WO2014125410A1 - N-substituted heterocyclic derivatives as kinase inhibitors - Google Patents

Abstract

The present invention provides N-substituted novel heterocyclic derivatives of formula (I) as protein kinase inhibitors, in which R₁, R₂ and 'n' have the same 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

N-SUBSTITUTED HETEROCYCLIC DERIVATIVES AS KINASE INHIBITORS

This application claims the benefit of Indian provisional application number 599/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 and subsequently in their pathways. 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, et al., (2003), Journal of Biological Chemistry 278:26258-26264; N. J. Horwood, et al., (2003), The Journal of Experimental Medicine 197: 1603-1611.

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 N-substituted heterocyclic 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 N-substituted heterocyclic derivatives of formula (I) which are useful as kinase inhibitors.

In one aspect, the present invention relates to the compound of formula (I)

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

the dotted line [— ] represents a single or a double bond;

Ri is selected from alkyl, cycloalkyl, -N(R_a)Rb, optionally substituted aryl, arylalkyl and optionally substituted heterocyclyl; wherein the optional substituent at each occurrence is independently selected from one or more R$;

R₂ is selected fro

R₃ is selected from optionally substituted aryl and heterocyclyl; wherein the optional substituent is selected from -N(R₆)R7 and -C(0)N(R₆)R₇;

R4 and R5 are independently selected from hydrogen and alkyl; R₆ and R₇ taken together with the nitrogen atom to which they are attached to form an optionally substituted 4-6 membered heterocyclyl ring containing 0-2 heteroatoms independently selected from N and O; wherein the optional substituent is alkyl;

Rs is selected from alkyl, alkoxy, halogen, haloalkyl, and -S(0)₂alkyl;

R_a and R_b are independently selected from hydrogen and optionally substituted aryl; wherein the optional substituents are selected from alkyl, halogen, alkoxy and haloalkyl; and

'n' is an integer selected from 1 and 2.

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

In further another aspect of the present invention, it relates to the use of compounds of formula (I), 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 N-substituted heterocyclic derivatives of formula (I) which are useful as k

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

the dotted line [— ] represents a single or a double bond;

Ri is selected from alkyl, cycloalkyl, -N(R_a)Rt_>, optionally substituted aryl, arylalkyl and optionally substituted heterocyclyl; wherein the optional substituent at each occurrence is independently selected from one or more R$;

R₂ is selected from

R₃ is selected from optionally substituted aryl and heterocyclyl; wherein the optional substituent is selected from -N(R₆)R7 and -C(0)N(R₆)R₇;

R4 and R5 are independently selected from hydrogen and alkyl;

R₆ and R₇ taken together with the nitrogen atom to which they are attached to form an optionally substituted 4-6 membered heterocyclyl ring containing 0-2 heteroatoms independently selected from N and O; wherein the optional substituent is alkyl;

Rs is selected from alkyl, alkoxy, halogen, haloalkyl, and -S(0)2alkyl;

R_a and R_b are independently selected from hydrogen and optionally substituted aryl; wherein the optional substituents are selected from alkyl, halogen, alkoxy and haloalkyl; and

'n' is an integer selected from 1 and 2.

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

According to another embodiment, specifically provided are compounds of formula (I), in which dotted line [— ] line represents single bond or double bond.

According to yet another embodiment, specifically provided are compounds of formula (I), in which Ri is alkyl, cycloalkyl and arylalkyl; in particular alkyl is methyl and isopropyl; cycloalkyl is cyclopropyl and arylalkyl is benzyl.

According to yet another embodiment, specifically provided are compounds of formula (I), in which Ri is optionally substituted aryl; in particular aryl is phenyl.

According to preceding embodiment, specifically pro ,

in which optional substituted aryl is selected from

According to yet another embodiment, specifically provided are compounds of formula (I), in which Ri is optionally substituted heterocyclyl.

According to preceding embodiment, specifically provided are compounds of formula (I), ptional substi from

According to yet another embodiment, specifically provided are compounds of formula (I), in which Ri is -N(R_a)R_b, wherein R_a and R are selected from hydrogen and optionally substituted aryl; in particular aryl is phenyl.

According to preceding embodiment, specifically provided are compounds of formula (I),

According to yet another embodiment, specifically provided are compounds of formula (I), in which R₃ is optionally substituted aryl; in particular aryl is phenyl.

According to the preceding embodiment, specifically provided are compounds of formula

(I), in which optional substituents are selected from

According to yet another embodiment, specifically provided are compounds of formula (I), in which R₃ is heterocyclyl; in particular heterocyclyl is pyridin-3-yl or pyridin-4-yl. According to yet another embodiment, specifically provided are compounds of formula (I), in which R₄ is hydrogen and R₅ is alkyl; in particular alkyl is methyl.

According to yet another particular embodiment, the compound of formula (I) is a compound of formula (la)

wherein, the dotted line [— ], Ri and 'n' are same as described in formula (I).

According to preceding embodiment, specifically provided are compounds of formula (la), in which 'n' is 1.

According to yet another particular embodiment, the compound of formula (I) is a compound of formula (lb)

wherein, the dotted line [— ], Ri and 'n' are same as described in formula (I).

According to preceding embodiment, specifically provided are compounds of formula (lb), in which 'n' is 1 or 2.

According to yet another particular embodiment, the compound of formula (I) is a compound of formula (Ic)

wherein, the dotted line [— ], Ri and 'n' are same as described in formula (I).

According to preceding embodiment, specifically provided are compounds of formula (Ic), in which 'n' is 1.

According to preceding embodiment, specifically provided are compounds of formula

(Ic), in which Ri is methyl, isopropyl, cyclopropyl and optionally substituted phenyl; wherein optional substituent is alkyl; in particular alkyl is methyl and i-butyl.

According to yet another particular embodiment, the compound of formula (I) is a compound of formula (Id)

wherein, the dotted line [— ], Ri and 'n' are same as described in formula (I).

According to preceding embodiment, specifically provided are compounds of formula (Id), in which dotted line [— ] line represents single bond.

According to preceding embodiment, specifically provided are compounds of formula (Id), in which 'n' is 1.

According to preceding embodiment, specifically provided are compounds of formula (Id), in which Ri is alkyl; in particular alkyl is methyl.

In further yet another particular embodiment of the present invention; the compound of formula (I) is selected from the group consisting of Compd

Compound Name

No.

1. 5-(l-(2,4-dimethoxybenzoyl)-lH-indol-4-yl)-l-methyl-3-((4-(morpholine-4-carbonyl) phenyl)amino)pyrazin-2(lH)-one;

2. 5-(l-(cyclopropanecarbonyl)-lH-indol-4-yl)-l-methyl-3-((4-(morpholine-4-carbonyl) phenyl)amino)pyrazin-2(lH)-one;

3. 5-(l-benzoyl-lH-indol-4-yl)-l-methyl-3-((4-(morpholine-4-carbonyl)phenyl)amino) pyrazin-2( lH)-one;

4. 5-( l-(4-(tert-butyl) benzoyl)- lH-indol-4-yl)- l-methyl-3-((4-(morpholine-4-carbonyl) phenyl)amino)pyrazin-2(lH)-one;

5. l-methyl-3-((4-(morpholine-4-carbonyl)phenyl)amino)-5-(l-(thiophene-2-carbonyl)- lH-indol-4-yl)pyrazin-2(lH)-one;

6. 5-(l-(3,5-difluorobenzoyl)-lH-indol-4-yl)-l-methyl-3-((4-(morpholine-4-carbonyl) phenyl)amino)pyrazin-2(lH)-one;

7. l-methyl-3-((4-(morpholine-4-carbonyl)phenyl)amino)-5-(l-(3-(trifluoromethyl) benzoyl)- lH-indol-4-yl)pyrazin-2(lH)-one;

8. 1 -methyl-5-( 1 -(morpholine-4-carbonyl)indolin-4-yl)-3-((4-(morpholine-4-carbonyl) phenyl)amino)pyrazin-2(lH)-one;

9. 5-(l-(4-(tert-butyl)benzoyl)indolin-4-yl)-l-methyl-3-((4-(morpholine-4-carbonyl) phenyl)amino)pyrazin-2(lH)-one;

10. l-methyl-3-((4-(morpholine-4-carbonyl)phenyl)amino)-5-(l-(4-(trifluoromethyl) benzoyl)indolin-4-yl)pyrazin-2(lH)-one;

11. 5-(l-(3,4-dimethoxybenzoyl)indolin-4-yl)-l-methyl-3-((4-(morpholine-4-carbonyl) phenyl)amino)pyrazin-2(lH)-one;

12. 5-(l-(4-fluorobenzoyl)indolin-4-yl)-l-methyl-3-((4-(morpholine-4-carbonyl)phenyl) amino )p yrazin-2( lH)-one;

13. l-methyl-5-(l-(5-methylpyrazine-2-carbonyl)indolin-4-yl)-3-((4-(morpholine-4- carbonyl)phenyl)amino)pyrazin-2(lH)-one;

14. 1 -methyl-5-( 1 -(4-methyl-3-(trifluoromethyl)benzoyl)indolin-4-yl)-3-((4-(morpholine- 4-carbonyl)phenyl)amino)pyrazin-2(lH)-one; 5-(l-(3-fluoro-4-methylbenzoyl)indolin-4-yl)-l-methyl-3-((4-(morpholine-4- carbonyl)phenyl)amino)pyrazin-2(lH)-one;

5-(l-benzoylindolin-4-yl)-l-methyl-3-((4-(morpholine-4-carbonyl)phenyl)amino) pyrazin-2( lH)-one;

1 -methyl-5-( 1 -(3-methylbenzoyl)indolin-4-yl)-3-((4-(morpholine-4-carbonyl)phenyl) amino )p yrazin-2( lH)-one;

1 -methyl-5-( 1 -(6-methylnicotinoyl)indolin-4-yl)-3-((4-(morpholine-4-carbonyl) phenyl)amino)pyrazin-2(lH)-one;

1 -methyl-5-( 1 -( 1 -methyl- 1 H-pyrrole-2-carbonyl)indolin-4-yl)-3-((4-(morpholine-4- carbonyl)phenyl)amino)pyrazin-2(lH)-one;

5-(l-(3-methoxy-2-methylbenzoyl)indolin-4-yl)-l-methyl-3-((4-(morpholine-4- carbonyl)phenyl)amino)pyrazin-2(lH)-one;

1 -methyl-5-( 1 -(3-(methylsulfonyl)benzoyl)indolin-4-yl)-3-((4-(morpholine-4- carbonyl)phenyl)amino)pyrazin-2(lH)-one;

l-methyl-5-(l-(l -methyl- lH-pyrazo le-4-carbonyl)indolin-4-yl)-3-((4-(morpholine-4- carbonyl)phenyl)amino)pyrazin-2(lH)-one;

N-(3,4-dimethylphenyl)-4-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5- oxo-4,5-dihydropyrazin-2-yl)indoline-l-carboxamide;

N-(5-chloro-2,4-dimethoxyphenyl)-4-(4-methyl-6-((4-(morpholine-4-carbonyl) phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)indoline-l-carboxamide;

N-(3,5-dimethylphenyl)-4-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5- oxo-4,5-dihydropyrazin-2-yl)indoline-l-carboxamide;

N-(2,4-difluorophenyl)-4-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5- oxo-4,5-dihydropyrazin-2-yl)indoline-l-carboxamide;

4-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin- 2-yl)-N-(3-(trifluoromethyl)phenyl)indoline- 1 -carboxamide;

N-(3-ethylphenyl)-4-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo- 4,5-dihydropyrazin-2-yl)indoline-l-carboxamide;

N-(2-ethylphenyl)-4-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo- 4,5-dihydropyrazin-2-yl)indoline-l-carboxamide; 4-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin- 2-yl)-N-(p-tolyl)indoline-l-carboxamide;

N-(4-ethylphenyl)-4-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo- 4,5-dihydropyrazin-2-yl)indoline-l-carboxamide;

5-(l-(4-(tert-butyl)benzoyl)-lH-indol-4-yl)-l-methyl-3-((3-(4-methylpiperazin-l-yl) phenyl)amino)pyrazin-2(lH)-one;

5-(l-acetylindolin-5-yl)-l-methyl-3-((4-(morpholine-4-carbonyl)phenyl)amino) pyrazin-2( lH)-one;

(4-((6-(l-(4-(tert-butyl)benzoyl)-lH-indol-4-yl)imidazo[l,2-a]pyrazin-8-yl)amino) phenyl)(morpholino)methanone ;

(4-((6-(l-(cyclopropanecarbonyl)-lH-indol-4-yl)imidazo[l,2-a]pyrazin-8-yl)amino) phenyl)(morpholino)methanone ;

(4-(8-((4-(morpholine-4-carbonyl)phenyl)amino)imidazo[l,2-a]pyrazin-6-yl)-lH- indol-l-yl)(3-(trifluoromethyl)phenyl)methanone;

(4-((6-(l-(2,4-dichlorobenzoyl)-lH-indol-4-yl)imidazo[l,2-a]pyrazin-8-yl)amino) phenyl)(morpholino)methanone ;

(4-((6-(l-(2,4-dimethoxybenzoyl)-lH-indol-4-yl)imidazo[l,2-a]pyrazin-8-yl)amino) phenyl)(morpholino)methanone ;

(4-((6-(l-(4-(tert-butyl)benzoyl)indolin-4-yl)imidazo[l,2-a]pyrazin-8-yl)amino) phenyl)(morpholino)methanone ;

(4-((6-(l-(cyclopropanecarbonyl)indolin-4-yl)imidazo[l,2-a]pyrazin-8-yl)amino) phenyl)(morpholino)methanone ;

l-(4-(8-((4-(morpholine-4-carbonyl)phenyl)amino)imidazo[l,2-a]pyrazin-6-yl) indolin- l-yl)-2-phenylethanone;

(4-((6-(l-(3-fluoro-4-methylbenzoyl)indolin-4-yl)imidazo[l,2-a]pyrazin-8-yl)amino) phenyl)(morpholino)methanone ;

(4-((6-(l-benzoylindolin-4-yl)imidazo[l,2-a]pyrazin-8-yl)amino)phenyl)

(morpholino)methanone;

(4-(8-((4-(morpholine-4-carbonyl)phenyl)amino)imidazo[l,2-a]pyrazin-6-yl)indolin- 1 -yl)(thiophen-2-yl)methanone; 45. (4-(8-((4-(morpholine-4-carbonyl)phenyl)amino)imidazo[l,2-a]pyrazin-6-yl)indolin- l-yl)(4-(trifluoromethyl)phenyl)methanone;

46. (4-((6-(l-(6-methylnicotinoyl)indolin-4-yl)imidazo[l,2-a]pyrazin-8-yl)amino)phenyl) (morpholino)methanone;

47. (l-methyl-lH-pyrazol-4-yl)(4-(8-((4-(morpholine-4-carbonyl)phenyl)amino)imidazo [l,2-a]pyrazin-6-yl)indolin-l-yl)methanone;

48. (4-((6-(l-(6-methylpicolinoyl)indolin-4-yl)imidazo[l,2-a]pyrazin-8-yl)amino)phenyl) (morpholino)methanone;

49. (4-((6-(l-(4-(tert-butyl)benzoyl)indolin-5-yl)imidazo[l,2-a]pyrazin-8-yl)amino) phenyl)(morpholino)methanone ;

50. (4-((6-(l-(4-methylbenzoyl)indolin-5-yl)imidazo[l,2-a]pyrazin-8-yl)amino)phenyl) (morpholino)methanone;

51. l-(5-(8-((4-(morpholine-4-carbonyl)phenyl)amino)imidazo[l,2-a]pyrazin-6-yl)

indolin- l-yl)ethanone;

52. (4-((6-(l-(cyclopropanecarbonyl)indolin-5-yl)imidazo[l,2-a]pyrazin-8-yl)amino) phenyl)(morpholino)methanone ;

53. 2-methyl-l-(5-(8-((4-(morpholine-4-carbonyl)phenyl)amino)imidazo[l,2-a]pyrazin- 6-yl)indolin- 1 -yl)propan- 1 -one;

54. l-(5-(8-((4-(morpholine-4-carbonyl)phenyl)amino)imidazo[l,2-a]pyrazin-6-yl)-3,4- dihydroquinolin- 1 (2H)-yl)ethanone ;

55. (4-((6-(l-(cyclopropanecarbonyl)-l,2,3,4-tetrahydroquinolin-5-yl)imidazo[l,2- a]pyrazin-8-yl)amino)phenyl)(morpholino)methanone;

56. l-(4-(8-(pyridin-4-ylamino)imidazo[l,2-a]pyrazin-6-yl)indolin-l-yl)ethanone;

57. l-(5-(8-(pyridin-3-ylamino)imidazo[l,2-a]pyrazin-6-yl)indolin-l-yl)ethanone; and

58. l-(5-(8-(pyridin-4-ylamino)imidazo[l,2-a]pyrazin-6-yl)indolin-l-yl)ethanone, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable stereoisomer thereof.

In further yet another particular embodiment, the definition of "compounds of formula (I)" inherently includes all stereoisomers of the compound of formula (I) 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 (I) is for instance specified as (R), this means that the compound is substantially free of (S) isomer; when the compound of formula (I) is for instance specified as E, this means that the compound is free of the Z isomer; when the compound of formula (I) 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 (I) 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-O- or -O-alkyl, wherein alkyl group is as defined above. Exemplary Q-Qo alkyl 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, - CH₂CH₂I, -CH₂CH₂CH₂F, -CH₂CH₂CH₂C1, -CH₂CH₂CH₂CH₂Br, -CH₂CH₂CH₂CH₂I, - CH₂CH₂CH₂CH₂CH₂Br, -CH₂CH₂CH₂CH₂CH₂I, -CH₂CH(Br)CH₃, -CH₂CH(C1)CH₂CH₃, and - CH(F)CH₂CH₃.

"Cycloalkyl" refers to a non-aromatic, saturated, monocyclic, bicyclic or polycyclic hydrocarbon ring system. Representative examples of a cycloalkyl include, but are not limited to cyclopropyl, cyclopentyl, cycloheptyl and cyclooctyl. A cycloalkyl can be unsubstituted or substituted with one or more 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.

"Arylalkyl" refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atom has been replaced with an aryl group as defined above. Examples of arylalkyl group include, but are not limited to benzyl, benzhydryl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl. An arylalkyl 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 (I) 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 (I) 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 N-substituted heterocyclic derivatives of formula (I).

An embodiment of the present invention provides the compounds according to formula (I) 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.

ACN (acetonitrile); AcCl (Acetyl chloride); atm (atmosphere); Brine solution (Saturated Sodium chloride solution); bs (broad singlet); CH₃COOK (Potassium acetate); CS₂CO₃ (Cesium carbonate); °C (degree Celsius); DMF (N,N-dimethylformamide); DMSO (Dimethyl sulfoxide); DMAP (4-Dimethylaminopyridine); DME (dimethoxyethane) ; DMA (Dimethyl amine); DIPEA/DIEA (N,N- Diisopropylethylamine) ; Et₂0 (diethyl ether); CH₂C1₂/DCM (dichloro methane); CDCI₃ (deuteriated chloroform); d (dublet); dd (doublet of dublet); EDCI.HC1 (l-(3-Dimethylaminopropyl)-3-carbodiimide hydrochloride); EtOH (ethanol); g (gram); H (hydrogen atom); H₂ (Hydrogen gas); HPLC (High-performance liquid chromatography); HOBt (1-Hydroxybenzotriazole); Hz (Hertz); H₂0 (water); HC1 (hydrochloricacid); h/hrs (hours); Fe (iron); IP A (Isopropyl alcohol); J (coupling constant); K₃CO₃ (potassium carbonate); LC/MS (Liquid chromatography-mass spectrometry); LiOH (Lithium hydroxide); mmol (millimol); MeOH (methanol); μπι (micro molar); m/z (molecular weight); M (molar); ml/mL (millilitre); mg (milligram); m (multiplet); MHz (megahertz); MS (ES) (mass spectroscopy-electro spray); min (minutes); nm (nanomolar); N₂ (nitrogen); NaHC03 (Sodium bicarbonate); NaH (Sodium hydride); NaO^lBu (Sodium tertiary butoxide); Na₂S0₄ (Sodium sulphate); Na₂C0₃ (Sodium carbonate); NIS (N-Iodosuccinamide); NBS (N- bromosuccinamide) ; NCS (N-chlorosuccinamide); NMR (nuclear magnetic resonance spectroscopy); ppm-δ (parts per million); ^JH (proton NMR); PMB (4-methoxy benzaldehyde) ; Pd(dppf)Cl₂.DCM ([1, 1 '-Bis (diphenylphosphino)ferrocene] dichloropalladium (II), complex with dichloro methane; Pd(PPh₃)₄ (Tetrakis(triphenylphosphine)palladium(O)); Pd(OAc)₂ (Palladium diacetate); Pd₂(dba)₃ (Tris(dibenzylideneacetone)dipalladium(O)); RT (20- 35°C/room temperature); S (singlet); TLC (Thin Layer Chromatography); THF (tetrahydrofuran); TEA (triethyl amine); TFA (trifluoroaceticacid); t (triplet); etc.

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

GENERAL MODES OF PREPARATION

Compounds of this invention may be made by synthetic chemical processes, examples of which are shown herein. 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.

A general approach for the synthesis of compounds of general formula (I) is depicted in below schemes. As used herein the below schemes the terms 'Ri', 'R₂', 'R₃', 'R4 ' , 'R5 ' and "n' represents all the possible substitutions as disclosed in formula (I).

A general approach for the synthesis of critical intermediates of the present invention are depicted in scheme-a, scheme-b and scheme-c.

Scheme-a:

Bromo compound of formula 1.0 and Bis(pinacolato)diboron can undergo Pd-catalysed reaction with suitable Pd-catalyst such as Pd(PPh₃)₄, Pd(dppf)Cl_2.DCM, Pd₂(dba)_3> Pd(OAc)₂ and the like, in presence of a suitable base such as TEA, DIPEA, Na₂C0_3> K₂C0_3> Cs₂C0₃ and the like and suitable organic solvents such as THF, ACN, DMF, DMA and DMSO at about 70°C to 110°C for about 2 to 8h to give the compound of formula of 1.1, which can further reacted with acid chlorides in presence of suitable bases such as NaH, TEA, DIPEA, Na₂C0_3> K₂C0_3> Cs₂C0₃ and the like, in suitable polar solvents such as THF, ACN, DMF, DMA and DMSO at about RT to 80°C for about 2 to 16h to provide compound of formula 1.2.

Scheme-b:

Substituted pyrizinone derivatives of compound of formula 1.3 and appropriate amines are reacted in presence of suitable bases such as TEA, DIPEA, NaH, NaO^lBu and the like, in suitable organic solvents (such as DMF, ACN, THF, Dioxane, DMA) at about 100°C to 110°C for about 6 to 16 h to get the compound of formula 1.4. The formula 1.4 undergo Pd-catalyzed reaction with formula 1.1 to provide formula 1.5. This coupling reaction can be carried out in suitable Pd-catalyst such as Pd(PPh₃)₄, Pd(dppf)Cl_2.DCM, Pd₂(dba)_3, Pd(OAc)₂ and the like, in presence of suitable bases such as Na₂C0_3> K₂C0_3> Cs₂C0₃ and the like, and their molar solutions in suitable solvents such as ACN, DMF, THF, Dioxane and the like, at a temperature of about 20°C to 100°C for about 6-24 h to get the compound of formula 1.5.

Scheme-c

Compound of formula 1.6 and appropriate amines are reacted in presence of suitable bases such as TEA, DIPEA, NaH, NaO^lBu and the like, in suitable organic solvents (such as DMF, THF, Dioxane, DMA, DMSO) at about 100°C to 110°C for about 6 to 16 h to get the compound of formula 1.7. The formula 1.7 undergo Pd-catalyzed reaction with formula 1.1 to provide formula 1.8. This coupling reaction can be carried out in suitable Pd-catalyst such as Pd(PPh₃)₄, Pd(dppf)Cl₂.DCM, Pd₂(dba)₃, Pd(OAc)₂ and the like, in presence of suitable bases such as Na₂C0_3> K₂C0_3> Cs₂C0₃ and the like, and their molar solutions in suitable solvents such as DMF, THF, ACN, Dioxane and the like, at a temperature of about 20°C to 100°C for about 6- 24 h to get the compound of formula 1.8.

A general approach for the synthesis of compounds of the present invention is depicted in scheme-I.

Scheme-I:

Method-C

Method-A: Conversion of compound of formula- 1.5 to formula I (Amide formation) can be carried out by the similar method described in scheme-a.

Method-B: The acid-amine coupling of compound of formula 1.5 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-hydroxybenzotriazole (HOBt) benzotriazole-l-yloxytris (dimethylamino)phosphoniumhexafluorophosphate and 2-(lH- benzotriazol-l-yl)-l, l,3,3-tetra methyluroniumhexafluoro phosphate or an azabenzotriazole- containing reagents such as 0-(7-azabenzotriazole-l-yl)-N or dicarboimides containing reagents 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 or DMAP and the like at a temperature of about 20-35°C for about 12-48h to provide compound of formula I.

Method-C: Compound of formula 1.5 treated with substituted aryl isocyanates in presence of suitable bases such as TEA, DIPEA, and the like, in suitable solvents such as THF, DCM at a temperature of about 0-35°C for about 2-12h to provide compound of formula I.

Scheme-II:

Conversion of compound formula- 1.8 to formula I (Amide formation reaction) carried out by the similar methods described in scheme-a and scheme-I.

Scheme-

1.7

Conversion of formula- 1.7 to formula I (Pd-Catalysed C-C bond formation) can be carried out by the similar method described in scheme-b.

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 (I) 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 3,5-dibromo-l-methylpyrazin-2(lH)-one:

(1) Oxalyl bromide, CH₂C1₂, DMF, 0°C-55°C,16 h.

To a suspension of methylamino acetonitrile hydrochloride (20 g, 142.0 mmol) in DCM (1300 mL), was added oxalyl bromide (54 mL, 188.67 mmol) followed by slow addition of DMF (1.5 mL) at 0°C. The reaction mixture was stirred at 55°C for 16 h. DCM was concentrated under reduced pressure, the residue obtained was purified by column chromatography by eluting with 2% MeOH/CH₂Cl₂ to afford the desired compound as a pale yellow solid (34 g, 92%); *H NMR (400 MHz, DMSO-d₆) δ 8.1 (s, 1H), 3.4 (s, 3H). LC-MS: 268.9 (M+l)⁺.

Intermediate-2: Synthesis of l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indolin-l-yl) ethanon

rmediate-2

(i) Bis(pinacolato)diborane, (PPh3)₂PdCl₂,CH₃COOK,l,4-Dioxane, 100°C, 2h;

(ii) CH3COCI, NaH, THF, 0°C to RT, lh.

Step-(i): Synthesis of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indoline:

To a stirred solution of 4-bromoindoline (1.0 g, 5.07 mmol), bis(pinacolato)diborane (1.54 g, 6.09 mmol) and CH₃COOK (1.50 g, 15.21 mmol) in 1,4-dioxane (20 mL) was added Pd(dppf)Cl₂.DCM complex (0.410 g, 0.50 mmol). The reaction mixture was purged with argon for 5 minutes and stirred at 100°C for 2h. After the reaction was completed it was cooled to room temperature and the solvent was evaporated under reduced pressure. The obtained residue was extracted with ethyl acetate (2 x 250 mL). The combined organic layer was washed with brine, dried over sodium sulphate and concentrated to get the crude product, ¹H NMR (400 MHz, CDCI₃): δ 7.07 (d, 1H, J=7.6 Hz), 6.94 (t, 1H, J=7.6 Hz), 6.69 (d, 1H, J=7.6 Hz), 3.45 (t, 2H, J=8.6 Hz), 3.15 (t, 2H, J=8.6 Hz), 1.24 (s, 12H); MS (ES) 246 (M+l)⁺.

Step-(ii): Synthesis of l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indolin-l-yl) ethanone: To a stirred solution of Intermediate-2a (20 g, 6.07 mmol) in THF was added NaH (.0.875 g, 18.23 mmol) at 0°C followed by Acetyl chloride (0.65 mL, 9.11 mmol). Then the reaction mixture allowed to room temperature for lh. Then the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 250 mL) The combined organic phases were washed with brine, dried over sodium sulphate and evaporated the solvent under vacuum to get the titled compound (1.5 g, 65%); LC-MS m/z 288 (M+l)⁺.

The below Intermediates-3 to 5 were prepared according to the above procedure by using appropriate reactants, reagents and solvents at suitable conditions.

Intermediate-6: Synthesis of l-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4- dihydroquinolin- 1 (2H)-yl)ethanone:

Intermediate-6

(i) CH3COCI, TEA, DCM, RT, 2h;

(ii) Bis(pinacolato)diborane, Pd(dppf)Cl₂ DCM complex, CH₃COOK, 1,4-dioxane, 100°C, 2h.

The process of these steps was adopted from step-(i) and (ii) of Intermediate-2. The obtained crude was used in the next step without purification.

The below Intermediate-7 was prepared according to the above procedure by using appropriate reactants, reagents and solvents at suitable conditions.

Intermediate-8 and 9: Synthesis of 5-(lH-indol-4-yl)-l-methyl-3-((4-(morpholine-4-carbonyl) phenyl)amino)pyrazin-2( lH)-one and 5-(indolin-4-yl)- l-methyl-3-((4-(morpholine-4-carbonyl) phenyl)amino)pyrazin-2( lH)-one:

Intermediate-9

(i) Morpholine, EDCI.HCl, HOBT, DMF, 0°C-RT, 16h; (ii) Pd/C, H₂, MeOH, RT, 4h; (iii) Intermediate- 1, DMA, 110°C, 16h; (iv) (lH-indol-4-yl)boronic acid, (PPh₃)₂PdCl₂, DCM, Na₂C0₃(2M), 1,4-Dioxane, 100°C, 2h; (v) NaCNBH₃, TFA, 0°C-RT, lh.

Step-(i): Synthesis of Morpholino(4-nitrophenyl) methanone: To a solution of 4-nitrobenzoic acid ( 10 g, 59.83 mmol) in DMF (100 mL) under inert atmosphere at 0°C morpholine (5.7 g, 65.82 mmol), EDCI.HC1 ( 14.8 g, 77.7 mmol), HOBT (10.5 g, 77.7 mmol) and DIPEA (43.4 mL 239.3 mmol) were added and stirred at room temperature for 16h. The reaction mixture was quenched with ice cold water. The residue was taken in water and extracted with CHCI₃ (2 x 500 mL). The combined organic phases were washed with brine, dried over sodium sulphate and evaporated the solvent under vacuum to get the desired product as a pale yellow solid (8.5 g, 60%); *H-NMR (400 MHz,DMSO-J₆): δ 8.3 (d, 2H, J=8 Hz), 7.7 (d, 2H, J=8.8 Hz), 3.66-3.28 (m, 8H).

Step-(ii): Synthesis of (4-aminophenyl)(morpholino)methanone:

To a solution Intermediate- 8a (8.5 g 35.9m mol) in methanol 200 mL, added 10% Pd/C

(850 mg) and stirred under H₂ atmosphere for 4h at RT. After the reaction was completed, the reaction solvent was filtered through celite pad and washed with excess of MeOH. The filtrate was evaporated by vacuum to get the desired product as a pale yellow solid (7.0 g, 94.53%); 1H- NMR (400 MHz, DMSO-J₆)-5 7.14 (d, 2H, J=8.4 Hz), 6.55 (d, 2H, J=8 Hz), 5.5 (bs, 2H), 3.66- 3.28 (m, 8H); MS (ES) m/z 207 (M+l)⁺.

Step-(iii): Synthesis of 5-bromo- l-methyl-3-((4-(morpholine-4-carbonyl) phenyl) amino) pyrazin-2( lH)-one:

Intermediate- 8b (0.5g, 1.87mmol), Intermediate- 1 (0.5 g, 2.49 mmol) in DMA (5 mL) were heated at 110°C for 16hrs. Then the reaction mixture was poured over crushed ice, the precipitate was filtered, dried under vacuum to get desired product as a yellow solid (400 mg, 57%); ^!H NMR (400 MHz, OMSO-d₆) δ 9.6 (s, 1H), 8.01 (d, 2H, J=8.8 Hz), 7.40 - 7.38 (m, 3H), 3.6-3.45 (m, 1 1H); MS (ES) m/z 395 (M+l)⁺.

Step-(iv): Synthesis of 5-( lH-indol-4-yl)-l-methyl-3-((4-(morpholine-4-carbonyl)phenyl) amino)pyrazin-2( lH)-one:

A solution of Na₂C0₃ (2M solution,0.5 mL) in 1,4-dioxane (15 mL) taken in a sealed tube was purged with argon gas for 5 minutes prior to the addition of Intermediate-8c (100 mg, 0.25 mmol) and (lH-indol-4-yl)boronic acid (45 mg, 0.30 mmol). The resulting mixture was again purged with argon gas. Then Pd(PPh₃)₂Cl₂.DCM ( 18 mg, 0.025 mmol) was added and again purged for 5 minutes with argon, stirred at 100°C for 2hrs. After the evaporation of the solvent under reduced pressure, the residue was taken in water and extracted with DCM (2 x 50 mL). The combined organic phases were washed with brine, dried over sodium sulphate and evaporated the solvent under vacuum. The obtained crude product was purified by column chromatography using 100-200 mesh silica gel and 4% MeOH in DCM as eluent to give the titled product as a pale brown solid (50 mg, 46%); 1H NMR (400 MHz, DMSO-J₆): δ 11.23(s, IH), 9.46(s, IH), 8.20 (d, 2H, J=9 Hz), 7.5 (s, IH), 7.42-7.37 (m, 5H), 7.19-7.15 (m, IH), 6.87 (s, IH), 3.66-3.45 (m, 1 IH); MS (ES) m/z 430 (M+l)⁺.

Step-(v): Synthesis of 5-(indolin-4-yl)-l-methyl-3-((4-(morpholine-4-carbonyl)phenyl)amino) pyrazin-2( lH)-one:

To a solution of Intermediate- 8 (1.0 g, 2.33 mmol) in TFA (lOmL), was added NaCNBH₃ (440 mg 6.99 mmol) portion wise at 0°C over a period of 20 minutes, which was stirred under N₂ atmosphere for lh at RT. After the reaction was completed, the reaction mixture was P adjusted to 7 with saturated Na₂C0₃ solution at 0°C. The residue was taken in water and extracted with DCM (2 x 250 mL). The organic layer was washed with brine, dried over sodium sulphate and evaporated the solvent under vacuum. The obtained crude product was purified by column chromatography using 100-200 mesh silica gel and 4% MeOH in DCM as eluent to give the titled product as a pale brown solid. 1H NMR (400 MHz, DMSO-J₆): δ 9.43 (s, IH), 8.10 (d, 2H, J=8.8 Hz), 7.38 (d, 2H, J=8.4 Hz), 7.33 (s, IH), 7.01-6.9 (m, IH), 6.97-6.85 (m, IH), 6.49 (d, IH, J=7.2 Hz), 3.59-3.42 (m, 13H), 3.4-3.38 (m, 2H); MS (ES) m/z 432 (M+l)⁺.

Intermediate- 10 and 11: Synthesis of (4-((6-(lH-indol-4-yl)imidazo[l,2-a]pyrazin-8-yl)amino) phenyl)morpholino)methanone and (4-((6-(indolin-4-yl)imidazo[ 1 ,2-a]pyrazin-8- yl)amino)phenyl)(morpholino)methanone:

Intermediate- 10 Intermediate- 11

(i) Br₂, Pyridine, CH₂C1₂, 0°C-RT, 16h; (ii) 2-chloro acetaldehyde, IP A, 100°C, 24h; (iii) Intermediate-8b, DIPEA, DMF, 110°C, 20h; (iv) (li/-indol-4-yl) boronic acid, (PPh₃)₂PdCl₂, Na₂C0₃(2M), 1,4-Dioxane, 110°C, 12h; (v) NaCNBH₃, TFA, 0°C-RT, lh.

Step-(i): Synthesis of 3,5-dibromopyrazin-2-amine: To a stirred solution of pyrazin-2-amine (0.5 g, 5.2 mmol) in DCM (10 mL), was added pyridine (0.95 mL, 11.05 mmol) at 0°C followed by bromine (0.56 mL, 11.05 mmol) which was stirred at RT for 16h. After the reaction was completed, it was cooled to room temperature, quenched with Na₂C0₃ (30 mL), extracted with DCM (2 x 100 mL). The combined organic phases were washed with brine, dried over sodium sulphate and concentrated. The obtained crude product was purified by column chromatography using 100-200 mesh silica gel and 2% MeOH in DCM as eluent to give the titled product as an off white solid (510 mg, 38%); MS (ES) m/z 254 (M+l)⁺.

Step-(ii): Synthesis of 6, 8-dibromoimidazo [1, 2-a] pyrazine:

To a stirred solution of Intermediate- 10a (0.2 g, 0.79 mmol) in IPA (5mL) was added

Chloro acetaldehyde (0.12 mL, 0.952 mmol), and stirred at 100°C for 24h. After the reaction was completed, the reaction mixture was cooled RT, pale brown solid was precipitated out, filtered the solid dried under vaccum to get the desired product (150 mg, 53%); 1H NMR (400 MHz, DMSO-J₆): δ 9.02(s, 1H), 8.24(s, 1H), 7.9(s, 1H); MS (ES) m/z 277.9 (M+l)⁺.

Step-(iii): Synthesis of (4-((6-bromoimidazo [1, 2-a] pyrazin-8-yl) amino) phenyl)(morpholino) methanone:

To a stirred solution of Intermediate- 10b (7.0 g, 19.6 mmol), Intermediate- 8b (4.0 g, 19.6 mmol) in 70 mL of DMF was added, DIPEA (10.68 mL, 58.82 mmol) and stirred at 110°C for 20h. The reaction mixture was distilled under a reduced pressure to remove the solvent. The residue was taken in water and extracted with DCM (2 x 250 mL). The combined organic phases were washed with brine, dried over sodium sulphate and concentrated. The obtained crude product was purified by column chromatography using 100-200 mesh silica gel and 5% MeOH in DCM as eluent to give the titled product as a pale brown viscous solid (4.8 g, 61%); *H NMR (400 MHz, DMSO-d₆): δ 10.21 (s, 1H), 8.33 (s, 1H), 8.07 (d, 2H, J=8 Hz), 7.98 (s, 1H), 7.97 (s, 1H), 7.43 (d, 2H, J=8.8 Hz), 3.61-3.51 (m, 8H); MS (ES) m/z 402 (M+l)⁺.

Step-(iv): Synthesis of (4-((6-(lH-indol-4-yl) imidazo[l, 2-a]pyrazin-8-yl)amino)phenyl) (morpholino)methanone:

To a stirred solution of Intermediate- 10c (2.0 g 49.7 mmol), (lH-indol-4-yl), boronic acid (0.961 g, 5.97 mmol), Na₂C0₃ 2M solution (10 mL) in 1,4-dioxane (20 mL) was added (PPh₃)₂PdCl₂ (0.279 g, 0.39 mmol). The reaction mixture was purged with argon for 5 minutes and stirred at 110°C for 12h. After cooling the reaction mixture to room temperature, it was diluted with water and extracted ethyl acetate (2 x 250 mL). The combined organic phases were washed with brine, dried over sodium sulphate and concentrated. The obtained crude product was purified by column chromatography using 100-200 mesh silica gel and 2% MeOH in DCM as eluent to give the titled product as a pale yellow solid (1.2 g, 54%); *H NMR (400 MHz, DMSO-J₆): δ 11.3 (s, IH), 9.90 (s, IH), 8.57 (s, IH), 8.30 (d, 2H, J=8.5 Hz), 8.13 (s, IH), 7.69 (s, IH), 7.57 (d, IH, J=8 Hz), 7.47 (t, 2H, J=3.5 Hz), 7.40 (d, 2H, J=9 Hz), 7.23 (t, IH, J=7 Hz), 6.94 (s, IH), 3.60 (bs, 4H), 3.52 (bs, 4H); MS (ES) m/z 439 (M+l)⁺.

Step-(v): Synthesis of (4-((6-(indolin-4-yl)imidazo[l,2-a]pyrazin-8-yl)amino)phenyl) (morpholino)methanone:

The process of this step was adopted from step-(v) of Intermediate-8 and 9. The desired product obtained as pale brown solid. *H NMR (400 MHz, DMSO-J₆): δ 9.9 (s, IH), 8.3 (s, lH), 8.1 (d, 2H, J=8.4 Hz), 8.06 (s, IH), 8.0 (s, IH), 7.7 (s, IH), 7.4 (d, 2H, J=8.4 Hz), 7.2-7.1 (m, 2H), 6.79 (d, IH, J=7.6 Hz), 3.6-3.4 (m, 10H), 3.2 (t, 2H, J=8.4 Hz); MS (ES) m/z 441 (M+l)⁺.

Intermediate- 12 : Synthesis of (4-((6-(indolin-5-yl)imidazo[l,2-a]pyrazin-8-yl)amino)phenyl) (morpholino)methanone:

(I) Pd(dppf)Cl₂.DCM complex, K₂C0₃, H₂0, 1,4-dioxane, 100°C, 12h.

The process of this step was adopted from step-(iv) of Intermediate- 10 and 11. The desired compound obtained as an off white solid (0.220g, crude). The obtained crude was used in the next step without analytical data.

Intermediate- 13 : Synthesis l,2-a]pyrazin-8-amine:

Intermediate- 10b Intermediate- 13

(i) pyridin-3-amine, DIPEA, DMF, 80^°C, 12h. The process of this step was adopted from step-(iii) of Intermediate- 10 and 11. H NMR (400 MHz, DMSO-d₆): δ 10.24 (s, 1H), 9.15 (s, 1H), 8.39-8.36 (m, 2H), 8.26 (s, 1H), 7.99 (s, 1H), 7.68 (s, 1H), 7.41-7.38 (m, 1H); MS (ES) m/z 290 (M+l)⁺.

Intermediate- 14 : Synthesis of 6-bromo-N-(pyridin-4-yl)imidazo[l,2-a]pyrazin-8-amine:

Intermediate- 10b Intermediate- 14

(i) pyridin-4-amine, DIPEA, DMF, 80^°C, 12h.

The process of this step was adopted from step-(iii) of Intermediate- 10 and 11. NMR (400 MHz, DMSO-i¾): δ 9.26 (d, 2H, J=8.0 Hz), 9.17 (d, 2H, J=9.6 Hz), 8.37 (s, 1H), 8.03 (s, 1H), 7.12 (d, 2H, J=8.0 Hz); MS (ES) m/z 290 (M+l)⁺.

Example-I: Synthesis of 5-(l-(2,4-dimethoxybenzoyl)-lH-indol-4-yl)-l-methyl-3-((4- (morpholine-4-carbonyl)phenyl)amino) pyrazin-2( -one (Compound- 1):

Compound- 1

Intermediate-8

Step(i): 2,4-dimethoxybenzoyl chloride, TEA, DMAP, DCM , 0°C- RT, 12h.

To a solution of Intermediate-8 (50 mg, 0.116 mmol) in DMF (2 mL) was added K₂CO₃ (48 mg, 0.348 mmol) followed by 2,4-dimethoxybenzoyl chloride (47 mg, 0.232 mmol) at 0°C. The reaction mixture was stirred at RT for 12h. The progress of the reaction was monitored by TLC. After the reaction was completed, it was cooled to room temperature. The residue was diluted with ice cold water and the solid formed was filtered and dried to get the crude product which was purified by column chromatography using silica gel to give the titled product as an off white solid (8 mg, 12%); *H NMR (400 MHz, CDC1₃): δ 8.4 (m, 2H), 7.96 (d, 2H, J=8.8 Hz), 7.49-7.41 (m, 5H), 7.18 (d, 4H, J=4 Hz), 6.56 (s, 1H), 3.89 (m, 8H), 3.69 (s, 9H); MS(ES): 594 (M+l)⁺.

The below compounds were prepared by procedure similar to the one described in Example-I with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below table.

2H),

1H,

4H),

Example-II: Synthesis of 5-(l-(3,4-dimethoxybenzoyl)indolin-4-yl)-l-methyl-3-((4- (morpholine-4-carbonyl)phenyl)amino)pyrazin-2( lH)-one (Compound- 11):

Step(i): 3,4-dimethoxybenzoic acid, EDCI.HC1, HOBT, DIPEA, DMF, 0°C-RT, 2h.

To a stirred solution of 3,4-dimethoxybenzoic acid (25 mg, 0.139 mmol) in DMF (5 mL), were added EDCI.HC1 (33 mg, 0.174 mmol), HOBT (23 mg, 0.174 mmol), DIPEA (0.062 mL, 0.348 mmol) and Intermediate-9 (50 mg, 0.116 mmol) at 0°C. The reaction mixture was stirred at room temperature for 2h. After the reaction was completed, ice water poured into the reaction mixture then the solid formed was filtered and dried under vacuum to get the desired crude product which was purified by column chromatography using 100-200 mesh silica gel and 4% MeOH in DCM as eluent to get the desired product (5 mg, 7%); *H NMR (400 MHz, OMSO-d₆): δ 9.47 (s, 1H), 8.06 (d, 2H, J=8.8 Hz), 7.4-7.38 (m, 3H), 7.33-7.05 (m, 5H), 7.05-7.03 (m, 1H), 4.07 (t, 2H, J=8 Hz), 3.84-3.79 (m, 7H), 3.6-3.42 (m, 12H); MS(ES): 596 (M+l)⁺.

The below compounds were prepared by procedure similar to the one described in Example-II with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below table.

(d, (d,

(m,

Hz), J=8

Example-Ill: Synthesis of N-(3,4-dimethylphenyl)-4-(4-methyl-6-((4-(morpholine-4-carbonyl) phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)indoline-l-carboxamide (Compound-23):

Intermediate-9 Compound-23 ^rt O

Step(i): 4-isocyanato-l,2-dimethylbenzene, TEA, DCM, 0°C-RT, 12h.

To a stirred solution of Intermediate-9 (70 mg, 0.16 mmol) in CH₂CI₂ (10 mL) cooled to 0°C was added triethylamine (0.67 mL, 0.486 mmol) followed by 4-isocyanato-l,2- dimethylbenzene (29 mg, 0.194 mmol) and stirred at RT for 12h. The reaction mixture was diluted with water and extracted with and DCM (2 x 100 mL). The combined organic phases were washed with brine, dried over sodium sulphate and concentrated. The obtained crude was purified by column chromatography using 100-200 mesh silica gel to give the titled product as an off-white solid (25 mg, 27%); ^!H NMR (400 MHz, CDC1₃): δ 8.4 (s, IH), 8.01 (d, IH, J=7.6 Hz), 7.8 (d, 2H, J=8.4 Hz), 7.44 (d, 2H, J=8 Hz), 7.27 (m, 2H), 7.15-7.12 (m, 3H), 6.89 (s, IH), 6.39 (s, IH), 4.09-4.05 (m, 2H), 3.64 (s, 11H), 3.43-3.39 (m, 2H), 2.26 (s, 6H); 579 MS(ES): (M+l)⁺.

The below compounds were prepared by procedure similar to the one described in Example-Ill with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below table.

Example-IV: Synthesis of 5-(l-(4-(tert-butyl)benzoyl)-lH-indol-4-yl)-l-methyl-3-((3-(4-methyl piperazin-l-yl) phenyl) amino) pyrazin-2(lH)-one (Compound-32):

(i) K₂C0₃, DMSO, 100°C, 20h; (ii) 10% Pd/C, H₂, MeOH, RT, 4h; (iii) Intermediate- 1, DMA, 110°C, 16h; (iv) (l f-indol-4-yl)boronic acid, (PP ₃)₂PdCl₂.DCM, Na₂C0₃, 1,4-Dioxane, 100°C, 2 ; (v) 4-(ter/-butyl) benzoyl chloride, K₂C0₃, CH₃CN, 80°C, 2h.

Step-(i): Synthesis of l-methyl-4-(3-nitrophenyl)piperazine:

To a stirred solution of 3-fluoro nitrobenzene (25 g, 177.3 mmol) in DMSO (125 mL) was added K₂C0₃ (36.67 g, 265.7 mmol) followed by N-Methyl piperizine (26.5 g, 265.9 mmol) at ambient temperature. The reaction mixture was stirred at 100°C for 20h. The reaction mixture was quenched with water, extracted with CHC1₃, the combined organic phases were washed with brine dried over sodium sulphate and concentrated. The obtained crude product was purified by column chromatography using 100-200 mesh silica gel and 4% MeOH in DCM as eluent to give the titled product as a white solid (15 g, 41%); MS (ES) m/z 222 (M+l)⁺.

Step-(ii): Synthesis of 3-(4-methylpiperazin-l-yl)aniline: To a stirred solution of compound-32a (15 g, 78.5 mmol) in MeOH was added 10% Pd/C (3 g) in MeOH slowly under inert atmosphere and stirred at RT for 4h in presence of H₂ atmosphere. After the reaction was completed, the reaction mixture was filtered through celite pad. Filtrate was concentrated to get the desired product as pale yellow solid (11 g, 87%); MS (ES) m/z 192 (M+1)⁺.

Step-(iii): Synthesis of 5-bromo-l-methyl-3-((3-(4-methylpiperazin-l-yl)phenyl)amino) pyrazin-2( lH)-one:

To a stirred solution of Intermediate- 1 (1 g, 3.75 mmol) in DMA (6 mL) was added compound-32b (0.78 g 4.13 mmol) and stirred at 110°C for 16h. After the reaction was completed, the reaction mixture was cooled to RT, poured into crushed ice; the solid formed was filtered and dried under vacuum to get the desired product (800 mg, 52%); MS (ES) m/z 378 (M+l)⁺.

Step-(iv): Synthesis of 5-(lH-indol-4-yl)-l-methyl-3-((3-(4-methylpiperazin-l-yl)phenyl) amino)pyrazin-2( lH)-one:

A stirred solution of Na₂C0₃ (2M solution, 0.5 mL) in dioxane (2 mL) taken in a sealed tube was purged with argon gas for 5 minutes prior to the addition of compound-32c (500 mg, 1.32 mmol), (lH-indol-4-yl) boronic acid (230 mg, 1.59 mmol) and PdCl₂(PPh₃)₂ (92 mg, 0.13 mmol). The resulting mixture was again purged with argon gas for 5 minutes and stirred at 100°C for 2h. After the evaporation of solvent under reduced pressure, the residue was taken in water and extracted with DCM (2 x 50 mL). The combined organic phases were washed with brine, dried over sodium sulphate and the solvent was evaporated, The obtained crude product was purified by column chromatography using 100-200 mesh silica gel and 4% MeOH in DCM as eluent to give the titled product as pale brown solid (500 mg, 90%); *H NMR (400 MHz, DMSO-J₆): δ 11.24 (s, 1H), 9.0 (s, 1H), 8.08 (s, 1H), 7.53 (s, 1H), 7.45-7.36 (m, 4H), 7.16-7.09 (m, 2H), 6.87 (s, 1H), 6.58-6.56 (m, 1H), 3.6 (s, 3H), 3.13 (s, 4H), 3.1 (s, 4H), 2.22 (s, 3H); MS (ES) m/z 415 (M+l)⁺.

Step-(v): Synthesis of 5-(l-(4-(tert-butyl)benzoyl)-lH-indol-4-yl)-l-methyl-3-((4-(4-methyl piperazin-l-yl)phenyl)amino)pyrazin-2(lH)-one:

To a solution of compound-32d (lOOmg, 0.24mmol) in CH₃CN (5mL) was added K₂C0₃ (670 mg, 0.72 mmol) followed by tert-butyl benzoylchloride (0.056 mL, 0.28 mmol) which was stirred at 80°C for 2h. After cooling the reaction mixture, it was diluted with water and extracted with and ethyl acetate (2 x 100 mL). The combined organic phases were washed with brine, dried over sodium sulphate and concentrated. The obtained crude product was purified by column chromatography using 100-200 mesh silica gel and 4% MeOH in DCM as eluent to give the titled product as a pale brown solid (30 mg, 23%); 1H NMR (400 MHz, OMSO-d₆): δ 9.07 (s, IH), 8.30 (d, IH, J=8 Hz), 7.95 (s, IH), 7.74 (d, 2H, J=8 Hz), 7.65 (s, IH), 7.63 (d, 2H, J=5 Hz), 7.56 (s, IH), 7.47 (d, IH, J=7 Hz), 7.44 (t, IH, J=8.3 Hz), 7.36 (d, IH, J=9 Hz), 7.2 (d, IH, J=4 Hz), 7.0 (t, IH, J=8.3 Hz), 6.55 (d, IH, J=2 Hz), 3.6 (s, 3H), 3.05 (t, 4H, J=5 Hz), 2.36 (s, 4H), 2.19 (s, 3H), 1.36 (s, 9H); MS (ES) m/z 575 (M+l)⁺.

Example-V: Synthesis of 5-(l-acetylindolin-5-yl)- l-methyl-3-((4-(morpholine-4-carbonyl) phenyl)amino)pyrazin-2( lH)-one (Compound-33)

Intermediate-3

Step(i): Intermediate-8c, (PPh₃)₂PdCl₂, Na₂C0₃, 1,4-Dioxane, 100°C, 24h.

The process of this step was adopted from step-(iv) of compound-32. The desired product obtained as a pale yellow solid (200 mg, 9%); 1H NMR (400 MHz, CDC1₃): δ 9.47 (s, IH), 8.18 (d, 2H, J=8.5 Hz), 8.08 (s, IH), 7.73 (s, IH), 7.71 (s, IH), 7.67 (d, IH, J=8.7 Hz), 7.44 (d, 2H, J=8.3 Hz), 4.13 (t, 2H, J=8 Hz), 3.6 (bs, 4H), 3.56 (s, 3H), 3.52 (s, 4H), 3.2 (d, 2H, J=8 Hz), 2.17 (s, 3H); MS (ES) m/z 474 (M+l)⁺.

Example- VI: Synthesis of (4-((6-( l-(4-(tert-butyl)benzoyl)- lH-indol-4-yl)imidazo[ l,2- a]pyrazin-8-yl)amino)phenyl)(morpholino)methanone (Compound-34):

- Step(i): 4-tert-Butyl benzoyl chloride, K₂C0₃, ACN, 80°C, 2h. To a stirred solution of Intermediate- 10 (100 mg, 0.228 mmol) in CH₃CN (2 mL) was added K₂C0₃ (95 mg, 0.684 mmol) followed by tert-butyl benzoylchloride (67 mg, 0.342 mmol) which was stirred at 80°C for 2h. After cooling the reaction mixture, diluted with ethyl acetate. The diluted reaction mixture was washed with brine, dried over sodium sulphate and concentrated. The obtained crude product was purified by column chromatography using 100- 200 mesh silica gel and 4% MeOH in DCM as eluent to give the titled product as a pale brown solid (10 mg, 7%); ^!H NMR (400 MHz, CDC1₃): δ 8.41 (s, 2H), 7.69 (dd, 2H, J=9.2 Hz, J=8 Hz), 7.44-7.39 (m, 2H), 7.32-7.26 (m, 6H), 7.25-7.20 (m, 2H), 7.18-7.1 (m, 2H), 6.25 (s, 1H), 3.69 (bs, 8H), 1.24 (s, 9H); MS(ES): 599 (M+l)⁺.

The below compounds were prepared by procedure similar to the one described in

Example-VI with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below table.

Example- VII: Synthesis of l-(4-(8-((4-(morpholine-4-carbonyl)phenyl)amino)imidazo[l,2- a]pyrazin-6-yl)indolin-l-yl)-2-phenylethanone (Compound-41):

Step(i): 2-phenylacetic acid, EDCI.HC1, HOBT, DIPEA, DMF, 0°C-RT, 12h.

To a stirred solution of 2-phenylacetic acid (33.9 mg, 0.249 mmol) in DMF (10 mL), were added EDCI.HC1 (56.4 mg, 0.295 mmol), HOBT (39.8 mg, 0.295 mmol), DIPEA (0.165 mL, 0.909 mmol) and Intermediate- 11 (100 mg, 0.227 mmol) at 0°C. The reaction mixture was stirred at room temperature for 12h. After the reaction was completed, ice water poured into the reaction mixture then the solid formed was filtered and dried under vacuum to get the desired crude product which was purified by column chromatography using 100-200 mesh silica gel and 4% MeOH in DCM as eluent to get the desired product (20 mg, 15%); ^!H NMR (400 MHz, CDCI₃): δ 8.39 (d, IH, J=6.4 Hz), 8.22 (s, IH), 7.94 (d, 2H, J=8.8 Hz), 7.78 (s, IH), 7.62 (s, 2H), 7.44 (d, 2H, J=8.3 Hz), 7.36-7.28 (m, 7H), 4.09 (t, 2H, J=8.3 Hz), 3.85 (s, 2H), 3.71 (bs, 8H), 3.39 (t, 2H, J=8.3 Hz); MS(ES): 558 (M+l)⁺.

The below compounds were prepared by procedure similar to the one described in Example-VII with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below table.

Ή NMR (400 MHz, DMSO-d₆): δ 9.92 (s, 1H), 8.70

(s, 1H), 8.36 (s, 1H), 8.15-8.07 (m, 3H), 7.94 (m, 1H),

46 7.70 (s, 1H), 7.49-7.37 (m, 5H), 4.07 (t, 2H, J=8.0 Hz),

3.58-3.50 (m, 8H), 3.37 (m, 2H), 2.54 (s, 3H); 559

0 (M+l)⁺.

Ή NMR (400 MHz, DMSO-d₆): δ 9.94 (s, 1H), 8.36 (s, 1H), 8.33 (s, 1H), 8.17 (d, 2H, J=8.8 Hz), 8.07 (d, 1H, J=1.0 Hz), 7.92 (s, 1H), 7.71 (d, 1H, J=1.0 Hz),

47

7.44 (s, 1H), 7.42 (d, 3H, J=1.0 Hz), 7.33 (t, 1H, 7.8 Hz), 4.35 (t, 2H, J=7.8 Hz), 3.90 (s, 3H), 3.59-3.50 (m, o

8H), 3.45 (t, 2H, J=7.9 Hz); 548 (M+l)⁺.

^JH NMR (400 MHz, DMSO-J₆): δ 9.92 (s, 1H), 8.37 (s, 1H), 8.24 (d, 1H, J=7.4 Hz,), 8.14 (d, 1H, J=8.4 Hz), 8.06 (d, 2H, J=1.0 Hz), 7.88 (t, 1H, J=7.8 Hz), 7.70 (d,

48 1H, J=1.0 Hz), 7.58 (d, 2H, J=7.3 Hz), 7.50 (d, 2H,

J=7.3 Hz), 7.41 (d, 2H, J=8.3 Hz), 4.17 (t, 2H, J=7.8

0 Hz), 3.57-3.49 (m, 8H), 3.36 (t, 2H, J=7.8 Hz), 2.53 (s,

3H); 559 (M+l)⁺.

Example- VIII: Synthesis of (4-((6-(l-(4-(tert-butyl)benzoyl)indolin-5-yl)imidazo[l,2-a]pyrazin- 8-yl)amino)phenyl)(morpholino)methanone (Compound-49):

Conditions: Intermediate- 10c, Pd( dppf)Cl₂ DCM complex, K₂C0₃,

H₂0, 1,4-Dioxane, 100°C, 12h. To a stirred solution of Intermediate- 10c (30 mg, 0.074 mmol), K₂CO₃ (25 mg, 0.18 mmol), Intermediate-5 (30 mg, 0.074 mmol) in 1,4-dioxane (5 mL) followed by Pd(dppf)Ci₂.DCM complex (6 mg, 0.007 mmol) was added. The reaction mixture was purged with argon for 5 minutes and stirred at 100°C for 12h. After the reaction was completed, it was cooled to room temperature. The obtained residue was diluted with water and extracted ethyl acetate (2 x50 mL). The combined organic layer was washed with brine, dried over sodium sulphate and concentrated. The obtained crude was purified by column chromatography using 100-200 mesh silica gel and 2% MeOH in CHC1₃ to get the pure desired product (5 mg, 12%); 1H NMR (400 MHz, DMSO-d₆): 59.94 (s, 1H), 8.66 (s, 1H), 8.25 (d, 2H, J=8.0 Hz), 8.0 (s, 1H), 7.90-7.67 (bs, 2H), 7.66 (s, 1H), 7.58-7.51 (m, 5H), 7.46 (d, 2H, J=8.4 Hz), 4.10 (t, 2H, J=8.4 Hz), 3.61-3.50 (m, 8H), 3.19 (t, 2H, J=8.4 Hz), 1.33 (s, 9H); MS(ES): 601(M+1)⁺.

The below compounds were prepared by procedure similar to the one described in Example-VIII with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below table.

Example-IX: Synthesis of (4-((6-(l-(cyclopropanecarbonyl)indolin-5-yl)imidazo[l,2-a]pyrazin- 8-yl)amino)phenyl)(morpholino)methanone (Compound-52):

Step(i): Cyclopropanecarbonyl chloride, NaH, THF, 0°C-RT, lh.

To a stirred solution of Intermediate- 11 (30 mg, 0.068 mmol) in THF (2 mL) was added NaH (3.2 mg, 0.136 mmol) followed by cyclopropanecarbonyl chloride (0.009 mL, 0.102mmol) at 0°C The reaction mixture was stirred at RT for lh. The progress of the reaction was monitored by TLC. After the reaction was completed, it was cooled to room temperature. The residue was diluted with water extractd with EtOAC (3 x 20 mL). The combined organic layer was washed with brine, dried over sodium sulphate and concentrated. The obtained crude was purified by column chromatography using 100-200 mesh silica gel and 2% MeOH in CHCI₃ to get the pure desired product (12 mg, 34%); ^!H NMR (400 MHz, DMSO-J₆): δ 9.93 (s, 1H), 8.62 (s, 1H), 8.26 (d, 2H, J=7.8 Hz), 8.12 (bs, 1H), 7.99 (s, 1H), 7.81-7.79 (m, 3H), 7.47 (d, 2H, J=8.4 Hz), 4.43 (bs, 2H), 3.81-3.62 (m, 10H), 2.21 (s, 1H), 0.90 (s, 4H); MS(ES): 508 (M+l)⁺.

The below compounds were prepared by procedure similar to the one described in Example-IX with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below table.

Example-X: Synthesis of l-(5-(8-((4-(morpholine-4-carbonyl)phenyl)amino)imidazo[l,2-a] pyrazi ydroquinolin-l(2H)-yl)ethanone (Compound-54):

C^omP^ound-⁵⁴

Intcrmcdiatc-6

Step (i): Intermediate- 10c, Pd(dppf)Cl₂.DCM complex, K₂C0₃, H₂0, 1,4-dioxane, 100°C, 2h.

To stirred solution of Intermediate- 10c (0.1 g, 0.248 mmol) in 1,4-dioxane (5 mL) was added K₂C0₃ (102 mg, 0.746 mmol) followed by Intermediate-6 (74 mg, 0.248 mmol) and Pd(dppf)Ci2.DCM complex (20 mg, 0.024 mmol) at RT. The reaction mixture was purged with argon for 5 minutes and stirred at 100°C for 2h. After the reaction was completed, it was cooled to room temperature. The obtained residue was diluted with water and extracted ethyl acetate (2 x50 mL). The combined organic layer was washed with brine, dried over sodium sulphate and concentrated. The obtained crude was purified by column chromatography using 100-200 mesh silica gel and 2% MeOH in CHC1₃ to get the pure desired product as an off- white solid (15 mg, 12%); ^!H NMR (400 MHz, DMSO-J₆): δ 9.92 (s, 1H), 8.18-8.14 (m, 3H), 8.03 (s, 1H), 7.70 (s, 1H), 7.49 (bs, 1H), 7.38 (d, 3H, J=8.3 Hz), 7.31 (s, 1H), 3.70 (t, 2H, J=6.3 Hz), 3.58-3.49 (m, 8H), 2.82-2.79 (m, 2H), 2.18 (s, 3H), 1.87-1.81 (m, 2H); 496 (M+l)⁺.

The below compounds were prepared by procedure similar to the one described in Example-X with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below table.

Comp. Characterization Data

Compound Structure

No 1H NMR/MS(ES)

Example-XI: Synthesis of l-(4-(8-(pyridin-4-ylamino)imidazo[l,2-a]pyrazin-6-yl)indolin-l-yl) ethanone (Compound-56):

Step(i): (PPh₃)₂PdCl₂, K₂C0₃, l,4-Dioxane/H₂0, 120°C, 6h.

To a stirred solution of Intermediate- 14 (0.1 g, 0.34 mmol) and Intermediate-2 (0.119 g, 0.413 mmol) in 1,4 dioxane (10 mL)/water (0.1 mL) was added K₂CO₃. The reaction mixture was purged with argon for 10 min. Then (PPh₃)₂PdCi₂ (0.014 g, 0.017 mmol) was added and allowed to stirred at 120°C for 6h. After the completion of the reaction,, it was cooled to room temperature. The obtained residue was diluted with water and extracted ethyl acetate (2 x 25 mL). The combined organic phases were washed with brine, dried over sodium sulphate and concentrated. The obtained crude was purified by using preparative TLC with 2% MeOH in dichloromethane as eluent to get the desired product as a white solid (20 mg, 16%); ¹H NMR (400 MHz, CDC1₃): δ 8.52 (d, 2H, J=8.0 Hz), 8.36 (d, 1H, J=8.0 Hz), 8.28 (s, 1H), 7.86 (s, 1H), 7.83 (d, 2H, J=6.4 Hz), 7.66 (d, 2H, J=2.4 Hz), 7.3 (m, 2H), 4.10 (t, 2H, J=8.0 Hz), 3.44 (t, 2H, J=8.4 Hz), 2.27 (s, 3H); MS (ES) m/z 371 (M+l)⁺.

The below compounds were prepared by procedure similar to the one described in Example-XI with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below table. Comp. Characterization Data

Compound Structure

No ^!H NMR/MS(ES)

^JH NMR (400 MHz, DMSO-J₆): δ 9.96 (s, 1H), 8.60 (m, 2H), 8.25 (d, 1H, J=3.6 Hz), 8.13 (m, 1H), 8.0 (s,

57 1H), 7.83-7.80 (m, 2H), 7.8 (s, 1H), 7.57-7.41 (m, 2H),

4.17 (t, 2H, J=8.0 Hz), 3.29 (t, 2H, J=14.8 Hz), 2.18 (s, 3H); 371 (M+l)⁺.

^JH NMR (400 MHz, DMSO-J₆): δ 10.18 (s, 1H), 8.68

^NH (s, 1H), 8.46 (bs, 2H), 8.18-8.03 (m, 4H), 7.84-7.70 (m,

58 2H), 7.58 (s, 1H), 4.18 (t, 2H, J=8.4 Hz), 3.27 (t, 2H,

J=8.4 Hz), 2.19 (s, 3H); 371 (M+l)⁺.

0

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 selected compounds were screened at μΜ 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 <2.0 μΜ were grouped as 'A' and the compounds exhibiting IC₅₀ value >2.0 μΜ were grouped as 'B'.

Groups Compound No.

A 9, 39, 40, 42, 51, 52, 53, 54, 55,

B 35, 44, 45, 47, 57, 58.

Claims

We claim:

1. A compound of formula (I)

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

the dotted line [— ] represents a single or a double bond;

Ri is selected from alkyl, cycloalkyl, -N(R_a)Rt_>, optionally substituted aryl, arylalkyl and optionally substituted heterocyclyl; wherein the optional substituent at each occurrence is independently selected from one or more Rs;

R₂ is selected fro

R₃ is selected from optionally substituted aryl and heterocyclyl; wherein the optional substituent is selected from -N(R₆)R7 and -C(0)N(R₆)R₇;

R4 and R5 are independently selected from hydrogen and alkyl;

R₆ and R₇ taken together with the nitrogen atom to which they are attached to form an optionally substituted 4-6 membered heterocyclyl ring containing 0-2 heteroatoms independently selected from N and O; wherein the optional substituent is alkyl;

Rs is selected from alkyl, alkoxy, halogen, haloalkyl, and -S(0)₂alkyl;

R_a and R are independently selected from hydrogen and optionally substituted aryl; wherein the optional substituents are selected from alkyl, halogen, alkoxy and haloalkyl; and

'n' is an integer selected from 1 and 2.

2. The compound according to claim 1 , wherein R4 is hydrogen.

3. The compound according to claim 1, wherein R5 is alkyl.

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

5. The compound according to claim 1 , wherein R₃ is pyridyl and optionally substituted phenyl.

6. The compound according to claim 5, wherein the optional substituent is selected from

7. The compound according to claim 1 , wherein Ri is optionally substituted phenyl.

8. The compound according to claim 7, wherein the optionally substituted phenyl is selected from

9. The compound according to claim 1 , wherein Ri is optionally substituted heterocyclyl.

10. The compound according to claim 9, wherein the optionally substituted heterocyclyl is selected from

1 1. The compound according to claim 1 , wherein Ri is -N(R_a)Ri

12. The compound according to claim 1 1 , wherein R_a is hydrogen and R is phenyl optionally substituted with alkyl, halogen, alkoxy and haloalkyl.

13. The compound according to claim 1 wherein the compound of formula (I) is a compound of formula (la)

wherein, the dotted line [— ], Ri and 'n' are same as described in claim 1.

14. The compound according to claim 1 wherein the compound of formula (I) is a compound of formula (lb)

wherein, the dotted line [— ], Ri and 'n' are same as described in claim 1.

15. The compound according to claim 1 wherein the compound of formula (I) is a compound of formula (Ic)

wherein, the dotted line [— ], Ri and 'n' are same as described in claim 1.

16. The compound according to claim 1 wherein the compound of formula (I) is a compound of formula (Id)

wherein, the dotted line [— ], Ri and 'n' are same as described in claim 1.

17. A compound selected from the group consisting of

11. 5-(l-(3,4-dimethoxybenzoyl)indolin-4-yl)-l-methyl-3-((4-(morpholine-4-carbonyl) phenyl)amino)pyrazin-2(lH)-one;

12. 5-(l-(4-fluorobenzoyl)indolin-4-yl)-l-methyl-3-((4-(morpholine-4-carbonyl)phenyl) amino )p yrazin-2( lH)-one;

13. 1 -methyl-5-( 1 -(5-methylpyrazine-2-carbonyl)indolin-4-yl)-3-((4-(morpholine-4- carbonyl)phenyl)amino)pyrazin-2(lH)-one;

14. 1 -methyl-5-( 1 -(4-methyl-3-(trifluoromethyl)benzoyl)indolin-4-yl)-3-((4-(morpholine- 4-carbonyl)phenyl)amino)pyrazin-2(lH)-one;

15. 5-(l-(3-fluoro-4-methylbenzoyl)indolin-4-yl)-l-methyl-3-((4-(morpholine-4- carbonyl)phenyl)amino)pyrazin-2(lH)-one;

16. 5-(l-benzoylindolin-4-yl)-l-methyl-3-((4-(morpholine-4-carbonyl)phenyl)amino) pyrazin-2( lH)-one;

17. 1 -methyl-5-( 1 -(3-methylbenzoyl)indolin-4-yl)-3-((4-(morpholine-4-carbonyl)phenyl) amino )p yrazin-2( lH)-one;

18. 1 -methyl-5-( 1 -(6-methylnicotinoyl)indolin-4-yl)-3-((4-(morpholine-4-carbonyl) phenyl)amino)pyrazin-2(lH)-one;

19. 1 -methyl-5-( 1 -( 1 -methyl- 1 H-pyrrole-2-carbonyl)indolin-4-yl)-3-((4-(morpholine-4- carbonyl)phenyl)amino)pyrazin-2(lH)-one;

20. 5-(l-(3-methoxy-2-methylbenzoyl)indolin-4-yl)-l-methyl-3-((4-(morpholine-4- carbonyl)phenyl)amino)pyrazin-2(lH)-one;

21. 1 -methyl-5-( 1 -(3-(methylsulfonyl)benzoyl)indolin-4-yl)-3-((4-(morpholine-4- carbonyl)phenyl)amino)pyrazin-2(lH)-one;

22. l-methyl-5-(l-(l -methyl- lH-pyrazo le-4-carbonyl)indolin-4-yl)-3-((4-(morpholine-4- carbonyl)phenyl)amino)pyrazin-2(lH)-one;

23. N-(3,4-dimethylphenyl)-4-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5- oxo-4,5-dihydropyrazin-2-yl)indoline-l-carboxamide;

24. N-(5-chloro-2,4-dimethoxyphenyl)-4-(4-methyl-6-((4-(morpholine-4-carbonyl)

phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)indoline-l-carboxamide;

25. N-(3,5-dimethylphenyl)-4-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5- oxo-4,5-dihydropyrazin-2-yl)indoline-l-carboxamide;

26. N-(2,4-difluorophenyl)-4-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5- oxo-4,5-dihydropyrazin-2-yl)indoline-l-carboxamide;

27. 4-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin- 2-yl)-N-(3-(trifluoromethyl)phenyl)indoline- 1 -carboxamide;

28. N-(3-ethylphenyl)-4-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo- 4,5-dihydropyrazin-2-yl)indoline-l-carboxamide;

29. N-(2-ethylphenyl)-4-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo- 4,5-dihydropyrazin-2-yl)indoline-l-carboxamide;

30. 4-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin- 2-yl)-N-(p-tolyl)indoline-l -carboxamide;

31. N-(4-ethylphenyl)-4-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo- 4,5-dihydropyrazin-2-yl)indoline-l-carboxamide;

32. 5-(l-(4-(tert-butyl)benzoyl)-lH-indol-4-yl)-l-methyl-3-((3-(4-methylpiperazin-l-yl) phenyl)amino)pyrazin-2(lH)-one;

33. 5-(l-acetylindolin-5-yl)-l-methyl-3-((4-(morpholine-4-carbonyl)phenyl)amino) pyrazin-2( lH)-one;

34. (4-((6-(l-(4-(tert-butyl)benzoyl)-lH-indol-4-yl)imidazo[l,2-a]pyrazin-8-yl)amino) phenyl)(morpholino)methanone ;

35. (4-((6-(l-(cyclopropanecarbonyl)-lH-indol-4-yl)imidazo[l,2-a]pyrazin-8-yl)amino) phenyl)(morpholino)methanone ;

36. (4-(8-((4-(morpholine-4-carbonyl)phenyl)amino)imidazo[l,2-a]pyrazin-6-yl)-lH- indol-l-yl)(3-(trifluoromethyl)phenyl)methanone;

37. (4-((6-(l-(2,4-dichlorobenzoyl)-lH-indol-4-yl)imidazo[l,2-a]pyrazin-8-yl)amino) phenyl)(morpholino)methanone ;

38. (4-((6-(l-(2,4-dimethoxybenzoyl)-lH-indol-4-yl)imidazo[l,2-a]pyrazin-8-yl)amino) phenyl)(morpholino)methanone ;

39. (4-((6-(l-(4-(tert-butyl)benzoyl)indolin-4-yl)imidazo[l,2-a]pyrazin-8-yl)amino) phenyl)(morpholino)methanone ;

40. (4-((6-(l-(cyclopropanecarbonyl)indolin-4-yl)imidazo[l,2-a]pyrazin-8-yl)amino) phenyl)(morpholino)methanone ;

41. l-(4-(8-((4-(morpholine-4-carbonyl)phenyl)amino)imidazo[l,2-a]pyrazin-6-yl) indolin- l-yl)-2-phenylethanone;

42. (4-((6-(l-(3-fluoro-4-methylbenzoyl)indolin-4-yl)imidazo[l,2-a]pyrazin-8-yl)amino) phenyl)(morpholino)methanone ;

43. (4-((6-(l-benzoylindolin-4-yl)imidazo[l,2-a]pyrazin-8-yl)amino)phenyl)

(morpholino)methanone;

44. (4-(8-((4-(morpholine-4-carbonyl)phenyl)amino)imidazo[l,2-a]pyrazin-6-yl)indolin- 1 -yl)(thiophen-2-yl)methanone;

45. (4-(8-((4-(morpholine-4-carbonyl)phenyl)amino)imidazo[l,2-a]pyrazin-6-yl)indolin- l-yl)(4-(trifluoromethyl)phenyl)methanone;

46. (4-((6-(l-(6-methylnicotinoyl)indolin-4-yl)imidazo[l,2-a]pyrazin-8-yl)amino)phenyl) (morpholino)methanone;

47. (l-methyl-lH-pyrazol-4-yl)(4-(8-((4-(morpholine-4-carbonyl)phenyl)amino)imidazo [l,2-a]pyrazin-6-yl)indolin-l-yl)methanone;

48. (4-((6-(l-(6-methylpicolinoyl)indolin-4-yl)imidazo[l,2-a]pyrazin-8-yl)amino)phenyl) (morpholino)methanone;

49. (4-((6-(l-(4-(tert-butyl)benzoyl)indolin-5-yl)imidazo[l,2-a]pyrazin-8-yl)amino) phenyl)(morpholino)methanone ;

50. (4-((6-(l-(4-methylbenzoyl)indolin-5-yl)imidazo[l,2-a]pyrazin-8-yl)amino)phenyl) (morpholino)methanone;

51. l-(5-(8-((4-(morpholine-4-carbonyl)phenyl)amino)imidazo[l,2-a]pyrazin-6-yl)

indolin- l-yl)ethanone;

52. (4-((6-(l-(cyclopropanecarbonyl)indolin-5-yl)imidazo[l,2-a]pyrazin-8-yl)amino) phenyl)(morpholino)methanone ;

53. 2-methyl-l-(5-(8-((4-(morpholine-4-carbonyl)phenyl)amino)imidazo[l,2-a]pyrazin- 6-yl)indolin- 1 -yl)propan- 1 -one;

54. l-(5-(8-((4-(morpholine-4-carbonyl)phenyl)amino)imidazo[l,2-a]pyrazin-6-yl)-3,4- di ydroquinolin- 1 (2H)-yl)ethanone ;

55. (4-((6-(l-(cyclopropanecarbonyl)-l,2,3,4-tetrahydroquinolin-5-yl)imidazo[l,2- a]pyrazin-8-yl)amino)phenyl)(morpholino)methanone;

56. l-(4-(8-(pyridin-4-ylamino)imidazo[l,2-a]pyrazin-6-yl)indolin-l-yl) ethanone;

57. l-(5-(8-(pyridin-3-ylamino)imidazo[l,2-a]pyrazin-6-yl)indolin-l-yl)ethanone; and

58. l-(5-(8-(pyridin-4-ylamino)imidazo[l,2-a]pyrazin-6-yl)indolin-l-yl)ethanone, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable stereoisomer thereof.

18. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula (I) 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 (I) according to any of the claims 1 to 17, their pharmaceutically acceptable salts or pharmaceutically acceptable stereoisomers 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 claims 1 to 17, in the manufacture of a medicament for use in the treatment of diseases associated with BTK kinase in animals including humans.