Cu catalyzed cross coupling reaction between diiodo indazole compound (VB) and dithio-2,2'-bis(N-methylbenzamide) (IV) to obtain compound (IIB)
and following steps a) and b) or steps c) and d),
e) a Heck reaction between compound (IIB) and compound 2-vinyl pyridine (X) by heating in the presence of a catalyst such as palladium(II)acetate (Pd(OAc)2 ), a ligand such as tri-o-tolylphosphine, a suitable base such as Proton Sponge (N,N,N',N'-Tetramethyl-naphthalene-1,8-diamine), a suitable additive such as LiBr, and a solvent such as DMA or NMP to provide compound (I).
The process is as depicted below in reaction scheme 4.

Scheme 4

In an embodiment, the present invention provides compound (I) in substantially pure form. As used herein, “substantially pure” refers to chemical purity of greater than about 97%, preferably greater than about 98%, and more preferably greater than about preferably 99.0% by weight.

Compound (I) obtained by the process of the present invention may be optionally purified according to methods known in the art or may be further converted into pharmaceutically acceptable salts. The desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

There is also provided by the present invention compound (I) or its pharmaceutically acceptable salts thereof prepared by a process as described above.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising compound of formula (I) or physiologically acceptable salts thereof, prepared by a process as described above, together with one or more pharmaceutically acceptable excipients. Such excipients are well known to those skilled in the art.

According to another aspect of the present invention, there is provided the use of compound of formula (I) or physiologically acceptable salts thereof, prepared by a process as described above in medicine.

According to another aspect of the present invention, there is compound of formula (I) or physiologically acceptable salts thereof, prepared by a process as described above for use in the treatment of advanced renal cell carcinoma (RCC) in a mammal.

According to another aspect of the present invention, there is provided the use of compound of formula (I) or its pharmaceutically acceptable salt thereof, prepared by a process as described above, in the manufacture of a medicament for treating advanced renal cell carcinoma (RCC) in a mammal.

According to another aspect of the present invention, there is provided a method of treating advanced renal cell carcinoma (RCC) in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of compound of formula (I) or its pharmaceutically acceptable salt thereof, prepared by a process as described above,, especially for administration twice-a-day.

A further aspect of the present invention provides a method of treating an advanced renal cell carcinoma (RCC) in a mammal, the method comprising administering to the mammal a therapeutically effective amount of Compound (I) or any of the pharmaceutical compositions described herein.

In a particular aspect of any of the preceding method embodiments, the method further comprises administering one or more anti-tumor agents, anti-angiogenesis agents, signal transduction inhibitors, or antiproliferative agents.

While emphasis has been placed herein on the specific steps of the preferred process, it will be appreciated that many steps can be made and that many changes can be made in the preferred steps without departing from the principles of the invention. These and other changes in the preferred steps of the invention will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the invention and not as a limitation.

The details of the invention given in the examples which are provided below are for illustration only and therefore these examples should not be construed to limit the scope of the invention.

Examples:
Example 1
Preparation of compound (VA)
Compound (VI) (20 g, 0.06242 moles) was dissolved in 130 ml acetic acid at
0-5°C. To this mixture was added a solution of sodium nitrite (6.97g, 0.1010 moles) dissolved in water (60 ml) at 0-5°C in 1 hour. The mixture was stirred for 1 hour at 0-5°C. A solution of potassium iodide (21.2 g, 0.1277 moles) and iodine (7.92 g, 0.03120 moles) dissolved in 60 ml water at 0-5°C, was added over 1 hour. The reaction mixture was stirred and the temperature was raised to 25-30°C and further stirred for 1 hour. The mixture is then quenched into a solution of 20% sodium thiosulfate (200 ml) at 25-30°C in 30 minutes. The reaction mixture was stirred for 2 hours, temperature raised to 45-50°C and further stirred for 2 hours. The solid was isolated by filtration, washed with hot water.
Wet weight: 29.0 g
The wet material was stirred twice in 10 % Potassium carbonate solution ( 200 ml) at 50-55°C for 2 hours. The solid was isolated by filtration, washed with hot water.
Wet weight: 27.0 g
The solid was stirred in mixture of ethyl acetate (45 ml) and heptane (80 ml) for 2 hours, cooled to 0-5°C, stirred further for 2 hours, filtered, washed with heptane and dried to provide 20.2 g of titled compound ( 75% yield with a purity of 95% by HPLC).

Example 2
Preparation of compound (IIA)
Under inert atmosphere, to a stirred solution of compound (VA) (15 g, 0.03478 moles) in IPA ( 150 ml), was added K2CO3 ( 14.3 g, 0.1036 moles), copper iodide (5.96 g, 0.03129 moles), ethylene diamine (5.85 g, 0.09733 moles) and compound (IV) ( 7.03 g, 0.04203 moles) at 25-30°C. The reaction mixture was heated to reflux and stirred for 8 hours. The mixture was cooled to 25-30°C, water (1500 ml) was added and the mixture was further stirred for 10 hours at 25-30°C. The solid was isolated by filtration and washed with water to provide 15 g of titled compound ( 90% yield with a purity of 85% by HPLC).

Example 3
Preparation of compound (I)
Compound (IIA) (10 g, 0.02125 moles) was stirred in methanol (100 ml) and water (10 ml) at 25-30°C. PTSA (20 g, 0.1161 moles) was added. The reaction mixture was heated to 60-65°C for 4 hours. The solvent was removed under vacuum. Ethyl acetate (20 ml) and 10% NaHCO3 solution (100 ml) were added. The reaction mixture was further stirred at 60-65°C for 2 hours and cooled to 25-30°C. The solid was isolated by filtration, washed with ethyl acetate and dried to provide 8 g of titled compound ( 97% yield with a purity of 85% by HPLC).

Example 4
Preparation of compound (IIA) without isolating compound (VA)
Compound (VI) (20 g, 0.06242 moles) was dissolved in 130 ml acetic acid -5-0°C. The mixture was added to a solution of sodium nitrite (6.97g, 0.1010 moles) dissolved in water (60 ml) at -5-0°C in 1 hour. The mixture was stirred for 1 hour at -5-0°C. MDC (160 ml) was added and stirred for 10 minutes. A solution of potassium iodide (21.2 g, 0.1277 moles) and iodine (7.92 g, 0.03120 moles) dissolved in 60 ml water, was added at -5-0°C in 1 hour. The reaction mixture was stirred for 1 hour. The mixture is then quenched into a solution of 20% sodium thiosulfate (200 ml) at -5-0°C in 1 hour. The temperature of the reaction mixture was raised to 25-30°C and was stirred for 30 minutes. The organic layer separated. Aqueous layer was extracted with MDC (2x 40 ml). The organic layers combined, washed with water (200 ml), followed by 5% Sodium bicarbonate solution (200ml) and water (200 ml).

The organic layer (200 ml) was loaded onto a column containing silica gel (40 g, mesh 60-120) and eluted with MDC (500 ml). The collected fractions were combined and concentrated under vacuum.
To the residue was added DMF (130 ml) at 25-30°C under inert atmosphere and stirred. To the reaction mixture was added K2CO3 (10.32 g, 0.0742 moles), copper iodide (0.885 g, 0.0046 moles), ethylene diamine (1.865 g, 0.0310 moles) and compound (IV) (18.65 g, 0.0562 moles) at 25-30°C. The reaction mixture was heated to 100°C for 2 hours. The mixture was cooled to 25-30°C, ethyl acetate (130 ml) was added and the mixture was further stirred for 1 hour at 25-30°C. A solution of 6% EDTA Disodium Salt (15.6 g, 0.0419 moles) dissolved in water (260 ml) was added to the reaction mixture at 25-30°C and stirred for 6 hours. The solid was isolated by filtration and washed with water followed by ethyl acetate and dried to provide 17.5 g of titled compound ( 60% yield with a purity of 98.5 to 99% by HPLC).

Example 5
Preparation of compound (I)
Compound (IIA) (15 g, 0.0319moles) was stirred in methanol (150 ml) and water (15 ml) at 25-30°C. PTSA (30.32 g, 0.1594 moles) was added. The reaction mixture was heated to 60-65°C for 6 hours. The solvent was removed under vacuum. The reaction mixture was cooled to 25-30°C, methanol (150 ml) was added. The reaction mixture was further stirred at 60-65°C for 1 hour and cooled to 10-15°C. Trimethylamine (16.04g, 0.1588 moles) and isopropyl acetate (75 ml) were added. The reaction mixture was stirred 25-30°C for 2 hours. 30 minutes.

The solid was isolated by filtration, washed with methanol (15 ml). The solid was stirred in a mixture of methanol : isopropyl acetate:: 1:1 (75 ml) at 60-65°C for 1 hour , cooled to 25-30°C and further stirred for 2 hours. The solid was isolated by filtration, washed with methanol: isopropyl acetate:: 1:1 (15 ml) and dried to provide 9.8 g of titled compound ( 80% yield with a purity of 99.6% by HPLC).

Example 6
Preparation of compound ( III ) from compound (IV)
Compound (IV) (20 g, 0.0602 moles) was stirred in ethanol (200 ml) and cooled to 0°C. Sodium borohydride ( 5.2g, 0.1374 moles) was added in portions over 1 hours, and the mixture was stirred for 5 hours at 0°C. A solution of hydrochloric acid ( 65 ml) was added to the mixture in over 30 minutes which adjusted the pH to 1-2. The reaction mixture was concentrated under reduced pressure at 45- 50°C to remove the ethanol. The residue was stirred in ethyl acetate (200 ml) and water ( 100 ml). The organic layer was separated, washed with water followed by a solution of saturated aqueous sodium chloride ( 60 ml). The organic layer was dried over sodium sulfate. The clear filtrate was concentrated under reduced pressure. n-Heptane ( 40 ml) was added and stirred. The solid was isolated by filtration to provide 14.5 g of titled compound (72% yield with a purity of 95% by HPLC).
Avoid exposure to air as the solid gets converted to disulfide.

Preparation of compound (IIA) using compound (III) without isolating compound (VA)

Compound (VI) (20 g, 0.06242 moles) was dissolved in 130 ml acetic acid at -5-0°C. The mixture was added to a solution of sodium nitrite (6.97g, 0.1010 moles) dissolved in water (60 ml) at -5-0°C in 1 hour. The mixture was stirred for 1 hour at -5-0°C. MDC (160 ml) was added and stirred for 10 minutes. A solution of potassium iodide (21.2 g, 0.1277 moles) and iodine (7.92 g, 0.03120 moles) dissolved in 60 ml water, was added at -5-0°C in 1 hour. The reaction mixture was stirred for 1 hour. The mixture is then quenched into a solution of 20% sodium thiosulfate (200 ml) at -5-0°C in 1 hour. The temperature of the rection mixture was raised to 25-30°C and was stirred for 30 minutes. The organic layer separated. Aqueous layer extracted with MDC (2x 40 ml). The organic layers combined, washed with water (200 ml), followed by 5% Sodium bicarbonate solution (200ml) and water (200 ml).

The organic layer was loaded onto a column containing silica gel (40 g, mesh 60-120) and eluted with MDC (500 ml). The collected fractions were combined and concentrated under vacuum.

To the residue was added DMF (140 ml) at 25-30°C under inert atmosphere and stirred. To the reaction mixture was added K2CO3 (10.32 g, 0.0742 moles), copper iodide (0.885 g, 0.0046 moles), ethylene diamine (1.865 g, 0.0310 moles) and compound (IV) (10.38 g, 0.0621 moles) at 25-30°C. The reaction mixture was heated to 100°C for 2 hours. The mixture was cooled to 25-30°C, ethyl acetate (140 ml) was added and the mixture was further stirred for 1 hour at 25-30°C. A solution of 6% EDTA Disodium Salt (16.8 g, 0.0451 moles) dissolved in water (280 ml) was added to the reaction mixture at 25-30°C and stirred for 6 hours. The solid was isolated by filtration and washed with water followed by ethyl acetate and dried to provide 17 g of titled compound (58% yield with a purity of 98% by HPLC).

Example 7
Preparation of compound (I)
Compound (IIA) (10 g, 0.02125 moles) was stirred in methanol (70 ml) at 25-30°C. Methane sulphonic acid (3.57g g, 0.0371 moles) was added. The reaction mixture was stirred at 25-30°C for about 10 minutes and then heated to 60-65°C for about 2 hours. The solvent was removed under vacuum. The reaction mixture was cooled to 25-30°C, stirred for about 1 hour and chilled further to 0-5°C and stirred for about 1 hour.
The solid was isolated by filtration, washed with methanol and dried to provide 7.0 g of titled compound ( 85.26% yield with a purity of 99.60% by HPLC).

Example 8
Preparation of compound (I)
Compound (IIA) (15 g, 0.0319moles) was stirred in methanol (135 ml) and water (15 ml) at 25-30°C. PTSA)(24.25g, 0.1275 moles) was added. The reaction mixture was heated to 60-65°C for 6 hours. The solvent was removed under vacuum. The reaction mixture was cooled to 25-30°C, an aq. methanol (135 ml in 15 ml water) was added. The reaction mixture was further stirred at 60-65°C for 1 hour and cooled to 10-15°C. Trimethylamine (-12.90 g, 17.77 ml/0.1274 moles) was added, the temperature raised to 25-30°C and stirred for about 2 hours. Isopropyl acetate (75 ml) were added. The reaction mixture was stirred 25-30°C for 2 hours.
The solid was isolated by filtration, washed with mixture of methanol: isopropyl acetate:: 1:1 (15 ml) and dried to provide 10.5 g of titled compound.

The solid was stirred in 10-15 volumes of acetic acid at about 60-65°C for 30 minutes. Distilled of solvent under reduced pressure. The reaction mass was cooled to 25-30°C and stirred in a mixture of DMF (25 ml) and ethyl acetate (75 ml). The reaction mixture was heated to 55-60°C, stirred for about 1 hour, cooled to 25-30°C and stirred further for about 2 hours.
The solid was isolated by filtration, washed with ethyl acetate and dried to provide 8.9 g of titled compound. (72.20% % yield with a purity of 99.60% by HPLC). ,CLAIMS:We claim,

1. A process for preparing compound (I)

or a pharmaceutically acceptable salt or solvate thereof, comprises the steps of: (a) reacting indazole compound (V) with dithio-2,2'-bis(N-methylbenzamide compound (IV)

in the presence of copper catalyst and a suitable ligand to form compound (II)

Formula II
wherein R1 is an activated substituent group, a substituted or unsubstituted aryl or heteroaryl, or a group of the formula CH=CH—R3 or CH=N—R3, where R3 is a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and R2 is H, or protecting group; wherein X is an activated substituent group; and
(b) converting compound (II) into compound (I).
2. A process as claimed in claim 1, wherein the protecting group is selected from tetrahydropyran, Boc, cbz, FMOC, trityl, benzyl, substituted benzyl and SEM-chloride.

3. A process as claimed in claim 1, wherein the activated substituent group X is preferably halide, more preferably chloride, bromide, and iodide.

4. A process as claimed in claim 1, wherein copper catalyst comprises CuI, Cu bronze, Cu(OAc)2, CuCl2, and Cu(OMe)2; preferably CuI.

5. A process as claimed in claim 1, wherein a suitable ligand comprises phenanthrolines, a-amino acids selected from L-proline, glycine, D-alanine and DL-serine, 1,3-diketones, imines, salicylamides, N,N'-Dimethyl-1,2-cyclohexanediamine (DMCyDA), 1,2- cyclohexanediamine (CyDA), 1,10- phenanthroline, Ethyl 2-oxocyclohexanecarboxylate, 2,9-Dimethyl -1,10- phenanthroline, N-methyl amino acetic acid, [1,1'-Binaphthalene]-2,2'-diol, D-Proline, N,N'-Dimethylethylenediamine ( DMEDA) , and Tetramethylethylene diamine (TMEDA or TEMED); preferably ethylenediamine and cyclohexanediamine.

6. A process as claimed in any preceding claim, wherein 0.5 to 2 moles of dithio-2,2'-bis(N-methylbenzamide (IV) used per mole of compound (V).

7. A process as claimed in any preceding claim, wherein the step (a) is carried out in the presence of a suitable base and a solvent.

8. A process as claimed in claim 7, wherein the base is selected from inorganic base selected from K2CO3, K3PO4, KHMDS and organic base selected from TEA and DIPEA.

9. A process as claimed in claim 7, wherein a suitable solvent include polar solvents selected from DMF, NMP, DMSO, dioxane, water and MeCN and non polar solvents selected from toluene and xylene.

10. A process as claimed in any preceding claim, wherein the step (a) is carried out at a temperature in the range of from about 0°C to about reflux temperature of the solvent used; preferably, at a temperature in the range of from about 25°C to about reflux temperature of the solvent used; more preferably at a temperature in the range of from about 50°C to about 100°C.

11. A process as claimed in any preceding claim, wherein the step (a), dithio-2,2'-bis(N-methylbenzamide) (IV) is insitu converted to 2-mercapto-N-methylbenzamide (III), without using any reduction reagent.

12. A process as claimed in any preceding claim, wherein the step (a) is carried out in the absence of a ligand.

13. A process as claimed in claim 1, wherein step (b) comprises deprotection of compound (II) with an acid in an alcoholic solvent.

14. A process as claimed in claim 13, wherein the acid is selected from inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, organic acid such as para-toluenesulfonic acid, methanesulfonic acid, or Lewis acids such as boron trifluoride etherate and the alcoholic solvent is selected from methanol, ethanol, n-propanol or isopropanol.

15. A process as claimed in claim 1, wherein the compound of formula (V) is a compound of formula (VA)

16. A process as claimed in claim 1, wherein the compound of formula (II) is a compound of formula (IIA )

17. A process for preparing compound (I) or a pharmaceutically acceptable salt or solvate thereof, comprises the steps of:
(a) reacting indazole compound (VA) with dithio-2,2'-bis(N-methylbenzamide compound (IV), in the presence of copper iodide catalyst and ethylenediamine to form compound (IIA); and
(b) deprotecting compound (IIA) with an acid in presence of a suitable solvent to obtain compound (I)

18. A process for preparing compound (I) ,or a pharmaceutically acceptable salt or solvate thereof, comprises the steps of:
a) Cu catalyzed cross coupling reaction between iodo indazole compound (VC) and dithio-2,2'-bis(N-methylbenzamide) (IV) to obtain compound (IIC;)
b) Iodination of compound (IIC) to obtain compound (IIB); or
c) Iodination of compound (VC) to obtain compound (VB);and
d) Cu catalyzed cross coupling reaction between diiodo indazole compound (VB) and dithio-2,2'-bis(N-methylbenzamide) (IV) to obtain compound (IIB)
and following steps a) and b) or steps c) and d),
e) a Heck reaction between compound (IIB) and compound 2-vinyl pyridine (X) by heating in the presence of a catalyst such as palladium(II)acetate (Pd(OAc)2 ), a ligand such as tri-o-tolylphosphine, a suitable base such as Proton Sponge (N,N,N',N'-Tetramethyl-naphthalene-1,8-diamine), a suitable additive such as LiBr, and a solvent such as DMA or NMP to provide compound (I).

19. A process for preparing compound (I) according to claim 18, or a pharmaceutically acceptable salt or solvate thereof, comprises the steps of:
a) Cu catalyzed cross coupling reaction between iodo indazole compound (VC) and dithio-2,2'-bis(N-methylbenzamide) (IV) to obtain compound (IIC;) and
b) Iodination of compound (IIC) to obtain compound (IIB); and
e) a Heck reaction between compound (IIB) and compound 2-vinyl pyridine (X) by heating in the presence of a catalyst such as palladium(II)acetate (Pd(OAc)2 ), a ligand such as tri-o-tolylphosphine, a suitable base such as Proton Sponge (N,N,N',N'-Tetramethyl-naphthalene-1,8-diamine), a suitable additive such as LiBr, and a solvent such as DMA or NMP to provide compound (I).

20. A process for preparing compound (I) according to claim 18, or a pharmaceutically acceptable salt or solvate thereof, comprises the steps of:
c) Iodination of compound (VC) to obtain compound (VB);
d) Cu catalyzed cross coupling reaction between diiodo indazole compound (VB) and dithio-2,2'-bis(N-methylbenzamide) (IV) to obtain compound (IIB);
and
e) a Heck reaction between compound (IIB) and compound 2-vinyl pyridine (X) by heating in the presence of a catalyst such as palladium(II)acetate (Pd(OAc)2 ), a ligand such as tri-o-tolylphosphine, a suitable base such as Proton Sponge (N,N,N',N'-Tetramethyl-naphthalene-1,8-diamine), a suitable additive such as LiBr, and a solvent such as DMA or NMP to provide compound (I).