WO2013157021A1

WO2013157021A1 - Bicyclic compounds, compositions and medicinal applications thereof

Info

Publication number: WO2013157021A1
Application number: PCT/IN2013/000257
Authority: WO
Inventors: Mahesh THAKKAR; Summon Koul; Debnath Bhuniya; Umesh SINGH
Original assignee: Advinus Therapeutics Limited
Priority date: 2012-04-20
Filing date: 2013-04-18
Publication date: 2013-10-24

Abstract

The present disclosure relates to a class of substituted bicyclic compounds of formula (I), their tautomers, polymorphs, stereoisomers, prodrugs, solvates, hydrates, N-oxides, co-crystals, pharmaceutically acceptable salts and pharmaceutical compositions containing them. The disclosure also relates to the process of preparation of compounds of Formula (I). These compounds are useful in the treatment, prevention, prophylaxis, management, or adjunct treatment of all medical conditions related to inhibition of Bruton's tyrosine kinase (Btk), such as inflammatory and/or autoimmune disorder, cell proliferation, rheumatoid arthritis, psoriasis, psoriatic arthritis, transplant rejection, graft-versus-host disease, multiple sclerosis, inflammatory bowel disease, allergic diseases, asthma, type 1 diabetes, myasthenia gravis, hematopoetic disfunction, B-cell malignancies, systemic lupus, erythematosus or other disorders.

Description

BICYCLIC COMPOUNDS, COMPOSITIONS AND MEDICINAL APPLICATIONS

THEREOF

Technical Field

The present disclosure relates to a class of substituted hetero-bicyclic compounds of formula (I), their tautomers, polymorphs, stereoisomers, prodrugs, solvates, hydrates, N-oxides, co-crystals, pharmaceutically acceptable salts and pharmaceutical compositions containing them. The disclosure also relates to the process of preparation of compounds of formula (I). These compounds are useful in the treatment, prevention, prophylaxis, management, or adjunct treatment of all medical conditions related to inhibition of Bruton's tyrosine kinase (Btk), such as inflammatory and/or autoimmune disorder, cell proliferation, rheumatoid arthritis, psoriasis, psoriatic arthritis, transplant rejection, graft-versus-host disease, multiple sclerosis, inflammatory bowel disease, allergic diseases, asthma, chronic obstructive pulmonary disease (COPD), type 1 diabetes, myasthenia gravis, hematopoetic disfunction, B-cell malignancies, systemic lupus erythematosus, non-Hodgkin's lymphoma, chronic lymphocytic leukemia, Mantle cell lymphoma or other disorders.

Background

Bruton's tyrosine kinase (Btk) belongs to tyrosine kinases, a subfamily of protein kinases that phosphorylate protein on the phenolic moiety of tyrosine residue. It is a non-receptor cytoplasmic tyrosine kinase and a key regulator for B-cell development, activation, signaling and survival (Schaeffer and Schwartzberg, Curr. Op. Imm. 2000, 282; Niiro and Clark, Nature Rev. Immumol. 2002, 945; Di Paolo and Currie, Nat. Chem. Biol. 2011, 7). Btk is expressed in all hematopoietic cell types, excluding plasma cells, T lymphocytes and natural killer cells. After activation by upstream B-cell antigen receptor or Toll like receptor-4, Btk induces PLC-y2 phosphorylation, which ultimately results in activation of nuclear factor κΒ (NFKB) and nuclear factor of activated T cell dependent pathways. Additionally, Btk is crucial for number of other hematopoetic cell signaling; such as, Fcy-mediated inflammatory cytokine production (such as TNF-a, IL1 β and IL6) in monocytes/macrophages, IgE mediated signaling in mast cells, inhibition of Fas/APO-1 apoptotic signaling in B-lineage lymphoid cells etc (Jeffries et al. J. Biol. Chem. 2003, 26258; Horwood et al., J. Experimental Med. 2003, 1603). Use of B-cell depleting protein based therapeutics (for example, Rituxan, a CD20 antibody) for the treatment of a number of autoimmune and/or inflammatory diseases provides enough evidence for the role of B-cells and the humoral immune system in the pathogenesis of autoimmune and/or inflammatory disease. And as Btk is essential for B-cell activation, this also provides an indirect rational for the role of Btk in autoimmune and/or inflammatory diseases.

Additional rationales for the involvement of Btk in various autoimmune and/or inflammatory diseases come from Btk deficient mouse models; for example, Btk deficiency has been shown to result in a marked amelioration of disease progression, in murine preclinical model of systemic lupus erythematosus (SLE). BTK deficient mice are resistant to develop collagen-induced arthritis (Jansson and Holmdahl Clin. Exp. Immumol. 1993, 459).

Pharmacological validation for the involvement of Btk in various autoimmune and/or inflammatory diseases comes from two different class of Btk inhibitors, for example, (a) an irreversible Btk inhibitor (Pan et al, Chem. Med. Chem. 2007, 58), and (b) a reversible Btk inhibitor (Di Paolo, Nat. Chem. Biol. 2010, 41). Both the type of inhibitors have demonstrated efficacy in a mouse model of arthritis. PCI-32765 (an irreversible Btk inhibitor), has shown promising clinical activity in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) (Burger et al, Blooa ' 2010, 32 & J Clin Oncol 2011, 6508). Thus, small molecule Btk inhibitors are expected to be useful to treat a disease process that involves B-cell

r

activation.

Several prior art literature describe the discovery of small molecule Btk inhibitors (for a recent review, Lou et al. J. Med. Chem. 2012). As for example, amino-pyrazolo-pyrimdine (WO201 1046964 A2) and imidazo[l,5-a]quinoxalines (Kim et al, Bio-org. Med. Chem. Lett. , 2011, 6258) based compounds, which utilize its acrylamide functionality for covalent modification of the target protein, are published as irreversible inhibitors. There are literature prior art disclosing reversible Btk inhibitors, such as, substituted amino-pyrimidine analogs (WO2010123870A1); imidazo[l ,2-f][l,2,4]triazine core based amide compounds (WO2010068810A2); various heterocyclic (e. g. imidazo[l ,2-a]pyrazine, aminopyrimidine, 2- pyridone etc); amide derivatives (WO2010068788A1 , WO2010068806A1); benzo[fj[l ,4]oxazepin analogs (WO2010122038A1); 3,4-dihydro-2H-isoquinoline or 2H- isoquinolin-l-one based analogs (WO2010100070A1 , WO2013024078); phenylimidazopyrazine analogs (WO2010006970A1); 3,5-disubstituted pyrid-2-one analogs (WO2007027729A1); azaindazole compounds (WO201 1019780A1); nicotinamide compounds (WO2010144647 A 1); carbazole carboxamide analogs (WO2010080481A1), pyrrolopyrimidine derivatives (WO2013008095).

Despite several discoveries in this area, there is no small molecule Btk inhibitor available in the market. The most advanced compounds in the clinical trials are irreversible inhibitors of Btk. Such an irreversible mechanism of action often encounters nonspecific binding with proteins including off-targets leading to safety concern particularly upon long term used such as off-target related adverse side effects, general hepatotoxicity and organ toxicity, antibody mediated reactions. Therefore, there is a need of Btk inhibitors with safer mechanism of action such as reversible mechanism of inhibition. These compounds will have medical application in the disease area of inflammation, autoimmune disorder and cell proliferation, rheumatoid arthritis, psoriasis, psoriatic arthritis, transplant rejection, graft-versus-host disease, multiple sclerosis, inflammatory bowel disease, allergic diseases and asthma, type 1 diabetes, myasthenia gravis, hematopoetic disfunction, B-cell malignancies, systemic lupus erythematosus.

Summary

The present disclosure provides bicyclic compounds of formula (I), their tautomers, polymorphs, stereoisomers, prodrugs, solvates, hydrates, N-oxides, co-crystals, pharmaceutically acceptable salts, pharmaceutical compositions containing them and methods of treating conditions and diseases that are mediated by Btk activity

wherein,

ring A represents a 5-7 membered ring which is unsaturated or partially unsaturated optionally having upto three heteroatom independently selected from Ο,,Ν or S; ring C, ring D and ring E are independently a monocyclic or a bicyclic ring system which is saturated, unsaturated or partially unsaturated and optionally have additional heteroatoms independently selected from O, N or S, said ring system is further optionally substituted with 1 to 4 substituents independently selected from halo, alkyl, alkenyl, alkynyl, nitro, cyano, - (CR^aR^b)_mOR⁸, -(CR^aR^b)_mSR⁸, -(CR^aR^b)_mNR⁹R¹⁰, oxo, alkylsulfonyl, -(CR^aR^b)_mCOOR⁸, - (CR^aR^b)_mC(0)NR⁹R¹⁰, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

X represents N or C (R¹);

Y represents -C(O) or -S(0)_p-;

Li is a bond or is selected from the group consisting of -(CR^aR^b)-, (Ci_-6)alkylene, (Ci. ₆)alkenylene and

wherein optionally one or more than one methylene groups of alkylene, alkenylene or alkynylene are independently replaced by hetero atoms or groups such as -0-, -S(0)_p-, -N(R⁶)-, -C(O)-, -C(=NR or -C(R')=N-, wherein R' is H, alkyl, cyano, hydroxy, hydroxyalkyl, haloalkyl or perhaloalkyl;

M is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, alkenyl, alkynyl, cyanoalkyl, acyl, cyanoalkylarbonyl, cyanoalkenylcarbonyl, -(CR R^b)_mOR⁸, -SR⁸, - (CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mNR⁹R ¹ °, -(CR^aR^b)_mC(0)NR⁹R^l° -(CR^aR^b)_mNR⁸C(0)NR⁹R¹⁰ thiocarbonyl, S(0)₂NR⁹R¹⁰, -NR⁸S(0)₂R⁸, -S(0)_pR⁸, - S0₃H, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylamino, aryl, arylalkyl, aryloxy, arylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocycloalkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroarylamino;

M is optionally substituted with one or more substituents independently selected from cyano, nitro, keto, oxo, halogen, haloalkyl, perhaloalkyl, hydroxyamino, -(CR^aR^b)_mOR⁸, - (CR^aR^b)_mC(0)R⁸, -OC(0)R⁸ _, -SR⁸, -(CR^aR^b)_mCOOR⁸, -(CR^aR )_mNR⁹R¹⁰, -(CR^aR^b)_mC(0)N R⁹R¹⁰ -(CR^aR^b)_mNR⁸C(0)N R⁹R¹⁰ -NR⁸C(0)R⁸ _, thiocarbonyl, -S(0)₂N R⁹R¹⁰, -NR⁸S(0)₂R⁸, - S(0)_pR⁸, -S0₃H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, heterocyclyl or heteroaryl;

wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, heterocyclyl or heteroaryl are optionally substituted with one or more substituents selected from hydroxy, alkyl, alkoxy, alkoxyalkyl, halogen, haloalkyl, perhaloalkyl, cyano, cyanoalkyl, amino, carboxy, carboxyalkyl, -OC(0)R⁸, -(CR^aR^b)_mC(0)N R⁹R¹⁰, -NR⁸C(0)R⁸ _, -SR⁸, -S(0)_pR⁸, - S(0)₂N R⁹R¹⁰ or -NR⁸S(0)₂R⁸;

U is a bond or is selected from the group consisting of cycloalkylene, cycloalkenylene, cycloalkylenecarbonyl, cycloalkylenealkoxy, cycloalkyleneamino, arylene, arylenecarbonyl, arylenealkoxycarbonyl, arylenealkoxycarbonylamino, aryleneaminocarbonyl, heterocyclylene, heterocyclylenealkyl, heterocyclylenecarbonyl, heterocyclylenealkylamino, heteroarylene, heteroarylenecarbonyl, heteroarylenealkylamino, (C].₆)alkylene, (Ci- )alkenylene or (Ci. ₆)alkynylene wherein one or more than one methylene groups of alkylene, alkenylene or alkynylene are optionally replaced by hetero atoms or groups such as -0-, -S(0)_p-, -N(R⁸)-, or -C(O);

T is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, alkenyl, alkynyl, cyanoalkyl, acyl, cyanoalkylarbonyl, cyanoalkenylcarbonyl, -(CR^aR^b)_mOR⁸, -SR⁸, (CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mN R⁹R¹⁰, -(CR^aR^b)_mC(0)NR⁹R¹⁰ -(CR^aR^b)_mNR⁸C(0)NR⁹R¹⁰ thiocarbonyl, S(0)₂NR⁹R¹⁰, -NR⁸S(0)₂R⁸, -S(0)_pR⁸, -S0₃H, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylamino, aryl, arylalkyl, aryloxy, arylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocycloalkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroarylamino;

U and T is optionally substituted with one or more substituents independently selected from cyano, nitro, keto, oxo, halogen, haloalkyl, perhaloalkyl, hydroxyamino, -(CR^aR^b)_mOR⁸, - (CR^aR^b)_mC(0)R⁸, -OC(0)R⁸ _, -SR⁸, -(CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mNR⁹R¹⁰,

(CR^aR^b)_mC(0)NR⁹R¹⁰ -(CR^aR^b)_mNR⁸C(0)_mR⁹R¹⁰ -NR⁸C(0)R⁸ thiocarbonyl, -S(0)₂N R⁹R¹⁰, - NR⁸S(0)₂R⁸, -S(0)_pR⁸, -S0₃H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, heterocyclyl or heteroaryl;

wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, heterocyclyl or heteroaryl are optionally substituted with one or more substituents selected from hydroxy, alkyl, alkoxy, alkoxyalkyl, halogen, haloalkyl, perhaloalkyl, cyano, cyanoalkyl, amino, carboxy, carboxyalkyl, -OC(0)R⁸, -(CR^aR^b)_mC(0)N R⁹R¹⁰, -NR⁸C(0)R⁸ _, -SR⁸, -S(0)_pR⁸, -

S(0)₂N R R¹⁰ or -NR⁸S(0)₂R⁸;

R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, -(CR^aR^b)_mC(0)R⁸, -(CR^aR^b)_mN R⁹R¹⁰, aminocarbonyl, alkoxycarbonylamino, alkylsulfonylamino, aminocarbonylamino, hydroxyamino, alkoxyamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, haloalkyl, perhaloalkyl, cycloalkyl, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy, -S0₃H, alkylthio, aminosulfonyl, alkylsulfonyl, or nitro; or when R¹ or R² or R³ or R⁴ or R⁵ are more than one, then any 2 R¹ or 2 R² or 2 R³ or 2 R⁴ or 2 R⁵ independently is optionally, taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have one or more additional heteroatoms independently selected from O, N or S;

R⁸ is selected from the group consisting of hydrogen, -(CR^AR^B)_MOR⁸, halogen, haloalkyl, - (CR^AR^B)_MC(0)R⁸, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl;

wherein alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl are optionally substituted with one or more substituents selected from hydroxy, alkyl, alkoxy, alkoxyalkyl, halogen, haloalkyl, perhaloalkyl, cyano, cyanoalkyl, amino, carboxy, carboxyalkyl, -OC(0)R⁸, -(CR^AR^B)_MC(0)N R⁹R¹⁰, -NR⁸C(0)R⁸ -SR⁸, -S(0)_PR⁸, -S(0)₂N R⁹R¹⁰ or -NR⁸S(0)₂R⁸;

R⁹ and R^!0 are independently selected from the group consisting of hydrogen, -(CR^AR^B)_MOR⁸, haloalkyl, -(CR^AR^B)_MC(0)R⁸, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl, or

R⁹ and R¹⁰ taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S, said ring system is further optionally substituted with 1 to 4 substituents independently selected from halo, alkyl, alkenyl, alkynyl, nitro, cyano, -(CR^AR^B)_MOR⁸, -SR⁸, -(CR^AR^B)_MNR⁹R¹⁰, oxo, alkylsulfonyl, -(CR^AR^B)_MCOOR⁸, -(CR^AR^B)_MC(0)N R⁹R'°, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R^A and R^B are independently selected from the group consisting of hydrogen, -OR⁶, halogen, haloalkyl, perhaloalkyl and alkyl;

R^A and R^B taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S;

m is 0-6;

n is 0 - 3;

p is 0, 1 or 2;

q is 1 or 2.

Detailed description Definitions

In the structural formulae given herein and throughout the present disclosure, the following terms have the indicated meaning, unless specifically stated otherwise.

The term "optionally substituted" as used herein means that the group in question is either unsubstituted or substituted with one or more of the substituents specified. When the group in question is substituted with more than one substituent, the substituent may be same or different.

The term "alkyl" refers to a monoradical branched or unbranched saturated hydrocarbon chain having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, preferably 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably 1 , 2, 3, 4, 5 or 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl, and the like.

The term "alkylene" refers to a diradical of a branched or unbranched saturated hydrocarbon chain, having 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 1 1 ,12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, preferably 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably 1 , 2, 3, 4, 5 or 6 carbon atoms. This term is exemplified by groups such as methylene (-CH₂-), ethylene (- CH₂CH₂-), the propylene isomers (e.g., -CH₂CH₂CH₂- and -CH(CH₃)CH₂-) and the like.

The term "substituted alkyl" or "substituted alkylene" refers to: 1) an alkyl group or alkylene group as defined above, having 1, 2, 3, 4 or 5 substituents, preferably 1 , 2 or 3 substituents, selected from the group consisting of alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, monoalkylamino, dialkylamino, arylamino, heteroarylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, carboxyalkyl, -SO₃H, aryl, aryloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -S(0)₂NR^aR^a, -NR^aS(0)₂R^a and -S(0)_pR^b, where each R^a is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl heteroarylalkyl, heterocyclyl and heterocyclylalkyl; heterocyclyloxy where R^b is hydrogen, alkyl, aryl, heteroaryl or heterocyclyl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1 , 2, or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and -S(0)_pR^c, where R^c is alkyl, aryl, or heteroaryl and p is 0, 1 or 2; or 2) an alkyl group or alkylene group as defined above that is interrupted by 1 , 2, 3, 4, 5, 6, 7, 8,_. 9 or 10 atoms independently selected from oxygen, sulphur and NR^d, where R^d is selected from hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl, carbonylalkyl, carboxyester, carboxyamide and sulfonyl. All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF₃, amino, substituted amino, cyano, or -S(0)_pR^c, in. which R^c is alkyl, aryl, or heteroaryl and p is 0, 1 , or 2;

or 3) an alkyl or alkylene as defined above that has 1 , 2, 3, 4 or 5 substituents as defined above, as well as interrupted by 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 atoms as defined above.

The term "alkenyl" refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, more preferably 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and even more preferably 2, 3, 4, 5 or 6 carbon atoms and having 1 , 2, 3, 4, 5 or 6 double bond (vinyl), preferably 1 double bond. Preferred alkenyl groups include ethenyl or vinyl(-CH=CH₂), 1- propylene or allyl (-CH₂CH=CH₂), isopropylene (-C(CH₃)=CH₂), bicyclo [2.2. 1] heptene, and the like.

The term "alkenylene" refers to a diradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, more preferably 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and even more preferably 2, 3, 4, 5 or 6 carbon atoms and having 1 , 2, 3, 4, 5 or 6 double bond (vinyl), preferably 1 double bond.

The term "substituted alkenyl" refers to an alkenyl group as defined above having 1 , 2, 3, 4 or 5 substituents, and preferably 1, 2, or 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarboriylamino, azido, cyano, halogen, thiocarbonyl, carboxy, carboxyalkyl, S0₃H, aryl, aryloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -S(0)₂NR^aR^a, -NR^aS(0)₂R^a and -S(0)_pR^b where each R^a is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl heteroarylalkyl, heterocyclyl, heterocyclylalkyl and heterocyclyloxy, where R^b is alkyl, aryl, heteroaryl or heterocyclyl and p is 0, 1 or 2. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1 , 2, or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and -S(0)_pR^c, where R^c is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.

The term "alkynyl" refers to a monoradical of an unsaturated hydrocarbon, preferably having from 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, more preferably 2, 3, 4, 5, 6,-7, 8, 9 or 10 carbon atoms and even more preferably 2, 3, 4, 5 or 6 carbon atoms and having 1 , 2, 3, 4, 5 or 6 sites of acetylene (triple bond) unsaturation, preferably 1 triple bond. Preferred alkynyl groups include ethynyl, (-C≡CH), propargyl (or prop-l-yn-3-yl,- CH₂C≡CH), homopropargyl (or but-l-yn-4-yl, -CH₂CH₂C≡CH) and the like.

The term "alkynylene" refers to a diradical of a branched or an unbranched unsaturated hydrocarbon group preferably having from 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, more preferably 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and even more preferably 2, 3, 4, 5 or 6 carbon atoms and having 1, 2, 3, 4, 5 or 6 sites of acetylene (triple bond) unsaturation, preferably 1 triple bond.

The term "substituted alkynyl" refers to an alkynyl group as defined above having 1 , 2, 3, 4 or 5 substituents, and preferably 1 , 2, or 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, -SO3H, aryl, aryloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -S(0)₂NR^aR^a, -NR^aS(0)₂R^a and -S(0)_pR^b, where each R^a is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl heteroarylalkyl, heterocyclyl, heterocyclylalkyl and heterocyclyloxy, where R^b is alkyl, aryl, heteroaryl or heterocyclyl and p is 0, 1 or 2. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1 , 2, or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and-S(0)_pR^c where R° is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.

The term "cycloalkyl" refers to unless otherwise mentioned, carbocyclic groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings or spirocyclic rings or bridged rings which may be saturated or partially unsaturated. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, 1 ,3,3- trimethylbicyclo[2.2.1]hept-2-yl, (2,3,3-trimethylbicyclo[2.2.1]hept-2-yl), or carbocyclic groups to which is fused an aryl group, for example indane, and the like.

The term "cycloalkylene" refers to a divalent cycloalkyl group as defined above. This term is exemplified by groups such as 1 ,4-cyclohexylene, 1 ,3-cyclohexylene, 1 ,2- cyclohexylene, 1 ,4-cyclohexenyl and the like..

The term "substituted cycloalkyl" refers to cycloalkyl groups having 1 , 2, 3, 4 or 5 substituents, and preferably 1, 2, or 3 substituents, selected from the group consisting of alkyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -C(0)R and -S(0)_pR^b, where R is hydrogen, hydroxyl, alkoxy, alkyl and cyclocalkyl, heterocyclyloxy where R^b is alkyl, aryl, heteroaryl or heterocyclyl and p is 0, 1 or 2. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1 , 2, or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and-S(0)_pR°, where R^c is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.

"Halo" or "Halogen", alone or in combination with any other term means halogens such as chloro (CI), fluoro.(F), bromo (Br) and iodo (I).

"Haloalkyl" refers to a straight chain or branched chain haloalkyl group with 1 to 6 carbon atoms. The alkyl group may be partly or totally halogenated. Representative examples of haloalkyl groups include but are not limited to fluoromethyl, chloromethyl, bromomethyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3-chloropropyl, 3-bromopropyl and the like.

The term "alkoxy" refers to the group R"'-0-, where R'" is optionally substituted alkyl or optionally substituted cycloalkyl, or optionally substituted alkenyl or optionally substituted alkynyl; or optionally substituted cycloalkenyl, where alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl are as defined herein. Representative examples of alkoxy groups include but are not limited to methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n- pentoxy, n-hexoxy, 1 ,2-dimethylbutoxy, trifluoromethoxy, and the like. The term "aminocarbonyl" refers to the group -C(0)NR'R^' where each R^' is independently hydrogen, alkyl, aryl, heteroaryl, heterocyclyl or both R' groups are joined to form a heterocyclic group (e. g. morpholino). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1 -3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and -S(0)_pR°, where R^c is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.

The term "acylamino" refers to the group -NR"C(0)R" where each R" is independently hydrogen, alkyl, aryl, heteroaryl, or heterocyclyl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and-S(0)_pR^c, where R° is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.

The term "acyloxy" refers to the groups -OC(0)-alkyl, -OC(0)-cycloalkyl, -OC(0)-aryl, - OC(0)-heteroaryl, and -OC(0)-heterocyclyl. Unless otherwise constrained by the definition, all substituents may be optionally further substituted by alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, or -S(0)_pR^c, where R^c is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.

"Alkoxyalkyl" refers to alkyl groups as defined above wherein at least one of the hydrogen atoms of the alkyl group is replaced by an alkoxy group as defined above. Representative examples of alkoxyalkyl groups include but are not limited to methoxymethyl, methoxyethyl, ethoxymethyl and the like.

"Aryloxyalkyl" refers to the group -alkyl-O-aryl. Representative examples of aryloxyalkyl include but are not limited to phenoxymethyl, naphthyloxymethyl, phenoxyethyl, naphthyloxyethyl and the like.

"Di alkylamino" refers to an amino group, to which two same or different straight chain or branched chain alkyl groups with 1 to 6 carbon atoms are bound. Representative examples of di alkylamino include but are not limited to dimethylamino, diethylamino, methylethylamino, dipropylamino, dibutylamino and the like.

"Cycloalkylalkyl" refers to an alkyl radical as defined above which is substituted by a cycloalkyl radical as defined above. Representative examples of cycloalkylalkyl include but are not limited to cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1 - cyclopentylethyl, 1-cyclohexylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, cyclobutylpropyl, cyclopentylpropyl, cyclohexylbutyl and the like.

"Aminoalkyl" refers to an amino group that is attached to (C| _6)alkylene as defined herein. Representative examples of aminoalkyl include but are not limited to aminomethyl, aminoethyl, 1 -aminopropyl, 2-aminopropyl, and the like. The amino moiety of aminoalkyl may be substituted once or twice with alkyl to provide alkylaminoalkyl and dialkylaminoalkyl respectively. Representative examples of alkylaminoalkyl include but are not limited to methylaminomethyl, methylaminoethyl, mefhylaminopropyl, ethylaminoethyl and the like. Representative examples of dialkylaminoalkyl include but are not limited to dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, N-methyl-N-ethylaminoethyl and the like.

The term "aryl" refers to an aromatic carbocyclic group of 6 to 20 carbon atoms having a single ring (e.g. phenyl) or multiple rings (e.g. biphenyl), or multiple condensed (fused) rings (e.g. naphthyl or anthranyl). Preferred aryls include phenyl, naphthyl and the like.

The term "arylene" refers to a diradical of an aryl group as defined above. This term is exemplified by groups such as 1 ,4-phenylene, 1 ,3-phenylene, 1 ,2-phenylene, l ,4'-biphenylene, and the like.

Unless otherwise constrained the aryl or arylene groups may optionally be substituted with 1 , 2, 3 4 or 5 substituents, preferably 1 , 2 or 3 substituents, selected from the group consisting of alkyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, carboxy, carboxyalkyl, - SO3H, aryl, aryloxy, heteroaryl, amino sulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -S(0)₂NR^aR^a, -NR^aS(0)₂R^a and -S(0)_pR^b where each R^a is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; where R^b is hydrogen, alkyl, aryl, heterocyclyl or heteroaryl and p is 0, 1 or 2. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1 , 2 or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and -S(0)_pR^c where R^c is hydrogen, alkyl, aryl, or heteroaryl and p is 0, 1 or 2. The term "arylalkyl" refers to an aryl group covalently linked to an alkylene group, where aryl and alkylene are defined herein.

"Optionally substituted arylalkyl" refers to an optionally substituted aryl group covalently linked to an optionally substituted alkylene group. Such arylalkyl groups are exemplified by benzyl, phenethyl, naphthylmethyl, and the like.

The term "aryloxy" refers to the group aryl-O- wherein the aryl group is as defined above, and includes optionally substituted aryl groups as also defined above.

The term "arylthio" refers to the group -S-aryl, where aryl is as defined herein including optionally substituted aryl groups as also defined above.

The term "substituted amino" refers to the group -NR R' where each R^' is independently ^* selected from the group consisting of hydrogen, alkyl, cycloalkyl, carboxyalkyl, alkoxycarbonyl, aryl, heteroaryl and heterocyclyl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1 , 2 or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and -S(0)_pR^c, where R^c is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.

The term "carboxyalkyl" refers to the groups -alkylene-C(0)OH.

The term "alkylcarboxyalkyl" refers to the groups -alkylene-C(0)OR^d where R^d is alkyl, cycloalkyl, where alkyl, cycloalkyl are as defined herein, and may. be optionally further substituted by alkyl, halogen, CF₃, amino, substituted amino, cyano, or -S(0)_pR^c, in which R^c is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.

The term "heteroaryl" refers to an aromatic cyclic group having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, or 15 carbon atoms and 1 , 2, 3 or 4 heteroatoms selected from oxygen, nitrogen and sulphur within at least one ring. Such heteroaryl groups can have a single ring (e.g. pyridyl or furyl) or multiple condensed rings (e.g. indolizinyl, benzothiazolyl, or benzothienyl), Examples of heteroaryls include, but are not limited to, [1 ,2,4] oxadiazole, [1 ,3,4] oxadiazole, [1,2,4] thiadiazole, [1 ,3,4] thiadiazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, furan, thiophene, oxazole, thiazole, triazole, triazine and the like.

The term "heteroarylene" refers to a diradical of a heteroaryl group as defined above. Unless otherwise constrained the heteroaryl or heterarylene groups can be optionally substituted with 1 , 2, 3, 4 or 5 substituents, preferably 1 , 2 or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, thiocarbonyl, carboxy, carboxyalkyl, -S0₃H, aryl, aryloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -S(0)₂NR^aR^a, - NR^aS(0)₂R^a and -S(0)_pR^b, where each R^a is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl heteroarylalkyl, heterocyclyl and heterocyclylalkyl; where R^b is hydrogen, alkyl, aryl, heterocyclyl or heteroaryl, and p is 0, 1 or 2. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and-S(0)_nR^c, where R^c is alkyl, aryl, or heteroaryl and n is 0,1 or 2.

The term "heteroarylalkyl" refers to a heteroaryl group covalently linked to an alkylene group, where heteroaryl and alkylene are defined herein.

"Optionally substituted heteroarylalkyl" refers to an optionally substituted heteroaryl group covalently linked to an optionally substituted alkylene group. Such heteroarylalkyl groups are exemplified by 3-pyridylmethyl, quinolin-8-ylethyl, 4-mefhoxythiazol-2-ylpropyl, and the like.

The term "heterocyclyl" refers to a saturated or partially unsaturated group having a single ring or multiple condensed rings or spirocyclic rings, or bridged rings unless otherwise mentioned, having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms, preferably 1 , 2, 3 or 4 heteroatoms, selected from nitrogen, sulphur, phosphorus, and/or oxygen within the ring.. Heterocyclic groups can have a single ring or multiple condensed rings, and include tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, dihydropyridinyl, tetrahydroquinolinyl and the like. Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 , 2, 3, 4 or 5, and preferably 1 , 2 or 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, -C(0)R where R is hydrogen, hydroxyl, alkoxy, alkyl and cyclocalkyl, thiocarbonyl, carboxy, carboxyalkyl, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, b b

alkoxyamino, nitro, and -S(0)_pR , where R is hydrogen, alkyl, aryl, heterocyclyl or heteroaryl and p is 0, 1 or 2. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and -S(0)R^c, where R^c is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term "heterocyclylalkyl" refers to a heterocyclyl group covalently linked to an alkylene group, where heterocyclyl and alkylene are defined herein.

"Optionally substituted heterocyclylalkyl" refers to an optionally substituted heterocyclyl group covalently linked to an optionally substituted alkylene group.

The term "heteroaryloxy" refers to the group heteroaryl-O-.

The term "thiol" refers to the group -SH.

The term "substituted alkylthio" refers to the group -S-substituted alkyl.

The term "heteroarylthio" refers to the group -S-heteroaryl wherein the heteroaryl group is as defined above including optionally substituted heteroaryl groups as also defined above. The term "sulfoxide" refers to a group -S(O).

"Substituted sulfoxide" refers to a group -S(0)R, in which R is substituted alkyl, substituted aryl, or substituted heteroaryl, as defined herein.

The term "sulfone" refers to a group -S(0)₂R.

The term "substituted sulfone" refers to a group -S(0)₂R, in which R is alkyl, aryl, or heteroaryl.

The compounds of the present disclosure may have the ability to crystallize in more than one form, a characteristic known as polymorphism, and all such polymorphic forms ("polymorphs") are encompassed within the scope of the disclosure. Polymorphism generally can occur as a response to changes in temperature or pressure or both, and can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics, and typically the x-ray diffraction patterns, solubility behavior, and melting point of the compound are used to distinguish polymorphs.

The compounds described herein may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), regioisomers, enantiomers or diastereomers. Accordingly, the chemical structures depicted herein encompass all possible enantiomers and stereoisomers of the illustrated or identified compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the person skilled in the art. The compounds may also exist in several tautomeric forms including the enol form, the keto form and mixtures thereof. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated or identified compounds.

Compounds may exist in unsolvated forms as well as solvated forms, including hydrated forms and as N-oxides. In general, compounds may be hydrated, solvated or N-oxides. Certain compounds may exist in multiple crystalline or amorphous forms. Also contemplated within the scope of the disclosure are congeners, analogs, hydrolysis products, metabolites and precursor or prodrugs of the compound. In general, unless otherwise indicated, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present disclosure.

"Prodrug" refers to a derivative of a drug molecule as, for example, esters, carbonates, carbamates, ureas, amides or phosphates that requires a transformation within the body to release the active drug. Prodrugs are frequently, although not necessarily, pharmacologically inactive until converted to the parent drug. Prodrugs may be obtained by bonding a promoiety (defined herein) typically via a functional group, to a drug.

"Promoiety" refers to a group bonded to a drug, typically to a functional group of the drug, via bond(s) that are cleavable under specified conditions of use. The bond(s) between the drug and promoiety may be cleaved by enzymatic or non-enzymatic means. Under the conditions of use, for example following administration to a patient, the bond(s) between the drug and promoiety may be cleaved to release the parent drug. The cleavage of the promoiety may proceed spontaneously, such as via a hydrolysis reaction, or it may be catalyzed or induced by another agent, such as by an enzyme, by light, by acid, or by a change of or exposure to a physical or environmental parameter, such as a change of temperature, pH, etc. The agent may be endogenous to the conditions of use, such as an enzyme present in the systemic circulation to which the prodrug is administered or the acidic conditions of the stomach or the agent may be supplied exogenously. "Pharmaceutically acceptable salt" embraces salts with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids, for example hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitric acid and organic acids, for example citric, fumaric, maleic, malic, mandelic, ascorbic, oxalic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p- toluenesulphonic acid. Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases, for example alkyl amines, arylalkyl amines and heterocyclic amines.

Other preferred salts according to the disclosure are quaternary ammonium compounds wherein an equivalent of an anion (M-) is associated with the positive charge of the N atom. M- may be an anion of various mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate, or an anion of an organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate and p-toluenesulphonate. M- is preferably an anion selected from chloride, bromide, iodide, sulphate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. More preferably M- is chloride, bromide, trifluoroacetate or methanesulphonate.

"Co-crystal" refers to a crystalline material comprising two or more compounds at ambient temperature (20 to 25[deg.]C, preferably 20[deg.]C), of which at least two are held together by weak interaction, wherein at least one of the compounds is a co-crystal former. Weak interaction is being defined as an interaction which is neither ionic nor covalent and includes for example: hydrogen bonds, van der Waals forces, and interactions.

"Pharmaceutical composition" refers to one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present disclosure encompass any composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier.

"Carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, including but not limited to peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered orally. Saline and aqueous dextrose are preferred carriers when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions are preferably employed as liquid carriers for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations and the like. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin. Such compositions will contain a therapeutically effective amount of the therapeutic, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration.

"Drug or pharmaceutically active agent" includes a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.

"Combined" or "in combination" or "combination" should be understood as a functional coadministration, wherein some or all compounds may be administered separately, in different formulations, different modes of administration (for example subcutaneous, intravenous or oral) and different times of administration. The individual compounds of such combinations may be administered either sequentially in separate pharmaceutical compositions as well as simultaneously in combined pharmaceutical compositions.

"Therapeutically effective amount" is an amount of a compound of Formula (I) or a combination of two or more such compounds, which inhibits, totally or partially, the progression of the condition or alleviates, at least partially, one or more symptoms of the condition. A therapeutically effective amount can also be an amount which is prophylactically effective. The amount which is therapeutically effective will depend upon the patient's size and gender, the condition to be treated, the severity of the condition and the result sought. For a given patient, a therapeutically effective amount can be determined by methods known to those of skill in the art.

The present disclosure provides compounds of formula (I), their tautomers, polymorphs, stereoisomers, prodrugs, solvates, hydrates, N-oxides, co-crystals, pharmaceutically acceptable salts, pharmaceutical compositions containing them and methods of treating conditions and diseases that are mediated by Btk activity

wherein,

'ring A represents a 5-7 membered ring which is unsaturated or partially unsaturated optionally having upto three heteroatom independently selected from O, N or S; .

ring C, ring D and ring E are independently a monocyclic or a bicyclic ring system which is saturated, unsaturated or partially unsaturated and optionally have additional heteroatoms independently selected from O, N or S, said ring system is further optionally substituted with 1 to ^' 4 substituents independently selected from halo, alkyl, alkenyl, alkynyl, nitro, cyano, - (C ^aR^b)_mOR⁸, -(CR^aR^b)_mSR⁸ _> -(CR^aR^b)_mNR⁹R¹⁰, oxo, alkylsulfonyl, -(CR^aR^b)_mCOOR⁸, - (C R^aR^b)_mC(0)NR⁹R ¹ °, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

X represents N or C (R¹);

Y represents -C(O) or -S(0)_p-;

Li is a bond or is selected from the group consisting of -(CR^aR^b)-, (Ci_-6)alkylene, (Ci_ 6)alkenylene or (Ci_-6)alkynylene wherein optionally one or more than one methylene groups of alkylene, alkenylene or alkynylene are independently replaced by hetero atoms or groups such as -Ο-, -S(0)p-, -N(R⁶)-, -C(O)-, -C(=NR')- or -C(R')=N-, wherein R' is H, alkyl, cyano, hydroxy, hydroxyalkyl, haloalkyl or perhaloalkyl;

M is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, alkenyl, alkynyl, cyanoalkyl, acyl, cyanoalkylarbonyl, cyanoalkenylcarbonyl, -(CR^aR^b)mOR⁸, -SR⁸, - (CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mNR⁹R ¹ °, -(CR^aR^b)_mC(0)NR⁹R¹⁰ -(CR^aR^b)_mNR⁸C(0)NR⁹R¹⁰ thiocarbonyl, S(0)₂NR⁹R¹⁰, -NR⁸S(0)₂R⁸, -S(0)_pR⁸, - S0₃H, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylamino, aryl, arylalkyl, aryloxy, arylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocycloalkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroarylamino;

M is optionally substituted with one or more substituents independently selected from cyano, nitro, keto, oxo, halogen, haloalkyl, perhaloalkyl, hydroxyamino, -(CR^aR^b)_mOR⁸, - (CR^aR^b)_mC(0)R⁸, -OC(0)R⁸ _, -SR⁸, -(CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mNR⁹R¹⁰, -(CR^aR^b)_mC(0)N R⁹R¹⁰ -(CR^aR^b)_mNR⁸C(0)N R R¹⁰ -NR⁸C(0)R⁸ _, thiocarbonyl, -S(0)₂N R⁹R¹⁰, -NR⁸S(0)₂R⁸, - S(0)_pR⁸, -S0₃H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, heterocyclyl or heteroaryl;

wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, heterocyclyl or heteroaryl are optionally substituted with one or more substituents selected from hydroxy, alkyl, alkoxy, alkoxyalkyl, halogen, haloalkyl, perhaloalkyl, cyano, cyanoalkyl, amino, carboxy, carboxyalkyl, -OC(0)R⁸, -(CR^aR^b)mC(0)N R⁹R¹⁰, -NR⁸C(0)R⁸ _, -SR⁸, -S(0)_pR⁸, - S(0)₂N R⁹R¹⁰ or -NR⁸S(0)₂R⁸;

U is a bond or is selected from the group consisting of cycloalkylene, cycloalkenylene, cycloalkylenecarbonyl, cycloalkylenealkoxy, cycloalkyleneamino, arylene, arylenecarbonyl, arylenealkoxycarbonyl, arylenealkoxycarbonylamino, aryleneaminocarbonyl, heterocyclylene, heterocyclylenealkyl, heterocyclylenecarbonyl, heterocyclylenealkylamino, heteroarylene, heteroarylenecarbonyl, heteroarylenealkylamino, (Ci_₆)alkylene, (Ci_-6)alkenylene or (Ci_ )alkynylene wherein one or more than one methylene groups of alkylene, alkenylene or alkynylene are optionally replaced by hetero atoms or groups such as -0-, -S(0)_p-, -N(R )-, or -C(O);

T is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, alkenyl, alkynyl, cyanoalkyl, acyl, cyanoalkylarbonyl, cyanoalkenylcarbonyl, -(CR^aR^b)_mOR⁸, -SR⁸, (CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mNR⁹R¹⁰, -(CR^aR^b)_mC(0)NR⁹R¹⁰ -(CR^aR^b)_mNR⁸C(0)NR⁹R'° thiocarbonyl, S(0)₂NR⁹R¹⁰, -NR⁸S(0)₂R⁸, -S(0)_pR⁸, -S0₃H, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylamino, aryl, arylalkyl, aryloxy, arylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocycloalkylamino, tieteroaryl, heteroarylalkyl, heteroaryloxy, or heteroarylamino;

(CR^aR^b)_mC(0)NR⁹R¹⁰ -(CR^aR^b)_mNR⁸C(0)_mR⁹R¹⁰ -NR⁸C(0)R⁸ _, thiocarbonyl, -S(0)₂N R⁹R¹⁰, - NR⁸S(0)₂R⁸, -S(0)_pR⁸, -SO₃H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, heterocyclyl or heteroaryl; >

R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, acyl, acylamino; acyloxy, -(CR^aR^b)_mC(0)R⁸, -(CR^aR^b)_mN R⁹R¹⁰, aminocarbonyl, alkoxycarbonylamino, alkylsulfonylamino, aminocarbonylamino, hydroxyamino, alkoxyamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, haloalkyl, perhaloalkyl, cycloalkyl, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy, -SO₃H, alkylthio, aminosulfonyl, alkylsulfonyl, or nitro; or when R¹ or R² or R³ or R⁴ or R⁵ are more than one, then any 2 R¹ or 2 R² or 2 R³ or 2 R⁴ or 2 R⁵ independently is optionally, taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have one or more additional heteroatoms independently selected from O, N or S;

R⁸ is selected from the group consisting of hydrogen, -(CR^aR^b)_mOR⁸, halogen, haloalkyl, - (CR^aR^b)_mC(0)R⁸, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl;

wherein alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl are optionally substituted with one or more substituents selected from hydroxy, alkyl, alkoxy, alkoxyalkyl, halogen, haloalkyl, perhaloalkyl, cyano, cyanoalkyl, amino, carboxy, carboxyalkyl, -OC(0)R⁸, -(CR^aR^b)_mC(0)N

R⁹R¹⁰, -NR⁸C(0)R⁸ _> -SR⁸, -S(0)_pR⁸, -S(0)₂N R⁹R¹⁰ or -NR⁸S(0)₂R⁸; R⁹ and R¹⁰ are independently selected from the group consisting of hydrogen, -(CR^aR^b)_mOR⁸, haloalkyl, -(CR^aR^b)_mC(0)R⁸, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl, or

R⁹ and R¹⁰ taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S, said ring system is further optionally substituted with 1 to 4 substituents independently selected from halo, alkyl, alkenyl, alkynyl, nitro, cyano, -(CR^aR^b)_mOR⁸, -SR⁸, -(CR^aR^b)_mNR⁹R¹⁰, oxo, alkylsulfonyt, -(CR^aR^b)_mCOOR⁸, -(CR^aR^b)mC(0)N R⁹R¹⁰, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R^a and R^b are independently selected from the group consisting of hydrogen, -OR⁶, halogen, haloalkyl, perhaloalkyl or alkyl;

m is 0-6;

n is 0 - 3;

p is 0, 1 or 2;

q is 1 or 2.

According to another embodiment, the present disclosure relates to compounds of formula (I) or its tautomers, polymorphs, stereoisomers, prodrugs, solvate, co-crystals or a pharmaceutically acceptable salts thereof, wherein,

ring A represents a 5 membered ring which is unsaturated or partially unsaturated optionally having upto three heteroatom independently selected from O, N or S;

ring C, ring D and ring E are independently a monocyclic or a bicyclic ring system which is saturated, unsaturated or partially unsaturated and optionally have additional heteroatoms independently selected from O, N or S, said ring system is further optionally substituted with 1 to 4 substituents independently selected from halo, alkyl, alkenyl, alkynyl, nitro, cyano, - (CR^aR^b)_mOR⁸, -(CR^aR )_mSR⁸, -(CR^aR^b)_mNR⁹R¹⁰, oxo, alkylsulfonyl, -(CR^aR^b)_mCOOR⁸, - (CR^aR^b)_mC(0)NR⁹R¹⁰, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

X represents N or C (R¹);

Y represents -C(O); Li is a bond or is selected from the group consisting of -(CR^aR^b)- or (Ci_₆)alkylene wherein optionally one or more than one methylene groups are independently replaced by hetero atoms or groups such as -0-, -S(0)p-, -N(R⁶)-, -C(O)-, -C(=NR or -C(R')=N-, wherein R' is H, alkyl, cyano, hydroxy, hydroxyalkyl, haloalkyl or perhaloalkyi;

M is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyi, alkyl, alkenyl, alkynyl, cyanoalkyl, acyl, cyanoalkylarbonyl, cyanoalkenylcarbonyl, -(CR^aR^b)_mOR⁸, -SR⁸, - (CR'R^_mCOOR⁸, -(CR^aR^b)_mNR⁹R¹⁰, -(CR^aR^b)_mC(0)NR⁹R¹⁰ -(CR^aR^b)_mNR⁸C(0)NR⁹R¹⁰ thiocarbonyl, S(0)₂NR⁹R¹⁰, -NR⁸S(0)₂R⁸, -S(0)_pR⁸, - S0₃H, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylamino, aryl, arylalkyl, aryloxy, arylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocycloalkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroarylamino;

M is optionally substituted with one or more substituents independently selected from cyano, nitro, keto, xo, halogen, haloalkyl, perhaloalkyi, hydroxyamino, -(CR^aR^b)_mOR⁸, - (CR^aR^b)_mC(0)R⁸, -OC(0)R⁸ -SR⁸, -(CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mNR⁹R¹⁰, -(CR^aR^b)_mC(0)N R⁹R¹⁰ -(CR^aR^b)_mNR⁸C(0)N R⁹R¹⁰ -NR⁸C(0)R⁸ _> thiocarbonyl, -S(0)₂N R⁹R¹⁰, -NR⁸S(0)₂R⁸, - S(0)_pR⁸, -S0₃H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, heterocyclyl or heteroaryl;

U is a bond or is selected from the group consisting of cycloalkylene, arylene, heterocyclylene, heteroarylene, (Ci^alkylene, (Ci_-6)alkenylene or (C| _6)alkynylene wherein one or more than one methylene groups of alkylene, alkenylene or alkynylene are optionally replaced by hetero atoms or groups such as -0-, -S(0)_p-, -N(R⁸)-, or -C(O);

T is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyi, alkyl, alkenyl, cyanoalkyl, acyl, -(CR^aR^b)_mOR⁸, -SR⁸, -(CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mN R⁹R¹⁰, -(CR^aR^b)_mC(0)NR⁹R¹⁰ - (CR^aR^b)_mNR⁸C(0)N R⁹R'° thiocarbonyl, S(0)₂NR⁹R¹⁰, -NR⁸S(0)₂R⁸, -S(0)_pR⁸, -S0₃H, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylamino, aryl, arylalkyl, aryloxy, arylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocycloalkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroarylamino;

U and T is optionally substituted with one or more substituents independently selected from cyano, nitro, keto, oxo, halogen, haloalkyl, perhaloalkyi, hydroxyamino, -(CR^aR^b)_mOR⁸, - (CR^aR^b)_mC(0)R⁸, -OC(0)R⁸ _, -SR⁸, -(CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mN R⁹R¹⁰, -(CR^aR^b)_mC(0)N R⁹R¹⁰ -(CR^aR^b)_mNR⁸C(0)_m R⁹R¹⁰ -NR⁸C(0)R⁸ _, thiocarbonyl, -S(0)₂N R⁹R¹⁰, -NR⁸S(0)₂R⁸, - S(0)_pR , -S0₃H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, heterocyclyl or heteroaryl;

R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, -(CR^aR^b)_mC(0)R⁸, -(CR^aR^b)_mN R⁹R¹⁰, aminocarbonyl, alkoxycarbonylamino, alkylsulfonylamino, aminocarbonylamino, hydroxyamino, alkoxyamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, haloalkyl, perhaloalkyl, cycloalkyl, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy, -SO₃H, alkylfhio, aminosulfonyl, alkylsulfonyl, or nitro; or when R¹ or R² or R³ or R⁴ or R⁵ are more than one, then any 2 R¹ or 2 R² or 2 R³ or 2 R⁴ or 2 R⁵ independently is optionally, taken together form a- monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have one. or more additional heteroatoms independently selected from O, N or S;

R⁸ is selected from the group consisting of hydrogen, -(CR^aR^b)_mOR⁸, halogen, haloalkyl, - (CR^aR )_mC(0)R⁸, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl;

wherein alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl are optionally substituted with one or more substituents selected from hydroxy, alkyl, alkoxy, alkoxyalkyl, halogen, haloalkyl, perhaloalkyl, cyano, cyanoalkyl, amino, carboxy, carboxyalkyl, -OC(0)R , (CR^aR^b)mC(0)N R⁹R¹⁰, -NR⁸C(0)R⁸ _, -SR⁸, -S(0)_pR⁸, -S(0)₂N R⁹R¹⁰ or -NR⁸S(0)₂R⁸; R⁹ and R¹⁰ are independently selected from the group consisting of hydrogen, -(CR^aR^b)_mOR⁸, haloalkyl, -(CR^aR^b)_mC(0)R⁸, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl, or

R⁹ and R¹⁰ taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or. S, said ring system is further optionally substituted with 1 to 4 substituents independently selected from halo, alkyl, alkenyl, alkynyl, nitro, cyano, -(CR^aR^b)_mOR⁸, -SR⁸, -(CR^aR^b)_mNR⁹R ¹ °, oxo, alkylsulfonyl, -(CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mC(0)N R⁹R¹⁰, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R^a and R^b are independently selected from the group consisting of hydrogen, -OR⁶, halogen, haloalkyl, perhaloalkyl or alkyl; R^a and R^b taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S;

m is 0-3;

n is 0 - 3;

p is 0, 1 or 2;

q is 1 or 2.

ring C, ring D and ring E are independently a monocyclic or a bicyclic ring system which is saturated, unsaturated or partially unsaturated and optionally have additional heteroatoms independently selected from O, N or S;

X represents N;

Y represents -C(O);

Li is a bond or is selected from the group consisting of -(CR^dR^b)- or (Ci_-6)alkylene wherein optionally one or more than one methylene groups are independently replaced by hetero atoms or groups such as -0-, -S(0)_p-, -N(R⁶)-, -C(O)-;

M is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, cyanoalkyl, acyl, - (CR^aR^b)_mOR⁸, -SR⁸, -(CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mNR⁹R¹⁰, -(CR^aR^b)_mC(0)NR⁹R ¹⁰ thiocarbonyl, S(0)₂NR⁹R¹⁰, -NR⁸S(0)₂R⁸, -S(0)_pR⁸, -S0₃H, cycloalkyl, aryl, heterocyclyl or heteroaryl;

M is optionally substituted with one or more substituents independently selected from cyano, nitro, keto, oxo, halogen, haloalkyl, perhaloalkyl, hydroxyamino, -(CR^aR^b)_mOR⁸, - (CR^aR^b)_mC(0)R⁸, -OC(0)R⁸ _, -SR⁸, -(CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mNR⁹R¹⁰, -(CR^aR^b)_mC(0)N

R⁹R¹⁰ -(CR^aR^b)_mNR⁸C(0)N R⁹R¹⁰ -NR⁸C(0)R⁸ _, thiocarbonyl, -S(0)₂N R⁹R¹⁰, -NR⁸S(0)₂R⁸, -

S(0)_pR⁸, or -S0₃H;

U is a bond or is selected from the group consisting of cycloalkylene, arylene, heterocyclylene, heteroarylene or (Ci_-6)alkylene wherein one or more than one methylene groups of alkylene, alkenylene or alkynylene are optionally replaced by hetero atoms or groups such as -0-, -S(0)_p-, - N(R⁸)-, or -C(0); T is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, alkenyl, cyanoalkyl, acyl, -(CR^aR^b)_mOR⁸, -SR⁸, -(CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mN R⁹R¹⁰, -(CR^aR^b)_mC(0)NR⁹R¹⁰ - (CR^aR^b)_mNR⁸C(0)N R⁹R¹⁰ thiocarbonyl, S(0)₂NR⁹R¹⁰, -NR⁸S(0)₂R⁸, -S(0)_pR⁸, -S0₃H, cycloalkyl, aryl, heterocyclyl or heteroaryl;

U and T is optionally substituted with one or more substituents independently selected from cyano, nitro, keto, oxo, halogen, haloalkyl, perhaloalkyl, hydroxyamino, -(CR^aR^b)_mOR⁸, - (CR^aR^b)_mC(0)R⁸, -OC(0)R⁸ _, -SR⁸, -(CR^aR^b)_mCOOR⁸, -(CR^aR^b)_nlN R⁹R¹⁰, -(CR^aR^b)_mC(0)N R⁹R¹⁰ -(CR^aR^b)_mNR⁸C(0)_m R⁹R¹⁰ -NR⁸C(0)R⁸ _, thiocarbonyl, -S(0)₂N R⁹R¹⁰, -NR⁸S(0)₂R⁸, - S(0)_pR⁸ or -S0₃H;

R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, -(CR^aR^b)_mC(0)R⁸, -(CR^aR^b)_mNR⁹R¹⁰, aminocarbonyl, alkoxycarbonylamino, alkylsulfonylamino, aminocarbonylamino, hydroxyamino, alkoxyamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, haloalkyl, perhaloalkyl, cycloalkyl, thiocarbonyl, cafboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy, -SO3H, alkylthio, aminosulfonyl, alkylsulfonyl, or nitro; or when R¹ or R² or R³ or R⁴ or R⁵ are more than one, then any 2 R¹ or 2 R² or 2 R³ or 2 R⁴ or 2 R⁵ independently is optionally, taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated or optionally have one or more additional heteroatoms independently selected from O, N or S;

R⁹ and R¹⁰ are independently selected from the group consisting of hydrogen, -(CR^aR^b)_mOR⁸, haloalkyl, -(CR^aR^b)_mC(0)R⁸, alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl or

R⁹ and R¹⁰ taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S;

m is 0-3;

n is 0 - 3; p is 0, 1 or 2;

q is 1 or 2.

ring A is selected from pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazole, oxadiazole, thiadiazole, dithiazole;

X represents N;

Y represents -C(O);

Li is a bond or (Ci.₆)alkylene wherein optionally one or more than one methylene groups are independently replaced by hetero atoms or groups such as -0-, -S(0)_p-, -N(R⁶)-, -C(O)-;

M is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, -(CR^aR^b)_mOR⁸, - SR⁸, -(CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mNR⁹R¹⁰ or -(CR^aR^b)_mC(0)NR⁹R¹⁰;

U is a bond or (Ci.₆)alkylene wherein one or more than one methylene groups of alkylene, alkenylene or alkynylene are optionally replaced by hetero atoms or groups such as -0-, -S(0)_p-, - N(R⁸)-, or -C(O);

T is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, acyl, -(CR^aR^b)_mOR⁸, - SR⁸, -(CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mN R⁹R¹⁰, -(CR^aR^b)_mC(0)NR⁹R¹⁰, cycloalkyl, aryl, heterocyclyl or heteroaryl;

R¹ , R², R³, R⁴, R⁵, R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkoxy, acyl, acylamino, acyloxy, -(CR^aR^b)_mC(0)R⁸, -(CR^aR^b)_mNR⁹R¹⁰, aminocarbonyl, alkoxycarbonylamino, alkylsulfonylamino, aminocarbonylamino, hydroxyamino, alkoxyamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, haloalkyl, perhaloalkyl, cycloalkyl, carboxy, alkylcarboxy, carboxyalkyl, carboxy alky loxy, alkylcarboxyalkyloxy, -S0₃H, alkylthio, aminosulfonyl, alkylsulfonyl, or nitro;

R⁸ is selected from the group consisting of hydrogen, -(CR^aR^b)_mOR⁸, halogen, haloalkyl, - (CR^aR^b)_mC(0)R⁸ or alkyl; R⁹ and R¹⁰ are independently selected from the group consisting of hydrogen, -(CR^aR^b)_mOR⁸ or haloalkyl or

m is 0-3;

n is 0 - 3;

p is 0, 1 or 2;

q is 1 or 2.

ring C, ring D and ring E are independently selected from cyclopropyl, cyclohexyl, phenyl, azetidine, pyrrolidine, piperidine, piperazine, morpholine, octahydro-indole, octahydro-isoindole, dihydro-imidazole, tetrahydro-benzothiophene, tetrahydro-indole, tetrahydro-isoindole, tetrahydro-benzoxazine, tetrahydro-imidazopyridine, aza-spirooctane, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazole, oxadiazole, thiadiazole, dithiazole, pyridine, pyrimidine or pyrazine ;

X represents N;

Y represents -C(O);

L] is a bond or (Ci_-6)alkylene wherein optionally one or more than one methylene groups are independently replaced by hetero atoms or groups such as -0-, -S(0)p-, -N(R⁶)-, -C(O)-;

M is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, -(CR^aR^b)mOR⁸, -

SR⁸, -(CR^aR^b)mCOOR⁸, -(CR^aR^b)mNR⁹R¹⁰ or -(CR^aR^b)mC(0)NR R¹⁰; U is a bond or (Ci_-6)alkylene wherein one or more than one methylene groups of alkylene, alkenylene or alkynylene are optionally replaced by hetero atoms or groups such as -0-, -S(0)_p-,_< - N(R⁸)-, or -C(0);

T is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, acyl, -(CR^aR^b)_mOR⁸, - SR⁸, -(CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mN R⁹R¹⁰, -(CR^aR^b)_mC(0)NR⁹R¹⁰ or cycloalkyl;

R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkoxy, acyl, acylamino, acyloxy, -(CR^aR^b)_mC(0)R⁸, -(CR^aR^b)_mNR⁹R¹⁰, aminocarbonyl, alkoxycarbonylamino, alkylsulfonylamino, aminocarbonylamino, hydroxyamino, alkoxyamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, haloalkyl, perhaloalkyl, cycloalkyl, carboxy, alkylcarboxy, carboxyalkyl, carboxy alky loxy, alkylcarboxyalkyloxy, -SO₃H, alkylthio, aminosulfonyl, alkylsulfonyl, or nitro;

R⁸ is selected from the group consisting of hydrogen, -(CR R^b)mOR⁸, halogen, haloalkyl, - (CR^aR^b)_mC(0)R⁸ or alkyl;

R⁹ and R¹⁰ are independently selected from the group consisting of hydrogen, -(CR^aR^b)_mOR⁸ or haloalkyl

m is 0-3;

n is 0 - 3;

p is 0, 1 or 2;

q is 1 or 2.

ring A is selected from pyrrole, imidazole, pyrazole, oxazole or isoxazole;

ring C, ring D and ring E are independently selected from phenyl, azetidine, pyrrolidine, piperidine, piperazine, morpholine, octahydro-indole, octahydro-isoindole, dihydro-imidazole, tetrahydro-benzothiophene, tetrahydro-indole, tetrahydro-isoindole, tetrahydro-benzoxazine, tetrahydro-imidazopyridine, aza-spirooctane, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazole, oxadiazole, thiadiazole, dithiazole, pyridine, pyrimidine or pyrazine ; X represents N;

Y represents -C(0);

L( is a bond or (Ci_-6)alkylene wherein optionally one or more than one methylene groups are independently replaced by hetero atoms or groups such as -0-, -S(0)_p-, -N(R⁶)- or -C(O)-;

M is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, -(CR^aR^b)mOR⁸, - SR⁸, -(CR^aR^b)mCOOR⁸, -(CR^aR^b)mNR⁹R¹⁰ or -(CR^aR^b)mC(0)NR⁹R¹⁰;

U is a bond or (Ci.₆)alkylene wherein one or more than one methylene groups of alkylene, alkenylene or alkynylene are optionally replaced by hetero atoms or groups such as -0-, -S(0)_p-, - N(R⁸)-, or -C(0);

T is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, acyl, -(CR^aR^b)_mOR⁸, - SR⁸, -(CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mN R⁹R¹⁰, -(CR^aR^b)_mC(O)NR⁹R^{l 0} or cycloalkyl;

R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkoxy, acyl, acylamino, acyloxy, -(CR^aR^b)_mC(0)R⁸, -(CR^aR^b)_mNR⁹R¹⁰, aminoca^'rbonyl, alkoxycarbonylamino, alkylsulfonylamino, aminocarbonylamino, hydroxyamino, alkoxyamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, haloalkyl, perhaloalkyl, cycloalkyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy, -SO₃H, alkylthio, aminosulfonyl, alkylsulfonyl, or nitro;

R⁸ is selected from the group consisting of hydrogen, -(CR^aR^b)_mOR⁸, halogen, haloalkyl, - (CR^aR^b)_mC(0)R⁸ or alkyl;

m is 0-3;

n is 0 - 3;

p is 0, 1 or 2;

q is 1 or 2.

ring A is pyrrole; ring C is selected from azetidine, pyrrolidine, piperidine, piperazine, morpholine, octahydro- indole, octahydro-isoindole, dihydro-imidazole, tetrahydro-benzothiophene, tetrahydro-indole, tetrahydro-isoindole, tetrahydro-benzoxazine, tetrahydro-imidazopyridine, aza-spirooctane, oxazole, isoxazole, thiazole or isothiazole;

ring D is selected from phenyl, pyridine, pyrimidine or pyrazine;

ring E is selected from azetidine, pyrrolidine, piperidine, piperazine, morpholine, octahydro- indole, octahydro-isoindole, dihydro-imidazole, tetrahydro-benzothiophene, tetrahydro-indole, tetrahydro-isoindole, tetrahydro-benzoxazine or tetrahydro-imidazopyridine;

X represents N;

Y represents -C(O);

Li is a bond or (C|_-6)alkylene wherein optionally one or more than one methylene groups are independently replaced by hetero atoms or groups such as -0-, -S(0)_p-, -N(R⁶)- or -C(O)-;

M is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyi or alkyl;

U is a bond or (Ci_-6)alkylene wherein one or more than one methylene groups of alkylene, alkenylene or alkynylene are optionally replaced by hetero atoms or groups such as -0-, -S(0)_p-, - N(R⁸)-, or -C(0);

T is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyi, alkyl, acyl, -(CR^aR^b)_mOR⁸, - SR⁸, -(CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mN R⁹R¹⁰, -(CR^aR^b)_mC(0)NR⁹R¹⁰ or cycloalkyl;

R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkoxy, acyl, acylamino, acyloxy, -(CR^aR^b)_mC(0)R⁸, -(CR^aR^b)_mNR⁹R¹⁰, azido, cyano, halogen, hydroxy, . hydroxyalkyl, haloalkyl, perhaloalkyi, cycloalkyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy, -S0₃H, alkylthio, alkylsulfonyl, or nitro;

R⁸ is selected from the group consisting of hydrogen, halogen, haloalkyl, -(CR^aR^b)_mC(0)R⁸ or alkyl;

R^a and R^b are independently selected from the group consisting of hydrogen, -OR⁶, halogen, haloalkyl, perhaloalkyi or alkyl;

m is 0-3;

n is 0 - 3;

p is 0, 1 or 2; q is 1 or 2.

The present invention also relates to the process of preparation of compounds of formula (I), or pharmaceutically acceptable salts thereof.

The compounds of formula (I) may be prepared as outlined in Schemes below:

Scheme 1: Preparation of compounds of formula (I)

I

Compounds of formula (I) may be prepared from reaction of intermediates of formulae (II) with formula (III) using Suzuki coupling reaction conditions as shown in Scheme 1 wherein PG is H or a protecting groups selected from Tosyl and LGi is leaving group selected from halogens, triflate and the like.

Scheme 2: Preparation of compounds of formula (II)

II compounds of formula (II) may be prepared from reaction of compound of formula (IV) with compound of formula (V) using Suzuki coupling reaction conditions as shown in Scheme 2 wherein PG is H or a protecting group selected from Tosyl; and LGi and LG₂ are leaving groups

III compounds of formula (III) may be prepared from reaction of compounds of formula (VI) with compounds of formula (VII) using amide coupling reaction conditions as shown in Scheme 3 Scheme 4: Alternate process for preparation of compound of formula (III)

(IX)

Scheme 5: Alternate process for preparation of compound of formula (I)

I

Alternatively, compounds of formula (I) may also be prepared from compounds of formulae (XII) using reductive amination reaction conditions as shown in Scheme 5 wherein PG is H or a protecting group selected from Tosyl and LGi is leaving groups selected from halogens, triflate and the like. Intermediates of formula (XII) may be prepared from compounds of formula (XI) with compounds of formula (III) using Suzuki coupling reaction conditions as shown in Scheme5.

Scheme 6: Alternate process for preparation of compound of formula (I)

Alternatively, compounds of formula (I) may also be prepared from compounds of formula (XV) using amide coupling reaction conditions as shown in Scheme 6 wherein PG is H or a protecting group selected from Tosyl and LG| is leaving groups selected from halogens, triflate and the like. .

Suzuki coupling: Suzuki coupling is the organic reaction of an aryl- or vinyl-boronic acid with an aryl- or vinyl-halide catalyzed by a palladium(O) complex such as tetrakis(triphenylphosphine)palladium [Chemical Reviews 95 (7): 2457-2483].

Reductive Amination: Reductive amination is a form of reaction that involves the conversion of a carbonyl group to an amine via an intermediate imine. The carbonyl group is most commonly a ketone or an aldehyde. The reaction is carried out with reducing agents that are more reactive toward protonated imines than ketones, and that are stable under moderately acidic conditions. These include sodium cyanoborohydride (NaBH₃CN) and sodium triacetoxyborohydride (NaBH(OCOCH₃)_3. [Organic Reactions, 1 , 59, 2002]

Amide Coupling: Amide coupling may be carried out using any suitable amide coupling regents such as oxalyl chloride, thionyl chloride, BOP-C1, DCC, HOBt, HOAt, HATU, EDCI, alkylchloroformate and the like in the presence of organic non-nucleophillic bases such as triethyl amine, di-isopropylethyl amine, pyridine, N-methyl pyrrolidine, N,N- dimethylaminopyridine, DBU, DABCO, other hindered amines and pyridines. The amide coupling reaction may be carried out in the presence of solvents such as dichloromethane, dichloroethane, DMF, dimethylacetamide, THF, acetonitrile or mixture of them may be used at a temperature ranging from -5 to 150 °C. The reaction may be carried out optionally in presence of catalytic amount of DMF. Amide coupling may also be carried out by heating ester and amine either in the absence of solvent or in presence of high boiling solvent like toluene, xylene, DMSO. Amide coupling may be carried out in presence of trialkyl aluminium (Chem. Commun., 2008, 1 100-1 102).

Wherever desired or necessary, in any of the above mentioned processes, any of the compounds of formula (I) may be converted into a pharmaceutically acceptable salt or vice versa or converting one salt form into another pharmaceutically acceptable salt form.

According to another embodiment the present invention provides co-crystals comprising a compound of formula (I) wherein compounds of formula (I) that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of forming co-crystals with suitable co-crystal formers. These co-crystals may be prepared from compounds of Formula (I) by known co-crystal forming procedures. Such procedures include grinding, heating, co- subliming, co-melting, or contacting in solution compounds of formula I with the co-crystal former under crystallization conditions and isolating co-crystals thereby formed.

According to another embodiment the present invention provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as active ingredient together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.

In another embodiment the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament.

In another embodiment the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder mediated by Btk.

According to another embodiment compositions can be prepared by mixing one or more compounds described herein, or pharmaceutically acceptable salts or tautomers thereof, with pharmaceutically acceptable carriers or the like, to treat or ameliorate a variety of Btk related conditions. The pharmaceutical compositions of the present disclosure can be manufactured by methods well known in the art such as conventional granulating, mixing, dissolving, encapsulating, lyophilizing, emulsifying or levigating processes, among others. The compositions can be in the form of, for example, granules, powders, tablets, capsule syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions. The instant compositions can be formulated for various, routes of administration, for example, by oral administration, transmucosal administration, rectal administration, topical administration or subcutaneous administration as well as intrathecal, intravenous, intramuscular, intraperitoneal, intranasal, intraocular or intraventricular injection. The compound or compounds of the instant invention can also be administered in a local rather than a systemic fashion, such as injection as a sustained release formulation.

Besides those representative dosage forms described above, pharmaceutically acceptable excipients and carries are generally known to those skilled in the art and are thus included in the instant invention. Such excipients and carriers are described, for example, in "Remington's Pharmaceutical Sciences" Mack Pub. Co., New Jersey (1991 ).

The formulations of the invention can be designed for to be short-acting, fast-releasing, long-acting, and sustained-releasing. Thus, the pharmaceutical formulations can also be formulated for controlled release or for slow release.

The pharmaceutical compositions of the present disclosure can also comprise, for example, micelles or liposomes, or some other encapsulated form, or can be administered in an extended release form to provide a prolonged storage and/or delivery effect. Therefore, the pharmaceutical formulations can be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections or as implants such as stents. Such implants can employ known materials such as silicones and biodegradable polymers.

The pharmaceutical compositions may contain, for example, from about 0.1 % by weight, to about 90% or more by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit can contain, for example, from about 0.1 to 500 mg or more of the active ingredient. The dosage as employed for adult human treatment can range, for example, from about 0.1 to 1000 mg per day, depending on the route and frequency of administration. Specific dosages can be adjusted depending on conditions of the BTK related condition, the age, body weight, general health conditions, sex, and diet of the subject, dose intervals, administration routes, excretion rate, and combinations of drugs. Any of the above dosage forms containing effective amounts are well within the bounds of routine experimentation and therefore, well within the scope of the instant invention. Generally, the total daily dose can typically range from about 1 mg/kg/day to about 500 mg/kg/day in single or in divided doses. Typically, dosages for humans can range from about 5 mg to about 100 mg per day, in a single or multiple doses.

A therapeutically effective dose or amount can vary depending upon the route of administration and dosage form. Some compositions of the instant invention is a formulation that exhibits a high therapeutic index. The therapeutic index is the dose ratio between toxic and therapeutic effects which can be expressed as the ratio between LD₅₀ and ED₅₀. The LD₅₀ is the dose lethal to 50% of the population and the ED50 is the dose therapeutically effective in 50% of the population. The LD50 and ED50 can be determined by standard pharmaceutical procedures in animal cell cultures or experimental models.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier. The pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and rectal administration, etc.

Compounds of the present invention may be useful in the treatment of an indication selected from: Autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD), transplant rejection; diseases in which antibody production, antigen presentation, cytokine production or lymphoid organogenesis are abnormal or are undesirable; including rheumatoid arthritis, systemic onset juvenile idiopathic arthritis (SOJIA), gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjogren's syndrome, autoimmune hemolytic anemia, anti-neutrophil cytoplasmic antibodies (ANCA)- associated vasculitides, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic autoimmune urticaria, allergy (atopic dermatitis, contact dermatitis, allergic rhinitis), atherosclerosis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, ulcerative colitis, morbus Crohn, pancreatitis, glomerolunephritis, Goodpasture's syndrome, Hashimoto's thyroiditis, Grave's disease, antibody-mediated transplant rejection (AMR), graft versus host disease, B cell-mediated hyperacute, acute and chronic transplant rejection; thromboembolic disorders, myocardial infarct, angina pectoris, stroke, ischemic disorders, pulmonary embolism; cancers of haematopoietic origin including but not limited to multiple myeloma; leukemia; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin lymphoma; lymphomas; polycythemia vera; chronic lymphocytic leukemia; Mantle cell lymphoma, essential thrombocythemia; myelofibrosis with myeloid metaplasia; and Waldenstroem disease.

In another embodiment, the invention provides a method of treating a disease which is treated by the modulation of Btk- comprising administration of a therapeutically acceptable amount of a compound of formula (I) or a salt thereof. In a further embodiment, the disease is selected from the afore-mentioned list.

The compound of the present invention may be administered either simultaneously with, or before or after, one or more other therapeutic agent. The compound of the present invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents.

According to another embodiment, compounds of Formula (I) of the invention can be used alone or in combination with one or more additional therapeutic agent selected from the group consisting of a BTK inhibitors such as Ibrutinib, AVL-292, ONO-4059; B-cell depleting protein based therapeutics such as Rituxan, a CD20 antibody; calcineurin inhibitor such as cyclosporin A or FK 506; a mTOR inhibitor such as rapamycin, 40-O-(2-hydroxyethyl)- rapamycin, CCI779, ABT578, AP23573, AP23464, AP23675, AP23841 , TAFA-93, biolimus-7 or biolimus-9; an ascomycin having immunosuppressive properties such as ABT-281 , ASM981 ; corticosteroids such as cortisone, dexamethasone, methylprednisolone, prednisolone, prednisone; cyclophosphamide; azathioprene; methotrexate; leflunomide; teriflunomide; mizoribine; etanercept; infliximab; a chemotherapeutic agent such as paclitaxel, gemcitabine, cisplatine, doxorubicin, 5-fluorouracil, imatinib, dasatinib, sunitinib, gefitinib, sorafenib, erlotinib, camptothecin, topotecan, daunomycin, etoposide, taxol, vinblastine, bortezomib, carfilzomib; mycophenolic acid or salt; mycophenolate mofetil; 15-deoxyspergualine or an immunosuppressive homologue, analogue or derivative thereof; NSAIDs such as Ibuprofen, flurbiprofen, naproxen, diclofenac, misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen, ketoprofen, sodium nabumetone, sulfasalazine, tolmetin sodium, hydroxychloroquine, celecoxib, valdecoxib, lumiracoxib, etoricoxib; JAK kinase inhibitors such as Tofacitinib, LY-3009104, VX-509, GLPG-0634, ASP-015K , N-benzyl-3,4- dihydroxy-benzylidene-cyanoacetamide a-cyano-(3,4-dihydroxy)-]N-benzylcinnamamide (Tyrphostin AG 490), prodigiosin 25-C (PNU 156804), [4-(4'-hydroxyphenyl)-amino-6,7- dimethoxyquinazoline] (WHI-P131), [4-(3'-bromo-4'-hydroxylphenyl)-amino-6,7- dimethoxyquinazoline] (WHI-P154), [4-(3ⁱ,5'-dibromo-4'-hydroxylphenyl)-amino-6,7- dimethoxyquinazoline] WHI-P97, KRX-21 1 , 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-amino]-piperidin-l-yl}-3-oxo-propionitrile, in free form or in a pharmaceutically acceptable salt form, e.g. mono-citrate (also called CP-690,550); SYK inhibitor such as fostamatinib; sphingosine-1 -phosphate receptor modulators such as FTY720 (fingolimod); immunosuppressive monoclonal antibodies such as monoclonal antibodies to leukocyte receptors like MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86 or their ligands; other immunomodulatory compounds such as a recombinant binding molecule having at least a portion of the extracellular domain of CTLA4 or a mutant thereof, e.g. an at least extracellular portion of CTLA4 or a mutant thereof joined to a non-CTLA4 protein sequence, e.g. CTLA41g (for ex. designated ATCC 68629) or a mutant thereof, e.g. LEA29Y; adhesion molecule inhibitors, e.g. LFA-1 antagonists, ICAM-1 or -3 antagonists, VCAM-4 antagonists or VLA-4 antagonists; or an anti-infectious agent. Further combination partners to a compound of formula (I) may be selected from a PI3K inhibitor (e.g. pan, or alpha, beta, gamma, delta selectives), TNF inhibitors, ILI beta inhibitors, IL 17 inhibitors, and inhibitors of IL6 or IL receptor.

In one embodiment, the invention provides methods of treating or preventing a condition associated with BTK in a subject, such as a mammal, i.e., a human or non-human mammal, comprising administering an effective amount of one or more compounds described herein to the subject. Suitable non-human subjects that can be treated include domestic or wild animals, companion animals, such as dogs, cats and the like; livestock, including horses, cows and other ruminants, pigs, poultry, rabbits and the like; primates, for example monkeys, such as macaques including rhesus monkeys and cynomolgus monkeys, marmosets; tamarins and the like, apes, including chimpanzees and orangutans; and rodents, such as rats, mice, gerbils, guinea pigs and the like. In one embodiment, the invention provides a product comprising a compound of formula (I) and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is the treatment of a disease or condition mediated by Btk kinases. Products provided as a combined preparation include a composition comprising the compound of formula (I) and the other therapeutic agent(s) together in the same pharmaceutical composition, or the compound of formula (I) and the other therapeutic agent(s) in separate form, e.g. in the form of a kit.

In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula (I) and another therapeutic agent(s). Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable excipient, as described above.

The invention also provides a compound of formula (I) for use in a method of treating a disease or condition mediated by Btk, wherein the compound of formula (I) is prepared for administration with another therapeutic agent. The invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by Btk, wherein the other therapeutic agent is prepared for administration with a compound of formula (I). The invention also provides a compound of formula (I) for use in a method of treating a disease or condition mediated by Btk , wherein the compound of formula (I) is administered with another therapeutic agent. The invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by Btk, wherein the other therapeutic agent is administered with a compound of formula (I).

Examples

The invention is further illustrated by the following examples which in no way should be construed as being further limiting. One skilled in the art will readily appreciate that the specific methods and results described are merely illustrative. Structures of the intermediates as well as the final compounds were confirmed by nuclear magnetic resonance spectra for proton (Ή NMR) and LCMS.

Intermediate l-III: Methyl 4-(4-chloro-7H-pyrrolo [2, 3-d] pyrimidin-6-yI) benzoate

1-1 1-11 INT-1-II

Step-1: Synthesis of ethyl 2-amino-5-(4-methoxycarbonylphenyl)-lH-pyrrole-3-carboxylate (1-1): Na metal (1.96 g, 85.3 mmol) was added portion wise to EtOH (210 mL) and stirred for 30 min to get clear solution. To this was added ethyl 3-amino-3-imino-propanoate hydrochloride (CAS: 57508-48-2, 14.25 g, 85.6 mmol) and stirred at room temperature for additional 30 min. Finally, methyl 4-(2-bromoacetyl) benzoate (1 1 g, 42.8 mmol) was added to the reaction mixture and was stirred for 16-20 h at room temperature. After completion of the reaction (as indicated by TLC and LCMS), reaction mixture was filtered through celite and the residue was washed with MeOH (50 mL x 2). The combined filtrate was concentrated under reduced pressure and the residue was purified using column chromatography (Si0₂, 40% EtOAc in hexane) to provide 1-1 (7 g, 56.7% yield). LCMS: m/z 289.1 (M + 1)⁺.

Step-2: Synthesis of methyl 4-(4-hydroxy-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzoate (l-II):

1-1 (7.5 g, 26 mmol) was added to a mixture of formamide (10 mL), formic acid (4 mL) and DMF (2 mL); and stirred at 150 °C for 16-20 h. After completion of the reaction (as indicated by TLC and LCMS), it was cooled to 0 °C and 2-propanol (35 mL) was added to it. After stirring for 15 min, the residue was filtered and washed with diethyl ether (10 mL) to provide l-II (6 g, 85.6% yield). LCMS: m/z 270.1 (M + 1)^+'

Step-3: Synthesis of Methyl 4-(4-chloro-7H-pyrrolo [2, 3-d]pyrimidin-6-yl)benzoate (INT-1- III): l-II (6 g, 22.3 mmol) was suspended in excess of POCl₃ (100 mL) and refluxed for 16- 20 h. After completion of the reaction (as indicated by TLC), POCl₃ was removed under reduced pressure. Saturated NaHC0₃ (100 mL) solution was added to the residue and stirred for 30 min. The solid was filtered and suspended in minimum quantity of MeOH (10 mL). After stirring for 30 min, it was filtered and dried to provide INT-1-III (5.8 g, 90% yield). LCMS: m/z 288.1 (M + l)⁺ _:. 'H NMR (CDC1₃; 400 MHz) 3.86 (s, 3H); 7.28 (s, 1H); 8.04 (d, J = 8.0 Hz, 2H); 8.16 (d, J = 8.4 Hz, 2H); 8.61 (s, 1 H); 13.18 (s, 1H). Following intermediate was synthesized as described for the synthesis of INT-l-HI.

Intermediate-I-VII: [4-[4-chloro-l -(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-2- yl]pheny 1] -(4-h droxy-4-methyl- 1 -piperidyl)methanone

l-V l-VI

Step-I: ethyl 4-[4-chIoro-l-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-2- yl]benzoate (I- VI): A solution of K₂C0₃ (6.7 g, 48.96 mmol) in water (10 mL) was added to a solution of I-V (4 g, 12.24 mmol) and ethyl-4-bromobenzoate (2.0 mL, 12.24 mmol) in 1 ,4- dioxane (40 mL); to which Argon was purged for 30 min. The intermediate I-V was prepared from 4-chloro-lH-pyrrolo[2,3-b]pyridine (CAS No. 55052-28-3) in two steps following the procedure mentioned in WO2010003133. Finally, Pd (PPh₃)₄ (1.4 g, 1.22 mmol) was added to it and purging was continued for 10 min more. The reaction mixture was, then, stirred at 90 °C for 12 h. It was, then, cooled to room temperature and diluted using EtOAc (100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure. The residue was finally purified using silica gel column chromatography (10% EtOAc in hexane) to provide I-VI (3.8 g, 72% yield). LCMS: m/z; 431 (M+l)⁺.

Step-II: To a solution of I-VI (2.0 g, 4.64 mmol) in THF (20 mL) was added NaOH (0.93 g, 23.2 mmol) in water (8 mL) and the reaction mixture was stirred at room temperature for 16 h. It was then acidified using 10% citric acid solution and extraction was carried out using EtOAc (30 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure to provide corresponding acid intermediate (1.3 g, 3.22 mmol), which was dissolved in DMF (15 mL). To this was added 4- methylpiperidin-4-ol (CAS: 3970-68-1) (0.97 g, 6.45 mmol), diisopropylethylamine (2.1 mL, 12.88 mmol) and HATU (1.83 g, 4.83 mmol) and the reaction mixture was stirred at room temperature for 16 h. It was, then, diluted using EtOAc (100 mL) and washed with water (100 mL x 2), brine (100 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was finally purified using silica gel column chromatography (20% acetone in hexane) to provide I-VII (0.7 g, 30% yield). LCMS: m/z; 500.2 (M+l)+.

'HNMR (CDC1₃, 400 MHz): δ -0.16 (s, 9H), 1.01 (t, J = 8.4 Hz, 2H), 1.36 (s, 3H), 1.72-1.75 (m, 4H), 3.41 -3.59 (m, 4H), 3.79 (t, J = 8.4 Hz, 2H), 4.40 (bs, 1 H), 5.69 (s, 2H), 6.76 (s, 1H), 7.19 (d, J = 5.6Hz, 1H), 7.56 (d, J= 8.0 Hz, 2H), 7.90 (d, J= 8.0 Hz, 2H), 8.26 (d, J = 5.6 Hz, 1H).

Following intermediate I-VIII was synthesized using similar procedure as described for the synthesis of I T-I-VII.

Intermediate 2-III: 4-tert-butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl) phen l]benzamide

2-1 2-11 INT-2-IH

INT-2-III was synthesized as described in: Ref: WO2009039397A2, WO2006099075A2.

Following intermediates were synthesized as described for the synthesis of INT-2-III.

7.63 (d,J=7.2Hz, 1H), 7.76-7.78 (m, 1H), 7.19 (br s,.

1H), 8.10(d,J=8.0Hz, 1H)

INT-2-X LCMS: m/z: 396.2 (M + 1 )⁺ Ή NMR (CDC1₃, 400

MHz): δ 0.83-0.87 (m, 2H), 1.13-1.18 (m, 2H), 1.42 (s, 12H), 1.98-2.04 (m, 1H), 2.61 (s, 3H, CH₃), 6.91 (d, J = 13.6 Hz, 1H)7.07 (d, J= 8.0 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 8.15 (t, J =8.4 Hz, 1H), 8.23 (d, J=8.0

Hz, 1H), 8.47 (d, J= 16.4 Hz, 1H)

LCMS: m/z: 379.2 (M+l)⁺. Ή NMR (DMSO-i¾, 400 MHz): δ 0.84-0.89 (m, 2H), 1.06-1.12 (m ,2H), 1.31

INT-2- (s, 12H), 2.02-2.12 (m, 1H), 2.42 (s, 3H, CH₃), 7.22 (t, XI J= 7.2 Hz, 1H), 7.49 (d, J= 7.6 Hz, 1H), 7.67 (dd, J =

8.0 Hz, J= 1.6 Hz, 1H), 7.84 (d,J=8.0Hz, 1H), 8.01 (d,J=8.0Hz, 1H), 8.54 (s, 1H), 10.19 (s, 1H).

INT-2- LCMS: m/z 379.2 (M+l)⁺. Ή NMR (CDC1₃, 400 XII MHz): δ 0.82-0.89 (m, 2H), 1.08-1.12 (m ,2H), 1.35

(s, 12H), 2.08-2.16 (m, 1H), 2.53 (s, 3H), 7.24-7.29 (m, 1H), 7.65 (d, J= 7.2 Hz, 1H), 8.00 (bs, 1H), 8.08 (d, J= 8.0 Hz, 1H), 8.92 (s, 1H), 10.19 (s, 1H).

LCMS: m/z: 392.2 (M + 1)⁺ Ή NMR (CDC1₃, 400 MHz): 0.57-0.61 (m, 2H), 0.85-0.91 (m, 2H), 1.24-

INT-2- 1.31 (m, 12H), 1.77-1.81 (m, 1H), 2.31 (s, 3H), 3.18 XIII

(s, 3H), 6.86 (d,J= 8.4 Hz, 2H), 7.03-7.15 (m, 3H), 7.25 (d, J= 7.6 Hz, 1H), 7.48 (d, J= 7.2 Hz, 1H)

INT-2-

LCMS:m/z:395.2 (M+ 1)⁺

XIII

Intermediate 3-III: N-[2-methyl-3-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)phenyl] isoindoline-2-carboxamide.

^2-1 2-11 INT-3-III

N-[2-methyl-3-(4, 4, 5, 5-tetramethyl-l , 3, 2-dioxaborolan-2-yl)phenyl] isoindoline-2- carboxamide (INT-3-III) was synthesized as described in; Ref: WO2009053269A1.

Following intermediates were synthesized as described for the synthesis of INT-3-III.

Number Structures Characterization data

LCMS: m/z: 385.4 (M + 1)⁺ Ή NMR (CDC1₃, 400

INT-3-IV MHz): δ 1.27 (s, 12H), 1.32-1.56 (m, 8H), 2.21-2.29

(m, 2H), 3.26-3.29 (m, 2H), 3.38-3.42 (m, 2H), 5.93 (s, 1H), 7.1 1 (app.t, J = 7.9 Hz, 1H), 7.43 (d, J= 7.4 Hz,

1H), 7.87 (d, J = 7.8 Hz, 1H).

INT-3-V LCMS: m/z: 371.4 (M + ί)⁺

Intermediate 4-III: Methyl 4-[4-chloro-2-(2, 2-dimethylpropanoylamino)-7H-pyrrolo [2, 3- d]pyrimidin-6-yl]benzoate

Step-1: Synthesis of methyl 4-(2-amino-4-hydroxy-7H-pyrrolo[2,3-d]pyrimidiii-6-yl) benzoate (4-1): A solution of 2,6-diamino-4-hydroxypyrimidine (CAS: 56-06-4, 1 g, 7.93 mmol), NaOAc (0.85 g, 10.32 mmol) in water (180 mL) was stirred at 100 °C for 30 min. Methyl 4-(2-bromoacetyl)benzoate (2.24 g, 8.72 mmol) was suspended in MeOH (25 mL) and was added slowly to the above solution. The reaction mixture was then, stirred at 100 °C for 16-20 h before it was cooled to room temperature. The residue was filtered and dried. It was then stirred in CH₂C1₂ (10 mL) and filtered to provide 4-1 (1.07 g, 44.5% yield). LCMS: m/z 285.2 (M + 1)⁺. Step-2: Synthesis of methyl 4-[2-(2, 2-dimethylpropanoylamiiio)-4-hydroxy-7H-pyrrolo[2, 3-d] pyrimidin-6-yl] benzoate (4-II): 4-1 (2.0 g, 7.04 mmol) was suspended in trimethylacetic anhydride (5 mL) and refluxed for 3-5 h. After completion of the reaction, the reaction mixture was cooled to room temperature and hexane (10 mL) was added to it. The residue was filtered and washed with diethyl ether (5 mL) to provide 4-H (1.9 g, 73.3% yield). LCMS: m/z 369.1 (M Step-3: Synthesis of methyl 4-[4-chloro-2-(2, 2-dimethylpropanoylamino)-7H-pyrrolo [2, 3- d] pyrimidin-6-yl] benzoate (INT-4-III): 4-H (1.9 g, 5.16 mmol) was suspended in excess of POCI₃ (20 mL) and refluxed for 3-5 h. After completion of the reaction (as indicated by TLC), POCl₃ was removed under reduced pressure and saturated NaHC0₃ solution (50 mL) was added to the residue. The solid obtained was filtered and dried. It was then stirred in MeOH (5 mL) for 15 min and filtered to provide INT-4-III (1 g, 50.2% yield). LCMS: m/z 387.2 (M + 1)⁺.

Following intermediate was synthesized as described for the synthesis of INT-4-III.

Intermediate 5-III: 4-chloro-6-(4-morpholinophenyl)-7H-pyrrolo[2, 3-d]pyrimidin-2- amine.

Step-1: Synthesis of 2-amino-6-(4-morphoIinophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol (5- II): A solution of 5-1 (3.7 g,l 3.03 mmol), 2,6-diamino-4-hydroxypyrimidine (CAS: 56-06-4, 1.5 g, 1 1.88 mmol) in DMF (1 1 mL) was stirred at 60 °C overnight. After completion of the reaction (as indicated by TLC), the reaction mixture was cooled to room temperature and poured over ice- cold water (150 mL). The resulting, solid was filtered, recrystallised using isopropanol (25 mL) and dried under vacuum to afford 5-II (2.3 g crude). LCMS: m/z 312.1 (M+l)⁺.

Step-2: Synthesis of 4-chloro-6-(4-morpholinophenyl)-7H-pyrrolo[2, 3-d] pyrimidin-2- amine (5-HI): 5-II (2.3 g, 7.4 mmol) was suspended in excess of POCl₃ (20 mL) and refluxed for 3-5 h. After completion of the reaction (as indicated by TLC), POCl₃ was removed under reduced pressure and saturated NaHC0₃ solution (100 mL) was added to the residue. Extraction was carried out using EtOAc (150 mL x 2); the combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure. The residue was purified using column chromatography (Si0₂, 40% acetone in hexane) to provide INT-5-III (0.165g, 6.8% yield) LCMS: m/z 330.3 (M + 1)⁺. Intermediate 6- VI: 4-chloro-6-iodo-7- -tolylsulfonyl)pyrrolo [2,3-d] pyrimidine

6-IV 6-V INT- 6-VI

4-chloro-7-(p-tolylsulfonyl) pyrrolo [2, 3-d] pyrimidine 6- VI was prepared from 4, 6-dihydroxy pyrimidine following the procedures mentioned in WO2010/083283.

Intermediate 7-II: 4-[[4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) phenyl] methyl] morpholine.

7-I ΙΝΤ-7-ΙΓ

4-[[4-(4,4,5, 5-tetramethyl-l, 3,2-dioxaborolan-2-yl)phenyl]methyl]morpholine (INT-7-II) was prepared from 1 -bromo-4-(bromomethyl)benzene (C AS No. 589-15-1) following the procedure mentioned in WO 2009/155565.

Following intermediates were synthesized as described for the synthesis of INT-7-II.

LCMS: m/z: 403.3 (M + 1)⁺

INT-7-V ^χ < > (WO2010055304)

BOC

Intermediate 8-1: 6-cyclopropyl-N-[2-ethyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]pyridine-3-carboxamide

Step 1 - Step 5: 3-bromo-2-[[tert-butyl(dimethyl)silyl]oxymethyl] aniline (step-5) was prepared from l-bromo-2-methyl-3-nitro-benzene, following the same sequence of procedures as mentioned in WO2012031004.

Step-6: Synthesis of N-[3-bromo-2-[[tert-butyI(dimethyl)siIyl]oxymethyl]phenyl]-6- cyclopropyl-pyridine-3-carboxamide:

To a solution of 6-cyclopropylpyridine-3-carboxylic acid (0.5 g, 3.06 mmol), 3-bromo-2-[[tert- butyl(dimethyl)silyl]oxymethyl]aniline (1.16 g, 3.67 mmol) and HOBt (0.495 g, 3.67 mmol) in DCM (15 mL) was added NMM (0.5 mL, 4-59 mmol) and EDCI.HCl (0.876 g, 4.59 mmol). The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (as indicated by TLC), water (10 mL) was added to it and extraction was carried out using DCM (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure. The residue was purified using column chromatography (Si0₂, 10% ethyl acetate in hexanes) to afford title compound (0.5 g, 35%). LCMS: m/z 461.2 (M + 1)⁺. Ή NMR (400 MHz, CDC1₃) δ 0.15 (s, 6H), 0.87 (s, 9H), 1.05-1.10 (m, 2H), 1.1 1-1.51 (m, 2H), 2.06-2.16 (m, 1H), 5.1 1 (s, 2H), 7.19-7.23 (aromatics, 2H), 7.33 (d, J = 8.0 Hz, 1H), 8.03 (dd, J = 8.0, 2.0 Hz, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.99 (d, J = 2.0 Hz, lH), 9.99 (s, lH).

Step-7 : Synthesis of N-[2-[[tert-butyl(dimethyl)siIyI]oxymethyl]-3-(4,4,5,5-tetramethyl- l,3_?2-dioxaborolan-2-yl)phenyl]-6-cyclopropyl-pyridine-3-carboxamide:

A solution of N-[3-bromo-2-[[tert-butyl(dimethyl)silyl]oxymethyl]phenyl]-6-cyclopropyl- pyridine-3-carboxamide (1.2 g, 2.60 mmol), bispinacolato diboron (0.793 g, .3.12 mmol) and potassium acetate (0.764 g, 7.80 mmol) in anhydrous dioxane (15 mL) was degassed for 10 minutes and Pd(dppf)Cl₂.DCM complex (0.212 g, 0.1 mol %) was added. The resulting reaction mixture was then heated at 95 °C for 16 h. After completion of reaction (monitored by TLC), solid was filtered. Filtrate was taken in water and ethyl acetate was added. The organic layer was extracted with ethyl acetate 2-3 times. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product so obtained was purified by silica gel column chromatography using 10% ethyl acetate in hexane as eluent to afford title compound.(l .05 g, 80 %). LCMS: m/z 509.5 (M + 1)⁺. .Ή NMR (400 MHz, CDC1₃) δ 0.12 (s, 6H), 0.86 (s, 9H), 1.04-1.15 (m, 4H), 1.36 (s, 12H), 2.06-2.16 (m, 1H), 5.27 (s, 2H), 7.21 (d, J = 8.4 Hz, 1H), 7.36 (app. t, J = 8.0 Hz, 1H), 7.61 (d, J = 7.2 Hz, 1H), 8.05 (dd, J = 8.0, 2.0, 1 H), 8.43 (d, J= 8.0 Hz, 1 H), 9.01 (d, J = 2.0 Hz, 1H), 10.1 1 (s, 1 H).

Example Al: 4-tert-ButyI-N-[2-methyl-3-[6-[4-(morpholine-4-carbonyl) phenyl]-7H- pyrrolo [ -d] pyrimidin-4-yl]phenyl]benzamide

Step-1: Synthesis of methyl 4-[4-[3-[(4-tert-butylbenzoyl)amino]-2-methyl-phenyl]-7H- pyrrolo[2,3-d]pyrimidin-6-yl]benzoate (8-1): INT-l-HI (0.1 g, 0.35 mmol) and ΓΝΤ-2-ΠΙ

(136 mg, 0.348 mmol) were added to a solution of Na₂C0₃ (73 mg, 0.69mmol) in dioxane-water (4 mL + 1 mL) and purged using Ar for 15 min. To the resulting solution, was added Pd(PPh₃)₄ (0.04 g, 0.03 mmol) under argon atmosphere and heated at 95 °C overnight. After completion of reaction (as indicated by TLC), the organic solvents were removed under reduced pressure. The reaction mixture was poured over ice-cold water. The resulting precipitate was filtered, dried and purified by column chromatography (Si0₂, 5% MeOH in CH₂C1₂) to provide 8-1 (0.08 g, 44% yield). LCMS: m/z 519.2 (M + 1)⁺.

Step-2: Synthesis of 4-[4-[3-[(4-tert-butylbenzoyl)amino]-2-methyl-phenyl]-7H-pyrrolo [2, 3-d] pyrimidin-6-yl] benzoic acid (8-II): To a solution of 8-1 (0.08 g, 0.15 mmol) in MeOH (5 mL) was added a solution of NaOH (0.025 g, 0.62mmol) in water (2 mL); and the reaction mixture was refluxed for 3 h. After completion of the reaction (as indicated by TLC), MeOH was removed under reduced pressure and was acidified using 10% acetic acid solution. The resultant solid was filtered, washed with water and dried under vacuum to afford 8-II (0.05 g, crude), which was used further without any purification. LCMS: m/z 505.3 (M + 1)⁺.

Step-3: Synthesis of 4-tert-butyl-N-[2-methyl-3-[6-[4-(morpholine-4-carbonyl) phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]benzamide (Example Al): To a solution of 8-II (0.05 g, 0.1 mmol) and morpholine (0.04 mL, 0.49 mmol) in DMF (3 mL) was added PyBOP (77 mg, 0.14 mmol) and the reaction mixture stirred at room temperature for 16 h. After completion of the reaction (as indicated by TLC), water (10 mL) was added to it and extraction was carried out using EtOAc (25 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure. The residue was purified using column chromatography (Si0₂, 5% MeOH in CH₂C1₂) to provide Al (0.030 g, 53.5 % yield). LCMS: m/z 574.3 (M + 1)⁺. ¹ H NMR (400 MHz, DMSO-d₆) δ: 1.33 (s, 9H); 2.20 (s, 3H); 3.30-3.40 (m, 2H); 3.50-3.60 (m, 6H); 6.90 (s, 1H); 7.42-7.46 (m, 2H); 7.50-7.57 (m, 5H); 7.96 (d, J= 8.4 Hz, 2H); 8.05 (d, J = 8.0 Hz, 2H); 8.87 (s, 1H); 9.96 (s, 1 H); 12.85 (s, 1 H). Following compounds were synthesized from their corresponding intermediates using the same sequence of procedures as described for preparation of Example Al from INT-1-III.

yl]phenyl]benzamide 8.88 (s, 1H), 9.02 (s, 1H), 11.39 (s, 1H)

(trifluoromethyl)benzamide

d]pyrimidin-4-yl]phenyl]benzamide

acid

methyl-phenyl]-7H-pyrrolo[2,3- 2H), 7.39-7.53 (m, 5H ), 7.91 (d, J= 8.4

A27 LCMS: m/z 559.1 (M+l)⁺. 2-XI

Ή NMR (DMSO-^₆, 400 MHz): δ 0.81- 0.88 (m, 2H),1.07-1.13 (m, 2H), 2.05- w< 2.12 (m, IH), 2.24 (s, 3H, CH₃), 2.80-

5 -cyclopropyl-N- [2-methyl-3 - [6- [4- 3.60 (m, 8H), 6.95 (s, IH), 7.34-7.44 (m,

(mo holine-4-carbonyl)phenyl] - 2H),7.48 (d, J = 8.0 Hz, 2H),7.68 (dd, J,

7H-pyrrolo[2,3-d]pyrimidin-4- = 8.4 Hz, J₂ = 2.4 Hz, 1H),7.99 (d, J = yl]phenyl]pyridine-2-carboxamide 7.2 Hz, IH), 8.04 (d, J = 8.4 Hz, 3H),

8.54 (s, IH), 8.85 (s, IH), 10.34 (s, I H),

12.82 (s, lH, NH).

A28 LCMS: m/z 559.1 (M+ l )⁺. 2-XII

Ή NMR (DMSO-i/_6> 400 MHz): δ 1.00- 1.06 (m, 4H), 2.20 (s, 3H, CH₃), 2.22- 2.24 (m, IH), 3.41-3.70 (m, 8H), 6.90 (s,

6-cyclopropyl-N-[2-methyl-3-[6-[4- IH), 7.40-7.54 (m, 6H), 8.05 (d, J= 8.4

(morpholine-4-carbonyl)phenyl]- Hz, 2H), 8.19 (dd, J, = 7.6 Hz, J₂ = 2.0

7H-pyrrolo[2,3-d]pyrimidin-4- Hz, I H), 8.87 (s, I H), 9.00 (s, I H),

yl]phenyl]pyridine-3-carboxamide 10.1 1 (s, IH), 12.85 (s, Ι Η, ΝΗ).

A29 LCMS: m/z 599.7 (M+l)⁺. 2-XIII

Ή NMR (DMSO-i _tf, 400 MHz): δ 0.55- 0.65 (m, 2H), 0.84-0.92 (m, 2H), 1.20- 1.30 (m, 3H), 1.34 (s, 3H, CH₃), 1.73-

^"a 1.82 (m, 3H), 2.12 (s, 3H, CH₃), 3.33- 4.41 (m, IH), 3.45 (s, 3H), 3.43-3.60 (m,

4-cyclopropyl-N-[3-[6-[4-(4- 2H), 4.34-4.46 (m, IH), 6.05 (s, IH), hydroxy-4-methyl-piperidine- 1 - 6.90 (d, J= 8.0 Hz, 2H), 7.32-7.34 (m, carbonyl)phenyl]-7H-pyrrolo[2,3- 4H), 7.43-7.45 (m, IH), 7.56 (d, J= 8.4 d]pyrimidin-4-yl]-2-methyl- Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H), 8.96 phenyl] -N-methyl-benzamide

(s, IH), 1 1.50 (s, ΙΗ, ΝΗ). A30 LCMS: m/z 613.7 (M+l)⁺. 2-IV

Ή NMR (DMSO-rf_tf, 400 MHz): δ 0.75- 0.73 (d, J = 12.8 Hz 2H), 1.02-1.00 (d,

J = 8 Hz 6H), 1.16 (m, 2H), 1.65 (m,

2H), 1.99 (m, 2H), 2.19 (s, 3H, CH₃),

2.70 (s, IH), 3.03 (s, 2H), 3.4 (s, I H),

2-[l-[4-[4-[3-[(4- 4.4 (s, 1 H),6.85 (s, 1H),7.21 -7.19 (d, J = cyclopropylbenzoyl)amino] -2- 8 Hz, 2H), 7.44-7.46 (m, 4H), 7.90-7.88 methyl-phenyl]-7H-pyrrolo[2,3- (d, J= 8 Hz, 2H) 8.02-8.00 (d, J= 8 Hz, d]pyrimidin-6-yl]benzoyl]-4- 2H),8.8 (s, IH), 9.90 (s,lH), 12.01 (s, piperidyl]acetic acid

I H), 12.90(s, lH).

A31 LCMS: w/z 574.2 (M+l)⁺. 2-IVX

Ή NMR (CD3OD, 400 MHz): δ 2.18 (s, 3H, CH₃),2.58-2.91 (m, 4H), 3.39-3.41

(m, 2H), 3.78-4.05 (m, 6H), 6.78 (s, IH), N-[2-methyl-3-[6-[4-(piperazine-l - 7.22 (s, 2H), 7.24-7.41 (m, 4H), 7.46- carbonyl)phenyl]-7H-pyrrolo[2,3- 7.49 (m, 2H), 7.68 (s, IH), 7.83 (s, IH), d]pyrimidin-4-yl]phenyl]-3,4- 8.78 (s, IH), 7.90-7.88 (d, J= 8 Hz, 2H) dihydro-2H- 1 ,4-benzoxazine-6- 8.02 (d, J= 8 Hz, 2H), 8.8 (s, IH), 9.90

carboxamide (s, lH), 12.01 (s, I H), 12.90(s, lH).

A32 LCMS: m/z 599.7 (M+l)⁺. 2-IV

Ή NMR (DMSO-i¼, 400 MHz): δ 0.75- 0.79 (m, 2H), 1.01-1.06 (m, 2H), 1.17 (s, 3H), 1.22-1.23 (m, I H), 1.35-1.48 (m, l-[4-[4-[3-[(4- 2H), 1.70-1.84-1.94 (m, IH), 2.00-2.04 cyclopropylbenzoyl)amino]-2- (m, IH), 2.19 (s, 3H, CH₃), 3.06-3.12 methyl-phenyl]-7H-pyrrolo[2,3- (m, 2H), 4.10-4.13 (m, 2H), 6.89 (s, IH), d]pyrimidin-6-yl]benzoyl]-4- 8.23 (d, J= 8.4 Hz, 2H), 7.39-7.52 (m, methyl-piperidine-4-carboxylic acid 5H), 7.91 (d, J = 8.4 Hz, 2H), 8.03 (d, J

= 8.4 Hz, 2H), 8.87 (s, I H), 9.94 (s,

Exaniple-Bl: N-[2-methyl-3-[6-[4-(4-methyIpiperazine-l-carbonyl)phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]phenyl]-4-(trifluoromethyl)benzamide

Step-1: Synthesis of 4-(4-chIor0-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzoic acid (9-1): To a suspension of INT-l-HI (1.0 g, 3.48 mmol) in a mixture of MeOH (25 mL) and H₂0 (7 mL) was added NaOH (0.42 g, 10.45 mmol) at room temperature and then stirred at 80 °C for 4 h. After completion of the reaction (as indicated by TLC), the solvent was removed in vacuo and the residue was acidified with saturated solution of citric acid. The resultant solid was filtered, washed with water and dried to afford the title compound 9-1 (1.0 g, quantitative). LCMS: m/z 274.0 (M + l)⁺.

Step-2: Synthesis of [4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl]-(4-methyl piperazin-l-yl)methanone (9-Π): A mixture of 9-1 (1.0 g, 3.66 mmol) and N-methylpiperazine (2.02 mL, 1.8.30 mmol) in DMF (8 mL) was treated with PyBOP (3.8 g, 7.32 mmol) at room temperature and then stirred for 6 h. After confirming the completion of the reaction by TLC, the mixture was treated with water (20 mL). The resultant solid was filtered and washed with water and dried to afford the title compound 9-II (0.48 g, 37% yield). LCMS: m/z 356.1 (M + 1)⁺. Step-3: N-[2-methyl-3-[6-[4-(4-methylpiperazine-l-carbonyl)phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]phenyl]-4-(trifluoromethyI)benzamide (Example-Bl): A solution of 9-H (0.15 g, 0.42 mmol), INT- 2-V (0.198 g, 0.51 mmol) and Na₂C0₃ (0.1 1 g, 1.05 mmol) in a mixture of dioxane (8 mL) and water (1.5 mL) was purged using Ar for 20 min. Pd(PPh₃)₄ (0.049 g, 0.042 mmol) was added in to this mixture and then stirred at 100 °C for 18 h. After confirming the completion of the reaction, it was cooled to room temperature and diluted with EtOAc (100 mL). The organic layer was washed succesively with water (25 mL), brine (20 mL), dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure. The resultant residue was purified using column chromatography (Si0₂, 6% MeOH in CH₂C1₂) followed by a further purification on a preparative TLC plate (Si0₂, 8% MeOH: CH₂C1₂) to afford title compound Bl (0.018 g, 7% yield). LCMS: m/z 599.1 (M + 1)⁺. Ή NMR (400 MHz, DMSO-d₆): δ 2.18 (s, 3H), 2.19 (s, 3H), 2.20-2.40 (m, 4H), 3.50-3.70 (m, 4H), 6.88 (s, 1H), 7.47-7.42 (m, 4H), 7.53 (d, J = 7.2 Hz, 1H), 7.92 (d, J= 7.6 Hz, 2H), 8.02 (d, J = 8.0 Hz, 2H), 8.19 (d, J= 7.6 Hz, 2H), 8.86 (s, 1H), 10.28 (s, 1H), 12.83 (s, 1H).

Following compounds were synthesized from their corresponding intermediates using the same sequence of procedures as used for preparation of Example-Bl from INT- l-III.

Example-Cl: 4-tert-butyl-N-[2-methyI-3-[6-(4-morpholinophenyl)-7H-pyrrolo[2, pyrimidin-4- l] phenyl] benzai ide

Step-1: Synthesis of 4-tert-butyl-N-[2-methyl-3-[6-(4-morpholinophenyl)-7H-pyrrolo[2, 3- d]pyrimidin-4-yl]phenyl]benzamide (Example-Cl): A solution of INT-l-VI (0.1 g, 0.32 mmol), INT- 2-ΠΙ (0.15 g, 0.38 mmol) and Na₂C0₃ (0.082 g, 0.77 mmol) in a mixture of dioxane (10 mL) and water (2 mL) was purged using Ar for 20 min. Pd(PPh₃)₄ (0.035 g, 0.031 mmol) was added in to this mixture and then stirred at 100 °C for 6 h. After completion of the reaction (as indicated by TLC), it was cooled to room temperature and poured over ice-cold water (50 mL). The resulting solid precipitate was filtered, washed with water, dried under vacuum to give crude product, which was purified using preparative TLC (Si0₂, 5% MeOH in CH₂C1₂) to afford title compound CI (0.13 g, 79% yield ). LCMS: m/z 546.2 (M + 1)⁺. Ή NMR (400 MHz, DMSO-d₆): δ 1.32 (s, 9H); 2.18 (s, 3H, CH₃); 3.20 (t, J = 4.8 Hz, 4H); 3.75 (t, J = 4.8 Hz, 4H); 6.65 (d, J = 2.0 Hz, lH); 7.02 (d, J = 8.8 Hz, 2H); 7.40-7.43 (m, 2H); 7.51 (dd, J, = 7.2 Hz, J = 2.0 Hz, 1H); 7.55 (d, J = 8.8 Hz, 2H); 7.84 (d, J = 8.8 Hz, 2H); 7.96 (d, J= 8.8 Hz, 2H); 8.79 (s, 1H); 9.95 (s, 1H).

Following compound was prepared from their corresponding intermediates (given in parentheses) using the same sequence of procedures as used for preparation of Example CI from

INT- 1-IV.

Example Dl: N-[3-[2-amino-6-[4-(morpholine-4-carbonyl)phenyl]-7H-pyrrolo[2, pyrimidin-4-yl]-2-methyl- henyl]-4-tert-butyl-benzamide

M

Step-1: Synthesis of methyl 4-[2-amino-4-[3-[(4-tert-butylbenzoyl)amino]-2-methyl- phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl]benzoate (10-1): 10-1 (0.14 g, 50% yield ) was prepared using INT-5-IV (0.16 g) following the procedure mentioned in step-1 of Example Al . LCMS: m/z ,534.4 (M + 1)⁺. Step-2: Synthesis of 4-[2-amino-4-[3-[(4-tert-butylbenzoyl)amino]-2-methyl-phenyl]-7H- pyrroIo[2,3-d]pyrimidin-6-yl]benzoic acid (10-11): 10-11 (0.10 g, 73% yield) was prepared from 10-1 (0.14 g) following the procedure mentioned in step-2 of Example Al LCMS: m/z 520.4 (M + l)⁺.

Step-3: Synthesis of N-[3-[2-amino-6-[4-(morphoIine-4-carbonyl)phenyl]-7H-pyrrolo [2,3- d]pyrimidin-4-yI]-2-methyl-phenyl]-4-tert-butyl-benzamide( Example Dl ): To a solution of 10-11 (0.10 g, 0.19 mmol) and morpholine (0.05 mL, 0.578 mmol) in DMF (2 mL) was added PyBOP (0.15 g, 0.28 mmol); and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (as indicated by TLC), water (5 mL) was added to it and the resultant solid was filtered, washed with water and recrystallised using diethyl ether (15 mL) to afford the title compound Dl (0.030 g, 27% yield). LCMS: m/z 589.5 (M + 1)⁺. Ή NMR (400 MHz, DMSO-d₆): δ 1.33 (s, 9H); 2.18 (s, 3H); 3.30-3.40 (m, 4H); 3.55-3.65 (m, 4H); 6.33 (bs, 2H); 6.55 (s, 1H); 7.35-7.37 (m, 2H); 7.43 (d, J = 7.6 Hz, 2H); 7.45-7.47 (m, 1 H); 7.55 (d, J = 8.8 Hz, 2H); 7.87 (d, J= 8.4 Hz, 2H); 7.95 (d, J = 8.4 Hz, 2H); 9.93 (s, 1H); 1 1.87 (s, 1H).

Following compound was prepared from their corresponding intermediates (given in parentheses) using the same sequence of procedures as used for preparation of Example Dl from INT- 5-IV.

Example El: N-[3-[2-amino-6-(4-morpholinophenyl)-7H-pyrroIo[2, 3-d]pyrimidin-4-yl]-2- methyI-phen l]-4-tert-butyl-benzamide

Step-1: Synthesis of N-[3-[2-amino-6-(4-morpholinophenyl)-7H-pyrrolo[2,3-d] pyrimidin-4- yl]-2-methyl-phenyI]-4-tert-butyl-benzamide(Exaniple El): To a suspension of INT-5-III

(0.07 g, 0.21 mmol), INT-2-IH (0.10 g, 0.25 mmol) in a mixture of toluene (7.5 mL) and EtOH ( 1.5 mL) was added a solution of Na₂C0₃ (0.13 g, 1.27 mmol) in water (3 ml ); and it was purged using argon for 20 min. PdCl₂(dppf) (0.017 g, 0.021 mmol) was added in to the reaction mixture and then stirred at 90 °C for 16 h. After completion of the reaction, it was cooled to room temperature and poured into ice cold water (15 mL). The resulting solid precipitate was filtered and washed with water (5 mL). The residue was purified by preparative TLC (Si0₂, 7% MeOH in CH₂C1₂) to afford title compound El (0.017 g, 15.4% yield). LCMS: m/z 561.1 (M + 1)⁺. Ή NMR (400 MHz, DMSO-d₆): δ 1.32 (s, 9H); 2.17 (s, 3H, CH₃); 3.15 (t, J = 4.8 Hz, 4H); 3.74 (t, J = 4.8 Hz, 4H); 6.16 (bs, 2H); 6.27 (d, J = 1.6 Hz, lH); 6.96 (d, J = 8.8 Hz, 2H); 7.33-7.35 (m, 2H); 7.44 (dd, J, = 2.4 Hz, J₂ = 7.2 Hz, 1H); 7.56 (d, J = 8.8 Hz, 2H); 7.67 (d, J = 8.8 Hz, 2H); 7.95 (d, j = 8.4 Hz, 2H); 9.92 (s, 1H); 1 1.63 (bs, Ι Η, ΝΗ).

Example Fl: N-[3-[2-amino-6-(6-morpholino-3-pyridyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]- 2-methyl-phenyl]-4-cyclopropyl-benzamide

Step-1: 4-chIoro-6-(6-morphoiino-3-pyridyI)-7H-pyrrolo [2, 3-d]pyrimidin-2-amine (11-1):

A solution of INT- 4-IV (0.14 g, 0.34 mmol) and ZnCl₂ (0.046 g, 0.34 mmol) in EtOH-H₂0 (5 mL + 0.25 mL) was stirred at 85 °C for 5 days. After completion of the reaction (as indicated by LCMS); the reaction mixture was filtered, the residue was washed with water (5 mL) and dried to provide 11-1 (0.09 g, 81% yield). LCMS: m/z 331. 1 (M + 1)⁺.

Step-2: N-[3-[2-amino-6-(6-morpholino-3-pyridyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2- methyl-phenyl]-4-cyclopropyl-benzamide (Example Fl): A solution of 11-1 (0.09 g, 0.27 mmol), INT-2-IV (0.15 g, 0.32 mmol) and Na₂C0₃ (0.063 g, 0.59 mmol) in dioxane-water (5 mL + 2.5 mL) was purged using argon for 10 min. Finally, Pd(PPh₃)4 (0.034 g, 0.027 mmol) was added to the reaction mixture and it was stirred at 90 °C for 3 h. After completion of the reaction, dioxane was removed under reduced pressure and diluted using EtOAc (40 mL). The organic layer was washed with brine (30 mL); dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure. The residue was purified using preparative TLC (Si0₂, 5% MeOH in CH₂C1₂) to provide title compound Fl (0.01 g, 6.7% yield). LCMS: m/z 546.3 (M + 1)⁺. Ή NMR (400 MHz, DMSO-d₆): δ 0.74-0.75 (m, 2H); 1.00-1.20 (m, 2H); 2.14 (s, 3H, CH₃); 1.90- 2.00 (m, 1H); 3.4-3.5 (m, 4H); 3.65-3.75 (m, 4H); 6.16 (bs, 2H); 6.31 (s, 1 H); 6.86 (d, J = 9.2 Hz, 1H); 7.20 (d, J = 8.0 Hz, 2H); 7.30-7.42 (m, 3H); 7.88 (d, J = 8.4 Hz, 2H); 7.94 (d, J = 8.8 hz, 1H); 8.57 (s, 1H); 9.86 (s, 1H); 1 1.67 (s, 1H, NH).

Example Gl: 5-cyclopropyl-N-[2-methyl-3-[6-[4-(morpholine-4-carbonyl)phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]thiophene-2-carboxamide

Step-1: Synthesis of methyl 4-[4-(2-methyl-3-nitro-phenyI)-7H-pyrrolo[2,3-d]pyrimidin-6- yl]benzoate (12-1): 12-1 (2.5 g crude) was prepared using INT-1-III (2.2 g) and 2-1 (2.4 g) following the procedure described in step-1 of Example-Al . LCMS: m/z 389.2 (M + 1)⁺.

Step-2: Synthesis of 4-[4-(2-methyI-3-nitro-phenyl)-7H-pyrroio [2, 3-d] pyrimidin-6-yl] benzoic acid (12-11): 12-11 (2 g, 83% yield) was obtained from 12-1 (2.5 g crude) following the procedure mentioned in step-2 of Example Al . LCMS: m/z 375.1 (M + 1)⁺.

Step-3: [4-[4-(2-methyl-3-nitro-phenyl)-7H-pyrroIo[2, 3-d]pyrimidin-6-yl]phenyl]- morpholino-methanone (12-111): 12-111 (1.1 g, 46.6% yield) was obtained from 12-11 (2 g, 5.34 mmol) following the procedure described in step-3 of Example-Al . LCMS: m/z 444.2 (M + 1 )⁺. Step-4: Synthesis of [4-[4-(3-amino-2-methyl-phenyl)-7H-pyrrolo[2, 3-d]pyrimidin-6-yl] phenyl]-morpholino-methanone (12-IV): To the solution of , 12-111 ( 1.1 g, 2.48 mmol) in methanol (15 mL) was added 10% Pd/C (0.6 g) and stirred under H₂ atmosphere for a period of 16 h. After completion of reaction, reaction mixture was filtered through celite, washed with 10% MeOH in CH₂C1₂ (50 mL) and the combined filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Si0₂, 2% MeOH in CH₂C1₂) to afford 12-IV (0.70 g, 68.6% yield). LCMS: m/z 414.2 (M + 1)⁺.

Step-5: Synthesis of 5-cyclopropyl-N-[2-methyl-3-[6-[4-(morphoIine-4-carbonyI)phenyl]- 7H-pyrrolo[2, 3-d] pyrimidin-4-yl] phenyl] thiophene-2-carboxamide (Example Gl): A solution of 5-cyclopropylthiophene-2-carboxylic acid (0.097 g, 0.58 mmol) in SOCl₂ (6 mL) was refluxed for 3 h. After consumption of acid, excess of SOCl₂ was removed under reduced pressure to provide corresponding acid chloride. This was added using CH₂C1₂ (3 mL) to a solution of 12-IV (0.2 g, 0.48 mmol) in anhydrous CH₂C1₂ (2 mL) and pyridine (0.05 mL, 0.72 mmol) at 0 °C; and the reaction mixture was stirred at room temperature for 20 min. After completion of the reaction, it was diluted using ethyl acetate (30 mL), washed with saturated NaHC0₃ solution (30 mL), brine (30 mL), dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure. The residue was purified using column chromatography (Si0₂, EtOAc) followed by preparative TLC (Si0₂, EtOAc) to afford the title compound Gl (0.010 g,^'3.7% yield). LCMS: m/z 564.3 (M + 1)⁺. Ή NMR (400 MHz, DMSO-d₆): δ 0.71-0.75 (m, 2H); 1.04-1.08 (m, 2H); 2.16 (s, 3H); 2.20-2.21 (m, 1H); 3.27-3.27 (m, 2H); 3.50-3.70 (m, 6H); 6.87 (d, J = 2.0 Hz, 1H); 6.91 (d, J = 3.6 Hz, 1H); 7.37-7.50 (m, 5H); 7.79 (d, J = 4.0 Hz, 1H); 8.03 (d, J= 8.4 Hz, 2H); 8.85 (s, 1H); 9.91 (bs, 1H).

Following compound was synthesized as described above, using 5,6,7,8-tetrahydroimidazo[l ,2- a]pyridine-2-carboxylic acid in step-5 (coupling was done using PyBOP in DMF).

Example HI: N-[2-methyl-3-[6-[4-(morpholine-4-carbonyl)phenyl]-7H-pyrrolo[2, pyrimidin-4-yl] phenyl] isoindoline-2-carboxamide

Step-1: Methyl 4-[4-[3-(isoindoline-2-carbonylamino)-2-methyl-phenyl]-7H-pyrrolo[2,3- d]pyrimidin-6-yI]benzoate (13-1): INT-1-III (0.3 g, 1.07 mmol) and INT- 3-III (0.48 g, 1.29 mmol) were added to a solution of Na₂C0₃ (0.29 g, 2.77 mmol) in dioxane-water (20 mL + 4 mL) and purged using argon for 15 min. Finally, Pd(PPh₃)₄ (0.123 g, 0.1 1 mmol) was added to it and stirred at 100°C for 3 h. After completion of the reaction, dioxane was removed under reduced pressure and the residues were dissolved in EtOAc (50 mL). The organic layer was washed with water (35 mL), brine (35 mL), dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure. The residue was subjected to column chromatography (Si0₂, 4% MeOH in CH₂C1₂) to provide 13-1 (0.35 g, 67.3% yield). LCMS: m/z 504.3 (M + 1)⁺. Step-2: 4-[4-[3-(isoindoIine-2-carbonylamino)-2-methyl-phenyl]-7H-pyrrolo[2,3-d] pyrimidin-6-yl] benzoic acid (13-11): To a solution of 13-1 (0.35 g, 0.71 mmol) in MeOH (5 mL) was added NaOH (0.14 g, 3.5 mmol) in water (5 mL) and the reaction mixture was re fluxed for 5 h. After completion of the reaction (as indicated by TLC), MeOH was removed under reduced pressure and it was acidified using 10% acetic acid solution. The resultant solid was filtered and dried under vacuum to provide 13-11 (0.29 g, 85% yield), which was used further without any purification. LCMS: m/z 490.2 (M + 1)⁺.

Step-3: N-[2-methyl-3-[6-[4-(morpholine-4-carbonyl)phenyI]-7H-pyrroIo[2,3-d]pyrimidin- 4-yl]phenyl]isoindoline-2-carboxamide (Example HI): To a solution of 13-11 (0.29 g, 0.6 mmol) and morpholine (0.24 mL, 3.01 mmol) in DMF (5 mL) was added PyBOP (0.47 g, 0.904 mmol) and stirred at room temperature for 16 h. After completion of the reaction (as indicated by TLC), water (40 mL) was added to it and extraction was carried out using EtOAc (25 mL x 2). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na₂S0₄, filtered and concentrated under reduce pressure. The residue was purified using column chromatography (Si0₂, 5% MeOH in CH₂C1₂) to provide 89% pure final product, which was finally crystallized from hot CH₃CN to provide desired compound HI (0.15 g, 45.4% yield). LCMS: m/z 559.4 (M + 1 )⁺. Ή NMR (DMSO, 400 MHz): δ 2.18 (s, 3H); 3.31 -3.35 (m, 2H); 3.50-3.70 (m, 6H); 4.79 (s, 4H); 6.85 (s, 1H); 7.29-7.37 (m, 5H); 7.49 (d, J = 8.4 Hz, 2H); 7.55 (d, J= 7.2 Hz, 1H); 7.96 (s, 1H); 7.03 (d, J = 8.4 Hz, 2H); 8.85 (s, 1H); 12.80 (s, 1H).

Following compounds were synthesized from their corresponding intermediates (given in parentheses) using the same sequence of procedures as used for preparation of Example HI using INT-1-III and INT-3-III.

(m,2H), 3.92 (brs, IH), 4.81 (s,

carbonylamino)-2-methyl-

Example II: N-[2-methyl-3-[6-(4-morpholinophenyI)-7H-pyrrolo[2,3-d]pyrimidin-4-yl] phenyl]isoindoline-2-carboxamide

Step-1 : N-[2-methyI-3-[6-(4-morpholinophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl] isoindoline-2-carboxamide (Example II): To a solution of INT-l-IV (0.1 g, 0.32 mmol) and INT- 3-III (0.144 g, 0.38 mmol) in dioxane (10 mL) was added a solution of Na₂C0₃ (0.084 g, 0.795 mmol) in water (2 mL); and the reaction mixture was purged using argon for 15 min. Finally, Pd(PPh₃)₄ (0.037 g, 0.038 mmol) was added to it and the reaction mixture was stirred at 100 °C for 5 h. After completion of the reaction, water (30 mL) was added to it and the resultant solid was filtered and dried. The crude product was purified by column chromatography (Si0₂, 4% MeOH in CH₂C1₂) followed by crystallization using MeOH (3 ml) to provide desired compound II (0.038 g, 22% yield). LCMS: m/z 531.3 (M + 1)⁺. Ή NMR (DMSO-d₆, 400 MHz) δ 2.17 (s, 3H, CH₃); 3.18-3.19 (m, 4H); 3.72-3.74 (m, 4H); 4.78 (s, 4H); 6.56 (s, 1H); 7.00 (d, J = 8.8 Hz, 2H); 7.16-7.19 (m, 1H); 7.28-7.37 (m, 5H);. 7.53 (d, J - 1.2 Hz, 1H); 7.81 (d, J = 8.8 Hz, 2H); 7.84-7.89 (m, 1H); 7.96 (s, 1H); 8.76 (s, lH).

Following compounds were synthesized from their corresponding intermediates using the same sequence of procedures as used for preparation of Example I 1 from INT-l-IV.

LCMS: m/z 533.3 (M+l)⁺. ΓΝΤ-2-

'H NMR (DMSO-<¾, 400 IV

MHz): δ 1.29 (s, 9H), 3.22 (t, J

O = 4.0 Hz, 4H), 3.76 (t, J = 4.0

Hz, 4H), 7.01 (d, J= 8.8 Hz,

16 4-cyclopropyl-N-[2-methyl-3- 1H), 7.22 (d, J = 8.8 Hz, 2H),

[8-(6-morpholino-3-pyridyl)- 7.36-7.41 (m, 1H), 7.48 -7.54

9H-purin-6- (m, 2H), 7.92 (d, J = 8.4 Hz,

yl]phenyl]benzamide

2H), 8.26-8.28 (m, 1H), 8.89 (s,

1H), 8.94 (s, 1H), 9.96 (s, 1H),

13.87 (s, 1H, NH)

Example Jl: N-[3-[2-amino-6-[4-(morpholine-4-carbonyl) phenyl]-7H-pyrro!o[2, 3-d] pyrimidin-4- l]-2-methyl-phenyl] isoindoline-2-carboxamide

14-11

Step-1: Methyl 4-[2-amino-4-[3-(isoindoline-2-carbonylamino)-2-methyl-phenyl]-7H- pyrrolo[2,3-d]pyrimidin-6-yI]benzoate (14-1): To a solution of INT-5-IV (0.4 g, 1.32 mmol) and INT- 3-III (0.5 g, 1.32 mmol) in dioxane (10 mL) was added a solution of Na₂C0₃ (0.28 g, 2.65 mmol) in water (4 mL); and the reaction mixture was purged using Ar for 15 min. Pd(PPh₃)4 (0.152 g, 0.132 mmol) was added to it and the reaction mixture was stirred at 100 °C for 5 h. After completion of the reaction, dioxane was removed under reduced pressure and water (25 mL) was added to it. The resultant solid was filtered and purified by column chromatography (Si0₂, 3%MeOH in CH₂C1₂) to provide 14-1 (0.35 g, 51% yield). LCMS: m/z 519.3(M + 1)⁺. Step-2: Methyl 4-[2-amino-4-[3-(isoindoline-2-carbonylamino)-2-methyl-phenylj-7H- pyrrolo[2,3-d]pyrimidin-6-yI]benzoate (14-11): To a solution of 14-1 (0.35 g, 0.67 mmol) in MeOH (5 mL) was added a solution of NaOH (0.197 g, 4.9 mmol) in water (1.5 mL); and the reaction mixture was refluxed for 5 h. After completion of the reaction, MeOH was removed under reduced pressure and was acidified using 10% citric acid solution. The resultant solid was filtered and dried under vacuum to provide 14-II (0.2 g, 58.8% yield). LCMS: m/z 505.3 (M + I )^' .

Step-3: N-[3-[2-amino-6-[4-(morpholine-4-carbonyl)phenyl]-7H-pyrrolo(2,3-d]pyrimidin-4- yl]-2-methyl-phenyljisoindoline-2-carboxamide (Example Jl): To a solution of 14-11 (0.13 g, 0.26 mmol) and morpholine (0.1 1 mL, 1.29 mmol) in DMF (2 mL) was added PyBOP (0.2 g, 0.39 mmol) and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, saturated NaHC0₃ solution (15 mL) was added to it and extraction was carried out using EtOAc (15 mL x 3). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure. The residue was purified using preparative TLC (Si0₂, 5% MeOH in CH₂C1₂) to provide desired compound Jl (0.037 g, 26% yield). LCMS: m/z 574.4 (M + 1)⁺. Ή NMR (DMSO-d₆, 400 MHz): 2.19 (s, 3H); 3.30-3.40 (m, 2H); 3.53.7 (m, 6H); 4.80 (s, 4H); 6.30 (bs, 2H); 6.54 (s, 1H); 7.22- 7.38 (m, 6H); 7:43 (d, J= 8.4 Hz, 2H); 7.51 (d, J = 7.6 Hz, l H); 7.86 (d, J = 8.0 Hz, 2H); 7.94 (s, 1H); 1 1.84 (s, 1H).

Example Kl: N-[3-[2-amino-6-(6-morpholino-3-pyridyl)-7H-pyrrol0[2,3-d] pyrimidin-4-yl]- 2-methyl-phenyI]isoindoIine-2-carboxamide

Step-1: N-[3-[2-(2,2-dimethyIpropanoylamino)-6-(6-morpholino-3-pyridyl)-7H-pyrroIo[2,3- d]pyrimidin-4-yl]-2-methyl-phenyl]isoindoline-2-carboxamide (15-1): To a solution of INT- 4-IV (0.45 g, 1.08 mmol) and INT-3-III (0.49 g, 1.3 mmol) in dioxane (44 mL) was added a solution of Na₂C0₃ (0.28 g, 2.72 mmol) in water (10 mL) and Ar was purged through it for 15 min. Finally, Pd(PPh₃)₄ (0.125 g, 0.108 mmol) was added to the reaction mixture and it was stirred at 100 °C for 5 h. After completion of the reaction, it was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure and the residue was diluted using water (30 mL). The resultant solid was filtered, dried and purified using column chromatography (Si<¾, 3% MeOH in CH₂C1₂) to provide 15-1 (0.55 g, 80% yield). LCMS: m/z 631.3 (M + 1)⁺.

Step-2: N-[3-[2-amino-6-(6-morpholino-3-pyridyl)-7H-pyrrolo[2,3-d]pyriinidin-4-yl]-2- methyl-phenyl]isoindoIine-2-carboxamide (Example Kl): To a solution of 15-1 (0.45 g, 0.71 mmol) in MeOH (16 mL) was added a solution of NaOH (0.285 g, 7.13 mmol) in water (8 mL); and the reaction mixture was stirred at 80 °C for 16 h. After completion of the reaction (as indicated by TLC), MeOH was removed under reduced pressure and the reaction mixture was acidified using 10% citric acid solution. The resultant solid was filtered and washed with water to provide crude product, which was finally purified using preparative HPLC to provide desired compound Kl (0.125 g, 32% yield). LCMS: m/z 547.2 (M + 1)⁺. Ή NMR (DMSO-d₆, 400 MHz) δ 2.18 (s, 3H, CH₃); 3.48 (t, J = 4.8 Hz, 4H); 3.69 (t, J = 4.8 Hz, 4H); 4.79 (s, 4H); 6.16 (bs, 2H); 6.30 (s, 1H); 6.87 (d, J = 8.8 Hz, 1H); 7.21 (d, J = 7.2 Hz, lH); 7.27-7.38 (m, 5H); 7.49 (d, J = 7.6 Hz, 1H); 7.92 (s, 1H); 7.95 (dd, J_/ = 2.4 Hz, J₂ = 8.8 Hz, 1H); 8.58 (d, J = 2.0 Hz, 1H); 1 1.67 (s, ΙΗ, ΝΗ). .

Example LI: N-[3-[2-amino-6-(4-morpholinophenyl)-7H-pyrroIo[2,3-d]pyrimidin-4-yl]-2- methyl-phenylJisoindoIine-2-carboxamide

1006756

Example LI (0.016 g, 10% yield) was synthesized using INT-9 0 mmol) and 3-III

(0.14 g, 0.39 mmol), as described for the synthesis of Example-Il. LCMS: m/z 546.4 (M + 1)⁺. 'H NMR (DMSO-d6, 400 MHz): δ 2.18 (s, 3H, CH₃); 3.15 (t, J = 4.8 Hz, 4H); 3.74 (t, J = 4.8 Hz, 4H); 4.80 (s, 4H); 6.14 (bs, 2H); 6.25 (d, J = 1.6 Hz, 1H); 6.96 (d, J = 8.8 Hz, 2H); 7.21 (d, J = 7.2 Hz, 1H); 7.26-7.39 (m, 5H); 7.49 (d, J = 7.6 Hz, 2H); 7.94 (s, 1H); 1 1.61 (s, ΙΗ, ΝΗ).

Example Ml: N-[2-methyl-3-[6-[4-(piperazin-l-ylmethyI)phenyl]-7H-pyrrolo[2,3-d] pyrimidin-4-yl] phenyl] isoindoline-2-carboxamide

Step-1: tert-butyl 4-[[4-{4-chloro-7-(p-tor_: 1007126 Olo[2,3-d]pyrimidin-6- yl]phenyI]methyI]pipera.cine-l-carboxylate (16-1): Argon was purged through a solution of INT-6-VI (1 g, 2.31 mmol), INT-7-V (1 g, 2.54 mmol) and K₂C0₃ (0.62 g, 4.6 mmol) in 1 ,4 dioxane-water (24 mL + 4.1 mL) for 30 minutes. Finally, PdCl₂(dppf) (0.188 g, 0,22 mmol) was added to the reaction mixture and it was allowed to stir at 100 °C for 4 h. After completion of the reaction (as indicated by TLC), it was cooled to room temperature and diluted using water ( 100 mL). Extraction was carried out using EtOAc (30 ml x 3); the combined organic layers were washed with water (60 mL), brine (60 mL), dried over Na₂S0₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Si0₂, 15 % EtOAc in hexane) to afford 16-1 (0.86 g, 64% yield). LCMS: m/z 582.1 (M + 1)⁺.

Step-2: tert-butyl 4-[[4-[4-[3-(isoindoIine-2-carbonylamino)-2-methyl-phenyl]-7-(p- toiylsulfonyI)pyrrolo[2,3-d]py»"iniidin-6-yl]phenyl]methyl]piperazine-l-carboxylate (16-11): 16-11 (0.3 g, 48% yield) was synthesized using 16-1 (0.45 g, 0.77 mmol) and INT-3-III (0.29 g, 0.77 mmol) following the procedure described in step-1 for the synthesis of Example HI . LCMS: m/z 798.4 (M + 1)⁺.

Step-3: tert-butyl 4-[[4-[4-[3-(isoindoline-2-carbonylamino)-2-methyl-phenyl]-7H- pyrrolo[2,3-d]pyrimidin-6-yI]phenyl]methyl]piperazine-l-carboxyIate (16-111): To a solution of 16-11 (0.3 g, 0.37 mmol) in THF: MeOH: H₂0 (3: 1 : 1 , 5 ml) was added LiOH-H₂0 (0.047 g, 1.12 mmol) and the reaction mixture was stirred at room temperature for 2 h.. After completion of the reaction (as indicated by TLC), solvent was removed under reduced pressure and the residue was diluted with water (15 mL). Extraction was carried out using EtOAc (10 mL x 3); the combined organic layers were washed with water (25 mL), brine (25 mL), dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure. The residue was purified using preparative TLC (Si0₂, 12% MeOH in CH₂C1₂) to afford 16-111 (0.1 1 g, 45 % yield). LCMS: w/z 644.4 (M + 1 )⁺.

Step-4: N-[2-methyI-3-[6-[4-(piperazin-l-yImethyl)phenyI]-7H-pyrrolo[2,3-d] pyrimidin-4- yl]phenyl]isoindoline-2-carboxamide (Example Ml): 16-111 (0.1 1 g, 0.17 mmol) was added to 4M HC1 in 1,4 dioxane (3 mL) and the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, solvent was removed under reduced pressure and saturated NaHC0₃ solution (15 mL) was added to the residue. Resulting solid was filtered, dried and purified by preparative TLC (Si0₂, 10% MeOH in CH₂C1₂) to provide title compound Ml (0.045 g, 48% yield). LCMS: m/z 544.4 (M + 1)⁺. Ή NMR (400 MHz, DMSO-d₆), δ 2.17 (s, 3H, CH₃); 2.22-2.40 (m, 4H); 2.62-2.66 (m,4H); 3.43 (s, 2H); 4.78 (s, 4H); 6.72 (s, 1 H); 7.28-7.33 (m, 4H); 7.35-7.37 (m, 4H); 7.54 (d, J - 7.2 Hz, 1H), 7.89 (d, J = 7.6 Hz, 2H), 7.96 (s, 1H), 8.81 (s, 1 H), 12.7 (bs, 1H).

Following compound were synthesized from their corresponding intermediate (given in parentheses) using the same sequence of procedures as used for preparation of Example Ml using INT- 6-VI and INT-3-III.

pyrrolo[2,3-d]pyrimidin-4- yl]phenyl]isoindoline-2- (s, IH), 8.84 (s, IH), 12.73 (s, IH,

carboxamide NH).

LCMS: m/z 583.4 (M+l)⁺.

M5 Ή NMR (DMSO-i¾, 400 MHz): δ

0.24-0.28 (m, 2H), 0.36-0.42 (m, 7-III 2H), 0.75-0.78 (m, 2H), 1.01 -1.07

4-cyclopropyl-N-[3-[6-[4-[(4- (m, 2H), 1.58-1.61 (m, I H), 1.98- cyclopropylpiperazin- 1 - 2.04 (m, IH), 2.18 (s, 3H, CH₃), yl)methyl]phenyl]-7H- 2.26-2.58 (m, 8H), 3.47 (s, 2H), pyrrolo[2,3-d]pyrimidin-4-yl]-2- 6.76 (s, IH), 7.22 (d, J= 8.4 Hz,

methyl-phenyl]benzamide 2H), 7.37-7.44 (m, 4H ), 7.51 (d, J

= 6.8 Hz, IH), 7.90-7.93 (m, 4H ),

8.84 (s, IH ), 9.93 (s, IH), 12.72(s,

IH, NH).

LCMS: m/z 557.4 (M+l)⁺.

M6 Ή NMR (DMSO-flfe, 400 MHz): δ

0.75-0.78 (m, 2H), 1.01 - 1.07 (m, 7-III 2H), 1.98-2,03 (m, I H), 2.18 (s,

3H, CH₃), 2.50-2.57 (m, 2H), 2.92

4-cyclopropyl-N-[2-methyl-3- (s, 2H), 3.15-3.18 (m, 2H), 3.57 (s,

[6- [4- [(3 -oxopiperazin- 1 - 2H), 6.78 (s, IH), 7.22 (d, J= 8.4 yl)methyl]phenyl]-7H- Hz, 2H), 7.38-7.44 (m, 3H ), 7.51 pyrrolo[2,3-d]pyrimidin-4- (d, J= 6.8 Hz, IH), 7.78 (s, IH), yl]phenyl]benzamide

7.90-7.95 (m, 4H), 8.84 (s, I H ),

9.93 (s, IH), 12.74 (s, ΙΗ, ΝΗ).

LCMS: m/z 572.4 (M+l)⁺.

M7 Ή NMR (DMSO-flfc, 400 MHz): δ

0.75-0.78 (m, 2H), 1.01-1.07 (m, 7-III 2H), 1.23(s, 3H), 1.44-1.52(m,

4H), 1.98-2.03 (m, I H), 2.18(s,

4-cyclopropyl-N- [3 - [6- [4- [(4- 3H, CH₃), 2.30-2.44 (m, 4H), hydroxy-4-methyl-l- 3.44-3.52 (m, 1H), 4.46-4.52 (m, piperidyl)methyl]phenyl]-7H- 1H), 6.77 (s, 1H), 7.22 (d, J = 8.0 pyrrolo[2,3-d]pyrimidin-4-yl]-2- Hz, 2H), 7.38-7.44 (m, 4H ), 7.51

methyl-phenyl]benzamide (d J= 7.2 Hz, 1H), 7.90-7.92 (m,

4H), 8.84 (s, 1H ), 9.94 (s, 1 H),

12.73 (s, 1H, NH)

LCMS: m/z 584.4 (M+l)⁺.

M8 Ή NMR (DMSO-i/₆, 400 MHz): S

0.26 (br s, 2H), 0.90 (d, J = 4.4 7-III Hz, 2H), 1.58 (br s, 1H), 2.19 (s,

N-[3-[6-[4-[(4- 3H, CH₃), 2.32-2.34 (m, 4H),

cyclopropylpiperazin- 1 - 2.49-2.51 (m, merged in DMSO yl)methyl]phenyl]-7H- signal, 4H), 3.47 (s, 2H), 4.80 (s, pyrrolo[2,3-d]pyrimidin-4-yl]-2- 4H), 6.74 (s, 1H), 7.30-7.39 (m,

methyl-phenyl]isoindoline-2- 8H), 7.56 (d, J = 7.2 Hz, 1H), 7.91 carboxamide (d, J = 7.6 Hz, 2H), 7.98 (s, 1 H),

8.83 (s, l H), 12.70 (s, 1 H, NH)

LCMS: m/z 568.3 (M+l )⁺.

M9 Ή NMR (DMSO-d₆, 400 MHz): δ

1.62-1.73 (m, 2H), 1.80- 1.86 (m, 7-III 3H), 2.19 (s, 3H, CH3), 2.22-2.29

N-[3-[6-[4-[(4-cyano-l- (m, 2H), 2.50-2.59 (m, 1H), 2.84- piperidyl)methyl]phenyl]-7H- 2.81 (m, l H), 3.50 (s, 2H), 4.80 (s, pyrrolo[2,3-d]pyrimidin-4-yl]-2- 4H), 6.74 (s, 1H), 7.30-7.39 (m,

methyl-phenyl]isoindoline-2- 8H), 7.56 (d, J = 6.8 Hz, 1 H), 7.91 carboxamide (d, J= 8.4 Hz, 2H), 7.98 (s, 1 H),

8.37 (s, 1 H), 12.70 (s, 1H, NH). M10 LCMS: m/z 558.4 (M+l)⁺. 7-TII

^•Γ ϊ ! r Ή NMR (DMSO 400 MHz): <5

0.88-1.04 (m, 2H), 1.39-1.44 (m,

2H), 1.55-1.69 (m, 3H), 1.82-1.88

(m, IH), 2.17 (s, 3H, CH₃), 2.57-

N-[3-[6-[4-[(3-amino-l- 2.70 (m, 3H), 3.40-3.49 (m, 2H), piperidyl)methyl]phenyl]-7H- 4.78 (s, 4H), 6.65 (s, IH), 7.29- pyrrolo[2,3-d]pyrimidin-4-yl]-2- 7.36 (m, 8H), 7.51-7.53 (m, IH), methyl-phenyl] isoindoline-2- 7.86-7.90 (m, 2H), 7.94 (s, IH), carboxamide

8.74 (s, IH), 12.69 (s, IH, NH).

Mi l LCMS: m/z 572 A (M+l)⁺. 7-III

Ή NMR (DMSO-<¾, 400 MHz): δ

0.98 (t, J = 6.8 Hz, 3H), 1.91 (s,

I H), 2.19 (s, IH), 2.28-2.48 (m, ^'

N-[3-[6-[4-[(4-ethylpiperazin- 1 - 10H), 3.37 (br s, IH), 3.49 (s, 2H), yl)methyl]phenyl]-7H-

4.80 (s, 4H), 6.74 (s, I H), 7.30- pyrrolo[2,3-d]pyrimidin-4-yl]-2- 7.39 (m, 9H), 7.56 (d, J= 7.2 Hz, methyl-phenyl]isoindoline-2-

IH), 7.91 (d, J = 8 Hz, IH), 7.98 carboxamide

(s, IH), 8.83 (s, IH), 12.70 (s, IH).

M12 LCMS: m/z 573.4 (M+l )⁺.. 7-III

Ή NMR (DMSO 400 MHz): δ

1.45 (t, J = 5.2 Hz, 4H), 1.89 (s,

3H, CH₃), 2.19 (s, 3H), 2.34-2.37

N-[3-[6-[4-[(4-hydroxy-4- (m, 4H), 3.48 (s, 2H), 4.10 (br s, methyl- 1- lH), 4.80 (s, 4H), 6.73 (s, I H), .

piperidyl)methyl]phenyl]-7H- 7.30-7.38 (m, 8H), 7.55 (dd, 7.2, 2 pyrrolo[2,3-d]pyrimidin-4-yl]-2-

Hz, IH), 7.90 (d, J = 8 Hz, 2H), methyl-phenyl]isoindoline-2- 7.99 (s, IH), 8.34 (s, IH), 12.86 (s, carboxamide

IH). M13 LCMS: m/z 568.4 (M+l)⁺. 7-III

Ή NMR (DMSO-i¾, 400 MHz): δ

1.53-1.56 (m, 1H), 1.63-1.68 (m,

2H),2.19(s,3H), 2.28-2.31 (m,

N-[3-[6-[4-[(3-cyano-l- 1H), 2.40-2.49(m, 1H), 2.60-2.63 piperidyl)methyl]phenyl]-7H- (m, 1H), 3.01-3.06 (m, 1H), 3.16 pyrrolo[2,3-d]pyrimidin-4-yl]-2- (d,J=5.2Hz, 1H), 3.53 (d, J =

methyl-pheny 1] isoindoline-2- 13.6 Hz, 2H), 13.60 (d,J= 13.6

carboxamide

Hz, 1H), 4.80 (s, 4H), 6.76 (s,

1H), 7.32-7.41 (m, 8H), 7.56 (d, J

= 6.8 Hz, 1H), 9,32 (d,J=7.6Hz,

2H), 7.97 (s, 1H), 8.38 (s, 1H),

12.70 (s, 1H).

M14 LCMS:m/_ 558.2 (M+l)⁺. 7-III

Ή NMR (DMSO-i , 400 MHz): δ

0.75-0.78 (m, 2H), 1.01-1.07 (m,

2H), 1.42-1.48(m, 1H), 1.58-1.78

N-[3-[6-[4-[(3-amino-l- (m, 3H), 1.94-2.06 (m,2H),

piperidyl)methyl]phenyl]-7H- 2.18(s,3H), 2.58-2.76 (m, 3H),

pyrrolo[2,3-d]pyrimidin-4-yl]-2- 3.40-3.54 (m, 3H), 6.77 (s, 1H), methyl-phenyl] -4-cyclopropyl- 7.23 (d,J=8.0Hz, 2H), 7.37- benzamide

7.42(m, 4H ), 7.5 l(d, J= 7.2 Hz,

1H), 7.90-7.92 (m, 4H), 8.84 (s,

1H), 9.95 (s, 1H), 12.74 (s, 1H)

Ml 5 LCMS: m/z 571.4 (M+l)⁺. 7-III

Ή NMR (DMSO-i/₆, 400 MHz): δ

0.75-0.78 (m, 2H), 0.97-1.07 (m,

5H), 1.98-2.04 (m, 1H), 2.18(s,

4-cyclopropyl-N- [3 - [6- [4- [(4- 3H), 2.28-2.50 (m, 10H), 3.50 (s, ethylpiperazin-1- 2H), 6.76 (s, 1H), 7.22 (d,J= 8.0 yl)methyl]phenyl]-7H- Hz, 2H), 7.37-7.52 (m, 5H ), 7.90- pyrrolo[2,3-d]pyrimidin-4-yl]-2- 7.93 (m, 4H), 8.84 (s, 1H ), 9.94

methyl-phenyl]benzamide (s, 1H), 12.73(s, 1H).

Example Nl : N-[2-methyl-3-[6-[4-[(4-methylpiperazin-l-yl) methyl]phenyI]-7H-pyrrolo[2, 3-d]pyrimidin-4- I] phen l]isoindoline-2-carboxamide

Step-1: 4-[4-chloro-7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin- ADV- 1007183 I): To a solution of INT-6-VI (0.8 g, 1.84 mmol) and (4-formylphenyl)boronic acid (CAS No.87199- 17-5, 0.29 g, 1.93 mmol) i CH₃CN (20 mL) was added 1M aqueous Na₂C0₃ ( 8 mL); and argon was purged through it for 30 min. Finally, PdCl₂(dppf) (0.18 g, 0.25 mmol) was added to the reaction mixture and it was stirred at 100 °C for 4 h. After completion of the reaction (as indicated by TLC), the reaction mixture was diluted with water (50 mL) and extraction was carried out using EtOAc (50 ml x 3). The combined organic layers were washed with water (75 mL), brine (75 mL), dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Si0₂, 15% EtOAc in hexane) to afford 17-1 (0.26 g, 34% yield). LCMS: m/z 412 .0 (M + 1 )⁺.

Step-2: N-[3-[6-(4-formylphenyl)-7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin-4-yl]-2-methyl- phenyl]isoindoline-2-carboxamide (17-11): 17—11 (0.26 g, 59% yield) was prepared from 17-1 (0.29 g, 0.70 mmol) and INT-3-III (0.26 g, 0.70 mmol) following the procedure described in step-1 for preparation of example HI . LCMS: m/z 628.3 (M + 1 )⁺. Step-3: N-[2-methyl-3-[6-[4-[(4-methylpiperazin-l-yI)methyl]phenyl]-7-(p-toIylsulfonyl) pyrrolo[2,3-d]pyi"imidin-4-yl]phenyl]isoindoline-2-carboxamide (17-111): To a solution of 17-11 (0.26 g, 0.41 mmol), AcOH (catalytic, 1 drop) and activated powdered molecular sieves (0.2 g) in CH₂C1₂ (5 mL) was added 1 -methylpiperazine (0.06 g, 0.62 mmol); and the reaction mixture was stirred at room temperature for 15 min. To this was added NaBH₃(CN) (0.039 g, 0.62 mmol) and the reaction mixture was allowed to stir at room temperature for 30 min. After completion of the reaction (as indicated by TLC), it was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc (50 mL), washed with water (50 mL) and brine (25 mL), dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure. The residue was purified using column chromatography (Si0₂, 5% MeOH in CH₂C1₂) to afford 17-111 (0.15 g, 50.8% yield). LCMS : m/z 713.3 (M + 1)⁺.

Step-4: N-[2-methyl-3-[6-[4-[(4-methyIpiperazin-l-yl)methyl]phenyl]-7H-pyrrolo[2,3-d] pyrimidin-4-yI]phenyl]isoindoline-2-carboxamide (Example Nl): Example Nl (0.042g, 38% yield) was prepared from 17-111 (0.15 g, 0.21 mmol) as described in step-3; example Ml . LCMS: m/z 558.4 (M + 1)⁺. Ή NMR (400 MHz, DMSO-d₆): δ 2.17 (s, 3H); 2.19 (s, 3H, CH₃); 2.30-2.45 (m, 8H); 3.49 (s, 2H); 4.80 (s, 4H); 6.74 (s, 1H); 7.30-7.35 (m, 4H); 7.37-7.39 (m, 4H); 7.56 (d, J = 7.2 Hz, 1H); 7.91 (d, J= 8.0 Hz, 2H); 7.98 (s, 1H); 8.84 (s, 1H); 12.70 (bs, 1 H, NH). Example Ol: N-[2-methyl-3-[6-(4-morpholinosulfonylphenyl)-7H-pyrrolo[2,3-d]pyrimidin- 4- I]phenyl]isoindoline-2-carboxamide

INT O-I: 4-[4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyI]sulfonylmorpholine was prepared from 4-chloro-6-iodo-7H-pyrroIo[2,3-d]pyrimidine, following the same sequence of procedures as mentioned in INT-9II

Step-I:N-[2-methyl-3-[6-(4-morpholinosulfonylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl]phenyl]isoindoline-2-carboxamide): O-II (0.26 g, 59 % yield) was prepared from O-I (0.29 g, 0.70 mmol) and INT-3-III (0.26 g, 0.70 mmol) following the procedure described in step-1 for preparation of example HI . LCMS: m/z 595.3 (M + 1)⁺. Ή NMR (DMSO-i/5, 400 MHz): δ 2.19 (s, 3H, CH₃); 2.89 (s, 4H), 3.61-3.63 (m, 4H), 3.47-3.48 (m, 4H), 7.00 (s, 1H), 7.32-7.31 (m, 6H), 7.56 (d, J = 7.6 Hz, 1 H), 7.78 (d, J = 7.6 Hz, 2H), 7.95 (s, 1H), 8.23 (d, J = 7.6 Hz, 2H), 8.88 (s, 1H); 12.94 (s, Ι Η, ΝΗ).

Following compound was synthesized from INT-O-I using the same sequence of procedures as used for preparation of Example O-II.

The below list of examples, but not to be limited to these numbers, can also be synthesized by following the general synthesis described above:

4-cyclopropyl-N-[2-methyl-3-[6-[4-[(4-methylpiperazin-l-yl)methyl]phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]phenyl]benzamide;

N-[3-[2-amino-6-[4-[(4-methylpiperazin-l-yl)methyl]phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]- 2-methyl-phenyl]-4-cyclopropyl-benzamide;

4-cyclopropyl-N-[3-[6-[4-[(4-ethylpiperazin-l-yl)methyl]phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4- yl]-2-methyl-phenyl]benzamide;

N-[3-[2-amino-6-[4-[(4-ethylpiperazin-l -yl)methyl]phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2- methyl-phenyl]-4-cyclopropyl-benzamide; 4-cyclopropyl-N- [3 - [6- [4- [(4-cyclopropylpiperazin- 1 -y l)methy l]pheny 1] -7H-pyrrolo [2 ,3 - d]pyrimidin-4-yl]-2-methyl-phenyl]benzamide;

N-[3-[2-amino-6-[4-[(4-cyclopropylpiperazin-l-yl)methyl]phenyl]-7H-pyrrolo[2,3-d]pyrimidin- 4-yl] -2-methyl -phenyl] -4 cyclopropy 1-benzamide ;

4-cyclopropyl-N- [2-methyl-3 - [6- [4- [(3 -oxopiperazin- 1 -yl)methy ljphenyl] -7H-pyrrolo [2 ,3 - d]pyrimidin-4-yl]phenyl]benzamide;

N- [3 - [2-amino-6- [4- [(3 -oxopiperazin- 1 -y l)methy l]pheny 1] -7H-pyrrolo [2 ,3 -d]pyrimidin-4-yl] -2- methyl-phenyl] -4-cyclopropyl-benzamide;

4-cyclopropyl-N-[3-[6-[4-[(4-hydroxy-4-methyl-l -piperidyl)methyl]phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-2-methyl-phenyl]benzamide;

N- [3 - [2-amino-6- [4- [(4-hydroxy-4-methyl- 1 -piperidyl)methyl]phenyl] -7H-pyrrolo [2,3 - d]pyrimidin-4-yl]-2-methyl-phenyl]-4-cyclopropyl-benzamide;

N- [3 - [6- [4- [(3 -amino- 1 -piperidyl)methyl]phenyl] -7H-pyrrolo [2,3 -d]pyrimidin-4-y 1] -2-methyl- phenyl] -4-cyclopropyl-benzamide ;

N-[3-[2-amino-6-[4-[(3-amino-l -piperidyl)methyl]phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2- methyl-phenyl]-4-cyclopropyl-benzamide;

N-[3-[2-amino-6-[4-[(4-methylpiperazin-l-yl)methyl]phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]- 2-methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[6-[4-[(4-ethylpiperazin-l-yl)methyl]phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methyl- phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[4-[(4-ethylpiperazin-l -yl)methyl]phenyl]-7H-pyrrolO[2,3-d]pyrimidin-4-yl]-2- methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[6-[4-[(4-cyclopropylpiperazin-l -yl)methyl]phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2- methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[4-[(4-cyclopropylpiperazin-l-yl)methyl]phenyl]-7H-pyrrolo[2,3-d]pyrimidin- 4-yl]-2-methyl-phenyl]isoindoline-2-carboxamide;

N-[2-methyl-3-[6-[4-[(3-oxopiperazin-l-yl)methyl]phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4- yl]phenyl]isoindoline-2-carboxamide;

N- [3 - [2-amino-6-. [4- [(3 -oxopiperazin- 1 -y l)methyl]pheny 1] -7H-pyrrolo [2 ,3 -d]pyrimidin-4-yl] -2- methyl-phenyl]isoindoline-2-carboxamide; N 3-[6-[4-[(4-hydroxy-4-methyl-l-piperidyl)methyl]phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]- 2-methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[4-[(4-hydroxy-4-rnethyl-l -piperidyl)methyl]phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-2-methyl-phenyl]isoindoline-2-carboxamide;

N- [3 - [6- [4-[(3 -amino- 1 -piperidyl)methyl]phenyl]-7H-pyrrolo[2,3 -d]pyrimidin-4-y l]-2-methy 1- phenyl]isoindoline-2-carboxamide;

N- [3 - [2-amino-6- [4- [(3 -amino- 1 -piperidy l)me

methyl-phenyl]isoindoline-2-carboxamide;

N- [3 - [2 -amino-6- [5 - [(4-methylpiperazin- 1 -yl)methyl] -2-pyridy l]-7H-pyrrolo [2,3 -d]pyrimidin-4- yl]-2-methyl-phenyl]-4-cyclopropyl-benzamide;

N-[3-[2-amino-6-[5-[(4-methylpiperazin-l-yl)methyl]-2-pyridyl]-7H-pyrrolo[2,3-d]pyrimidin-4- yl]-2-methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[5-(moφholinomethyl)-2-pyridyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methyl- phenyl] -4-cyclopropyl-benzamide ;

N-[3-[2-amino-6-[5-(morpholinomethyl)-2-pyridyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methyl- phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[5-[(4-hydroxy-4-methyl-l-piperidyl)methyl]-2-pyridyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl] -2-methyl -phenyl] -4-cyclopropyl-benzamide ;

N-[3-[2-amino-6-[5-[(4-hydroxy-4-methyl-l -piperidyl)methyl]-2-pyridyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-2-methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[5-(morpholinomethyl)-2-pyridyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2- (hydroxymethyl)phenyl]-4-cyclopropyl-benzamide;

N-[3-[2-amino-6-[5-(morpholinomethyl)-2-pyridyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2- (hydroxymethyl)phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[l-(l-methyl-4-piperidyl)pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2- methyl-phenyl]-4-cyclopropyl-benzamide;

N-[3-[2-amino-6-[l-(l-methyl-3-piperidyl)pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2- methyl-phenyl]-4-cyclopropyl-benzamide;

N-[3-[2-amino-6-[l-(l -methyl-4-piperidyl)pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2- methyl-phenyl]isoindoline-2-carboxamide; N-[3-[2-amino-6-[l -(l-methyl-3-piperidyl)pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2- methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[4-[(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl]phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl]-2-n ethyl-phenyl]isoindoline-2-carboxamide;

N 3-[2-amino-6-[4-(3-methyl-3,8-diazabicyclo[3.2 ]octan-8-yl)phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-2-methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[4-[(l -methyl-4-piperidyl)oxy]phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2- methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[4-(l-methylazetidin-3-yl)oxyphenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2- methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[4-[(3,4-dimethylpiperazin-l-yl)methyl]phenyl]-7H-pyrrolo[2,3-d]pyrimi yl]-2-methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[4-[(2,4-dimethylpiperazin-l -yl)methyl]phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4- yl]-2-methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[4-(3,4-dimethylpiperaz

methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[4-(2,4-dimethylpiperazin-l -yl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2- methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2ⁱamino-6-[4-(3-azabicycIo[3.3.2]decan-3-ylmethyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin- 4-yl]-2-methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[4-(3-azabicyclo[3.3.2]decan-3-yl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2- methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2-amind-6-[4-(5-methyl^:2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-2-methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[4-[(5-methyl-2,5-diazabicyclo[2.2. l]heptan-2-yl)methyl]phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl]-2-methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[4-[4-(2-hydroxyethyl)piperazin-l -yl]phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4- yl]-2-methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[4-[l-(4-methylpiperazin-l-yl)cyclopropyl]phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-2-methyl-phenyl]isoindoline-2-carboxamide; N-[3-[2-amino-6-[4-(6-methyl-6-azaspiro[2^]octan-2-yl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4- yl]-2-methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[l -(l-methyl-4-piperidyl)-3,6-dihydro-2H-pyridin-4-yl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-2-methyl-phenyl]isoindoline-2-carboxamide;

N-[3 - [2-amino-6- [ 1 -( 1 -ethyl-4-piperidy l)-3 ,6-dihydro-2H-pyridin-4-yl]-7H-pyrrolo[2,3 - d]pyrimidin-4-yl]-2-methyl-phenyl]isoindoline-2-carboxamide;

4-cyclopropyl-2-fluoro-N-[2-(hydroxymethyl)-3-[6-[4-(morpholine-4-carbonyl)phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]benzamide;

2- fluoro-4-(l-hydroxycyclopropyl)-N-[2-(hydroxymethyl)-3-[6-[4-(morpholine-4- carbonyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]benzamide;

4-(l-hydroxycyclopropyl)-N-[2-(hydroxymethyl)-3-[6-[4-(mo holine-4-carbonyl)phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]benzamide;

4-(l -hydroxy- l-methyl-ethyl)-N-[2-(hydroxymethyl)-3-[6-[4-(morpholine-4-carbonyl)phenyl]- 7H-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]benzamide;

4-cyclopropyl-N-[2-(hydroxymethyl)-3-[6-[4-(mo holine-4-carbonyl)phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]phenyl]benzamide;

4-cyclopropyl-N-[5-fluoro-2-(hydroxymethyl)-3-[6-[4-(morpholine-4-carbonyl)phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]benzamide;

4-cyclopropyl-N-[3-(hydroxymethyl)-4-[6-[4-(rno holine-4-carbonyl)phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-2-pyridyl]benzamide;

4-cyclopropyl-2-fluoro-N-[3-(hydroxymethyl)-4-[2-[4-(piperazine-l -carbonyl)phenyl]-lH- pyrrolo[2,3-b]pyridin-4-yl]-2-pyridyl]benzamide;

4-cycldpropyl-2-fluoro-N-[3-(hydroxymethyl)-4-[2-[4-(4-methylsulfonylpiperazine-l- carbonyl)phenyl]-lH-pyrrolo[2,3-b]pyridin-4-yl]-2-pyridyl]benzamide;

4-[4-[4-[2-[(4-cyclopropyl-2-fluoro-benzoyl)amino]-3-(hydroxymethyl)-4-pyridyl]-lH- pyrrolo[2,3-b]pyridin-2-yl]benzoyl]-N,N-dimethyl-piperazine- l-carboxamide;

4-cyclopropyl-N-[4-[2-[4-(4-ethylpiperazine-l-carbonyl)phenyl]-lH-pyrrolo[2,3-b]pyridin-4-yl]-

3- (hydroxymethyl)-2-pyridyl]-2-fluoro-benzamide;

N-[4-[2-[4-(azetidine-l-carbonyl)phenyl]-lH-pyrrolo[2,3-b]pyridin-4-yl]-3-(hydroxymethyl)-2- pyridyl]-4-cyclopropyl-2-fluoro-benzamide; 4-cyclopropyl-N-[4-[2-[4-(dimethylcarbamoyl)phenyl]-lH-pyrrolo[2,3-b]pyridin-4-yl]-3- (hydroxymethyl)-2-pyridyl]-2-fluoro-benzamide;

4-cyclopropyl-2-fluoro-N-[3-(hydroxymethyl)-4-[2-[l -(oxetan-3-yl)imidazol-4-yl]-lH- pyrrolo[2,3-b]pyridin-4-yl]-2-pyridyl]benzamide;

4-cyclopropyl-2-fluoro-N-[3-(hydroxymethyl)-4-[2-[l-(oxetan-3-yl)pyrazol-4-yl]-lH- pyrrolo[2,3-b]pyridin-4-yl]-2-pyridyl]benzamide;

4-cyclopropyl-2-fluoro-N-[3-(hydroxymethyl)-4-[6-[4-(piperazine-l -carbonyl)phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl]-2-pyridyl]benzamide;

4-cyclopropyl-2-fluoro-N-[3-(hydroxymethyl)-4-[2-[l-(4-hydroxy-4-methyl- cyclohexyl)imidazol-4-yl]-lH-pyrrolo[2,3-b]pyridin-4-yl]-2-pyridyl]benzamide;

4-cyclopropyl-2-fluoro-N-[3-(hydroxymethyl)-4-[2-[l -(4-hydroxy-4-methyl-cyclohexyl)pyrazol- 4-yl]-lH-pyrrolo[2,3-b]pyridin-4-yl]-2-pyridyl]benzamide;

N-[4-[2-[5-(azetidine-l-carbonyl)-2-pyridyl]-lH-pyrrolo[2,3-b]pyridin-4-yl]-3-(hydroxymethyl)- 2-pyridyl]-4-cyclopropyl-2-fluoro-benzamide;

4-cyclopropyl-2-fluoro-N-[3-(hydroxymethyl)-4-[6-[5-(piperazine-l-carbonyl)-2-pyridyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl]-2-pyridyl]benzamide;

4-cyclopropyl-2-fluoro-N-[3-(hydroxymethyl)-4-[6-[5-(morpholine-4-carbonyl)-2-pyridyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl]-2-pyridyl]benzamide;

6-[4-[2-[(4-cyclopropyl-2-fluoro-benzoyl)amino]-3-(hydroxymethyl)-4-pyridyl]-7H-pyrrolo[2,3- d]pyrimidin-6-yl]-N,N-dimethyl-pyridine-3-carboxamide;

4-[6-[4-[2-[(4-cyclopropyl-2-fluoro-benzoyl)amino]-3-(hydroxymethyl)-4-pyridyl]-l H- pyrrolo[2,3-b]pyridin-2-yl]pyridine-3-carbonyl]-N,N-dimethyl-piperazine-l -carboxamide;

4-[6-[4-[2-[(4-tert-butyl-2-fluoro-benzoyl)amino]-3-(hydroxymethyl)-4-pyridyl]-l H-pyrrolo[2,3- b]pyridin-2-yl]pyridine-3-carbonyl]-N,N-dimethyl-piperazine- 1 -carboxamide;

4-tert-butyl-2-fluoro-N-[3-(hydroxymethyl)-4-[6-[5-(morpholine-4-carbonyl)-2-pyridyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl]-2-pyridyl]benzamide;

4-tert-butyl-2-fluoro-N-[3-(hydroxymethyl)-4-[2-[5-( l -methyl-4-piperidyl)-2-pyridyl]-l H- pyrrolo[2,3-b]pyridin-4-yl]-2-pyridyl]benzamide;

4 ert-butyl-N-[4 2-[5-(l-ethyl-4-piperidyl)-2-pyridyl]-lH-pyrrolo[2,3-b]pyridin-4-yl]-3- (hydroxymethyl)-2-pyridyl]-2-fluoro-benzamide; 4-tert-butyl-2-fluoro-N-[3-(hydroxymethyl)-4-[2-[5-(l -methylsulfonyl-4-piperidyl)-2-pyridyl]- lH-pyrrolo[2,3-b]pyridin-4-yl]-2-pyridyl]benzamide;

4 ert-butyl-2-fluoro-N-[3-(hydroxymethyl)-4-[2-[5-(oxetan-3-yl)-2-pyridyl]-l H-pyrrolo[2,3- b]pyridin-4-yl] -2-pyridy l]benzamide ;

2-fluoro-4-( 1 -hydroxy- 1 -methyl-ethyl)-N- [3 -(hydroxymethyl)-4- [2- [5 -( 1 -methylsulfonyl-4- piperidyl)-2-pyridyl] - 1 H-pyrrolo [2,3 -b]pyridin-4-yl] -2-pyridyl]benzamide ;

2-fluoro-4-(l -hydroxy- l-methyl-ethyl)-N-[3-(hydroxymethyl)-4-[2-[5-(oxetan-3-yl)-2-pyridyl]- lH-pyrrolo[2,3-b]pyridin-4-yl]-2-pyridyl]benzamide;

N-[2-(hydroxyrnethyl)-3-[2-[5-(l-rnethylsulfonyl-4-piperidyl)-2-pyridyl]-l H-pyrrolo[2,3- b]pyridin-4-yl]phenyl]isoindoline-2-carboxamide; ^■

N- [3 -(hydroxymethyl)-4- [2- [5 -( 1 -methylsulfony 1-4-piperidy l)-2-pyridy 1] - 1 H-pyrrolo [2,3 - b]pyridin-4-yl]-2-pyridyl]isoindoline-2-carboxamide;

N-[3-(hydroxymethyl)-4-[2-[4-(l-methylsulfonyl-4-piperidyl)phenyl]-lH-pyrrolo[2,3-b]pyridin- 4-yl]-2-pyridyl]isoindoline-2-carboxamide;

N.[3-(hydroxymethyl)-4-[2-[4-(oxetan-3-yl)phenyl]-lH-pyrrolo[2,3-b]pyridin-4-yl]-2- pyridyl]isoindoline-2-carboxamide;

N-[3-(hydroxymethyl)-4-[2-[5-(oxetan-3-yl)-2-pyridyl]-lH-pyrrolo[2,3-b]pyridin-4-yl]-2_^ pyridyl]isoindoline-2-carboxamide;

N- [4- [2- [5 -( 1 -ethyl -4-piperidyl)-2-pyridyl] - 1 H-pyrrolo [2 ,3 -b]pyridin-4-yl] -3 -(hydroxymethyl)- 2-pyridyl]isoindoline-2-carboxamide;

' N-[3-(hydroxymethyl)-4-[2-[5-(morpholine-4-carbonyl)-2-pyridyl]-lH-pyrrolo[2,3-b]pyridin-4- yl]-2-pyridyl]isoindoline-2-carboxamide;

N-[2-(hydroxymethyl)-3-[2-[5-(morpholine-4-carbonyl)-2-pyridyl]-lH-pyrrolo[2,3-b]pyridin-4- yl]phenyl]isoindoline-2-carboxamide;

N-[3 -(hydroxymethyl)-4- [2-[ 1 -(4-hydroxy-4-methyl-cyclohexyl)pyrazol-4-yl] - 1 H-pyrrolo [2,3 - b]pyridin-4-yl]-2-pyridyl]isoindoline-2-carboxamide;

N-[2-(hydroxymethyl)-3-[2-[l-(4-hydroxy-4-methyl-cyclohexyl)pyrazol-4-yl]-lH-pyrrolo[2,3- b]pyridin-4-yl]phenyl]isoindoline-2-carboxamide

N-[3-[2-[l -(dimethylcarbamoyl)-3,6-dihydro-2H-pyridin-4-yl]-lH-pyrrolo[2,3-b]pyridin-4-yl]-^ (hydroxymethyl)phenyl]isoindoline-2-carboxamide; N- [3 - [2-[l -(azetidine- 1 -carbony l)-3 ,6-dihydro-2H-pyridin-4-yl]- 1 H-pyrrolo[2,3 -b]pyridin-4-yl]- 2-(hydroxymethyl)phenyl]isoindoline-2-carboxamide;

N-[2-(hydroxymethyl)-3 - [2-( 1 -methyl-3 ,6-dihydro-2H-pyridin-4-yl)- 1 H-pyrrolo[2,3 -b]pyridin-4- yl]phenyl]isoindoline-2-carboxamide;

N-[3-(hydroxymethyl)-4-[2-(l -methyl-3, 6-dihydro-2H-pyridin-4-yl)-lH-pyrrolo[2,3-b]pyridin-4- yl]-2-pyridyl]isoindoline-2-carboxamide;

N-[3-(hydroxymethyl)-4-[2-[l -(2-hydroxypropanoyl)-3,6-dihydro-2H-pyridin-4-yl]-lH- pyrrolo[2,3-b]pyridin-4-yl]-2-pyridyl]isoindoline-2-carboxamide;

N-[2-(hydroxymethyl)-3-[2-[l -(2-hydroxypropanoyl)-3,6-dihydro-2H-pyridin-4-yl]-lH- pyrrolo[2,3-b]pyridin-4-yl]phenyl]isoindoline-2-carboxamide;

N-[3-[2-[l-(2-cyanoacetyl)-3,6-dihydro-2H-pyridin-4-yl]-lH-pyrrolo[2,3-b]pyridin-4-yl]-2- (hydroxymethyl)phenyl]isoindoline-2-carboxamide;

N-[4-[2-[l -(2-cyanoacetyl)-3,6-dihydro-2H-pyridin-4-yl]-lH-pyrrolo[2,3-b]pyridin-4-yl]-3- (hydroxymethyl)-2-pyridyl]isoindoline-2-carboxamide;

N-[3-(hydroxymethyl)-4-[2-(l-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl)-lH-pyrrolo[2,3- b]pyridin-4-yl]-2-pyridyl]isoindoline-2-carboxamide and

N-[2-(hydroxymethyl)-3-[2-(l -methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl)-lH-pyrrolo[2,3- b]pyridin-4-yl]phenyl]isoindoline-2-carboxamide.

Biological activity

Recombinant Human Bruton's tyrosine kinase (Btk) inhibition assay.

Full length human BTK (hBTK, Genbank#NM_000061.2) was cloned into pFastBac- HTB vector (Invitrogen, cat# 10359-016). hBTK gene was expressed with N'-terminal 6XHis tag in Sf9 cells using Bac-to-Bac ^(R) Baculovirus expression system (Invitrogen, cat#10359-016) and the recombinant protein was purified by Ni-NTA method. The elution buffer for hBTK consisted of 50 mM Hepes pH 8.0, 300 mM NaCl, 10% glycerol, 1 mM dithiothreitol and 200 mM imidazole.

The inhibition assays were performed using the generic tyrosine kinase assay kit from Cis Bio (HTRF^® KinEASE - TK™ # 62TK0PEB). The assay is based on the principle of fluorescence resonance energy transfer (FRET) between the Europium Cryptate labeled anti- phosphotyrosine antibody and streptavidin labeled fluorophore, XL-665. In an uninhibited kinase reaction the biotinylated peptide substrate (Tk-Biotin) gets phosphorylated at an intermediate tyrosine site which is captured by anti-phosphotyrosine antibody which eventually acts as a FRET donor. The streptavidin labeled XL-665 binds strongly to the Tk-Biotin substrate and act as a FRET acceptor. The resultant FRET signal is measured at 665 nm. A ratio of this specific fluorescence (665nm) to the background fluorescence (620nm), conferred by the free antibody, is directly proportional to the kinase activity. Inhibition of the kinase activity by a pharmacological intervention such as a Btk inhibitor of the present disclosure will result into decreased FRET signal.

The Btk inhibition assays were performed using 20 ng/ml of rhBtk in a final volume of ΙΟμΙ reaction buffer containing 77 μΜ ATP and 1 μΜ TK-Biotin Substrate in 50mM HEPES pH 7.0, 5mM MgC12, ImM DTT, 0.01 % Tween 20 and 50nM SEB^®; with a range of concentrations of the inhibitors. The kinase reaction was carried out at the K_M of ATP (77μΜ) as well as that of Tk-Biotin substrate (Ι μΜ). After 90 min, the reaction was stopped by addition of SA-XL665 at a concentration of 62.5nM in HTRF^® detection buffer containing EDTA. Finally 5μ1 of T antibody-cryptate was added to the reaction and the plate was incubated for additional 60 min. The fluorescence was read using the Flexstation (Molecular Devices) with excitation at 340 nm and emissions at 620nm (for Cryptate) and 665nm (for FRET). A ratio of the 2 emissions was calculated for each well and expressed as follows:

Specific signal = Ratio (Sample) - Ratio (Negative)

Ratio = (665nm/620nm) X l O⁴

Mean Ratio =∑ Ratio / 3 (triplicates)

For each data point, % inhibition is calculated based on uninhibited reaction which is considered as 100% activity over no enzyme or substrate controls. Dose response data is then fit using a four parameter logistic equation using Graph-pad Prism 5 software to determine inhibition constant 50 ( IC50).

Compounds of present disclosure are considered to be active if IC₅₀ of the recombinant human Btk (hBtk) enzyme inhibition is below 10 μΜ, and more specifically below 1.0 μΜ·

Inhibition of B cell activation as measured by CD69 expression in mouse splenocytes:

To test the effect of BTK inhibitors in suppressing B-cell receptor (BCR) mediated activation of B cells, we developed a flow cytometry based assay to analyze CD69 expression in B cell population among total splenocyte from the mouse. C57/BL6 mouse spleens were dissected out and splenocytes were isolated by mincing the tissue with a syringe plunger followed by RBC lysis (0.85% ammonium chloride) and several washes in PBS. Finally, cell were cultured in RPMI medium with 10% FBS.

Test compounds were diluted half log starting from 2mM in 100% DMSO (200X). 1X10⁵ splenocytes were incubated with luL of diluted test compounds in 200uL culture medium in a U- bottom 96 well plate (Greiner) at 37°C with 5% C0₂ for 30 mins. Control wells received luL of 100% DMSO without any compound. The cells were stimulated with 3ug/mL goat anti-mouse IgM (Sigma, cat#M8644) and incubated for 18-20 hrs. After the stimulation, cells were washed in cold PBS with 1% FBS and stained with 1 : 100 dilutions of anti-CD69-PE (eBioscience, cat# 12-0691-83) and anti-CD 19-PeCy5 (eBioscience, cat#l 5-0193-83) for lhr on ice. Then the cells were washed 3 times with PBS with 1% FBS and analyzed by Guava Easycyte Mini flow cytometer system (Millipore). Flow cytometry data were analyzed using Weasel software (WEHI, Melbourne). First B cells were gated using CD 19 markers. Then expression of CD69 was analyzed as percentage of CD69 +ve cells within CD 19. Percent activity for each data point was calculated using following formula:

(Experimental - No stimulation control)

% Activity = 100 X

(No compound control - No stimulation control) Percentage activity was fit using sigmoid dose response with variable slope logistic equation in Graph-pad Prism 5 software to determine inhibition constant 50 (IC50).

Compounds of present disclosure are considered to be active in the B-cell specific functional assay (inhibition of CD69 expression) if IC₅o values are less than 10 μΜ.

Data for representative compounds of the present disclosure are given below in Table 1 :

Table 1: /zBTK and mouse spleenocyte IC₅₀ values:

A6 17 59

^■ A7 423 -

A8 3 143

A9 0.7 21

A10 2 31

Al l 3 100

A12 8.5 90

A13 5 234

A14 . 5 140

A15 5 37

A16 6 22

A17 ^■5 63

A18 2.5 >10000

A19 4 > 10000

A20 3.5 53

A21 2.3 1910

A22 3.6 2577

A23 16 . -

A24 12 -

A25 3.3 -

A26 2.7 - A27 86 , - A28 17 -

A29 1046 -

A30 1.4 2000

A31 156: -

A32 4 -

B l >1000 -

B2 >1000 -

B3 >1000

B4 >1000 -

CI 69 -

C3 2800 -

C2 >1000

Dl 4 44

D2 2 156

El 53_. -

Fl 26 96

Gl 41 545

G2 >1000 -

HI 28 227 H2 15 784

H3 27 -

H4 8 -

H5 14 204

H6 33 -

H7 16 -

H8 12 129

H9 20 105

H10 42 -

Hl l 31 -

H12 ■ 22 -

H13 24 ^■ 0.1

11 24 338

12 ^■ >1000 -

13 > 1^.000 -

14 >1000 -

15 >1000 -

16 870 -

Jl 4 400

Kl 29 204

LI 34 .98

Ml 3.6 41

M2 173 -

M3 25 218

M4 148 -

M5 3.6 -

M6 7 -

M7 3 . -

M8 6.5 -

M? 16 -

M10 81 -

Mi l 4.5 -

M12 18.5 -

M13 36.5 -

M14 2.5

M15 2.5 -

Nl 10 108

01 33.5 -

02 20.5 - Although the subject matter has been described in considerable detail with reference to certain preferred embodiments thereof, other embodiments are possible. As such, the spirit and scope of the present disclosure should not be limited to the description of the preferred embodiment contained therein.

Claims

I/We Claim:

1. A compound of formula (I)

or their tautomers, polymorphs, stereoisomers, prodrugs, solvates, hydrates, N-oxides, co- crystals, pharmaceutically acceptable salts, pharmaceutical compositions containing them and methods of treating conditions and diseases that are mediated by BTK activity, wherein,

ring A represents a 5-7 membered ring which is unsaturated or partially unsaturated optionally having upto three heteroatom independently selected from O, N or S;

ring C, ring D and ring E are independently a monocyclic or a bicyclic ring system which is saturated, unsaturated or partially unsaturated and optionally have additional heteroatoms independently selected from O, N or S, said ring system is further optionally substituted with 1 to 4 substituents independently selected from halo, alkyl, alkenyl, alkynyl, nitro, cyano, - (CR^aR^b)_mOR⁸, -(CR^aR^b)_mSR⁸, -(CR^aR^b)_mNR R¹⁰, oxo, alkylsulfonyl, -(CR^aR^b)_mCOOR⁸, - (CR^aR^b)_mC(0)NR⁹R¹⁰, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

X represents N or C (R¹);

Y represents -C(0) or -S(0)_p-;

Li is a bond or is selected from the group consisting of -(CR^aR^b)-, (C)_-6)alkylene, (Ci_ )alkenylene or (Ci_-6)alkynylene wherein optionally one or more than one methylene groups of alkylene, alkenylene or alkynylene are independently replaced by hetero atoms or groups such as -0-, -S(0)_p-, -N(R⁶)-, -C(O)-, -C(=NR')- or -C(R')=N-, wherein R' is H, alkyl, cyano, hydroxy, hydroxyalkyl, haloalkyl or perhaloalkyl; M is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, alkenyl, alkynyl, cyanoalkyl, acyl, cyanoalkylarbonyl, cyanoalkenylcarbonyl, -(CR^aR^b)_mOR⁸, -SR⁸, - (CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mNR⁹R¹⁰, -(CR^aR^b)_mC(0)NR⁹R ¹⁰ -(CR^aR^b)_mNR⁸C(0)NR⁹R¹⁰ thiocarbonyl, S(0)₂NR⁹R¹⁰, -NR⁸S(0)₂R⁸, -S(0)_pR⁸, -S0₃H, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylamino, aryl, arylalkyl, aryloxy, arylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocycloalkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroarylamino;

M is optionally substituted with one or more substituents independently selected from cyano, nitro, keto, oxo, halogen, haloalkyl, perhaloalkyl, hydroxyamino, -(CR^aR^b)_mOR⁸, - (CR^aR^b)_mC(0)R⁸, -OC(0)R⁸ _, -SR⁸, -(CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mNR⁹R ¹ °, -(CR^aR^b)_mC(0)N

R⁹R¹⁰ -(CR^aR^b)_mNR⁸C(0)N R⁹R¹⁰ -NR⁸C(0)R⁸ _, thiocarbonyl, -S(0)₂N R⁹R¹⁰,

NR⁸S(0)₂R⁸, -S(0)_pR⁸, -S0₃H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, heterocyclyl or heteroaryl;

wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, heterocyclyl or heteroaryl are optionally substituted with one or more substituents selected from hydroxy, alkyl, alkoxy, alkoxyalkyl, halogen, haloalkyl, perhaloalkyl, cyano, cyanoalkyl, amino, carboxy, carboxyalkyl, -OC(0)R⁸, -(CR R^b)_mC(0)N R⁹R¹⁰, - NR⁸C(0)R⁸ _, -SR⁸, -S(O)_pR⁸, -S(O)₂N R⁹R^{l 0} or -NR⁸S(0)₂R⁸;

U is a bond or is selected from the group consisting of cycloalkylene, cycloalkenylene, cycloalkylenecarbonyl, cycloalkylenealkoxy, cycloalkyleneamino, arylene, arylenecarbonyl, arylenealkoxycarbonyl, arylenealkoxycarbonylamino, aryleneaminocarbonyl, heterocyclylene, heterocyclylenealkyl, heterocyclylenecarbonyl, heterocyclylenealkylamino, heteroarylene, heteroarylenecarbonyl, heteroarylenealkylamino, (Ci_-6)alkylene, (C_]-6)alkenylene or (C|. ₆)alkynylene wherein one or more than one methylene groups of alkylene, alkenylene or alkynylene are optionally replaced by hetero atoms or groups such as -0-, -S(0)_p-, -N(R⁸)-, or -

C(O);

T is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, alkenyl, alkynyl, cyanoalkyl, acyl, cyanoalkylarbonyl, cyanoalkenylcarbonyl, -(CR^aR^b)_mOR⁸, . -SR⁸, - (CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mN R⁹R¹⁰, -(CR^aR^b)_mC(0)NR⁹R¹⁰ -(CR^aR^b)_mNR⁸C(0)NR⁹R¹⁰ thiocarbonyl, S(0)₂NR⁹R¹⁰, -NR⁸S(0)₂R⁸, -S(0)_pR⁸, -S0₃H, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylamino, aryl, arylalkyl, aryloxy, arylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocycloalkylamino, heteroaryl, heteroarylaikyl, heteroaryloxy, or heteroarylamino;

U and T is optionally substituted with one or more substituents independently selected from cyano, nitro, keto, oxo, halogen, haloalkyl, perhaloalkyl, hydroxyamino, -(CR^aR^b)_nlOR⁸, - 5 (CR^aR^b)_mC(0)R⁸, -OC(0)R⁸ _, -SR⁸, -(CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mNR⁹R¹⁰,

(CR^aR^b)_mC(0)NR⁹R¹⁰ -(CR^aR )_mNR⁸C(0)_mR⁹R¹⁰ -NR⁸C(0)R⁸ _, thiocarbonyl, -S(0)₂N R⁹R¹⁰, -NR⁸S(0)₂R⁸, -S(0)_pR⁸, -S0₃H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, heterocyclyl or heteroaryl;

wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, 10 heterocyclyl or heteroaryl are optionally substituted with one or more substituents selected from hydroxy, alkyl, alkoxy, alkoxyalkyl, halogen, haloalkyl, perhaloalkyl, cyano, cyanoalkyl, amino, carboxy, carboxyalkyl, -OC(0)R⁸, -(CR^aR^b)_mC(0)N R⁹R¹⁰, -

NR⁸C(0)R⁸ -SR⁸, -S(0)_pR⁸, -S(0)₂N R⁹R¹⁰ or -NR⁸S(0)₂R⁸;

R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl, 15 alkynyl, alkoxy, acyl, acylamino, acyloxy, -(CR^aR^b)_mC(0)R⁸, -(CR^aR^b)_mN R⁹R¹⁰, aminocarbonyl, alkoxycarbonylamino, alkylsulfonylamino, aminocarbonylamino, hydroxyamino, alkoxyamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, haloalkyl, perhaloalkyl, cycloalkyl, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy, -S0₃H, alkylthio, aminosulfonyl, alkylsulfonyl, or 20 nitro; or when R¹ or R² or R³ or R⁴ or R⁵ are more than one, then any 2 R¹ or 2 R² or 2 R³ or

2 R⁴ or 2 R⁵ independently is optionally, taken together form a monocyclic or a bicyclic ring . system which is saturated or partially unsat rated and optionally have one or more additional heteroatoms independently selected from O, N or S;

R⁸ is selected from the group consisting of hydrogen, -(CR^aR^b)_mOR⁸, halogen, haloalkyl, - 25. (CR^aR^b)_mC(0)R⁸, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylaikyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl;

wherein alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylaikyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl are optionally substituted with one or more substituents selected from hydroxy, alkyl, alkoxy, alkoxyalkyl, halogen, haloalkyl, 30 perhaloalkyl, cyano, cyanoalkyl, amino, carboxy, carboxyalkyl, -OC(0)R⁸, -

(CR^aR^b)_mC(0)N R⁹R¹⁰, -NR⁸C(0)R⁸ _, -SR⁸, -S(0)_pR⁸, -S(0)₂N R⁹R¹⁰ or -NR⁸S(0)₂R⁸; R⁹ and R¹⁰ are independently selected from the group consisting of hydrogen, - (CR^aR^b)_mOR⁸, haloalkyl, -(CR^aR^b)_mC(0)R⁸, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl, or R⁹ and R¹⁰ taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S, said ring system is further optionally substituted with 1 to 4 substituents independently selected from halo, alkyl, alkenyl, alkynyl, nitro, cyano, -(CR^aR^b)_mOR⁸, -SR⁸, - (CR^aR^b)_mNR⁹R¹⁰, oxo, alkylsulfonyl, -(CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mC(0)N R⁹R¹⁰, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl,. heteroaryl, or heteroarylalkyl;

R^a and R^b taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S; . m is 0-6;

n is 0 - 3;

p is 0, 1 or 2;

q is 1 or 2.

A compound according to claim 1 wherein, ring A represents a 5 membered ring which is unsaturated or partially unsaturated optionally having upto three heteroatom independently selected from O, N or S;

ring C, ring D and ring E are independently a monocyclic or a bicyclic ring system which is saturated, unsaturated or partially unsaturated and optionally have additional heteroatoms independently selected from O, N or S, said ring system is further optionally substituted with 1 to 4 substituents independently selected from halo, alkyl, alkenyl, alkynyl, nitro, cyano, - (CR^aR^b)_mOR⁸, -(CR^aR^b)_mSR⁸, -(CR^aR^b)_mNR⁹R ¹ °, oxo, alkylsulfonyl, -(CR^aR^b)_mCOOR⁸, - (CR^aR^b)_mC(0)NR⁹R¹⁰, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

X represents N or C (R¹);

Y represents -C(O); Li is a bond or is selected from the group consisting of -(CR^aR^b)- or (Ci_-6)alkylene wherein optionally one or more than one methylene groups are independently replaced by hetero atoms or groups such as -0-, -S(0)_p-, -N(R⁶)-, -C(O)-, -C(=NR')- or -C(R')=N-, wherein R' is H, alkyl, cyano, hydroxy, hydroxyalkyl, haloalkyl or perhaloalkyl;

M is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, alkenyl, alkynyl, cyanoalkyl, acyl, cyanoalkylarbonyl, cyanoalkenylcarbonyl, -(CR^aR^b)_mOR⁸, -SR⁸, - (CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mNR⁹R ¹ °, -(CR^aR^b)_mC(0)NR⁹R¹⁰ -(CR^aR^b)_mNR⁸C(0)NR⁹R¹⁰ thiocarbonyl, S(0)₂NR⁹R¹⁰, -NR⁸S(0)₂R⁸, -S(0)_pR⁸, -S0₃H, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylamino, aryl, arylalkyl, aryloxy, arylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocycloalkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroarylamino;

M is optionally substituted with one or more substituents independently selected from cyano, nitro, keto, oxo, halogen, haloalkyl, perhaloalkyl, hydroxyamino, -(CR^aR^b)_mOR⁸, - (CR^aR^b)_mC(0)R⁸, -OC(0)R⁸ _, -SR⁸, -(CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mNR⁹R¹⁰, -(CR^aR^b)_mC(0)N R⁹R¹⁰ -(CR^aR^b)_mNR⁸C(0)N R⁹R¹⁰ -NR⁸C(0)R⁸ _; thiocarbonyl, -S(0)₂N R⁹R¹⁰,

NR⁸S(0)₂R⁸, -S(0)_pR⁸, -SO3H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, heterocyclyl or heteroaryl;

U is a bond or is selected from the group consisting of cycloalkylene, arylene, heterocyclylene, heteroarylene, (C]_-6)alkylene, (Ci_-6)alkenylene or (Ci_-6)alkynylene wherein one or more than one methylene groups of alkylene, alkenylene or alkynylene are optionally replaced by hetero atoms or groups such as -0-, -S(0)_p-, -N(R )-, or -C(O);

T is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, alkenyl, cyanoalkyl, acyl, -(CR^aR^b)_mOR⁸, -SR⁸, -(CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mN R⁹R¹⁰, -(CR^aR^b)_mC(0)NR⁹R¹⁰ - (CR^aR^b)_mNR⁸C(0)N R⁹R¹⁰ thiocarbonyl, S(0)₂NR⁹R¹⁰, -NR⁸S(0)₂R⁸, -S(0)_pR⁸, -S0₃H, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylamino, aryl, arylalkyl, aryloxy, arylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocycloalkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroarylamino;

U and T is optionally substituted with one or more substituents independently selected from cyano, nitro, keto, oxo, halogen, haloalkyl, perhaloalkyl, hydroxyamino, -(CR^aR^b)_mOR⁸, - (CR^aR^b)_mC(0)R⁸, -OC(0)R⁸, -SR⁸, -(CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mN R⁹R¹⁰, -(CR^aR^b)_mC(0)N

R⁹R¹⁰ -(CR^aR^b)_mNR⁸C(0)_m RV° -NR⁸C(0)R⁸ _, thiocarbonyl, -S(0)₂N R⁹R¹⁰, -NR⁸S(0)₂R⁸, -S(0)_pR , -S0₃H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, heterocyclyl or heteroaryl;

R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, -(CR^aR^b)_mC(0)R⁸, -(CR^aR^b)_mN R⁹R¹⁰, aminocarbonyl, alkoxycarbonylamino, alkylsulfonylamino, aminocarbonylamino, hydroxyamino, alkoxyamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, haloalkyl, perhaloalkyl, cycloalkyl, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy, -SO₃H, alkylthio, aminosulfonyl, alkylsulfonyl, or nitro; or when R¹ or R² or R³ or R⁴ or R⁵ are more than one, then any 2 R¹ or 2 R² or 2 R³ or 2 R⁴ or 2 R⁵ independently is optionally, taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have one or more additional heteroatoms independently selected from O, N or S;

wherein alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl are optionally substituted with one or more substituents selected from hydroxy, alkyl, alkoxy, alkoxyalkyl, halogen, haloalkyl, perhaloalkyl, cyano, cyanoalkyl, amino, carboxy, carboxyalkyl, -OC(0)R⁸, - (CR^aR^b)mC(0)N R⁹R¹⁰, -NR⁸C(0)R⁸ _, -SR⁸, -S(0)_pR⁸, -S(0)₂N R⁹R¹⁰ or -NR⁸S(0)₂R⁸; R⁹ and R¹⁰ are independently selected from the group consisting of hydrogen, - (CR^aR^b)_mOR⁸, haloalkyl, -(CR^aR^b)_mC(0)R⁸, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl, or R⁹ and R¹⁰ taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S, said ring system is further optionally substituted with 1 to 4 substituents independently selected from halo, alkyl, alkenyl, alkynyl, nitro, cyano, -(CR^aR^b)_mOR⁸, -SR⁸, - (CR^aR^b)_mNR⁹R¹⁰, oxo, alkylsulfonyl, -(CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mC(0)N R⁹R¹⁰, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; R^a and R^b are independently selected from the group consisting of hydrogen, -OR⁶, halogen, haloalkyl, perhaloalkyl or alkyl;

R^a and R^b taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S; m is 0-3;

n is 0 - 3;

p is 0, 1 or 2;

q is 1 or 2.

X represents N;

Y represents -C(O);

Li is a bond or is selected from the group consisting of -(CR^aR^b)- or (Ci_₆)alkylene wherein optionally one or more than one methylene groups are independently replaced by hetero atoms or groups such as -0-, -S(0)_p-, -N(R⁶)-, -C(O)-;

M is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, cyanoalkyl, acyl, -(CR^aR^b)_mOR⁸, -SR⁸, -(CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mNR⁹R¹⁰, -(CR^aR^b)_mC(0)NR⁹R¹⁰ thiocarbonyl, S(0)₂NR⁹R¹⁰, -NR⁸S(0)₂R⁸, -S(0)_pR⁸, -S0₃H, cycloalkyl, aryl, heterocyclyl or heteroaryl;

M is optionally substituted with one or more substituents independently selected from cyano, nitro, keto, oxo, halogen, haloalkyl, perhaloalkyl, hydroxyamino, -(CR^aR^b)_mOR⁸, - (CR^aR^b)_mC(0)R⁸, -OC(0)R⁸ _, -SR⁸, -(CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mNR⁹R¹⁰, -(CR^aR^b)_mC(0)N R⁹R'° -(CR^aR^b)_mNR⁸C(0)N R⁹R¹⁰ -NR⁸C(0)R⁸ _, thiocarbonyl, -S(0)₂N R⁹R¹⁰, NR⁸S(0)₂R⁸, -S(0)_pR⁸, or -S0₃H;

U is a bond or is selected from the group consisting of cycloalkylene, arylene, heterocyclylene heteroarylene or (Ci-6)alkylene wherein one or more than one methylene groups of alkylene alkenylene or alkynylene are optionally replaced by hetero atoms or groups such as -0-, -S(0)_p- , -N(R⁸)-, or -C(O);

T is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, alkenyl, cyanoalkyl, acyl, -(CR^aR^b)_mOR⁸, -SR⁸, -(CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mN R R¹⁰, -(CR^aR^b)_mC(0)NR⁹R ¹⁰ - (CR^aR^b)_mNR⁸C(0)N R⁹R¹⁰ thiocarbonyl, S(0)₂NR R¹⁰, -NR⁸S(0)₂R⁸, -S(0)_pR⁸, -S0₃H, cycloalkyl, aryl, heterocyclyl or heteroaryl;

U and T is optionally substituted with one or more substituents independently selected from . cyano, nitro, keto, oxo, halogen, haloalkyl, perhaloalkyl, hydroxyamino, -(CR^aR^b)_mOR⁸, - (CR^aR^b)_mC(0)R⁸, -OC(0)R⁸ _; -SR⁸, -(CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mN R⁹R¹⁰, -(CR^aR^b)_mC(0)N R⁹R¹⁰ -(CR^aR^b)_mNR⁸C(0)m R⁹R¹⁰ -NR⁸C(0)R⁸ _, thiocarbonyl, -S(0)₂N R⁹R¹⁰, -NR⁸S(0)₂R⁸, -S(0)_pR⁸ or -S0₃H;

R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, acyl, acylamino, acyloxy, -(CR^aR^b)_mC(0)R⁸, -(CR^aR^b)_mN R⁹R¹⁰, aminocarbonyl, alkoxycarbonylamino, alkylsulfonylamino, aminocarbonylamino, hydroxyamino, alkoxyamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, haloalkyl, perhaloalkyl, cycloalkyl, thiocarbonyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy, -S0₃H, alkylthio, aminosulfonyl, alkylsulfonyl, or nitro; or when R¹ or R² or R³ or R⁴ or R⁵ are more than one, then any 2 R¹ or 2 R² or 2 R³ or 2 R⁴ or 2 R⁵ independently is optionally, taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated or optionally have one or more additional heteroatoms independently selected from O, N or S;

R⁹ and R¹⁰ are independently selected from the group consisting of hydrogen, - (CR^aR^b)_mOR⁸, haloalkyl, -(CR^aR^b)_mC(0)R⁸, alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl or

m is 0-3;

n is 0 - 3;

p is 0, 1 or 2;

q is 1 or 2.

A compound according to claim 1 wherein, ring A is selected from pyrrole, imidazole, pyrazole, oxazole, . isoxazole, thiazole, isothiazole, triazole, oxadiazole, thiadiazole, dithiazole;

X represents N;

Y represents -C(O);

L] is a bond or (Ci_-6)alkylene wherein optionally one or more than one methylene groups are independently replaced by hetero atoms or groups such as -0-, -S(0)_p-, -N(R⁶)-, -C(O)-;

M is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, -(CR R )_mOR , - SR⁸, -(CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mNR⁹R¹⁰ or -(CR^aR^b)_mC(0)NR⁹R¹⁰;

U is a bond or (Ci_-6)alkylene wherein one or more than one methylene groups of alkylene, alkenylene or alkynylene are optionally replaced by hetero atoms or groups such as -0-, - S(0)_p-, -N(R⁸)-, or -C(0);

T is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, acyl, - (CR^aR^b)_mOR⁸, -SR⁸, -(CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mN R⁹R¹⁰, -(CR^aR^b)_mC(0)NR⁹R¹⁰, cycloalkyl, aryl, heterocyclyl or heteroaryl;

R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkoxy, acyl, acylamino, acyloxy, -(CR^aR^b)_mC(0)R⁸, -(CR^aR^b)_mNR⁹R ¹ °, aminocarbonyl, alkoxycarbonylamino, alkylsulfonylamino, aminocarbonylamino, hydroxyamino, alkoxyamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, haloalkyl, perhaloalkyl, cycloalkyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy, - S0₃H, alkylthio, aminosulfonyl, alkylsulfonyl, or nitro; R⁸ is selected from the group consisting of hydrogen, -(CR^aR^b)_mOR⁸, halogen, haloalkyl, - (CR^aR^b)_mC(0)R⁸ or alkyl;

R⁹ and R¹⁰ are independently selected from the group consisting of hydrogen, -(CR^aR^b)_mOR⁸ or haloalkyl or

R⁹ and R¹⁰ taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S; R^a and R^b are independently selected from the group consisting of hydrogen, -OR⁶, halogen, haloalkyl, perhaloalkyl or alkyl;

n is 0 - 3;

p is 0, 1 or 2;

q is 1 or 2.

A compound according to claim 1 wherein ring A is selected from pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazole, oxadiazole, thiadiazole, dithiazole;

ring C, ring D and ring E are independently selected from cyclopropyl, cyclohexyl, phenyl, azetidine, pyrrolidine, piperidine, piperazine, morpholine, octahydro-indole, octahydro- isoindole, dihydro-imidazole, tetrahydro-benzothiophene, tetrahydro-indole, tetrahydro- isoindole, tetrahydro-benzoxazine, tetrahydro-imidazopyridine, aza-spirooctane, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazole, oxadiazole, thiadiazole, dithiazole, pyridine, pyrimidine or pyrazine ;

X represents N;

Y represents -C(O);

Li is a bond or (Ci_-6)alkylene wherein optionally one or more than one methylene groups are independently replaced by hetero atoms or groups such as -0-, -S(0)_p-, -N(R⁶)-, -C(O)-; M is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, -(CR^aR^b)_mOR⁸, - SR⁸, -(CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mNR⁹R¹⁰ or -(CR^aR^b)_mC(O)NR⁹R^l0 _; U is a bond or (Ci_₆)alkylene wherein one or more than one methylene groups of alkylene, alkenylene or alkynylene are optionally replaced by hetero atoms or groups such as -0-, - S(0)_p-, -N(R⁸)-, or -C(0);

T is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, acyl, - (CR^aR^b)_mOR⁸, - SR⁸, - (CR^aR^b)_mCOOR⁸, - (CR^aR^b)_mN R⁹R¹⁰, - (CR^aR^b)_mC(0)NR⁹R¹⁰ or cycloalkyl; .

R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkoxy, acyl, acylamino, acyloxy, -(CR^aR^b)_mC(0)R⁸, -(CR^aR^b)_mNR⁹R¹⁰, aminocarbonyl, alkoxycarbonylamino, alkylsulfonylamino, aminocarbonylamino, hydroxyamino, alkoxyamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, haloalkyl, perhaloalkyl, cycloalkyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy, - SO3H, alkylthio, aminosulfonyl, alkylsulfonyl, or nitro;

m is 0-3;

n is 0 - 3;

p is 0, 1 or 2;

q is 1 or 2.

A compound according to claim 1 wherein, ring A is selected from pyrrole, imidazole, pyrazole, oxazole or isdxazole;

ring C, ring D and ring E are independently selected from phenyl, azetidine, pyrrolidine, piperidine, piperazine, morpholine, octahydro-indole, octahydro-isoindole, dihydro- imidazole, tetrahydro-benzothiophene, tetrahydro-indole, tetrahydro-isoindole, tetrahydro- benzoxazine, tetrahydro-imidazopyridine, aza-spirooctane, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazole, oxadiazole, thiadiazole, dithiazole, pyridine, pyrimidine or pyrazine ;

X represents N; Y represents -C(O);

L] is a bond or (Ci_ )alkylene wherein optionally one or more than one methylene groups are independently replaced by hetero atoms or groups such as -0-, -S(0)_p-, -N(R⁶)- or -C(O)-; M is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, -(CR^aR^b)_mOR⁸, - SR⁸, -(CR^aR^b)_mCOOR⁸, -(CR^aR^b)_mNR⁹R¹⁰ or -(CR^aR^b)_mC(0)NR⁹R¹⁰;

U is a bond or (Ci_-6)alkylene wherein one or more than one methylene groups of alkylene, alkenylene or alkynylene are optionally replaced by hetero atoms or groups such as -0-, -S(0)_p- , -N(R⁸)-, or -C(0);

T is selected from hydrogen, cyano, halogen, haloalkyl, perhaloalkyl, alkyl, acyl, - (CR^aR^b)_mOR⁸, - SR⁸, - (CR^aR^b)_mCOOR⁸, - (CR^aR^b)_mN R⁹R¹⁰, - (CR^aR^b)_mC(0)NR⁹R¹⁰ or cycloalkyl;

R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkoxy, acyl, acylamino, acyloxy, -(CR^aR^b)_mC(0)R⁸, -(CR^aR^b)_mNR⁹R¹⁰, aminocarbonyl, alkoxycarbonylamino, alkylsulfonylamino, aminocarbonylamino, hydroxyamino, alkoxyamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, haloalkyl, perhaloalkyl, cycloalkyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy, - S0₃H, alkylthio, aminosulfonyl, alkylsulfonyl, or nitro;

m is 0-3;

n is 0 - 3;

p is 0, 1 or 2;

q is 1 or 2.

A compound according to claim 1 wherein, ring A is pyrrole;

ring C is selected from azetidine, pyrrolidine, piperidine, piperazine, morpholine, octahydro- indole, octahydro-isoindole, dihydro-imidazole, tetrahydro-benzothiophene, tetrahydro- indole, tetrahydro-isoindole, tetrahydro-benzoxazine, tetrahydro-imidazopyridine, aza- spirooctane, oxazole, isoxazole, thiazole or isothiazole;

ring D is selected from phenyl, pyridine, pyrimidine or pyrazine;

ring E is selected from azetidine, pyrrolidine, piperidine, piperazine, morpholine, octahydro- indole, octahydro-isoindole, dihydro-imidazole, tetrahydro-benzothiophene, tetrahydro- indole, tetrahydro-isoindole, tetrahydro-benzoxazine or tetrahydro-imidazopyridine;

X represents N; .

Y represents -C(O);

Li is a bond or, (Ci_-6)alkylene wherein optionally one or more than one methylene groups are independently replaced by hetero atoms or groups such as. -0-, -S(0)_p-, -N(R⁶)- or -C(O)-;

M is selected from hydrogen, cyano, halogen, haloalkyi, perhaloalkyl or alkyl;

U is a bond or (Ci.₆)alkylene wherein one or more than one methylene groups of alkylene, alkenylene or alkynylene are optionally replaced by hetero atoms or groups such as -0-, -S(0)_p-

, -N(R⁸)-, or -C(O); ·

T is selected from hydrogen, cyano, halogen, haloalkyi, perhaloalkyl, alkyl, acyl, -

(CR^aR^b)_mOR⁸, - SR⁸, - (CR^aR^b)_mCOOR⁸, - (CR^aR^b)_mN R⁹R¹⁰, - (CR^aR^b)_mC(0)NR⁹R ¹⁰ or cycloalkyl;

R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are independently selected from hydrogen, alkyl, alkoxy, acyl, acylamino, acyloxy, -(CR^aR^b)_mC(0)R⁸, -(CR^aR^b)_mNR⁹R¹⁰, azido, cyano, halogen, hydroxy, hydroxyalkyl, haloalkyi, perhaloalkyl, cycloalkyl, carboxy, alkylcarboxy, carboxyalkyl, carboxyalkyloxy, alkylcarboxyalkyloxy, -S0₃H, alkylthio, alkylsulfonyl, or nitro; .

R⁸ is selected from the group consisting of hydrogen, halogen, haloalkyi, -(CR^aR^b)_mC(0)R⁸ or alkyl;

R⁹ and R¹⁰ are independently selected from the group consisting of hydrogen, -(CR^aR^b)_mOR⁸ or haloalkyi

R^a and R^b are independently selected from the group consisting of hydrogen, -OR⁶, halogen, haloalkyi, perhaloalkyl or alkyl;

m is 0-3;

n is 0 - 3;

p is 0, 1 or 2;

q is 1 or 2. A compound of formula (I) as claimed in claim 1 or its tautomers, polymorphs, stereoisomers, prodrugs, solvate, co-crystals or a pharmaceutically acceptable salts thereof, which is selected from a group consisting of:

4-tert-butyl-N-[2-methyl-3-[6-[4-(mo holine-4-carbonyl) phenyl] -7H-pyrrolo [2, 3-d] pyrimidin-4-yl]phenyl]benzamide;

N-[2-methyl-3-[6-[4-(morpholine-4-carbonyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4- yl]phenyl]-4,5,6,7-tetrahydrobenzothiophene-2-carboxamide;

4-tert-butyl-N- [2-methyl-3 - [6- [4-(4-methylpiperazine- 1 -carbony l)pheny 1] -7H-pyrrolo [2,3 - d]pyrimidin-4-yl]phenyl]benzamide;

4-tert-butyl-N-[2-methyl-3-[6-[4-(piperidine-l-carbonyl)phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]phenyl]benzamide;

4-tert-butyl-N-[3-[6-[4-(3-hydroxyazetidine-l-carbonyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin- 4-yl]-2-methyl-phenyl]benzamide;

4-cyclopropyl-N-[2-methyl-3-[6-[4-(morpholine-4-carbonyl)phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]phenyl]benzamide;

N- [2-methyl-3 -[6- [4-(mo holine-4-carbonyl)phenyl]-7H-pyrrolo [2,3 -d]pyrimidin-4- yl]phenyl]-4-(trifluoromethyl)benzamide;

4-cyclopropyl-N-[3-[6-[4-(4-hydroxypiperidine-l-carbonyl)phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-2-methyl-phenyl]benzamide;

4-cyclopropyl-N-[2-methyl-3-[6-[4-(piperazine-l-carbohyl)phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]phenyl]benzamide;

4-cyclopropyl-N-[2-methyl-3-[6-[4-(4-methylpiperazine-l -carbonyl)phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]phenyl]benzamide;

4-cyclopropyl-N- [3- [6- [4-(3 -hydroxypiperidine- 1 -carbonyl)pheny l]-7H-pyrrolo[2,3 - d]pyrimidin-4-yl]-2-methyl-phenyl]benzamide;

4-cyclopropyl-N- [2-methyl-3 - [6- [4-(piperidine- 1 -carbonyl)pheny l]-7H pyrrolo [2,3- d]pyrimidin-4-yl]phenyl]benzamide;

4-cyclopropyl-N- [3 - [6- [4-(3 -methoxyazetidine- 1 -carbony l)phenyl] -7H-pyrrolo [2 ,3 - d]pyrimidin-4-yl]-2-methyl-phenyl]benzamide;

4-cyclopropyl-N-[3-[6-[4-[(3R)-3-hydroxypyrrolidine-l-carbonyl]phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-2-methyl-phenyl]benzamide; 4-cyclopropyl-N-[2-methyl-3-[6-[4-(pyrrolidine-l-carbonyl)phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]phenyl]benzamide;

4-cyclopropyl-N-[3-[6-[4-(4-methoxypiperidine-l-carbonyl)phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-2-methyl-phenyl]benzamide;

4-cyclopropyl-N- [3 - [6- [4-(3 -methoxyazetidine- 1 -carbony l)pheny 1] -7H-pyrrolo [2 , 3 - d]pyrimidin-4-yl]-2-methyl-phenyl]benzamide;

(2S)-l-[4-[4-[3-[(4-cyclopropylbenzoyl)amino]-2-methyl-phenyl]-7H-pyrrolo[2,3- d]pyrimidin-6-yl]benzoyl]pyrrolidine-2-carboxylic acid;

(2S)- 1 - [4- [4-[3 -[(4-cyclopropylbenzoyl)amino] -2-methyl-phenyl]-7H-pyrrolo [2,3 - d]pyrimidin-6-yl]benzoyl]piperidine-2-carboxylic acid;

4-cyclopropyl-N-[3-[6-[4-(4-hydroxy-4-methyl-piperidine-l-carbonyl)phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl]-2-methyl-phenyl]benzamide;

l-[4-[4-[3-[(4-cyclopropylbenzoyl)amino]-2-methyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6- yl]benzoyl]piperidine-3-carboxylic acid;

1 - [4-[4-[3-[(4-cyclopropylbenzoyl)amino]-2-methyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6- yl]benzoyl]piperidine-4-carboxylic acid;

6-cyclopropyl-N-[2-(hydroxymethyl)-3-[2-[5-(4-hydroxy-4-methyl-piperidine-l-carbonyl)-2- pyridyl]-lH-pyrrolo[2,3-b]pyridin-4-yl]phenyl]pyridine-3-carboxamide;

6-cyclopropyl-N- [2-(hydroxymethyl)-3 - [2- [4-(4-hydroxy-4-methy 1-piperidine- 1 - carbonyl)phenyl]-lH-pyrrolo[2,3-b]pyridin-4-yl]phenyl]pyridine-3-carboxamide;

2- chloro-4-cyclopropyl-N-[2-methyl-3-[6-[4-(morpholine-4-carbonyl)phenyl]-7H- pyrrolo[2,

3-d]pyrimidin-4-yl]phenyl]benzamide;

4- cyclopropyl-2-fluoro-N-[2-methyl-3-[6-[4-(morpholine-4-carbonyl)phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]benzamide;

5- cyclopropyl-N-[2-methyl-3-[6-[4-(morpholine-4-carbonyl)phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]phenyl]pyridine-2-carboxamide;

6- cyclopropyl-N-[2-methyl-3-[6-[4-(mo holi e-4-carbonyl)phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]phenyl]pyridine-3-carboxamide;

4-cyclopropyl-N- [3 - [6- [4-(4-hydroxy-4-methyl-piperidine- 1 -carbonyl)phenyl] -7H- pyrrolo[2,3-d]pyrimidin-4-yl]-2-methyl-phenyl]-N-methyl-benzamide; 2-[l-[4-[4-[3-[(4-cyclopropylbenzoyl)amino]-2-methyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin 6-yl]benzoyl]-4-piperidyl]acetic acid;

N- [2-methyl-3 -[6- [4-(piperazine- 1 -carbonyl)phenyl]-7H-pyrrolo [2,3 -d]pyrimidin-4- yl]phenyl]-3,4-dihydro-2H-l ,4-benzoxazine-6-carboxamide;

l-[4 4-[3-[(4-cyclopropylbenzoyl)amino]-2-methyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6- yl]benzoyl]-4-methyl-piperidine-4-carboxylic acid;

N-[2-methyl-3-[6-[4-(4-methylpiperazine-l-carbonyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4 yl]phenyl] -4-(trifluoromethy l)benzamide ;

4-methoxy-N- [2-methy 1-3 - [6- [4-(4-methylpiperazine- 1 -carbony l)phenyl] -7H-pyrrolo [2 ,3 - d]pyrimidin-4-yl]phenyl]benzamide;

N-[2-methyl-3-[6-[4-(piperazine-l-carbonyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4- yl]phenyl] -4-(trifluoromethyl)benzamide ;

4-methoxy-N-[2-methyl-3-[6-[4-(piperazine-l-carbonyl)phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]phenyl]benzamide;

4-tert-butyl-N-[2-methyl-3-[6-(4-morpholinophenyl)-7H-pyrrolo[2, 3-d] pyrimidin-4 yl]phenyl] benzamide;

4- tert-butyl-N-cyclopropyl-N-[2-methyl-3-[6-(4-morpholinophenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl]phenyl]benzamide;

N-[2-methyl-3-[8-(6-morpholino-3-pyridyl)-9H-purin-6-yl]phenyl]isoindoline-2- carboxamide;

N-[3-[2-amino-6-[4-(moφholine-4-carbonyl)phenyl]-7H-pyrrolo[2, 3-d] pyrimidin-4-yl]-2 methyl-phenyl]-4-tert-butyl-benzamide;

N-[3-[2-amino-6-[4-(mo holine-4-carbo yl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2- methy 1-phenyl] -4-cyclopropyl-benzamide ;

N-[3 - [2-amino-6-(4-morpholinophenyl)-7H-pyrrolo [2, 3 -d]pyrimidin-4-yl] -2-methy 1 phenyl] -4-tert-buty 1-benzamide ;

N-[3-[2-amino-6-(6-mo holino-3-pyridyl)-7H-pyrΓolo[2,3-d]pyrimidin-4-yl]-2-methyl- pheny 1] -4-cyclopropyl-benzamide ;

5- cyclopropyl-N-[2-methyl-3-[6-[4-(moφholine-4-carbonyl)phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]phenyl]thiophene-2-carboxamide; N-[2-methyl-3-[6-[4-(morpholine-4-carbonyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4- yl]phenyl]-5,6,7,8-tetrahydroimidazo[l,2-a]pyridine-2-carboxamide;

N- [2-methyl-3 - [6- [4-(morpholine-4-carbonyl)phenyl] -7H-pyrrolo [2, 3-d] pyrimidin-4- yl]phenyl] isoindoline-2-carboxamide;

N-[3 -[6- [4-(3 -hydroxypiperidine- 1 -carbonyl)phenyl]-7H-pyrrolo [2,3 -d]pyrimidin-4-yl] -2- methyl-phenyl]isoindoline-2-carboxamide;

N-[2-methyl-3-[6-[4-(piperidine-l-carbonyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4- y ljphenyl] isoindoline-2-carboxamide ;

N-[2-methyl-3-[6-[4-(piperazine-l-carbonyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4- yl]phenyl]isoindoline-2-carboxamide;

N-[2-methyl-3-[6-[4-(4-methylpiperazine-l-carbonyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4- yl]phenyl]isoindoline-2-carboxamide;

N- [3 - [6- [4-(3 -hydroxyazetidine- 1 -carbonyl)pheny 1] -7H-pyrrolo [2 ,3 -d]pyrimidin-4-yl] -2- methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[6-[4-[(3R)-3-hydroxypyrrolidine-l-carbonyl]phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4- yl]-2-methyl-phenyl]isoindoline-2-carboxamide;

N-[2-methyl-3-[6-[4-(pyrrolidine-l-carbonyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4- yl]phenyl]isoindoline-2-carboxamide;

N-[3-[6-[4-(4-methoxypiperidine-l-carbonyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2- methyl-phenyl]isoindoline-2-carboxamide;

N- [3 - [6- [4-(3 -methoxy azetidine- 1 -carbonyl)phenyl] -7H-pyrrolo [2 ,3 -d]pyrimidin-4-yl] -2- methyl-phenyl]isoindoline-2-carboxamide;

(2S)-l-[4-[4-[3-(isoindoline-2-carbonylamino)-2-methyl-phenyl |-7H-pyrrolo[2,3- d]pyrimidin-6-yl]benzoyl]pyrrolidine-2-carboxylic acid;

l-[4-[4-[3-(isoindoline-2-carbonylamino)-2-methyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6- yl]benzoyl]piperidine-3-carboxylic acid;

1 - [4- [4- [3 -(isoindoline-2-carbonylamino)-2-methyl-phenyl] -7H-pyrrolo [2 ,3 -d]pyrimidin-6- yl]benzoyl]piperidine-4-carboxylic acid;

N-[2-methyl-3-[6-(4-morpholinophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]

phenyl]isoindoline-2-carboxamide; N-[2-methyl-3-[6-(4-morpholinophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]pheny]]- l ,3,3a,4,5,6,

7,7a-octahydroisoindole-2-carboxamide;

N-[2-methyl-3-[6-(4-morpholinophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]-2- azaspiro[3.4]octane-2-carboxamide;

N-(4 ert-butylphenyl)-2-methyl-3-[6-(4-mo holinophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl]benzamide;

N-(4-tert-butylphen l)-3-[6-(4-mo holi o henyl)-7H-pyrrolo[2,3-d]pyπmidin-4- yljbenzamide;

4-cyclopropyl-N-[2-methyl-3-[8-(6-mo holino-3-pyridyl)-9H-puri -6-yl]phenyl]benzamide; N-[3-[2-amino-6-[4-(moφholine-4-carbonyl) phenyl]-7H-pyrrolo[2, 3-d] pyrimidin-4-yl]-2- methyl-phenyl] isoindoline-2-carboxamide;

N-[3-[2_:amino-6-(6-moφholino-3-pyΓidyl)-7H-pyrrolo[2,3-d] pyrimidin-4-yl]-2-methyl- phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-(4-mo holinophenyl)-7H-pyrΓolo[2,3-d]pyrimidin-4-yl]-2-rnethyl- phenyl]isoindoline-2-carboxamide;

N- [2-methyl-3 - [6- [4-(piperazin- 1 -ylmethyl)phenyl] -7H-pyrrolo [2 ,3 -d] pyrimi din-4- yl]phenyl]isoindoline-2-carboxamide ;

N- [2 -methyl-3 - [6- [3 -(piperazin- 1 -ylmethy l)phenyl] -7H-pyrrolo [2 ,3 -d]pyrimidin-4- yl]phenyl]isoindoline-2-carboxamide;

N-[2-methyl-3-[6-[4-(mo holinomethyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4- yl]phenyl]isoindoline-2-carboxamide;

N-[2-methyl-3-[6-[3-(mo holinomethyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4- y ljphenyl] isoindoline-2-carboxamide ;

4-cyclopropyl-N-[3-[6-[4-[(4-cyclopropylpiperazin-l -yl)methyl]phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-2-methyl-phenyl]benzamide;

4-cyclopropyl-N-[2-methyl-3-[6-[4-[(3-oxopiperazin-l -yl)methyl]phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yi]phenyl]benzamide;

4-cyclopropyl-N-[3-[6-[4-[(4-hydroxy-4-methyl-l-piperidyl)methyl]phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-2-methyl-phenyl]benzamide; N-[3-[6-[4-[(4-cyclopropylpiperazin-l-yl)methyl]phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]- 2-methyl-phenyl]isoindoline-2-carboxamide;

N- [3 - [6- [4- [(4-cyano- 1 -piperidyl)methyl]phenyl] -7H-pyrrolo [2 ,3 -d]pyrimidin-4-yl] -2- methyl-phenyl]isoindoline-2-carboxamide;

N- [3 - [6- [4- [(3 -amino- 1 -piperidyl)methyl]phenyl] -7H-pyrrolo [2 ,3 -d]pyrimidin-4-yl] -2- methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[6-[4-[(4-ethylpiperazin-l-yl)methyl]phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2- methyl-phenyl]isoindoline-2-carboxamide;

N- [3 - [6- [4- [(4-hydroxy-4-methyl- 1 -piperidyl)methyl]phenyl] -7H-pyrrolo [2,3 -d]pyrimidin-4- yl]-2-methyl-phenyl]isoindoline-2-carboxamide; .

N- [3 - [6- [4- [(3 -cyanp- 1 -piperidyl)methyl]phenyl] -7H-pyrrolo [2,3 -d]pyrimidin-4-yl] -2- methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[6-[4-[(3-amino-l -piperidyl)methyl]phenyl]-7H-pyiTolo[2,3-d]pyrimidin-4-yl]-2- methyl-phenyl]-4-cyclopropyl-benzamide;

4-cyclopropyl-N-[3-[6-[4-[(4-ethylpiperazin-l-yl)methyl]phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-2-methyl-phenyl]benzamide;

N-[2-methyl-3-[6-[4-[(4-methylpiperazin-l-yl) methyl]phenyl]-7H-pyrrolo[2, 3-d]pyrimidin- 4-yl] phenyl]isoindoline-2-carboxamide;

N- [2 -methyl-3 - [6-(4-morpholinosulfonylphenyl)-7H-pyrrolo [2 ,3 -d]pyrimidin-4- yl]phenyl]isoindoline-2-carboxamide;

4-cyclopropyl-N-[2-methyl-3-[6-(4-mo holinosulfonylphenyl)-7H-pyrrolo[2,3-d]pyrimidin- 4-yl] phenyl] benzamide ;

4-cyclopropyl-N-[2-methyl-3-[6-[4-[(4-methylpiperazin- 1 -yl)methyl]phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]benzamide;

N-[3-[2-amino-6-[4-[(4-methylpiperazin-l-yl)methyl]phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4- yl]-2-methyl-phenyl]-4^cyclopropyl-benzamide;

N 3-[2-amino-6-[4-[(4-ethylpiperazin-l -yl)methyl]phenyl]-7H-pyrrolo[2,3-d]pyrimidin-^ yl]-2-methyl-phenyl]-4-cyclopropyl-benzamide; 4-cyclopropyl-N- [3 - [6- [4- [(4-cyclopropylpiperazin- 1 -y l)methy l]phenyl] -7H-pyrrolo [2,3 - d]pyrimidin-4-yl]-2-methyl-phenyl]benzamide;

N-[3-[2-amino-6-[4-[(4-cyclopropylpiperazin-l-yl)methyl]phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl] -2-methyl-phenyl] -4-cyclopropyl-benzamide ;

4-cyclopropyl-N-[2-methyl-3-[6-[4-[(3-oxopiperazin-l-yl)methyl]phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]phenyl]benzamide;

N-[3-[2-amino-6-[4-[(3-oxopiperazin-l-yl)methyl]phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4- yl]-2-methyl-phenyl]-4-cyclopropyl-benzamide;

4-cyclopropyl-N-[3-[6-[4-[(4-hydroxy-4-methyl-l-piperidyl)methyl]phenyl]-7H-pyrrolo[2,3- djpyrimidin-4-yl]-2-methyl-phenyl]benzamide;

N-[3-[2-amino-6-[4-[(4-hydroxy-4-methyl-l-piperidyl)methyl]phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-2-methyl-phenyl]-4-cyclopropyl-benzamide;

N- [3 - [6- [4- [(3 -amino- 1 -piperidyl)methyl]phenyl] -7H-pyrrolo [2 ,3 -d]pyrimidin-4-yl] -2- methyl-phenyl]-4-cyclopropyl-benzamide;

N-[3-[2-amino-6-[4-[(3-amino-l-piperidyl)methyl]phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4- yl] -2 -methy 1-phenyl] -4-cy clopropy 1 -benzamide;

N-[3-[2-amino-6-[4-[(4-methylpiperazin-l -yl)methyl]phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4- yl]-2-methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[4-[(4-ethylpiperazin-l-yl)methyl]phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4- yl]-2-methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[6-[4-[(4-cyclopropylpiperazin-l-yl)methyl]phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]- 2-methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[4-[(4-cyclopropylpiperazin-l-yl)methyl]phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-2-methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[4-[(3-oxopiperazin-l-yl)methyl]phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4- yl]-2-methyl-phenyl]isoindoline-2-carboxamide; N-[3-[6-[4-[(4-hydroxy-4-methyl-l-piperidyl)methyl]phenyl]-7H-pyrrolo[2,3-d]pyrimidin yl]-2-methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[4 (4-hydroxy-4-methyl-l-piperidyl)methyl]phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-2-methyl-phenyl]isoindoline-2-carboxamide;

N- [3 - [6- [4- [(3 -amino- 1 -piperidyl)methyl]phenyl] -7H-pyrrolo [2 ,3 -d]pyrimidin-4-y 1] -2- methyl-phenyl]isoindoline-2-carboxan ide;

N-[3-[2-amino-6-[4-[(3-amino-l -piperidyl)methyl]phenyl]-7H^yrrolo[2,3-d]pyrimidin-4- yl]-2-methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[5-[(4-methylpiperazin-l-yl)methyl]-2-pyridyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-2-methyl-phenyl]-4-cyclopropyl-benzamide; ·

N-[3-[2-amino-6-[5-[(4-methylpiperazin-l-yl)methyl]-2-pyridyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-2-methyl-phenyl]isoindoline-2-carboxamide;

N- [3 -[2-amino-6-[5 -(morpholinomethyl)-2-pyridyl] -7H-pyrrolo [2,3 -d]pyrimidin-4-yl]-2- methyl-phenyl]-4-cyclopropyl-benzamide;

N-[3-[2-amind-6-[5-(morpholinomethyl)-2-pyridyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2- methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[5-[(4-hydroxy-4-methyl-l-piperidyl)methyl]-2^yridyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-2-methyl-phenyl]-4-cyclopropyl-benzamide;

N-[3-[2-amino-6-[5-[(4-hydroxy-4-methyl-l-piperidyl)methyl]-2-pyridyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-2-methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[l -(l-methyl-4-piperidyl)pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl] 2-methyl-phenyl]-4-cyclopropyl-benzamide;

N-[3-[2-amino-6-[l-(l -methyl-3-piperidyl)pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrirnidin-4-yl] 2-methyl-phenyl]-4-cyclopropyl-benzamide;

N- [3 - [2-amino-6-[ 1 -( 1 -methyl-4-piperidyl)pyrazol-4-y l]-7H-pyrrolo[2,3 -d]pyrimidin-4-yl] 2-methyl-phenyl]isoindoline-2-carboxamide; N- [3 -[2-amino-6- [ 1 -( 1 -methyl-3 -piperidyl)pyrazol-4-yl]-7H-pyrrolo[2,3 -d]pyrimidin-4-yl]- 2-methyl-phenyl]isoindoIine-2-carboxamide;

N-[3-[2-amino-6-[4-[(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl]phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl]-2-methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[4-(3-methyl-3,

8-diazabicyclo[3.2.1]octan-8-yl)phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl] -2-methyl-phenyl] isoindoline-2-carboxamide ;

N-[3-[2-amino-6-[4-[(3,4-dimethylpiperazin-l -yl)methyl]phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-2-methyl-phenyl]isoindoIine-2-carboxamide;

N-[3-[2-amino-6-[4-[(2,4-dimethylpiperazin-l-yl)methyl]phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-2-methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[4-(3,4-dimethylpiperazin-l -yl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-

2-methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[4-(2,4-dimethylpiperazin-l-yl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylJ- 2-methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[4-(3-azabicyclo[3.3.2]decan-3-ylmethyl)phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-2-methyl-phenyl]isoindoline-2-carboxamide;

N- [3 - [2-amino-6-[4-(3-azabicyclo[3.3.2]decan-3 -yl)phenyl] -7H-pyrrolo [2,3 -d]pyrimidin-4- yl]-2-methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[4-(5-methyl-2,5-diazabicyclo[2.2, l]heptan-2-yl)phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-2-methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[4-[(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl]phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl]-2-methyl-phenyl]isoindoline-2-carboxamide;

N- [3 - [2-amino-6- [4- [4-(2-hydroxyethyl)piperazin- 1 -yljphenyl] -7H-pyrrolo [2,3 -djpyrimidin- 4-yl]-2-methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[4-[l-(4-methylpiperazin-l-yl)cyclopropyl]phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl] -2-methyl-phenyl] isoindoline-2-carboxamide ; N-[3-[2-amino-6-[4-(6-methyl-6-azaspiro[2.5]octan-2-yl)phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-2-methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[l -(l-methyl-4-piperidyl)-3,6-dihydro-2H^yridin-4-yl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-2-methyl-phenyl]isoindoline-2-carboxamide;

N-[3-[2-amino-6-[l-(l-ethyl-4-piperidyl)-3,6-dihydro-2H-pyridin-4-yl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-2-methyl-phenyl]isoindoline-2-carboxamide;

4-cyclopropyl-2-fluoro-N-[2-(hydroxymethyl)-3-[6-[4-(morpholine-4-carbonyl)phenyl]-7H- pyrrolo [2,3 -d]pyrimidin-4-y l]phenyl]benzamide ;

2-fluoro-4-( 1 -hydroxycyclopropyl)-N-[2-(hydroxymethyl)-3 - [6- [4-(morpholine-4- carbonyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]benzamide;

4-(l-hydroxycyclopropyl)-N-[2-(hydroxymethyl)-3-[6-[4-(morpholine-4-carbonyl)phenyl]- 7H-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]benzamide;

4-( 1 -hydroxy- 1 -methyl-ethyl)-N- [2-(hydroxymethyl)-3 - [6- [4-(morpho line-4- carbonyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]benzamide;

4-cyclopropyl-N-[2-(hydroxymethyl)-3-[6-[4-(morpholine-4-carbonyl)phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]benzamide;

4-cyclopropyl-N-[3-(hydroxyniethyl)-4-[6-[4-(morpholine-4-carbonyl)phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl].-2-pyridyl]benzamide;

4-cyclopropyl-2-fluoro-N-[3-(hydroxymethyl)-4-[2-[4-(piperazine- 1 -carbonyl)phenyl]- l.H- pyrrolo[2,3-b]pyridin-4-yli-2-pyridyl]benzamide;

4-cyclopropyl-2-fluoro-N-[3-(hydroxymethyl)-4-[2-[4-(4-methylsulfonylpiperazine-l- carbonyl)phenyl]-lH-pyrrolo[2,3-b]pyridin-4-yl]-2-pyridyl]benzamide;

4-[4-[4-[2-[(4-cyclopropyl-2-fluoro-benzoyl)amino]-3-(hydroxymethyl)-4-pyridyl]- l H- pyrrolo[2,3-b]pyridin-2-yl]benzoyl]-N,N-dimethyl-piperazine-l -carboxamide;

4-cyclopropyl-N- [4- [2- [4-(4-ethylpiperazine- 1 -carbonyl)pheny 1]- 1 H-pyrrolo [2 ,3 -b]pyridin- 4-yl] -3 -(hydroxymethy l)-2-pyridy 1] -2-fluoro-benzamide ;

N-[4-[2-[4-(azetidine-l-carbonyl)phenyl]-lH-pyrrolo[2,3-b]pyridin-4-yl]-3- (hydroxymethyl)-2-pyridyl]-4-cyclopropyl-2-fluoro-benzamide; 4-cyclopropyl-N-[4-[2-[4-(dimethylcarbamoyl)phenyl]-lH-pyrrolo[2,3-b]pyridin-4-yl]-3- (hydroxymethyl)-2-pyridyl]-2-fluoro-benzamide;

4-cyclopropyl-2-fluoro-N- [3 -(hydroxymethyl)-4- [2- [ 1 -(oxetan-3 -y l)imidazol-4-yl] - 1 H- pyrrolo[2,3-b]pyridin-4-yl]-2-pyridyl]benzamide;

4-cyclopropyl-2-fluoro-N-[3-(hydroxymethyl)-4-[2-[l -(oxetan-3-yl)pyrazol-4-yl]-lH- ^"pyrrolo[2,3-b]pyridin-4-yl]-2-pyridyl]benzamide;

4-cyclopropyl-2-fluoro-N-[3-(hydroxymethyl)-4-[2-[l-(4-hydroxy-4-methyl- cyclohexyl)imidazol-4-yl]- 1 H-pyrrolo[2,3-b]pyridin-4-yl]-2-pyridyl]benzamide;

4-cyclopropyl-2-fluoro-N-[3-(hydroxymethyl)-4-[2-[l -(4-hydroxy-4-methyl- cyclohexyl)pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridin-4-yl]-2-pyridyl]benzamide;

N-[4-[2-[5-(azetidine-l-carbonyl)-2-pyridyl]-lH-pyrrolo[2,3-b]pyridin-4-yl]-3-

(hydroxymethyl)-2-pyridyl]-4-cyclopropyl-2-fluoro-benzamide;

4-cyclopropyl-2-fluoro-N-[3-(hydroxymethyl)-4-[6-[5-(piperazine-l-carbonyl)-2-pyridyl]- 7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-pyridyl]benzamide;

4-cyclopropyl-2-fluoro-N-[3-(hydroxymethyl)-4-[6-[5-(morpholine-4-carbonyl)-2-pyridyl]- 7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-pyridyl]benzamide;

6-[4-[2-[(4-cyclopropyl-2-fluoro-benzoyl)amino]-3-(hydroxymethyl)-4-pyridyl]-7H- pyrrolo [2,3 -d]pyrimidin-6-yl] -N,N-dimethyl-pyridine-3 -carboxamide ;

4- [6- [4- [2- [(4-cyclopropyl-2-fluoro-benzoyl)amino] -3 -(hydroxymethy l)-4-pyridyl] - 1 H- pyrrolo[2,3-b]pyridin-2-yl]pyridine-3-carbonyl]-N,N-dimethyl-piperazine-l -carboxamide; 4-[6-[4-[2-[(4-tert-butyl-2-fluoro-benzoyl)amino]-3-(hydroxymethyl)-4-pyridyl]-l H- pyrrolo[2,3-b]pyridin-2-yl]pyridine-3-carbonyl]-N,N-dimethyl-piperazine-l -carboxamide; 4-tert-butyl-2-fluoro-N-[3-(hydroxymethyl)-4-[6-[5-(morpholine-4-carbonyl)-2-pyridyl]-7H- pyrrolo [2 ,3 -d]pyrimidin-4-yl] -2-pyridyl]benzamide ;

4-tert-buty 1-2-fluoro-N- [3 -(hydroxymethy l)-4 - [2- [5 -( 1 -methyl-4-piperidyl)-2-pyridyl] - 1 H- pyrrolo[2,3-b]pyridin-4-yl]-2-pyridyl]benzamide;

4-tert-butyl-N-[4-[2-[5-(l-ethyl-4-piperidyl)-2-pyridyl]-lH-pyrrolo[2,3-b]pyridin-4-yl]-3- (hydroxymethyl)-2-pyridyl]-2-fluoro-benzamide; 4-tert-butyl-2-fluoro-N-[3-(hydroxymethyl)-4-[2-[5-(l -methylsulfonyl-4-piperidyl)-2- pyridy 1] - 1 H-pyrrolo [2 ,3 -b]pyridin-4-y 1] -2-pyridy l]benzamide ;

4-tert-butyl-2-fluoro-N-[3-(hydroxymethyl)-4-[2-[5-(oxetan-3-yl)-2-pyridyl]-lH-pyrrolo[2,3- b]pyridin-4-yl]-2 -pyridy l]benzamide;

2-fluoro-4-(l -hydroxy- l-methyl-ethyl)-N-[3-(hydroxymethyl)-4-[2-[5-(l-methylsulfonyl-4- piperidyl)-2-pyridyl]-lH-pyrrolo[2,3-b]pyridin-4-yl]-2-pyridyl]benzamide;

2-fluoro-4-( 1 -hydroxy- 1 -methyl-ethyl)-N- [3 -(hydroxymethyl)-4- [2- [5-(oxetan-3-yI)-2- pyridyl]-lH-pyrrolo[2,3-b]pyridin-4-yl]-2-pyridyl]benzamide;

N-[2-(hydroxymethyl)-3-[2-[5-(l-methylsulfonyl-4-piperidyl)-2-pyridyl]-l H-pyrrolo[2,3- b]pyridin-4-yl]phenyl]isoindoline-2-carboxamide;

N- [3 -(hydroxymethyl)-4- [2- [5 -( 1 -methy Isulfony l-4-piperidyl)-2-pyridyl] - 1 H-pyrrolo [2,3 - b]pyridin-4-yl]-2-pyridyl]isoindoline-2-carboxamide;

N-[3-(hydroxymethyl)-4-[2-[4-(l-methylsulfonyl-4-piperidyl)phenyl]-lH-pyrrolo[2,3- b]pyridin-4-yl]-2-pyridyl]isoindoline-2-carboxamide;

N-[3-(hydroxymethyl)-4-[2-[4-(oxetan-3-yl)phenyl]-lH-pyrrolo[2,3-b]pyridin-4-yl]-2- pyridyl]isoindoline-2-carboxamide;

N-[3-(hydroxymethyl)-4-[2-[5-(oxetan-3-yl)-2-pyridyl]-lH-pyrrolo[2,3-b]pyridin-4-yl]-2- pyridyl]isoindoline-2-carboxamide;

N-[4-[2-[5-(l-ethyl-4-piperidyl)-2-pyridyl]-lH-pyrrolo[2,3-b]pyridin-4-yl]-3- (hydroxymethyl)-2-pyridyl]isoindoline-2-carboxamide;

N- [3 -(hydroxymethyl)-4- [2- [5 -(morpholine-4-carbonyl)-2 -pyridy 1] - 1 H-pyrrolo [2 ,3 - b]pyridin-4-yl]-2-pyridyl]isoindoline-2-carboxamide;

N-[2-(hydroxymethyl)-3-[2-[5-(morpholine-4-carbonyl)-2-pyridyl]-lH-pyrrolo[2,3- b]pyridin-4-yl]phenyl]isoindoline-2-carboxamide;

N-[3-(hydroxymethyl)-4-[2-[l -(4-hydroxy-4-methyl-cyclohexyl)pyrazol-4-yl]-lH- pyrroloi2,3-b]pyridin-4-yl]-2-pyridyl]isoindoline-2-carboxamide;

N-[2-(hydroxymethyl)-3-[2-[l -(4-hydroxy-4-methyl-cyclohexyl)pyrazol-4-yl]-l H- pyrrolo[2,3-b]pyridin-4-yl]phenyl]isoindoline-2-carboxamide;

N-[3-[2-[l-(dimethylcarbamoyl)-3,6-dihydro-2H-pyridin-4-yl]-lH-pyrrolo[2,3-b]pyridin-4- yl]-2-(hydroxymethyl)phenyl]isoindoline-2-carboxamide; N- [3 - [2- [ 1 -(azetidine- 1 -carbony l)-3 ,6-dihydro-2H-pyridin-4-yl] - 1 H-pyrrolo [2,3 -b]pyridin-4- yl]-2-(hydroxymethyl)phenyl]isoindoline-2-carboxamide;

N- [2-(hydroxymethyl)-3 - [2-( 1 -methyl-3 ,6-dihydro-2H-pyridin-4-y 1)- 1 H-pyrrolo [2 ,3 - b]pyridin-4-yl]phenyl]isoindoline-2-carboxamide;

N-[3-(hydroxymethyl)-4-[2-(l-methyl-3,6-dihydro-2H-pyridin-4-yl)-lH-pyrrolo[2,3- b]pyridin-4-yl]-2-pyridyl]isoindoline-2-carboxamide;

N- [2-(hydroxymethyl)-3 - [2- [ 1 -(2-hydroxypropanoyl)-3 ,6-dihydro-2H-pyridin-4-y 1] - 1 H- pyrrolo[2,3-b]pyridin-4-yl]phenyl]isoindoline-2-carboxamide;

N-[3-[2-[l -(2-cyanoacetyl)-3,6-dihydro-2H-pyridin-4-yl]-lH-pyrrolo[2,3-b]pyridin-4-yl]-2- (hydroxymethyl)phenyl]isoindoline-2-carboxamide;

N-[4-[2-[l-(2-cyanoacetyl)-3,6-dihydro-2H-pyridin-4-yl]-lH-pyrrolo[2,3-b]pyridin-4-yl]-3- (hydroxymethyl)-2-pyridyl]isoindoline-2-carboxamide;

N- [3 -(hydroxymethyl)-4- [2-( 1 -methylsulfonyl-3 ,6-dihydro-2H-pyridin-4-yl)- 1 H-pyrrolo [2,3 - b]pyridin-4-yl]-2-pyridyl]isoindoline-2-carboxamide

N-[2-(hydroxymethyl)-3-[2-(l-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl)-lH-pyrrolo[2,3- b]pyridin-4-yl]phenyl]isoindoline-2-carboxamide.

9. A process of preparation of compounds of formula (I) as claimed in any of claims 1 to 8 or its tautomers, polymorphs, stereoisomers, prodrugs, solvate, co-crystals or pharmaceutically acceptable salts thereof.

10. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof of as claimed in any of claims 1 to 8 together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.

1 1. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any of claims 1 to 8 together with a pharmaceutically acceptable carrier, optionally in combination with one or more additional therapeutic agent.

12. A pharmaceutical composition as claimed in claim 1 1 wherein the additional therapeutic agent is selected from BTK inhibitors like Ibrutinib, AVL-292, ONO-4059; B-cell depleting protein based therapeutics like Rituxan, a CD20 antibody; calcineurin inhibitor like cyclosporin A or FK 506; a mTOR inhibitor like rapamycin, 40-O-(2-hydroxyethyl)- rapamycin, CCI779, ABT578, AP23573, AP23464, AP23675, AP23841 , TAFA-93, biolimus-7 or biolimus-9; an ascomycin having immunosuppressive properties like ABT- 281 , ASM981 ; corticosteroids like cortisone, dexamethasone, methylprednisolone, prednisolone, prednisone; cyclophosphamide; azathioprene; methotrexate; leflunomide; teriflunomide; mizoribine; etanercept; infliximab; a chemotherapeutic agent like paclitaxel, gemcitabine, cisplatine, doxorubicin, 5-fluorouracil, imatinib, dasatinib, sunitinib, gefitinib, sorafenib, erlotinib, camptothecin, topotecan, daunomycin, etoposide, taxol, vinblastine, bortezomib, carfilzomib; mycophenolic acid or salt; mycophenolate mofetil; 15- deoxyspergualine or an immunosuppressive homologue, analogue or derivative thereof;

NSAIDs like Ibuprofen, flurbiprofen, naproxen, diclofenac, misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen, ketoprofen, sodium nabumetone, sulfasalazine, tolmetin sodium, hydroxychloroquine, celecoxib, valdecoxib, lumiracoxib, etoricoxib; JAK kinase inhibitors like Tofacitinib, LY-3009104, VX-509, GLPG-0634, ASP- 015K , N-benzyl-3,4-dihydroxy-benzylidene-cyanoacetamide -cyano-(3,4-dihydroxy)-]N- benzylcinnamamide (Tyrphostin AG 490), prodigiosin 25-C (PNU156804), [4-(4'- hydroxyphenyl)-amino-6,7-dimethoxyquinazoline] (WHI-P131), [4-(3'-bromo-4'- hydroxylphenyl)-amino-6,7-dimethoxyquinazoline] (WHI-P154), [4-(3',5'-dibromo-4'- hydroxylphenyl)-amino-6,7-dimethoxyquinazoline] WHI-P97, KRX-21 1 , 3-{(3R,4R)-4- methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-l-yl}-3-oxo- propionitrile, in free form or in a pharmaceutically acceptable salt form, e.g. mono-citrate (also called CP-690,550); SYK inhibitor like fostamatinib; sphingosine-1 -phosphate receptor modulators like FTY720 (fingolimod); immunosuppressive monoclonal antibodies like monoclonal antibodies to leukocyte receptors like MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86 or their ligands; other immunomodulatory compounds like a recombinant binding molecule having at least a portion of the extracellular domain of CTLA4 or a mutant thereof, e.g. an at least extracellular portion of CTLA4 or a mutant thereof joined to a non-CTLA4 protein sequence, e.g. CTLA41g (for ex. designated ATCC 68629) or a mutant thereof, e.g. LEA29Y; adhesion molecule inhibitors, e.g. LFA-1 antagonists, ICAM-1 or -3 antagonists, VCAM-4 antagonists or VLA-4 antagonists; or an anti-infectious agent. Further combination partners to a compound of formula (I) may be selected from a PI3K inhibitor (e.g. pan, or alpha, beta, gamma, delta selectives), TNF inhibitors, ILI beta inhibitors, ILI 7 inhibitors, and inhibitors of IL6 or IL receptor.

13. A method of modulating Btk activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

14. A compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, for use as a medicament.

15. Use. of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disorder or disease mediated by Btk.