WO2014125408A2

WO2014125408A2 - Substituted 1h-pyrrolopyridinone derivatives as kinase inhibitors

Info

Publication number: WO2014125408A2
Application number: PCT/IB2014/058881
Authority: WO
Inventors: Anima BORUAH; Srikanth CHITTY VENKATA; Subramanya Hosahalli; Sunil Kumar Panigrahi
Original assignee: Aurigene Discovery Technologies Limited
Priority date: 2013-02-12
Filing date: 2014-02-10
Publication date: 2014-08-21
Also published as: WO2014125408A3

Abstract

The present invention provides novel substituted 1H-Pyrrolopyridinone derivatives of formula (1) as protein kinase inhibitors, in which R₁, R₂, R₃, R₄, R₅, R₆ and 'p' have the meanings given in the specification, and pharmaceutically acceptable salts thereof that are useful in the treatment and prevention in diseases or disorder, in particular their use in diseases or disorder where there is an advantage in inhibiting kinase enzyme, more particularly BTK enzyme. The present invention also provides methods for synthesizing and administering the kinase inhibitor compounds. The present invention also provides pharmaceutical formulations comprising at least one of the kinase inhibitor compounds together with a pharmaceutically acceptable carrier, diluent or excipient therefor.

Description

SUBSTITUTED 1H-PYRROLOPYRIDINONE DERIVATIVES AS KINASE

INHIBITORS

This application claims the benefit of Indian provisional application number 598/CHE/2013 filed on 12^th February 2013 which hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to compounds useful for the treatment and prevention of diseases or disorder, in particular their use in diseases or disorder associated where there is an advantage in inhibiting kinase enzyme activity, and more particularly Bruton's tyrosine kinase (Btk). The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of diseases or disorder associated with Btk.

BACKGROUND OF THE INVENTION

Protein Kinase enzymes are known to be the key regulators of cell activities that constitute one of the largest and most functionally diverse gene families. Protein kinases participate in the signalling events that control the activation, growth and differentiation of cells in response to extracellular mediators and to changes in the environment. In general, these protein kinases fall into several groups; those which preferentially phosphorylate serine and/or threonine residues and those which preferentially phosphorylate tyrosine residues.

Many diseases and/or disorders are associated with aberrant, abnormal or deregulated activity of one or more kinases. These diseases and/or disorders include, but are not limited to cancers, allergic diseases and/or disorders, autoimmune diseases and/or disorders, inflammatory diseases and/or disorder and/or conditions associated with inflammation and pain, proliferative diseases, hematopoietic disorders, hematological malignancies, bone disorders, fibrosis diseases and/or disorders, metabolic disorders, muscle diseases and/or disorders respiratory diseases and/or disorders, pulmonary disorders, genetic developmental diseases, neurological and neurodegenerative diseases/or disorders, chronic inflammatory demyelinating neuropathies, cardiovascular, vascular or heart diseases and/or disorders, ophthalmic/ocular diseases and/or disorders, wound repair, infection and viral diseases. Therefore, inhibition of one or more of kinases would have multiple therapeutic indications. Bruton's Tyrosine Kinase (Btk) is a member of the Tec family of tyrosine kinases, and is a critical regulator of early B-Cell development as well as mature B-cell activation, signaling and survival (Kurosaki, Curr Op Imm, 2000, 276-281; Schaeffer and Schwartzberg, Curr Op Imm 2000, 282-288). Btk also plays role in a number of other hematopoietic cell signalling pathways, e.g., Toll like receptor (TLR) and cytokine receptor-mediated TNF-a production in macrophages, IgE receptor signalling in Mast cells, inhibition of Fas/APO-1 apoptotic signalling in B-lineage lymphoid cells, and collagen-stimulated platelet aggregation (C. A. Jeffries, etal., (2003), Journal of Biological Chemistry 278:26258-26264; N. J. Horwood, et al., (2003), The Journal of Experimental Medicine 197 : 16031611 ) .

B-cell signaling through the B-cell receptor (BCR) leads to a wide range of biological outputs, which in turn depend on the developmental stage of the B-cell. After BCR stimulation, Btk is recruited to the cell membrane and phosphorylated in the activation loop by src family kinases. Subsequent Btk auto-phosphorylation stabilizes the active confirmation and fully activates Btk kinase activity. Activated Btk phosphorylates phospho lipase (PLCy), initiating calcium mobilization and generating diacylglycerol (DAG) as secondary signals, eventually leading to transcriptional activation and amplification of BCR stimulation (Satterthwaite AB, Witte ON (2000), Immunol. Rev. 175: 120-127; Khan WN (2001), Immunol. Res. 23: 147-156. Aberrant BCR mediated signalling can cause deregulated B-cell proliferation and/or formation of pathogenic antibodies leading to multiple autoimmune and/or inflammatory diseases. In view of the apparent Btk's role in B-cell activation, inhibitors of Btk may be useful as inhibitors of B-cell mediated pathogenic activity.

Evidence for the role of Btk in autoimmune and/or inflammatory disease are available in Btk-deficient mouse models e.g. in standard murine preclinical models of Systemic Lupus Erythematosus(SLE), Btk deficiency has been shown to result in a marked reduction of disease progression (Minoru Satoh et al (2003) Int. Immunol. 15 (9): 1117-1124. Btk deficient mice are also resistant to developing collagen- induced arthritis and are less susceptible to Staphylococcus- induced arthritis (Svensson et al (1998) Clin Exp Immunol. March; 111(3): 521-526. Thus, inhibition of Btk activity appears to be useful for the treatment of autoimmune and/or inflammatory diseases such as SLE, rheumatoid arthritis, multiple vasculitides, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, and asthma. In addition, Btk has been reported to play a role in apoptosis, thus inhibition of Btk activity is useful for the treatment of B-cell lymphoma and leukaemia. They may also be useful as part of other therapeutic regimens for the treatment of disorders, alone or in combination with protein kinase compounds well known by the one skilled in the art.

The novel substituted lH-Pyrrolopyridinone derivatives according to the present invention may possess inhibitory activity of one or more protein kinases including Btk and are, therefore, expected to be useful in the treatment of kinase-associated diseases or disorders.

SUMMARY OF THE INVENTION

The present invention relates to substituted lH-Pyrrolopyridinone derivatives of formula ( 1 ) which are useful as kinase inhibitors.

In one aspect, the resent invention relates to the compound of formula (1)

or a pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof; wherein,

Ri is selected from hydrogen, alkyl, -C(0)OR_a and -C(0)N(R_b)R_c;

R₂ is selected from alkyl, cyanoalkyl, cycloalkylalkyl and aryl;

R₃ and R5 are selected from hydrogen and alkyl;

R₄ is selected from hydrogen, halogen, alkyl, hydroxyalkyl, alkoxy and -CH₂OC(0)alkyl;

R₆ is selected from hydrogen, halogen, alkyl, -N(R_b)R_c, haloalkyl, haloalkyloxy, cyanoalkyl and optionally substituted cycloalkyl; wherein the optional substituents are selected from alkyl and haloalkyl;

R_a is selected from hydrogen and alkyl;

R_b and R_c are independently selected from hydrogen and alkyl; alternatively, ¾ and R_c can be taken together with the nitrogen atom to which they are attached to form 3 to 6 membered cyclic ring having 0 to 3 heteroatoms independently selected from N, O and S ; and

'p' is an integer selected from 1, 2, and 3.

In another aspect of the present invention, it relates to the pharmaceutical composition comprising substituted lH-Pyrrolopyridinone derivatives of formula (1) and process for preparing them.

In further another aspect of the present invention, it relates to the use of compounds of formula (1), its pharmaceutically acceptable salts or pharmaceutically acceptable stereoisomers thereof, including mixtures thereof in all suitable ratios wherever applicable as a medicament for the treatment and prevention of disorders or diseases by inhibitory action on Bruton's tyrosine kinase (Btk) enzyme thereof.

DETAILED DESCRIPTION OF THE INVENTION

Embodiments of the present invention provide substituted lH-Pyrrolopyridinone derivatives of formula ( 1) which are useful as kinase inhibitors.

One of the embodiment of the present invention provide the compound of formula ( 1)

Ri is selected from hydrogen, alkyl, -C(0)OR_a and -C(0)N(R_b)R_c;

R₂ is selected from alkyl, cyanoalkyl, cycloalkylalkyl and aryl;

R₃ and R5 are selected from hydrogen and alkyl;

R4 is selected from hydrogen, halogen, alkyl, hydroxyalkyl, alkoxy and -CH₂0C(0)alkyl; R₆ is selected from hydrogen, halogen, alkyl, -N(Rb)R_c, haloalkyl, haloalkyloxy, cyanoalkyl and optionally substituted cycloalkyl; wherein the optional substituents are selected from alkyl and haloalkyl;

R_a is selected from hydrogen and alkyl;

R_b and R_c are independently selected from hydrogen and alkyl;

alternatively, R and R_c can be taken together with the nitrogen atom to which they are attached to form 3 to 6 membered cyclic ring having 0 to 3 heteroatoms independently selected from N, O and S ; and

'p' is an integer selected from 1, 2, and 3.

The embodiment below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified.

According to one embodiment, specifically provided are compounds of formula (1), in which Ri is selected from hydrogen, alkyl, -C(0)OR_a and -C(0)N(Rb)R_c; in particular alkyl is methyl.

According to preceding embodiment, specifically provided are compounds of formula (1), wherein -C(0)OR_a and -C(0)N(R_b)R_c are selected from -C(0)OH , -C(0)OCH₂CH₃,

According to another embodiment, specifically provided are compounds in which R₂ is selected from alkyl, cyanoalkyl, cycloalkylalkyl and aryl; in particular alkyl is methyl, ethyl and isopropyl; cyanoalkyl is propionitrile; cycloalkylalkyl is cyclopropylmethyl; and aryl is phenyl.

According to yet another embodiment, specifically provided are compounds of formula (1), wherein R₃ and R5 are hydrogen.

According to yet another embodiment, specifically provided are compounds of formula (1), wherein R4 is halogen, alkyl, hydro xyalkyl, alkoxy and -CH₂OC(0)alkyl; in particular halogen is fluoro; alkyl is methyl; alkoxy is methoxy; and hydroxy alkyl is hydroxymethyl.

According to yet another embodiment, specifically provided are compounds of formula (1), wherein R₆ is selected from halogen, alkyl, -N(Rb)R_c, haloalkyl, cyanoalkyl and optionally substituted cycloalkyl. According to preceding embodiment, specifically provided are compounds of formula ( 1 ), wherein particularly halogen is fluoro; alkyl is methyl, isopropyl and tert-butyl; haloalkyl is l , l , l-trifluoropropan-2-yl and trifluoromethane; cyanoalkyl is 2-cyanopropane; and - N(Rb)R_c,wherein R and R_c are alkyl, in particular alkyl is methyl.

According to one of the preceding embodiment, specifically provided are compounds of formula ( 1 ), wherein optionally substituted cycloalkyl is cyclopropyl optionally substituted with methyl and trifluromethyl.

According to yet another embodiment, specifically provided are compounds of formula ( 1 ), wherein p is selected from 1 , 2 and 3.

According to further yet another particular embodiment of the present invention; the compound of formula ( 1) is a com ound of formula ( la)

( la),

wherein, R_{1 ;} R₂, R4 and R₆ are same as defined in formula ( 1).

According to preceding embodiment, the compound of formula ( l a) is a compound of formula ( lb)

wherein, R_{1 ;} R₂ and R4 are same as defined in formula ( 1). According to preceding embodiment, specifically provided are compounds formula

(lb), in particular Rj is hydrogen, -C(0)OH, -C(0)OCH₂CH₃, -C(0)N(CH₃)₂ and

.

According to one of the preceding embodiment, specifically provided are compounds of formula (lb), in particular R₂ is methyl and ethyl.

According to one of the preceding embodiment, specifically provided are compounds of formula (lb), in particular R4 is methyl, hydroxymethyl and methoxy.

According to further yet another particular embodiment of the present invention; the compound of formula (1) is selected from the group consisting of

Comp.

IUPAC Names

No.

4-yl)-2-methylphenyl)benzamide;

11. 4-(tert-butyl)-N-(3-(3,6-dimethyl-7-oxo-6,7-di ydro-lH-pyrrolo[2,3-c]pyridin-4- yl)-2-methylphenyl)benzamide;

12. 4-(tert-butyl)-N-(3-(6-(2-cyanoethyl)-7-oxo-6,7-di ydro-lH-pyrrolo[2,3-c]pyridin- 4-yl)-2-(hydroxymethyl)phenyl)benzamide;

13. 4-(tert-butyl)-N-(3-(6-(cyclopropylmethyl)-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridin-4-yl)-2-(hydroxymethyl)phenyl)benzamide;

14. 4-(tert-butyl)-N-(2-(hydroxymethyl)-3-(6-isopropyl-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridin-4-yl)phenyl)benzamide;

15. 4-(tert-butyl)-N-(3-(6-ethyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridin-4-yl)-2- (hydroxymethyl)phenyl)benzamide;

16. 4-(dimethylamino)-N-(2-(hydroxymethyl)-3-(6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridin-4-yl)phenyl)benzamide;

17. 4-(tert-butyl)-N-(2-methoxy-3-(6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridin-4-yl)phenyl)benzamide;

18. 4-(3-(4-(tert-butyl)benzamido)-2-methylphenyl)-6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo [2, 3-c]pyridine-2-carboxylic acid ;

19. 4-fluoro-N-(2-(hydroxymethyl)-3-(6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridin-4-yl)phenyl)benzamide;

20. 4-cyclopropyl-2-fluoro-N-(2-(hydroxymethyl)-3-(6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridin-4-yl)phenyl)benzamide;

21. 4-(tert-butyl)-N-(2-fluoro-3-(6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridin- 4-yl)phenyl)benzamide;

22. 4-cyclopropyl-N-(2-(hydroxymethyl)-3-(6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridin-4-yl)phenyl)-2-methylbenzamide;

23. 4-cyclopropyl-N-(2-(hydroxymethyl)-3-(6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo

[2,3-c]pyridin-4-yl)phenyl)benzamide;

24. N-(2-(hydroxymethyl)-3-(6-methyl-7-oxo-6,7-di ydro-lH-pyrrolo[2,3-c]pyridin-4- Comp.

IUPAC Names

No.

yl)phenyl)-4-(trifluoromethyl)benzamide;

25. 4-(2-cyanopropan-2-yl)-N-(2-(hydroxymethyl)-3-(6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-c]pyridin-4-yl)phenyl)benzamide;

26. N-(2-(hydroxymethyl)-3-(6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridin-4- y l)phenyl) -4- isopropylbenzamide ;

27. N-(2-(hydroxymethyl)-3-(6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridin-4- yl)phenyl)-4-( 1 -methylcyclopropyl)benzamide;

28. 4-cyclopropyl-2,6-difluoro-N-(2-(hydroxymethyl)-3-(6-methyl-7-oxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridin-4-yl)phenyl)benzamide;

29. N-(2-(hydroxymethyl)-3-(6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridin-4- yl)phenyl)-4-( 1 -(trifluoromethyl)cyclopropyl)benzamide ; and

30. N-(2-(hydroxymethyl)-3-(6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridin-4- yl)phenyl)-4-( 1,1,1 -trifluoropropan-2-yl)benzamide,

or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable stereoisomer thereof.

In further yet another particular embodiment, the definition of "compounds of formula (1)" inherently includes all stereoisomers of the compound of formula (1) either as pure stereoisomer or as a mixture of two or more stereoisomers. The word stereoisomers include enantiomers, diasteroisomers, racemates, cis-isomers, trans-isomers and mixture thereof.

The absolute configuration at an asymmetric atom is specified by either R or S. Resolved compounds whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light. When a specific stereoisomer is identified, this means that said stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 5%, in particularly less than 2% or 1% of the other isomers. Thus when a compound of formula (1) is for instance specified as (R), this means that the compound is substantially free of (S) isomer; when the compound of formula (1) is for instance specified as E, this means that the compound is free of the Z isomer; when the compound of formula (1) is for instance specified as cis-isomer, this means that the compound is free of the trans-isomer.

In further yet another particular embodiment, the compounds and pharmaceutically compositions of the present invention are used in the treatment and/or prevention of diseases and/or disorders in which aberrant, abnormal or deregulated activity of Bruton's tyrosine kinase (Btk) contribute to the pathology and/or symptomology of diseases and/or disorders associated with Btk.

In further yet another particular embodiment, the compounds of formula (1) are useful as medicament in treatment of diseases and/or disorders associated with Btk, which includes but are not limited to cancer, autoimmune and inflammatory disorders such as multiple sclerosis and rheumatoid arthritis.

Diseases and/or disorders associated with aberrant, abnormal or deregulated activity of Btk include, but are not limited to allergic disorders and/or autoimmune and/or inflammatory diseases and/or conditions associated with inflammation and pain, cancers, proliferative diseases, hematopoietic disorders, hematological malignancies, bone disorders, fibrosis diseases and/or disorders, metabolic disorders, muscle diseases and/or disorders respiratory diseases and/or disorders, pulmonary disorders, genetic developmental diseases, neurological and neurodegenerative diseases/or disorders, chronic inflammatory demyelinating neuropathies, cardiovascular, vascular or heart diseases and/or disorders, ophthalmic/ocular diseases and/or disorders, wound repair, infection and viral diseases.

In particular, the compounds according to the present invention possess potential of providing cancer cell growth inhibiting effects and are effective in treating cancers, autoimmune and inflammatory diseases; in particular cancer includes all types of solid cancers and malignant lymphomas but not limited to leukaemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, brain tumour & etc; and particularly the compounds according to the present invention are used in the treatment of autoimmune and/or inflammatory diseases and/or conditions associated with inflammation and pain include, but are not limited to acid reflux, heart burn, acne, allergies and allergen sensitivities, bronchitis, carditis, celiac disease, chronic pain, cirrhosis, colitis, dementia, dermatitis, diabetes, dry eyes, edema, emphysema, eczema, fibromyalgia, gastroenteritis, gingivitis, heart disease, hepatitis, high blood pressure, insulin resistance, interstitial cystitis, joint pain/arthritis/rheumatoid arthritis, atherosclerosis, sarcoid, spinal cord injury, stroke, chronic inflammatory demyelinating neuropathy, radiation induced demyelination, hereditary demyelinating condition, a prion-induced demyelination, encephalitis- induced demyelination, Sjogren's disease, tissue graft rejection, and hyperacute rejection of transplanted organs, Kaposi's sarcoma associated with HIV, asthma, systemic lupus erythematosus (and associated glomerulonephritis), juvenile cystic kidney disease, and type I nephronophthisis (NPHP), dermatomyositis, multiple sclerosis, scleroderma, vasculitis (ANCA- associated and other vasculitides), autoimmune hemolytic and thrombocytopenic states, Good pasture's syndrome (and associated glomerulonephritis and pulmonary hemorrhage), chronic idiopathic thrombocytopenic purpura (ITP), Addison's disease, Parkinson's disease, Guam- Parkinson dementia, supranuclear palsy, Alzheimer's disease, diabetes, septic shock and myasthenia gravis, Kufs disease, and Pick's disease, as well as memory impairment, brain ischemia, and schizophrenia, periodontal disease, polyarteritis, polychondritis, psoriasis, scleroderma, sinusitis, Sjogren's syndrome, spastic colon, systemic candidiasis, tendonitis, urinary tract infections, vaginitis, inflammatory cancer (e.g., inflammatory breast cancer) and the like.

Without limiting the scope of present invention, the following definitions are provided in order to aid those skilled in the art in understanding the detailed description of the present invention.

"Alkyl" refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms; in particular alkyl is Q-Qo alkyl group which may have 1 to 10 (inclusive) carbon atoms in it; in more particular alkyl is Ci-C₆ alkyl group which may have 1 to 6 (inclusive) carbon atoms in it and in more preferred particular alkyl is C_\- C₄ alkyl group which may have 1 to 4 (inclusive) carbon atoms in it. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert -butyl, isopentyl, neopentyl, and isohexyl. An alkyl group can be unsubstituted or substituted with one or more suitable groups.

"Alkoxy" refers to the group alkyl-0- or -O-alkyl, where alkyl group is as defined above. Exemplary Ci-Cioalkyl group containing alkoxy groups include but are not limited to methoxy, ethoxy, n-propoxy, zso-propoxy, n-butoxy and i-butoxy. An alkoxy group can be unsubstituted or substituted with one or more suitable groups. "Halogen" or "halo" includes fluorine, chlorine, bromine or iodine.

"Haloalkyl" refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with - F, -CI, -Br or -I. Representative examples of an haloalkyl group include, but are not limited to -CH₂F, -CC1₃, -CF₃, -CH₂C1, -CH₂CH₂Br, - CH(CF₃)CH₃, -CH₂CH₂I, -CH₂CH₂CH₂F, -CH₂CH₂CH₂C1, -CH₂CH₂CH₂CH₂Br, - CH₂CH₂CH₂CH₂I, -CH₂CH₂CH₂CH₂CH₂Br, -CH₂CH₂CH₂CH₂CH₂I, -CH₂CH(Br)CH₃, - CH₂CH(C1)CH₂CH₃, and -CH(F)CH₂CH₃.

"Haloalkyloxy" refers to the group haloalkyl-O- or -O-haloalkyl, where haloalkyl group is as defined above. Exemplary haloalkoxy groups include but are not limited to -OCH₂F, - OCCl₃, -OCF₃, -OCH₂Cl, -OCH₂CH₂Br, -OCH₂CH₂I, -OCH₂CH₂CH₂F, -0CH₂CH₂CH₂C1 and the like.

"Hydroxy" refers to -OH group.

"Hydroxyalkyl" refers to the an alkyl group substituted with one or more hydroxy groups; the alkyl group and hydroxy group are same as defined above, wherein one or more of the alkyl group's hydrogen atom has been replaced with hydroxy group. Representative examples of an hydroxyalkyl group includes but are not limited to -CH₂OH, -CH₂CH₂OH, - CH₂CH(OH)CH₃, -CH₂CH(OH)CH₂CH₃ and the like.

"Cyanoalkyl" refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with -CN. Representative examples of an cyanoalkyl group include, but are not limited to -CH₂CN, -CH₂CH₂CN, -C(CH₂)₂CN, -CH₂CH₂CH₂CN and the like.

"Amino" refers to an -N- group, the nitrogen atom of said group being attached to a hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl or any suitable groups. Representative examples of an amino group include, but are not limited to -NH₂, -NHCH₃ and -NH-cyclopropyl. An amino group can be unsubstituted or substituted with one or more of the suitable groups.

"Aryl" refers to an optionally substituted monocylic, bicyclic or polycyclic aromatic hydrocarbon ring system of about 6 to 14 carbon atoms. Examples of a C₆-Ci4 aryl group include, but are not limited to phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl and acenaphthyl. Aryl group can be unsubstituted or substituted with one or more suitable groups. "Cycloalkyl" refers to a C₃-C10 non-aromatic, saturated, monocyclic, bicyclic or polycyclic hydrocarbon ring system. Representative examples of a C₃-C12 cycloalkyl include, but are not limited to, cyclopropyl, cyclopentyl, cycloheptyl, cyclooctyl and dodecahydros-indacen- 4-yl. A cycloalkyl can be unsubstituted or substituted with one or more suitable groups.

"Cycloalkylalkyl" refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atom has been replaced with an cycloalkyl group as defined above. Examples of cycloalkylalkyl group include, but are not limited to cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl and the like. A cycloalkylalkyl group can be unsubstituted or substituted with one or more suitable groups.

The term "Heterocyclyl" includes the definitions of "heterocycloalkyl" and "heteroaryl". The term "Heterocycloalkyl" refers to a non-aromatic, saturated or partially saturated, monocyclic or polycyclic ring system of 3 to 10 member having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(0)₂, NH and C(O). Exemplary heterocycloalkyl groups include piperdinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,3-dioxolanyl, 1,4- dioxanyl and the like. A heterocycloalkyl group can be unsubstituted or substituted with one or more suitable groups.

"Heteroaryl" refers to an unsaturated, monocyclic, bicyclic, or polycyclic aromatic ring system containing at least one heteroatom selected from oxygen, sulphur and nitrogen. Examples of C5-C10 heteroaryl groups include furan, thiophene, indole, azaindole, oxazole, thiazole, thiadiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4- triazole, l-methyl-l,2,4-triazole, IH-tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline. Bicyclic heteroaryl groups include those where a phenyl, pyridine, pyrimidine or pyridazine ring is fused to a 5 or 6-membered monocyclic heterocyclyl ring having one or two nitrogen atoms in the ring, one nitrogen atom together with either one oxygen or one sulfur atom in the ring, or one O or S ring atom. A heteroaryl group can be unsubstituted or substituted with one or more suitable groups.

"Hetero atom" refers to a sulfur, nitrogen or oxygen atom. "Optionally substituted or substituted" as used herein means that at least one or two hydrogen atoms of the optionally substituted group has been substituted with suitable groups as exemplified but not limited to alkyl, alkenyl, alkoxy, alkynyl, aryl, amido, amino, carboxy, cyano, cycloalkyl, guanidine, halogen, imidamide, hydroxy, nitro, haloalkyl, haloalkyoxy, heterocyclyl, oxo(=0), thio(=S), -P(0)₃H, -P(0)₂NH₂, -P(0)₂NH(alkyl), -P(0)₂NH(cycloalkyl),- P(0)₂NH(heterocyclyl), -P(0)₂NH(aryl), -C(0)(alkyl), -C(0)(aryl), -C(0)(cycloalkyl), - C(0)(heterocyclyl), or two substituents on the same carbon atom combined together to form an optionally substituted 3-8 member ring containing 0-3 heteroatoms independently selected form N, O and S in any stable combination.

"Comprise" or "Comprising" is generally used in the sense of include, that is to say permitting the presence of one or more features or components.

"Pharmaceutically acceptable salt" or "pharmaceutically acceptable derivatives" is taken to mean an active ingredient, which comprises a compound of the formula (1) in the form of one of its salts, in particular if this salt form imparts improved pharmacokinetic properties on the active ingredient compared with the free form of the active ingredient or any other salt form of the active ingredient used earlier. The pharmaceutically acceptable salt form of the active ingredient can also provide this active ingredient for the first time with a desired pharmacokinetic property which it did not have earlier and can even have a positive influence on the pharmacodynamics of this active ingredient with respect to its therapeutic efficacy in the body.

The use of the term "including" as well as other forms, such as "include", "includes" and "included" is not limiting.

As used herein, the terms "treat", "treating" or "treatment" encompass either or both responsive and prophylaxis measures, e.g., measures designed to inhibit or delay the onset of the disease or disorder, achieve a full or partial reduction of the symptoms or disease state, and/or to alleviate, ameliorate, lessen, or cure the disease or disorder and/or its symptoms. The terms "treat," "treating" or "treatment", include, but are not limited to, prophylactic and/or therapeutic treatments.

As used herein the terms "subject" or "patient" are well-recognized in the art, and, are used interchangeably herein to refer to a mammal, including dog, cat, rat, mouse, monkey, cow, horse, goat, sheep, pig, camel, and, most preferably, a human. In some embodiments, the subject is a subject in need of treatment or a subject with a disease or disorder. However, in other embodiments, the subject can be a normal subject. The term does not denote a particular age or sex. Thus, adult and newborn subjects, whether male or female, are intended to be covered.

As used herein the term "therapeutically effective amount" refers to a sufficient amount of a compound or a composition being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.

"Pharmaceutically acceptable" means that, which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.

Pharmaceutical formulations can be adapted for administration via any desired suitable method, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods. Such formulations can be prepared using all processes known in the pharmaceutical art by, for example, combining the active ingredient with the excipient(s) or adjuvant(s).

A therapeutically effective amount of a compound of the formula (1) and of the other active ingredient depends on a number of factors, including, for example, the age and weight of the animal, the precise disease condition which requires treatment, and its severity, the nature of the formulation and the method of administration, and is ultimately determined by the treating doctor or vet. However, an effective amount of a compound is generally in the range from 0.1 to 100 mg/kg of body weight of the recipient (mammal) per day and particularly typically in the range from 1 to lOmg/kg of body weight per day. Thus, the actual amount per day for an adult mammal weighing 70 kg is usually between 70 and 700 mg, where this amount can be administered as an individual dose per day or usually in a series of part-doses (such as, for example, two, three, four, five or six) per day, so that the total daily dose is the same. An effective amount of a salt or solvate or of a physiologically functional derivative thereof can be determined as the fraction of the effective amount of the compound per se. In a further aspect, the present invention relates to a process for preparing of 1H- pyrrolopyridinone derivatives of formula (1).

An embodiment of the present invention provides the compounds according to formula (1) may be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimization procedures. The intermediates or compounds synthesized herein may be used in the further step with isolating or without isolating. Moreover, by utilizing the procedures described in detail, one of ordinary skill in the art can prepare additional compounds of the present invention claimed herein. All temperatures are in degrees Celsius (°C) unless otherwise noted.

In a further aspect, the compounds of the present invention can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the present invention also embraces isotopically-labeled variants of the present invention which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses. Exemplary isotopes that can be incorporated in to compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as ²H ("D"), ³H, ⁿC, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵0, ¹⁷0, ¹⁸0, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶C1, ¹²³I and ¹²⁵I. Isotopically labeled compounds of the present inventions can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

The abbreviations used in the entire specification may be summarized herein below with their particular meaning. Ar (Argon); ACN (acetonitrile); brine (NaCl solution); AIBN (2-2'- Azoisobutyronitrile) ; Pd(dppf)Ci₂ ([1 , 1 '-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) complex with dichloromethane); Pd(PPh₃)₂Ci₂ (Bis(triphenylphosphine)palladium(II) dichloride); TFA (Trifluoroaceticacid); Pd(OAc)₂ (palladiumacetate); NMU(Nitrosomethylurea) ; CH₃MgBr (methylmagnesiumbromide); Cy₃P (tricyclohexylphosphine); TBAF (tetrabutyl ammonium fluoride); CO (g) (carbon monoxide gas); DBU (l ,8-diazabicyclo[5.4.0] undec-7-ene); bs (broad singlet); J (coupling constant); °C (degree Celsius); DMF (Ν,Ν-dimethyl formamide); DMSO (Dimethyl sulfoxide); DIPEA/DIEA (N, N- Diisopropyl ethyl amine); Et₂0 (diethyl ether); CH₂C1_2/DCM (dichloromethane); DMAP (dimethyl amino pyridine); CDC1₃ (deuteriated chloroform); d (doublet); dd (doublet of doublet); EDCI.HC1 (l-(3-Dimethyl aminopropyl)-3- carbodiimide hydrochloride); EtOH (ethanol); g (gram); H (hydrogen atom); HPLC (High- performance liquid chromatography); HOBT ( 1-Hydroxy benzotriazole); h/hrs (hours); Fe(iron); HATU ( l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-/?]pyridinium 3-oxid hexafluorophosphate); IPA (Isopropyl alcohol); LC/MS (Liquid chromatography-mass spectrometry); LiOH.H₂0 (Lithium hydroxide monohydrate); mmol (millimol); MeOH (methanol); μηι (micro molar); m/z (molecular weight); M (molar); KOAc (Potassium acetate); ml (millilitre) ; mg (milligram); m (multiplet); MHz (megahertz); MS (ES) (mass spectroscopy- electro spray); min (minutes); nm(nano molar); N₂ (nitrogen); NBS (N-bromosuccinamide); NH₄CI (ammoniumchloride); NMR (nuclear magnetic resonance spectroscopy); ppm-5(parts per million); 1H (proton NMR); R.T (room temperature range (20°C to35°Q); s (singlet); TLC (Thin Layer Chromatography); Pd₂(dba)₃ [(trisdibenzylideneacetone)dipalladium] ; TBDMS-C1 (tert- butyldimethylsilylchloride); THF (tetrahydrofuran); TEA (Triethylamine) ; t (triplet); Pd(PPh₃)₄ (Tetrakis(triphenyl phosphine)palladium); Hz (Hertz); SEM (2-(Trimethylsilyl)ethoxymethyl); LDA (Lithium diisopropylamide) ; NaOAC (Sodium Acetate); NaOBu¹ (Sodium tert-butoxide) ; AcOH (Acetic acid), PG (Protecting Group) etc.

GENERAL MODES OF PREPARATION

Another embodiment of the present invention provides methods useful for making the compounds of formula (1) are set forth in the Examples below and generalized in below schemes. One of skill in the art will recognize that below schemes can be adapted to produce the compounds of formula ( 1) and pharmaceutically accepted salts of compounds of formula ( 1) according to the present invention. Wherein all symbols/variables are as defined earlier unless otherwise stated. The process is represented herein with below schemes. .

Compounds of the invention may be prepared using the synthetic transformations illustrated in below schemes. Starting materials are commercially available, may be prepared by the procedures described herein, by literature procedures, or by procedures that would be well known to one skilled in the art of organic chemistry. It is meant to be understood that the order of the steps in the processes may be varied, that reagents, solvents and reaction conditions may be substituted for those specifically mentioned, and that vulnerable moieties may be protected and deprotected, as necessary. Scheme- 1:

5-bromo-2-chloro-3-nitropyridine derivative was reacted with Ri-CH=CHMgBr (Ri is hydrogen, methyl and the like) in presence of suitable solvents such as THF, Diethyl ether, 1,4- dioxane and the like at suitable temperature range of about -78°C to -20°C to give compound of formula la, which was protected with protecting group such as tosyl, SEM, and the like in presence of suitable base such as NaH, TEA, DIPEA, NaOBu¹ in presence of suitable solvents at appropriate reaction conditions resulted in the formation of compound lb. Compound lb undergoes partial hydrolysis in acidic conditions such as HCl, AcOH at appropriate reaction conditions to give compound lc, which was N-alkylated with suitable alkyl halides such as methyl iodide, ethyl iodide, isopropyl bromide, bromo propionitrile, cyclopropane methyl bromide and the like, in presence of a suitable base such as Na₂C0_3> K₂C0_3> Cs₂C0₃ and suitable solvents such as THF, DMF, DMA and DMSO to provide compound of formula Id; alternatively N-arylation (copper iodide/copper acetate/Pd-catalyzed C-N coupling reaction) can undergo with aryl boronate esters/acids, heteroaryl boronate esters/acids in presence of suitable coupling conditions in presence of suitable palladium catalysts in presence of suitable base such as DIPEA, TEA, Na₂C0₃, K₂C0₃, Cs₂C0₃, NaOBu and the like to get compound Id. Compound Id further undergoes Pd-catalyzed (such as Pd(dppf)Cl₂, Pd(PPh₃)₄, Pd₂(dba)_3, Pd(dppf)Cl_2.DCM, Pd(OAc)₂) C-C coupling reaction with appropriate boronic esters (compound le) in presence of suitable base, solvents and at suitable coupling conditions to give compound If. If R4 of compound If is protected with any suitable protecting groups such as TBDMS, it undergoes deprotection with TBAF, HC1 and the like, followed by another deprotection to provide compound of formula 1. If R4 is unprotected, compound If was deprotected in presence of suitable deprotecting agents such as 20 % aq. NaOH, KOH, LiOH.H₂0 to provide compound of formula 1.

Scheme-2:

Formu a 1

Compound of formula Id was reacted with ethyl chloroformate in presence of suitable solvents such as THF, Diethyl ether and the like at about temperature range of -80°C to -50°C to provide compound of formula 2a, which on further undergoes Pd-catalyzed C-C coupling reaction with appropriate boronic esters of formula (le) in presence of suitable Pd-catalyst such as Pd(dppf)Cl₂, Pd(dppf)Cl_2.DCM, Pd(PPh₃)₄, Pd₂(dba)_3, Pd(OAc)₂ and the like, in presence of suitable base Na₂C0_3, K₂C0_3, Cs₂C0₃, K₃P0₄, NaOBu¹ and the like, in presence of suitable polar solvents such as THF, DMF, DMA, Dioxane, DMSO and the like to provide compound of formula 2b. Compound of formula 2b undergoes any of the deprotection steps as stated in scheme- 1 to get the compound of formula (1).

Scheme-3:

Compound of formula 3 a was reacted with sodium nitrite in presence of sulphuric acid and water to provide compound of formula 3b, which on N-alkylation with alkyl iodide in presence of suitable bases such as Na₂C0_3> K₂C0_3> Cs₂C0₃ and the like, in suitable polar solvents such as THF, DMF, DMA and DMSO to provide compound of formula 3c. Further compound of formula 3c was reacted with diethyl oxalate in presence of DBU to provide compound of formula 3d. Compound of formula 3d undergoes reductive cyclization in presence of iron powder and acetic acid to give compound 3e, which on ester hydrolysis in presence of suitable deprotecting agents such as 10% aq.NaOH, KOH, LiOH.H₂0 in suitable solvents such as MeOH, EtOH, THF, DMF, DMSO and the like to provide compound of formula 3f. The acid-amine coupling of compounds of formula 3f was carried out by a conventional amide bond formation method by using a suitable coupling reagents such as benzotriazole-containing coupling reagents such as 1 -hydro xybenzotriazole (HOBt), benzotriazole-l-yloxytris (dimethylamino)phosphonium hexafluorophosphate and 2-(lH-benzotriazol-l-yl)-l, l,3,3-tetra methyluroniumhexafluoro phosphate and an azabenzotriazole-containing reagent such as 0-(7-azabenzotriazole-l-yl)-N and also the dicarboimides containing reagent such as l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, dicyclohexylcarbodiimide, HATU and the like, in a suitable solvent such as DMF, THF, DMSO or DCM and the like, in the presence of suitable bases such as TEA, DIPEA and/or DMAP and the like at a temperature of about 20-35°C for about 12-48 h to provide compound of formula 3g. Further compound 3g undergoes Pd-catalyzed C-C coupling reaction with appropriate boronic esters of compound of formula le followed by deprotection as stated in scheme-1 to give compound of formula ( 1).

EXAMPLES

Although the invention has been illustrated by certain of the preceding examples, it is not to be construed as being limited thereby; but rather, the invention encompasses the generic area as hereinbefore disclosed. Various modifications and embodiments can be made without departing from the spirit and scope thereof.

The MS data provided in the examples described below were obtained as follows:

Mass spectrum: LC/MS Agilent 6120 Quadrapole LC/MS.

The NMR data provided in the examples described below were obtained as follows:

'H-NMR: Varian 400 MHz.

The microwave chemistry was performed on a CEM Explorer.

The procedure for the compounds of Formula (1) are detailed herein below stepwise including the general synthesis of various intermediates involved in process of manufacture of the compounds according to the present invention.

Intermediate- 1: Synthesis of N-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(4,4,5,5-tetra methyl- 1,3, 2-dioxaborolan-2-yl)phenyl)-4-(dimethylamino)benzamide

Conditions: a) NBS, AIBN, CC1₄, 100°C, 18h; b) KOAc, DMF, 70°C, lh; c) 10% aq.KOH, 100°C, 2h;

d) TBDMS-C1, Et₃N, DCM, 0°C to RT, 24h; e) Fe, NH₄C1, Ethanol/Water (1 : 1), 70°C, 3h;

f) 4-(dimethylamino)benzoyl chloride, DMAP, DCM, 0"C to RT, lh; g) Bis(pinacolato)diboron, KOAc,

Pd(dppf)Cl₂. DCM complex, 1,4-dioxane, 120°C, 3h.

(Ref . for steps a to c: WO2005/67933A1)

(Ref. for steps d to e: US 7943618B2) Step-f: Synthesis of N-(3-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-4-(dimethyl amino)benzamide (1.7)

To a cold solution of 3-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)aniline (1.0 g, 3.10 mmol) in DCM (10 ml) was added DMAP (0.46 g, 3.70 mmol) and N,N dimethyl benzoyl chloride (0.58 g, 3.10 mmol). The reaction mixture was slowly warmed to RT and stirred for about 1 h. DCM was evaporated under reduced pressure, the resulting crude material was dissolved in ethyl acetate and washed with water. The organic layer was washed with brine solution, dried and concentrated. The obtained crude was purified using column chromatography eluted with 8 % EtOAc in hexane to afford title compound as a brown solid (0.25 g, 17 %). ¹H NMR (400 MHz, DMSO-d₆) δ 9.72 (s, 1H), 7.90-7.76 (m, 3H), 7.42-7.26 (m, 2H), 6.75 (d, J=8.0 Hz, 2H), 4.97 (s, 2H), 3.00 (s, 6H) 0.81 (s, 9H), 0.11 (s, 6H); LC/MS: 463 (M+l)⁺.

Step-g: Synthesis of N-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(4,4,5,5-tetramethyl-L3,2- dioxaborolan-2-yl)phenyl)-4-(dimethylamino)benzamide (Intermediate- 1 )

A sealed tube was charged with N-(3-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl) phenyl)-4-(dimethylamino)benzamide (0.25 g, 0.50 mmol) and Bis(pinacolato)diboron (0.2 g, 0.80 mmol) in 1,4-dioxane (10 ml). The reaction mixture was degassed with argon for 10 min followed by the addition of potassium acetate (0.15 g, 1.60 mmol) and l, l,-bis(diphenyl phosphino)ferrocine]dichloropalladium(II) complex with DCM (0.02 g, 0.05 mmol). The reaction mixture was heated to 120°C for 3 h. The reaction mixture was cooled to RT, diluted with EtOAc and filtered through a Celite pad and washed with EtOAc. The organic layer was washed with water and brine, dried and concentrated. The residue obtained was purified using column chromatography eluting with 15 % of EtOAc in hexane to afford title compound as a yellow solid (0.15 g, 55 %). 1H NMR (400 MHz, DMSO-d₆) δ 9.74 (s, 1H), 8.13 (d, J=7.2 Hz, 1H), 7.75 (d, J=8.8 Hz, 2H), 7.45-7.32 (m, 2H), 6.74 (d, J=9.2 Hz, 2H), 5.13 (s, 2H), 3.00 (s, 6H), 1.31 (s, 12H), 0.82 (s, 9H), 0.11 (s, 6H); LC/MS: 510 (M+l)⁺.

The intermediates prepared by following the same or analogous process outlined for obtaining Intermediate -1 are included in below table along with their physicochemical characteristics.

Intermediate-7: Synthesis of N-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl) henyl)-4-cvclopropyl-2-methylbenzamide

c) LiOII.II₂0, MeOII, II₂0, TIIF, 70°C, 2h d) i) SOCl₂, reflux, 2h ii) DIPEA, DCM, 0°C to RT,1.5h e) Bis(pincalato)diboron, KOAc, 1,4-dioxane, Pd(dppf)Cl₂.DCM 110°C, 12h. Step-a: Synthesis of methyl 4-bromo-2-methylbenzoate

To a stirred solution of 4-bromo-2-methyl benzoic acid (10 g, 46.511 mmol) in DMF (50 ml) at 0°C, was added K₂C0₃ (12.8 g, 93.023 mmol) and methyl iodide (3.4 ml, 55.813 mmol). The reaction mixture was slowly warmed to room temperature and stirred for about 3 h. The reaction mixture was diluted with ice cold water and the product was extracted with ethyl acetate. The combined organic layer was washed with brine, dried and concentrated to afford desired compound (10.0 g, 88 %). 1H NMR (400 MHz, DMSO-d₆) δ 7.74 (d, J=8.4 Hz, 1H), 7.60 (s, 1H), 7.52 (d, J=6.4 Hz, 1H), 3.82 (s, 3H), 2.50 (s, 3H); LC/MS: 230.9 (M+2)⁺ _.

Step-b: Synthesis of methyl 4-cyclopropyl-2-methylbenzoate

Methyl 4-bromo-2-methylbenzoate (2.0 g, 8.73 mmol), cyclopropylboronicacid (1.1 g,

13.10 mmol), potassium phosphate (3.7 g, 17.46 mmol), tricyclohexylphosphine (0.245 g, 0.87 mmol) and palladium(II) acetate (0.195 g, 0.87 mmol) were combined in a sealed tube under nitrogen, then toluene (10 mL) and H₂0 (1 mL) was added in one portion. The reaction mixture was sealed and heated to 120°C for a period of 16 h. The reaction mixture was allowed to cool and diluted with EtOAc and washed with water. The organic extracts were washed with water and brine, dried and concentrated. The crude obtained was purified by column chromatography using 2-5 % of EtOAc in hexane to afford the titled compound (1.3 g, 81 %). ^!H NMR (400 MHz, DMSO-dg) δ 7.72 (d, J=8.0 Hz, 1H), 7.01-6.97 (m, 2H), 3.78 (s, 3H), 2.50 (s, 3H), 1.92- 1.91 (m, 1H), 1.02-1.00 (m, 2H), 0.75-0.73 (m, 2H); LC/MS: 191 (Μ+1)^+'

Step-c: Synthesis of 4-cyclopropyl-2-methylbenzoic acid

To a stirred solution of methyl 4-cyclopropyl-2-methylbenzoate (1.3 g, 6.84 mmol) in THF (9 mL), MeOH (6 mL) and water (3 ml) was added lithium hydroxide monohydrate (0.842 g, 20.52 mmol). The reaction mixture was stirred at 70°C for 2 h, excess solvent was removed under reduced pressure. The aqueous layer was acidified with 10 % HC1 solution and then extracted with EtOAc. The organic extracts were dried and concentrated to afford the title compound (1.2 g, 99 %). *H NMR (400 MHz, DMSO-d₆): δ 7.52 (d, J=7.6 Hz, 1H), 6.75-6.74 (m, 2H), 1.84-1.81 (m, 1H), 0.92-0.87 (m, 2H), 0.64-0.60 (m, 2H).

Step-d: Synthesis of N-(3-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-4-cyclopropyl -2-methylbenzamide 4-cyclopropyl-2-methylbenzoic acid (0.550 g, 3.13 mmol) and thionyl chloride (10 ml) were refluxed for 2h, thionyl chloride was concentrated under reduced pressure. The residue obtained was dissolved in DCM (15 ml) and stirred at 0°C. A solution of 3-bromo-2-(((tert- butyldimethylsilyl)oxy)methyl)aniline (1.18 g, 3.75 mmol) and DIPEA (1.7 ml, 9.37 mmol) were added. The reaction mixture was stirred at 1-1.5 h at same temperature, diluted the reaction mixture with DCM and washed with water. The organic extracts were washed with water and brine dried and concentrated. The obtained crude was purified by column chromatography using 2% of EtOAc in hexane as an eluent to afford the desired compound (1.0 g, 67 %). LC/MS: 476 (M+2) ^+·

Step-e: Synthesis of N-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)-4-cyclopropyl-2-methylbenzamide (Intermediate-7)

The process of this step was adopted similar to step-g of intermediate- 1. The desired compound obtained as off white solid (1.2 g, 89 %). 1H NMR (400 MHz, DMSO-d₆) δ 9.56 (s, 1H), 8.06 (d, 1H), 7.46-7.29 (m, 3H), 7.00-6.96 (m, 2H), 5.06 (s, 2H), 2.39 (s, 3H), 1.96-1.93 (m, 1H), 1.25-1.13 (m, 12H), 0.99-0.95 (m, 2H), 0.88-0.81 (m, 2H), 0.76-0.71 (s, 9H), 0.032-0.02 (s, 6H).

The intermediates prepared by following the same or analogous process outlined for obtaining Intermediate-7 are included in below table along with their physicochemical characteristics

Intermediate-11: Synthesis of 4-(tert-butyl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-L3,2- dioxaborolan-2- l)phenyl)benzamide

1 1.1 11.2 Intermediate-11

Conditions : a) Bis(pinacolato)diboron, CH₃COOK, Pd(dppf)Cl₂.DCM, 120°C, 2h;

b) 4-tert butylbenzoic acid, EDCI.HC1, HOBT, DIPEA, DMF, 0°C- T, 12h.

(Reference for step a: WO2008/33858 A2)

Step-b: Synthesis of 4-(tert-butyl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2- yPphenyPbenzamide (Intermediate- 11)

To a cold solution of 4-tert butyl benzoic acid (26 g, 111.23 mmol) in DMF (100 ml) were added EDCI.HC1 (25.1 g, 131.45 mmol), HOBT (17.74 g, 131.45 mmol) and DIPEA (37 ml, 202.24 mmol). The reaction mixture was stirred at same temperature for 10 min followed by the addition of 2-methyl-3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)aniline (18 g, 101.12 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 12 h. The reaction mixture was poured into ice (200 ml), the solid obtained was collected by filtration, washed with cold water and dried under vacuum to afford the title compound as off white solid (33 g, 83 %); ^!H NMR (400 MHz, DMSO-d₆) δ 9.81 (s,lH), 7.92 (d, J=8.4 Hz, 2H), 7.55-7.53 (m, 3H), 7.40 (d, J=6.8 Hz, 1H), 7.23-7.21 (m, 1H), 2.37 (s, 3H), 1.31 (s, 9H); LC/MS : 394 (M+l)⁺.

Intermediate-12: Synthesis of N-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(4,4,5,5- tetramethyl-1 ,2-dioxaborolan-2-yl)phenyl)-4-(2-cyanopropan-2-yl)benzamide

Conditions: a) CH₃I, NaH, DMF, RT, 2h b) DIPEA, Pd(dppf)Cl₂.DCM, Ethanol, 80°C, 12h

c) LiOH.H₂0,THF, MeOH, H₂0, RT,12h d) 1) Oxalyl chloride, DCM, RT, 2h 11) TEA, DCM, 0°C to RT 2h e) Bis(pmacolato)diboron, Pd(dppf)Cl₂. DCM, KOAc, 1 ,4-dioxane, 110°C, 12h

Reference for step-a: US2009/0012323 Al

Step-b: Synthesis of ethyl 4-(2-cyanopropan-2-yl)benzoate

A 100 ml autoclave was charged with 2-(4-bromophenyl)-2-methylpropanenitrile (2.0 g, 8.9 mmol), [l, l,-bis(diphenylphosphino)ferrocine]dichloropalladium (II) complex with DCM (0.735 g, 0.9 mmol), DIPEA (3.2 ml, 17.8 mmol) and EtOH (20 ml). The reaction mixture was pressurized with 60 psi of carbon monoxide, and stirred at about 80°C for about 12 h. The mixture was cooled to RT and concentrated. The obtained crude was purified by column chromatography using 10 % of EtOAc in hexane as an eluent to afford the title compound (1.8 g, 94 %). LC/MS: 218 (M+l)⁺.

Step-c: Synthesis of 4-(2-cyanopropan-2-yl)benzoic acid

To a stirred solution of ethyl 4-(2-cyanopropan-2-yl)benzoate(1.8 g, 8.3 mmol) in EtOH (3 ml), THF (9 ml) and water (3 ml) was added lithium hydroxide monohydrate (0.525 g, 12.5 mmol) at 0°C. The reaction mixture was slowly warmed to room temperature and stirred for 12 h. Excess solvent was concentrated under reduced pressure. The reaction mixture was poured into ice water and acidified with 2N HCl solution. The precipitated solid was collected by filtration washed with water and dried under vaccum to afford the desired compound (1.4 g, 93 %). ^!H NMR (400 MHz, DMSO-d₆) δ 13.05 (s, 1H), 7.94 (d, J=6.4 Hz, 2H), 7.67 (d, J=8.4 Hz, 2H), 1.71 (s, 6H).

Step-d: N-(3-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-4-(2-cyanopropan-2-yl) benzamide

The process of this step was adopted from step-d of intermediate-7 to obtain the title compound (1.2 g, 33 %). 1H NMR (400 MHz, DMSO-d₆) δ 9.7 (s, 1H), 8.33 (d, J=7.6 Hz, 1H), 7.96 (d, J=8.4 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H), 7.3-7.2 (m, 2H), 5.11 (s, 2H), 1.76 (s, 6H), 0.88 (s, 9H), 0.15 (s, 6H); LC/MS: 488.2 (M+l)⁺.

Step-e: Synthesis of N-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(4,4,5,5-tetramethyl-L3,2- dioxaborolan-2-yl)phenyl)-4-(2-cyanopropan-2-yl)benzamide (Intermediate- 12)

The process of this step was adopted from step-g of intermediate- 1 to obtain the title compound (1.2 g, 92 %). *H NMR (400 MHz, DMSO-d₆) δ 9.7 (s, 1H), 8.33 (d, J=7.6 Hz, 1H), 7.96 (d, J=8.4 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H), 7.3-7.2 (m, 2H), 5.11 (s, 2H), 1.76 (s, 6H), 1.16 (s, 12H), 0.88 (s, 9H), 0.15 (s, 6H).

Intermediate-13: N-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(4,4,5,5-tetramethyl-L3,2-dioxa borolan-2-yl)phenyl)-4-(l-(trifluoromethyl)cyclopropyl)benzamide

Conditions: a) MeMgBr, THF, 10°C to RT, 3h b) Pyridine, thionyl chloride, DMAP, DCM, 80°C, 3h

c) NMU, 20% KOH, ether, 0°C to RT, 16h d) Xylene, 140°C, 16h e) CO (g) 80psi, DIPEA, Pd(dppf)Cl₂.DCM, Ethanol, 80°C, 24h f) 20% NaOH, MeOH, THF, RT, 4h g) t) thionyl chloride, 80°C, 2h h) DIPEA, DMAP, DCM, 0°C to RT, 16h h) Bis(pinacolato)diboron, Pd(dppf)Cl₂. DCM, OAc, 1,4-dioxane, 80°C, 2h

Step-a: Synthesis of 2-(4-bromophenyl)- 1, 1, 1 -trifluoropropan-2-ol

To a solution of l-(4-bromophenyl)-2,2,2-trifluoroethanone (0.5 g, 1.98 mmol) in THF (5 ml) was added methyl magnesium bromide drop wise (1 ml, 2.97 mmol, 3 M in ether) at 10°C. After completion of addition, the reaction mixture was warmed to room temperature and stirred for about 3 h. The reaction mixture was quenched with saturated ammonium chloride solution and the product extracted with EtOAc. The organic layer was washed with water and brine, dried and evaporated to afford the desired compound (0.5 g, 94 %). *H NMR (400 MHz, DMSO-d₆) δ 7.61-7.59 (m, 2H), 7.54-7.52 (m, 2H), 6.70 (s, 1H), 1.67 (s, 3H).

Step-b: Synthesis of l-bromo-4-(3,3,3-trifluoroprop-l-en-2-yl)benzene To a cooled solution of 2-(4-bromophenyl)-l, l, l-trifluoropropan-2-ol (0.2 g, 0.743 mmol) in THF (2 ml) to was added pyridine (0.176 g, 2.23 mmol) and S0C1₂ (0.26 g, 2.23 mmol) followed by DMAP (10 mg). The reaction mixture was heated to 80°C for 3h, cooled to RT and diluted with ethyl acetate and washed with brine. The organic extracts were dried and concentrated. The obtained crude was purified by column chromatography eluting with 2 % EtOAc in hexane to afford the title compound (0.050 g, 27 %). ^!H NMR (400 MHz, CDC1₃) δ 7.53-7.51 (m, 2H), 7.36-7.31 (m, 2H), 5.98 (d, J=1.5 Hz, 1H), 5.77 (d, J=1.5 Hz, 1H).

Step-c: Synthesis of 3-(4-bromophenyl)-3-(trifluoromethyl)-4,5-dihydro-3H-pyrazole

To a stirred biphasic mixture of 20 % KOH (200 ml) and ether (450 ml) was added N- Nitroso-N-methylurea (10 g) portionwise at 0°C. The biphasic mixture was stirred at the same temperature for 15 min. The organic layer that contains diazo methane was separated and added to a solution of l-bromo-4-(3,3,3-trifluoroprop-l-en-2-yl)benzene (1 g, 4.0 mmol) in ether (50 ml) at 0°C. The reaction mixture was slowly warmed to room temperature and stirred for a period of 16 h. The reaction mixture was concentrated and subjected to column chromatography using 5-10 % of EtOAc in hexane to afford the desired compound (0.61 g, 52 %). *H NMR (400 MHz, DMSO-dg) δ 7.69 (d, J=8.8 Hz, 2H), 7.59 (d, J=8.3 Hz, 2H), 4.89-4.71 (m, 2H), 2.51-2.26 (m, 1H), 2.19-2.12 (m, 1H).

Step-d: Synthesis of l-bromo-4-(l-(trifluoromethyl)cyclopropyl)benzene

A mixture of 3-(4-bromophenyl)-3-(trifluoromethyl)-4,5-dihydro-3H-pyrazole (0.6 g, 2.0 mmol) and xylene (10 ml) was heated at 140°C for a period of 16 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography using 1-5 % of EtOAc in hexane to afford the desired compound (0.3 g, 55 %). *H NMR (400 MHz, DMSO-d₆) δ 7.59 (d, J=8.8 Hz , 2H), 7.42 (d, J=8.3 Hz, 2H), 1.35-1.33 (m, 2H), 1.12 (m, 2H).

Step-e: Synthesis of ethyl 4-(l-(trifluoromethyl)cyclopropyl)benzoate

The process of this step was adopted from step-b of intermediate- 12 to obtain the title compound (1.8 g, 90 %). 1H NMR (400 MHz, DMSO-d₆) δ 7.97 (dd, J₁₌2.0 Hz, J₂=6.9 Hz, 2H), 7.61 (d, J=8.4 Hz, 2H), 4.35-4.29 (q, 2H), 1.41-1.38 (m, 2H), 1.32 (t, J=6.8 Hz, 3H), 1.18 (m, 2H).

Step-f: Synthesis of 4-(l-(trifluoromethyl)cyclopropyl)benzoic acid To a stirred solution of ethyl 4-(l-(trifluoromethyl)cyclopropyl)benzoate (1.75 g, 7.0 mmol) in MeOH (1 ml) and THF (10 ml) was added 20 % NaOH solution (2 ml). The reaction mixture was stirred at RT for a period of 4 h. The reaction mixture was poured into ice cold water and acidified with 10 % HC1 solution. The precipitated solid was collected by filtration, washed with water and dried under vaccum to afford the desired compound (1.31 g, 83 %). ¹H NMR (400 MHz, DMSO-d₆) δ 13.05 (bs, IH), 7.96-7.94 (m, 2H), 7.59-7.57 (d, J=8.3 Hz, 2H), 1.40-1.37 (m, 2H), 1.17 (m, 2H); LC/MS: 229.2 (M-l)^~.

Step-g: Synthesis of N-(3-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-4-( 1 - (trifluoromethyDcyclopropyPbenzamide

The process of this step was adopted from step-d of intermediate-7 to obtain the title compound (0.5 g, 27 %). *H NMR (400 MHz, DMSO-d₆) δ 10.05 (s, IH), 7.93-7.91 (d, J=8.3 Hz, 2H), 7.80-7.78 (d, J=7.8 Hz, IH), 7.63-7.61 (d, J=8.3 Hz, 2H), 7.50-7.48 (m, IH), 7.32-7.28 (m, IH), 4.95 (s, 2H), 1.41-1.38 (m, 2H), 1.19 (m, 2H), 0.77 (s, 9H), 0.01 (s, 6H); LC/MS: 526.2 (M-l)-.

Step-h: Synthesis of N-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(4,4,5,5-tetramethyl-L3,2- dioxaborolan-2-yl)phenyl)-4-( 1 -(trifluoromethyl)cyclopropyl)benzamide (Intermediate- 13)

The process of this step was adopted from step-g of Intermediate- 1 to obtain the title compound (0.8 g crude) and was proceeded for the next step without further purification.

Intermediate-14: Synthesis of N-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(4,4,5,5-tetra meth l- 1 ,3,2-dioxaborolan-2-yl)phenyl)-4-( 1 , 1 J-trifluoropropan-2-yl)benzamide

Conditions: a) CO (g) 80psi, DIPEA, Pd(dppf)Cl₂.DCM, Ethanol, 80°C, 16h b) 10% Pd/C, EtOH, H₂, RT, 16h c) LiOH. H₂0, THF, EtOH, H₂0, RT, 16h d) ι) thionyl chloride, 80°C, 2h h) DIPEA, DMAP, DCM, 0°C to RT 16h e) Bis(pinacolato)diboron, Pd(dppf )C1₂. DCM, KOAc, 1,4-dioxane, 100°C, lh

Step-a: Synthesis of ethyl 4-(3,3 -trifluoroprop-l-en-2-yl)benzoate The process of this step was adopted from step-b of intermediate- 12 to obtain the desired compound (2.8 g, 58 %). ^!H NMR (400 MHz, DMSO-d₆) δ 8.03 (d, J=8.8 Hz, 2H), 7.66 (d, J=8.3 Hz, 2H), 6.28-6.22 (m, 2H), 4.37-4.31 (q, 2H), 1.33 (t, J=7.4 Hz, 3H).

Step-b: Synthesis of ethyl 4-(l,l J -trifluoropropan-2-yl)benzoate

To a stirred solution of ethyl 4-(3,3,3-trifluoroprop-l-en-2-yl)benzoate (2.8 g, 11.5 mmol) in ethanol (30 ml) was added 10% Pd/C (0.3 g). The reaction mixture was stirred under H₂ at RT for a period of 16 h. The reaction mixture was filtered through a Celite pad and washed with EtOAc. The filtrate was concentrated under reduced pressure to afford the title compound (2.6 g, 92 %). *H NMR (400 MHz, DMSO-d₆) δ 7.97 (d, J=8.3 Hz, 2H), 7.56 (d, J=8.3 Hz, 2H), 4.35-4.29 (q, 2H), 3.96-3.92 (m, 1H), 1.46 (d, J=6.8 Hz, 3H), 1.32 (t, J=6.8 Hz, 3H); LC/MS: 247.1 (M+l)⁺.

Step-c: Synthesis of 4-( 1, 1,1 -trifluoropropan-2-yi) benzoic acid

To a stirred solution of ethyl 4-( 1 , 1 , 1 -trifluoropropan-2-yl)benzoate (2.6 g, 11.0 mmol) in EtOH (5 ml), THF (5 ml) and water (2 ml) was added lithium hydroxide monohydrate (0.92 g, 22.0 mmol). The reaction mixture was stirred at RT for a period of 16 h. The reaction mixture was poured into ice cold water and acidified with 10 % HC1 solution. The precipitated solid was collected by filtration, washed with water and dried under vacuum to afford the desired compound (2.1 g, 91 %). *H NMR (400 MHz, DMSO-d₆) δ 12.80 (bs, 1H), 7.95 (d, J=7.8 Hz, 2H), 7.53 (d, J=8.3 Hz, 2H), 3.95-3.90 (m, 1H), 1.47-1.45 (d, J=7.3 Hz, 3H); LC/MS: 217.1 (M- 1)^".

Step-d: Synthesis of N-(3-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-4-( 1,1,1- trifluoropropan-2-yl)benzamide

The process of this step was adopted from step-d of intermediate-7 to obtain the title compound (1.1 g, 30 %). *H NMR (400 MHz, DMSO-d₆) δ 10.03 (s, 1H), 7.93 (d, J=7.8 Hz, 2H), 7.80 (d, J=7.8 Hz, 1H), 7.57 (d, J=7.8 Hz, 2H), 7.49 (d, J=7.8 Hz, 1H), 7.32-7.28 (m, 1H), 4.96 (s, 2H), 3.97-3.82 (m, 1H), 1.48 (d, J=7.3 Hz, 3H), 0.78 (s, 9H), 0.02 (s, 6H); LC/MS: 518.1 (M+2)⁺.

Step-e: Synthesis of N-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)-4-( 1, 1, 1 -trifluoropropan-2-yl)benzamide (Intermediate- 14) The process of this step was adopted from step-g of intermediate- 1 to obtain the title compound (1.41 g, crude) and was proceeded for the next step without purification.

Intermediate-15: Synthesis of N-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(4,4,5,5-tetra methyl- 1,3, 2-dioxaborolan-2-yl)phenyl)-4-(l-methylcyclopropyl)benzamide

1.6 15.5 Intermediate-15

Conditions: a) isopropenyl boronate ester, 2M Na₂C0₃,Pd(dppf)Cl₂.DCM complex, l,4-Dioxane,110°C, 6hb) Diethyl Zinc, diiodomethane, TFA, DCM,0°C-RT,16h c) LiOH.H₂0, MeOH, THF,H₂0, RT, 12h d) i) thionyl chloride, DCM, 0°C, 2h ii) compound 1.6, TEA, DCM, 0°C to RT, 12h e) Bis(pinacolato)diboron, Pd(dppf)Cl₂.DCM , KOAc, 1,4-dioxane, 100°C, lh

Step-a: Synthesis of methyl 4-(prop-l-en-2-yl) benzoate

A sealed tube was charged with methyl 4-bromobenzoate (1 g, 4.65 mmol) in 1,4- dioxane (10 ml). Then isopropenyl boronic acid pinacol ester (1 g, 5.58 mmol), 2M sodium carbonate (2 ml) and Pd(dppf)Cl₂.DCM (0.41 g, 0.465 mmol) were added before purging with nitrogen for 10 min. The reaction mixture was heated to 110°C for about 6 h. The reaction mixture was diluted with water and the product was extracted with EtOAc. The organic layer was dried and concentrated. The obtained crude was purified using column chromatography eluted in 100 % n-hexane to afford the title compound (0.5 g, 61.12 %). *H NMR (400 MHz, DMSO-dg) δ 8.0 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.8 Hz, 2H), 5.47 (s, 1H), 5.19 (s, 1H), 3.19 (s, 3H), 2.17 (s, 3H).

Step-b: Synthesis of methyl 4-(l-methylcyclopropyl)benzoate

To a stirred solution of diethyl zinc (4.68 ml, 4.68 mmol, 1M in heptane) at 0°C was added a solution of TFA (1.11 g, 9.79 mmol) in DCM (10 ml) drop wise. The reaction mixture was stirred at 0°C for 20 min and then a solution of CH₂I₂ (2.68 g, 10.8 mmol) in DCM (10 ml) was added. After stirring for an additional 20 min a solution of methyl 4-(prop-l-en-2-yl) benzoate (0.15 g, 0.85 mmol) in DCM (10 ml) was added. The reaction mixture was slowly warmed to room temperature and stirred for 16 h. Reaction mixture was diluted with ice water and the product was extracted with ethyl acetate. The organic extracts were washed with brine and dried. The crude material obtained was purified using column chromatography eluted in hexane to afford the title compound (0.15 g, 93 %). ^!H NMR (400 MHz, DMSO-dg) δ 7.87 (d, J=8.8 Hz, 2H), 7.21 (d, J=8.8 Hz, 2H), 3.82 (s, 3H), 1.36 (s, 3H), 0.85 (m, 2H), 0.75 (m, 2H). Step-c: Synthesis of 4-(l-methylcyclopropyl) benzoic acid

To a stirred solution of methyl 4-(l-methylcyclopropyl) benzoate (0.15 g, 0.78 mmol) in MeOH (10 ml), THF (2 ml) and water (1 ml) was added lithium hydroxide monohydrate (0.1 g, 2.36 mmol). The reaction mixture was stirred at RT for a period of 12 h. The excess solvent was concentrated under reduced pressure; the residue was dissolved in water and acidified with IN HC1. The precipitated solid was collected by filtration to afford the title compound (0.080 g, 57.97 %). *H NMR (400 MHz, DMSO-d₆) δ 12.76 (s, 1H), 7.85 (d, J=8.3 Hz, 2H), 7.31 (d, J=8.3 Hz, 2H), 1.40 (s, 3H), 0.93-0.82 (m, 4H).

Step-d: Synthesis of N-(3-bromo-2-(((tert-butyldimethylsilyl) oxy) methyl) phenyl)-4-(l- methylcyclopropyPbenzamide

To a stirred solution of 4-(l-methylcyclopropyl) benzoic acid (0.156 g, 0.88 mmol) in

DCM (10 ml) was added thionyl chloride (0.7 ml) at 0°C. The reaction mixture was allowed to stir at 0°C for 2 h. Solvent was concentrated under reduced pressure, the residue obtained was re- dissolved in DCM (10 ml) and cooled to 0°C. Then TEA (0.5 ml. 3.79 mmol) and 3-bromo-2- (((tert-butyldimethylsilyl)oxy)methyl)aniline (0.2 g, 0.632 mmol) were added. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with ice water and the product was extracted with DCM. The organic layer dried and concentrated. The crude material obtained was purified using column chromatography eluted in 2% EtOAc-hexane to afford the title compound (0.2 g, 66 %). 1H NMR (400 MHz, DMSO-d₆) δ 9.91 (s, 1H), 8.34 (d, J=7.6 Hz, 1H), 7.86 (d, J=8.4 Hz, 2H), 7.32-7.26 (m, 3H), 7.22 (t, Ji=8.4 Hz, J₂=7.6 Hz, 1H), 5.10 (s, 2H), 1.59 (s, 3H), 0.94-0.81 (m, 13H), 0.15 (s, 6H).

Step-e: Synthesis of N-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)-4-( 1 -methylcyclopropyPbenzamide (Intermediate- 15)

The process of this step was adopted from step-g of intermediate- 1 to obtain the desired product (0.2 g, 91 %). *H NMR (400 MHz, CDC1₃) δ 9.66 (s, 1H), 8.37 (d, J=7.6 Hz, 1H), 7.86 (d, J=8.8 Hz, 2H), 7.38-7.30 (m, 2H), 7.13-7.03 (m, 2H), 4.82 (s, 2H), 1.44 (s, 3H), 1.35 (s, 12H), 0.93-0.72 (m, 13H), 0.10 (s, 6H).

Intermediate-16: Synthesis of 2-(4-(tert-butyl)benzarmdo)-6-(4A5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)benzyl acetate

Conditions: a) 4-tert.Butyl benzoyl chloride, DMAP, DCM, 0°C to RT, lh.b) TBAF, THF, 0°C to RT , lh. c) TEA, acetyl chloride, DCM, 0°C to RT, 2h.

d) Bis(pinacolato)diboron, Pd(dppf)C12. DCM, KOAc, Dioxane, 100°C, 1.5h.

Step-a: Synthesis of N-(3-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-4-(tert- butyPbenzamide

The process of this step was adopted from step-f of Intermediate- 1 and the desired compound was obtained as a pale brown liquid (6.0 g, 89 %). 1H NMR (400 MHz, DMSO-d₆): 9.96 (bs, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.88-7.83 (m, 3H), 7.63 (d, J=8.8 Hz, 1H), 7.55-7.51 (m, 1H), 7.29 (t, J=8.0 Hz, 1H), 4.96 (s, 2H), 1.32 (s, 9H), 1.31 (s, 6H), 0.78 (s, 9H).

Step-b: Synthesis of N-(3-bromo-2-(hvdroxymethyl)phenyl)-4-(tert-butyl)benzamide

To a cold solution of N-(3-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-4- (tert-butyl)benzamide (0.50 g, 0.001 mmol) in dry THF (30 ml) was added TBAF (3 ml, 1.0 M in THF) drop wise. After completion of addition the reaction mixture was slowly warmed to room temperature and stirred for about lh. The reaction mixture quenched with water (10 ml) and the product was extracted with ethyl acetate (2x100 ml). The combined organic layer was washed with brine (20 ml). The organic layer was dried and evaporated to get the desired compound as an off white solid (0.3 g, 80 %). 1H NMR (400 MHz, DMSO-d₆) δ 10.45 (s, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.91 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.4 Hz, 1H), 7.33 (t, Ji=8.4 Hz, J₂=7.6 Hz, 1H), 6.01 (t, J₁₌5.2 Hz, J₂=5.6 Hz, 1H), 4.86 (d, J=4.8 Hz, 2H), 1.36 (s, 9H); LC/MS: 362.1 (M+l)⁺.

Step-c: Synthesis of 2-bromo-6-(4-(tert-butyl)benzamido)benzyl acetate

To a cold solution of N-(3-bromo-2-(hydroxymethyl)phenyl)-4-(tert-butyl)benzamide (0.25 g, 0.69 mmol) in DCM (5 ml) and TEA (0.14 g, 1.38 mmol) was added acetyl chloride (0.081 g, 1.03 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 2 h. The reaction mixture was diluted with DCM and washed with water and brine. The organic layer was dried and concentrated. The crude material obtained was purified by column chromatography to afford the target compound as an off white solid (0.25 g, 90 %). ^!H NMR (400 MHz, DMSO-d₆) δ 10.17 (s, 1H), 7.90 (d, J=8.4 Hz, 2H), 7.62 -7.48 (m, 4H), 7.39 (t, J₁₌8.0 Hz, J₂=8.0 Hz, 1H), 5.18 (s, 2H), 1.98 (s, 3H), 1.32 (s, 9H), LC/MS: 404.1 (M+l)⁺.

Step-d: Synthesis of 2-(4-(tert-butyl)benzamido)-6-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2- yPbenzyl acetate (Intermediate- 16)

The process of this step was adopted from step-g of Intermediate- 1 and the desired compound was obtained as colour less liquid (0.2 g, 72 %). *H NMR (400 MHz, DMSO-d₆) δ 10.04 (s, 1H), 7.91 (d, J=8.8 Hz, 2H), 7.60-7.54 (m, 3H), 7.48-7.41 (m, 2H), 5.23 (s, 2H), 1.92 (s, 3H), 1.32 (d, J=8.0 Hz, 12H), 1.16 (s, 9H); LC/MS: 452.3 (M+l)⁺.

Intermediate-17: Synthesis of 2-(4-isopropylbenzamido)-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzyl acetate

c) Bis(pinacolato)diboron, Pd(dppf)Cl₂. DCM, KOAc, dioxane, 100°C, lh.

Step-a: Synthesis of N-(3-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-4-isopropyl benzamide The process of this step was adopted from step-f of intermediate- 1 to obtain 17.2 (0.8 g, 9.0 %) and 17.2A (0.7 g); LC/MS for 17.2A: 350.1 (M+l)⁺.

Step-b: Synthesis of N-(3-bromo-2-(hydroxymethyl)phenyl)-4-isopropylbenzamide

The process of this step was adopted from step-c of Intermediate- 16 to obtain the desired compound (0.65 g, 89 %). 1H NMR (400 MHz, DMSO-d₆) δ 10.15 (s, 1H), 7.88 (d, J=8.3 Hz, 2H), 7.61-7.5 (m, 2H), 7.42-7.35 (m, 3H), 5.18 (s, 2H), 2.99-2.96 (m, 1H), 1.98 (s, 3H), 1.24 (d, J=6.8 Hz, 6H).

Step-c: Synthesis of 2-(4-isopropylbenzamido)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yDbenzyl acetate (Intermediate- 17)

The process of this step was adopted from step-g of intermediate- 1 to obtain the desired compound (0.5 g, 68 %).

Intermediate-18: Synthesis of 4-bromo-6-methyl-l-tosyl-lH-pyrrolor2,3-clpyridin-7(6H)-one (Method-A)

Conditions: a) Vinyl magnesium bromide, dry THF, -78°C to -20°C, 8 h. b) p-TsCl, NaH, THF, 0-5°C, RT, 6h c) CH₃COOH, 120°C, 48 h. d) Mel, DMF, Cs₂C0₃, 3h.

Step-a: Synthesis of 4-bromo-7-chloro-lH-pyrrolo^r2,3-clpyridine

Vinyl magnesium bromide (400 ml, 1.0 M in THF) was added slowly to a stirred solution of 5-bromo-2-chloro-3-nitropyridine (20 g, 84.74 mmol) in dry THF (800 ml) at -78°C. The reaction mixture was slowly warmed to -20°C and stirred at same temperature for a period of 8 h. Reaction mixture was quenched with 20 % of NH₄CI (600 ml) and the product was extracted with ethyl acetate (2 x 500 ml). The combined organic layers were washed with water (200 ml) and brine (200 ml), dried and concentrated. The obtained crude was triturated with diethyl ether (2 x 100 ml) to afford the title compound as a brown solid (8 g, 40 %). 1H NMR (400 MHz, DMSO-dg) δ 12.48 (bs, 1H), 8.07 (s, 1H), 7.82 (t, J=3.2 Hz, 1H), 6.61 (s, 1H); LC/MS: 232 (M+l)⁺. Step-b: Synthesis of 4-bromo-7-chloro-l-tosyl-lH-pyrrolor2,3-clpyridine

Under Nitrogen atmosphere 60 % NaH (0.46 g, 19.1 mmol) was suspended in dry THF (5 ml). To this a solution of 4-bromo-7-chloro-lH-pyrrolo[2,3-c]pyridine (1.1 g, 4.78 mmol) in dry THF (5 ml) was added drop wise at 0-5 °C. The reaction mixture was left to stir for further 15 min after completion of addition, p-Toluenesulphonylchloride (1 g, 5.26 mmol) in dry THF (10 ml) was added to the reaction mixture. The resulting reaction mixture was slowly warmed to room temperature and stirred for about 6 h. The reaction mixture was diluted with ice water (100 ml). The organic layer was extracted with EtOAc. The organic layer was washed with water (100 ml), brine (50 ml), dried and concentrated. The obtained crude was purified by chromatography using 2 % MeOH in DCM as the eluent to afford tile compound as pale yellow solid (1.0 g, 55 %). 1H NMR (400 MHz, DMSO-d₆) δ 8.38 (s, 1H), 7.85 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 3H), 7.08 (d, J=4.0 Hz, 1H), 2.26 (s, 3H); LC/MS : 387(M+2)⁺.

Step-c: Synthesis of 4-bromo-l-tosyl-lH-pyrrolor2.3-clpyridin-7(6H)-one

To a solution of 4-bromo-7-chloro-l-tosyl-lH-pyrrolo[2,3-c]pyridine (14 g, 36.30 mmol), acetic acid (120 ml) was heated to reflux for about 48 h and excess acetic acid was removed under reduced pressure. The crude material was triturated with pentane (2 x 200 ml) and diethyl ether (2 x 150 ml). The precipitated solid was filtered and dried under vacuum to afford the title compound as pale brown solid (8.0 g, 61 %). ^!H NMR (400 MHz, DMSO-d₆) δ 11.51 (bs, 1H), 8.04 (s, 1H), 7.94 (d, J=8.0 Hz, 2H), 7.41 (d, J=7.6 Hz, 2H), 7.30 (s, 1H), 6.60 (s, 1H), 2.37 (s, 3H); LC/MS: 368 (M+2)⁺.

Step-d: Synthesis of 4-bromo-6-methyl-l-tosyl-lH-pyrrolo[2,3-clpyridin-7(6H)-one

(Intermediate- 18)

To a solution of 4-bromo-l-tosyl-lH-pyrrolo[2,3-c]pyridin-7(6H)-one (0.1 g, 0.27 mmol) in DMF (5 ml) was added Cs₂C0₃ (0.177 g, 0.54 mmol) and methyl iodide (0.03 ml, 0.546 mmol). The reaction mixture was stirred at room temperature for 3 h and diluted with ice cold water. The product was extracted with EtOAc (2 x 10 mL). The combined organic layer was successively washed with water, brine and dried. The crude residue was purified by column chromatography eluting with 2 % MeOH in DCM to afford tile compound (90 mg, 87 %). LC/MS: 381(M+1)⁺. Intermediate-18 was also synthesized by following an alternative scheme (Method-B) and the experimental protocol is mentioned below.

Intermediate-18: Synthesis of 4-bromo-6-methyl-l-tosyl-lH-pyrrolor2,3-clpyridin-7(6H)-one (Method-B)

Conditions: a) NaOAc, Br₂, AcOH, 15-20°C, RT, 2h b) NaN0₂, H₂S0₄, H₂0, 0°C to RT, 2h,

100°C, 4h. c) K₂C0₃, CH₃I, DMF, RT, 2h. d) DMF-DMA, DMF, 90°C, 2h. e) Fe, AcOH, 110°C, 2h. f) p-TsCl, NaH, THF. 0-5°C RT, 4h

Step-a: Synthesis of 5-bromo-4-methyl-3-nitropyridin-2-amine

To a solution of 4-methyl-3-nitropyridin-2-amine (25 g, 163 mmol) in AcOH (250 ml) was added NaOAc (26.7 g, 326 mmol) and cooled to 15-20°C. Bromine (78.24 g, 489 mmol) in AcOH (200 ml) was added over 30 min and stirred at room temperature for a period of 2 h. The reaction mixture was poured into ice water, the solid formed was filtered and dried to afford title compound as a yellow solid (32 g, 84 %); 1H NMR (400 MHz, DMSO-d₆) δ 8.28 (s, 1H), 7.05 (s, 2H), 2.31 (s, 3H).

Step-b: Synthesis of 5-bromo-4-methyl-3-nitropyridin-2-ol

To a solution of 5-bromo-4-methyl-3-nitropyridin-2-amine (28 g, 121 mmol) in water (900 ml) was added H₂S0₄ (28 ml) followed by NaN0₂ (20.91 g, 303 mmol) in water (100 ml) drop wise at 0°C. The reaction mixture was slowly warmed to room temperature for 2h, the reaction mixture was heated at 100°C for 4h. The solid formed in reaction mixture was filtered and dried to afford title compound as a pale yellow solid (24.0 g, 85 %); 1H NMR (400 MHz, DMSO-de) δ 12.97 (s, 1H), 8.01 (s, 1H), 2.21 (s, 3H); LC/MS: 233 (M+l)⁺.

Step-c: Synthesis of 5-bromo-L4-dimethyl-3-nitropyridin-2(lH)-one To a solution of 5-bromo-4-methyl-3-nitropyridin-2-ol (24 g, 103 rnmol) in DMF (200 ml) was added K₂CO₃ (21.39 g, 155 mmol) and CH₃I (21.86 g, 155 mmol). The reaction mixture was stirred at room temperature for 2h. The reaction mixture was poured into ice cold water, the solid formed was filtered and dried under vacuum to afford title compound as off white solid (23.5 g, 92 %). ^!H NMR (400 MHz, DMSO-d₆) δ 8.40 (s, 1H), 3.51 (s, 3H), 2.21 (s, 3H).

Step-d: Synthesis of (E)-5-bromo-4-(2-(dimethylamino)vinyl)- l -methyl-3-nitropyridin-2( lH)- one

To a stirred solution of 5-bromo- l ,4-dimethyl-3-nitropyridin-2( lH)-one ( 10.0 g, 40.48 mmol) in DMF (50 ml) under nitrogen atmosphere was added DMF-DMA ( 10.7 ml, 80.97 mmol). The resulting reaction mixture was heated to 90°C for a period of 2h. The reaction mixture was cooled to room temperature and diluted with ice cold water. The product was extracted with DCM and washed with water and brine, dried and concentrated under vacuum to afford the title compound ( 10 g, 83 %). *H NMR (400 MHz, DMSO-d₆) δ 8.09 (s, 1H), 7.02 (d, J=13.6 Hz, 1H), 4.09 (d, J=13.6 Hz, 1H), 3.38 (s, 3H), 2.9 (s, 6H).

Step-e: Synthesis of 4-bromo-6-methyl- lH-pyrrolo[2,3-clpyridin-7(6H)-one

To a stirred solution of (E)-5-bromo-4-(2-(dimethylamino)vinyl)- l-methyl-3- nitropyridin-2( lH)-one ( 10 g, 33.1 1 mmol) in AcOH ( 100 ml) was added iron-powder (9.2 g, 165.56 mmol). The reaction mixture was heated at 1 10°C for a period of 2 h, cooled to room temperature and filtered through celite pad, washed with EtOAc. The combined organic layers were washed with saturated NaHC0₃ solution and brine. The organic layer was dried and concentrated under vacuum. The obtained crude compound was purified by column chromatography using 10 % EtOAc in hexane to afford title compound (3.0 g, 40 %). LC/MS: 229.2 (M+2)⁺.

Step-f: Synthesis of 4-bromo-6-methyl- l-tosyl- lH-pyrrolor2,3-clpyridin-7(6H)-one

(Intermediate- 18)

Under nitrogen atmosphere NaH (60 %, 1.2 g, 53.9 mmol) was suspended in dry THF (30 ml). A solution of 4-bromo-6-methyl- lH-pyrrolo[2,3-c]pyridin-7(6H)-one (3.5 g, 15.4 mmol) in dry THF ( 10 ml) was added drop wise at 0-5°C. The reaction mixture was left to stir for further 15 min, p-Toluenesulphonylchloride (3.51 g, 18.50 mmol) in dry THF ( 10 ml) was added to the reaction mixture. The resulting reaction mixture was slowly warmed to room temperature and stirred for about 4 h. The reaction mixture was diluted with ice water (100 ml). The precipitated solid was collected by filtration, washed with water and dried under vacuum to afford the title compound as brown solid (3 g, 50 %). 1H NMR (400 MHz, DMSO-d₆) δ 8.06 (d, J=3.58 Hz, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.80 (s, 1H), 7.42 (d, J=8.4 Hz, 2H), 6.60 (s, 1H), 3.39 (s, 3H), 2.38 (s, 3H); LC/MS :383 (M+2)⁺.

Example- 1: Synthesis of 4-(tert-butyl)-N-(2-methyl-3-(6-methyl-7-oxo-6,7-dihydro-lH- rrolo[2,3-c]pyridin-4-yl)phenyl)benzamide (Compound-1)

Conditions: a) Pd(dppf)Cl₂.DCM, 2M. ₂C0₃, 1,4-dioxane, 120°C, 6h. b) 20% NaOH, EtOH, it 2h.

Step-a: Synthesis of 4-(tert-butyl)-N-(2-methyl-3-(6-methyl-7-oxo-l-tosyl-6,7-dihydro-lH- pyrrolo[2,3-clpyridin-4-yl)phenyl)benzamide

A sealed tube was charged with intermediate- 18 (0.04 g, 0.105 mmol), intermediate- 11 (0.041 g, 0.105 mmol) in 1,4-dioxane (10 ml), 2M K₂C0₃ (1 ml) and Pd(dppf)Cl₂.DCM (0.008 g, 0.010 mmol). The reaction mixture was degassed for 15 min and then heated to 100°C for about 6 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (10 ml) and filtered through a celite pad and washed with ethyl acetate (10 ml). The organic layer was washed with water and brine, dried and concentrated. The obtained residue was purified by column chromatography eluting with 2 % MeOH in DCM to get the desired compound as off white solid. (30 mg, 50 %). *H NMR (400 MHz, DMSO-d₆) δ 9.30 (s, 1H), 8.01-7.99 (m, 3H), 7.96 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.45-7.38 (m, 5H), 7.29 (t, J=7.6 Hz, 1H), 6.14 (s, 1H), 3.46 (s, 3H), 2.39 (s, 3H), 2.02 (s, 3H), 1.32 (s, 9H); LC/MS: 568 (M+l)⁺.

Step-b: Synthesis of 4-(tert-butyl)-N-(2-methyl-3-(6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo

[2,3-clpyridin-4-yl)phenyl)benzamide (Compound-1)

To a stirred solution of 4-(tert-butyl)-N-(2-methyl-3-(6-methyl-7-oxo-l-tosyl-6,7- dihydro-lH-pyrrolo[2,3-c]pyridin-4-yl)phenyl)benzamide (0.030 g, 0.0510 mmol) in EtOH (5 ml) was added 20 % aq. NaOH solution (2 ml). The reaction mixture was stirred at room temperature for a period of 3 h. The excess solvent was removed under reduced pressure and diluted with water, the solid obtained was collected by filtration, washed with water and dried under vacuum. The crude compound was purified by column chromatography using mixture of 2-3% MeOH in DCM as an eluent to get the desired compound as an off white solid (5 mg, 23 %). ^!H NMR (400 MHz, DMSO-d₆) δ 12.0 (bs, 1H), 9.90 (s, 1H), 7.93 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.0 Hz, 2H), 7.36-7.16 (m, 4H), 7.14 (s, 1H), 5.91 (s, 1H), 3.56 (s, 3H), 2.06 (s, 3H), 1.32 (s, 9H); LC/MS: 414 (M+l)⁺.

Example-2: Synthesis of 4-(tert-butyl)-N-(2-(hydroxymethyl)-3-(6-methyl-7-oxo-3a,6,7,7a- tetrah dro- lH-pyrrolo[2,3-c]pyridin-4-yl)phenyl)benzamide (Compound-2)

Conditions: a)Pd(dppf)Cl₂.DCM, 2M.Na₂C0₃, 1,4-dioxane, 120°C, 6 h. b) TDAF, dry TIIF, RT, 2 h.

c) 20% NaOH, EtOH, RT, 2 h.

Step-a: Synthesis of 4-(tert-butyl)-N-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(6-methyl-7- oxo-l-tosyl-6,7-dihydro-lH-pyrrolor2,3-clpyridin-4-yl)phenyl)benzamide

A sealed tube was charged with intermediate- 18 (0.3 g, 0.787 mmol), intermediate-2 (0.4 g, 0.787 mmol) in 1,4-dioxane (15 ml), 2M sodium carbonate (1 ml) and Pd(dppf)Cl₂.DCM (0.064 g, 0.078 mmol). The reaction mixture was degassed with nitrogen for 15 min then heated at 120°C for about 6 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (25 ml), filtered through a celite pad and washed with ethyl acetate (20 ml). The combined filtrates were evaporated under reduced pressure. The residue obtained was purified by column chromatography eluting with 2% MeOH in DCM to get the desired compound as an off white solid (0.25 g, 45 %). LC/MS: 698 (M+l)⁺.

Step-b: Synthesis of 4-(tert-butyl)-N-(2-(hvdroxymethyl)-3-(6-methyl-7-oxo-l-tosyl-6,7- dihydro-lH-pyrrolor2,3-clpyridin-4-yl)phenyl)benzamide To a cold solution of 4-(tert-butyl)-N-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(6- methyl-7-oxo-l-tosyl-6,7-dihydro-lH-pyrrolo[2,3-c]pyridin-4-yl)phenyl)benzamide (0.250 g, 0.358 mmol) in dry THF (5 ml) was added TBAF (2 ml, 1.0 M in THF) drop wise. Upon completion of addition the reaction mixture was slowly warmed to room temperature and stirred for about 2 h. The reaction mixture quenched with saturated ammonium chloride solution (15 ml) and the product was extracted with ethyl acetate (2x100 ml). The combined organic layers washed with brine (20ml). The organic layer was dried and evaporated to dryness under reduce to get the desired compound as a brown solid (0.1 g, 47 %); LC/MS: 584 (M+l)⁺.

Step-c: Synthesis of 4-(tert-butyl)-N-(2-(hydroxymethyl)-3-(6-methyl-7-oxo-3a,6,7,7a- tetrahydro-lH^yrrolo[2 -clpyridin-4-yl)phenyl)benzamide (Compound-2)

The process of this step was adopted from step-b of Example - 1. The desired compound was obtained as brown solid (0.035 g, 47 %). *H NMR (400 MHz, DMSO-d₆) δ 12.13 (bs, 1H), 10.44 (s, 1H), 8.17 (d, J=8.0 Hz, 1H), 7.87 (d, J=8.0 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H), 7.45-7.29 (m, 2H), 7.17 (s, 1H), 7.10 (d, J=8.0 Hz, 1H), 6.04 (s, 1H), 5.84 (t, J=4.4 Hz, 1H), 4.59 (bs, 2H), 3.56 (s, 3H), 1.32 (s, 9H); LC/MS: 430 (M+l)⁺.

Example-3: Synthesis of 4-(tert-butyl)-N-(2-methyl-3-(7-oxo-6-phenyl-6,7-dihydro-lH- rrolo[2,3-c]pyridin-4-yl)phenyl)benzamide (Compound-3)

Conditions: a) Copper(II)acetate, Pyridine, DCM, RT, 12h. b) Intermediate- 11 , Pd(dppf )C1₂.DCM, 2M Na₂C0₃, 1,4-dioxane, 120°C, 6 h. c) 20% NaOH, EtOH, RT, 2 h.

Step-a: Synthesis of 4-bromo-6-phenyl-l-tosyl-lH-pyrrolor2,3-clpyridin-7(6H)-one

To a stirred solution of intermediate- 18.3 (0.5 g, 1.4 mmol) in DCM (20 ml) was added phenyl boronic acid (0.342 g , 2.8 mmol), copper acetate (0.382 g, 2.1 mmol) and pyridine (2.0 ml). The reaction mixture was allowed to stir at room temperature for a period of 12 h. The reaction mixture was diluted with DCM and washed with water and brine. The organic extracts were dried and concentrated. The obtained crude was purified by column chromatography using 10 % EtOAc in hexane as an eluent to afford the desired compound (0.5 g, 80 %). 1H NMR (400 MHz, DMSO-dg) δ 8.13 (d, J=3.6 Hz, 1H), 7.92 (d, J=8.6 Hz, 2H), 7.72 (s, 1H), 7.49-7.33 (m, 7H), 6.67 (d, J=3.2 Hz, 1H), 2.36 (s, 3H); LC/MS: 443 (M+l)⁺.

Step-b: Synthesis of 4-(tert-butyl)-N-(2-methyl-3-(7-oxo-6-phenyl-l-tosyl-6,7-dihydro-lH- pyrrolor2,3-clpyridin-4-yl)phenyl)benzamide

The process of this step was adopted from step-a of Example- 1 to isolate the desired compound (0.080 g, 20 %).

Step-c: Synthesis of 4-(tert-butyl)-N-(2-methyl-3-(7-oxo-6-phenyl-6J-dihydro-lH-pyrrolor2,3- cl pyr idin-4- vDphen vDbenzamide (Co mpound- 3 )

The process of this step was adopted from step-b of Example- 1 and the desired compound was obtained as an off white solid (0.010 g, 16 %). 1H NMR (400 MHz, DMSO-d₆) δ 12.27 (s, 1H), 9.9 (s, 1H), 7.93 (d, J=8.4 Hz, 2H), 7.55-7.43 (m, 6H), 7.39-7.22 (m, 5H), 7.01 (s, 1H), 6.01 (s, 1H), 2.13 (s, 3H), 1.32 (s, 9H); LC/MS: 476.2 (M+l)⁺.

Example -4: Synthesis of 2-(4-(tert-butyl)benzamido)-6-(6-methyl-7-oxo-6,7-dihydro-lH- rrolo[2,3-c]pyridin-4-yl)benzylacetate (Compound-4)

Conditions: a) 20 % NaOH, EtOH, 60°C, 30mm b) Pd(dppf)Cl₂.DCM, 2M.K₂C0₃, 1 ,4-dioxane, 80°C, 12 h.

c) TEA, acetyl chloride, DCM, 2h, 0°C to RT.

Step-a: Synthesis of 4-bromo-6-methyl-lH-pyrrolor2,3-clpyridin-7(6H)-one

To a stirred solution of intermediate- 18 (0.4 g, 1.05 mmol) in EtOH (20 ml) was added 20 % aq. NaOH solution (10 ml). The reaction mixture was heated at 60°C for a period of 30 min, excess solvent was removed under reduced pressure and diluted with ice cold water. The precipitate was collected by filtration, washed with water and dried under vacuum to afford the title compound as crude (0.3 g). 1H NMR (400 MHz, DMSO-d₆) δ 12.4 (bs, IH), 7.52 (s, IH), 7.36 (s, IH), 6.25 (m, IH), 3.49 (s, 3H); LC/MS: 229.1 (M+2)⁺.

Step-b: Synthesis of 4-(tert-butyl)-N-(2-(hydroxymethyl)-3-(6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-clpyridin-4-yl)phenyl)benzamide

The process of this step was adopted from step-a of Example-2. The desired compound was obtained as light brown solid (0.03 g, 7.9 %). 1H NMR (400 MHz, DMSO-d₆) δ 12.1 (bs, IH), 10.43 (s, IH), 8.17 (d, J=8.3 Hz, IH), 7.87 (d, J=8.3 Hz, 2H), 7.58 (d, J=8.8 Hz, 3H), 7.39 (t, J=7.8 Hz, IH), 7.29-7.28 (m, IH), 7.16 (s, IH), 7.13-7.09 (m, IH), 6.03 (s, IH), 4.59 (bs, 2H), 3.56 (s, 3H), 1.32 (s, 9H); LC/MS: 430.2 (M+l)⁺.

Step-c: Synthesis of 2-(4-(tert-butyl)benzamido)-6-(6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- clpyridin-4-yl)benzyl acetate (Compound-4)

The process of this step was adopted from step-c of intermediate- 16. The desired compound was obtained as light brown solid (5 mg, 15.2 %). 1H NMR (400 MHz, DMSO-d₆) δ 12.12 (s, IH), 10.02 (s, IH), 7.90 (d, J=8.4 Hz, 2H), 7.56-7.48 (m, 4H),7.30-7.26 (m, 2H), 7.17 (s, IH), 5.95 (s, IH), 5.0 (bs, 2H), 3.68 (s, 3H), 1.76 (s, 3H), 1.32 (s, 9H); LC/MS: 472.3 (M+l)⁺.

Example-5: Synthesis of 4-(3-(4-(tert-butyl)benzamido)-2-(hydroxymethyl)phenyl)-6- meth l-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Compound-5)

Conditions: a) LDA, ethyl chloroformate, THF, -78°C to RT, 2hb) Intermediate-16, Pd(dppf)Cl₂.DCM, 2M.K₂C0₃, 1,4-dioxane, 80°C, 2 h. c) 10% NaOH, EtOH, 80°C, 2h.

Step-a: Synthesis of ethyl 4-bromo-6-methyl-7-oxo-l-tosyl-6J-dihydro-lH-pyrrolor2,3- clpyridine-2-carboxylate LDA was prepared by adding n-BuLi (8.6 ml, 13.0 mmol, 1.5 M in hexane) to a solution of diisopropyl amine (1.01 g, 10.0 mmol) in THF (50 ml) at -78°C. The reaction mixture was stirred at same temperature for 30 min. The solution was warmed to room temperature and cooled to -78°C. A solution of intermediate- 18 (2 g, 5.0 mmol) in THF (50 ml) was added to the LDA solution and the mixture was stirred for 30 min at -78°C. Ethylchloro formate was added drop wise (1.62 ml, 15.0 mmol). Upon completion of addition, the reaction mixture was stirred at same temperature for 30 min. The reaction mixture was quenched with saturated aqueous ammonium chloride solution, extracted the reaction mixture with ethyl acetate. The organic layer was washed with water and brine, dried and evaporated. The crude material was purified using column chromatography eluted with 30-40 % EtOAc in hexane to afford the title compound as crude (0.22 g). LC/MS: 453.1 (M+l)⁺.

Step-b: Synthesis of ethyl 4-(2-(acetoxymethyl)-3-(4-(tert-butyl)benzamido)phenyl)-6-methyl-7- oxo-l-tosyl-6.7-dihydro-lH-pyrrolor2.3-clpyridine-2-carboxylate

The process of this step was adopted from step-a of Example-2 to obtain the desired compound as crude (0.35g). LC/MS: 698.2 (M+l)⁺.

Step-c: Synthesis of 4-(3-(4-(tert-butyl)benzamido)-2-(hydroxymethyl)phenyl)-6-methyl-7-oxo- 6.7-dihydro- lH-pyrrolor2.3-clpyridine-2-carboxylic acid (Compound-5)

To a stirred solution of compound-5b (0.350 g, 0.5 mmol) in EtOH (2 ml) was added 10 % aqueous NaOH solution (2 ml), THF (2 ml) and water (1 ml). The reaction mixture was heated at 80°C for a period of 2 h, excess solvent was removed under reduced pressure and diluted with ice cold water. The reaction mass was acidified with 10 % HC1 and extracted with ethyl acetate. The organic extracts were washed with water and brine, dried and concentrated. The obtained crude was purified by preparative HPLC to afford the title compound (5 mg, 5 %) as an off white solid. 1H NMR (400 MHz, DMSO-d₆) δ 12.73 (bs, 2H), 10.39 (s, 1H), 8.17 (d, J=8.0 Hz, 1H), 7.88 (d, J= 8.4 Hz, 2H), 7.59-7.39 (m, 4H), 7.24-7.10 (m, 2H), 5.80 (s, 1H), 4.57 (bs, 2H), 3.56 (s, 3H), 1.32 (s, 9H); LC/MS: 474.2 (M+l)⁺.

Example-6: Synthesis of ethyl 4-(3-(4-(tert-butyl)benzamido)-2-(hydroxymethyl)phenyl)-6- methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2-carboxylate (Compound-6)

Conditions: a) DBU, diethyl oxalate, RT, 16h b) Fc, AcOH, 100°C, 4h c) Intcrmcdiatc-2, Pd(dppf )C1₂.DCM, 2M K₂C0₃, 1,4-dioxane, 80°C, 2 h d) ) TBAF, dry THF, 0°C to RT, 2 h

Step-a: Synthesis of ethyl 3-(5-bromo-l-methyl-3-nitro-2-oxo-L2-dihydropyridin-4-yl)-2- oxopropanoate

To a solution of 5-bromo-l,4-dimethyl-3-nitropyridin-2(lH)-one (10 g, 41 rnmol) in diethyl oxalate (100 mL) was added l,8-diazabicyclo[5.4.0]undec-7-ene (24.93 g, 164 mmol) and stirred at room temperature for 16 h. The reaction mixture was concentrated under vacuum to remove volatiles, quenched with 1M NaHS0₄ solution and extracted with EtOAc. The organic layer was washed with brine, dried and concentrated. The obtained crude material was purified by column chromatography was using 50-80 % EtOAc in hexane to afford title compound as brown viscous liquid (6.1 g, 43 %). LC/MS: 349 (M+2)⁺.

Step-b: Synthesis of ethyl 4-bromo-6-methyl-7-oxo-6J-dihydro-lH-pyrrolor2,3-clpyridine-2- carboxylate

To a stirred solution of ethyl 3-(5-bromo-l-methyl-3-nitro-2-oxo-l,2-dihydropyridin-4- yl)-2-oxopropanoate (6 g, 18 mmol) in AcOH (60 ml) was added iron powder (3.02 g, 54 mmol). The reaction mixture was heated at 100°C for 4h. The reaction mixture was filtered through celite pad, washed with EtOAc. The organic layer was washed with brine, dried and concentrated under vacuum. The obtained crude compound was purified by column chromatography using 50- 80 % EtOAc in hexane to afford title compound as a pale brown solid (1.5 g, 29 %). ^JH NMR (400 MHz, DMSO-dg) δ 13.24 (s, 1H), 7.63 (s, 1H), 6.82 (d, J=2.5 Hz, 1H), 4.32-4.27 (m, 2H), 3.50 (s, 3H), 1.34-1.30 (t, J=7.4 Hz, 3H).

Step-c: Synthesis of ethyl 4-(3-(4-(tert-butyl)benzamido)-2-(((tert-butyldimethylsilyl)oxy) methyl)phenyl)-6-methyl-7-oxo-6,7-dihvdro-lH-pyrrolo[2,3-clpyridine-2-carboxylate The process of this step was adopted from step-a of Example-2. The desired compound was obtained as brown solid (0.35 g, 56 %). LC/MS: 616.4 (M+l)⁺.

Step-d: Synthesis of ethyl 4-(3-(4-(tert-butyl)benzamido)-2-(hydroxymethyl)phenyl)-6-methyl- 7-oxo-6,7-dihydro-lH-pyrrolor2,3-clpyridine-2-carboxylate (Compound-6)

The process of this step was adopted from step-b of Example-2. The desired compound was obtained as off white solid (80 mg, 33 %). *H NMR (400 MHz, DMSO-d₆) δ 12.97 (s, IH), 10.38 (s, IH), 8.17 (d, J=8.3 Hz, IH), 7.87 (d, J=8.3 Hz, 2H), 7.58 (d, J=8.3 Hz, 2H), 7.43- 7.39 (m, IH), 7.25 (s, IH), 7.10 (d, J=7.3 Hz, IH), 6.61 (d, J=2.0 Hz, IH), 5.80 (t, J=4.4 Hz, IH), 4.56 (bs, 2H), 4.28-4.22 (q, 2H), 3.57 (s, 3H), 1.27 (t, J=6.8 Hz, 3H), 1.32 (s, 9H); LC/MS: 502.3 (M+l)⁺.

Example-7: N-(3-(2-(azetidine-l-carbonyl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridin-4-yl)-2-(hydrox methyl)phenyl)-4-(tert-butyl)benzamide (Compound-7)

a) EDCI.HC1, HOBt, azetidine hydrochloride, DIPEA, DMF, RT, 48h.

Step-a: synthesis of N-(3-(2-(azetidine-l-carbonyl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- clpyridin-4-yl)-2-(hydroxymethyl)phenyl)-4-(tert-butyl)benzamide (Compound-7)

The process of this step was adopted from step-b of intermediate- 11. The desired compound was obtained as off white solid (0.018 g, 3 %). 1H NMR (400 MHz, DMSO-d₆) δ 12.35 (bs, IH), 10.41 (bs, IH), 8.19 (d, J=7.4 Hz, IH), 7.87 (d, J=8.8 Hz, 2H), 7.58 (d, J=8.8 Hz, 2H), 7.42-7.38 (m, IH), 7.20 (bs, IH), 7.11-7.10 (m, IH), 6.32 (s, IH), 5.87 (bs, IH), 4.58 (m, 2H), 4.36 (m, 2H), 4.01 (m, 2H), 3.55 (s, 3H), 2.28-2.20 (m, 2H), 1.32 (s, 9H); LC/MS: 513.3 (M+H)⁺.

Example-8: Synthesis of 4-(3-(4-(tert-butyl)benzamido)-2-(hydroxymethyl)phenyl)-N,N,6- trimethyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2-carboxamide (Compound-8)

Conditions: a) 10% NaOH, MeOH, THF, T 16h.

b) Ν,Ν-dimethyl amine hydrochloride, EDCI.HC1, HOBT, DIPEA, DMF, RT 16h.

c) lntermediate-2, Pd(dppf)Cl₂.DCM, 2M ₂C0₃, 1,4-dioxane, 80"C, 2 h. d) TBAF, dry THF, RT, 2 h.

Step-a: Synthesis of 4-bromo-6-methyl-7-oxo-6 -dihydro-lH-pyrrolor2 -clpyridine-2- carboxylic acid

To a stirred solution of ethyl 4-bromo-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridine-2-carboxylate (0.25 g, 0.8 mmol) in MeOH (2 ml) and THF (2 ml) was added 10 % NaOH solution (1 ml). The reaction mixture was stirred at room temperature for a period of 16 h. Excess solvent was concentrated under reduced pressure. The reaction mixture was poured into ice water and acidified with 10 % HCl solution. The precipitated solid was collected by filtration, washed with water and dried under vacuum to afford the desired compound (0.2 g, 88 %). ¹H NMR (400 MHz, DMSO-d₆) δ 13.20 (bs, 1H), 13.01 (s, 1H), 7.61 (s, 1H), 6.79 (d, J=2.1 Hz, 1H), 3.50 (s, 3H); LC/MS: 273.0 (M+2)⁺.

Step-b: Synthesis of 4-bromo-N,N,6-trimethyl-7-oxo-6,7-dihydro-lH-pyrrolor2,3-clpyridine-2- carboxamide

The process of this step was adopted from step-b of intermediate- 11. The desired compound was obtained as off white solid (0.15 g, 68 %). 1H NMR (400 MHz, DMSO-d₆) δ 12.66 (bs, 1H), 7.59 (s, 1H), 6.49 (s, 1H), 3.50 (s, 3H), 3.10 (bs, 3H), 2.99 (bs, 3H); LC/MS: 300.0 (M+2)⁺.

Step-c: Synthesis of 4-(3-(4-(tert-butyl)benzamido)-2-(((tert-butyldimethylsilyl)oxy)methyl) phenyl)-N,N,6-trimethyl-7-oxo-6,7-dihvdro-lH-pyrrolo[2,3-clpyridine-2-carboxamide

The process of this step was adopted from step-a of Example-2 to obtain the title compound as crude (0.5 g). LC/MS: 615.3 (M+l)⁺.

Step-d: Synthesis of 4-(3-(4-(tert-butyl)benzamido)-2-(hvdroxymethyl)phenyl)-N,N,6-trimethyl- 7-oxo-6,7-dihydro-lH-pyrrolor2,3-clpyridine-2-carboxamide (Compound-8) The process of this step was adopted from step-b of Example-2. The desired compound was obtained as off white solid (0.010 g, 4 %). 1H NMR (400 MHz, DMSO-d₆) δ 12.37 (s, IH), 10.41 (s, IH), 8.19 (d, J=7.2 Hz, IH), 7.88 (d, J=8.4 Hz, 2H),7.62 (d, J=10.4 Hz, 2H), 7.42 (t, Ji=8.0 Hz, J₂=7.6 Hz, IH), 7.22 (s, IH), 7.15 (d, J=7.2 Hz, IH), 6.33(s, IH), 5.85(t, J=4.4 Hz, IH), 4.59 (bs, 2H), 3.56 (s, 3H), 3.26-3.07 (m, 6H), 1.32 (s, 9H); LC/MS: 501.3 (M+l)⁺.

Example-9: Synthesis of 4-(3-(4-cyclopropyl-2-fluorobenzamido)-2-(hydroxymethyl) phenyl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2-carboxylicacid

(Compound-9)

Conditions: a) Intermediate-8, Pd(dppf)Cl₂.DCM, 2M Na₂C0₃, 1,4-dioxane, 80°C, 3 h.

b) TBAF, THF, 0°C to RT, lh. c) LiOH. H₂0. EtOH, THF, H₂0, 50°C, 4 h.

Step-a: Synthesis of ethyl 4-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(4-cyclopropyl-2- fluorobenzamido)phenyl)-6-methyl-7-oxo-6 -dihydro-lH-pyrrolor2,3-clpyridine-2-carboxylate

The process of this step was adopted from step-a of Example-2. The desired compound was obtained as brown solid (0.18 g, 43 %). LC/MS: 618.3 (M+H)⁺.

Step-b: Synthesis of ethyl 4-(3-(4-cyclopropyl-2-fluorobenzamido)-2-(hydroxymethyl)phenyl)-6- methyl-7-oxo-6,7-dihvdro-lH-pyrrolo[2,3-clpyridine-2-carboxylate

The process of this step was adopted from step-b of Example-2. The desired compound was obtained as grey solid (0.12g, 81%). LC/MS: 504.2 (M+H)⁺.

Step-c: Synthesis of 4-(3-(4-cyclopropyl-2-fluorobenzamido)-2-(hydroxymethyl)phenyl)-6- methyl-7-oxo-6,7-dihydro- lH-pyrrolor2,3-clpyridine-2-carboxylic acid (Compound-9)

To a stirred solution of ethyl 4-(3-(4-cyclopropyl-2-fluorobenzamido)-2-(hydroxy methyl)phenyl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2-carboxylate (0.12 g, 0.2 mmol) in EtOH (2 ml), THF (2 ml) and water (1 ml) was added lithium hydroxide monohydrate (0.0096 g, 4.0 mmol). The reaction mixture was stirred at 50°C for a period of 4 h. Excess solvent was removed under reduced pressure, diluted the reaction mixture with ice cold water and acidified with 10 % HC1 solution. The precipitated solid was collected by filtration, washed with water and dried under vacuum. The crude material material was purified by preparative HPLC to afford the desired compound (0.008 g, 7 %). *H NMR (400 MHz, DMSO- d₆) δ 12.98 (s, IH), 12.70 (s, IH), 10.20 (d, J=6.8 Hz, IH), 8.15 (d, J=8.4 Hz, IH), 7.83 (t, J=8.0 Hz, 1H),7.42 (t, J₁₌8.0 Hz, J₂=7.6 Hz, IH), 7.23 (s, IH), 7.12-7.06 (m, 3H), 6.57 (s, IH), 5.60 (s, IH), 4.50 (bs, 2H), 3.31(s, 3H), 2.08 (m, IH), 1.05 (m, 2H), 0.80 (m, 2H); LC/MS: 476.2 (M+l)⁺.

The compounds prepared by following same or analogous process according to the above examples with appropriate variations in reactants, reagents, solvents and reaction conditions and their physicochemical characteristics are summarized herein below table.

LC/MS: 469 (M+l)⁺.

^!H NMR (400 MHz-DMSO-dg) δ 12.12 (bs, IH), 10.44 (s, IH), 8.16 (d, J=7.2 Hz, IH), 7.88 (d, J=8.0 Hz, 2H), 7.58 (d, J=8.0 Hz, 2H), 7.31 (t, J=2.8 Hz, IH), 7.30 (s, IH), 7.21 (s, IH), 7.14 (d, J=6.8 Hz, IH), 6.08 (s, IH), 5.85 (t, J=4.8 Hz, IH), 4.63 (bs, 2H), 3.89-3.80 (m, 2H), 1.32 (s, 9H), 1.09 (m, IH)

0.49-0.42 (m, 4H); LC/MS: 470 (M+l)⁺.

^!H NMR (400 MHz-DMSO-dg) δ 12.14 (bs, IH), 10.43 (bs, IH), 8.31 (s, IH), 8.11 (d, J=7.6 Hz, IH), 7.88 (d, J=8.4 Hz, 2H), 7.61 (d, J=10.8 Hz, 2H), 7.41 (t, J=7.6 Hz, IH), 7.39 (s, IH), 7.31-7.17 (m, 2H), 6.08 (s, IH), 5.30-5.28 (m, IH), 4.6 (s, 2H), 3.32 (s, 3H), 3.30 (s, 3H), 1.23-1.22 (m, 9H); 0 LC/MS: 458 (M+l)⁺.

^!H NMR (400 MHz-DMSO-dg) δ 12.1 (s, IH), 10.4 (s, IH), 8.16 (d, J=7.6 Hz, IH), 7.87 (d, J=8.6 Hz, 2H), 7.58 (d, J=8.8 Hz, 2H), 7.42-7.29 (m, 2H), 7.18 (s, IH), 7.13 (d, J=7.6 Hz, IH), 6.05 (s, IH), 5.83 (t, J=4.4 Hz, IH), 4.59 (bs, 2H), 4.05 (q, J=6.8 Hz, 2H), 1.32 (s, 9H), 1.28 (t, J=6.8 Hz, 3H); LC/MS: o ^H

444.3 (M+l)⁺.

^!H NMR (400 MHz-DMSO-dg) δ 12.12 (bs, IH), 10.26 (s, IH), 8.20 (d, J=8.4 Hz, IH), 7.77 (d, J=8.8 Hz, 2H), 7.36 (t, J=7.6 Hz, IH), 7.29 (s, IH), 7.16 (s, IH), 7.05 (d, J=7.2 Hz, IH), 6.79 (d, J=8.8 Hz, 2H), 6.04 (s, IH), 5.85 (t, J=4.4 Hz, IH), 4.58 (bs, H 2H), 3.56 (s, 3H), 3.0 (s, 6H); LC/MS: 417(M+1)⁺.

29 ^!H NMR (400 MHz, DMSO-dg) δ 12.12 (s, 1H),

10.47(s, 1H), 8.14 (d, J=7.6 Hz, 1H), 7.95 (d, J=8.4 Hz, 2H),7.66 (d, J=8.4 Hz, 2H) 7.42-7.28 (m, 2H), 7.17-7.11 (m, 2H), 6.34 (s, 1H), 5.80 (t, Ji=4.4 Hz, J₂=5.2 Hz, 1H), 4.59 (bs, 2H), 3.56 (s, 4H), 3.09 (s, 3H); LC/MS: 482.2 (M+l)⁺.

30 ^!H NMR (400 MHz, DMSO-dg) δ 12.11 (s, 1H),

10.47 (s, 1H), 8.14 (d, J=7.6 Hz, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.61 (d, J=8 Hz, 2H), 7.42-7.29 (m, 2H), 7.17-7.11 (m, 2H), 6.03 (s, 1H), 5.79 (s, 1H), 4.59 (bs, 2H), 3.80 (m, 1H), 3.56 (s, 3H), 1.49 (d, J=7.2 Hz, 3H); LC/MS: 470.2 (M+l)⁺.

Although the present application has been illustrated by certain of the preceding examples, it is not to be construed as being limited thereby; but rather, the present application encompasses the generic area as herein before disclosed. Various modifications and embodiments can be made without departing from the spirit and scope thereof. For example, the following compounds are also included in the scope of the present application

PHARMACOLOGICAL ACTIVITY

The activity of the compounds is determined by BTK TR-FRET kinase assay. This assay measures the phosphorylation of Ulight fluorescence acceptor labelled substrate by full length human recombinant BTK enzyme and the detection using Eu-labeled antiphosphotyrosine antibody. The binding of antibody to the phosphorylated tyrosine brings Eu closer to Ulight label. Due to the proximity, Eu excited at 340 nm, can transfer energy to Ulight label which emits at 665 nm. TR-FRET assays are usually done as ratiometric measurements. The output signal is measured as the ratio of 665 nm emission of Ulight to 615 nm emission of Eu and it is proportional to the level of Ulight peptide phosphorylation. Stock solutions of test compounds at 20 mM DMSO are prepared. Compounds are serially diluted in 384-well pplypropylene plates. Diluted compounds are incubated with 5 ng of recombinant BTK enzyme and incubated for 30 minutes at room temperature. After the incubation, 40 nM Ultra light poly GT substrate mix from Perkin Elmer and 6 μΜ ATP were added to the reaction and incubated for 30 min at room temperature. Reactions are quenched after 30 min by addition of 40 mM EDTA. After stopping the reaction, 0.5 nM of Eu-labelled antiphosphotyrosine antibody was added to the reaction. The degree of phosphorylation of Ultra Light poly GT substrate was measured using a time -resolved fluorimeter (Perkin Elmer WALLAC 1420 Multi label Counter Victor 3) as ratio of specific 665 nm energy transfer signal to reference europium 615 nm signals. The compounds IC₅₀ was determined by fitting the dose response data to sigmoidal curve fitting equation using GraphPad Prism software V5. The compounds were screened at nM concentration and the results are summarized in table below.

IC₅₀ values of the selected compounds of present invention were provided in below table, Compounds exhibiting IC₅₀ values <500 nM were grouped as 'a', compounds exhibiting IC₅₀ value in the range 500.01 nM to 1000 nM were grouped as 'b' and the compounds exhibiting IC₅₀ value >1000.01 nM were grouped as 'c'. % inhibition of the selected compounds of the present invention at 1 μΜ and 10 μΜ are detailed in the below table.

Table: BTK inhibition activity of the selected compounds.

Claims

We claim:

1. A compound of formula ( 1 )

Ri is selected from hydrogen, alkyl, -C(0)OR_a and -C(0)N(R_b)R_c;

R₂ is selected from alkyl, cyanoalkyl, cycloalkylalkyl and aryl;

R₃ and R5 are selected from hydrogen and alkyl;

R4 is selected from hydrogen, halogen, alkyl, hydroxyalkyl, alkoxy and -CH₂OC(0)alkyl;

R₆ at each occurrence is selected from hydrogen, halogen, alkyl, -N(Rb)R_c, haloalkyl, haloalkyloxy, cyanoalkyl and optionally substituted cycloalkyl; wherein the optional substituent is selected from alkyl and haloalkyl;

R_a is selected from hydrogen and alkyl;

R_b and R_c are independently selected from hydrogen and alkyl;

'p' is an integer selected from 1, 2, and 3.

2. The compound according to claim 1 , wherein R₃ and R5 are hydrogen.

3. The compound according to claim 1, wherein Ri is hydrogen or alkyl

4. The compound according to claim 3, wherein alkyl is methyl.

5. The compound according to claim 1, wherein Ri is -C(0)OR_a or -C(0)N(Rb)R_c-

6. The compound of claim 5, wherein Ri is selected from -C(0)OH , -C(0)OCH₂CH₃,

7. The compound according to claim 1, wherein R₂ is alkyl.

8. The compound of claim 7, wherein alkyl is methyl, ethyl or isopropyl.

9. The compound according to claim 1, wherein R4 is alkyl, hydroxyalkyl and alkoxy.

10. The compound of claim 9, wherein R4 is selected from methyl, hydroxymethyl and methoxy.

11. The compound according to claim 1, wherein R₆ is selected from alkyl, cyanoalkyl and haloalkyl.

12. The compound according to claim 11, wherein R₆ is selected from methyl, isopropyl,

13. The compound according to claim 1, wherein R₆ is optionally substituted cycloalkyl.

14. The compound according to claim 13, wherein cycloalkyl is cyclopropyl and the optional substituent is selected from methyl and trifluro methyl.

15. The compound accordin to claim 1 is a compound of formula (la)

wherein, Ri , R₂, R4 and R₆ are same as described in claim 1.

16. The compound according to claim 15 is a compound of formula (lb)

wherein, R_1; R₂ and R4 are same as described in claim 1.

17. A compound selected from the group consisting of

Comp.

IUPAC Names

No.

11. 4-(tert-butyl)-N-(3-(3,6-dimethyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridin-4- yl)-2-methylphenyl)benzamide;

12. 4-(tert-butyl)-N-(3-(6-(2-cyanoethyl)-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridin-4-yl)-2-(hydroxymethyl)phenyl)benzamide;

13. 4-(tert-butyl)-N-(3-(6-(cyclopropylmethyl)-7-oxo-6,7-di ydro-lH-pyrrolo[2,3- c]pyridin-4-yl)-2-(hydroxymethyl)phenyl)benzamide;

14. 4-(tert-butyl)-N-(2-(hydroxymethyl)-3-(6-isopropyl-7-oxo-6,7-di ydro-lH- pyrrolo[2,3-c]pyridin-4-yl)phenyl)benzamide;

17. 4-(tert-butyl)-N-(2-methoxy-3-(6-methyl-7-oxo-6,7-di ydro-lH-pyrrolo[2,3- c]pyridin-4-yl)phenyl)benzamide;

18. 4-(3-(4-(tert-butyl)benzamido)-2-methylphenyl)-6-methyl-7-oxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridine-2-carboxylic acid;

20. 4-cyclopropyl-2-fluoro-N-(2-(hydroxymethyl)-3-(6-methyl-7-oxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridin-4-yl)phenyl)benzamide;

21. 4-(tert-butyl)-N-(2-fluoro-3-(6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridin-4-yl)phenyl)benzamide;

22. 4-cyclopropyl-N-(2-(hydroxymethyl)-3-(6-methyl-7-oxo-6,7-di ydro-lH- pyrrolo[2,3-c]pyridin-4-yl)phenyl)-2-methylbenzamide;

23. 4-cyclopropyl-N-(2-(hydroxymethyl)-3-(6-methyl-7-oxo-6,7-di ydro-lH- pyrrolo[2,3-c]pyridin-4-yl)phenyl)benzamide;

24. N-(2-(hydroxymethyl)-3-(6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridin- 4-yl)phenyl)-4-(trifluoromethyl)benzamide; Comp.

IUPAC Names

No.

25. 4-(2-cyanopropan-2-yl)-N-(2-(hydroxymethyl)-3-(6-methyl-7-oxo-6,7-dihydro- lH-pyrrolo[2,3-c]pyridin-4-yl)phenyl)benzamide;

26. N-(2-(hydroxymethyl)-3-(6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridin- 4-yl)phenyl)-4-isopropylbenzamide;

27. N-(2-(hydroxymethyl)-3-(6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridin- 4-yl)phenyl)-4-( 1 -methylcyclopropyl)benzamide;

28. 4-cyclopropyl-2,6-difluoro-N-(2-(hydroxymethyl)-3-(6-methyl-7-oxo-6,7- dihydro-lH-pyrrolo[2,3-c]pyridin-4-yl)phenyl)benzamide;

29. N-(2-(hydroxymethyl)-3-(6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridin- 4-yl)phenyl)-4-(l -(trifluoromethyl)cyclopropyl)benzamide; and

30. N-(2-(hydroxymethyl)-3 -(6-methyl-7-oxo-6,7-dihydro- 1 H-pyrrolo [2,3 -c]pyridin- 4-yl)phenyl)-4-(l , 1 , 1 -trifluoropropan-2-yl)benzamide,

18. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula (1) according to any of claims 1 to 17, their pharmaceutically acceptable salts or pharmaceutically acceptable stereoisomers, in admixture with at least one pharmaceutically acceptable carrier or excipient including mixtures thereof in all ratios, for use as a medicament.

19. A method of treating a disease in an animal in which inhibition of protein kinase activity can prevent, inhibit or ameliorate the pathology and/or symptomology of the disease, which method comprises administering to the animal a therapeutically effective amount of at least one compound of formula (1) according to any of the claims 1 to 17, their pharmaceutically acceptable salts or pharmaceutically acceptable stereoisomer thereof.

20. A method for inhibiting BTK which comprises administering to a subject in need thereof an effective amount of a compound according to any of claims 1 to 17.

21. Use of a compound according to any of claim 1 to 17, in the manufacture of a medicament for use in the treatment of diseases associated with BTK kinase in animals including humans.