WO2013042137A1

WO2013042137A1 - Bicyclic heterocycles as irak4 inhibitors

Info

Publication number: WO2013042137A1
Application number: PCT/IN2012/000615
Authority: WO
Inventors: Boruah ANIMA; Subramanya Hosahalli; Mukherjee SUBHENDU
Original assignee: Aurigene Discovery Technologies Limited
Priority date: 2011-09-19
Filing date: 2012-09-14
Publication date: 2013-03-28
Also published as: AR087919A1

Abstract

The present invention provides bicyclic heterocycle kinase enzyme inhibitor compounds of formula (I), which may be therapeutically useful as kinase inhibitor, more particularly IRAK4 inhibitors. ( I ) in which A, R, R¹,R², m, n and p have the meanings given in the specification, and pharmaceutically acceptable salts thereof that are useful in the treatment and prevention of diseases or disorder, in particular their use in diseases or disorder where there is an advantage in inhibiting kinase enzyme, more particularly IRAK4 enzyme.The present invention also provides pharmaceutical formulations comprising at least one of the kinase inhibitor compounds of formula (I) together with a pharmaceutically acceptable carrier, diluent or excipient therefor.

Description

"BICYCLIC HETEROCYCLES AS IRAK4 INHIBITORS

This application claims the benefit of Indian provisional application number 3206/CHE/201 1 filed on September 19, 201 1 which hereby incorporated by reference.

TECHNICAL FIELD

This invention relates to compounds useful for treatment of cancer and inflammatory diseases associated with lnterleukin-1 Receptor Associated Kinase (IRAK), and more particularly compounds that modulate the function of IRAK-4. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of diseases associated with IRAK- 4.

BACKGROUND

Kinases are^' key regulatory enzymes of large number of cell activities and constitute one of the largest and most functionally diverse gene families. Kinase enzymes participate in the signalling events that control the activation, growth and differentiation of cells in response to extracellular mediators and to changes in the environment. In general, these protein kinases fall into several groups; those which preferentially phosphorylate serine and/ or threonine residues and those which preferentially phosphorylate tyrosine residues [S. K. Hanks and T. Hunter, FASEB. J., 1995, 9, pages 576-596]. The serine/threonine kinases include for example, protein kinase C isoforms [A. C. Newton, J. Biol. Chem., 1995, 270, pages 28495-28498] and a group of cyclin-dependent kinases such as cdc2 [J. Pines, Trends in Biochemical Sciences, 1995, 18, pages 195-197]. The tyrosine kinases include membrane-spanning growth factor receptors such as the epidermal growth factor receptor [S. Iwashita and M. Kobayashi, Cellular Signalling, 1992, 4, pages 123-132], and cytosolic non-receptor kinases such as p56tck, p59fYn, ZAP-70 and csk kinases [C. Chan et. a\., Ann. Rev. Immunol., 1994, 12, pages 555-592].

Protein kinases play key roles in regulating the different cell processes which include, but are not limited to, proliferation, differentiation, apoptosis, motility, transcription, translation, signalling process and various regulatory mechanisms, by adding phosphate groups to the target protein residues (Hardie, G. and Hanks, S., The Protein Kinase Facts Book, I and II, Academic Press, San Diego, CA: 1995). This phosphorylation event acts as molecular on/off switches that can modulate or regulate the target position biological function. Phosphorylation of targeted proteins occurs in response to variety of extracellular signals. The appropriate protein kinase functions in signaling pathways to activate or deactivate. Uncontrolled signalling due to defective control of protein phosphorylation is known to contribute to various diseases. In the case of cancer, kinases are known to regulate many aspects of the cell growth, invasion that intrudes upon and destroys adjacent tissues and sometimes metastasis, or spreading to other locations in the body via lymph or blood.

The kinase enzymes family members include enzymes that control cell growth, migration, activation, proliferation, differentiation, signalling, survival and regulation of the cell cycle. Many diseases and/or disorders are associated with aberrant, abnormal or deregulated activity of one or more kinases. These diseases and/or disorders includes, but are not limited to cancers, allergic diseases and/or disorders, autoimmune diseases and/or disorders, inflammatory diseases and/or disorder and/or conditions associated with inflammation and pain, proliferative diseases, hematopoietic disorders, hematological malignancies, bone disorders, fibrosis diseases and/or disorders, metabolic disorders, muscle diseases and/or disorders respiratory diseases and/or disorders, pulmonary disorders, genetic developmental diseases, neurological and neurodegenerative diseases/or disorders, chronic inflammatory demyelinating neuropathies, cardiovascular, vascular or heart diseases and/or disorders, ophthalmic/ocular diseases and/or disorders, wound repair, infection and viral diseases. Therefore, inhibition of one or more of kinases would have multiple therapeutic indications.

In particular, Interleukin-1 (IL-1) Receptor-Associated Kinase-4 (IRAK-4) is a serine/threonine kinase enzyme that plays an essential role in signal transduction by Toll/IL-1 receptors (TIRs). Diverse IRAK enzymes are key components in the signal transduction pathways mediated by interleukin-1 receptor (IL-1 R) and Toll-like receptors (TLRs) (Janssens, S., and Beyaert, R„ Mol. Cell 1 1 , 293-302; 2003). There are four members in the mammalian IRAK family: IRAK-1 , IRAK-2, IRAK-M, and IRAK-4. These proteins are characterized by a typical N-terminal death domain that mediates interaction with MyD88-family adaptor proteins and a centrally located kinase domain. The IRAK proteins, as well as MyD88, have been shown to play a role in transducing signals other than those originating from IL-1 R receptors, including signals triggered by activation of IL-18 receptors (Kanakaraj, et al. J. Exp. Med. 189(7): 1 129 38 (1999)) and LPS receptors (Yang, et al., J. Immunol. 163:639 643 (1999); Out of four members in the mammalian IRAK family, IRAK-4 is considered to be the "master IRAK". Under overexpression conditions, all IRAKs can mediate the activation of nuclear factor-kB (NF- kB) and stress-induced mitogen activated protein kinase (MAPK)-signaling cascades. However, only IRAK- 1 and IRAK-4 have been shown to have active kinase activity. While IRAK-1 kinase activity could be dispensable for its function in IL-1 -induced NF-kB activation (Kanakaraj et al (1998); J. Exp. Med. 187, 2073-2079 and Li, X., Commane, M et al (1999). Mol. Cell. Biol. 19, 4643-4652), IRAK-4 requires its kinase activity for signal transduction (Li, S., Strelow, A., Fontana, E.J., and Wesche, H. (2002); Proc. Natl. Acad. Sci. USA 99, 5567-5572 and Lye, E et al (2004); J. Biol. Chem. 279;). Given the central role of IRAK4 in Toll-like/IL-l R signaling and immunological protection, IRAK4 inhibitors have been implicated as valuable therapeutics in inflammatory diseases, sepsis, and autoimmune disorders (Wietek, C, and L. A. O Neill. 2002; Mol. Interv. 2: 212-215).

Mice lacking IRAK-4 are viable and show complete abrogation of inflammatory cytokine production in response to IL- 1, IL- 18 or LPS (Suzuki, et al in Nature 2002, 416, 750). Similarly, human patients lacking IRAK-4 are severely immunocompromised and are not responsive to these cytokines (Medvedev et al; J. Exp. Med. 2003, 198, 521 and Picard et al; Science 2003, 299, 2076). Knock-in mice containing inactive IRAK4 were completely resistant to lipopolysaccharide- and CpG-induced shock ( Kim TW, Staschke K, Bulek K, et al.; J Exp Med 2007 ; 204 : 1025 -36 and Kawagoe T, Sato S, Jung A, et al. J Exp Med 2007 ; 204 : 1013 -24) and illustrated that IRAK4 kinase activity is essential for cytokine production, activation of MAPKs and induction of NF- B regulated genes in response to TLR ligands (Koziczak-Holbro M, Joyce C, Gluck A,et al; J Biol Chem 2007 ; 282 : 13552 -60). Inactivation of IRAK4 kinase (IRAK4 KI) in mice leads to resistance to EAE due to reduction in infiltrating inflammatory cells into CNS and reduced antigen specific CD4+ T-cell mediated IL-17 production (Kirk A et al ; The Journal of Immunology July 1, 2009 vol. 183 no. 1 568-577).

Despite various disclosures on different kinase inhibitors, however, with the rise in number of patients affected by kinase enzyme mediated diseases, there appears to be unmet need for newer drugs that can treat such diseases more effectively. There is still need for newer kinase inhibitors including multikinase inhibitors, which may be further useful in treatment of disorders owing to variations in various kinases activity and possessing broader role. They may also be useful as part of other therapeutic regimens for the treatment of disorders, alone or in combination with protein kinase compounds well known by the one skilled in the art.

SUMMARY OF THE INVENTION

In one aspect according to the present invention, it comprises bicyclic heterocycle kinase enzyme inhibitor com ounds of formula (I).

and its derivatives, pro-drugs, N-oxides, stereoisomers, solvates, pharmaceutically acceptable salts and biologically active metabolites thereof;

wherein,

X is selected from O, S, and NH;

A is selected from aryl or heteroaryl;

R at each occurrence is independently selected from hydrogen, cyano, halo, hydroxy, -N0_2, -NR³R⁴, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyi or optionally substituted heteroaryl; wherein the optional substituent, in each occurrence, is independently selected from halo, alkyl, haloalkyl, cyano, -NR⁵R⁶ or-COOR⁷;

R¹ at each occurence is independently selected from hydrogen, halogen, alkyl, aryl, heterocycloalkyi, heterocycloalkylalkyl, heteroaryl, Y-arylalkyl or -Y-cycloalkyl; wherein cycloalkyl, aryl, heterocycloalkyi, heterocycloalkylalkyl, heteroaryl and arylalkyl can be optionally substituted with hydroxy, alkyl, haloalkyl, cyano or halo;

Y is selected from direct bond, O, -C(O)- or NR⁷;

R² at each occurence is independently selected from hydrogen, carboxy, cyano, hydroxy, hydroxyalkyl, alkyl, aryl, heteroaryl, -S0²R⁵ or oxo;

R³ and R⁴ are independently selected from hydrogen, hydroxyalkyl, aminoalkyl, optionally substituted alkyl, optionally substituted heterocyclyl, optionally substituted aryl; wherein the optional substituent, in each occurrence, is independently selected from halo, haloalkyl or -COOR⁷; R^s and R⁶are independently selected from hydrogen, alkyl, -COR⁷ or -COOR⁷;

R⁷at each occurrence is independently selected from hydrogen or alkyl; and

m, n and p are selected from 1, 2 or 3.

In another aspect of the present application, it provides processes for preparation of bicyclic heterocycle kinase enzyme inhibitor compounds of formula(I).

In yet another aspect the present patent application provides pharmaceutical composition comprising bicyclic heterocycle kinase enzyme inhibitor compounds of formula(I).

In yet further aspect of the present application, it provides use of bicyclic heterocycle kinase enzyme inhibitor compounds of formula(I) for the treatment and prevention in diseases or disorder, in particular their use in diseases or disorder where there is an advantage in inhibiting kinase enzyme, more particularly IRAK4 enzyme.

More particularly, the invention relates to the use of novel bicyclic heterocycle kinase enzyme inhibitor compounds of formula (I) and pharmaceutically acceptable derivatives, solvates, tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios as a medicament, by inhibiting IRAK or IRAK4 other.related kinases.

Novel bicyclic heterocycle kinase enzyme inhibitor compounds of formula (I) of the present invention possess therapeutic role of inhibiting IRAK or IRAK4 other related kinases useful in the area ofdiseases and/or disorders include, but are not limited to cancers, allergic diseases and/or disorders, autoimmune diseases and/or disorders, inflammatory diseases and/or disorder and/or conditions associated with inflammation and pain, proliferative diseases, hematopoietic disorders, hematological malignancies, bone disorders, fibrosis diseases and/or disorders, metabolic disorders, muscle diseases and/or disorders respiratory diseases and/or disorders, pulmonary disorders, genetic developmental diseases, neurological and neurodegenerative diseases and/or disorders, chronic inflammatory demyelinating neuropathies, cardiovascular, vascular or heart diseases and/or disorders, ophthalmic/ocular diseases and/or disorders, wound repair, infection and viral diseases. Therefore, inhibition of one or more of kinases would have multiple therapeutic indications. DETAILED DESCRD?TION OF THE INVENTION

The present invention provides for compounds of formula (I) as defined above, pharmaceutical compositions employing such compounds, and methods of using such compounds for the treatment and prevention in diseases or disorder, in particular their use in diseases or disorder where there is an advantage in inhibiting kinase enzyme, more particularly IRA 4 enzyme. These derivatives are useful as medicament in treatment of cancer, autoimmune and inflammatory disorders such as multiple sclerosis and rheumatoid arthritis, allergic diseases, autoimmune and inflammatory disorders associated with inflammation and pain such as multiple sclerosis and rheumatoid arthritis, proliferative diseases, hematopoietic disorders, hematological malignancies, bone disorders, fibrosis disorders, metabolic disorders, muscle disorders, respiratory disorders, pulmonary disorders, genetic developmental diseases, neurological and neurodegenerative disorders, chronic inflammatory demyelinating neuropathies, cardiovascular, vascular or heart diseases, ophthalmic/ocular disorders, wound repair, infection and viral diseases.

In one embodiment of the present application, it provides novel bicyclic heterocycle kinase enzyme inhibitor compounds of formula (I):

and it's derivatives, pro-drugs, N-oxides, stereoisomers, solvates, pharmaceutically acceptable salts and biologically active metabolites thereof;

wherein,

X is selected from O, S, and NH;

A is selected from aryl or heteroaryl;

R at each occurrence is independently selected from hydrogen, cyano, halo, hydroxy, -N0_2, -NR³R⁴, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl or optionally substituted heteroaryl; wherein the optional substituent, in each occurrence, is independently selected from halo, alkyl, haloalkyl, cyano, -NR⁵R⁶ or -COOR⁷; R¹ at each occurence is independently selected from hydrogen, halogen, alkyl, aryl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, Y-arylalkyl or -Y-cycloalkyl; wherein cycloalkyl, aryl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and arylalkyi can be optionally substituted with hydroxy, alkyl, haloalkyl, cyano or halo;

Y is selected from direct bond, O, -C(O)- or NR.⁷;

R² at each occurence is independently selected from hydrogen, carboxy, cyano, hydroxy, hydroxyalkyi, alkyl, aryl, heteroaryl, -S0²R⁵ or oxo;

R³ and R⁴ are independently selected from hydrogen, hydroxyalkyi, aminoalkyl, optionally substituted alkyl, optionally substituted heterocyclyl, optionally substituted aryl; wherein the optional substituent, in each occurrence, is independently selected from halo, haloalkyl or -COOR⁷;

R⁵ and R⁶ are independently selected from hydrogen, alkyl, COR⁷ or -COOR⁷;

R⁷at each occurrence is independently selected from hydrogen or alkyl;

m, n and p are selected from 1 , 2 or 3.

According to another embodiment, specifically provided are compounds of the formula (I) wherein X is S.

According to yet another embodiment specifically provided are compounds of the formula (I) wherein X is O.

According to yet another embodiment, specifically provided are compounds of the formula (I) wherein A is heteroaryl for example pyridine.

According to yet another embodiment, specifically provided are compounds of the formula (I) wherein A is aryl for example phenyl.

According to yet another embodiment specifically provided are compounds of the formula (I) wherein R is optionally substituted heteroaryl (for example pyrazole, pyridine, pyrimidine, quinoline, indazole or 7-azaindole).

According to yet another embodiment, specifically provided are compounds of the formula (I) wherein R¹ is hydrogen, alkyl (for example C_)-4 alkyl), heterocycloalkyl (for example piperidine, pyrrolidine or morpholine), heterocycloalkylalkyl (for example pyrrolidin-l -ylmethyl), Y-cycloalkyl (for example Y is a bond, NH or NCH3 and cycloalkyl is cyclopropyl), aryl (for example phenyl) or heteroaryl (for example pyridine). In a particular embodiment, the invention provides compounds of formula (IA):

(IA) wherein, R, R' . R² _, 'm', 'n' and 'p' are as defined in formula (I).

According to yet another embodiment, the invention provides compounds of formula (IB):

(IB) wherein, R, R¹, R² 'm', 'n' and 'p' are as defined in formula (I).

In yet another embodiment according to the present patent application, it provides a pharmaceutical composition comprising the compound of formula (I) of the present invention and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein.

In yet another embodiment according to the present patent application, it provides a pharmaceutical composition comprising at least one compound according to formula (I), (IA) and/or (IB) and/or pharmaceutically usable derivatives, tautomers, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios, eventually one further active ingredient, and excipients.

In a particular embodiment according to the present patent application, it provides inhibitors for IRAK-4, a novel member of the IRAK family of protein kinases.

Modulators, recombinant forms, or fragments of IRAK-4 can be used to interfere with the IL-l/Toll receptor family proinflammatory signaling cascade, and can therefore be useful for the treatment of a large number of inflammatory diseases, including, but not limited to, (a) pulmonary diseases and diseases of the airway, such Adult Respiratory Disease Syndrome (ARDS), Chronic Obstructive Pulmonary Disease (COPD), pulmonary fibrosis, interstitial lung disease, asthma, chronic cough, and allergic rhinitis; b) transplantation; c) the autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and diabetes (e.g., type 1 diabetes mellitus); d) cancer including solid tumors, skin cancer, and lymphoma; e) cardiovascular diseases including stroke and atherosclerosis; f) diseases of the central nervous system including neurodegenerative diseaeses; g) non-CD 14 mediated sepsis; h) osteoarthritis^ i) osteoporosis; j) psoriasis and diseases of the skin such as rash and contact and atopic dermatitis; k) inflammatory bowel disease such as Crohn's disease and ulcerative colitis; 1) Behcet's syndrome; m)ankylosing spondylitis; n) sarcoidosis; o) gout; p) ophthalmic diseases and conditions; and h) CD 14 mediated sepsis.

In preferred embodiments, modulators that inhibit IRAK-4 activity or levels are used to treat any of the above-recited inflammatory diseases. In one embodiment, compounds are screened using high throughput screening (HTS), to identify those compounds that can bind to and/or inhibit the activity of an isolated IRAK-4 fragment thereof. In another embodiment, IRAK-4 proteins are recombinantly expressed in cells, and potential modulators of IRAK-4 are assayed by measuring an indicator of IRAK-4 activity, such as NF-KB activity.

The present invention also provides methods to treat diseases or conditions associated with IL-l/Toll receptor activity, such as inflammatory diseases For example, IRAK-4 activity and/or expression can be altered in cells of a patient with an inflammatory disease including, but not limited to the following : ( a) pulmonary diseases and diseases of the airway including, but not limited to, Adult Respiratory Disease Syndrome (ARDS), Chronic Obstructive Pulmonary Disease (COPD), pulmonary fibrosis, interstitial lung disease, asthma, chronic cough, and allergic rhinitis, b) transplantation, c) the autoimmune diseases including, but not limited to, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and diabetes (e g , type 1 diabetes mellitus), d) cancer including, but not limited to, solid tumors, skin cancer and lymphoma, e) cardiovascular diseases including, but not limited to, stroke and atherosclerosis, f) diseases of the central _' nervous system including, but not limited to, neurodegenerative diseases, g) non-CD 14 mediated sepsis, h) osteoarthritis, I) osteoporosis, j) psoriasis and diseases of the skin including, but not limited to, rash and contact and atopic dermatitis, k) inflammatory bowel disease (including, but not limited to, Crohn's disease and ulcerative colitis), 1) Behcet's syndrome, m)ankylosing spondylitis, n) sarcoidosis, o) gout, p) ophthalmic diseases and conditions, and q) CD14 mediated sepsis In such patients, the inhibition of IRAK-4 in, e g , IL-1 responsive cells will block the transduction of the IL- 1 initiated signal, thereby preventing NF-KB activation and thus providing a treatment for the disorder. The compounds and pharmaceutical compositions of the present invention are used in the treatment and/or prevention of diseases and/or disorders in which aberrant, abnormal or deregulated activity of IRAK, IRAK,, IRAK4_, Abl, ALK, AMPK, Aurora, Axl, Bcr-Abl, BIK, Bmx, BRK, BTK, c-Kit, CSK, cSrc, CDK1 , CHK2, CK1, CK2,CLK2, CaMKII, CaMKIV, DYRK2, EGFR, EphB l, FES, FGFR1 , FGFR2, FGFR3, Fltl, Flt3, FMS, Fyn, GSK3P, IGF-1R, ΙΚΚα, ΙΚΚβ, IR, IRAK4, ITK, JAK2, JAK3, JNKlal, JNK2a, KDR, Lck, Lyn, MAPK1, MAPKAP-K2, MEK1 , MET, MKK4, MKK6, MST2, NEK2, NLK, p70S6K, PAK2, PDGFR, PDGFRa, PDK 1, Pim-2, Plk3, PKA, PKBa, PKCa, PKC9, PKD2, c-Raf, RET, ROCK-I, ROCK-II, Ron, Ros, Rskl, SAPK2a, SAPK2b, SAPK3, SAPK4, SGK, SIK, Syk,TAKl , TBK1 , Tie2, TrkA, TrkB, W K3, and ZAP-70 kinase contributes to the pathology and/or symptomology of such diseases and/or disorders. Such diseases and/or disorders mediated by one or more of these kinases are provided herein.

Diseases and/or disorders associated with aberrant, abnormal or deregulated activity of IRAK, IRAK,, IRAK4_, Abl, ALK, AMPK, Aurora, Axl, Bcr-Abl, BIK, Bmx, BRK, BTK, c-Kit, CSK, cSrc, CDK1 , CHK2, CK1 , CK2,CLK2, CaMKII, CaMKIV, DYRK2, EGFR, EphB l , FES, FGFR1, FGFR2, FGFR3, Fltl , Flt3, FMS, Fyn, GS¾ IGF-1R, ΙΚΚα, ΙΚΚβ, IR, IRAK4, ITK, JAK2, JAK3, JNKl al , JNK2a, KDR, Lck, Lyn, MAPK1, MAPKAP-K2, MEK1 , MET, MKK4, MKK6, MST2, NEK2, NLK, p70S6K, PAK2, PDGFR, PDGFRa, PDK1 , Pim-2, Plk3, PKA, PKBa, PKCa, PKCG, PKD2, c-Raf, RET, ROCK-I, ROCK-II, Ron, Ros, Rskl, SAPK2a,SAPK2b, SAPK3, SAPK4, SGK, SIK, Syk,TAK l ,TBK l, Tie2, TrkA, TrkB, WNK3, and ZAP-70 kinases include, but are not limited to allergic disorders and/or autoimmune and/or inflammatory diseases and/or conditions associated with inflammation and pain, cancers, proliferative diseases, hematopoietic disorders, hematological malignancies, bone disorders, fibrosis diseases and/or disorders, metabolic disorders, muscle diseases and/or disorders respiratory diseases and/or disorders, pulmonary disorders, genetic developmental diseases, neurological and neuro-degenerative diseases/or disorders, chronic inflammatory demyelinating neuropathies, cardiovascular, vascular or heart diseases and/or disorders, ophthalmic/ocular diseases and/or disorders, wound repair, infection and viral diseases. Allergic disorders and/or autoimmune and/or inflammatory diseases and/or conditions associated with inflammation and pain include, but are not limited to, acid reflux, heartburn, acne, allergies and allergen sensitivities, bronchitis, carditis, celiac disease, chronic , pain, cirrhosis, colitis, dementia, dermatitis, diabetes, dry eyes, edema, emphysema, eczema, fibromyalgia, gastroenteritis, gingivitis, heart disease, hepatitis, high blood pressure, insulin resistance, interstitial cystitis, joint pain/arthritis/rheumatoid arthritis, atherosclerosis, sarcoid, spinal cord injury, stroke, chronic inflammatory demyelinating neuropathy, Crohn's disease, metabolic syndrome (syndrome X), myositis, nephritis, osteopenia, congenital metabolic disorder, irritable bowel syndrome, neuropathy with abnormal myelination, drug-induced demyelination, radiation induced demyelination, hereditary demyelinating condition, a prion-induced demyelination, encephalitis-induced demyelination, Sjogren's disease, tissue graft rejection, and hyperacute rejection of transplanted organs, Kaposi's sarcoma associated with HIV, asthma, systemic lupus erythematosus (and associated glomerulonephritis), juvenile cystic kidney disease, and type I nephronophthisis (NPHP), dermatomyositis, multiple sclerosis, scleroderma, vasculitis (ANCA-associated and other vasculitides), autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome (and associated glomerulonephritis and pulmonary hemorrhage), chronic idiopathic thrombocytopenic purpura (ITP), Addison's disease, Parkinson's disease, Guam-Parkinson dementia, supranuclear palsy, Alzheimer's disease, diabetes, septic shock and myasthenia gravis, Kuf s disease, and Pick's disease, as well as memory impairment, brain ischemia, and schizophrenia, periodontal disease, polyarteritis, polychondritis, psoriasis, scleroderma, sinusitis, Sjogren's syndrome, spastic colon, systemic candidiasis, tendonitis, urinary tract infections, vaginitis, inflammatory cancer (e.g., inflammatory breast cancer) and the like.

Pain of neuropathic or inflammatory origin include, but are not limited to, acute pain, chronic pain, neuromuscular pain, dental pain, arthritis pain, cancer-related pain and migraine.

Cancers and proliferative diseases include, but are not limited to breast cancer, colorectal cancer, non-small cell lung cancer, ovarian, renal, sarcoma, melanoma, head & neck, hepatocellular, thyroid, multidrug-resistant leukemia, lymphoma, multiple myeloma, esophageal, large bowel, pancreatic, mesothelioma, carcinoma (e.g. adenocarcinoma, including esophageal adenocarcinoma), sarcoma (e.g. spindle cell sarcoma, liposarcoma, leiomyosarcoma, abdominal leiomyosarcoma, sclerosing epithelioid sarcoma) and melanoma (e.g. metastatic malignant melanoma).

The subject treated in the present methods is a mammal, preferably mice, rat, rabbit, dog, horse, monkey or a human being, male or female, in whom modulation of IRAK, IRAK,, IRAK4_, Abl, ALK, AMPK, Aurora, Axl, Bcr-Abl, BIK, Bmx, BRK, BTK, c-Kit, CSK, cSrc, CDK1 , CHK2, CK1 , CK2,CLK2, CaMKII, CaMKIV, DYRK2, EGFR, EphB l , FES, FGFR1, FGFR2, FGFR3, Fltl , Flt3, FMS, Fyn, GSK3p, IGF-1R, IKKa, ΙΚΚβ, IR, IRAK4, ITK, JAK2, JAK3, JNKl al , JNK2a, KDR, Lck, Lyn, MAPK1, MAPKAP-K2, MEK1 , MET, MKK4, MKK6, MST2, NEK2, NLK, p70S6K, PAK2, PDGFR, PDGFRa, PDK1 , Pim-2, Plk3, PKA, PKBa, PKCa, PKC0, PKD2, c-Raf, RET, ROCK-I, ROCK-II, Ron, Ros, Rskl, SAPK2a, SAPK2b, SAPK3, SAPK4, SGK, SIK, Syk,TAKl, TBK1 , Tie2, TrkA, TrkB, WNK3, and ZAP-70 receptor activity may be desired. "Modulation" as used herein is intended to encompass antagonism, agonism, partial antagonism, inverse agonism and/or partial agonism. The term "therapeutically effective amount" means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in art to which the subject matter herein belongs. As used herein, the following definitions are supplied in order to facilitate the understanding of the present invention.

"Alkyl" or "optionally substituted alkyl" refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms, for example, a group may have from 1 to 12 (inclusive) carbon atoms in it. Examples of Ci-Cealkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl. Examples of CpCsalkyl groups include, but are not limited to, methyl, propyl, pentyl, hexyl, heptyl. An alkyl group which can be unsubstituted or substituted with one or more suitable groups.

"Alkoxy" refers to the group alkyl-O- or -O-alkyl, where alkyl group is as defined above. Exemplary Ci -Cioalkyl group containing alkoxy groups include but are not limited to methoxy, ethoxy, w-propoxy, wo-propoxy, «-butoxy and r-butoxy. An alkoxy group can be unsubstituted or substituted with one or more suitable groups or having linear or branched chain of alkyl chain.

"Amino" refers to an -N- group, the nitrogen atom of said group being attached to a hydrogen, alkyl, cycloaikyl, aryl or any suitable groups. Representative examples of an alkyl amino group include, but are not limited to -NHCH3, -NHCH₂-phenyl, and -NH- cyclopropyl. An amino group can be unsubstituted or substituted with one or more of the suitable groups.

"Aminoalkyl" refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atom has been replaced with an amino group as defined above. Representative examples of an aminoalkyl group include, but are not limited to - CH2NH2, -CH₂CH₂NH₂, -CH(CH₃)NH₂, -CH₂CH(CH₃)NH₂. An aminoalkyl group can be unsubstituted or substituted with one or more suitable groups.

"AryP'or "optionally substituted aryl" refers to an optionally substituted monocytic, bicyclic or polycyclic aromatic hydrocarbon ring system of about 6 to 14 carbon atoms. Aryls can also be fused to nonaromatic rings. Examples of a

group include, but are not limited to, phenyl, -naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, and acenaphthyl. An aryl group can be unsubstituted or substituted with one or more suitable groups.

"Arylalkyl" refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atom has been replaced with an aryl group as defined above. Examples of arylalkyl group include, but are not limited tobenzyl, benzhydryl, 1- phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, · 1 -naphthylmethyl, 2- naphthylmethyl. An arylalkyl group can be unsubstituted or substituted with one or more suitable groups.

"Cyano" refers to -CN group.

"Carboxyl or carboxy -" refers to an -COO- group which can be further substituted with suitable groups.

"Cycloaikyl" or "optionally substituted cycloaikyl" refers to a non-aromatic, saturated or unsaturated, monocyclic, bicyclic or polycyclic hydrocarbon ring system. Representative examples of a cycloaikyl include, but are not limited to, cyclopropyl, cyclopentyl, cycloheptyl, cyclooctyl, decahydronaphthalen- l-yl, octahydro-lH-inden-2-yl and decahydro- lH-benzo[7]annulen-2-yl. A cycloaikyl can be unsubstituted or substituted with one or more suitable groups. Additionally, each of any two hydrogen atoms on the same carbon atom of the carbocyclic ring can be replaced by an oxygen atom to form an oxo (=0) substituent.

"Heterocyclic ring'Or "Heterocyclyl" refers to a monocyclic, bicyclic, or polycyclic aromatic or nonaromatic, saturated or unsaturated ring system containing at least one heteroatom selected from oxygen, sulfur or nitrogen. A heteroocyclic ring can be unsubstituted or substituted with one or more suitable groups.

"Heteroaryl" or "optionally substituted heteroaryl" refers to a 5-15 membered mono-, bi-, or other multi-cyclic, aromatic ring system containing one or more heteroatoms, for example one to four heteroatoms, such as nitrogen, oxygen, or sulfur. Heteroaryls can also be fused to nonaromatic rings. Examples of heteroaryl groups include but are not limited to, furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazble, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N- methylpyrrole, pyrazole, N-methylpyrazole, 1 ,3,4-oxadiazole, 1,2,4-triazole, 1-methyl- 1 ,2,4-triazole, 1 H-tetrazole, 1 -methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline. Bicyclic heteroaryl groups include those where a phenyl, pyridine, pyrimidine or pyridazine ring is fused to a 5 or 6-membered monocyclic heteroaryl ring having one or two nitrogen atoms in the ring, one nitrogen atom together with either one oxygen or one sulfur atom in the ring, or one O or S ring atom. Examples of monocyclic heteroaryl groups include but are not limited to 2H-tetrazole, 3H-1,2,4- triazole, furan, thiophene, oxazole, thiazole, isoxazole, isothiazole, imidazole, and pyrrole. A heteroaryl group can be unsubstituted or substituted with one or more suitable groups.

"Heterocycloalkyl" or "optionally substituted heterocycloalkyl" refers to monocyclic, bicyclic and polycyclic groups in which at least one ring atom is a heteroatom. A Heterocycloalkyl may be saturated or partially saturated. Exemplary heterocycloalkyl groups include but are not limited to aziridine, oxirane, oxirene, thiirane, pyrroline, pyrrolidine, dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, dithiolane, piperidine, 1,2,3,6-tetrahydropyridine-l-yl, tetrahydropyran, pyran, thiane, thiine, piperazine, oxazine, 5,6-dihydro-4H-l,3-oxazin-2-yl, 2,5- diazabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.2]octane, 3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2. l]octane,6-oxa-3,8-diazabicyclo[3.2.1 ]octane, 7-oxa-2,5- diazabicyclo[2.2.2]octane, thiazine, dithiane, and dioxane. A heterocycloalkyl group can be unsubstituted or substituted with one or more suitable groups. "Heterocycloalkylalky Prefers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms have been replaced with a heterocycloalkyi group as defined above. Heterocycloalkylalkyl moieties include but are not limited to pyrrolidin- l -ylmethyl, 2-pyridylmethyl, 1-piperazinylethyl, 4-morpholinylpropyl, and 6- piperazinylhexyl. A heterocycloalkylalkyl group can be unsubstituted or substituted with one or more suitable groups.

"Halogen" or "halo" includes fluorine, chlorine, bromine or iodine.

"Haloalkyl" refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with -F, -CI, -Br, or -I. Examples of an haloalkyl group include, but are not limited to, -CH₂F, -CCI3, -CF₃, -CH₂CF₃, - CH₂CH(Br)CH₃, -CH₂ CH(C1)CH₂CH₃, -CH(F)CH₂CH₃ and -C(CH₃)₂(CH₂C1).

"Heteroatom" refers to a sulfur, nitrogen, or oxygen atom.

"Hydroxylalkyl-"or "Hydroxyalkyl" refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms have been replaced with hydroxyl groups. Examples of hydroxylalkyl moieties include but are not limited to - CH₂OH, -CH₂CH₂OH, -CH₂CH₂CH₂OH, -CH₂CH(OH)CH₂OH, -CH₂CH(OH) CH₃, - CH(CH₃)CH₂OH.

"Hydroxy" refers to -OH group.

"Nitro" refers to -N0₂ group.

"Oxo" refers to =0 group.

"Thio" refers to =S group.

"Optionally substituted" as used herein means that at least one hydrogen atom of the optionally substituted group has been substituted with suitable substitutions as exemplified but not limited to halogen, hydroxy, cyano, nitro, oxo, thio,carbonyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyi, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring. "Comprise" or "comprising" is generally used in the sense of include, that is to say permitting the presence of one or more features or components.

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

The term "prodrug derivatives" or "prodrug" is taken to mean compounds of the formula (I) which have been modified with, for example, alkyl or acyl groups, sugars or oligopeptides and which are rapidly cleaved in the organism to form the active compounds. These also include biodegradable polymer derivatives of the compounds according to the invention, as described, for example, in Int. J. Pharm. 1 15, 61 -67 (1995).

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

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

As used herein the terms "subject" or "patient" are well-recognized in the art, and, are used interchangeably herein to refer to a mammal, including dog, cat, rat, mouse, monkey, cow, horse, goat, sheep, pig, camel, and, most preferably, a human. In some embodiments, the subject is a subject in need of treatment or a subject with a disease or disorder. However, in other embodiments, the subject can be a normal subject. The term does not denote a particular age or sex. Thus, adult and newborn subjects, whether male or female, are intended to be covered. . As used herein the term "therapeutically effective amount," refers to a sufficient amount of a compound or a composition being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs,, symptoms, or causes of a disease, or any other desired alteration of a biological system.

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

The term "stereoisomers" refers to any enantiorhers, diastereoisomers, or geometrical isomers of the compounds of Formula (I), (IA) and/or (IB), wherever they are chiral or when they bear one or more double bond. When the compounds of the formula (I), (IA) and/or (IB) and related formulae are chiral, they can exist in racemic or in optically active form. Since the pharmaceutical activity of the racemates or stereoisomers of the compounds according to the invention may differ, it may be desirable to use the enantiomers. In these cases, the end product or even the intermediates can be separated into enantiomeric compounds by chemical or physical measures known to the person skilled in the art or even employed as such in the synthesis. In the case of racemic amines, diastereomers are formed from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (for example N-benzoylproline or N- benzenesulfonylproline), or the various optically active camphorsulfonic acids. Also advantageous is chromatographic enantiomer resolution with the aid of an optically active resolving agent (for example dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chirally derivatised methacrylate polymers immobilised on silica gel).

Pharmaceutical formulations can be adopted for administration via any desired suitable method, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods. Such formulations can be prepared using all processes known in the pharmaceutical art by, for example, combining the active ingredient with the excipient(s) or adjuvant(s). Pharmaceutical formulations adopted for oral administration can be administered as separate units, such as, for example, capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or oil-in-water liquid emulsions or water-in-oil liquid emulsions. For example, in the case of oral administration as tablet or capsule, the active-ingredient component can be combined with an oral, non-toxic and pharmaceutically acceptable inert excipient, such as, for example, ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a pharmaceutical excipient comminuted in a similar manner, such as, for example, an edible carbohydrate, such as, for example, starch or mannitol. A flavour, preservative, dispersant and dye may likewise be present.

Capsules are produced by preparing a powder mixture as described above and filling shaped gelatine shells therewith. Glidants and lubricants, such as, for example, highly disperse silicic acid, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form can be added to the powder mixture before the filling operation. A disintegrant or solubiliser, such as, for example, agar-agar, calcium carbonate or sodium carbonate, may likewise be added in order to improve the availability of the medicament after the capsule has been taken.

In addition, if desired or necessary, suitable binders, lubricants and disintegrants as well as dyes can likewise be incorporated into the mixture. Suitable binders include starch, gelatine, natural sugars, such as, for example, glucose or beta-lactose, sweeteners made from maize, natural and synthetic rubber, such as, for example, acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. The lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. The disintegrants include, without being restricted thereto, starch, methylcellulose, agar, bentonite, xanthan gum and the like. The tablets are formulated by, for example, preparing a powder mixture, granulating or dry-pressing the mixture, adding a lubricant and a disintegrant and pressing the entire mixture to give tablets. A powder mixture is prepared by mixing the compound comminuted in a suitable manner with a diluent or a base, as described above, and optionally with a binder, such as, for example, carboxymethylcellulose, an alginate, gelatine or polyvinyl-pyrrolidone, a dissolution retardant, such as, for example, paraffin, an absorption accelerator, such as, for example, a quaternary salt, and/or an absorbant, such as, for example, bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting it with a binder, such as, for example, syrup, starch paste, acadia mucilage or solutions of cellulose or polymer materials and pressing it through a sieve. As an alternative to granulation, the powder mixture can be run through a tableting machine, giving lumps of non-uniform shape which are broken up to form granules. The granules can be lubricated by addition of stearic acid, a stearate salt, talc or mineral oil in order to prevent sticking to the tablet casting moulds. The lubricated mixture is then pressed to give tablets. The active ingredients can also be combined with a free-flowing inert excipient and then pressed directly to give tablets without carrying out the granulation or dry-pressing steps. A transparent or opaque protective layer consisting of a shellac sealing layer, a layer of sugar or polymer material and a gloss layer of wax may be present. Dyes can be added to these coatings in order to be able to differentiate between different dosage units.

Oral liquids, such as, for example, solution, syrups and elixirs, can be prepared in the form of dosage units so that a given quantity comprises a pre-specified amount of the compounds. Syrups can be prepared by dissolving the compounds in an aqueous solution with a suitable flavour, while elixirs are prepared using a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersion of the compounds in a non-toxic vehicle. Solubilisers and emulsifiers, such as, for example, ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavour additives, such as, for example, peppermint oil or natural sweeteners or saccharin, or other artificial sweeteners and the like, can likewise be added.

The dosage unit formulations for oral administration can, if desired, be encapsulated in microcapsules. The formulation can also be prepared in such a way that the release is extended or retarded, such as, for example, by coating or embedding of particulate material in polymers, wax and the like.

New morpholine substituted derivatives of formula (I), (IA) and/or (IB) and salts, solvates and physiologically functional derivatives thereof and the other active ingredients can also be administered in the form of liposome delivery systems, such as, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from suitable lipids or phospholipids or both, such as, for example, cholesterol, stearylamine or phosphatidylcholines or the like. Pharmaceutical compounds adapted for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

Pharmaceutical formulations adapted for topical application in the mouth encompass lozenges, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can be administered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in which the carrier substance is a solid comprise a coarse powder having a particle size, for example, in the range 20-500 microns, which is administered in the manner in which snuff is taken, i.e. by rapid inhalation via the nasal passages from a container containing the powder held close to the nose. Suitable formulations for administration as nasal spray or nose drops with a liquid as carrier substance encompass active-ingredient solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalation encompass finely particulate dusts or mists, which can be generated by various types of pressurised dispensers with aerosols, nebulisers or insufflators.

Pharmaceutical formulations adapted for vaginal administration can be administered as pessaries, tampons, creams, gels, pastes, foams or spray formulations. Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions comprising antioxidants, buffers, bacteriostatics and solutes, by means of which the formulation is rendered isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions, which may comprise suspension media and thickeners. The formulations can be administered in single-dose or multidose containers, for example sealed ampoules and vials, and stored in freeze-dried (lyophilised) state, so that only the addition of the sterile carrier liquid, for example . water for injection purposes, immediately before use is necessary.

Injection solutions and suspensions prepared in accordance with the recipe can be prepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularly mentioned constituents, the formulations may also comprise other agents usual in the art with respect to the particular type of formulation; thus, for example, formulations which are suitable for oral administration may comprise flavours.

A therapeutically effective amount of a compound of the formula (I), (IA) and (IB) and of the other active ingredient depends on a number of factors, including, for example, the age and weight of the animal, the precise disease condition which requires treatment, and its severity, the nature of the formulation and the method of administration, and is ultimately determined by the treating doctor or vet. However, an effective amount of a . compound is generally in the range from 0.1 to 100 mg/kg of body weight of the recipient (mammal) per day and particularly typically in the range from 1 to 10 mg/kg of body weight per day. Thus, the actual amount per day for an-adult mammal weighing 70 kg is usually between 70 and 700 mg, where this amount can be administered as an individual dose per day or usually in a series of part-doses (such as, for example, two, three, four, five or six) per day, so that the total daily dose is the same. An effective amount of a salt or solvate or of a physiologically functional derivative thereof can be determined as the fraction of the effective amount of the compound per se.

In an embodiment, specific compounds of formula (I) without any limitation are enumerated as follows:

Table-I: Bicyclic heterocycle kinase enzyme inhibitor compounds of the present invention.

22. N-(7-isobutyl-2-moφholinobenzo[d]oxazol-6-yl)-[2,4'-bipyridine]-6- Comp.

IUPAC NAME

No

carboxamide;

23. N-(7-isobutyl-2-moφholinobenzo[d]oxazol-6-yl)-6-(l H-pyrrolo[2,3-b]pyridin- 5-yl)picolinamide;

24 -(2-moφholino-4-phenylbenzo[d]oxazol-6-yl)-6-(l H-pyrroloi2,3-b]pyridίn- 5-yl)picolinamide;

25 6'-amino-N-(2-mo holino-4-phenylbenzo[d]oxazol-6-yl)-[2,3^,-bipyrid^ne]-6- earboxamide;

26 N-(2-moφhoIino-4-(pyridin-4-yI)benzo[d]oxazol-6-yl)-[2,4'-bipyridine]-6- carboxamide;

27 6'-amino-N-(2-moφholino-4-(pyridin-4-yl)benzo[d]oxazol-6-yl)-[2,3'- bipyridine]-6-carboxamide;

28 N-(2, -dimoφholinobenzo[d]thiazol-6-yl)-6-(lH-pyrrolo[2,3-b]pyridin-5- y picolinamide;

29 6'-amino-N-(5-cyclopropyl-2-moφholinobenzo[d]thiazol-6-yl)-[2,3'- bipyridine]-6-carboxamide;

30 N-(5-cyclopropyl-2-mo holinobenzo[d]thiazol-6-yl)-6-(l H-pyrazol-5- y picolinamide;

31 N-(5-(cyclopropyl(methyl)amino)-2-moφholinobenzo[d]thiazol-6-yl)-6-(l H- pyrazol-5-yl)picolinamide;

32 6'-amino-N-(5-isobutyl-2-moφholinobenzo[d]thiazol-6-yl)-[2,3'-bipyridine]-6- carboxamide;

33 6'-amino-N-(2-moφholino-5-(pyrrolidin-l-ylmethyl)benzo[d]thiazol-6-yl)- [2,3'-bipyridine]-6-carboxamide;

34. tert-butyl (l-(6-((2-moφholinobenzo[d]oxazol-6-yl)c rbamoyl)pyridin-2- yl)pyrrolidin-3-yl)carbamate;

35. 6-(3-aminopyrrolidin- l-yl)-N-(2-moφholinobenzo[d]oxazol-6- y picolinamide;

36. 2'-fluoro-N-(2-mo holinobenzo[d]oxazol-6-yl)-[2,4'-bipyridine]-6- carboxamide;

37. N-(2-mo holinobenzo[d]oxazoI-6-yl)-[2,3'-bίpyridine]-6-carboxamide;

38. N-(2-moφholinobenzo[d]oxazol-6-yl)-6-(pyrimidin-5-yl)picolinamide; Comp.

IUPAC NAME

No

39. N-(2-mo holinobenzo[d]o azol-6-yl)-[2,4^l-bipyridine]-6-carboxamide;

4G. 6-(2-aminopyrimidίn-5-yl)-N-(2-mo holinobenzotd]oxazol-6-yl)

picolinamide;

41. 6'-amino-N-(2-moφholinobenzo[d]oxazol-6-yl)-[2,3'-bipyridine]-6- carboxamide;

42. 6'-acetamido-N-(2-moφholinobenzo[d]oxazol-6-yl)-[2,3'-bi yridine]-6- carboxamide;

43. 6-(l H-indazol-5-yl)-N-(2-moφholinobenzo[d]oxazol-6-yl)picolinamide;

^' 44. N-(2-moφholinobenzo[d]oxazol-6-yl)-6-(quinolin-6-yl)picolinamide;

45. N-(2-moφholinobenzo[d]oxazol-6-yl)-6-(lH-pyrrolo[2₎3-b]pyridin-5- y picolinamide;

46. N-(2-moφholinobenzo[d]oxazol-6-yl)-6-(l H-pyrazoI-5-yl)picolinamide;

47. N-(5-chloro-2-moφholinobenzo[d]oxazol-6-yl)-6-(lH-pyrrolo[2,3-b]pyridin- 5-yl)picolinamide;

48. 6'-amino-N-(2-moφholino-lH-benzo[d]imidazol-6-yl)-[2,3'-bipyridine]-6- carboxamide;

49. 6'-amino-N-(2-moφholinobenzo[d]thiazol-6-yl)-[2,3'-bipyridine]-6- carboxamide;

50. tert-butyl 4-((6-((2-moφholinobenzo[d]o azol-6-yl)carbamoyl)pyridin-2-yl) amino)piperidine- l-carboxylate;

51. tert-butyl 3-((6-((2-moφholinobenzo[d]oxazol-6-yl)carbamoyl)pyridίn-2-yl) amino)pyrrolidine-l -carboxylate;

^■ 52. N-(2-moφholinobenzo[d]oxazol-6-yl)-6-((3-(trifluoromethyl)phenyl)

amino)picolinamide;

53. 6-((2-aminoethyl)amino)-N-(2-moφholinobenzo[d]oxazol-6-yl)picolinamide;

54. 6-((2-hydroxyethyl)amino)-N-(2-moφholinobenzo[d]o azol-6- yl)picolinamide;

55. 6-((2-aminoethyl)arnino)-N-(2-rrlOφholinobenzo[d]thiazol-6-yl)picolinarnide;

56. 6-((2-hydroxyethyl)amino)-N-(2-moφholinobenzo[d]thiazol-6- yl)picolinamide;

57. N-(2-moφholinobenzo[d]oxazol-6-yl)-3-nitrobenzamide; and Comp.

IUPAC NAME

No

58. N-(2-(2,6-dimethylrno holino)benzo[cl]oxazol-6-yl)-[2,4'-bipyridine]-6- carboxamide. or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention relates to a process for preparing bicyclic heterocycle kinase enzyme inhibitor compounds of formula (I), (IA) and (IB).

An embodiment of the present invention provides the IRAK4 inhibitors as bicyclic heterocycle kinase enzyme inhibitor compounds according to of formula (I), (IA) and/or (IB) may be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimisation procedures. Moreover, by Utilizing the procedures described in detail, one of ordinary skill in the art can prepare additional compounds of the present invention claimed herein. All temperatures are in degrees Celsius (°C) unless otherwise noted.

In a further aspect, the compounds of the present invention can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the present invention also embraces isotopically-labeled variants of the present invention which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in_, nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses. Exemplary isotopes that can be incorporated in to compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as ²H ("D"), ³H, ⁿC, ^,3C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵0, ¹⁷0, ¹⁸0, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶C1, ^,231 and ^{l 25}I. Isotopically labeled compounds of the present inventions can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non- isotopically labeled reagent.

The following abbreviations refer respectively to the definitions below:

Ar (Argon); ACN (acetonitrile); brine (NaCl solution); Xanthophos (4,5- Bis(diphenyl phosphino)-9,9-dimethylxanthene); bs (broad singlet); J (coupling constant); CS2CO3 (cesium carbonate); °C (degree Celsius); DMF (dimethyl formamide) ;DME (dimethoxy ethane); DIPEA/DIEA (N, N- Diisopropyl ethyl amine); CH₂C1₂/DCM (dichloromethane); DMAP (dimethyl amino pyridine);CDC (deuteriated chloroform); d (doublet); dd (doublet of doublet); EDC.HCI (l-(3-Dimethyl aminopropyl)-3-carbodiimide hydrochloride); EtOH (ethanol); Et₂0 (diethyl ether); g (gram); H (hydrogen); HOBt (1- Hydroxy benzotriazole); HC1 (hydrochloric acid); h (hours); mrnol (millimole); M (molar); ml (milli litre); mg (milli gram); m (multiplet); MHz (mega hertz); MS (ES) (mass spectroscopy -electro spray); min (minutes); N₂ (nitrogen); NMR (nuclear magnetic resonance spectroscopy); K₂C0₃ (potassium carbonate); Pd₂ (dba)₃ (tris dibenzylidene acetone) dipalladium; Pd(OAc)₂(Palladiumdiacetate); Na₂S04 (Sodium sulphate); s (singlet); TLC (Thin Layer Chromatography); THF (tetrahydrofuran); TFA (trifluoro acetic acid); t (triplet); H₂0 (water); t-BuOK (potassium tert-butoxide) ;t-BuONa or NaOtBu (sodium tert-butoxide); H₂SC>4 (sulphuric acid); CS₂(Carbon disulfide);KOH(Potassium hydroxide); H 0₃(Nitric acid); R.T(Room temperature: 20-35°C); K₃P0₄(Tripotassium- phosphate); Na₂C0₃(Sodium carbonate) ; NaHC0₃(Sodium bicarbonate); KF(Potassium fluoride); Pd(Pph₃)₄(Tetrakis(triphenylphosphine)palladium(0)); Pd(dppf)Cl₂ ([1, 1 '- Bis(diphenylphosphino) ferrocene] dichloropalladium(II) complex with dichloromethane) ; (Cy)₃P(TricycIohexylphosphine); Conc.(Concentrated); DMSO(Dimethyl sulfoxide); nM(nanomolar); ppm-8(parts per million); Hz(Hertz); MeOH(methanol); KH₂P0₄ (potassium dihydrogen phosphate); μM(micro molar); LC/MS(Liquid chromatography- mass spectrometry); m/z(molecular weight); NMP (N-Methylpyrrolidone); X.phos(2- Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl); Fe(iron); HPLC(High-performance liquid chromatography); ES-MS(Electrospray Ionisation Mass Spectrometry).

Another embodiment of the present invention provides methods useful for making the compounds of Formula (I) are set forth in the Examples below and generalized in Schemes 1 -6. One of skill in the art will recognize that Schemes 1 -6 can be adapted to produce the compounds of Formula (I) and pharmaceutically accepted salts of compounds of Formula (I) according to the present invention. Wherein all symbols/variables are as defined earlier unless otherwise stated. The process is represented by Schemes 1 -6.

Scheme-1

Compound-57

As shown in the scheme 1 , the novel compounds of the present invention (formula 1.5) can be synthesized from benzoxazole or benzothiazole 1.1 which has a halogen (F, CI, Br) and nitro substituents.

The compound 1.1 can undergo coupling reaction with the heterocycles to provide 1.2, which can be Pd-catalyzed or Cu-catalysed or neat reaction. The coupling reaction can be carried out in a suitable solvent such as non-polar solvents such as 1, 4-dioxane, toluene and the like or polar solvents such as THF and the like. The suitable reagents for Buchwald-Hartwig coupling reaction or base catalysed reactions can be carried out in a suitable base such as t-BuONa, K^CC^_, CS2CO3 and the like, catalysts such as Pd(OAc) 2, Pd₂ (dba)3_ BINAP,CuI and the like and precatalysts such as xantophos, Ru-Phos, and the like at a temperature of about 80-150° C for about 12-48 h in conventional method or under microwave heating for about 15 min to lh.

The nitro group of compound 1.2 can be reduced to amino group of compound 1.3 by using suitable reducing agents such as palladium carbon, platinum(IV) oxide, Raney nickel, Iron in acidic media, zinc dust in ammonium media and the like at a temperature of about 25-100°C for about l -3h or 12-48h.

The coupling of the amine compound 1.3 to an acid can be carried out by a conventional amide bond formation method such as using a suitable coupling reagent. Some non-limiting examples of suitable coupling reagents include benzotriazole- containing coupling reagents such as N-hydroxybenzotriazole, benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate and 2-(lH-benzotriazol-l-yl)- 1, 1 ,3,3-tetramethyluronium hexafluorophosphate; an 'azabenzotriazole-containing reagent such as 0-(7-Azabenzotriazole-l-yl)-N,N,N',N'-tetramethyluroniumhexafluorophosphate; and dicarboimides such as l-Ethyl-3-(3-dimemylarmnopropyl)-carbodiimide, and dicyclohexyl carbodimide. The coupling reaction can be carried out in a suitable organic solvent. Some suitable organic solvent include aprotic solvent. Some suitable organic solvent include polar aprotic organic solvent such as DMF, THF, DMSO or methylene chloride and the like. To afford the amide compound 1.4 the coupling reaction can be carried out in the presence of suitable bases such as tertiary amines (e.g., TEA, DIPEA and/or DMAP) and the like at a temperature of about 20-35 °C for about 12-24h. The reaction progress can be monitored at 20-35°C by conventional methods such as TLC or NMR.

C-C bond formation of compound 1.4 can be carried out by suitable boronate esters or boronic acids, organotin compounds, alkenes, alkynes and the like, coupling reagents such as catalysts Pd (dppf) Cl₂, Pd (PPh₃)₄, (Cy)₃P, Pd(OAC)₂, Cu(OAC)₂, Pd(dba)₂, Cul and the like, bases Na₂C0₃, Cs₂C0_3, K₃P0₄, F, NaOBu', CsF, LiCl, NaOAc and the like, by using the solvents such as non-polar solvents such as 1, 4-dioxane, toluene and the like or polar solvents such as DMF, acetonitrile, water and the like at ambient temperature or at an elevated temperature like 80-150°C for about 3-42 h to provide the compound 1.5(a) by using the suitable deprotecting agents such as TFA, diethylether-HCl and the like.

For compound 1.5(b) the compound 1.4 can undergo condensation with alicyclic amine derivatives at a temperature of about 80- 150°C in sealed tube or conventional heating for about 12-48 h or under microwave heating for 15 min to 1 h.

Scheme-2

As shown in the scheme 2, a compound 2.5 can be synthesized from benzoxazole or benzothiazole 2-1 which has a halogen and a nitro substituents.

The compound 2.1 can undergo Pd-catalyzed C-C bond formation reaction with the R¹ as specified in scheme-2 to provide 2.2. Conversion of compound 2.2 to compound 2.5 (reduction, amide formation, C-C bond formation and deprotection) can be carried out by the similar methods described in scheme 1.

Scheme-3

As shown in the scheme 3, a compound 3.3 can be synthesized from benzoxazole or benzothiazole 3.1 with R¹ is piperidine.

Compound 3.1 undergo dehydrohalogenation in the presence of bases like sodium bicarbonate, sodium carbonate, potassium carbonate and the like in suitable organic solvents such as polar organic solvent such as methanol at a temperature of about 20-35°C for about 3- 6 h, to provide carbamate compound 3.2.

Microwave irradiation assisted removal of phenoxide ion from compound 3.2 followed by reacting with A-Br yield the compound 3.3 in the presence of base DMAP and the like and solvent such as THF-Toluene (1 : 1), ACN - Toluene(l : l ) and the like at a temperature of about 150- 200°C for about 10-20 minutes. Scheme-4

^•As shown in the scheme 4, compound 4.5 can be synthesized from benzoxazole or benzothiazole 4.1.

Alkylation of Compound 4.1 can be carried out under suitable Grignard conditions using Grignard reagent, THF, Κ ηΟ¼, acetone: water (1 : 1) and the like at a temperature of about 0°C to ambient temperature for about 5 minutes to 1 hour.

Conversion of compound 4.2 to compound 4.5 (reduction, amide formation and Suzuki coupling) can be carried out by the similar methods described in scheme 1.

Scheme-5

As shown in the scheme 5, a compound 5.6 can be synthesized from 5.1 (benzo[d]thiazole-2(3H)-thione) bromo derivative.

Compound 5.1 on nitration with mixture of Conc.r^SC and Conc.HN0₃ provides 5.2, which on condensation with morpholine at a temperature of about 80-100°C in sealed tube for about 2-17 h gives 5.3. Conversion of compound 5.3 to compound 5.6 (reduction, amide formation and C- C bond formation) can be carried out by the similar methods described in scheme 1.

-6

0₂Ν^_γΝΗ_{2 cs} O^^^K Brominatior i O_j ^ S

As shown in the scheme 6, the key intermediate 6-c can be synthesized from ' substituted o-phenylenediamine 6-a.

The compound 6-a and carbon disulphide in presence of base like KOH in single step at a temperature of about 75-90°C for about 5-18 h provide compound 6-b, which is brominated by using Br₂ and acetic acid-HBr at temperature about 0-30°C for about 2-4 h, to provide compound 6-c.

The other key intermediate 6-f can be synthesized from 2-aminobenzenethiol 6-d. The compound 6-d and carbon disulphide in presence of base like KOH in single step at a temperature of about 75-90°C for about 5- 18h provide compound 6-e, which undergo nitration using suitable nitrating reagents such as HN0₃:H₂S0₄ at a temperature about 0- 30°C for about 2-4 h, to provide compound 6-f.

Condensation of compound 6-c and 6-f with morpholine can be carried out by similar method described in the scheme 5, yielding compound 6.1.

Conversion of compound 6.1 to compound 6.4 (reduction, amide formation, C-C bond formation and deprotection) can be carried out by the similar methods described in scheme 1. EXAMPLES

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

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

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

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

Ή-NMR: Varian 400 MHz.

The microwave chemistry was performed on a CEM Explorer.

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

Intermediate 1 : 5-chloro-2-morpholino-6-nitrobenzo[d]oxazole.

(i) CS₂, OH,Ethanol, 70-80°C, 17h; (ii)Morpholine, 90-100°C, 2h;

Step-1 : 5-chloro-6-nitrobenzo[d]oxazole-2-thiol.

To a solution of 2-amino-4-chloro-5-nitrophenol (2g, 10.781 mmol) in ethanol (30 ml), was added potassium hydroxide (0.75g, 12.938 mmol) followed Carbon disulfide (20ml). The reaction mixture was stirred at 70-80°C for 17h. The progress of the reaction was monitored by TLC and then it was cooled to 20-30°C, after concentrating the mixture under reduced pressure, it was extracted with water (30 ml) and dichloromethane (2x30 ml). The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude product(2.3g,92%). Ή NMR (400 MHz, DMSO-£/₆): δ (ppm)7.88 (s, 1H), 7.24(s, 1H). MS (ES) m/e 231 (M+H) ⁺.

Step-2: 5-οη1θΓθ-2^οφηο1ίηο-6-ηίίπΛ6ηζο|^]οχ3ζοΐ6.

5-chloro-6-nitrobenzo[d]oxazole-2-thiol (Step 1, 2.3 g) was taken in a sealed tube, to this morpholine (23 mL) was added. The reaction mixture was stirred at 90-100°C for 2h. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to 20- 30°C, poured slowly into the crushed ice and the solid formed was filtered off and dried under vacuum. The crude compound was purified by column chromatography using 100- 200 mesh silica gelusing and 33% hexane /ethyl acetate as an eluent to get the desired compound as yellow color solid (800 mg, 28%). Ή NMR (400MHz, DIVISOR) δ 8.28 (s, 1 H), 7.59 (s, 1H), 3.75-3.73 (m, 4H), 3.68-3.66 (m, 4H). MS (ES) m/e 284 (M+H)⁺

Step land 2: The process of these steps may be adopted from step 1 and 2 of intermediate 1.

Step-3: 5-fluoro-2-mo hoIino-6-nitrobenzo[d]oxazoIe.

To a solution of 5-fluoro-2-morpholinobenzo[d]oxazole (0.8g, 4.0mmol) in H₂S0₄(5ml), was added a mixture of H₂S0₄: HN0₃ (1 : 1 ; 2ml) at 0°C. The reaction mixture was stirred at 20-30°C for 5h. The progress of the reaction was monitored by TLC. After the reaction was completed, it was poured slowly into the crushed ice and the solid formed was filtered off and dried under vacuum to get the crude compound as yellow colour solid (700 mg, 73%). Ή NMR (400 MHz, DMSO-i/₆): δ (ppm) 8.26 (d, J = 2.2 Hz, 1H), 7.43 (d, J = 2.2 Hz, 1H), 3.75-3.73 (m, 4H), 3.70-3.67 (m, 4H).

Intermediate3: 4-(5-bromo-6-nitrobenzo[d]thiazol-2-yl)morpholine.

Step-1 : 5-bromobenzo[d]thiazole-2-thiol.

To a solution of 2,5-dibromoaniline (5g, 21.0mmol) in NMP (30 ml), was added potassium O-ethyl carbonodithioate (6.81 g, 42.0 mmol) .The reaction mixture was stirred at 120^°C for 8-14h. The progress of the reaction was monitored by TLC. After the reaction was completed, it was cooled to 20-30°C, then neutralized with acetic acid and the solid formed was filtered and dried under vacuum to get the crude compound as solid (4.5 g, 95%). Ή NMR (400 MHz, DMSO-c/₆): δ (ppm) 7.66 (d, J = 8.3 Hz, 1Η),7.47-7.45 (m, 1 H), 7.41

(s, 1 H). MS (ES) m/e 244 (M⁺-2, 100%).

Step-2; 4-(5-bromobenzo[d]thiazol-2-yl) morpholine.

The compound was prepared from 5-bromobenzo[d]thiazole-2-thiol (step-1) by following the same process described for step-2 of Intermediate 1. Ή NMR (400MHz, DMSO-cfe) δ 7.55 (d, J = 8.3 Hz, 1H), 7.62 (d, J = 1.5 Hz, 1 H), 7.25-7.22 (m, 1 H), 3.74-3.71 (m, 4H), 3.57-3.55 (m, 4H). MS (ES) m/e 299 (M+, 100%).

Step-3: 4-(5-bromo-6-nitrobenzo[d]thiazol-2-yl) morpholine.

The compound was prepared from 4-(5-bromobenzo[d]thiazol-2-yl) morpholine (step-2) by following the same process described for step-3 of Intermediate 2. MS (ES) m/z 344 (M+, 100%).

Intermediate 4; 2-morpholino-6-nitrobenzo[d]oxazole.

17h;

Step land2: The process of these steps may be adopted from step 1 and 2 of intermediate-

Intermediate 5: 4-bromo-2-morphoIinobenzo[d]oxazol-6-amine.

(i)

(iii) Fe powder, Conc.HCl, Ethanol, H₂0, 70-80°C, 3K.

Stepland 2: The process of these steps may be adopted from step 1 and 2 of intermediate-

Step-3: To a solution of 4-bromo-2-rnorpholino-6-nitrobenzo[d]oxazole (0.3g, 0.9 mmol, step-1) in ethanol (5 ml), was added iron powder (0.9g) , 2-3 drops of Conc.Hcl and H₂0 (0.5ml).The reaction mixture was stirred at 70-80 C for 3h. The progress of the reaction was monitored by TLC. The reaction was cooled to 20-30°C, filtered through celite with ethyl acetate washings. The filtrate was dried under vacuum to get the crude (0.25g, 95%). MS (ES) m/e 299(M+, 70%).

Intermediate 6: potassium trifluoro (isobutyl) borate.

To a solution of potassium hydrogen fluoride (6g, 78.4mmol) in ¾0 (30 ml), was added isobutyl boronic acid (2.0g, 19.6 mmol) in methanol at I O C. The reaction mixture was stirred at IO C for 2h. The progress of the reaction was monitored by TLC. After the reaction was completed, solvents were evaporated under vaccum. The residue dissolved in acetone and filtered off. The filtrate was concentrated under vaccum to crude required product (2.4g, 95%).

Intermediate 7: (pyrrolidin-l-ylmethyl) boronic acid.

(i) pyTOlidine,2-(bromomethyl)-4,4,5,5-tetramethyl-l ,3,2-dioxaborolane, Triethyl amine, THF, 0°C-30°C, 2h; 5N NaOH, 10min, 20°C-30°C

To a solution of 2-(bromomethyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (6g, 78.4mmol) in THF (30 ml), was added triethylamine (2.0 g, 19.6 mmol) followed by the addition of pyrrolidine at 0 C.The reaction mixture was stirred at 20-30°C for 2h. The progress of the reaction was monitored by TLC. After the reaction was completed, 5N sodium hydroxide solution was added and stirred for 10 minutes. Solvents were evaporated under vaccum to get crude required product (2.4g, 95%). MS (ES) m/e 130 (M⁺).

Compound-1: Synthesis of N-(2-morphoIino-5-(piperidin-l-yi)benzo[d]oxazol-6-yl)-6- (lH-pyrazol-5-yl)picoIinamide.

Stepl :2-morpholino-6-nitro-5-(piperidin- 1 -vO benzo[d]oxazole.

1,4-dioxane (5 ml) was added to a mixture of 5-chloro-2-morpholino-6- nitrobenzo[d]oxazole (0.5 g, 1.76mmol, Intermediate 1) , piperidine (0.44 g, 5.2 mmol), Xanthophos (0.1 g, 0.17 mmol), Pd(OAC)₂ (0.019 g, 0.008 mmol) and K₂C0₃ (0.486 g, 0.3.52 mmol) in a sealed tube. The above mixture was degassed with Argon and heated to 100-120°C. The mixture was stirred at the same temperature for 50h. The reaction mass was cooled to room temperature; water (10 ml) was added and extracted the aqueous layer with ethyl acetate (2 x 30 ml). The organic layer was washed with brine, dried over sodium sulfate and evaporated the solvent under vacuum to get the desired crude product which was purified by column chromatography using 230-400 mesh silica gel and 50% ethyl acetate in petroleum ether as eluent to get the pure product as a yellow gum (0.3 gram, 45%). MS (ES) m/e 333 (M+l, 100%).

To a solution of 2-morpholino-6-nitro-5-(piperidin-l -yl)benzo[d]oxazole (0.3g, 0.9 mmol, step-1 ) in ethanol (5 ml), was added iron powder (0.9g) ,2-3 drops of Conc.Hcl and H₂0 (0.5ml).The reaction mixture was stirred at 70-80 C for 3h. The progress of the reaction was monitored by TLC. After the reaction was completed, it was cooled to room temperature, then filtered through celite and washed with ethyl acetate. The filtrate was dried under vacuum to get the crude (0.25g, 95%). MS (ES) m/e 302 (M+ l , 70%).

Step 3:6-bromo-N-(2-morpholino-5-(piperidin-l-yl) benzo[d]oxazol-6-yl) picolinamide.

To a solution of 2-ηιο ΐΊθ1ίηο-5-(ρίρ6Γί(ϋη-1

(0.25g, 0.83 mmol, step-2) in DMF (7 ml), was added 6-bromopicolinic acid (0.2 g, 1.03 mmol), EDC- HC1 (0.208g, 1.08mmol), HOBT (0. 1 12g, 0.8 mmol), DMAP (lOmg) .The reaction mixture was stirred at room temperature for 24-48h. The progress of the reaction was monitored by TLC. After the reaction was completed, it was poured slowly into the crushed ice and the solid formed was filtered and dried under vacuum to get the crude compound as yellow colour solid (30mg, 7.5%). MS (ES) m/e 486 (M+ l , 100%).

Step4;N-(^"2-morpholino-5-(piperidin-l -vl)benzordloxazol-6-vl)-6-(lH-pvrazol-5-vl) picolinamide.

20-30°C, 2h.

1,4-dioxane (5 ml) was added to a mixture of 6-bromo-N-(2-morphoIino-5- (piperidin-l-yl)benzo[d]oxazol-6-yl)picolinamide (0.07 g, 0.14 mmol ,step-3) , 1 - (tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.12 g,0.43 mmol), Pd(dppf)Cl₂ (0.005 g, 0.007 mmol), Cs₂C0₃ (0.093 g, 0.28 mmol) and H₂0 (0. 1 ml) in a sealed tube. The above mixture was degassed with Argon and heated to 100-120°C. The mixture was stirred at the same temperature for 3h. The reaction mass was cooled to 20-30°C; water (10 ml) was added and the extracted the aqueous layer with ethyl acetate (2 x 30 ml). The organic layer was washed with brine, dried over sodium sulfate and evaporated the solvent under vacuum to get the desired crude product which was which was purified by column chromatography using 100-200 mesh silica gel and 2% MeOH in DCM as eluent to get the pure product. It was further treated with diethylether- HCl (3 ml) for 2h. The progress of the reaction was monitored by TLC. The reaction mass was neutralized with aqueousNaHCC solution. DCM layer was separated and concentrated under reduced pressure to get yellow solid as a pure product (0.015mg,21 %). Ή NMR (400MHz, DMSO-< ) δ 13.21 (bs, I H), 1 1.1 (s, IH), 8.59 (s, IH), 8.22-8.12 (m, 3H), 7.96 (s, IH), 7.29 (s, I H), 7.12 (s, IH), 3.74-3.57 (m, 8H), 2.89 (m, 4H), 1.79-1.50 (m, 6H). MS (ES) m/z 474 (M+l , 100%).

Compound-2: Synthesis of N-(2-morpholino-5-phenyIbenzo[d]oxazol-6-yl)-6-(lH- pyrrolo[2,3-b]pyridin-5-yI)picoIinamide.

Stepl :2-morpholino-6-nitro-5-phenylbenzordloxazole.

(i) phenylboronic acid, K₃P0₄, Pd₂(dba)₃, X-Phos, toluene, DMF, 100-120°C, 24h;

Toluene (5 ml) was added to a Intermediate 1, phenylboronic acid (0.15 g, 1.26 mmol), Pd₂(dba)₃ (0.048 g, 0.05 mmol), X-phos (0.05 g, 0.105 mmol), K₃P0₄ (0.56 g, 2.64 mmol) and DMF(0.5 ml) in a sealed tube. The above mixture was degassed with Argon and heated to 100- 120°C. The mixture was stirred at the same temperature for 24h.The reaction mass was cooled to 20-30°C; water (10 ml) was added and extracted the aqueous layer with ethyl acetate (2 x 30 ml). The organic layer was washed with brine, dried over sodium sulfate and evaporated the solvent under vacuum to get the desired crude product which was which was purified by column chromatography using 100-200 mesh silica gel and 30% ethyl acetate in hexane as eluent to get the pure product(0.28 g, 82%). MS (ES) m/e 324 (M- l , 100%).

Step2:N-(2-morpholino-5-phenvlbenzord1oxazol-6-vl)-6-(lH-pvrrolor2,3-blpyridin-5- y picolinamide.

(i) Fe powder, Conc.HCl, ethanol, H₂0, 70-80°C, 2h;

(ii) 6-bromopicolinic acid ,EDC-HC1, HOBT, DMF, 20-30°C, 24h;

(iii) 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrrolo[2,3-b]pyridine, Cs₂C0₃, Pd(dppf)Cl₂,

1,4-dioxane, H₂0, 100- 120°C, 2h.

Step (i, ii and iii): The process of these steps are adopted from step 2 to step 4 of compound- 1.

Ή NMR (400MHz, DMSO-<¾ δ 10.36 (bs. lH), 9.09 (s, lH), 8.79 (s, 1H), 8.60 (s, 1H), 8.23 (d, J = 6.8 Ηζ, ΙΗ), 8.02-7.87 (m, 3H), 7.53-7.38 (m, 7H), 6.63 (d, J = 2.0 Ηζ, ΙΗ), 3.86-3.72 (m, 8H). MS (ES) m/e 517 (M+l , 100%).

Compound-3: Synthesis of 6'-amino-N-(2-morpholino-5-phenyIbenzo[d]oxazol-6-yl)- [2,3'-bipyridine]-6-carboxamide.

Stepl :6'-((4-methoxvbenzvl)amino)-N-(2-morpholino-5-phenylbenzoidloxazol-6-vl)-r2.3'-

Acetonitrile(l ml) was added to a mixture of 6-bromo-N-(2-morpholino-5- phenylbenzo[d]oxazol-6-yl)picolinamide (0.09g, step-2(ii) of compound-2), N-(4-methoxy benzyl)-5-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl)pyridin-2-amine,(0.128g,0.37 mmol), Pd (dppf)Cl₂ (O.O l Sg, 0.0018mmol), Na₂CO₃(0.039g, 0.37 mmol) and H₂0 (0.2 ml) in a sealed tube. The above mixture was degassed with Argon and heated to 100- 120°C. The mixture was stirred at the same temperature for 2h.The reaction mass was cooled to 20-30°C; water (10 ml) was added and extracted the aqueous layer with ethyl acetate (2 x 30 ml). The organic layer was washed with brine, dried over sodium sulfate and evaporated the solvent under vacuum to get the desired crude product which was purified by column chromatography using 100-200 mesh silica gel and 2% MeOH in DCM as eluent. DCM fraetion was concentrated under reduced pressure to get the desired product (0.04g, 35%).

Ή NMR (400MHz, DMSO-rf₆) δ 10.29 (bs, 1H), 8.83 (s, 1H), 8.45 (s, 1 H), 8.12 (s, lH),7.85-7.83 (m, lH), 7.73-7.71 (m, 1 H), 7.48-7.26 (m, 7H), 6.95-6.93 (m, 2H), 6.33-6.31 (m, 1H), 5.13 (bs, 1H), 4.56-4.54 (m, 4H), 3.84-3.82 (m, 4H), 3.73-3.72(m, 7H). MS (ES) m/e 613 (M+l , 100%). .

SteE2:6'-amino-N-(2-morpholino-5-phenylbenzo[d]oxazol-6-yl)-[2,3'-bipyridine]-6- carboxamide.

TFA (3ml) was added to 6'-((4-methoxybenzyl) amino)-N-(2-morpholino-5- phenylbenzo[d]oxazol-6-yl)-[2,3'-bipyridine]-6-carboxamide (0.04 g,0.06mmol, step-1 ), then heatedthe reaction mixture at 60-70°C for 17h. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mass was cooled to 30°C and concentrated the mixture under reduced pressure, it was extracted with aqueous solution of NaHCC>3 (5 ml) and dichloromethane (2x5 ml). The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude which was purified by column chromatography using 100-200 mesh silica gel and 5% MeOH in DCM as eluent to get the pure product (0.0 lg, 31 %). Ή NMR (400MHz, CDC1₃) δ 10.27 (bs, 1 H), 8.18 (s, 1H), 8.40 (s, l H), 8.15 (d, J = 7.2 Hz, 1H), 7.87 (t, J = 7.6 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1 H), 7.53-7.42 (m, 5H), 7.40 (d, J = 2.1 Hz, 1 H), 6.48 (d, J = 2.1 Hz, 1 H), 4.80 (bs, 2H), 3.86-3.71(m, 8H).MS (ES) m/e 493(M+ 1 , 100%).

Compound-4; Synthesis of N-(2-morpholino-5-(piperidin-l-yl)benzo[d]oxazol-6-yl)-6- (lH-pyrazol-4-yl)picoIinamide.

Stepl:N-(2-morpholino-5-(piperidin-l -vl)benzofdloxazol-6-yl)-6-(lH-pyrazol-4- yl)picolinamide.

(i)4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole, Cs₂C0₃ ,Pd(dppf)Cl₂ 1.4-dioxane. H,0. 100-120°C. 2h.

N-(2-morpholino-5-(piperidin-l -yl) benzo[d]oxazol-6-yl)-6-(l H-pyrazol-4-yl)picolinamide (0.0 lg, 21%) was prepared from 6-bromo-N-(2-mo holino-5-(piperidin-l-yl)benzo [d] oxazol-6-yl)picolinamide (0.04g, step-3 of compound- 1 ) by following the same process used in step-4 of compound- 1.

Ή NMR (400MHz, DMSO-cfe) δ 1 1.13 (bs, 1 H), 8.67 (s, 1 H), 8.28 (bs, 1H), 8.18 (d, J = 7.6 Hz, 2H),7.90 (t, J = 7.8 Hz, 1 H),7.66 (d, J = 7.9 Hz, 1H), 7.26 (s, 1H), 7.25 (s, 1H) , 3.84-3.67 (m, 8H), 2.86 (bs, 4H), 1.82-1.79 (m, 6H). MS (ES) m/e 474(M+1, 100%).

Compound-5: Synthesis of N-(2-morpholino-5-(pyrroIidin-l-yl)benzo[d]oxazol-6-yl)- 6-(lH-pyrrolo[2,3-b]pyridin-5-yl)picoIinamide.

Stepl:2-morpholino-6-nitro-5-(pvrrolidin-l -vl) benzo[d]oxazo!e.

|(i) pyrrolidine, K₂CQ₃, Pd(OAC)₂, xanthphos, 1 ,4-dioxane, 100-120°C, 2h. |

2-morpholino-6-nitro-5-(pyrrolidin- l-yl)benzo[d]oxazole(0.45g,76%>) was prepared from 5-fluoro-2-morpholino-6-nitrobenzo[d]oxazole(0.5g,Intermediate-2) by following the same process used in step-1 of compound-1.

Ή-NMR (400MHz, OMSO-d₆): 57.87 (s, 1H), 6.85 (s, 1H), 3.73-3.71 (m, 4H), 3.66-3.62 (m, 4H), 3.31 (bs, 4H), 1.90 (bs, 4H).

Step2:N-(2-morpholino-5-(pyrrolidin-l -yl)benzo[d1oxazol-6-yl)-6-(lH-pyrrolor2,3-b1 pyridin-5-yl)picolinamide.

Step (i, ii and iii):The process of these steps are adopted from step 2 to step 4 of compound- 1.

Ή NMR(400 MHz, DMSO-i/₆) δ 1 1.96 (bs, 1H), 1 1.25 (s, 1H), 9.15 (d, J = 1.9 Hz, lH), 8.75 (d, J = 2.0 Hz, 1 H), 8.60 (s, 1 H), 8.34-8.32 (m, 1H), 8.18-8.13 (m, 2H), 7.59-7.57 (m, 1 H), 7.38 (s, 1 H), 6.57-6.56 (m, 1H), 3.74-3.72 (m, 4H), 3.66-3.57 (m, 4H), 3.15-3.10 (m,4H), 2.18-2.14 (m, 4H). MS (ES) m/e 510(M+ 1 , 100%).

Compound-6: Synthesis of 6'-amino-N-(5-(cyclopropyIamino)-2-morpholinobenzo [d]oxazoI-6-yl)-[2,3'-bipyridine]-6-carboxamide.

Step_l^N-cyclopropyl-2-morpholino-6-nitrobenzo[d]oxazol-5-amine.

N-cyclopropyl-2-moφholino-6-nitrobenzo[d]oxazol-5-amine(0.7g,70%) was prepared from 5-fluoro-2-mo holino-6-nitrobenzo[d]oxazole(lg,Intermediate-2) by treating with cyciopropanamine in sealed tube at 100^°C for 8-14h. The progress of the reaction was monitored by TLC. After the reaction was completed, it was extracted with water (15ml) and dichioromethane (2x 15ml). The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude. MS (ES) m/e 305(M+1, 50%).

Steg2:6-bromo-N-(5-(cyclopropylamino)-2-morpholinobenzo[d]oxazol-6-yl)

picolinamide.

Step Π and ii):The process of these steps are adopted from step 2 and step 3 of compound- 1.

Step3:6'-amino-N-(5-(cvclopropvlamino)-2-morpholinobenzord]oxazol-6-yl)-r2,3'- bipyridine]-6-carboxamide.

(i) N-(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyridin

Na₂C0₃, Pd(dppf)Cl₂, ACN, H₂0, 80-100°C, 8-14h; TFA, 60-70°C, 8-14h.

6'-amino-N-(5-(cyclopropylamino)-2-mo holinobenzo[d]oxazol-6-yl)-[2,3'-bipyridine]-6- carboxamide (0.03g,61%) was prepared from 6-bromo-N-(5-(cyclopropyIamino)-2- moφholinobenzo[d]o azoI-6-yl)picolinamide(0.07g, step-3) by following the same process used in step-1 and 2 of compound-3.

Ή NMR (400 MHz, DMSO-< ):6 1 1.63 (s, IH), 8.90 (s, IH), 8.61 (s, IH), 8.55 (s, IH), 8.37- 8.03 (m, 2H), 7.39 (s, IH), 6.80-6.62 (s, IH), 3.80-3.59 (m, 15H), 2.88-2.64 (m, 2H). MS (ESI): 472 (M+l , 60%).

Compound-7:Synthesis of 6^,-amino-N-(5-(4-hydroxypiperidin-l-yl)-2-morpholino benzo[d]oxazoI-6-yl)-[2,3'-bipyridine]-6-carboxamide.

Stepl: l -(2-morpholino-6-nitrobenzord1oxazol-5-yl) piperidin-4-ol.

l-(2-mo holino-6-nitrobenzo[d]oxazol-5-yl)piperidin-4-ol.(0;7g, 60%>) was prepared from 5-ί1υοΓθ-2-πιθ ηο1ίηο-6-ηίΐΗ^6ηζο[^]οχ3Ζοΐ6 (l g,Intermediate-2) by treating with piperidin-4-ol and toluene as solvent in sealed tube at 100-120 C for overnight. The progress of the reaction was monitored by TLC. After the reaction was completed, it was extracted with water (15ml) and dichloromethane (2x 15ml). The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude.MS (ESI): 349 (M+l , 100%).

Stej22:6'-amino-N-(5-(4-hydroxypiperidin-l -yl)-2-morpholinobenzo[d]oxazol-6-yl)-[2,3'- bipyridine]-6-carboxamide.

Step (i and ii); The process of these steps are adopted from step 2 and 3 of compound-1.

Step (iii): The compound-7(0.035g, 51%) was prepared from6-bromo-N-(5-(4- hydroxypiperidin- l -yl)-2-mo holinobenzo[d]oxazol-6-yl)picolinamide by following the same process used in step- 1 and 2 of compound-3.

Ή NMR (400 MHz, DMSC s):5 1 1.15 (s, 1 H), 8.90 (s, 1 H), 8.62 (s, 1H), 8.32 (s, 1H), 8.04 (m, 4H), 6.99-7.32 (m, 2H) 4.81 -4.71 (m, 1H), 3.40-3.33 (m, 8H), 3.0-2.90 (m, 2H), 2.70-2.60 (m, 2H), 2.0-1.8 (m, 4H). MS (ES): 516 (M+l, 100%).

Compound-8: Synthesis of 6'-amino-N-(5-(3-hydroxypyrroIidin-l-yl)-2-morpholino benzo[d]oxazol-6-yl)-[2,3'-bipyridine]-6-carboxamide.

Stepl :6'-amino-N-(5-(3-hydroxvpyrrolidin- 1 -vl)-2-morpholinobenzordloxazol-6-yl)-r2,3'- bipyridine]-6-carboxamide.

The compound(0.025g, 35%) was prepared from 5-fluoro-2-morpholino-6- nitrobenzo[d]oxazole (lg,Intermediate-2) by following the same process as given below.

Step (i): Step 1 of compound 7.

Step (ii and iii): Step 2 and step 3 of compound 1.

Step (iv): Step 1 and step 2 of compound 3.

'H NMR (400 MHZ, DMSO-rf₆):5 1 1.03 (s, 1 H), 8.81 (s, 1H), 8.51 (s, 1H), 8.21 (d, J = 7.3 Hz, 1H), 8.1 1 -7.99 (m, 3H), 7.33 (s, 1H), 6.61 -6.59 (m, IH), 6.44 (s, 1H) , 5.01-5.00 (m, 1H), 4.45 (s, 1 H), 3.73-3.71 (m, 4H), 3.58-3.42 (m, 4H), 3.38-3.12 (m, 4H), 3.81-2.84 (m, 1 H), 2.20-2.08 (m, 1 H), 1.90-1.89 (m, 1 H). MS (ESI): 502 (M+ l , 90%).

Compound-9: Synthesis of 6'-amino-N-(5-(benzyloxy)-2-morpholinobenzo[d]oxazol-6- yI)-[2,3'-bipyridine]-6-carboxamide.

Stepl :5-(benzvloxv)-2-morpholino-6-nitrobenzo[dloxazole.

To a solution of 5-fluoro-2-mo holino-6-nitrobe zo[d]oxazole (lg,3.0mmol, Intermediate-2) in THF (15 ml), was added phenylmethanol (0.8 g,4.5mmol) and K.2CO3(1.5g,9.0mmol).The reaction mixture was heated to 60-70°C for 36h. The progress of the reaction was monitored by TLC. After the reaction, was completed, it was extracted with water (15ml) and ethylactate (2 15ml). The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude (0.7g).MS (ESI): 355 (M+l , 90%).

Step2:6'-amino-N-(5-(benzvloxv)-2-morpholinobenzord1oxazol-6-vl)-r2,3'-bipvridine1-6- carboxamide.

The Compound (0.034g, 51%) was prepared from 5-(benzyloxy)-2-morpholino-6- nitrobenzo[d]oxazole (step- 1 ) by following the same process as given below.

Step (i and ii): Step 2 and step 3 of compound 1.

Step (iii): Step 1 and step 2 of compound 3.

Ή NMR (400 MHz, DMSO-i¾):6 10.33 (s, 1H), 8.84 (s, 1H), 8.33-8.24 (m, 1H), 8.19- 8.09 (m, 1 H), 8.17-8.15 (m, 1 H), 7.91 (s, 1H), 7.75 (s, 1H), 7.47-7.38 (m, 5H), 6.88-6.79 (m, l H), 6.60-6.46(bs,2H), 5.16 (s, 2H), 3.57-3.54 (m, 4H), 3.48-3.33 (m, 4H). MS (ESI): 523 (M+l , 90%).

Compound-10: Synthesis of N-(5-(4-hydroxypiperidin-l-yI)-2-morpholinobenzo

[d]oxazol-6-yl)-6-(lH-pyrazol-5-yl) picolinamide.

Stepl:6-bromo-N-(5-(4-hydroxypiperidin-l -yl)-2-morpholinobenzo[d1oxazol-6-yl) picolinamide.

Step (i); The process of this stepis adopted from step 1 of compound 7.

Step (ii and iii): The process of these steps are adopted from step 2 and step 3 of compound 1.

Step2: N-(5-(4-hydroxypiperidin-l -yl)-2-morpholinobenzo[d]oxazol-6-yl)-6-(lH-pyrazol- 5-yl)picolinamide.

(i) 1 -(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-

1 H- pyrazole, Cs₂C0₃, Pd(dppf)CI₂, 1,4-dioxane, H₂0, 100-120°C, 3h; Diethylether- HC1, 20°C-30°C, 10-15 min.

The compound (0.05g, 52%) was prepared from 6-bromo-N-(5-(4-hydroxypiperidin-l -yl)- 2-mo holinobenzo[d]oxazol-6-yI)picolinamide (O. lg, step-1) by following the same process used in step-4 of compound- 1.

Ή NMR (400 MHz, OMSO- ₆):8 1 1.04 (s, 1 H), 8.56 (s, 1H), 8.22 (s, 1H), 8.20-8.18 (m, 2H), 8.12-8.10 (m, 1 H), 7.30 (s, 1H), 7.12-7.1 1 (m, 1H), 3.73-3.71 (m, 4H), 3.59-3.57 (m, 4H), 2.99-2.97 (m, 2H), 2.75-2.67 (m, 2H), 1.94-1.93 (m, 2H), 1.74-1.72 (m, 2H).MS (ESI): 490 (M+l , 100%).

Com ound-11 : Synthesis of N-(5-(3-hydroxypyrroIidin-l-yl)-2-morpholinobenzo

[d]oxazol-6-yl)-6-(lH-pyrazol-5-yl) picolinamide.

Stepl :6-bromo-N-(5-(3-hvdroxypyrrolidin-l -yl)-2-morpholinobenzo[d1oxazol-6-yl) picolinamide.

Step (i); The process of this step are adopted from step 1 of compound 7.

Step (ii and iii): The process of these steps are adopted from step 2 and step 3 of compound 1. MS (ESI): 488 (M+l , 100%).

Ste 2:N-(5-(^"3-hvdroxvpvrrolidin-l -vl)-2-mo holinobenzoΓd1o azol-6-vl^')-6-(ΊH-pvra2ol -5-yl) picolinamide.

(i) I-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyI-l ,3,2-dioxaborolan-2-yl)-l H-pyrazole,

Cs₂C0₃,Pd(dppf)CI_2>l ,4-dioxane, H₂0, 100-120°C, 3h; Diethylether-HCl, 0°C-35°C, 10-15min.

N-(5-(3-hydroxypyrrolidin-l-yI)-2-morpholinobenzo[d]oxazol-6-yl)-6-(lH-pyrazol-5-yl) picolinamide (0.03g,41%) was prepared from 6-bromo-N-(5-(3-hydroxypyrrolidin-l -yl)-2- mo holinobenzo[d] oxazoI-6-yf)picolinamide(0.1g, step-1) by following the same process used in step-4 of compound- 1.

Ή NMR (400 MHz, DMSO-i/₆):5 13.20-13.30 (bs, IH), 10.92 (s, IH), 8.18-8.07 (m, 3H), 7.84 (s, IH), 7.61 (s, IH), 7.23 (s, IH), 7.07 (s, IH), 5.05 (s, IH), 4.43 (s, IH), 3.73-3.71 (m, 4H), 3.59-3.58 (m, 4H), 3.10 (m, I H), 2.99-2.91 (m, IH), 2.67 (s, IH), 2.50 (s, IH), 2.33 (s, IH), 1.86-1.58 (m, IH). MS (ESI): 476 (M+l, 90%).

Compound-12: Synthesis of N-(5-(benzyIoxy)-2-morpholinobenzo[d]oxazoI-6-yl)-6- (lH-pyrazol-5-yl) picolinamide. Stepl :N-(5-(benzvloxv)-2-morpholinobenzoidloxazol-6-yl)-6-bromopicolinamicle.

Step (i): The process of this step are adopted from step 1 of compound 9.

Step (ii and iii): The process of these steps are adopted from step 2 and step 3 of compound 1. MS (ESI): 509 (M+l , 90%).

Step2: N^'- 5-(benzvloxv)-2-mo holinobenzoΓd^oxazol-6-vΠ-6-(lH-pyrazol-5-yl^') picolinamide.

(i)

l H-pyrazole,Cs2CO3,Pd(dppf)Cl₂, l ,4-dioxane,H2O, 100-120^oC,3h; Diethylether- HC1, 0°C-30°C, 10-15min.

N-(5-(benzyloxy)-2-morpholinobenzo[d]oxazol-6-yl)-6-(l H-pyrazol-5-yl)picolinamide (0.045g, 53%) was prepared from N-(5-(benzyloxy)-2-morpholinobenzo[d]oxazol-6-yl)-6- bromo picolinamide (O. l g, step-1 ) by following the same process used in step-4 of compound- 1.

Ή NMR (400 MHz, DMSO-<¾): δ 13.20 (bs, 1H), 10.64 (s, 1H), 8.55 (s, 1H), 8.16-8.04 (m, 3H), 7.64-7.56 (m, 3H), 7.40-7.34 (m, 4H), 6.27 (s, 1H), 5.26 (s, 2H), 3.74-3.72 (m, 4H), 3.60-3.57 (m, 4H). MS (ESI): 497 (M+l , 90%).

Compound-13: Synthesis of 6'-amino-N-(2-morpholino-5-(piperidin-l-yl) benzo[d] thiazol-6-yl)-[2,3'-bipyridine]-6-carboxamide.

Stepl :4-(6-nitro-5-(piperidin-l -yl)benzofdlthiazol-2- yl)morpholine.

(i) piperidine, sealed tube,100°C,2h

4-(6-nitro-5-(piperidin-l -yl)benzo[d]thiazol-2-yl)mo holine (0.2g, 83%) was prepared from 4-(5-bromo-6-nitrobenzo[d]thiazol-2-yl)morpholine(Intermediate-3, 0.25 g),it was treated with piperidine in sealedtube atl OO°C for 2h. After the reaction was completed, it was poured slowly into the crushed ice and the solid formed was filtered and dried under vacuum to get the crude compound.

Ή NMR (400 MHz, DMSO-efe): δ 8.45 (s, 1H), 7.18 (s, 1H), 3.74-3.72 (m, 4H), 3.62-3.60 (m, 4H),2.94-2.91 (m, 4H)1.63-1.61 (m, 4H), 1.49- 1.45 (m, 2H). MS (ESI): 349 (M+l , 90%).

Step2:6'-amino-N-(2-morpholino-5-(piperidin-l-yl)benzordlthiazol-6-vl)- 2,3'-bipvridine1 -6-carboxamide.

e'-amino-N^-morpholino-S-ipiperidin-l-y benzotdJthiazol-e-y -p^'-bipyridineJ-e- carboxamide (0.02g,40%) was prepared from 4-(6-nitro-5-(piperidin-l -yl)benzo[d] thiazol-2-yl) mo holίne (O. lg, step-1) by following the same process as given below.

Step (i and ii): Step 2 and step 3 of compound 1.

Step (iii): Step 1 and step 2 of compound 3. Ή NMR (400 MHz, DMSO-d₆):5 8.89-8.87 (m, 2H), 8.36-8.33 (m, 1H), 8.12-8.05 (m, 3H),7.43 (s, 1H), 6.60-6.58 (m, 1H), 6.48 (s, 2H), 3.74-3.66 (m, 4H), 3.54-3.53 (m, 4H), 2.84-2.82 (m, 4H), 1.75 (m, 4H), 1.75-1.72 (m, 2H). MS (ESI): 516 (M+1 , 100%).

Compound-14: Synthesis of N-(2-morpholino-5-(piperidin-l-yl)benzo[d]thiazol-6-yI)- 6-(lH-pyrazol-5-yI) picolinamide. , ^{' '} -bromo-N-(2-morpholino-5-(piperidin-l -yl) benzo[d]thiazol-6-yl)picolinamide

Step (i): The process of this step is adopted from Step-1 of compound 13.

Step (ii and iii); The process of these steps are adopted from step 2 & 3 respectively of compound- 1.

Ή NMR (400 MHz, DMSO-<4):5 1 1.04 (s, 1 H), 8.82 (s, 1H), 8.19 (d, J = 7.3 Ηζ, ΙΗ), 8.05 (t, J = 6.8 Hz, 1 H), 7.95 (d, J = 7.3 Hz, 1H), 7.42 (s, 1 H), 3.74-3.72 (m, 4H), 3.53-3:51 (m, 4H), 2.89-2.73 (m, 4H), 1.87-1.86 (m, 4H), 1.62-1.58 (m, 2H). MS (ESI): 502 (M+1, 90%).

Step2:N-(2-morpholino-5-(piperidin-l -yl)benzord1thiazol-6-vl)-6-(lH-pvrazol-5-vl) picolinamide.

(i) l-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)

-l H-pyrazole,Cs₂C0₃, Pd(dppf)Cl₂, 1,4-dioxane, H₂0, 100-120°C, 3h;

Diethylether-HCl, 0°C-30°C, 10-15 min.

N-(2-mo holino-5-(piperidin-l-yl)benzo[d]thiazol-6-yl)-6-(lH-pyrazol-5-yl) picolinamide(0.005g,35%) was prepared from 6-bromo-N-(2-mo holino-5-(piperidin-l- yl)benzo[d]thiazol-6-yl)picolinamide (0.05g) obtained from step-1 by following the same process used in step-4 of compound- 1.

Ή NMR (400 MHz, DMSO-fl¾):6 1 1.02 (bs, 1H), 8.95 (s, 1H), 8.25-8.22 (m, lH), 8.00- 7.98 (m, 2H), 7.72 (s, 1H), 7.46 (s, 1H), 7.06 (s, 1H), 3.86-3.83 (m, 4H), 3.63-3.61 (m, 4H), 2.91-2.82 (m, 4H), 1.86-1.84 (m, 4H), 1.25-1.22 (m, 2H). MS (ESI): 490 (M+1, 100%).

Compound-15: Synthesis of 6'-amino-N-(2-morpholino-5-(piperidin-l-yl)benzo[d] oxazol-6- l)-[2,3'-bipyridine]-6-carboxamide.

(i) N-(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl)pyridin

Na₂C0₃, Pd(dppf)Cl₂, ACN, H₂0, 80- 100°C, 8-14h; TFA, 60-70°C, 8-14h.

The compound (0.01g,25%) was prepared from 6-bromo-N-(2-mo holino-5-(piperidin-l- yl)benzo[d]oxazol-6-yl)picolinamide(0.05g,step-3 of compound-1) by following the same process used in step 1 and step 2 of compound 3.

Ή NMR (400 MHz, CDC1₃):5 1 1.30 (s, 1 H), 8.80 (d, J = 2.5 Hz, 1H), 8.72 (s, 1H), 8.43- 8.40 (dd, J l=8.3Hz, J2=2.4Hz, 1H), 8.22(d, J = 7.3 Hz, 1 H), 7.94 (t, J = 7.8 Hz, 1H), 7.83- 7.81 (m, 1H), 6.62 (d, J = 8.8 Hz, lH), 4.73 (bs, 2H), 3.84-3.67 (m, 8H), 2.85 (bs, 4H), 1.77-1.76 (m, 6H). MS (ESI): 500 (M+ 1, 100%).

Compound-16: Synthesis of 6'-amino-N-(5-(2-hydroxyphenyI)-2-morphoIino benzo[d]oxazol-6-yl)-[2,3'-bipyridine]-6-carboxamide.

Stepl;2-(2-morpholino-6-nitrobenzordloxazol-5-yl) phenol.

(i) (2-hydroxyphenyl)boronic acid,K-OtBu,Pd(PPh₃)₄

DME, H₂0, microwave, 90°C, 30min To a solution of 5-chloro-2-mo holino-6-nitrobenzo[d]oxazole (0.25g, 8.81 mmol, Intermediate- 1) in DME (1.5ml), was added (2-hydroxyphenyl)boronic acid (0.145 g, 10.58mmol),potassium t-butoxide (0.19g, 1.76mmol) , Pd(Pph₃)₄(0.05g, 0.04mmol) and 0.3ml of water. The reaction mixture was stirred at 90 C for 30min. The progress of the reaction was monitored by TLC. After the reaction was completed, it was extracted with water (15ml) and ethyl acetate (2x 15ml). The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude which was purified by column chromatography using 100-200 mesh silica gel and 25% ethyl acetate in hexane as eluent to get the pure product (0.16g, 26%). MS (ESI): 342 (M+1 , 80%).

Step2: 6'-amino-N-(5-(2-hydroxyphenyl)-2-moφholinobenzo[d]oxazol-6-yl)-[2,3'-bi

5-yl)phenol (0.16g, step- 1 ) by following the same process as given below.

Step (i and ii); Step 2 and step 3 of compound 1.

Step (iii): Step 1 and step 2 of compound 3.

Ή NMR (400 MHz, DMSO-i/₆): δ 10.22 (s, 1H), 8.65 (s, 1 H), 8.48 (d, J = 1.9 Hz, 1H), 8.1 l (d, J = 7.3Hz, 1 H), 7.83(t, J = 7.8 Hz, 1 H), 7.67 (d, J = 7.3 Hz, 1H), 7.58(d, J = 2.5 Ηζ, Ι Η), 7.38-7.36 (m, 1H), 7.24-7.21 (m, 2H),7.1 1 (d, J = 7.8 Hz, 1H), 7.03 (t, J = 7.2 Hz, 1 H) , 6.52 (d, J = 8.8 Ηζ, Ι Η), 4.73 (bs, 2H), 3.82-3.65(m, 9H) . MS (ESI): 509 (M+l, 100%). Compound-17: Synthesis of N-(5-cycIopropyl-2-morpholinobenzo[d]oxazol-6-yl)-6 (lH-pyrazol-5-yl) picolinamide.

Stepl: 5-cyclopropyl-2-mo hoIino-6-nitrobenzo[d]oxazole

(i) CycIopropylboronic acid, K₃P0₄, KF, (Cy)₃P, Pd(OAC)₂, Toluene, H₂0, 100- 120°C, 24h;

To a solution of 5-chloro-2-morpholino-6-nitrobenzo[d]oxazole (0.6 g, 1.82 mmol,Intermediate-l ) in toluene(l Oml), was added cyclopropylboronic acid (0.47g,5.47mmol), K3PO4 (0.77g,3.64mmol), (Cy₃)P (0.51 g, 0.18 mmol), Pd(OAC)₂ (0.020 g, 0.09 mmol), KF (0.21 g, 0.364 mmol), and 1ml of water. The reaction mixture was stirred . at 100-120^°C for 24h. The progress of the reaction was monitored by TLC. After the reaction was completed, it was extracted with water (15ml) and ethyl acetate (2x 15ml). The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude, which was which was purified by column chromatography using 100-200 mesh silica gel and 25% ethyl acetate in hexane as eluent to get the pure product(0.15g, 28%).MS (ESI): 290 (M+ 1 , 80%).

Step_2:N-(5-cyclopropyl-2-morpholinobenzo[d]oxazol-6-yl)-6-(l H-pyrazol-5-yl) picolinamide.

The compound (0.08 g, 40%) was prepared from 5-cyclopropyl-2-morpholinobenzo[d] oxazol-6-amine (step-1) by following the same process used in step 2, 3 and 4 of compound- 1. Ή NMR (400 MHz, CDC1₃):5 10.77 (s, 1H), 8.57 (s, 1 H), 8.27(d, J = 7.3 Hz, 1H), 8.10- 7.96 (m, 2H), 7.71 (d, J = 2 Hz, 1H), 7.25 (s, 2H), 6.95 (d, J = 1.5 Hz, 1 H), 3.84-3.64 (m, 8H), 3.50-3.45 (m, 1H), 2.08-2.01 (m, 2H), 1.39- 1.20 (m, 2H) . MS (ESI): 431 (M+l, 100%).

Compound-18: Synthesis of 5-bromo-N-(2-morpholino-5-(piperidin-l-yl) benzo

[d]oxazol-6-yl)-lH-pyrrolo[2,3-b]pyridine-l-carboxamide.

Stepl:phenyl (2-mo holino-5-(piperidin-l -yl) benzo[d]oxazol-6-yl) carbamate.

J (i) Phenyl carbonochloridate, NaHCQ₃, Methanol, H₂Q ,20-30°C, 3h [

To a solution of 2-moφholino-5-(piperidin-l -yl)benzo[d]oxazol-6-amine (1.65g, 5.46mmol, step-2 of compound- 1) in methanol-H₂0 (1 : 1 ,30 ml), was added NaHC0₃(1.37g, 16.38mmol). The reaction mixture was stirred for 30min at 20-30°C. To this phenyl carbonochloridate (0.854 g, 5.46mmol) was added. The reaction mixture was stirred at same temperature for another 3h. The progress of the reaction was monitored by TLC. After the reaction was completed, it was poured into crushed ice, and then solid formed was filtered and dried under vacuum to get the pure product (2g, 86%). Ή NMR (400 MHz,

δ 9.3 (bs, 1 H), 7.60-7.2(m,4H), 7.0-6.8 (m, 3H), 3.7-3.69 (m, 4H), 3.4-3.39 (m, 4H), 2.7-2.69 (m, 4H), 1.6-1.58 (m, 4H), 1.60-1.58 (m, 2H). MS (ESI): 423 (M+l , 100%).

Step2;5-bromo-N-(2-morpholino-5-(piperidin-l -yl)benzofd1oxazol-6-vl)-lH-pyrrolof2.3- b]pyridine-l -carboxamide.

200°C, microwave, 10 min. To a solution of phenyl (2-mo holino-5-(piperidin-l-yl)benzo[d]oxazol-6-yl)carbamate (0.05g,0.12mmol, step- 1 ) in THF-Toluene (1 : 1, 2 ml), was added 5-bromo-lH- pyrrolo[2,3-b]pyridine (0.47g, 0.24 mmol) and DMAP (0.03g, 0.24 mmol), stirred the reaction mixture for lOmin at 200 C under microwave irradiation. The progress of the reaction was monitored by TLC. After the reaction was completed, it was extracted with water ( 15ml) and ethyl acetate (2x l 5ml). The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude, which was which was purified by column chromatography using 100-200 mesh silica gel and 25% ethyl acetate in hexane as eluent to get the pure product (0.02g, 33%).

Ή NMR (400 MHz, CDCl₃):512.20(s, lH), 8.48 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.16 (d, J = 3.9 Hz, 1 H), 8.1 1 (d, J = 2.5 Hz, 1 H), 7.29 (s, 1 H), 6.56 (d, J = 3.9 Hz, 1H), 3.84-3.82 (m, 4H), 3.69-3.67 (m, 4H), 2.86-2.84 (m, 4H), 1.84-1.82 (m, 6H). MS (ESI): 525 (M+, 50%), 527(M+2, 50%).

Compound-19: Synthesis of N-(2-morpholino-5-(piperidin-l-yl) benzo[d]oxazol-6-yl)- 6-(lH-pyrrolo [2, 3-b] pyridin-5-yl) picolinamide.

Stepl : N-(2-morpholino-5-(piperidin-l-yl) benzo[d]oxazol-6-yl)-6-(l H-pyrrolo [2, 3-b] pyridin-5-yl) picolinamide.

(i) 5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrrolo[2,3-*]pyridine, Cs₂C0₃, Pd(dppf)Cl₂, 1,4-Dioxane, H₂0, 100-120°C, 8-14h; .

The compound (O.Olg, 31 .2%) was prepared from 6-bromo-N-(2-morpholino-5-(piperidin- l -yl)benzo[d]oxazol-6-yl) picolinamide (0.03g, step-3 of compound-1) by following the same process used in step-4 of compound-1.

Ή-NMR (400MHz, DMSO- ) : 1 1.39 (bs, 1H), 9.16 (bs, 1H), 9.05 (s, 1 H), 8.80 - 8.70 (m, 2H), 8.30 (d, J = 0.98Hz, 1 H), 8.02 - 7.96 (m, 2H), 6.62 (d, J = 1.4Hz, 1 H), 3.84 - 3.67 (m, 8H), 2.86 (bs, 4H), 1.76 - 1.25 (m, 6H). MS (ESI): 524(M+1, 50%). Compound-20: Synthesis of N-(7-methyl-2-morphoIinobenzo[d]oxazol-6-yl)-6-(lH- pyrrolo [2,3-b]pyridin-5-yI)picolinamide.

Stepl:7-methyl-2-morpholino-6-nitrobenzordl oxazole.

(i) Methyl magnesiumbromide, DryTHF, 0°C, 15min; KMn0₄, Acetone - H₂O(l : l ), 0°C, 5min;

To a solution of intermediate-4 (0.5g, 2.0mmol) in dry THF was added methylmagnesium bromide (2M in diethylether) (0.46 g, 4.0 mmol) at 0 C under argon. Stirred the reaction mixture for lOmin at 0 C and then quenched with Mn0₄ (0.2g, 1.3mmol) in acetone- water and stirred for 5min at same tempetature. Progress of the reaction was monitored by TLC. After the reaction was completed, it was extracted with water (15ml) and DCM (2x 15ml). The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude, which was purified by column chromatography using 100-200 mesh silica gel and 25% ethyl acetate in hexane as eluent to get the pure product (0.02g, 33%).

MS (ESI): 264 (M+ 1 , 60%).

Step2:N-(7-methyl-2-morpholinobenzordloxazol-6-yl)-6-(lH-pvrrolor2,3-b]pyridin-5-yn picolinamide.

Step (i, ii and iii): The process of these steps are adopted from step 2, 3 and 4 of compound- 1.

Ή-NMR (400MHz, DMSO-<¾) δ 10.14 (s, lH), 9.06 (s, 1H), 9.05 (bs, 1H), 8.59 (d, J=1.83Hz, 1H), 8.27 (d, J = 7.3Hz, 1 H), 8.03 - 7.97 (m, 2H), 7.87 (d, J = 7.94Hz, 1H), 7.61 - 7.39 (m, 2H), 6.63 (s, I H), 3.86 - 3.70 (m, 8H), 2.50 (s, 3H). MS (ES) m/e 454.9(M+1, 100%).

Compound-21 : Synthesis of N-(7-methyl-2-morpholinobenzo[d]oxazoI-6-yl)-[2,4'- bipyridine]-6-carboxamide.

Stepl: N-(7-methyl-2-morpholinobenzord1oxazol-6-yl)-[2, 4'-bipyridine]-6-carboxamide

(i) Pyridin -ylboronic acid, Cs₂C0₃, Pd(dppf)Cl₂, 1 ,4-dioxane, H₂0, 100-120°C, 2h

The compound (0.015g, 37.5%) was prepared from 6-bromo-N-(7-methyl-2- morpholir)obenzo[d]oxazol-6-yl) picolinamide (0.04g, step-2(ii) of compound-20) by following the same process used in step-4 of compound-1.

Ή NMR (400MHz, OMSO-d₆) δ 10.52 (s, IH), 8.75 (d, J=5.86Hz, 2H), 8.42-8.18 (m, 5H), 7.38 (d, J=8.3Hz, I H), 7.18 (d, J=7.3Hz, I H), 3.74-3.37 (m, 8H), 2.35 (s, 3H) MS (ES) m/e 416 (M+l , 100%).

Compound-22: Synthesis of N-(7-isobutyl-2-morpholinobenzo[d]oxazol-6-yl)-[2, 4'- bipyridine]-6-carboxamide.

Ste -(7-isobutvl-2-morpholinobenzordloxazol-6-vl)-r2. 4'-bipyridine]-6-carboxamide.

Step (i): The process of this step is adopted from step 1 of compound-20.

Step (ii iii and iv): The process of these steps are adopted from step 2, 3 and 4 of compound-1. Ή NMR (400MHz,, DMSO-cfe) δ 10.1 (bs, IH), 8.81 (d, J=5.6Hz, 2H), 8.4 (d, J=7.53Hz, IH), 8.1-7.93 (m, 5H), 7.3 (d, J=8.6Hz, IH), 3.86-3.68 (m, 8H), 2.82 (d, J=7.6Hz, 2H), 2.14-2.10 (m, I H), 1.0 (d, J=6.4Hz, 6H). MS (ES) m/e 458(M+1 , 100%).

Compound-23: Synthesis of N-(7-isobutyl-2-morpholinobenzo[d]oxazol-6-yl)-6-(lH- pyrro!o[2,3-b]pyridin-5-yl)picolinamide.

Stepl :N-(7-isobutvl-2-morpholinobenzord1oxazol-6-vl)-6-(lH-pvrrolor2,3-b1pyridin-5- y pic

The compound (0.008g, 21%) was prepared from 6-bromo-N-(7-isobutyl-2- mo holinobenzo[d]oxazόl-6-yl) picolinamide (0.045g, step-l(iii) of compound-22) by following the same process used in step-4 of compound- 1.

Ή NMR (400MHz, DMSO-tf₆) δ 10.24 (bs, I H), 9.01 (s, I H), 8.97 (bs, I H), 8.6 (s, IH), 8.28 (dd, J,=7.25Hz, J₂=0.8Hz, I H), 8.1- (d, J=8.6Hz, IH), 8.038-7.96 (m, IH), 7.61-7.3 (d,J=8.6Hz, I H), 6.62 (q, J= 1.79Hz, IH), 4.7 (d, J=1.6Hz, IH), 4.26 (d, J=1.8Hz, IH), 3.86-3.68 (m, 8H), 2.84 (d, J=7.54Hz, IH), 1.01 (d, J=4.7Hz, 6H). MS (ESI): 498(M+2, 100%).

Compound-24: Synthesis of N-(2-morpholino-4-phenylbenzo[d]oxazol-6-yl)-6-(lH- pyrrolo[2,3-b]pyridin-5-yl)picolinamide.

Step -moφholino-4-phenylbenzo[d]oxazol-6-amine.

The compound (0. lg, 83%) was prepared from 4-bromo-2-moφholinobenzo[d]oxazol-6- amine (0.13g, from intermediate-5) by following the same process used in step-4 of compound- 1. MS (ESI): 296 (M+l , 100%). Step2: N-(2-morpholino-4-phenylbenzofd1oxazol-6-yl)-6-(l H-pyrrolo[2,3-b1pyridin-5-yl) picolinamide.

(i) 6-bromopicoIinic acid ,EDC-HC1, HOBT, DMF, 20-30°C, 24h; (ii) 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrrolo[2,3-b]pyridine, Cs₂C0_3> Pd(dppf)Cl₂,l,4-dioxane, H₂0, 100- 120°C, 2h. |

Step (i and ii): The process of these steps are adopted from step 3 and 4 of compound- 1. Ή NMR (400MHz, DMSO-<4) δ 10.69 (bs, I H), 9.27 (bs, I H), 8.96 (bs, IH), 8.31 (d, J=7.9Hz, I H), 8.15-8.00 (s, 5H), 7.56-7.49 (m, 5H), 6.60 (bs, I H), 3.76-3.66 (m, 4H), 3.65- 3.64(m, 4H). MS (ES) m/e 5 15(M-1 , 100%).

Compbund-25: Synthesis of 6'-ahiino-N-(2-morpholino-4-phenylbenzo[d]oxazol-6-yl)- [2,3'-bipyridine]-6-carboxamide.

Stepl:6'-amino-N-(2-morpholino-4-phenvlbenzordloxazol-6-vl)-f2.3'-bipyridine1-6- carboxamide.

The compound (O. lg, 83%) was prepared from 6-bromo-N-(2-morpholino-4- phenylbenzo[d]oxazol-6-yl) picolinamide (0.13g, from compound-24) by following the same process used in step-1 and 2 of compound-3.

Ή NMR (400MHz, DMSO-i/ ) δ 10.58 (s, I H), 8.95 (s, IH), 8.41 -8.39 (m, 2H), 7.96-8.13 (m, 3H), 7.52-7.37 (m, 3H), 6.60 (s, l H), 6.58 (s, I H), 6.38 (s, 2H), 3.75-3.63 (m, 4H), 3.41-3.33 (m, 4H). MS (ESI): 493 (M+l, 100%).

Compound-26: Synthesis of N-(2-morpholino-4-(pyridin-4-yl)benzo[d]oxazoI-6-yl)- [2,4*-bipyridine]-6-carboxamide. Stepl:N-(2-rnorpholino-4-(pvridin-4-Yl)benzord1oxazol-6-yl)-r2,4'-bipyridinel-6-carbo

Step (i, ii and iii): The process of these steps are adopted from step 4, 3 and 4 respectively of compound-1. ^

Ή NMR (400MHz, DMSO-i ₆) δ 10.72 (s, 1H), 8.78 (d, J=6Hz, 2H), 8.69 (d, ,J=5Hz, 2H), 8.41 (d, J=5Hz, 3H,), 8.25-8.22 (m, 3H), 8.12-8.13 (m, 3H), 3.77-3.75 (m, 4H) 3.68-3.67 (m, 4H). MS (ES) m/e 479 (M+l , 100%).

Compound-27: Synthesis of 6'-amino-N-(2-morpholino-4-(pyridin-4-yI) benzo [d] oxazoI-6-yl)-[2,3'-bipyridine]-6-carboxamide.

Stepl : 6'-amino-N-(2-mo holino-4-(pyridin-4-yl)benzo[d]oxazol-6-yl)-[2,3^,-bipyridineJ* 6-carboxamide.

(i) A'-(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyridin

Na₂C0₃, Pd(dppf)CI₂, ACN, H₂0, 80- 100°C, 8-14h.; TFA,60-70°C, 8-14h.

The compound (O. l g, 83%) was prepared from 6-bromo-N-(2-morpholino-4-(pyridin-4-yl) benzo[d]oxazol-6-yl) picoiinamide (0.13g, from compound-26) by following the same process used in step-1 and 2 of compound-3. Ή NMR (400MHz, DMSO-i¾) δ 10.76 (s, 1H), 9.04 (s, 1H), 8.82 (s, 3H), 8.42 (s, 1H), 8.25-8.12 (m, 5H), 7.05 (s, 1 H), 7.83-7.81 (m, 1H), 3.77-3.70 (m, 8H). MS (ESI): 494 (M+l, 100%).

Compound-28: Synthesis of N-(2,5-dimorpholinobenzo[d]thiazol-6-yI)-6-(lH- pyrrolo[2,3-b]pyridin-5-yl)picoIinamide.

Stepl; 5-bromo-6-nitrobenzo[d]thiazole-2(3H)-thione.

(i) Conc.H₂S0₄, Conc.HNO₃, 10min, 0 - 30°C

To a solution of 5-bromobenzo[d]thiazole-2(3H)-thione ( l g,2.0mmol, from step-l(i) intermediate-3) in Conc.H₂S0₄ was added mixture of Conc.H₂S0₄ and Conc.HNC>3 (1 :0.8) (0.46 g, 4.0 mmol) at 0 C. Stirred the reaction mixture for lOmin at 0 C. Progress of the reaction was monitored by TLC. After the reaction was completed, it was poured into crushed ice and the solid formed was filtered under vaccum to get yellow solid as pure product. (0.02g, 33%). 291 (M⁺, 50%), 289(M-2, 100%).

Step-2:N-(2,5-dimorpholinobenzord1thiazol-6-vl)-6-(lH-pvrrolor2,3-blpvridin-5-vl) picolinamide.

(i) Morpholine, 90-100°C, 2h; (ii) Fe powder, Conc.HCl, ethanol, H₂0, 70-80°C, l h; (iii) 6- bromopicolinic acid ,EDC-HCI, HOBT, DMF, 30°C, 24h; (iv) 5-(4,4,5,5-tetramethyl- 1 ,3,2- dioxaboro!an-2-yl)-lH-pyrrolo[2,3-b]pyridine, Cs₂C0₃, Pd(dppf)Cl₂, l,4-dioxane, H₂0, 100-120°C, 2h.

Step (i): The process of this step is adopted from step 2 of intermediate- 1.

Step (ii, iii and iv): The process of these steps are adopted from step 2, 3 and 4 of compound- 1. Ή NMR (400MHz, DMSO-c/₆) δ 1 1.97 (bs, IH), 1 1.20 (bs, IH), 9.22 (s, IH), 8.95 (s, IH), 8.87 (s, I H), 8.33 (d, J = 6.4 Hz, I H), 8.19-8.16 (m, 2H), 7.59-7.51 (m, 2H), 6.61 (s, IH), 3.81 -3.74 (m, 8H), 3.54-3.52 (m, 4H), 2.92-2.89 (m, 4H). MS (ES) m/e 542 (M+l, 60%).

Compound-29; Synthesis of 6^,-amino-N-(5-cyclopropyl-2-morpholinobenzo[d]thiazol- 6-yI)-[2,3'-bipyridine]-6-carboxamide.

Stepl:6'-amino-N-(5-cyclopropyl-2-morpholinobenzordlthiazol-6-yl)-[2,3'-bipyridine1-6- carboxamide.

(iii) 6-bromopicolinic acid ,EDC-HC1, HOBT, DMF, 30°C, 24h;

(iv) 7V-(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine, Na₂C0₃, Pd(dppf)Cl₂, ACN, H₂0, 80-100°C, 8-14h; TFA, 60-70°C, 8- 14h.

Step (i): The process of this stepis adopted from step-1 of compound- 17.

Step (ii and iii); The process of these steps are adopted from step-2and 3of compound-1.

Step (iv): The process of this stepis adopted from step-1 and 2 of compound-3.

Ή NMR (400MHz, DMSO-^s) δ 10.795 (s, IH), 8.824 (d, J=2.4Hz, I H), 8.64 (s, I H),

8.22-8.19 (m, I H), 8.08-8.00 (m, 3H), 7.32 (s, IH), 6.56 (d, J = 8.9Hz, IH), 6.42 (s, 2H),

3.74-3.72(m, 4H), 3.54-3.52 (m, 4H), 2.13-2.1 1 (m, LH), 1.055-1.008 (m, 2H), 0.79-0.76

(m, 2H). MS (ESI): 473(M+1 , 100%).

Compound-30: Synthesis of N-(5-cycIopropyl-2-morpholinobenzo[d]thiazol-6-yl)-6- (lH-pyrazol-5-yl) picolinamide.

Stepl :N-(5-cvclo ropvl-2-moφholinobenzoΓdlthiazol-6-yl)-6- l H- yrazol-5-yl) picolinamide.

(i) Cyclo propyl boronicacid, ₃P0₄, F, (Cy)₃P, Pd(OAC)₂, toluene, H₂0, 100-120°C, 24h;

(ii) Fe powder, Conc.HCI, ethanol, H₂0, 70-80°C, 1 h;

(iii) 6-bromopicolinic acid, EDC-HCI, HOBT, DMF, 20-30°C, 24h;

(iv) l-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole, Cs₂C0₃, Pd(dppf)Cl₂, l ,4-dioxane, H₂O, 100-120°C, 3h; Diethylether-HCI, 0°C-30°C, 10-15 min.

Step (i); The process of this step is adopted from step l of compound- 17.

Step (ii, iii and iv): The process of these steps are adopted from step 2, 3 and 4 of compound- 1.

Ή NMR (400 MHz, CDC1₃):5 13.83 (s, 1 H), 10.83 (s, 1H), 8.64 (s, 1 H), 8.22-8.04 (m, 4H), 7.33-7.04 (m, 2H), 3.75-3.72 (m, 4H), 3.55-3.51 (m, 4H), 2.16-2.09 (m, 1H), 1.33- 1.29 (m, 1H), 1.25-1.23 (m, 1 H), 1. 10- 1.08 (m, 2H). MS (ESI): 445 (M- l, 100%).

Compound-31 : Synthesis of N-(5-(cyclopropyl (methyl) amino)-2- morpholinobenzo[d]thiazoI-6-yl)-6-(lH-pyrazol-5-yl) picolinamide.

Stepl : N-cyclopropyl-2-moφhoIino-6-nitrobenzo[d]thiazol-5-amine.

lntermediate-3

(i) Cyclo propyl amine, ΒΓΝΑΡ, NaO-But, Pd(dba)₃, Toluene,! 00- 120°C, 18h

To a solution of intermediate-3 (2g, 5.8mmol) in toluene (25ml), was added cyclopropylamine (0.53g, 9.3mmol), Pd₂(dba)₃ (0.053g, 0.058mmol), ΒΓΝΑΡ (0.108g, 0.174mmol) and NaOt-Bu (0.83g, 8.72mmol).The reaction mixture was degased for 10- 20min under argon and reaction was continued at 100-120°C for 18h. The progress of the reaction was monitored by TLC. After the reaction was completed, it was extracted with water (15ml) and ethylactate (2x 15ml). The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude (1.2g, 64%). MS (ESI): 321 (M+l , 90%).

Step2: N-cyclopropyl-N-methyl-2-mo holino-6-nitrobenzo[d]thiazol-5-amine. (i) NaH, CH₃I, DMF, 0-30°C, 5 - 6h

To a solution of NaH in DMF(lOml) was added N-cyclopropyl-2-morpholino-6- nitrobenzo[d]thiazol-5-amine (lg, 5.8mmol, step-1) in DMF at 0 C.The reaction mixture was stirred for 40 min at this temperature, then methyliodide was added at 0°C and reaction was continued for 5-6h. The progress of the reaction was monitored by TLC. After the reaction was completed, it was extracted with water (15ml) and ethylactate (2x 15ml). The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude (1.2g, 64%). MS (ESI): 335 (M+l, 90%).

Step3: N-(5-(cycIopropyl (methyl) amino)-2-morpholinobenzo[d]thiazol-6-yl)-6-(l H- pyrazol-5-yl) picolinamide.

Step (i) To a solution of N-cyclopropyl-N-methyl-2-mo holino-6-nitrobenzo[d]thiazol-5- amine(l g) from step-2 in Ethyl acetate( 100ml) was added Pd/c(0.6g) The reaction mixture was stirred at 20-30°Cfor 48h under H₂ atmosphere at 70psi, The progress of the reaction was monitored by TLC. After the reaction was completed, solvents were concentrated under reduced pressure to get the crude (1.2g, 64%). MS (ESI): 335 (M+l , 90%).

Step (ii and iii): The process of these steps are adopted from step-3 and 4 of compound- 1. Ή NMR (400 MHz, CDC1₃):5 13.30 (s, IH), 10.96 (s, l H), 8.86 (s, 1H), 8.19 (d, J = 7.3 Hz, 1 H), 8.13-8.07 (m, 2H), 7.97 (s, 1H), 7.69 (m, 1H), 6.94 (s, l H), 3.75-3.73 (m, 4H), 3.55-3.53 (m, 4H), 2.81 (s, 3H), 2.69-2.67 (m, 1 H), 0.64-0.60 (m, 2H), 0.47-0.46 (m, 2H). MS (ESI): 476 (M+l, 100%). Cotnpound-32; Synthesis of 6'-amino-N-(5-isobutyl-2-morpholinobenzo[d]thiazol-6- yl)-[2,3'-bipyridine]-6-carboxamide.

(i) Intermediate-6, ₂C0₃, Ru-Phos, Pd(OAC)₂, Toluene, H₂O, 100-120°C, 36h; (ii)Zinc dust, NH4CI, THF, H₂0, 0-30°C, 2h; (iii) 6-bromopico!inic acid ,EDC-HCI, HOBT, D F, 20-30°C, 24h; (iv) iV-(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-y!)pyridin-2- amine, Na₂C0₃, Pd(dppf)Cl₂, ACN, H₂0, 100-120°C, 8-14h; TFA,60-70°C,8-14h.

Step (i): The process of this stepis adopted from step-1 of compound-17.

Step (ii): To a solution of 4-(5-isobutyl-6-nitrobenzo[d]thiazol-2-yl)mo holine(1.9g, 6.5 mmol, step-1) in THF (20 ml) was added a saturatedsolution of NH4Cl(5.5g, 4.1mmol) and

H₂0 (10ml), cooled to 0^°C. To this zinc dust (3.38g, 552.0mmol) was added and the reaction mixture was stirred at 20-30 C for 3h. The progress of the reaction was monitored by TLC. After the reaction was completed, reaction mixture filtered through celite and washed with ethyl acetate. The filtrate was washed with brine solution and ethyl acetate layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to get the crude. (1.5g, 93%). MS (ES) m/e 292(M+ 1 , 70%).

Step (iii): The process of this stepis adopted from step-3 compound- 1.

Step (iv): The process of this stepis adopted from step-1 and 2 of compound-3.

Ή NMR (400MHz, DMSO-i¾) δ 10.35 (s, 1H), 8.86 (d, J = 2.4Hz, 1 H), 8.40 (s, 1H), 8.30

(dd, J,=8.8Hz, J₂=8.8Hz, 1H), 8.10-8.02 (m, 2H), 7.97 (dd, J,=7.3Hz, J₂=7.3Hz, 1H), 7.37

(s, l H), 6.57 (d, J=8.8Hz, 1H), 6.40 (bs, 2H), 3.75-3.73 (m, 4H), 3.56-3.53 (m,4H), 2.68

(m, 2H), 1.97-1.91 (m, 1H), 0.89 (s, 6H). MS (ESI): 489 (M+l, 100%).

Com ound-33: Synthesis of 6'-amino-N-(2-morpholino-5-(pyrrolidin-l-ylmethyl) benzo[d]thiazo!-6-yI)-[2,3'-bipyridine]-6-carboxamide.

Step (i): The process of this stepis adopted from step-1 of compound-17.

Step (ii): The process of this step is adopted from step-ii of compound-32.

Step (iii): The process of this stepis adopted from step-3 compound- 1.

Step (iv): The process of this stepis adopted from step-1 and 2 of compound-3.

Ή-NMR (400MHz, DMSO-i/₆) 6 1 1.45 (s, 1H), 8.75 (d, J = 8Hz, 1 H), 8.74 (d, J = 6Hz,

1 H), 8.14 (d, J = 7.8Hz, 1 H), 8.03 - 7.98 (m, 3H), 7.44 (s, 1H), 6.56 (d, J = 8Hz, 1H), 6.37

(bs, 2H), 3.75 (t, J, = 8Hz, J₂ = 8Hz, 6H), 3.55 - 3.53 (m, 4H), 2.67 - 2.60 (m, 4H), 1.66 (s,

4H). MS (ESI): 516 (M+l , 100%).

Compound-34: Synthesis of tert-butyl (l-(6-((2-morphoIinobenzo[d]oxazo!-6-yI) carbamoyl)pyridin-2-yI)pyrroIidin-3-yl)carbamate.

Step-1 : 6-bromo-N- 2-mor hoIinobenzo d oxazol-6- l icolinamide.

Step (i and ii): Starting material taken from intermediate-4 and the process of these steps are adopted from step 2 and 3of compound-1.

Step-2: tert-butyl (l-(6-((2-morpholinobenzo[d]oxazol-6-yl)carbamoyl)pyridin-2-yI) pyrrolidin-3-yl) carbamate.

To a solution of 6-6Γοηιο-Ν-(2-ηιθ Ηο1ίηο56ηζο[(1]ο 3ζο1-6^1)ρίοο1ίη3ηηΐ(ΐ6 (0.25g, 0.62 mmolfromstep-1) in 1 ,4-dioxane (5ml) was added tert-butyl pyrrolidin-3- ylcarbamate(0.138g, 0.74mmol), Pd(OAC)₃(0.0069g, 0.03mmol), xanthphos(0.035g, 0.06 mmol) and Cs2CC>3₍0.83g,8.72mmol). The reaction mixture was degased for 10-20min under argon and reaction was continued at 100-120°C for 18h. The progress of the reaction was monitored by TLC. After the reaction was completed, it was extracted with water (15ml) and ethylactate (2x 15ml). The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude (1.2g, 64%). 'H NMR (400MHz, DMSO-(4) δ 1 1.95 (bs, 1H), 10.18 (s, 1H), 8.06 (s, 1H), 7.71 -7.65 (m, 1 H), 7.55-7.48 (m, 1 H), 7.32-7.23 (m, 3H), 6.70-6.68 (m, 1 H), 4.18 (s, 1H), 3.74-3.54 (m, 10H), 2.32-2.08 (m, 1H), 1.95-1.89 (m, 1 H) 1.40 (s,9H). MS (ES) m/e 509(M+1 , 100%).

Compound-35: Synthesis of 6-(3-aminopyrrolidin-l-yl)-N-(2-morpholinobenzo

[d]oxazoI-6- l) icolinamide.

To a solution of compound-34 (0.06g, 0.14mmol) in DCM (5ml), was added trifluoro acetic acid (0.2ml) at 0°C.The reaction was continued at 20-30°Cfor 3h. The progress of the reaction was monitored by TLC. After the reaction was completed, it was extracted with water ( 15ml) and ethylactate (2x 15ml). The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude (0.02g, 33%). Ή NMR (400MHz, DMSO-</₆) δ 10.18 (s, I H), 8.08 (s, IH), 7.72-7.66 (m, IH), 7.51-7.4? (m, IH), 7.35-7.28 (m, 2H), 6.74-6.72 (m, IH), 5.75 (s, IH), 3.86-3.68 (m, 10H), 3.17-3.12 (m, I H), 2.94-1.95 (m, 3H), 1.23 (s, IH). MS (ES) m/e 409(M+1, 100%).

CompQund-36: Synthesis of 2'-fluoro-N-(2-morpholinobenzo[d]oxazoI-6-yl)-[2,4'- bipyridine]-6-carboxamide.

(i) (2-fluoropyridin-4-yl)boronic acid, Pd(Pph₃)₄, Cs₂C0₃, H₂0, 1,4-dioxane, 100-120^°C, 12h

2'-fluoro-N-(2-morpholinobenzo[d]oxazol-6-yl)-[2,4'-bipyridine]-6-carboxamide (0.005g, 9.8%) was prepared from 6-bromo-N-(2-mo holinobenzo[d]oxazol-6-yl) picolinamide (0.05g, 0.12mmol) from step-1 of compound-34 by following the same process in step 4 of compound- 1. - Ή NMR(400MHz, DMSO- ) 510.03 (s, H), 7.69-7.64 (m, 3H), 7.57-7.45 (m, 6H), 3.84- 3.70 (m, 8H). MS (ES) m/e 420 (M+l, 100%).

Compound-37: Synthesis of N-(2-morpholinobenzo[d]oxazol-6-yI)-[2, 3'-bipyridine]- 6-carboxamide.

(i) Pyridin-3-ylboronic acid, Pd(Pph₃)₄, Cs₂C0₃, H₂0, 1 ,4-dioxane, 100-120°C, 12h

N-(2-moφholinobenzo[d]oxazol-6-yl)-[2,3^,-bipyridine]-6-carbo amide (0.0 lg, 25%) was prepared from 6-bromo-N-(2-mo holinobenzo[d]oxazol-6-yl)picolinamide (0.05g, 0.12mmol) from step-1 of compound-34 by following the same process in step 4 of compound- 1.

Ή NMR (400MHz, OMSO-d₆) 610.61 (s, I H), 9.58 (s, IH), 8.77-8.70 (m, 2H), 8.34-8.31 (m, IH), 8.20-8.09 (m, 3H), 7.64-7.51 (m, 2H), 7.32 (d, J=8.4Hz, J H), 3.59-3.39 (m, 8H). MS (ES) m/e 402(M+ 1 , 100%).

Compound-38: Synthesis of N-(2-morpholinobenzo[d]oxazol-6-yl)-6-(pyriniidin-5-yl) picolinamide. (i) Pyrimidin-5-ylboronic acid, Pd(Pph₃)₄, Cs₂C0₃, H2O, 1 ,4-dioxane,100-120°C,12h

Ν-(2-Γηο 1ιο1ίηο5εηζο[(1]οχ ζο1-6- Ί)-6-(ρ>'πηΊΪ(ϋη-5->Ί) picolinamide (0.005g, 10%) was prepared from 6-bromo-N-(2-mo holinobenzo[d]oxazol-6-yl) picolinamide (0.05g, 0.12mmol) from step-1 of compound-34 by following the same process in step 4 of compound- 1.

Ή NMR (400MHz, DMSO-cfe) δ 10.66 (s, IH), 9.81 (s, 2H), 9.32 (m, IH), 8.43 (d,

J=9.2Hz, I H), 8.25-8.20 (m, 2H), 8.19^' (s, IH), 7.65-7.62 (m, IH), 7.33 (d, J=8Hz, IH),

3.75-3.72 (m, 4H), 3.61 -3.58 (m, 4H); MS (ES) m/e 403(M+1, 100%).

Compound-39; Synthesis of N-(2-morpholinobenzo[d]oxazol-6-yl)-[2,4'-bipyridine]-6- carboxamide.

(i) Pyridin-4-ylboronic acid, Pd(PPh₃)₄, Cs₂C0₃, H₂0, 1 ,4-dioxane, 100-120°C, 12h

N-(2-moφholinobenzo[d]oxazol-6-yl)-[2,4'-bipyridine]-6-carboxamide (0.01g,20%) was prepared from 6-bromo-N-(2-mo holinobenzo[d]oxazol-6-yI) picolinamide (0.05g, 0.12mmol) from step-1 of compound-34 by following the same process in step 4 of compound- 1.

Ή NMR (400MHz, DMSO-rf₆) 810.61 (s, IH), 8.76 (d, J=6Hz, 2H), 8.41 -8.37 (m, 3H), 8.23-8.09 (m, 3H), 7.63 (d, J=9.6Hz, IH), 7.33 (d, J=8.4Hz, I H), 3.74-3.59 (m, 8H). MS (ES) m/e 402 (M+l, 100%).

Compound-40: Synthesis of 6-(2-aminopyrimidin-5-yI)-N-(2-morphoIinobenzo[d] oxazol-6-yl) picolinamide.

(i) 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrimidin-2-amine, Pd(dppf)CI₂, Na₂C0₃,

H₂O ACN, 80-100'C, 12h. 6-(2-aminopyrimidin-5-yl)-N-(2-mo holinobenzo[d]oxazol-6-yl)picolinarnide (0.002g, 3.9%) was prepared from 6-bromo-N-(2-morpholinobenzo[d]oxazol-6-yl)picolinamide (0.05g, 0.12mmol) from step-1 of compound-34 by following the same process in step 4 of compound-1.

Ή NMR (400MHz, DMSO-c/₆): 510.56 (s, 1H), 9.24 (s, 2H), 8.56-8.00 (m, 2H), 7.96-7.30 (m, 4H), 7.07 (s, 1H), 3.73-3.59 (m, 8H). MS (ES) m/e 418 (M+l , 100%).

Compound-41 : Synthesis of 6'-amino-N-(2-morpholinobenzo[d]oxazol-6-yl)-[2,3'- bipyridine]-6-carboxamide.

(i) A'-(4-methoxybenz l)-5-(4,4,5,5-tetramethyl- l ,3_>2-dioxaborolan-2-yl)pyridin-2-amine,

Na,CO,,Pd(dppf)CI,, ACN, H,Q, SO- l Of C, 8- 14h; TFA, 60-70°C, 8-14h.

6'-amino-N-(2-morpholinobenzo[d]oxazol-6-yl)-[2,3'-bipyridine]-6-carboxamide (0.003g,

5%) was prepared from 6-bromo-N-(2-morpholinobenzo[d]oxazol-6-yl) picolinamide

(0.08g, O. Hmmol) from step- 1 of compound-34 by following the same process in step 1 and 2 of compound-3.

Ή NMR (400MHz, DMSO-i¾ δ 10.58 (s, 1 H), 8.96 (s, 1 H), 8.88 (d, J=8Hz, 1H), 8.21 - 8.08 (m, 5H), 7.59 (d, J=7.2Hz, 1 H), 7.33 (d, J=8Hz, 1 H), 7.04 (d, J=9.6Hz, 1H), 3.74-3.59 (m, 8H). MS (ES) m/e 417 (M+l, 100%).

Compound-42: Synthesis of 6'-acetamido-N-(2-morpholinobenzo[d]oxazol-6-yl)-[2, 3'-bipyridine]-6-carboxamide.

(i) AC₂0, DCM, Et₃N, 20-30°C, 8-14h

To a stirred solution of compound-41 (0.03g, 0.072mmol) in DCM was added triethyl amine (0.02 l g, 0.2mmol) and acetic anhydride (0.014mg, 0.14mmol). Stirring was continued for 8-14h at 20-30°C. The progress of the reaction was monitored by TLC. After the reaction was completed, it was extracted with water (15ml) and ethylactate (2x 15ml). The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude (0.005g, 15%).

Ή NMR (400MHz, DMSO- ) δ 10.7.0 (bs, 1H), 10.58 (bs, 1H), 9.31 (s, 1H), 8.77 (d, J = 5.6 Hz, 1 H), 8.28-8.08 (m, 4H), 7.64 (d, J=10Hz, 2H), 7.32 (d, J=8.8Hz, 1H), 3.72-3.58 (m, 4H), 3.55-3.53 (m, 4H), 2.15 (s, 3H). MS (ESI): 459 (M+l, 90%).

Compound-43: Synthesis of 6-(lH-indazol-5-yl)-N-(2-morpholinobenzo[d]oxazol-6- yl)picolinamide.

(i) 5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-l /-indazole, Cs₂C0₃, Pd(dppf)Cl₂, 1,4-Dioxane, H₂0, 100-120^°C, 8-14h.

6-(l H-indazol-5-yl)-N-(2-moφholinobenzo[d]oxazol-6-yl)picolinamide (0.015g,30%) was prepared from 6-bromo-N-(2-morpholinobenzo[d]oxazol-6-yl) picolinamide (0.05g, 0.12mmol) from step- 1 of compound-34 by following the same process in step 4 of compound- 1.

Ή NMR (400MHz, DMSO- /₆) δ 13.29 (bs, 1H), 10.65 (bs, 1H), 8.50 (s, 1H), 8.32 (d, J=6.9Hz, 1H), 8.17-8.09 (m, 5H), 7.91 (d, J=8.6Hz, 1H), 7.33 (d, J=8.5Hz, 1H), 3.75-3.73 (m, 4H), 3.61 -3.59 (m, 4H). MS (ES) m/e 441 (M+l, 60%).

Compound-44: Synthesis of N-(2-morpholinobenzo[d]oxazol-6-yl)-6-(quinolin-6-yl) picolinamide.

N-(2-mo holinobenzo[d]oxazol-6-yl)-6-(quinolin-6-yl)picolinamide (0.015g,30%) was prepared from 6-bromo-N-(2-mo holinobenzo[d]oxazol-6-yl) picolinamide (0.05g, 0.12mmol) from step- 1 of compound-34 by following the same process in step 4 of compound- 1 . Ή NMR (400MHz, DMSO-i¾) 510.7 (bs, 1H), 9.95 (s, 1H), 9.34 (s, 1H), 8.49 (d, J=7.9Hz,

1 H), 8.26-8.1 1 (m, 4H), 7.85 (d, J=7.3Hz, 1H), 7.73-7.66 (m, 2H), 7.34 (d, J=8.6Hz, 1 H),

3.75-3.73(m, 4H), 3.63-3.59 (m, 4H). MS (ES) m/e 452(M+1 , 100%).

Compound-45: Synthesis of N-(2-morpholinobenzo[d]oxazoI-6-yl)-6-(lH-pyrroIo[2,3- b]pyridin-5-yl)picolinamide.

(i) 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrrolo[2,3-b]pyridine, Cs₂C0₃, Pd(dppf)CI₂,1 ,4- dioxane, H₂0, 100-120°C, 2h.

N-(2-moφholίnobenzo[d]oxazol-6-yl)-6-(l H-pyrrolo[2,3-b]pyridin-5-yl)picolinamide (0.015g, 30%) was prepared from 6-bromo-N-(2-morpholinobenzo[d]oxazol-6-yl) picolinamide (0.05g, 0.12mmol) from step-1 of compound-34 by following the same process in step 4 of compound- 1.

'HNMR (400MHz, DMSO-e?₆) δ 81 1.84 (s, 1H), 10.62 (s, 1 H), 9.235 (d, J=1.96Hz, 1H), 8.955 (d, J=1.96Hz, l H), 8.31 -8.29 (m, 1 H), 8.14-8.07 (m, 2H), 7.66 (d, J=1.9, 1H), 7.33 (d, J=1.92, 1 H), 6.58 (s, 1 H), 3.75-3.72 (m, 4H), 3.61 -3.58 (m, 4H). MS (ES) m/e 441 (M+l , 100%).

Compound-46: Synthesis of N-(2-morpholinobenzo[d]oxazoI-6-yl)-6-(lH-pyrazoI-5-yI) picolinamide.

(i) l-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)- l H-pyrazole, Cs₂C0₃₎ Pd(dppf)Cl₂, l ,4-dioxane, H₂0, 100- 120°C, 3h; Diethylether-HCl, 0°C-30°C, 10- 15 min.

N-(2-mo holinobenzo[d]oxazol-6-yl)-6-(l H-pyrazol-5-yl)picolinamide (0.003g,26%) was prepared from 6-bromo-N-(2-morpholinobenzo[d]oxazol-6-yl) picolinamide (0.05g, 0.12mmol) from step-1 of compound-34 by^' following the same process in step 4 of compound- 1. Ή NMR (400MHz, DMSO-4 δ 10.77 (bs, IH), 8.21 -8.05 (m, 4H), 7.66 (s, IH), 7.63- 7.41 (m, IH), 7.36 (d, J=8.4Hz, I H), 7.32 (d, J=8.4Hz, IH), 7.08 (bs, IH), 3.75-3.60 (m, 8H). MS (ES) m/e 391 (M+1 , 60%),

Compound-47: Synthesis of N-(5-chloro-2-morpholinobenzo[d]oxazol-6-yI)-6-(lH- pyrrolo[2,3-b]pyridin-5-yl)picoIinamide.

(i) Fe powder, Conc.HCl, ethano!, H₂0, 70-80°C, l h;

(ii) 6-bromopicolinic acid, EDC-HCI, HOBT, DMF, 0-30°C, 8-14h;

(iii) 5-(4,4,5,5-tetrameth l- l ,3,2-dioxaborolan-2-yl)-l H-pynOlo[2,3-b]pyridine,

Cs₂C0₃, Pd(dppf)Cl₂,l ,4-dioxane, H₂0, 100- 120°C, 2h.

Step (i, ii and iii): The process of these steps are adopted from step 2 ,3 and 4 of compound- 1. Ή NMR (400MHz, DMSO-c/₆) 51 1 .8 (bs, IH), 10.97 (s, I H), 9.12 (d, J=1.96Hz, IH), 8.75 (d, J=1.96Hz, IH), 8.56 (s, IH), 8.82-8.12 (m, 3H), 7.50-7.48 (m, 2H), 6.56-6.54 (m, l H), 3.78-3.64 (m, 8H). MS (ES) m/e 475 (M+, 100%).

Compound-48: Synthesis of 6'-amino-N-(2-morphoIino-lH-benzo[d]imidazol-6-yI)- '-bipyridine]-6-carboxamide.

Step (0: The process of this step was adopted from step 1 of intermediate- 1. MS (ES) m/e 196(M+1 , 100%).

Step-(ii):2-bromo-5-nitro-lH-benzofdlimidazole.

To a cooled solution of acetic acid in HBr (5ml) was added 5-nitro- l H-benzo[d]imidazole- 2-thiol (3.5g, 8.0mmol, step-(i)) followed by the addition of Br₂ at 0 C and stirring was continued at 20-30 C for 2h. The progress of the reaction was monitored by TLC. After the reaction was completed, it was extracted with water (15ml) and ethylactate (2x 15ml). The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude (1.2g,64%).MS (ESI): 240 (M+1, 100%), 242(M+1 , 100%)

Step (iii); The process of this step is adopted from step 2of intermediate-1.

Step (iv and v): The process of these steps are adopted from step 2 and 3 of compound- 1.

Step (vi): The process of these steps are adopted from step 1 and 2 of compound-3.

Ή NMR (400MHz, DMSO-i¾ 612.0 (bs, 2H), 10.38 (bs, 1 H), 8.90 (d, J=2.0Hz, 1H), 8.41 -8.38 (m, 1 H), 8.07-7.94 (m, 3H), 7.37 (bs, 1H), 7.22-7.20 (m, l H), 6.59-6.50 (m, 1H), 6.37 (bs, 1 H), 3.75-3.20 (m, 4H), 3.48-3.47 (m, 4H). MS (ES) m/e 416(M+1, 100%).

Compound-49: Synthesis of 6'-amino-N-(2-morphoIinobenzo[d]thiazol-6-yl)-[2,3'- bipyridine]-6-carboxamide.

(i) CS₂ ,ΚΟΗ, Ethanol, 75°C, 18h; (ii) HN0₃, H₂S0₄, 0°C-30°C, 2h (iii) Morpholine, 90-100°C, 4h; (iv) Fe powder, Conc.HCl, Ethanol, H₂0, 70-80°C, 3h; (v) 6-bromopicolinic acid, EDC-HC1, HOBT, DMF,20-30°C, 8-14h;(vi) A'-(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaboroIan-2- yl)pyridin-2-amine, Na₂C0₃, Pd(dppf)Cl₂, ACN, H₂0, 80-100°C, 8-14h; TFA, 60-70°C, 8-14h. Step (i): The process of this step was adopted from step 1 of intermediate- 1. MS (ES) m/e 168 (M+l , 100%).

Step-(ii): The process of this step was adopted from step 1 of compound-28.MS (ES) m/e 213 (M+l, 100%).

Step (iii): The process of this step is adopted from step 2of intermediate- 1.

Step (iv and v); The process of these steps are adopted from step 2 and 3 of compound- 1.

.Step (vi): The process of these steps are adopted from step 1 and 2 of compound-3.

Ή NMR (400MHz, DMSO-</₆) δ 10.57'(s, 1 H), 8.97 (s, 1 H), 8.34(d, J = 2.5 Hz, 1H), 8.18-

8.05 (m, 3H), 7.74 (d, J = 6.0 Hz, 3H), 3.75-3.67 (m, 8H). MS (ES) m/e 433 (M+l , 100%).

Compound-50: Synthesis of tert-butyl 4-((6-((2-morpholinobenzo[d]oxazol-6- yl)carbamoyl)pyridin-2-yI)amino)piperidine-l-carboxylate.

(i) ferf-butyl 4-aminopiperidine-1-carboxylate, Cs₂C0₃, Pd(OAC)₂, Xanthphos,1 ,4-dioxane, 120°C, 16h tert-butyl 4-((6-((2-moφholinobenzo[d]oxazol-6-yl)carbamoyl)pyridin-2-yl)amino) piperidine- l -carboxylate (0.004g,31 %) was prepared from 6-bromo-N-(2- morpholinobenzo[d]oxazol-6-yl) picolinamide (0.1g,2.48mmol) from step- 1 of compound- 34 by following the same process in step-(ii) of compound-34.

Ή NMR (400MHz, DMSO-^) 512.40 (bs, 1H), 10.1 (s, 1H), 7.80 (s, 1H), 7.67-7.65 (m, 1 H), 7.42-7.40 (m, 2H), 6.88-6.87 (m, 1H), 6.72-6.70 (m, 1H), 7.34-7.32 (m, 1H), 3.75- 3.72 (m, 8H), 3.39-3.29 (m, 2H), 2.67-2.60 (m, 1H), 1.98-1.96 (m, 2H), 1.41 (s, 9H), 0.89- 0.83 (m, 2H). MS (ES) m/e 523 (M+l, 100%).

Compound-51 : Synthesis of tert-butyl 3-((6-((2-morpho!inobenzo[d]oxazol-6-yl) carbamoyl)pyridin-2-yI)amino)pyrroIidine-l-carboxylate.

(i)ferr-butyl 3-aminopyrrolidine-1-carboxylate, Cs₂C0₃, Pd(OAC)₂,Xanthphos,1 ,4-dioxane,120°C, 16h tert-butyl 3-((6-((2-mo holinobenzo[d]oxazol-6-yl)carbamoyl)pyridin-2-yl)amino) pyrrolidine- 1-carboxy late (0.004g,31%) was prepared from 6-bromo-N-(2- mo holinobenzo[d]oxazol-6-yl) picolinamide (0.1g,2.48mmol) from step-1 of compound- 34 by following the same process in step-2 of compound-34.

Ή NMR (400MHz, DMSO-i¾) 810.52 (bs, IH), 8.206-8.202 (m, IH), 7.63-7.62 (m, IH), 7.33-7.31 (m, I H), 7.26-7.21 (m, IH), 6.61-6.58 (m, IH), 4.69-4.67 (m, I H), 4.429 (bs, IH), 3.84-3.79 (m, 4H), 3.69-3.52 (m, 4H), 331 (bs, 2H), 2.34-2.25 (m, IH), 2.0-1.56 (m, IH), 1.40 (s, 9H), 0.88-0.86 (m, I H). MS (ES) m/e 509(M+1 , 100%). '

Compound-52: Synthesis of N-(2-morphoIinobenzo[d]oxazol-6-yI)-6-((3-(trifluoro methyl) phenyl)amino)picolinamide.

(i) 3-(trifluoromethyl)aniline, Cs₂C0₃, Pd(OAC)₂, Xanthphos, 1 ,4-dioxane, 120°C, 16

N-(2-moφholinobenzo[d]o azol-6-yl)-6-((3-(trifluoromethyl)phenyl)amino)picolinamide (0.005g,9%) was prepared from 6-bromo-N-(2-mo holinobenzo[d]oxazol-6-yl) picolinamide (0.05g,0.12mmol) from step- 1 of compound-34 by following the same process in step-(ii) of compound-34.

Ή NMR (400MHz, DMSO-< ₆) 510.06 (s, I H), 9.72 (s, IH), 8.29 (s, IH), 8.04 (s, IH), 7.87-7.83 (m, 2H), 7.75-7.54 (m, 2H), 7.41 (d, J=1.6Hz, IH), 7.30 (m, 2H), 7.09 (d, J=8.4Hz, I H), 3.72-3.57 (m, 8H). MS (ES) m/e 482(M+1 , 60%).

Compound-53: Synthesis of 6-((2-aminoethyI)amino)-N-(2 morpholinobenzo[d]oxazol-6-yl)picolinamide.

6-bromo-N-(2-mo holinobenzo[d]o azol-6-yl) picolinamide (O. lg, 0.21mmol) from step- 1 of compound-34 was taken in ethane- l ,2-diamine(5ml) and strried the reaction mixture at 100 Cfor 48hours. The progress of the reaction was monitored by TLC. The reaction mass was extracted with water (15ml) and ethylactate (2x 15ml). The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude (0.02g, 1 1%).

Ή NMR (400MHz, DMSO-i/₆) δΐ θ.22 (s, IH), 8.07 (s, I H), 7.60-7.40 (m, 2H), 7.39-7.20 (m, 2H), 6.87 (bs, I H), 6.71 (d, J=8.4Hz, I H), 3.72-3.58 (m, 8H), 3.40-2.76 (m, 4H). MS (ES) m/e 383(M+l , 100%).

Compound-54: Synthesis of 6-((2-hydroxyethyI)amino)-N-(2-morpholinobenzo

6-((2-hydrox ethyl)amino)-N-(2-mo holinobenzo[d]oxazol-6-yl)picolinamide

(0.015g, 16%) was prepared from 6-bromo-N-(2-mo holinobenzo[d]oxazol-6-yl) picolinamide (0.1g,0.24mmol) from step-1 of compound-34 by following the same process in compound-53.

Ή NMR (400MHz, DMSO-^) 510.22 (s, I H), 8.06 (s, I H), 7.57 (t, J=8Hz, IH), 7.47 (d, J= 10Hz, IH), 7.29 (d, J=8.8Hz, I H), 7.24 (d, IH, J=7.2Hz), 6.83 (bs, IH), 6.75 (d, J=8.4Hz, I H), 4.75 (s, I H), 4.72-3.71 (m, 4H), 3.62-3.47 (m, 8H). MS (ES) m/e 384(M+1, 100%).

Compound-55: Synthesis of 6-((2-aminoethyl)amino)-N-(2-morpholinobenzo[d]

6-((2-aminoethyl)amino)-N-(2-mo holinobenzo[d]thiazol-6-yl)picolinamide (0.025g, 26%) was prepared from 6-bromo-N-(2-morpholinobenzo[d]thiazol-6-yl)picolinamide (0.1g,0.24mmol) from step-v of compound-49 by following the same process in compound-53. Ή NMR (400MHz, DMSO-c/₆) 510.2 (s, IH), 8.3 (s, IH), 7.70-7.61 (m, 2H), 7.50-7.36 (m, 5H), 6,82 (bs, IH), 6.77 (s, IH), 3.81-3.78 (m, 4H), 3.63-3.56 (m, 4H), 3.20-3.15 (m, IH), 2.80-2.77(m, I H). MS (ES) m/e 399(M+1, 100%).

Compound-56: Synthesis of 6-((2-hydroxyethyl)amino)-N-(2-morpholinobenzo[d]

6-((2-hydroxyethyl)amino)-N-(2-mo holinobenzo[d]thiazol-6-yl) icolinamide (0.015g, 17%) was prepared from 6-bromo-N-(2-mo holinobenzo[d]thiazol-6-yl)picolinamide (0.1 g,0.24mmol) from step-v of compound-49 by following the same process in compound-53.

Ή NMR (400MHz, DMSO-c/₆) 610.20 (s, IH), 8.305 (d, J=2Hz, IH), 7.64-7.54 (m, 2H), 7.48-7.46 (m, IH), 7.26-7.24 (m, I H), 6.86 (bs, IH), 6.76-6.74 (m, IH), 4.74-4.72 (m, lH), 3.63-3.60 (m,4H), 3.59-3.48 (m, 8H). MS (ES) m/e 400(M+1 , 80%).

Compound-57: S nthesis of N- 2-mor holinobenzo d oxazol-6- l -3-nitrobenzamide.

N-(2-morpholinobenzo[d]oxazol-6-yl)-3-nitrobenzamide (0.025g, 17%) was prepared from 2-morpholinobenzo[d]oxazol-6-amine (0.05g,0.23mmol) from step-(i) of compound-34 by following the same process in step-(ii) compound-34.

Ή NMR (400MHz, DMSO- ) 510.63 (bs, I H), 8.79 (s, IH), 8.45-8.40 (m, 2H), 8.01 (d, J=1.6Hz, I H), 7.87-7.83 (m, IH), 7.49-7.46 (m, IH), 7.30 (d, J=8.6Hz, IH), 3.74-3.58 (m, 4H), 3.32-3.29 (m, 4H). MS (ES) m/e 369(M+1, 100%).

Compound-58; N-(2-(2,6-dimethyImorpholino)benzo[d]oxazol-6-yl)-[2,4'-bipyridine]- 6-carboxamide.

(i) CS₂ , OH, Ethano!, 75°C,18h; (ii)2,6-Dimethyl morpholine, 95°C, 3h;(iii) Fe powder, Conc.HCl, ethanol, H₂0, 80°C, 2h; (iv) 6-bromopicolinic acid, EDC-HC1, HOBT, D F, 25°C, 8-12h; (v) pyridin-4-ylboronic acid, K₃P0₄, Pd(dppOCl₂,To!uene/EtoH(2: l ), H₂0, 1 I 0°C, 2h.

Step (i and ii): The process of these steps may be adopted from step 1 and 2 of intermediate-4.

Step (iii,iv and v): The process of these steps may be adopted from step i,ii and iii of step- 2 in Compound-2.

Ή NMR (400MHz, DMSO- ) 610.61 (bs, 1 H), 8.77 (bs, 2H), 8.38-8.08 (m, 6H), 7.60- 7.56 (m, 1 H), 7.31 (d, J=7.8Hz, 1 H), 4.01 -3.98 (m, 2H), 3.70-3.65 (m, 2H), 2.83-2.77 (m, 2H), 1.76(s, 6H). MS (ES) m/e 430(M+1 , 100%).

Biological Activity:

1) Invitro studv:Compounds were screened in the TR-FRET assay with IRAK4 kinase obtained from Upstate-Millipore. 5 nanogram of IRAK4 kinase was used for the assay. The compound was incubated with the kinase for 30 minutes at room temperature. After the incubation, substrate mixture [Biotin Histone H3 as substrate at a concentration of Ι ΟΟηΜ and ATP at a concentration of 20 μΜ] was added. The above reaction was stopped by the addition of 40mM EDTA after the 30 minutes kinase reaction followed by the addition of 0.5nM of Eu-labelled antiphospho tyrosine antibody from Perkin Elmer. The fluorescence excitation at 340nm and emission at 615nm/665nm was measured. The compounds were initially screened at 1 μΜ and 10 μΜ concentration. The potent compounds were taken for the dose response studies. For IC₅o determination, l/3^rd serial dilution was made from the original stock with the highest concentration of 10μΜ and the dose- response curve fitting was done using GraphPad software. The compounds were screened at 1 μΜ concentration and the results are summarized in table below along with the IC₅o (μΜ) details for selected examples. The IC50 values of the compounds are set forth in below Table wherein "A" refers to an IC₅o value of less than 50 nM, "B" refers to IC₅₀ value in range of 50.01 to 250 nM and "C" refers to IC₅₀ value of greater than 250 nM.

2) Protocol for Cytokine modulating effect of NCE on Lipopolysaccharide (LPS)- induced elevated serum levels of tumor necrosis factor-a (TNF-a) in rats.

Procedure: Female Wistar rats were procured from in-house and acclimatized for 4 days, were maintained at controlled temperature on 12h light dark cycle (6.30 am to 6.30 pm) and provided standard chow and water ad libitum.Animals were fasted for 14-16 hours and were dosed with with respective doses of (Compound 49) 1 hour before LPS administration. Dexamethasone was given 0.5hr before LPS administration. LPS (0.3mg/kg) was administered intraperitoneally. Animals were bled after 1 hour of LPS injection. Blood was allowed to clot and centrifuged at 10,000 rpm for 10 minutes and serum was separated frozen at -80°C till analysis. TNFa levels were measured by sandwich ELISA according to the manufacturer's instructions (R& D Systems).

Groups:

^• Compound 49 showed significant inhibition (53%) of elevated serum TNF- a levels in RAT IP LPS model at 30 mg/Kg p.o.

Claims

WE CLAIM:

1 . A compound of for -

wherein,

X is selected from O, S, and NH;

A is selected from aryl or heteroaryl;

R at each occurrence is independently selected from hydrogen, cyano, halo, hydroxy, -N0_2, -NR³R⁴, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyi, optionally substituted heterocycloalkyl or optionally substituted heteroaryl; wherein the optional substituent, in each occurrence, is independently selected from halo, alkyl, haloalkyl, cyano, -NR⁵R⁶ or -COOR⁷;

R¹ at each occurence is independently selected from hydrogen, halogen, alkyl, aryl, heterocycloalkyl, heterocycloalkylalkyi, heteroaryl, Y-arylalkyl or -Y-cycloalkyl; wherein cycloalkyi, aryl, heterocycloalkyl, heterocycloalkylalkyi, heteroaryl and arylalkyl can be optionally substituted with hydroxy, alkyl, haloalkyl, cyano or halo;

Y is selected from direct bond, O, -C(O)- or NR⁷;

R³ and R⁴ are independently selected from hydrogen, hydroxyalkyl, aminoalkyl, optionally substituted alkyl, optionally substituted heterocyclyl, optionally substituted aryl; wherein the optional substituent, in each occurrence, is independently selected from halo, haloalkyl or -COOR⁷;

R⁵ and R⁶are independently selected from hydrogen, alkyl, COR⁷ or -COOR⁷; R⁷at each occurrence is independently selected from hydrogen or alkyl; and m, n and p are selected from 1, 2 or 3.

2. The compound of claim 1 , wherein X is S.

3. The compound of claim 1 , wherein X is O.

4. The compound of claim 1 , wherein A is heteroaryl.

5. The compound of claim 4, wherein the heteroaryl is pyridine.

6. The compound of claim 1 , wherein R is optionally substituted heteroaryl.

7. The compound of claim 6, wherein the heteroaryl is selected from the group consisting of pyrazole, pyridine, pyrimidine, quinoline and 7-azaindole.

8. The compound of claim 1 , wherein R¹ is hydrogen, alkyl, heterocycloalkyl, heterocycloalkylalkyl or -Y-cycloalkyl.

9. The compound of claim 8, wherein the hetereocycloalkyl is piperidine, pyrrolidine or morpholine.

10. The compound of claim 8, wherein the heterocycloalkylalkyl is pyrrolodin- 1 - ylmethyl.

1 1. The compound of claim 8, wherein the alkyl is CM alkyl.

12. The compound of claim 8, wherein Y is direct bond or NR⁷ and cycloalkyl is cyclopropyl.

13. A compound according to claim 1 , having the formula (IA):

wherein, R, R'. R² _, 'm', 'n' and 'p' are as defined in ^'claim- 1. 14. A compound of formula (IB) according to claim 1 , having the formula (R¹)n (R²)p

(IB) wherein, R, R' , R² _, 'm', 'n' and 'p' are as defined in claim-1.

15. The compound of claim 1 , wherein the compound is selected from consisting of

bipyridine]-6-carboxamide;

14. N-(2-moφholino-5-(piperidίn-l-yl)benzo[d]thiazol-6-yl)-6-(lH-pyrazol-5- y picolinamide;

15. 6'-amino-N-(2-mo holino-5-(piperidin-l -yl)benzo[d]o azol-6-yl)-[2,3'- bipyridine]-6-carboxamide;

16. 6'-amino-N-(5-(2-hydroxyphenyl)-2-mo holinobenzo[d]oxazol-6-yl)-[2,3'- bipyridine]-6-carboxamide;

17. N-(5-cyclopropyl-2-mo holinobenzo[d]oxazol-6-yl)-6-( l H-pyrazol-5- yI)picolinamide;

18. 5-bromo-N-(2-moφholino-5-(piperidin- 1 -yl)benzo[d]oxazol-6-y 1)- 1 H- pyrrolo[2,3-b]pyridine-l -carboxamide;

19 N-(2-moφholino-5-(piperidin-l -yl)benzo[d]o azol-6-yl)-6-(lH-pyrrolo[2,3- b]pyridin-5-yl)picolinamide;

20 N-(7-methyl-2-moφholinobenzo[d]oxazol-6-yl)-6-(lH-pyrrolo[2,3-b]pyridin-5- yl)picolinamide;

21 N-(7-methyl-2-moφholinobenzo[d]oxazol-6-yl)-[2,4'-bipyridine]-6-carboxamide;

22. N-(7-isobutyl-2-moφholinobenzo[d]oxazol-6-yl)-[2,4^,-bipyridine]-6- carboxamide;

23. N-(7-isobutyl-2-moφholinobenzo[d]oxazol-6-yl)-6-(lH-pyrrolo[2,3-b]pyridin-5- yl)picolinamide;

24 N-(2-moφholino-4-phenylbenzo[d]oxazol-6-yl)-6-(lH-pyrrolo[2,3-b]pyridin-5- yl)picolinamide;

25 6'-amίno-N-(2-moφholino-4-phenylbenzo[d]oxazol-6-yl)-[2,3'-bipyridine]-6- carboxamide;

26 N-(2-moφholino-4-(pyridin-4-yl)benzo[d]oxazol-6-yl)-[2,4'-bipyridine]-6- carboxamide;

28 N-(2,5-dimoφholinobenzo[d]thiazol-6-yl)-6-(lH-pyrrolo[2,3-b]pyridin-5- yl)picolinamide; _f

29 6'-amίno-N-(5-cyclopropyl-2-mo holinobenzo[d]thiazol-6-yl)-[2,3'-bipyridine]- 6-carboxamide;

30 N-(5-cyclopropyl-2-moφholinobenzo[d]thiazol-6-yl)-6-(l H-pyrazol-5- yl)picolinamide;

31 Ν-(5-(ςγοΙορΓοργ1(Γη6ΐΗγ1)3ΐτιίηο)-2-ηιο 1ιο1ΐηοΒ6ηζο[ ]ΛΪ3ζο1-6^1)-6-(1 Η- pyrazol-5-yl)picolinamide;

32 6'-amino-N-(5-isobutyl-2-mo holinobenzo[d]thiazol-6-yl)-[2,3'-bίpyridine]-6- carboxamide;

33 6'-amino-N-(2-moφholino-5-(pyrrolidin-l -yln^ethyl)benzo[d]thiazol-6-yl)-[2,3'- bipyridine]-6-carboxamide;

34. tert-butyl (l-(6-((2-mo holinobenzo[d]oxazol-6-yl) carbamoyl)pyridine

-2-yl)pyrrolidin-3-yl)carbamate;

35. 6-(3-aminopyrrolidίn-l -yl)-N-(2-mo holinobenzo[d]o azol-6-yl)picolinamide;

36. 2'-fluoro-N-(2-moφholinobenzo[d]oxazol-6-yl)-[2,4'-bipyridine]-6-carbo amide;

37. N-(2-moφholίnobenzo[d]o azol-6-yl)-[2,3'-bipyridine]-6-carboxamide;

38. N-(2-moφholίnobenzo[d]ox zol-6-yl)-6-(pyrimidin-5-yl)picolinamide;

39. N-(2-moφholinobenzo[d]oxazol-6-yl)-[2,4'-bipyridine]-6-carboxamide;

40. 6-(2-aminopyrimidin-5-yl)-N-(2-moφholinobenzo[d oxazol-6-yl) picolinamide;

41 . 6'-amino-N-(2-mo holinobenzo[d]oxazol-6-yl)-[2,3'-bipyridine]-6-carboxamide;

42. 6^,-acetamido-N-(2-moφholinobenzo[d]oxazol-6-yl)-[2,3'-bipyridine]-6- carboxamide;

43. 6-(lH-indazol-5-yl)-N-(2-moφholinobenzo[d]o azol-6-yl)picolinamide;

44. N-(2-moφholinobenzo[d]oxazol-6-yI)-6-(quinolin-6-yl)picolinamide;

45. N-(2-moφholinobenzo[d]oxazol-6-yl)-6-(lH-pyrrolo[2,3-b]pyridin-5- yl)picolinamide;

46. N-(2-moφhol!nobenzo[d]oxazol-6-yl)-6-(l H-pyrazol-5-yl)picolinamide;

47. N-(5-chloro-2-moφholinobenzo[d]oxazol-6-yl)-6-(l H-pyrrolo[2,3-b]pyridin-5- yl)picolinamide;

48. 6'-amino-N-(2-moφholino- lH-benzo[d]imidazol-6-yl)-[2,3'-bi yΓidine]-6- carboxamide;

49. 6^,-amino-N-(2-moφholinobenzo[d]thi zol-6-yl)-[2,3'-bipyridine]-6-carboxamide;

50. tert-butyl 4-((6-((2-mo holinobenzo[d]oxazol-6-yl)carbamoyl)pyridin-2-yl) amino)piperidine- 1 -carboxylate;

51. tert-butyl 3-((6-((2-moφholinobenzo[d]oxazol-6-yl)carbamoyl)pyridin-2-yl) amino)pyrrolidine-l -carboxylate;

52. N-(2-mo holinobenzo[d]oxazol-6-yl)-6-((3-(trifluoromethyl)phenyl)

amino)picolinamide;

53. 6-((2-aminoethyl)arnino)-N-(2-rno holinobenzo[d]oxazol-6-yl)picolinan^ide;

54. 6-((2-hydroxyethyl)amino)-N-(2-moφholinobenzo[d]o azol-6-yl)picolinamide;

55. 6-((2-aminoethyl)amino)-N-(2-rno holinobenzo[d]thiazol-6-yl)picolinan^ide;

56. 6-((2-hydroxyethyl)amino)-N-(2-moφholinobenzo[d]thiazol-6-yl)picolinarnide;

57. N-(2-moφholinobenzo[d]oxazol-6-yl)-3-nitrobenzamide; and

58. N-(2-(2,6-dimethylmoφholino)benzo[d]oxazol-6-yl)-[2,4'-bipyridine]-6- carboxamide.

16. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula (I) according to claim 1 , their pharmaceutically acceptable derivatives, salts, solvates, tautomers, hydrates or individual isomers and mixtures of isomers thereof or respective N-oxide, in admixture with at least one pharmaceutically acceptable excipient including mixtures thereof in all ratios, for use as a medicament.

17. A method of treating a disease in an animal in which inhibition of protein kinase activity can prevent, inhibit or ameliorate the pathology and/or symptomology of the disease, which method comprises administering to the animal a therapeutically effective amount of at least one compound of Formula (I) according to claim 1, their pharmaceutically acceptable salts, of individual isomers and mixtures of isomers thereof or respective N-oxide.

18. The method of claim 17, wherein the protein kinase disorders are selected from cancers, allergic disorders, autoimmune disorders, inflammatory disorder and/or conditions associated with inflammation and pain, proliferative diseases, hematopoietic disorders, hematological malignancies, bone disorders, fibrosis disorders, metabolic disorders, muscle disorders, respiratory disorders, pulmonary disorders, genetic developmental diseases, neurological and neurodegenerative disorders, chronic inflammatory demyelinating neuropathies, cardiovascular, vascular or heart disorders, ophthalmic/ocular disorders, wound repair, infection and viral diseases.

19. The method of claim 17, wherein the protein kinase is selected from the group consisting of Abl, ALK, AMP , Aurora, Axl, Bcr-Abl, BIK, Bmx, BRK, BTK, c- Kit, CSK, eSrc, CDK1 , CHK2, CK1 , CK2,CLK2, CaMKII, CaMKIV, DYRK2, EGFR, EphB l , FES, FGFR1 , FGFR2, FGFR3, Fltl , Flt3, FMS, Fyn, GSK3P, IGF- 1 R, ΙΚΚα, Ι Κβ, IR, IRAK4, ITK, JAK2, JAK3, JN lal, JNK2a, KDR, Lck, Lyn, MAPK1, MAP AP-K2, MEK1, MET, MKK4, MKK6, MST2, NEK2, NLK, p70S6K, PAK2, PDGFR, PDGFRa, PDKl , Pim-2, PIk3, PKA, PKBa, PKCa, PKC0, PKD2, c-Raf, RET, ROCK-I, ROCK-II, Ron, Ros, Rskl, SAPK2a,SAPK2b, SAPK3, SAPK4, SGK, SIK, Syk,TAKl, TBKl , Tie2, TrkA, TrkB, WNK3, and ZAP-70.

^' 20. The method of claim 17, wherein the kinase is IRAK4.