OA17319A

OA17319A - Novel 3,5-Disubstituted - 3H - Imidazo [4,5B] Pyridine and 3,5- Disubstituted -3H [1,2,3]Triazolo [4,5-B] Pyridine compounds as modulators of C-Met protein Kinases.

Info

Publication number: OA17319A
Application number: OA1201400441
Authority: OA
Inventors: Swaroop Kumar Venkata Satya VAKKALANKA; Dhanapalan Nagarathnam; Srikant Viswanadha; Meyyappan Muthuppalaniappan; Govindarajulu Babu; Prashant K. Bhavar
Original assignee: Rhizen Pharmaceuticals Sa
Priority date: 2012-03-30
Filing date: 2013-02-27
Publication date: 2016-05-23

Abstract

The present invention provides compounds useful as C-met protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of Cmet kinase mediated diseases or disorders with them.

Description

NOVEL 3,5-DISUBSTlTUTED-3H-IMIDAZO[4,5-B]PYRIDINE AND 3,5- DISUBSTITUTED *3H-[1,2,3]TRIAZOLO[4,5-B] PYRIDINE COMPOUNDS AS MODULATORS OF C-MET

PROTEIN KINASES

This application claims the benefit of Indian Provisional Patent Application No. 1262/CHE/2012 dated 30” March 2012 ail of which is hereby incorporated by reference.

FIELD OF THE INVENTION

The présent invention provides compounds useful as protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prévention and/or amelioration of kinase mediated diseases or disorders with them.

BACKGROUND OF THE INVENTION

In the recent past, immense research has been dedicated to the discovery and understanding of the structure and fondions of enzymes and bio-molecules associated with various diseases. One such important class of enzymes that has been the subject of extensive research is protein kinase.

In general, protein kinases represent a set of structurally related phosphory! transferases having conserved structures and catalytic fonctions. Thèse enzymes modify proteins by chemically adding phosphate groups (phosphorylation). Phosphorylation involves the removal of a phosphate group from ATP and covalently attaching it to amino acids that hâve a free hydroxyl group such as serine, threonine or tyrosine. Phosphorylation usually results in a functional change of the target protein (substrate) by altering enzyme activity, cellular localization or association with other proteins. Up to 30% of ali proteins may be modified by kinase activity.

This class of proteins are dassified into subsets depending upon the substrate they act upon, such as tyrosine kinase, serine/theronîne kinase, histidine kinase and the like. These proteins can also be dassified based on their localization into receptor tyrosine kinases (RTKs) or nonreceptor tyrosine kinases. '

Receptor tyrosine kinases (RTKs) hâve an extracellular portion, a transmembrane domain, and an intracellular portion, while non-receptor tyrosine kinases are entirely intracellular. Receptor tyrosine kinase mediated signal transdudion is typically inrtiated by an extracellular interaction . ASSIGNMENT

TICIS ASSIGNMENT by Incozen Therapeutic; Pvt LtdL, a company organhed under and pursuant lo the laws of India having its principal place of business at 450-Aîexandria Knowledge Park, Shameerpet, Hyderabad-500 078, INDIA (hereînafter referred to as Assigner);

WÏTEREAS, Assignor owns en interest to the patent applications (hereafter the “Incozen Patent Applications) entitled * NOVEL 33-DISUBSTITUEI>JH-IMIDAZOI4^B]PYRn>INE AND 3,5- DISUBSTTTUED -3H-(1,2,3ITRIAZOLO[4,5-B] PYRJCDINE COMPOUNDS AS MODULATORS OF C-MET PROTEIN KINASES”, and as set forth in International Patent Application No. PCT/ID2013/051577, filed February 27,2013, and its priority application, nemely, Indien Patent Application No. 1262/CHE/20I2, filed March 30,2012; and

WHEREAS, Rhlzen Pharmaceuticals SA, a company otganized under and pursuani to the laws of Swltzeriand having its principal place of business at Fritz Courvoisier 40,2300 La Chatix-de· Fonds, Swltzeriand (hereînafter referred to u Assignée), is desrous of acquiring the right, title and interest In and to the Incozcn Patent Applications la tbe U.S. and aD countries throughout the worid except INDIA, and in and to any Letters Patent lo be obtained therefore and thereon.

NOW, THEREFORE, in considération of One Dollar (Si.00) and other good and sufficient considération, the reccipt of which is hereby acknowledged, Assignor hu sold, asstgned, transferred and set over, and by these présents do scll, assign, transfer and set over, unto Assignée, its successors, legal représentatives and assigns, Assignons entire right, title and interest in and to the Incozen Patent Applications, and in and to any and ali direct and indirect divisions, continuations and continuations-in-part of the Incozen Patent Applications, and any and ail Letten Patent tn the U.S. and ail countries throughout the worid which may be granted therefor and thereon, and reissues, reexamînatlons and extensions of said Letters Patent, and ali rights under the International Convention for the Protection of Industrial Property, the same to be held and enjoyed by Assignée, for its own use and benefit and the use and benefit of its successors, legal représentatives and assigns, to the fiill end of the term or terms for which Letten Patent may be granted and/or extended, as fùliy and entirely as the same would bave been held and enjoyed by Assignor, had this sale and assignment not been made.

The Assignor hereby covenants and agréés to and with said Assignée, its successors and assigns, that whenever Assignée, its ccunsetor représentative, or the counselor représentative of rts 1 successors or assigns, shalt advise that an amendment to, or a division o£ or any other proceeding or action in connection with the Incozen Patent Applications, induding interférence proceedings, is lawful and désirable, or that a reissue or continuation or extension of such application or patent issuing therefrom is lawful and désirable, Asstgnor will sign ail papers and drawings, take ail rightfül oaths and affidavits, and do ail acts necessary or required to be done for the procurement of ail lawftil rights associated with the Incozen Patent Applications, or for the reissue or continuation or extension of the same, will do ail acts necessary or required to secure in said Assignée, its successors or assigns, the title to and tull benefit of al! rights hereby assigned, without charge to said Assignée or its successors or assigns, but at its expense; and Assigner hereby appoints every présent or future oSicer of said Assignes as Assignons agent to sign ail such papers and to do il! such necessary acts on its behalÇ to the fùllest extent permitted by law;

Tbe Assigner hereby authorizes and requests the Commissioner of Patents and Trademarks and any other granting authority to issue any Letters Patent resulting from the Incozen Patent Applications to the Assignée.

INCOZEN THERAPEimCS PVT. LTD.

Date: 5*September,2ÛH

Name: Swaroop Kumar V.S. Vakkalanka

Title: MD Λ CEO

International Application No. PCT/ 182013/051577

FURTHER INFORMATION CONTINUED FROM PCT/ÎSA/ 210

This International Searching Authority found multiple (groups of) inventions in this international application, as follows:

1. claims: 16, 17(conpletely); 1-15, 18-29, 31-45(partially)

Compounds of formula (IA-I) or according to Claims 28 and 29 wherein E is selected from C0NH-0-(CRxRy)p-0Rx and C0NH-0-(CRxRy)p-[cycloalkyl]-(CRxRy)p-0Rx, and related claims thereto.

2. claims: 1-15, 18-29, 31-45(all partially)

Compounds of formula (IA-I) or according to Claims 28 and 29 wherein E is selected from C0NH-(CRxRy)p-0Rx and CONH-(CRxRy)p-[cycloalkyl]-(CRxRy)p-ORx, and related claims thereto.

3. claims: 1-15, 18-29, 31-45(all partially)

Compounds of formula (IA-I) or according to Claims 28 and 29 wherein E is selected from CONH-(CRxRy)p-NRxRy and CONH-(CRxRy)p-[cycloalkyl]-(CRxRy)p-NRxRy, and related claims thereto.

4. claims: 1-15» 18-27, 31-45(all partially)

Conpounds of formula (IA-I) wherein E is selected from CONH-(CRxRy)p-S(O)qRx and CONH-(CRxRy)p-[cycloalkyl]-(CRxRy)p-S(0)qRx, and related claims thereto.

5. claims: 28, 31-45(all partially)

Compounds according to Claim 28 wherein the substituent équivalent to D of formula (IA-I) is an oximether, and related claims thereto.

6. claims: 28, 29, 31-45(all partially)

Compounds according to Claims 28 and 29 wherein the substituent équivalent to D of formula (IA-I) is an hydrazone, and related claims thereto.

7. claims: 29, 31-45(all partially)

The compound according to Claim 29 which represents Exemple 106 wherein the substituent équivalent to D of formula (IA-I) is acetyl, and related claims thereto.

International Application No. PCT/ IB2013/051577

FURTHER INFORMATION CONTINUED FROM PCT/ÎSA? £10

8. daims: 30-45(partially)

Compounds according to Claim 30 wherein the substituent équivalent to E of formula (IA-I) is an ami de, not covered by inventions (1) to (4), and related claims thereto.

9. claims: 30-45(partially)

Compounds according to Claim 30 wherein the substituent équivalent to E of formula (IA-I) is a carboxylate, and related claims thereto.

with a spécifie growth factor (ligand), followed by receptor dimerization, stimulation of the intrinsic protein tyrosine kinase activity, and phosphorylation of amino acid residues. The ensuing conformational change leads to the formation of complexes with a spectrum of cytoplasmic signalling molécules and facilitâtes a myriad of responses such as cell division, différentiation, metabolic effects, and changes in the extracellular microenvironment.

At présent, at least twenty (20) distinct RTK subfamilies hâve been identified. One subfamily of the RTKs is designated as the Met subfamily (c-Met, Ron and Sea). For a detailed discussion of protein kinases, see, Plowman et al., DN&P 7(6): 334-339, 1994, Blume- Jensen, P. et a!.. Nature, 2001, 411(6835):355-365 and Manning, G. et ai. Science, 2002, 298(5600): 19121934.

Kinases hâve also been dassified either based on the pathway or the diseases in which they are involved (visitwww.reactionbiology.com/pages/kinase.htm). c-Met has been identified as involved in oncogenesis.

Protein kinases exert their physiological fonctions through phosphorylation of proteins (or substrates) thereby modulating the cellular activities of the substrate in various biological contexts. Protein kinases are known to control a wide variety of biological processes such as cell growth, survival and différentiation, organ formation and morphogenesis, neovascularisation, tissue repair and régénération, ln addition to their fonctions in normal tissues/organs, many protein kinases also play specialized rôles in a host of human diseases including cancer. A subset of protein kinases (also referred to as oncogenic protein kinases), when dysregulated, can cause tumor formation and growth and contribute to tumor maintenance and progression (Blume- Jensen P et al, Nature, 2001,411(6835):355-365). Thus far, oncogenic protein kinases represent one of the largest and most attractive groups of protein targets for therapeutic intervention and drug development

Both receptor and non-receptor protein kinases hâve been found to be attractive targets for small molécule drug discovery due to their impact on cell physiology and signalling. Dysrégulation of protein kinase activity thus leads to altered cellular responses including uncontrolled cell growth associated with cancer, ln addition to oncological indications, altered kinase signalling is implicated in numerous other pathological diseases. These include, but are not limited to immunological disorders, cardiovascular diseases, inflammatory diseases, and degenerative diseases.

A significant number of tyrosine kinases (both receptor and nonreceptor) are associated with cancer (see Madhusudan S, Ganesan TS. Tyrosine kinase inhibitors in cancer therapy. Clin. Biochem., 2004, 37(7):618-35.). Clinical studies suggest that over expression or dysrégulation of tyrosine kinases may also be of prognostic value. For example, members of the HER family

of RTKs hâve been implicated in breast, colorectal, head and neck and lung cancer. Mutation of c-Kit tyrosine kinase is associated with decreased survival in gastrointestinal stromal tumors (GIST). In acute myelogenous leukemia, Flt-3 mutation predicts shorter disease free survival. VEGFR expression, which is important for tumor angiogenesis, ls associated with a lower survival rate in lung cancer. Tie-1 kinase expression is inversely correlated to survival in gastric cancer. BCR-Abl expression is an important predictor of response in chronic myelogenous leukemia while Src tyrosine kinase expression is co-related to the stage of colorectal cancer. Modulation (particularly inhibition) of cell prolifération and angiogenesis, the two key cellular processes needed for tumor growth and survival is an attractive goal for development of smallmolecule drugs (Matter A. Drug Disc. Technol., 2001, 6, 1005-1024). Anti-angiogenic therapy represents a potentially important approach for the treatment of solid tumors and other diseases associated with dysregulated vascularisation including ischémie coronary artery disease, diabetic retinopathy, psoriasis and rheumatoid arthritis. Similarly, cell antiproliférative agents are désirable to slow or inhibit the growth of tumors.

Some of the kinases implicated in cancer are c-Met, RON (récepteur d’origine nantais) receptor, Vascular Endothélial Growth Factor (VEGF) receptor, Epidermal growth factor receptor kinase (EGF-R kinase), Eph receptors, c-Kit, and Flt-3.

A number of small molécule kinase modulators hâve found their way into the dinic which either act selectively on either one or multiple kinases. These indude Gefitinib (AstraZeneca), a EGFR kinase inhibitor; Gfeevec (Novartis), a dual c-Kit and Abl kinase inhibitor approved for the treatment of Chronic Myeloid Leukemia (CML) and gastrointestinal stroma cancers; Dasatinib (BMS), a dual BCR/ABL and Src family tyrosine kinases inhibitor, and Sunitinib (Pfizer) a multi kinase inhibitor targeting PDGF-R.VEGF-R, RET, KIT(CD117), CSF-1R and flt-3.

The kinase, c-Met, is the prototypic member of a subfamily of heterodimeric receptor tyrosine kinases (RTKs) which indude Met, Ron and Sea (see Birchmeier, C. et a/., Nat. Rev. Mol. Cell Biol., 2003, 4(12):915-925; Christensen, J. G. et al.. Cancer Lett., 2005, 225(1): 1-26). Expression of c-Met occurs in a wide variety of cell types induding épithélial, endothélial and mesenchymal cells where activation of the receptor induces cell migration, invasion, prolifération and other biological activities assodated with invasive cell growth. As such, signal transduction through c-Met receptor activation is responsable for many of the characteristics of tumor cells.

The only high affinity endogenous ligand for c-Met is the hépatocyte growth factor (HGF), also known as scatter factor (SF). Binding of HGF to c-Met induces activation of the receptor via autophosphorylation resulting in an increase of receptor dépendent signalling, which promûtes cell growth and invasion. Both c-Met and HGF are widely expressed in a variety of organs, but

their expression is normally confined to cells of épithélial and mesenchymal origin. Anti-HGF antibodies or HGF antagonists hâve been shown to inhibit tumor metastasis in vivo (see, Maulik et al„ Cytokine & Growth Facta· Reviews, 2002, 13, 41-59). The biological fonctions of c-Met (or c-Met signalling pathway) in normal tissues and human malignandes such as cancer hâve been well documented (Christensen, J.G. et al., Cancer Lett., 2005, 225(1): 1-26; Corso, S. et al., Trends in Mol. Med., 2005, Il (6):284-292).

Tumor growth progression involves the recruitment of new blood vessels into the tumor as well as invasion, adhesion and prolifération of malignant cells. c-Met over expression has been demonstrated on a wide variety of tumor types including breast, colon, rénal, lung, squamous cell myeloid leukemia, hemangiomas, melanomas, astrocytomas, and glioblastomas. Additionally activating mutations in the kinase domain of c-Met hâve been identified in hereditary and sporadic rénal papilloma and squamous cell cardnoma. See Maulik et a! Cytokine & growth Fador reviews 2002,13,41-59; Longati et al Curr Drug Targets 2001,2,4155; Funakoshi et al Clinica Chimica Ada 2003 1-23. Thus modulation of c-Met offers an attractive opportunity to target key oncogenic processes thus limiting cell prolifération, survival and metastasis.

Dysregulated c-Met pathway is linked to tumor formation, growth, maintenance and progression (Birchmeier, C. et al., Nat. Rev. Mol. Cell. Biol. 2003, 4(12):915-925; Boccacdo, C. et al., Nat. Rev. Cancer 2006, 6(8):637-645; Christensen, J.G. et al., Cancer Lett. 2005, 225(1): 1-26). HGF and/or c-Met are over expressed in significant portions of most human cancers, and are often assodated with poor dinical outcomes such as more aggressive disease, disease progression, tumor metastasis and shortened patient survival. Further, patients with high levels of HGF/c-Met proteins are more résistant to chemotherapy and radiotherapy. In addition to abnormal HGF/c-Met expression, the c-Met receptor can also be activated in cancer patients through genetic mutations (both germline and somatic) and gene amplification. Although gene amplification and mutations are the most common genetic alterations that hâve been reported in patients, the receptor can also be activated by délétions, troncations, and gene rearrangement, as well as abnormal receptor processing and defective négative regulatory mechantsms.

The various cancers in which c-Met is implicated indude but are not Iimited to cardnomas (e.g., bladder, breast, cervical, cholangiocardnoma, colorectal, esophageal, gastric, head and neck, kidney, liver, lung, nasopharygeal, ovarian, pancréas, prostate, thyroid); musculoskelétal sarcomas (e.g., osteosarcaoma, synovial sarcoma, rhabdomyosarcoma); soft tissue sarcomas (e.g., MFH/fibrosarcoma, leiomyosarcoma, Kaposi's sarcoma); hematopoietic malignandes (e.g., multiple myeloma, lymphomas, adult T cell leukemia, acute myelogenous leukemia.

chronic myeloid leukemia); and other neoplasms (e.g., glioblastomas, astrocytomas, melanoma, mesothelioma and Wilm's tumor (www.vai.org/met/; Christensen, J.G. et al., Cancer Lett 2005, 225(1): 1-26). c-Met inhibitors may also be usefui ln preventative and adjuvant therapy settings. ln addition, certain cancers (e.g., papillary rénal cell carcinoma, and some gastric and lung cancers) may be treated with c-Met Inhibitors as they are belîeved to be driven by c-Met mutation/genetic alteration and dépendent on c-Met for growth and survtval. These cancers are expected to be sensitive to treatment.

The notion that activated c-Met contributes to tumor formation and progression and could therefore be a potentiai target for effective cancer intervention has been further validated by numerous predinical studies (Birchmeier, C. et al., Nat Rev. Mol. Cell Biol. 2003, 4(12):915925; Christensen, J.G. et al., Cancer Lett. 2005, 225(l): 1-26; Corso, S. et al., Trends in Mol. Med. 2005, 11(6):284- 292). For example, studies hâve demonstrated that the tpr-met fusion gene, over expression of c-Met, and activated c-Met mutations caused oncogenic transformation of various model cell lines and resulted in tumor formation and metastasis in mice. Conversely, significant anti-tumor and anti-metastasïs activities hâve been demonstrated in vitro and in vivo with agents that spedfically impair and/or block HGF/o-Met signalling. Those agents indude anti-HGF and anti-oMet antibodies, HGF peptide antagonists, decoy c-Met receptor, c-Met peptide antagonists, dominant négative c-Met mutations, c-Met spedfic antisense oligonudeotides and ribozymes, and sélective small molécule c-Met kinase inhibitors (Christensen, J.G. et al., Cancer Lett. 2005, 225(1): 1-26). ln addition to its established rôle in cancer, abnormal HGF/c-Met signalling is also implicated in atherosderosis, lung fibrosis, rénal fibrosis and régénération, liver diseases, allergie disorders, inflammatory and autoimmune disorders, cerebrovascular diseases, cardiovascular diseases, and conditions assodated with organ transplantation. See Ma, H. et al., Atherosderosis. 2002,164(l):79-87; Crestani, B. et al., Lab. Invest 2002,82(8): 1015-1022; Sequra-Flores, A.A. et al., Rev. Gastroenterol. Mex. 2004, 69(4)243-250; Morishita, R. et al., Curr. Gene Ther. 2004, 4(2)199-206; Morishita, R. et al., Endocr. J. 2002, 49(3)273-284; Liu, Y., Curr. Opin. Nephrol. Hypertens. 2002, I I (l):23-30; Matsumoto, K. et al., Kidney Int. 2001, 59(6):2023-2038; Balkovetz, D.F. et al., Int. Rev. Cytol. 1999, 186:225-250; Miyazawa, T. et al., J. Cereb. Blood Flow Metab. 1998, 18(4)345-348; Koch, A.E. et al., Arthritis Rheum. 1996, 39(9):1566-1575; Futamatsu, H. et al.. Cire. Res. 2005, 96(8)823- 830; Eguchi, S. et al., Clin. Transplant. 1999,13(6)536-544.

c-Met îs thus an attractive target from a dinical perspective mainly because of its upstream localisation which aids in early détection and timrting metastasis and implications in the growth and métastasés of most types of cancers. These observations suggest that c-Met kinase inhibitors would be an effective treatment for tumors driven by c-Met, and also would prevent disseminated micro métastasés from further progression.

A family of novel compounds hâve been discovered which exhibit c-Met modulating ability and hâve an ameliorating effect against disorders related to abnormal c-Met activity such as Johnson & Johnson’s JNJ-38877605, Amgen’s AMG-458, Eisai’s E-7050 and Pfizer’s PF04217903. However, to date, none of them hâve been used In a clinical study.

AMG-458

JNJ-38877605

More recently Dussault et. al., Anti-Cancer Agents in Médicinal Chemistry, 2009, 9(2), 221-229, hâve provided additional insight about a receptor tyrosine kinase namely, RON (récepteur d’origine nantais) which is dosely related to c-Met. Both c-MET and RON receptors upon activation can induce cell migration, invasion, prolifération and survival. Moreover, both possess oncogenic activity in vitro and in vivo and are often dysregulated in human cancers.

While c-Met is now a well-accepted target for anti-cancer treatment, less is known about the rôle of RON in cancer. Despite their common attributes, c-Met and RON are adivated by different mechanisms in cancer cells. Due to a signifîcant homology between the two RTKs, some small molécule kinase inhibitors of c-Met hâve inhibitory activity on RON suggesting that both receptors might be involved in cancer progression. The review (Dussault et al., supra) discusses the relevance of both c-Met and RON deregulation In human cancers and the progress made In identifying small molécule kinase Inhibitors that can block the activity of these targets in vitro and In animal models. One of the compounds discussed in the review, AMG458, inhibited c-Met and RON with ICsjs of 4 and 9 nM respectively.

Various research groups around the world such as Amgen, Arquel, AstraZeneca, Bristol-Myers

Squibb, Exelixis, Eisai, Incyte, MethylGene, Pfizer, SGX Pharma, SmithKIine Beecham,

Schering, Vertex, Xcovery, Novartis and others hâve been working on targeting either single, dual or multiple kinase targets.

Patent literature belonging to some of these applicants include the following patents and/or patent publications: US 7,446,199; US 7,470,693; US 7,459,562; US 7,439,246; US 7,432,373; US 7,348,325; US 7,173,031; US 7,314,885; US 7,169,800; US 2010/0105656, US 2009/0012076; US 2008/0312232; US 2008/0161305; US 2007/0244116; US 2007/0225307; US 2007/0054928; US 2007/0179130; US 2007/0254868; US 2007/0191369; US 2006/0173055; US 2006/0135537; US 2005/0148574; US 2005/0137201; US 2005/0101650; WO 2009/002806; WO 2008/088881; WO 2008/051805; WO 2008/102870; WO 2008/078085; WO 2008/060866; WO 2008/54702; WO 2008/036272; WO 2007/111904; WO 2007/064797; WO 2006/052913; WO 2006/021881; WO 2006/021886; WO 2006/021884; WO 2006/108059; WO 2006/014325; WO 2006/052913; WO 2005/07891; WO 2005/030140; WO 2005/040345; WO 2005/028475; and WO 2005/016920.

International Publication Nos. WO 2009/058728, WO 2009/058729, WO 2009/058730 and WO 2009/058739 all assigned to Schering Corporation dîsdose a sériés of thiazole carboxamide compounds as protein kinase inhibitors and more specifically to be inhibiting Aurora, MEK1 and/or CDK2 kinases.

Further review and literature disclosure on protein kinase molécules hâve been given by Isabelle Dussault ef.a/.,(see; Anti-Cancer Agents in Médicinal Chemistry, 2009, 9, 221-229) , Ted L Underiner ef.a/.,(see; Anti-Cancer Agents in Médicinal Chemistry, 2010, 10, 7-27) and Stephen Claridge et.al (see; Bioorganic & Médicinal Chemistry Letters 18 (2008) 2793-2798). All of these patents and/or patent applications and literature disdosures are incorporated herein as reference in their entirety for all purposes.

Despite the advances made in the area of kinases and in particular the rôle that c-met, RON, EGFR or KDR pathway plays in human diseases, challenges remain in term of the complexifies of the target involved, the protein structure of the kinases, specificity issues for various kinase inhibitors, side effects and desired dinical benefits expected form the small molécule inhibitors. Accordingly, there still remains an unmet and dire need for small molécule compounds having spedfidty towards either one, two or multiple kinase inhibitors in order to regulate and/or modulate transduction of kinases, particularly c-Met, RON, EGFR or KDR for the treatment of diseases and disorders associated with kinases-mediated events.

Further a reference is made herein to International Patent Application No. PCT/IB2011/052120, filed May 13, 2011 and U.S. Patent Application No. 13/108,642 filed May 16, 2011 which generally disclose 3,5-Disubstitued-3H-lmidazo[4,5-b]Pyridine and 3,5- Disubstitued -3H17319 [1,2,3]rriazolo[4,5-b] Pyridine compounds as modulators of Protein Kinases ail of which are incorporated herein by reference in their entirety for ail purposes.

The c-Met pathway plays an important rôle In the above described human diseases including cancer. There are no c-Met inhibitors or antagoniste that are currently available for treating these human disorders that are characterized by abnormal HGF/c-Met signaling. Therefore, there is a dear unmet medical need for compounds whîch inhîbit c-Met and other kinases. The compounds, compositions, and pharmaceutical methods provided herein help meet this need.

SUMMARY OF THE INVENTION

The présent invention is direded to compounds useful as protein kinase modulators and în particular as inhibitors of c-Met.

In one embodiment, the compound of the présent invention has the formula I:

R*

^L’^Cy*

d) or a tautomer, stereoisomer, enantiomer, diastereomer, sait (e.g., pharmaceutically acceptable sait), prodrug (e.g., ester), or N-oxide thereof, wherein

XisCR¹ or N;

Cy¹ and Cy² may be same or different and are independently selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocydic group, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

LJs absent or selected from -O-, -S(=O)_q-, -NR*-, -{CR*R^b)n-, -C(-Y)-, -C(=Y)-C(=Y)-, CR*R^b-C(=Y)-CR*R^b-, -CR’R^b-Y-CR*R^b-, -C(=Y)-NR·-, -NR*-C(=Y>NR^e-, -S(=O)_q-NR*-, NR*-S(=O)_q-NR*-, -NR*-NR^a-, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl;

L₂ is selected from -O-, -S(=O)_q-, -NR¹-, -(CR^aR^b)n-, -C(=Y)-. -C(=Y)-C(=Y)-, -CR^aR^bC(=Y)-CR*R^b-, -CR*R^b-Y-CR^aR^b-, -C(=Y)-NR^a-, -NR*-C(=Y)-NR^a-, -S(=O)q-NR‘-, -NR’ S(=O)_q-NR·-, -NR’-NR’-, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl;

each occurrence of R¹ and R² may be same or different and is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, «OR·, *S(=O)q-R^a, -NR*R^b, -C(=Y)-R^a, CR^aR^b-C(=Y)-R^a, -CR'R^b-Y-CR^aR^bR^b. -C(=Y)-NR^aR^b, -NR^aR^b-C(=Y)-NR^aR^b. -S(=O)qNR^aR^b, -NR^a-S(=O)q-NR*R^b, -NR“R^b-NR^aR^b, substituted or unsubstituted C145 alkyl, substituted or unsubstituted Cj-β alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted 0« cycloalkyl, substituted or unsubstituted C^e cycloalkylalkyl, and substituted or unsubstituted C34 cycloalkenyl;

each occurrence of R^a and R^b may be same or different and are independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted C,^ alkyl, substituted or unsubstituted C₂_e alkenyl, substituted or unsubstituted C24 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cydoalkylalkyl, and substituted or unsubstituted Cj-β cycloalkenyl, or when two R^a and/or R^b substituents are directly bound to a common atom, they may be joined to form a substituted or unsubstituted, saturated or unsaturated 3-10 member ring, which may optionally include one or more heteroatoms which may be same or different and are selected from O, NR^C or S;

each occurrence of R^e is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted Ci_e alkyl, substituted or unsubstituted C» alkenyl, substituted or unsubstituted C™ alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cydoalkylalkyl, and substituted or unsubstituted Cjg cydoalkenyl;

each occurrence of Y is independently selected from O, S, and NR^a;

each occurrence of n independently represents 0,1,2,3 or 4; and each occurrence of q independently represents 0,1 or 2.

Another embodiment is a compound of formula (IA):

or a tautomer, stereoisomer, enantiomer, diastereomer, sait (e.g., pharmaceutically acceptable sait), prodrug (e.g., ester), or N-oxide thereof, wherein each occurrence of R² is independently hydrogen, nitro, hydroxy, cyano, halogen, -OR*, -S(=O)q-R·, -NR^aR^b, or -C(=O)-R^a, wherein R^aand R^b in the R² group are independently hydrogen, hydroxy, or substituted or unsubstituted C14 alkyl; and ail the other variables (i.e., Cy¹, Cy² and L²) are as defined above in relation to compound of formula (I).

Further preferred is a compound of formula (I) and (IA) wherein Cy¹ is selected from: (The line ( ^) in the structures shown below represents the point of attachment of the structure to the rest of the compound.)

d+ V- V V- VV ¥- V¥-'V».>«.

vyci oytf ώήχί Ύ“^/ .zV-tf «•o-ytf ow oytf aV^

Λ'-^ A-V “-ycr y A =—yo’oycf o-yA/^r^

05V

Y/# W û-V# ^Cù-M/ “-W <n^ °^

JTW cT’rtf ~₀-Μ^

Yet another embodiment is a compound of formula (IA-I):

R¹

’-^cy² (IA-I) or a tautomer, stereoisomer, enantiomer, diastereomer, sait (e.g., pharmaceutically acceptable sait), prodrug (e.g., ester), or N-oxide thereof, wherein

D is substituted or unsubstituted monocydic aryl or substituted or unsubstituted monocydic heteroaryl;

wherein D is substituted with a group E which is selected from -C0NH-O-(CR^,lR^y)p-OR^x, -CONH-iCR’ROp-OR”. -CONH-(CR*R*)p-NR^xR^¥, .CONH-(CR^IR^y)p-S(O)qR^x, -CONH-O(CR^xR^y)p-[cydoalkyl]-(CR^xR^ï)p-OR^x, -CONH-(CR^xR^y)p-[cydoalkyn-(CR^xR^y)p-OR^x; -CONH(CR^xR^ï)p-[cydoalkyl]-(CR^xR^ï)p-NR^xR^¥, -CONH-(CR’^,R^y)p-[cydoalky1]-(CR^,R^y)_p-S(0)_qR^x; and

D can be optionally be further substituted with one to four substituents independentiy seleded from R¹;

each occurrence of R and R^¥ is independentiy selected from hydrogen, hydroxy, haiogen, carboxyl, cyano, nitro, oxo (=0), thîo (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cydoalkyi, substituted or unsubstituted cydoalkenyl, substituted or unsubstituted cydoalkylalkyl, substituted or unsubstituted cydoalkenylalkyl, substituted or unsubstituted heterocycyl, substituted or unsubstituted heterocydylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, -COOR¹, -C(O)R^Z, -C(S)R^l, -C(O)NR^IR^I, -qOJONR’R¹, NR^ZR^Z, -NR’CONRW, -N(R^Z)SOR^Z, ^(R’JSOaR’, -(=N-N(R^Z)R^I), -NR^ZC(O)OR^Z, , NR^ZC(O)R^Z-, -NR*C(S)R^y -NROiSJNR’R’. -SONR^ZR^Z-, -SO2NR^ZR^Z-, -OR¹, OR^OJNR’R¹, -OR^ZC(O)OR^Z-, -OC(O)R^Z, -OC(0)NR^ZR^Z, -R^INR^IC(O)R^I, -ROR¹, R^IC(O)OR^I, -R^ïC(O)NR^IR^ï, -R^ZC(O)R^Z, -R^ZOC(O)R^Z, -SR¹, -SOR^Z, -SO2R^Z, and -ONO₂, or any two of R^x and R^y which are directiy bound to a common atom may be joined to form (i) a substituted or unsubstituted, saturated or unsaturated 3-14 membered ring, which may optionally indude one or more heteroatoms which may be the same or different and are selected from O, NR¹ or S, or (ii) an oxo (=0), thio (-S) or imino (=NR^Z), wherein each occurrence of R¹ is independentiy hydrogen, hydroxy, haiogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cydoalkyi, substituted or unsubstituted cydoalkenyl, substituted or unsubstituted cydoalkylalkyl, substituted or unsubstituted cydoalkenylalkyl, substituted or unsubstituted heterocycyl, substituted or unsubstituted 15 heterocydcyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, and -ONO₂, or any two of R¹ which are dîrectly bound to a common atom may be joined to form (i) a substituted or unsubstituted, saturated or unsaturated

3-14 membered ring, which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NR (where R* is H or alkyl) or S, or (ii) an oxo (=0), thio (=S) or imino (=NR²);

each occurrence of p independently represents 0,1-7 or 8;

q is an integer from 0,1 or 2;

each occurrence of R² is independently hydrogen, nitro, hydroxy, cyano, halogen, -OR*, -S(=O)_q-R*, -NR*R^b or-C(=O)-R^a wherein each occurrence of R’and R^b in group R² is independently hydrogen, hydroxy, or substituted or unsubstituted alkyl; and ail other variables are the same as defined above with respect to Formula I and (IA-l).

Yet another embodiment is a compound of formula (IA-1):

(IA-1) or a tautomer, stereoisomer, enantiomer, diastereomer, sait (e.g., pharmaceutically acceptable sait), prodrug (e.g., ester), or N-oxide thereof, wherein

Dis E ;

X¹, X² and X³ are each independently selected from -CR¹-, -CR^CR¹-, -CR*=N-, N=CR^Z-, -N=N-, -O-, -S- or -N-;

and ail the other variables (such as R², R¹, X, L₂· R*, R^Y, E, p, q and Cy²) are as defined above with respect to Formula I and (IA-1).

Further preferred îs a compound of formula (l-AI), wherein Cy² is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

Further preferred is a compound of formula (l-AI), wherein Cy² is selected from

Ό, $ A XC A XX} XQ XXj XX XX XX? XÙ ’JÇÛ X& X& XQ 'XQ 'XX? ’XQ 'XQ jÇÙ A XO XQ-ÇQ JÇQ X’ Xp -ÇQ ’^xj 'jçq '^x? ^çq

OaOxA^Akxcj. jp? X?» X? XQ Ά AxA> A? joqxq a A A

XQXOXOXQXQXQXCxXO ΧΟΧΟΧΟΧΟΧΟΧΟΧΟΧΟ χο-χο- W XAO

Xi, οφ XÔXÛ'^ÜXÛ _£$ Χφ XX XQ XQ XX xx? XX1 A A

Further preferred is a compound of formula (IA-1) wherein E is -CONH-O-(CR^xR*)p-OR^x, CONH-(CR^,'R^y)p-OR^xor-CONH-(CR^xR^ï)p-NR^xR^Y; wherein ail the variables are as defined above.

Further preferred is a compound of formula (IA-1) wherein E is -CONH-0-(CR^xR^y)p-lcycloalkyl](CR’R^p-OR*. -CONH-(CR^xR^Y)p-[cycloalkyf]-(CR^xR^Y)p-OR^x*, -CONH-(CR’RX[cycloalky1](CR^xR^Y)p-NR^xR^Y.or -CONH-(CR^xR^Y)p-{cycloalkyl]-(CR^xR^Y)p-S(0)_qR^x; wherein ail the variables are as defined above.

Further prefemed is a compound of formula (IA-1) wherein D is substituted with one to four substituents selected from hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.

Further preferred is a compound of formula (IA-1 ) wherein L₂ is -CR’R⁶-.

Further preferred is a compound of formula (IA-I) wherein L₂ is -CHz-, -CH(OH)-, -CHF-, -CF_r,

-CH (CH₃)-or-C(CH₃)2-.

Further preferred is a compound of formula (IA-Ι) wherein L₂ is -CH₂

Yet another embodiment is a compound of formula (IA-I):

(IA-I) or a tautomer, stereoisomer, enantiomer, diastereomer, sait (e.g., pharmaceutically acceptable sait), prodrug (e.g., ester), or N-oxide thereof, wherein

L₂ -Cy² is ^R R° each occurrence of R* and R” is independently selected from hydrogen, halogen, and substituted or unsubstituted (Cm) alkyl, or both R and R^b, together with the carbon atom to which they are attached, form a saturated 3 to 6 member cyclic ring which may optionally indude one or more heteroatoms which may be same or different and are selected from O, NR’ and S (where R* is R¹);

Z is selected from CR^c, S, O, NR‘, R'C=CR^C, -N=CR^c-, and -R^eC=N-;

Z, is selected from N, NR^C and CR^C;

Z₂ and Z₃ are independently selected from C or N;

R^c is absent or selected from hydrogen, hydroxy and halogen; and ail other variables are the same as defined above.

Yet another embodiment is a compound of formula (IA-I):

or a tautomer, stereoisomer, enantiomer, diastereomer, sait (e.g., pharmaceutically acceptable sait), prodrug (e.g., ester), or N-oxide thereof, wherein

ail the variables are as defined above.

Further preferred is a compound of formula (IA-Ι) wherein X¹ and X² is CR¹ and X³ is independently selected from -CR^z=CR^zor-S-,

Further preferred is a compound of formula (IA-1) wherein X’ is CH , X² is CR¹ and X³ is CR^Z=CR^Z

Further preferred is a compound of formula (IA-1) wherein Rz is Hydrogen, Halogen or substituted or unsubstituted C^ alkyl.

Further preferred is a compound of formula (IA-1) wherein R¹ is hydrogen, chlore, fluoro , -CH₃15 or -CF₃.

Further preferred is a compound of formula (IA-1) wherein D is selected from

Η^Ν

O o o o

Further preferred is a compound of formula (1A-I) wherein D is selected from

xrV? /-crVZ, .'T'tâ /Ά?’. ?”, A*?.

JT .JT

ΝΗ / _ο.ΝΗ i ΝΗ ά ΝΗ <5=, έπ> ά ΝΗ ά ΝΗ / c ,έ χ χ χ λ ,χ λ ,χ .

X X X ,C X Ρ .£/ Γ .£/ .

i- :i ,ï ,f .Y ,ί ί t .t .

~*Η ^nh t „t

Further preferred is a compound of formula (I), (IA) or (IA-1) wherein X is N or CR¹ and R¹ is H, substituied or unsubstituted C₁₄ alkyl, NH₂ ,OH, CN or CONH₂.

Further preferred is a compound of formula (I), (IA) or (IA-1) wherein R¹ is H or Cu alkyl (e.g., methyl).

Further preferred is a compound of formula (I), (IA) or (IA-1) wherein each of R² is H.

Further preferred is a compound of formula (IA-1) wherein D is

E is selected from -CONR^M-O-(CR^,R*)p-OR^x, -CONR^x-(CR^xR^y)_p-OR^x', -CONR^CR-RV

NR^xR^y .CONR^x-(CR^xR^y)_p-S(O)qR^x. -CONR^x-0-(CR^xR^y)p-[cycloalkyn-(CR^xR^y)p-OR^x, 15 CONR^x-(CR^xR^y)p-[cycloalkyl]-ÎCR^xR^ï)p-OR^x-, -CONR^x-(CR^xR^y)p-[cycloalkyl]-(CR^xR^y)pNR^XR*. or.CONR^x-(CR^xR^y)p-[cycloalkyl]-(CR^xR^y)p-S(O)qR^x; and

R^z is as defined above.

Further preferred is a compound of formula (IA-1) wherein E is selected from

⁰ V7 ⁰ °

OH J^jJ^N^x'^a^^Z*^XOH

Further preferred is a compound of formula (IA-1) wherein E is selected from

Further preferred is a compound of formula (IA-1) wherein each occurrence of R¹ is selected from hydrogen, halogen or substituted or unsubstituted alkyl,

Further preferred is a compound of formula (IA-1) wherein each occurrence of R¹ is selected from hydrogen, fluoro, chlore, methyl or CF₃

Further preferred is a compound of formula (IA-1) wherein X is N, CR¹ and R¹ is H, substituied or unsubstituted C,₄ alkyl, NH₂, OH, CN or CONH₂

Further preferred is a compound of formula (IA-l) wherein X is N, CH or C-CH₃.

Further preferred is a compound of formula (IA-Ι) wherein X is N.

Further preferred is a compound of formula (IA-Ι) wherein each occurrence of R² is H.

Further preferred is a compound of formula (IA-Ι) wherein each of R* and R” is hydrogen, alkyl or halogen.

Further preferred is a compound of formula (IA-Ι) wherein R and R^b both are hydrogen.

Further preferred is a compound of formula (IA-Ι) wherein R* methyl and R^b is hydrogen.

Further preferred is a compound of formula (IA-1) wherein R* is fluoro and R^b is hydrogen.

Further preferred is a compound of formula (IA-1) wherein R* and R^b both are fluoro.

Further preferred is a compound of formula (IA-1) wherein R* and R^b both are methyl.

Further preferred is a compound of formula (IA-1) wherein Z is CR^C, N, S, O, HC=CH-, or N=CH-.

Further preferred is a compound of formula (IA-1) wherein Zt is CH or N.

Further preferred is a compound of formula (IA-1) wherein Z₂ is CH or N.

Further preferred is a compound of formula (1A-I) wherein Z₃ is CH or N.

Further preferred is a compound of formula (IA-1) wherein Z is -HC=CH-, -S- or -O-, Zi is CH, Z₂is C; and Z₃ is C or N.

Further preferred is a compound of formula (IA-1) wherein Z is -HC=CH-, Z, is CH, Z₂ is C and Z₃ is C.

Further preferred is a compound of formula (IA-1) wherein Z is -CH-, Z, is CH, Z₂ is C and Z₃ is N.

Further preferred ls a compound of formula (IA-1) wherein Z is -S-, Zi is CH, Z₂ is C and Z₃ is C. Further preferred is a compound of formula (IA-1) wherein Z is-O-, Z, is CH, Z₂ is C and Z₃ is C. Further preferred is a compound of formula (IA-l) wherein Z is -CH-, Zi is NH, Z₂ is C and Z₃ is C.

Further preferred is a compound of formula (IA-1), wherein each occurrence of R^cis hydrogen or fluoro.

In one embodiment, in the compound of formula (IA-1), (a) the bicyclic ring containing ring atoms Z, Zi, Z₂ and Zi is quinoline, benzo[d]thiazol-6-yl, or an N-oxide thereof, which is optionally substituted with one or two halogen (e.g., F), (b) R, R^b, and each R^c are hydrogen, (c) each R² is hydrogen, and (d) D is substituted phenyl.

For example, D may be N-(2-Hydroxy-ethoxy)-benzamide (i.e.,Ph-C0NH-O-CH₂CH₂-OH), where the phenyl group may optionally be further substituted by one, two, or three substituents selected from halogens (e.g., F, or Cl), alkyl (e.g., methyl or ethyl) and fluorinated methyl (e.g., CF₃). In one preferred embodiment, the 2-hydroxy-ethoxy group (-O-CH2-CH2-OH) is at the para-position (relative to the phenyl group attachment to the bicyclic core). In another preferred embodiment, the 2-hydroxy ethoxy group is at the para-position (relative to the phenyl group attachment to the bicyclic core), and the phenyl group is substituted at one or both the 3- and 5positions of the phenyl group with the substituents independently selected from halogens (such as F or Cl) or alkyl (such as methyl).

Altematively, D can be

In one embodiment, the bicyclic ring containing ring atoms Z and Zi in the compound of formula 10 (MA) is quinoline or an N-oxide thereof, which is optionally substitued with one or two halogen (e.g., F).

ln one embodiment, the bicyclic ring containing ring atoms Z and Zi in the compound of formula (MA) is benzo[d]thiazol-6-yl or an N-oxide thereof, which is optionally substitued with one or two halogen (e.g., F).

In one embodiment, the monocydic ring D containing ring atoms X, X¹ X² and X³ in the compound of formula (MA) is N-(2-Hydroxy-ethoxy)-benzamide (i.e.,Ph-C0NH-O-CH₂CH2-OH), where the phenyl group may optionally be further substituted by one or two substituents selected from halogens (e.g., F, or Cl), alkanes (e.g., methyl or etthyl) and fluorinated methyl (e.g.,-CF₃).

In a preferred embodiment, each R²is hydrogen.

In one embodiment the représentative compounds of the présent invention include those specified below and pharmaceutically acceptable salts thereof. The présent invention should not be construed to be limited to them.

N-(2-amino-2-oxoethyl)-4-(3-(quinolin-7-ylmethyl)-3H-[1_I2,3]triazolo[4,5-b]pyridin-5yljbenzamide

N-(2-(methyla mino)-2-oxoethyl )-4-(3-(q uinolin-6-ylmethyl )-3H-{1,2,3]triazo1o[4,5-b]pyridi n-5-yl ) benzamide:

N-(3-amino-3-oxopropyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5yl)benzamide:

N-(3-(methylamino)-3-oxopropyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5yljbenzamide:

2-chloro-N-(2-(pyrrolidin-1-yl)ethy1)-4-(3-(quinolin-7-y!methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5y!)benzamide:

2-ch!oro-N-(2-hydroxyethoxy)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4_l5-b] pyridin-5yljbenzamide:

6a. 2-chloro-N-(2-hydroxyethoxy)-4-(3-(quinolin-6-yîmethyl)-3H-[1,2,3]triazolo[4,5-

b]pyridin-5-yl) benzamide hydrochloride:

6b. 2-chloro-N-(2-hydroxyethoxy)-4-(3-(qutnolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5bJpyridin-5-yl)benzamide 4-methy!benzenesulfonate

6c. 2-chloro-N-(2-hydroxyethoxy)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4_l5-b]pyridin-5y!)benzamide hydrobromide:

6d. sodium (2-chloro-4-(3-(quinolin-6-yimethyl)-3H-[1,2,3]triazolo[4_l5-b]pyridin-5yl)benzoyl)(2-hydroxyethoxy)amide:

2-chloro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-{1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(2- hyd roxyethoxy)benza mîde:

7a. 2-chloro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1.2,3]triazolo[4,5-b]pyridin-5’yl>M(2-hydroxyethoxy)benzamide hydrochloride:

7b. sodium (2-chloro-4-(3-{(7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin5-yl)benzoyl)(2-hydroxyethoxy)amide:

7c. 2-chloro-4-(3-((7-fluoro-2-oxo-1,2-dihydroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5b]pyridin-5-yl)-N-(2-hydroxyethoxy)benzamide:

2.6- difïuoro-N-{2-hydroxyethoxy)-4-(3-(quÎnolin-6-ylmethy1)-3H-[1_l2_l3]triazolo[4,5-bJpyridin-5yljbenzamide:

8a. 2,6-difluoro-N-(2-hydroxyethoxy)-4-(3-(quinolin-6-ylmethyl)-3H-{1,2,3]triazolo[4,5-

b]pyridin-5-y1)benzamide hydrochloride:

8b. sodium (2,6-difluoro-4-(3-(quinolin-6-y!rnethy1)-3H-[1,2,3]triazolo[4,5-b]pyridin-5yl)benzoy!)(2-hydroxyethoxy)amide:

2.6- difluoro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-{1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(2hydroxyethoxyjbenzamîde

9a. 2,6-difluoro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2_l3ltriazolo[4,5-b]pyridin-5-yl)N-(2-hydroxyethoxy)benzamide hydrochloride

9b. sodium (2,6-difluoro-4-(3-((7-fluoroquÎnolin-6-y1)methyl)-3H-[1,2,3]triazo1o[4,5b]pyridin-5-yl)benzoyl)(2-hydroxyethoxy)amide:

2-fluoro-N-(2-hydroxyethoxy)-4-(3-(quinolin-6-ylmethyl)-3H-[1 _t2,3]triazolo[4,5-b]pyridin-5yl)benzamide:

2-{2-chloro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamidooxy)ethy! acetate:

(S)-2-(2-chloro-4-(3-{quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5yl )benzamidooxy)ethyl 2-(tert-butoxycarbonyla mi no)pro panoate:

(S)-2’{2-chloro-4-(3-(quinolin-6-y1methyl)-3H-[1,2_l3]triazolo[4,5-b]pyridin-5y!)benzamidooxy)ethyt 2-aminopropanoate:

2-(2-chloro-4-(3^quÎnolin-6-ylmethyl)-3H-{1,2,3]triazolo[4,5-blpyridin-5-yl)benzamidooxy)ethyl pivalate:

2-(2-chloro-4-(3-(quinolin-6-ylmethyl)-3H-[1₍2_l3]triazolo[4,5-b]pyridin-5-yl)benzamidooxy)ethyl isobutyrate:

2-{2-chloro-4-(3-(quinolin-6-ylmethyl)-3H-{1,2,3]triazolo[4_l5-b]pyridin-5-yl)benzamîdooxy)ethyl 2 benzamidoa cetate :

2-chforo-N-(2-hydroxyethoxy}-4-(3-((2-methylquinolin-6-yl)methyl)-3H-[1.2,3]triazolo[4_l5b]pyridin-5-y1)benzamide:

4-(3-(benzo[d]thiazol-6-ylmethyl)-3H-{1,2,3]triazolo[4,5-b]pyridin-5-yl)-2-chloro-N-(2hyd roxyethoxy)be nza m ide:

4-(3-(benzo[d]thiazol-6-ylmethy1)-3H-[1,2,3]triazolo[4_l5-b]pyridir>-5-y1)-2,6-difluoro-N-(2hydroxyethoxy)benzamide:

19a. sodium (4-(3-(benzo[d]thiazol-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-y1)-2,6difluorobenzoyl)(2-hydroxyethoxy)amide:

4-(3-(benzo[d]thiazo1-6-y!methyl)-3H-[1,2_l3]triazolo[4,5-b]pyridin-5-y1)-2-fluoro-N-(2hydroxyethoxyjbenza mide :

2,6-difluoro-N-(2-hydroxyethoxy)-4-(3-{(2-methylquinolin-6-yl)methyl )-3H-{1 ^.SJtriazolo^.S-

b]pyridin-5-yl)benzamide

21a. 2,6-difluoro-N-(2-hydroxyethoxy)-4-(3-((2-methylquinolin-6-y1)methyl)-3H[1 .Z.SJtriazolo^.S-bJpyridin-S-ylJbenzamide hydrochloride:

N-(2-hydroxyethoxy)-4-(3-(quinolin-6-ylmethyl)-3H-[1 .Z.SJtriazolo^.S-ypyridin-S-ylJbenzamide:

N-(2-hydroxyethoxy)-4-{3-(quinolin-6-ylmethyl)-3H-[1_l2_l3]triazolo[4_>5-b]pyridin-5-y1)-2(trifl uoromethyl Jbenzam ide:

4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-i1,2,3]triazolo[4,5-blpyridin-5-y!)-N-(2-hydroxyethoxy)-2- (trifluoromethyl)benzamide:

24a. 4-(3-((7-fluoroquÎnolin-6-yl)methy1)-3H-[1.2,3]triazolo[4,5-b]pyridin-5-yl)-N-(2hydroxyethoxy)-2-(trifluoramethyl)benzamide hydrochloride:

N-(2-hydroxyethoxy)-2-methyl-4-(3-(quinolin-6-y1methyl)-3H-[1,2,3]triazo!o[4,5-b]pyridin-5yljbenzamide:

25a. N-(2-hydroxyethoxy)-2-methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5b]pyridin-5-y!)benzamide hydrochloride:

25b. N-(2-hydroxyethoxy)-2-methyl-4-(3-{quinolin-6-ylmethyl)-3H-[1_l2,3]triazolo[4,5b]pyridin-5-yl)benzamide hydrobromide:

25c. N-(2-hydroxyethoxy)-2-methy1-4-(3-{quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5b]pyridin-5-yl)benzamide 4-methylbenzenesulfonate:

25d. N-(2-hydroxyethoxy)-2-methyl-4~(3-((2-oxo-1,2-dihydroquinolin-6-yl)methyl)-3H- [1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

25e. 6-((5-(4-{2-hydroxyethoxycarbamoyl)-3-methylphenyl)-3H-[1,2,3]ίΓΪ3ζοΙο[4,5b]pyridin-3-yl)methy!)quinoline 1 -oxide

4-(3-{(7-fluoroquinolin-6-y1)methy!)-3H-{1,2,3]triazolo[4,5-blpyridin-5-yl)-N-(2-hydroxyethoxy)-2methylbenzamide:

26a. 4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-{1_l2,3]triazolo[4,5-b]pyridin-5-yl)-N-{2hydroxyethoxy)-2-methylbenzamide hydrochloride:

2-fluoro-4-(3-((7-fIuorOquinolin-6-yl)methyl}-3H-{1,2_>3]triazolo[4,5-b]pyridin-5-yl)-N-(2hyd roxyethoxy)be nza mide:

27a. 2-fluoro-4-(3-((7-fluoroquinolin-6-yl)methy1)-3H-{1_>2,3ltriazolo[4,5-b]pyridin-5-yl)-N(2-hydroxyethoxy)benzamide hydrochloride:

2-chloro-N-(2-hydroxypropoxy}-4-(3-(quinolin-6-ylmethy1)-3H-['l,2₎3]triazolo[4₁5-b]pyridin-5yl)benzamide:

ethyl 2-(2-chloro-4-{34quÎnolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5yl)benzamidooxy)acetate:

2-chloro-N-(2-hydrOxy-2-methy1propoxy)-4-{3-(quinolin-6-yfmethyf)-3H-[1,2,3}triazolo[4_l5b]pyridin-5-yl)benzamide:

(S)-2-chloro-N-(2-hydroxypropoxy)-4-(3-{quinolin-6-y!methyl)-3H-[1,2_l3]triazo!o[4,5-bÎpyridin-5y1)be nza mide:

(R) -2-chloro-N-(2-hydroxypropoxy)-4-{3-(quinolin-6-ylmethy!)-3H-[1,2,3]triazolo[4,5-b]pyridin-5yljbenzamide:

N-(2-hydroxy-2-methylpropoxy)-2-methy1-4-(3-(quinolin-6-ylmethy1)-3H-[1.2_l3)triazolo[4,5b]pyridin-5-yl)benzamide:

2,6-difluoro-N-(2-hydroxy-2-methylpropoxy)-4-{3-(quinolin-6-ylmethyl}-3H-[1,2_l3]triazo!o[4,5b]pyridin-5-yl)benzamide:

2-fluoro-N-(2-hydroxy-2-methylpropoxy)-4-(3-(quinolin-6-ylmethy1)-3H-[1,2,3]triazolo[4,5b]pyridin-5-yl)benzamide:

(S) -N-(2-hydroxypropoxy)*2-<nethyi-4-{3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5yî)benzamide

N-(2-hydroxy-2-methyîpropoxy)-2-methy!-4-(3-((2-oxo-1,2-dÎhydroquinolin-6-yl)methy!)-3H- [1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide (R)-N-{2-hydroxypropoxy)'2-methyl-4-(3-{quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5yljbenzamide

N-(1-hydroxy-2-methyl propan-2-y!oxy)-2-m ethy1-4-( 3-(quinoli n-6-yl methyl)-3H- [1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

2-ch!oro-N-(1-hydroxy-2-methy!propan-2-yloxy)-4-(3-(quinolin-6-y!methyl)-3H-{1,2_I3]triazolo[4_l5b]pyridin-5-yl)benzamide

N-(2-hydroxy-2-methyl-propoxy)-2-methyl-4-{3-(1-oxy-quinolin-6-ylmethyl)-3H[1,2,31triazolo[4,5-b]pyridin-5-yl]-benzamide

N-hydroxy-2-methyl-4-(3-quino!in-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-benzamide

2-{2-methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamidooxy)ethyl acetate

2-(2-methyl-4-(3-(quinolin-6-y1methy!)-3H-(1.2,3]triazolo[4,5-b]pyridin-5-yl)benzamidooxy)ethy1 isobutyrate

2-(2-methy1-4-(3-{quinolin-6-ylmethy1)-3H-[1,2,3]triazo!o[4,5-b]pyridin-5-yl)benzamidooxy)ethyl pivalate

2-(2-methyl-4-(3-(quino!in-6-ylmethyl)-3H-[1,2_l3]triazolo[4_l5-b]pyridin-5-yi)benzamidooxy)ethyl benzoate

2-(2-methyl-4-(3-(quino1in-6-y!methyl)-3H-[1,2_l3]triazolo[4,5-b]pyridin-5-yl)benzamidooxy)ethyl furan-2-carboxylate

1- (3-((7-fluoroquinolÎn-6-yl)methyl)-3H-[1_l2,3]triazolo[4_l5-b]pyridin-5-yl)ethanone

2- (1 -(3-{quinolin-6-ylmethyl)-3H-Î1,2,3]triazolo[4,5-b]pyridin-5-yl)ethylidene) hydrazinecarboxamide hydrochloride

2-(1-(3-{quinolin-6-yimethyl)-3H-{1,2,3]triazolo[4,5-b]pyridïn-5-yl)ethylidene) hydrazinecarbothioamide

6-((5-{1-(2-(pyridin-2-yl)hydrazono)ethyi)-3H-[1_l2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

2-{amino(3-(quinoIin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)methylene) hydrazinecarboxamide:

tert-butyi 2-(1-(3-(quinolin-6-ylmethyl)-3H-[1_I2,3]triazolo[4,5-b]pyridin-5-yl)ethylidene) hydrazinecarboxylate:

(E/Z)-1-(1-(3-(quinonn-6-yîmethyl)-3H-i1,2,3]triazolo[4,5-b]pyridin-5yl)ethylideneamino)imidazolidine-2,4-dione:

N-ethyl^-ÎI-tS-iquinolin-e-ylmethylJ-SH-II^.SJtriazolo^.S-bJpyridîn-S-ylJethylidene) hydrazinecarbothioamide:

2-(1 -(3-(quinolin-6-ylmethyl)-3H-{1,2,3]triazolo[4,5-b]pyridin-5-y!)ethylidene) hydrazinecarbothioamide hydrochloride:

2-(1-(3-( (7-fluoroquînolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)ethylidene) hydrazinecarbothioamide:

Methyl 2-{1 -(3-(quinolin-6-ylmethyl)-3H-{1 _t2,3]triazolo[4,5-b]pyridin-5-yl)ethylidene) hydrazinecarboxylate:

1-(3-((7-fluoroquinolin-6-y!)methy1)-3H-[1,2_I3]triazoloI4,5-b]pyridin-5-yl)ethanone oxime:

-(3-((7-fluoroquinolin-6-y1)methyl)-3H-{1,2,3]triazolo[4,5-b]pyridin-5-yl)ethanone O-methyl oxime:

-(3-((7«fluoroquinolin-6-yl)methyl)-3H-{1,2,3]triazolo[4,5-b]pyridin-5-yl)ethanone 0-2hydroxyethyl oxime:

1-(3-(quinolin-6-ylmethyl)-3H-{1,2,3]triazoIo[4,5-b]pyridin-5-yl)ethanone 0-2-hydroxyethyl oxime:

1-(3-(qutnolin-6-ylmethyl)-3H-I1,2,3]triazolo[4,5-b]pyridin-5-yl)ethanone O-2-aminoethyl oxime:

1-(2-(1-(3-(quinolin-6-ylmethy1)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-y1) ethylideneamînooxy)ethyl)urea:

-(3-( (7-fluoroquinolin-6-yl)methyl}-3H-[1,2,3]triazolo[4,5-b]pyridin-5-y1)ethanone O-methyî oxime hydrochloride:

-(3-((7-fluoroquino!in-6-yl)methyl)-3H-{1,2,3]triazolo[4,5-b]pyridin-5-yl)ethanone oxime hydrochloride:

1-(3-( (7-fluoroquinolin-6-yl)methy1}-3H-[1,2_l3]triazolo[4_l5-b]pyridÎn-5-yl)ethanone 0-2hydroxyethyl oxime hydrochloride:

N-(3-Dimethylamino-propyl)-4-(3-quinolin-6-ylmethyl-3H-(1,2,3Jtriazolo[4,5-b]pyridin-5-yl)benzamide dihdrochloride

In another embodiment the représentative compounds of the présent invention indude those specified below and pharmaceutically acceptable salts thereof. The présent invention should not be construed to be limited to them.

101. 2-chforo-N-(2-(dimethylamino)ethy1)-4-(3-(quinolin-6-ylnnethyl)-3H-imidazoI4,5b]pyridin-5-y!)benzamide:

102. 2-chloro-N-(3-(dimethylamino)propyl)-4-(3-(quinolin-6-ylmethyl)-3H-imÎdazo[4₁5-b] pyridin-5-yl)benzamide:

103. 2-chloro-N-methoxy-4-(3-(quinolin-6-ylmethyl)-3H-îmidazo[4₁5-b]pyridin-5- yljbenzamide:

104. N-(2-(dimethylamino)ethy!)-2,6-difluoro-4-(3-(quinolin-6-ylmethyl)-3H-imidazo[4,5b]pyridin-5-yl)benzamide:

105. 2.6-difluoro-N-methoxy-4-(3-(quinolin-6-ylmethyi)-3H-imidazo[4,5-b]pyridin-5-y1) benzamide:

106.1- {3-(quinolin-6-ylmethy1)-3H-imidazo[4_l5-b]pyridin*5-yl)ethanone:

107. 2-(1-(3-(quinolin-6-ylmethyl)-3H-imidazo[4_l5-b]pyridin-5-y1)ethylidene) hydrazinecarboxamide:

108. 2-(1 -(3-(quinolin-6-ylmethyl)-3H-lmidazo[4,5-b]pyridin-5-yl)ethylidene) hydrazinecarbothioamide:

109. (R)-2-fluoro-N-(2-hydroxypropyl)-4-{3-{quinolin-6-y!methyl)-3H-imidazo[4₁5-b]pyridin-5ytjbenzamide

110. (SJ^-fluoro-N-fZ’hydroxypiOpylJ^S-iquinolin-e-ylmethylï-SH-imidazo^.S-bJpyridin-

5-yl)benzamide

111. N-(2-Hydroxy-ethoxy)-2-methyl-4-(3-quinolin-6-ylmethyl-3H-imidazo[4₁5-b]pyridin-5yl)-benzamide

112. N-(2-Hydroxy-2-methyl-propoxy)-2-methy!-4-(3-quinolin-6-ylmethyl-3H-imidazo[4₁5b]pyridin-5-yl)-benzamide

113. 2-Chloro-N-(2-hydroxy-ethoxy)-4-{3-quinolin-6-ylmethyl-3H-imidazo[4,5-b]pyridin-5yl)-benzamide

114. 2-Chloro-N-(2-hydroxy-2-methyl-propoxy)-4-(3-quinolin-6-ylmethyl-3H-imidazo[4,5b]pyridin-5-y!)-benzamide

In yet another embodiment the représentative compounds of the présent invention include those specified below and pharmaceutically acceptable salts thereof. The présent invention should not be construed to be limited to them.

1001. 6-{(5-(4-carbamoyl-3,5-difluorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl) methyl) quinoline 1-oxide

1002.6-{(5-(4-carbamoy!-3-chlorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)-7fluoroquinoline 1-oxide:

1003. 2,6-difluoro-4-(3-(quinolin-6-ylmethyl)-3H-{1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

2.2.2- trifluoroacetate:

1004. 2-chloro-4-(3-((2-oxo-1,2-dihydroqutnofin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5b]pyridin-5-yl)benzamÎde:

1005. 2,6-difIuoro-4-(3-((2-oxo-1,2-dihydroquinolin-6-yl)methyl)-3H-[1,2,3]1π3ζοΐο[4,5b]pyridin-5-yl)benzamide:

1006.4<34benzo[dlthiazol-6-ylmethyl)-3H-[1.2.3]triazolo[4,S-b]pyridir>-5-yl}-2.6d ifl uorobenzamide :

1007. 2,6-difluoro-4-(3-({7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl) benzamide:

1008. 2-Chloro-4-(3-(quinolin-6-ylmethy1)-3H-imidazo[4₁5-b]pyridin-5-yl)benzamide:

1009. 2-chloro-4-(3-(quinolin-6-ylmethy!)-3H4midazo[4,5-b]pyridin-5-y!)benzamide hydrochloride:

1010. 2,6-difluoro-4-(3-(quÎnolin-6-ylmethyl)-3H4midazo[4,5-b]pyridin-5-yl)benzamide:

1011. Methyl 2-chloro-4-(3-(quinolin-6-ylmethyl)-3H-imidazo[4,5-b]pyridin-5-yl)benzoate:

1012. 2-chloro-4-(3-(quinolin-6-y1methyl)-3H-imidazo[4,5-b]pyridin-5-yl)benzoic add:

1013. 2-chloro-N-ethyl-4-(3-(quinolin-6-ylmethyl)-3H-imidazo[4,5-b]pyridin-5-yl)benzamide:

1014. Methyl 2,6-difluoro-4-(3-(quinolin-6-ylmethyl)-3H-imidazo[4,5-b]pyridÎn-5yl)benzoate:

1015. 2,6-difluoro-4-(3-(qutnolin-6-ylmethyl)-3H4midazo[4,5-b]pyridin-5-yl)benzoic add:

1016. N-ethyl-2,6-difluoro-4-(3-(quinolin-6-ylmethyl)-3H-imidazo[4,5-b]pyridin-5-yl) benzamide:

1017. 2-chloro-N-methyl-4-(3-{quinolin-6-yîmethyl}-3H4midazoI4,5-b]pyridin-5-yl) benzamide:

1018. 2-methyl-4-(3-{quinolin-6-ylmethyl)-3H-imîdazo[4,5-b]pyridin-5-yl)benzamide:

1019. 2-chloro-4-(3-(quinolin-6-ylmethyl)-3H4midazo[4,5-b]pyridin-5-yl)benzamide 2,2,2trifluoroacetate:

1020. 2-ch!oro-4-(2-methyl-3-(quinolin-6-ylmethyl)-3H4midazo[4,5-b]pyridin-5-y!) benzamide:

1021. 2-ch1oro-4-(3-(1 -(quinolin-6-yl)ethyl)-3H-imidazo[4,5-b]pyridin-5-y!)benzamide:

1022. 2-chloro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-5-yl) benzamide:

1023. 2-chloro-4-(3-((5,7-difluoroquinolin-6-yl)methyl}-3H-imidazo[4,5-b]pyridin-5-yl) benzamide:

1024. 4-(3-Quinolin-6-ylmethyl-3H4midazo[4,5-b]pyridin-5-yl)-2-trifluoromethyl-benzamide

1025. 4-[3-(7-Fluoro-quinolin-6-y1methy1)-3H-imidazo[4,5-b]pyridin-5-yl]-2-methy1benzamide

1026. 4-[3-(7-Auoro-quinolin-6-ylmethyl)-3H-imidazo[4,5-bJpyridin-5-yl]-2-trifluoromethylbenzamide

1027. 4-(3-(5,7-DifIuoro-quinolin-6-ylmethyl)-3H-imidazo[4,5-b]pyridin-5-yl]-2-methylbenzamide

1028. 4-(3-(5,7-Difluoro-quinolin-6-ylmethyl)-3H-imidazo[4,5-b]pyridin-5-yl]-2trifluoromethyl-benzamide

1029. 4-[3-(7-Fluoro-quinolin-6-ylmethyl)-3H-imidazo[4,5-b]pyridin-5-yl]-2-niethylbenzamîde hydrochloride

1030. 2,N-Dimethy!-4-(3-quinolin-6-ylniethyl-3H-imidazo[4,5-b]pyridin-5-yl)-benzamide

1031. 5-(3-Quinolîn-6-ytmethyl-3H-imidazo[4,5-b]pyridin-5-y1)-pyridine-2-carboxylic add methylamide

1032. 5-(3-Quinolin-6-ylmethy1-3H-{1,2,3]triazolo[4,5-b]pyridin-5-yl)-2,3-dihydro-isoindol-1 one

1033. 5-(3-Quinolin-6-ylmethyl-3H-imidazo[4,5-b]pyridin-5-yl)-2,3-dihydrio-isoindof-1-one

TABLE 1

E x	Structure	E x	Structure	Ε X	Structure
1	ο M	7		1 0
2	_Ί!ν_ϊχΑ^,:	:	_ ί X > F ^{N N}> L. 1	1 1
3		7 b		1 2	°Ύ

E x	Structure	E X	Structure	E x •	Structure
4		7 c	i	1 3	X
5	<r/\	8	Λ	1 4	T
6		8 a		1 5	#%
6 a		8 b	/V-H p _ ί l'N Ύ^Τ ^N *t ^V“'S\ i T ,ΝΝ·ρ 1 oe₉ \^/ CH	1 6	#% y A
6 b	ί t, «M	9		1 7	w
6 c	d *	9 a	na OH	1 8	#% il
6 d	AA	9 b		1 9	•Az H·”

E x	Structure	E x	Structure	E x	Structure
1 9 a		2 5 b		3 0	„nh α Λ V
2 0		2 5 c	t	3 1	° V G
2 1	s CH	2 5 d		3 2
2 1 a	c *	2 5 e		3 3	xx Y
2 2		2 6		3	x% Ol
2 3	—<b	2 6 a		3 5	XX
2 4	—	2 7			χχ HQ. J

E x	Structure	E x	Structure	E x	Structure
2 4 a		2 7 a		3 7	Y
2 5		2 8	X	3 8	γΥ “Y
2 5 a		2 9	ίΎ% ΓΤ ^N v_yi	3 9	~NH \ ?
4 0	çr**^{1 α} VJ £	5 o		6 0	vx^
4 1		5 1	yW £ Ύ£> Ô	6 1
4 2	r» ^N^K'^r(ys_&. «r ‘ U	5 2	^vrV·'^ ~r x£? HjN'^O	6 2
4 3	J I *N sVv ^NH 1 \ 0	5 3	x Yb	6 3	•«1

E x	Structure	E x •	Structure	E x	Structure
4 4	V	5 4	*λ>	6 4	Ογ»Ι **<ï
4 5	A 0	5		6 5	VAjl ,na VXn
4 6	AA °z	5 6	AX Λ	6 6
4 7	5	5 7	jYL< HjN^S F	6 7	c “ '
4 8		5 8	yOC X	6 8	ΛΟ V x^w-.
4 9	•Axe}	5 9

TABLE 2

Ex

Structure

Ex

Structure

Ex

Structure

Ex	Structure	Ex	Structure	Ex	Structure
101		106		111
102		107	M,N%	112	if
103		108	£ 'co	113
104		109	xÇCr^	114	if
105	.çç^-q	110

TABLE 3

Ex	Structure	Ex	Structure	Ex	Structure
1001	γγΚ-	101 2		1023	a
1002	_ J j7^ 9 ίηρ * ·{ V η,ν α ''λ	101 3		1024	NH, CF,

Ex	Structure	Ex	Structure	Ex	Structure
1003		101 4		1025
1004		101 5	-γψ5>	1026
1005	ïf^	101 6		1027
1006		101 7		1028	Xi. >
1007	'γγθν\ —V	101	ψ/% NHj ¹	1029
1008	pXX? —Y	101 9	pXO -Y CFjCOCH	1030
1009	-9¾	102 0	-9¾	1031
1010	γνί-Φ *-Υ	102 1	pXO *~cV	1032
1011	pXO ° 'i	102		1033

Yet another embodiment of the présent invention is a method for treating a proliférative disease via modulation of a protein kinase (such as c-Met) by administering to a patient in need of such treatment an effective amount of at least one compound of formula (I), (IA) or (IA-l) as defined above.

Yet another embodiment of the présent invention is a method for treating a proliférative disease via modulation of a protein kinase (such as c-Met) by administering to a patient in need of such treatment an effective amount of at least one compound of formula (I), (IA) or (IA-Ι) as defined above, in combination (simultaneously or sequentially) with at least one other anti-cancer agent. In a preferred embodiment, the proliférative disease is cancer.

More particularly, the compounds of formula (I), (IA) or (IA-1) and pharmaceutically acceptable esters or salts thereof can be administered for the treatment, prévention and/or amelioration of c-Met, RON, EGFR or KDR kinase associated diseases or disorders, induding but not limited to, cancer and other proliférative diseases or disorders.

The compounds of formula (I), (IA) or (IA-1) are useful In the treatment of a variety of cancers, induding, but not limited to, the following:

cardnoma, Induding that of the bladder, breast, colon, kidney, liver, lung, induding small cell lung cancer, esophagus, gall bladder, ovary, pancréas, stomach, cervix, thyroid, prostate, and skin, induding squamous cell cardnoma;

hematopoietic tumors of lymphoid lineage, induding leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-ce II lymphoma, Hodgkin's lymphoma, nonHodgkins lymphoma, hairy cell lymphoma and Burkett’s lymphoma;

hematopoietic tumors of myeloid lineage, induding acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia;

tumors of mesenchymal origin, induding fibrosarcoma and rhabdomyosarcome;

tumors of the central and peripheral nervous system, induding astrocytoma, neuroblastome, glioma and schwannomas; and other tumors, induding melanoma, seminoma, teratocardnoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.

Due to the key rôle of protein kinases in the régulation of cellular prolifération in general, inhibitors could act as réversible cytostatic agents which may be useful in the treatment of any disease process which features abnormal cellular prolifération, e.g., benîgn prostatic hyperplasia, familial adenomatosis polyposts, neuro-fibromatosis, atherosderosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophie scar formation, inflammatory bowel disease, transplantation rejection, endotoxic shock, and fungal infections.

The compounds of the présent invention as modulators of apoptosis, are useful in the treatment of cancer (including but not limited to those types mentioned herein above), viral infections (including but not limited to herpevinjs, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), prévention of AIDS development in HIV-infected individuals, autoimmune diseases (including but not limited to systemic lupus, erythematosus, autoimmune mediated glomerulonephritis, rheumatoîd arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabètes mellitus), neurodegenerative disorders (including but not limited to Alzheimerts disease, AIDS-related dementia, Parkinson’s disease, amyotrophie latéral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration), myelodysplastic syndromes, aplastic anémia, ischémie injury associated with myocardial infarctions, stroke and reperfusion injury, arrhythmia, a the ras de rosi s, toxin-induced or alcohol related liver diseases, hematological diseases (including but not limited to chronic anémia and aplastic anémia), degenerative diseases of the musculoskeletal System (including but not limited to osteoporosis and arthritis) aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain.

The compounds of présent invention can modulate the level of cellular RNA and DNA synthesis. These agents are therefore usefu! in the treatment of viral infections (induding but not limited to HIV, human papillonna virus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus).

The compounds of the présent invention are useful in the chemoprevention of cancer. Chemoprevention is defined as inhibiting the development of invasive cancer by either blocking the initiating mutagenic event or by blocking the progression of pre-malignant cells that hâve already suffered an insult or inhibiting tumor relapse. The compounds are also useful in inhibiting tumor angiogenesis and metastasis. One embodiment of the Invention is a method of inhibiting tumor angiogenesis or metastasis in a patient in need thereof by administering an effective amount of one or more compounds of the présent Invention.

Another embodiment of the présent invention is a method of treating an immune system-related disease (e.g., an autoimmune disease), a disease or disorder involving inflammation (e.g., asthma, chronic obstructive pulmonary disease, rheumatoîd arthritis, inflammatory bowel disease, glomerulonephritis, neuroinflammatory diseases, multiple sclerosis, uveitis and disorders of the immune system), cancer or other proliférative disease, a hepatic disease or disorder, a rénal disease or disorder. The method includes administering an effective amount of one or more compounds of the présent invention.

Examples of immune disorders indude psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory musde disease, allergie rhinitis, vaginitis, interstitia! cystitis, sderoderma, osteoporosis, eczema, allogeneic or xenogeneic transplantation (organ, bone marrow, stem cells and other cells and tissues) graft rejection, graft-versus-host disease, lupus erythematosus, inflammatory disease, type I diabètes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g., Hashimoto's and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anémia, multiple sderosis, cystic fibrosis, chronic relapsing hepatitis, primary biliary dnrhosis, allergie conjunctivitis and atopie dermatitis.

In one embodiment, the compounds described herein are used as immunosuppresants to prevent transplant graft rejections, allogeneic or xenogeneic transplantation rejection (organ, bone marrow, stem cells, other cells and tissues), and graft - versus - host disease. In other embodiments, transplant graft rejections resuit from tissue or organ transplants. In further embodiments, graft-versus-host disease results from bone marrow or stem cell transplantation. One embodiment is a method of preventing or decreasing the risk of transplant graft rejection, allogeneic or xenogeneic transplantation rejection (organ, bone marrow, stem cells, other cells and tissues), or graft - versus - host disease by administering an effective amount of one or more compounds of the présent invention.

The compounds of the présent invention are also useful in combination (administered together or sequentially) with known anti-cancer treatments such as radiation therapy or with cytostatic or cytotoxic or anticancer agents, such as for example, but not limited to, DNA interactive agents, such as dsplatin or doxorubidn; topoisomerase II inhibitors, such as etoposide; topoisomerase I inhibitors such as CPT-11 or topotecan; tubulin interacting agents, such as paclitaxel, docetaxel or the epothilones (for example ixabepilone), either naturally occurring or synthetic; hormonal agents, such as tamoxifen; thymidilate synthase inhibitors, such as 5fluorouracil; and anti-metabolites, such as methotrexate, other tyrosine kinase inhibitors such as Iressa and OSI-774; angiogenesis inhibitors; EGF inhibitors; VEGF inhibitors; CDK inhibitors; SRC inhibitors: c-Kit inhibitors; Her1/2 inhibitors and monoclonal antibodies directed against growth factor receptors such as erbitux (EGF) and herceptin (Her2) and other protein kinase modulators as well.

The compounds of the présent invention are also useful in combination (administered together or sequentially) with one or more stéroïdal anti-lnflammatory drugs, non-steroidal antiinflammatory drugs (NSAIDs) or Immune Sélective Anti-lnflammatory Dérivatives (ImSAIDs).

The invention further provides a pharmaceutical composition comprising one or more compounds of the présent invention (such as a compound having formula (I), (IA) or (IA-I) together with a pharmaceutically acceptable carrier. The pharmaceutical composition may further comprise one or more of the active ingrédients identified above, such as other anticancer agents. In one embodiment, the pharmaceutical composition indudes a therapeutically effective amount of one or more compounds of formula (I), (IA) or (IA-1).

Yet another embodiment is a method of treating leukemia in a patient in need thereof by administering a therapeutically effective amount of a compound of the présent invention. For example, the compounds of the présent invention are effective for treating carcinoma of the bladder, cardnoma of the breast, carcinoma of the colon, carcinoma of the kidney, carcinoma of the liver, carcinoma of the lung, small cell lung cancer, esophageal cancer, gall bladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, skin cancer, squamous cell cardnoma; cholangiocardnoma cancer .tumors of mesenchyma! origin, fibrosarcoma, rhabdomyosarcome; tumors of the central and peripheral nervous system, astrocytoma, neuroblastoma, glioma, schwannoma; melanoma, seminoma, teratocardnoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicutar cancer and Kapost's sarcoma, synovial sarcoma, rhabdomyosarcoma, MFH/fibrosarcoma, leiomyosarcoma, multiple myeloma, lymphoma, glioblastoma, astrocytoma, melanoma, mesothelioma, Wilm's tumor , hematopoietic tumors of lymphoid lineage, leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin’s lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma and Burkett’s lymphoma; hematopoietic tumors of myeloid lineage, acute myelogenous leukemias, chronic myelogenous leukemias, myelodysplastic syndrome, promyelocytic leukemia.

Yet another embodiment is a pharmaceutical composition comprising one or more compounds having formula (I), (IA) or (IA-1) together with a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

As used herein the following définition shall apply unless otherwise indicated. Further many of the groups defined herein can be optionally substituted. The listing of substituents in the définition is exemplary and ls not to be construed to limit the substituents defined elsewhere in the spécification.

The term ‘alkyl’ refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest ofthe molécule bya single bond, e.g., methyl, ethyl, npropyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl).

The term substituted or unsubstituted (C_v3) alkyl refers to an alkyl group as defined above having up to 3 carbon atoms The term substituted or unsubstituted (C,^) alkyl refers to an alkyl group as defined above having up to 4 carbon atoms, and the term substituted or unsubstituted (Ci-β) alkyl refers to an alkyl group as defined above having up to 6 carbon atoms.

The term ‘alkenyl ‘ refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be a straight or branched or branched chain having about 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyf), iso-propenyl, 2-methyl-1-propeny!, 1butenyl, and 2-butenyl.

The term substituted or unsubstituted (C_w) alkenyl refers to an alkenyl group as defined above having up to 4 carbon atoms.

The term “alkynyl* refers to a straight or branched chain hydrocarbyl radicals having at least one carbon-carbon triple bond, and having in the range of about 2 up to 12 carbon atoms (with radicals having in the range of about 2 up to 10 carbon atoms presently being preferred) e.g., ethynyl, propynyl, and butnyl.

The term substituted or unsubstituted (Ci-e) alkynyl refers to an alkynyl group as defined above having up to 4 carbon atoms.

The term “alkoxy” dénotés an alkyl group as defined above attached via an oxygen linkage to the rest of the molécule. Représentative examples of these groups are -OCH₃ and -OC2H5. The term “substituted alkoxy” refers to an alkoxy group where the alkyl constituent is substituted (i.e., -O-(substituted alkyl) wherein the term “substituted alkyl’ is the same as defined above for “alkyl. For example “alkoxy refers to the group -O-alkyl, induding from 1 to 8 carbon atoms of a straight, branched, cydic configuration and combinations thereof attached to the parent structure through oxygen. Examples indude méthoxy, ethoxy, propoxy, isopropoxy, cydopropyloxy, and cydohexyloxy.

The term “C^ alkoxy refers to an alkoxy group as defined above having up to 3 atoms.

The term “cydoalkyi* dénotés a non-aromatic mono or multicydic ring System of about 3 to 12 carbon atoms such as cydopropyl, cydobutyl, cydopentyl, and cydohexyl. Examples of multicydic cycloalkyl groups indude perhydronapththyl, adamantyi and norbomyl groups, bridged cydic groups, and sprirobicyclic groups, e.g., sprio (4,4) non-2-yl.

The term “C« cydoalkyi* refera to a cydoalkyi group as defined above having up to 6 atoms.

The term “cydoalkylalky!* refera to a cydic ring-containing radical containing in the range of about 3 up to 8 carbon atoms diredly attached to an alkyl group which are then attached to the main strudure at any carbon from alkyl group that results in the création of a stable strudure such as cydopropylmethyl, cydobuyyfethyl, and cydopentylethyl.

The term C34 cydoalkyfalkyT refers to a cydoalkylalkyl group as defined above having up to 6 atoms.

The term cycloalkenyl refers to cyclic ring-containing radicals containing ln the range of about 3 up to 8 carbon atoms with at least one carbon-carbon double bond, such as cydopropenyl, cydobutenyl, and cyclopentenyl. The term cycloalkenylalkyr refers to a cycloalkenyl group directly attached to an alkyl group which are then attached to the main structure at any carbon from alkyl group that results in the création of a stable structure

The term ’C^ cycloalkenyl refers to a cycloalkenyl group as defined above having up to 6 atoms.

The term aryl refers to aromatic radicals having in the range of 6 up to 20 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.

The term arylalkyl* refers to an aryl group as defined above directly bonded to an alkyl group as defined above. e.g., -CH₂CeH₅ and -Î^HsCeHs.

The term heterocydic ring refers to a non-aromatic 3 to 15 member ring radical which, consists of carbon atoms and at least one heteroatom selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention, the heterocydic ring radical may be a mono-, bi-, tri- or tetracydic ring System, which may indude fused, bridged or spiro ring Systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocydic ring radical may be optionally oxidized to various oxidation states. ln addition, the nitrogen atom may be optionally quatemized. The heterocydic ring radical may be attached to the main strudure at any heteroatom or carbon atom that results ln the création of a stable strudure.

The term heterocydyl refers to a heterocylic ring radical as defined above. The heterocylcyl ring radical may be attached to the main strudure at any heteroatom or carbon atom that results ln the création of a stable strudure.

The term heterocydylalkyl* refers to a heterocylic ring radical as defined above directly bonded to an alkyl group. The heterocydylalkyl radical may be attached to the main strudure at carbon atom in the alkyl group that results ln the création of a stable strudure. Examples of such heterocydoalkyl radicals Indude, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, Imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, odahydroindolyl, odahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinudidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thîamorpholinyl, 1oxo-thiomorpholinyl, and 1,1-dioxo-thiomorphoIinyl.

The term ’heteroaryT refera to an optionaily substituted 5 to 14 member aromatic ring having one or more heteroatoms seleded from N, O, and S as ring atoms. The heteroaryl may be a mono-, bi- or tricyclic ring system. Examples of such heterocyclic ring or heteroaryl radicals include, but are not limited to, oxazolyl, thlazolyl, imidazolyl, pymoïyl. furanyl, pyridinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, carbazolyl, quinolyl , isoquinolyl, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, dnnolinyl, dioxolanyt, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, tetrazoyl, tetrahydroisoquinolyl, plperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2oxopyrrolidinyl, 2-oxoazepinyi, azepinyl, 4-piperidonyl, pyrrolidinyl, pyridazinyl, oxazolinyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, isoindolyl, îndolinyl, isoindolinyl, octahydroindolyl, odahydroisoindolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl, oxadiazolyl, chromanyl, and isochromanyl. The heteroaryl ring radical may be attached to the main strudure at any heteroatom or carbon atom that results in the création of a stable strudure. The term substituted heteroaryl’ also indudes ring systems substituted with one or more oxide (-O-) substituents, such as pyridinyl N-oxides.

The term ‘heteroaryfalkyl’ refera to heteroaryl ring radical as defined above diredly bonded to an alkyl group. The heteroaryfalkyl radical may be attached to the main strudure at any carbon atom from alkyl group that results in the création of a stable strudure.

The term heterocydylalkyr refers to a heterocylic ring radical as defined above directiy bonded to an alkyl group. The heterocydylalkyl radical may be attached to the main strudure at carbon atom In the alkyl group that results in the création of a stable strudure.

The term cyclic ring refers to a cydic ring containing 3-10 carbon atoms.

The term ‘substituted’ unless otherwise specified, refera to substitution with any one or any combination of the following substituents and may be the same or different which one or more are seleded from the groups such as hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio(=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cydoalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cydoalkylalkyl, substituted or unsubstituted cydoalkenylalkyl, substituted or unsubstituted heterocycyl, substituted or unsubstituted heterocydcyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or 49 unsubstituted heteroarytalkyl, -COOR’, -C(O)R‘, -C(S)R, -C(O)NR’R’·, -C(O)ONRR, -NRR, NR’CONRR', -N(R')SOR', -N(R’)SO₂R', -(=N-N(R)R·), - NR’C(O)OR’, -NRR‘. -NR'C(O)R·-, NRC(S)R' -NRC(S)NRR”, -SONR’R'-, -SO₂NRR'-, -OR‘, -OR’C(O)NRR', -ORC(O)OR‘-, OC(O)R, -OC(O)NRR’,- RNRC(O)R, -ΡΟΗ, -RC(O)OR’, -RC(O)NR'R~, -R'C(O)R“, ROC(O)R', -SR’, -SOR’, -SO₂R, -ONO₂ wherein R’, R and R” in each of the above groups can be hydrogen, hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thïo(=S), imino (=NR’), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cydoalkylalkyl, substituted or unsubstituted cydoalkenylalkyl, substituted or unsubstituted heterocycyl, substituted or unsubstituted heterocydcyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, or any two of R, R and R” may be joined to form a substituted or unsubstituted saturated or unsaturated 3-10 membered ring, which may optionally indude heteroatoms which may be the same or different and are selected from O, NR^X or S or form oxo (=0), thio(=S) or imino (=NR’). Substitution or the combinations of substituents envisioned by this invention are preferably those that resuit in the formation of a stable or chemically feasible compound. The term stable as used herein refers to the compounds or the structure that are not substantially altered when subjected to conditions to allow for their isolation, production, détection and preferably their recovery, purification and Incorporation into a pharmaceutical composition.

The term halo, halide, or, altematively, halogen means fluoro, chloro, bromo or iodo. The terms haloalkyl, haloalkenyl, hafoalkynyT and haloalkoxy indude alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof. For example, the terms fluoroalkyl and fluoroalkoxy indude haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine.

The term protecting group or PG refers to a substituent that is employed to block or protect a particular functionality. Other functional groups on the compound may remain reactive. For example, an amino-protecting group is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino- protecting groups indude, but are not limited to, acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyfoxycarbonyl (CBz) and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a hydroxy-protecting group refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable hydroxy-protecting groups indude, but are not limited to, acetyl and silyl. A carboxy-protecting group refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Suitable carboxy-protecting groups indude, but are not limited to, -CH₂CH₂SO₂Ph, cyanoethyl, 2-(trimethyisiïyt)ethyl. 2- (trimethy1sily!)ethoxyniethyl, - 2-(p-toluenesulfonyl)ethyl, 2(p-nitrophenylsulfenyl}ethyl, 2- (dipheny!phosphino)-ethy!, and nitroethyt. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic

Synthesis, John Wiley & Sons, New York, 1991.

The term stereoisomer refers to compounds, which hâve identical chemical composition, but differ with regard to arrangement of the atoms and the groups in space. These include enantiomers, diastereomers, geometrica! isomers, atropisomer or conformational isomers.

Ail the stereoisomers of compounds described herein are within the scope of this invention. Racemic mixtures are also encompassed within the scope of this invention. Therefore, single stereochemical isomers as well enantiomeric, diastereoîsomeric and géométrie (or conformational) mixtures ofthe présent compounds fall within the scope of the invention.

Certain of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The présent chemical entities, pharmaceutical compositions and methods are meant to include ail such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. For the instance the non-limiting example of intermediate mixutures include a mixture of isomers in a ratio of 10:90, 13:87, 17:83, 20:80, or 22:78. Optically active (R> and (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of géométrie asymmetry, and unless specifîed otherwise, it is intended that the compounds include both E and Z géométrie isomers.

The term tautomers refera to compounds, which are characterized by relatively easy interconversion of isomeric forms in equilibrium. These isomers are intended to be covered by this invention. Tautomers are structurally distinct isomère that interconvert by tautomerization. Tautomerization is a form of isomerization and includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry. Prototropic tautomerization or proton-shift tautomerization involves the migration of a proton accompanfed by changes in bond order, often the interchange of a single bond with an adjacent double bond. Where tautomerization is possible (e.g. in solution), a chemical equilibrium of tautomers can be reached. An example of tautomerization is keto-enol tautomerization. A spécifie example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A spedfic example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.

A leaving group or atom is any group or atom that will, under the reaction conditions, deave from the starting material, thus promoting reaction at a specified site. Suitable examples of such groups unless otherwise specified are halogen atoms and mesyloxy, pnitrobenzensulphonyloxy and tosyloxy groups.

The term prodrug refers to a compound, which is an inactive precursor of a compound, converted into its active form in the body by normal metabolic processes. Prodrug design is discussed generally in Hardma, et al. (Eds.), Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed., pp. 11-16 (1996). A thorough discussion is provided in Higuchi, et al., Prodrugs as Novel Delivery Systems, Vol. 14, ASCD Symposium Sériés, and in Roche (ed.), Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987). To îllustrate, prodrugs can be converted into a pharmacologically active form through hydrolysis of, for example, an ester or amide linkage, thereby introducing or exposing a functional group on the résultant product. The prodrugs can be designed to react with an endogenous compound to form a water-soluble conjugate that further enhances the pharmacological properties of the compound, for example, increased drculatory half-life. Altematively, prodrugs can be designed to undergo covalent modification on a functional group with, for example, glucuronic acid, sulfate, glutathione, amino acids, or acetate. The resulting conjugate can be inactivated and excreted in the urine, or rendered more potent than the parent compound. High molecular weight conjugates also can be excreted into the bile, subjected to enzymatic cleavage, and released back into the circulation, thereby effectîvely increasing the biological half-life of the originally administered compound.

The term ester refers to a compound, which is formed by reaction between an add and an alcohol with élimination of water. An ester can be represented by the general formula RCOOR'. These prodrugs and esters are intended to be covered within the scope of this invention.

Additionally the instant invention also indudes the compounds which differ only in the presence of one or more isotopically enriched atoms for example replacement of hydrogen with deuterium or tritium, or the replacement of a carbon by^13C- or ^14C-enriched carbon.

The compounds of the présent invention may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (³H), iodine-125 (¹²⁵l) or carbon-14 (¹⁴C). Ail isotopic variations of the compounds of the présent invention, whether radioactive or not, are encompassed within the scope of the présent invention.

Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases such as U, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn; salts of organic bases such as Ν,Ν'-diacetylethylenediamîne, glucamine, triethylamine, choline, hydroxide, dicydohexylamine, metformin, benzylamîne, trialkylamine, and thiamine; chiral bases such as alkylphenylamine, glycinol, and phenyl glycinol; salts of naturel amino acids such as glycine, alanine, valine, leudne, isoleudne, norleudne, tyrosine, cystine, cysteine, méthionine, proline, hydroxy proline, histidine, omithine, lysine, arginine, and serine: quatemary ammonium salts of the compounds of invention with alkyl halides, alkyl sulphates such as Mel and (MeJjSO^ non-natural amino adds such as D-isomers or substituted amino adds; guanidine; and substituted guanidine wherein the substituents are selected from nitro, amino, alkyl, alkenyl, alkynyl, ammonium or substituted ammonium salts and aluminum salts. Salts may indude add addition salts where appropriate which are sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acétates, tartrates, maleates, dtrates, fumarates, sucdnates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycérophosphates, and ketoglutarates. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, ail combinations and subcombinations of ranges and spedfic embodiments therein are intended to be induded. The term about when referrîng to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary from, for example, between 1% and 15% of the stated number or numerical range. The term comprising (and related terms such as comprise or comprises or having or induding) indudes those embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, that consist of or consist essentially of the described features.

The following abbreviations and terms hâve the indicated meanings throughout HGFR is hépatocyte growth factor receptor; AIDS = Acquired Immuno Defidency Syndrome; HIV = Human Immunodefidency Virus; Mel = Methyi lodide; POCI₃ = Phosphorous Oxychloride; KCNS = Potassium IsoThiocyanate; TLC = Thin Layer Chromatography; MeOH = Methanol; and CHCI₃ = Chloroform.

Abbreviations used herein hâve their conventional meaning within the chemical and biological arts.

The term cell prolifération refers to a phenomenon by which the cell number has changed as a resuit of division. This term also encompasses cell growth by which the cell morphology has changed (e.g., increased in size) consistent with a proliférative signal.

J

The term co-administration, administered in combination with, and their grammatical équivalents, as used herein, encompasses administration of two or more agents to an animal so that both agents and/or their métabolites are présent in the animal at the same time. Coadministration includes simultaneous administration in separate compositions, administration at 5 different times in separate compositions, or administration in a composition in which both agents are présent.

The term effective amount or therapeutically effective amount refers to that amount of a compound described herein that is sufficient to effect the intended application including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary 10 depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and âge of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art The term also applies to a dose that will induce a particular response in target cells, e.g. réduction of platelet adhesion and/or cell migration. The spécifie dose will vary 15 depending on the particular compounds chosen, the dosing regimen to be followed, whether it Is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physica! delivery system in which It is carried.

As used herein, treatment, treating, or ameliorating are used interchangeably. These terms refers to an approach for obtaining bénéficia! or desired results including but not limited to 20 therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant éradication or amelioration of the underiying disorder being treated. Also, a therapeutic benefit is achieved with the éradication or amelioration of one or more of the physiological symptoms associated with the underiying disorder such that an improvement is observed in the patient, notwithstandîng that the patient may still be afflicted with the underiying disorder. For 25 prophylactic benefit, the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosîs of this disease may not hâve been made.

A therapeutic effect, as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above. A prophylactic effect indudes delaying or eliminating 30 the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

The term subject or patient’ refers to an animal, such as a mammal, for example a human.

The methods described herein can be useful in both human therapeutics and veterinary applications. In some embodiments, the patient is a mammal, and in some embodiments, the patient is human.

Radiation therapy” means exposing a patient, using routine methods and compositions known to the practitioner, to radiation emitters such as alpha-partide emitting radionudides (e.g., actinium and thorium radionudides), low linear energy transfer (LET) radiation emitters (i.e. beta emitters), conversion électron emitters (e.g. strontium-89 and samarium- 153-EDTMP, or high-energy radiation, induding without limitation x-rays, gamma rays, and neutrons.

Signal transduction” is a process during which stimulatory or inhibitory signais are transmitted into and within a cell to elidt an intracellular response. A modulator of a signal transduction pathway refers to a compound which modulâtes the activity of one or more cellular proteins mapped to the same spedfic signal transduction pathway. A modulator may augment (agonist) or suppress (antagonist) the activity of a signaling molécule.

The term sélective Inhibition” or selectively inhibit as applied to a biologically active agent refers to the agent's ability to selectively reduce the target signaling activity as compared to offtarget signaling activity, via direct or indirect interaction with the target

The term pharmaceutically acceptable carrier or pharmaceutically acceptable exdpient indudes, but is not limited to, any and ail solvents, dispersion media, coatings, antibacteriai and antifungal agents, isotonie and absorption delaying agents, one or more suitable diluents, fillers, salts, désintégrants, binders, lubricants, glidants, wetting agents, controlled release matrices, colorants/flavoring, carriers, exdpients, buffers, stabilizers, solubilizers, and combinations thereof. Except insofar as any conventional media or agent is incompatible with the active ingrédient, its use in the therapeutic compositions of the invention is contemplated. Supplementary active ingrédients can also be incorporated into the compositions.

Inhibition of omet kinase may be of therapeutic benefit in treatment of various conditions, e.g., conditions characterized by an inflammatory response induding but not limited to autoimmune diseases, allergie diseases, and arthritic diseases.

Inflammatory response as used herein is characterized by redness, heat, swelüng and pain (i.e., inflammation) and typically involves tissue injury or destruction. An inflammatory response is usually a localized, protective response elidted by injury or destruction of tissues, which serves to destroy, dilute or wall off (sequester) both the injurious agent and the injured tissue. Inflammatory responses are notably associated with the influx of leukocytes and/or leukocyte (e.g., neutrophil) chemotaxis. Inflammatory responses may resuit from infection with pathogenic organisms and viruses, noninfectious means such as trauma or reperfusion following myocardial infarction or stroke, immune responses to foreign antigens, and autoimmune diseases. Inflammatory responses amenable to treatment with the methods and compounds according to the invention encompass conditions associated with reactions of the spécifie defense System as well as conditions associated with reactions of the non-spedfic defense system.

The therapeutic methods of the invention include methods for the amelioration of conditions associated with inflammatory cell activation. Inflammatory cell activation refers to the induction by a stimulus (including but not limited to, cytokines, antigens or auto-antibodies) of a proliférative cellular response, the production of soluble mediators (induding but not limited to cytokines, oxygen radicals, enzymes, prostanoids, or vasoadive amines), or cell surface expression of new or increased numbers of mediators (induding but not limited to, major histocompatibility antigens or cell adhesion molécules) in inflammatory cells (induding but not limited to monocytes, macrophages, T lymphocytes, B lymphocytes, granulocytes (polymorphonudear leukocytes induding neutrophils, basophils, and eosinophils) mast cells, dendritic cells, Langerhans cells, and endothélial cells). It will be appredated by persons skilled in the art that the activation of one or a combination of these phenotypes In these cells can contribute to the initiation, perpétuation, or exacerbation of an inflammatory condition.

Autoimmune disease as used herein refers to any group of disorders In which tissue injury is assodated with humoral or cell-mediated responses to the body*s own constituents. Transplant rejection as used herein refers-to any immune response directed against grafted tissue (induding organs or cells (e.g., bone marrow), characterized by a loss of function of the grafted and surrounding tissues, pain, swelling, leukocytosis, and thrombocytopenia). Allergie disease as used herein refers to any symptoms, tissue damage, or loss of tissue function resulting from allergy. Arthritic disease as used herein refers to any disease that is characterized by inflammatory lésions of the joints attributable to a variety of étiologies. Dermatitis as used herein refers to any of a large family of diseases of the skin that are characterized by inflammation of the skin attributable to a variety of étiologies.

The relative efficacies of compounds as inhibitors of an enzyme activity (or other biological activity) can be establîshed by determining the concentrations at which each compound inhibits the activity to a predefined extent and then comparing the results. Typically, the preferred détermination is the concentration that inhibits 50% of the activity in a biochemical assay, i.e., the 50% inhibitory concentration or IC50. IC50 déterminations can be accomplished using conventional techniques known in the art In general, an IC50 can be determined by measuring the activity of a given enzyme in the presence of a range of concentrations of the inhibitor under study. The experimentally obtained values of enzyme activity then are plotted against the inhibitor concentrations used. The concentration ofthe inhibitor that shows 50% enzyme activity 56 (as compared to the activity in the absence of any inhibitor) is taken as the IC50 value.

Analogously, other inhibitory concentrations can be defined through appropriate déterminations of activity. For example, in some settings it can be désirable to establish a 90% inhibitory concentration, i.e., IC90, etc.

Accordingly, a c-met sélective inhibitor altematively can be understood to refer to a compound that exhibits a 50% inhibitory concentration (IC50) with respect to c-met kinase, that is at least 10-fold, in another aspect at least 20-fold, and in another aspect at least 30-fold, lower than the IC50 value with respect to any or ail of the other class receptor tyrosine kinase (RTK) family members. In an alternative embodiment of the invention, the term c-met kinase sélective inhibitor can be understood to refer to a compound that exhibits an IC50 with respect to c-met kinase that is at least 50-fold, in another aspect at least 100-fold, in an additional aspect at least 200-fold, and in yet another aspect at least 500-fold, lower than the IC50 with respect to any or ail of the other RTK family members. A c-met kinase sélective inhibitor is typically administered in an amount such that it selectively inhibits c-met activity, as described above.

The methods of the invention may be applied to cel! populations in vivo or ex vivo. In vivo means within a living individual, as within an animal or human or in a subject's body. In this context, the methods of the invention may be used therapeutically or prophylactically in an individual. Ex vivo or “In vitro’ means outside of a living individual. Examples of ex vivo cell populations indude in vitro cell cultures and bioiogical samples including but not limited to fluid or tissue samples obtained from individuals. Such samples may be obtained by methods known in the art Exemplary bioiogical fluid samples indude blood, cerebrosplnal fluid, urine, and saliva. Exemplary tissue samples indude tumors and biopsies thereof. In this context, the invention may be used for a variety of purposes, induding therapeutic and experimental purposes. For example, the invention may be used ex vivo or in vitro to détermine the optimal schedule and/or dosing of administration of a c-met kinase sélective inhibitor for a given indication, cell type, individual, and other parameters. Information gleaned from such use may be used for experimental or diagnostic purposes or in the dinic to set protocols for in vivo treatment. Other ex vivo uses for which the invention may be suited are described below or will become apparent to those skilled in the art.

Pharmaceutical Compositions

The invention provides a pharmaceutical composition comprising one or more compounds of the présent invention. The pharmaceutical composition may indude one or more additional adive ingrédients as described herein. The pharmaceutical composition may be administered for any of the disorders described herein !n some embodiments, the invention provides pharmaceutical compositions for treating diseases or conditions related to an undesirable, over-active, harmful or deleterious immune response in a mammal. Such undesirable immune response can be associated with or resuit in, e.g., asthma, emphysema, bronchitis, psoriasis, allergy, anaphylaxsis, auto-immune diseases, rhuematoid arthritis, graft versus host disease, and lupus erythematosus. The pharmaceutical compositions of the présent invention can be used to treat other respiratory diseases including but not limited to diseases affecting the lobes of lung, pleural cavity, bronchial tubes, trachea, upper respiratory tract, or the nerves and muscle for breathing.

In some embodiments, the invention provides pharmaceutical compositions for the treatment of disorders such as hyperproliferative disorder including but not limited to cancer such as acute myeloid leukemia, thymus, brain, lung, squamous cell, skin, eye, retinoblastoma, intraocular melanoma, oral cavity and oropharyngeal, bladder, gastric, stomach, pancreatic, bladder, breast, cervical, head, neck, rénal, kidney, liver, ovarian, prostate, colorectal, esophageal, testicular, gynecological, thyroid, CNS, PNS, AIDS related (e.g. Lymphoma and Kaposi's Sarcoma) or Viral-lnduced cancer. In some embodiments, the pharmaceutical composition is for the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e. g., psoriasis), restenosis, or prostate (e. g., benign prostatic hypertrophy (BPH)).

The invention also relates to a composition for treating a disease related to vasculogenesis or angiogenesis in a mammal which can manifest as tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, Inflammatory bowel disease, atherosderosis, skin diseases such as psoriasis, eczema, and sderoderma, diabètes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi’s sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer. The invention also provides compositions for the treatment of liver diseases (induding diabètes), pancreatitis or kidney disease (induding proliférative glomerulonephritis and diabètes- induced rénal disease) or pain in a mammal.

The invention further provides a composition for the prévention of blastocyte implantation in a mammal.

The subject pharmaceutical compositions are typically formulated to provide a therapeutically effedive amount of a compound of the présent invention as the active ingrédient, or a pharmaceutically acceptable sait, ester, or prodrug thereof. Where desired, the pharmaceutical compositions contain a compound of the présent invention as the active ingrédient or a pharmaceutically acceptable sait and/or coordination complex thereof, and one or more pharmaceutically acceptable exdpients, carriers, such as inert solid dïluents and fillers, diluents, including stérile aqueous solution and various organic solvents, perméation enhancers, solubilizers and adjuvants.

The subject pharmaceutical compositions can be administered alone or in combination with one or more other agents, which are also typically administered in the form of pharmaceutical compositions. Where desired, the subject compounds and other agent(s) may be mixed into a préparation or both components may be formulated into separate préparations to use them In combination separately or at the same time.

Methods indude administration of an Inhibitor by itself, or In combination as described herein, and in each case optionally induding one or more suîtable diluents, fillers, salts, disintegrants, binders, lubricants, glidants, wetting agents, controlled release matrices, colorants/flavoring, carriers, exdpients, buffers, stabilizers, solubilizers, and combinations thereof.

Préparations of various pharmaceutical compositions are known in the art See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Prindples of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 2003; Goodman and Gilman, eds., The Pharmacologîcal Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sdences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thîrty-Second Edition (The Pharmaceutical Press, London, 1999), ail of which are incorporated by référencé herein in their entirety.

The compounds or pharmaceutical composition of the présent invention can be administered by any route that enables delivery of the compounds to the site of action, such asoral routes, Intraduodenal routes, parentéral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical administration (e.g. transdermal application), rectal administration, via local delivery by cathéter or stent or through inhalation. The compounds can also be administered intraadiposally or intrathecally.

The compositions can be administered in solid, semî-solid, liquid or gaseous form, or may be in dried powder, such as lyophilized form. The pharmaceutical compositions can be packaged in forms convenient for delivery, including, for example, solid dosage forms such as capsules, sachets, cachets, gelatins, papers, tablets, capsules, suppositories, pellets, pills, troches, and lozenges. The type of packaging will generally dépend on the desired route of administration. Implantable sustalned release formulations are also contemplated, as are transdermal formulations.

Routes of Administration

In the methods according to the invention, the inhibitor compounds may be administered by various routes. For example, pharmaceutical compositions may be for injection, or for oral, nasal, transdermal or other forms of administration, including, e.g., by intravenous, intradermal, intramuscular, intramammary, intraperitoneal, intrathecal, intraocular, retrobulbar, intrapulmonary (e.g., aerosolized drugs) or subcutaneous injection (including depot administration for long term release e.g., embedded-under the-splenic capsule, brain, or In the cornea); by sublingual, anal, or vaginal administration, or by surgical implantation, e.g., embedded under the splenic capsule, brain, or in the cornea. The treatment may consist of a single dose or a plurality of doses over a period of time. In general, the methods of the invention involve administering effective amounts of a modulator of the invention together with one or more pharmaceutically acceptable diluents, preservatives, solubilizers, emulsîfiers, adjuvants and/or carriers, as described above.

The subject pharmaceutical composition may, for example, be in a form suitable for oral administration as a tabiet, capsule, pîll, powder, sustained release formulations, solution, suspension, for parentéral injection as a stérile solution, suspension or émulsion, for topîcal administration as an ointment or cream or for rectal administration as a suppository. The pharmaceutical composition may be in unit dosage forms suitable for single administration of predse dosages. The pharmaceutical composition will indude a conventional pharmaceutical carrier or exdpîent and a compound according to the invention as an active ingrédient In addition, it may indude other medidnal or pharmaceutical agents, carriers, and adjuvants.

In one aspect, the invention provides methods for oral administration of a pharmaceutical composition of the invention. Oral solid dosage forms are described generally in Remington's Pharmaceutical Sdences, supra at Chapter 89. Solid dosage forms indude tablets, capsules, pills, troches or lozenges, and cachets or pellets. Also, liposomal or proteinoid encapsulation may be used to formulate the compositions (as, for example, proteinoid microspheres reported in U.S. Pat. No. 4,925,673). Liposomal encapsulation may inciude liposomes that are derivatized with various polymers (e.g., U.S. Pat. No. 5,013,556). The formulation may Indude a compound of the invention and inert ingrédients which protect against dégradation in the stomach and which permit release of the biologically active material in the intestine.

Toxidty and therapeutic efficacy of the met kinase compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animais, e.g., for determining the

LD50 (the dose léthal to 50% of the population) and the ED50 (the dose therapeutically effective In 50% of the population). Additionally, this information can be determined in cell cultures or experimental animais additionally treated with other thérapies induding but not limited to radiation, chemotherapeutic agents, photodynamic thérapies, radiofrequency ablation, anti-angiogenic agents, and combinations thereof.

The amount ofthe compound administered will be dépendent on the mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discrétion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g/day, preferably about 0.05 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adéquate, while in other cases still larger doses may be employed without causing any harmful side effect, e.g. bydividing such larger doses Into several small doses for administration throughout the day.

In some embodiments, a compound of the invention is administered in a single dose. Typicaliy, such administration will be by Injection, e.g., intravenous injection, in order to introduce the agent quickly. However, other routes may be used as appropriate. A single dose of a compound of the invention may also be used for treatment of an acute condition.

In practice of the methods of the invention, the pharmaceutical compositions are generally provided in doses ranging from 1 pg compound/kg body weight to 1000 mg/kg, 0.1 mg/kg to 100 mg/kg, 0.1 mg/kg to 50 mg/kg, and 1 to 20 mg/kg, given in daily doses or in équivalent doses at longer or shorter intervals, e.g., every other day, twice weekly, weekly, or twice or three times daily. The Inhibitor compositions may be administered by an initial bolus followed by a continuous infusion to maintain therapeutic circulating levels of drug product. Those of ordinary skîll in the art will readily optimize effective dosages and administration regimens as determined by good medical practice and the dinical condition of the individual to be treated. The frequency of dosing will dépend on the pharmacokinetic parameters of the agents and the route of administration. The optimal pharmaceutical formulation will be determined by one skilled ln the art depending upon the route of administration and desired dosage [see, for example, Remington’s Pharmaceutical Sdences, pp. 1435-1712, the disdosure of which is hereby incorporated by référencé]. Such formulations may influence the physical state, stability, rate of in vivo reiease, and rate of in vivo dearance of the administered agents. Depending on the route of administration, a suitable dose may be calculated according to body weight, body surface area or organ size. Further refinement of the calculations necessary to détermine the appropriate dosage for treatment involving each of the above mentioned formulations is routinely made by those of ordinary skill in the art without undue expérimentation, espedally in light of the dosage information and assays disdosed herein, as well as the pharmacokinetic data observed in human dinical trials. Appropriate dosages may be ascertained by using established assays for determining blood level dosages in conjunction with an appropriate phystdan considering various factors which modify the action of drugs, e.g., the drug's spécifie activity, the severity of the indication, and the responsiveness of the individual, the âge, condition, body weight, sex and diet of the individual, the time of administration and other clinical factors. As studies are conducted, further information will emerge regarding the appropriate dosage levels and duration of treatment for various diseases and conditions capable of being treated with the methods of the invention.

In some embodiments, a compound of the invention is administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be about once a month, once every two weeks, once a week, or once every other day. In another embodiment a compound of the invention and another agent are administered together about once per day to about 6 times per day. In another embodiment the administration of a compound of the invention and an agent continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6,10,14,28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and malntained as long as necessary.

Administration of the agents of the Invention may continue as long as necessary. In some embodiments, an agent of the invention is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, an agent of the invention is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, an agent of the Invention is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.

An effective amount of a compound of the invention may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenousfy, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant

The compounds of the invention may be administered in dosages. It ls known in the art that due to intersubject variability in compound pharmacokinetics, individualizatîon of dosing regimen is necessary for optimal therapy. Dosing for a compound of the invention may be found by routine expérimentation in light of the instant disclosure.

When a compound of the invention, is administered In a composition that comprises one or more agents, and the agent has a shorter half-life than the compound of the invention unit dose forms ofthe agent and the compound of the invention may be adjusted accordingly.

The inhibitors of the invention may be covalently or noncovaîently associated with a carrier molécule including but not limited to a linear polymer (e.g., polyethylene glycol, polylysine, dextran, etc.), a branched-chain polymer (see U.S. Pat. Nos. 4,289,872 and 5,229,490; PCT Publication No. WO 93/21259), a lipid, a cholestérol group (such as a steroid), or a carbohydrate or oligosaccharide. Spécifie examples of carriers for use in the pharmaceutical compositions of the invention include carbohydrate-based polymers such as trehalose, mannitol, xytitol, sucrose, lactose, sorbitol, dextrans such as cyclodextran, cellulose, and cellulose dérivatives. Also, the use of liposomes, microcapsules or microspheres, inclusion complexes, or other types of carriers is contemplated.

Other carriers include one or more water soluble polymer attachments such as polyoxyethylene glycol, or polypropylene glycol as described U.S. Pat. Nos. 4,640,835, 4,496,689, 4,301,144, 4,670,417,4,791,192 and 4,179,337. Still other useful carrier polymers known in the art include monomethoxy-polyethylene glycol, poly-(N-vinyl pyrrolidone)-polyethylene glycol, propylene glycol homopolymers, a polypropylene oxidelethylene oxide co-polymer, polyoxyethylated polyols (e.g., glycerol) and polyvinyl alcohol, as well as mixtures of these polymers.

Derivitization with bifunctional agents is useful for cross-linking a compound of the invention to a support matrix or to a carrier. One such carrier is polyethylene glycol (PEG). The PEG group may be of any convenient molecular weight and may be straight chain or branched. The average molecular weight of the PEG can range from about 2 kDa to about 100 kDa, in another aspect from about 5 kDa to about 50 kDa, and in a further aspect from about 5 kDa to about 10 kDa. The PEG groups will generally be attached to the compounds of the invention via acylation, reductive alkylation, Michael addition, thiol alkylation or other chemoselective conjugation/ligation methods through a reactive group on the PEG moiety (e.g., an aldéhyde, amino, ester, thiol, d-haloacetyl, maleimido or hydrazino group) to a reactive group on the target inhibitor compound (e.g., an aldéhyde, amino, ester, thiol, a-haloacetyi, maleimido or hydrazino group). Cross-linking agents can include, e.g., esters with 4-azidosalicylic acid, homobifunctional imidoesters, including disuednimidyl esters such as 3,3'-dithiobîs (sucdnimidylpropionate), and bifundional maleimides such as bis-N-maleimido-1,8-octane. Derivatizing agents such as methyl-3-[(p-azidophenyl}dithiolpropioimidate yield photoactivatable intermediates that are capable of forming crosslinks In the presence of light Altematively, reactive water-insoluble matrices such as cyanogen bromide-activated carbohydrates and the reactive substrates described in U.S. Pat. Nos. 3,969,287; 3,691,016; 4,195,128; 4,247,642; 4,229,537; and 4,330,440 may be employed for inhibitor immobiïization.

Method of Treatment

The invention also provides methods of using the compounds or pharmaceutical compositions of the présent invention to treat disease conditions, including but not limited to diseases associated with malfunctioning of c-met kinase and family.

The treatment methods provided herein comprise administering to the subject a therapeuticaily effective amount of a compound of the invention. In one embodiment, the présent invention provides a method of treating an inflammation disorder, including autoimmune diseases In a mammal. The method comprises administering to said mammal a therapeuticaily effective amount of a compound of the présent invention.

The disorders, diseases, or conditions treatable with a compound provided herein, indude, but are not limited to, inflammatory or allergie diseases, Induding systemlc anaphyiaxis and hypersensitivity disorders, atopie dermatitis, urtîcaria, drug allergies, insect sting allergies, food allergies (induding celiac disease and the like), anaphyiaxis, sérum sickness, drug reactions, insect venom allergies, hypersensitivity pneumonitis, angîoedema, erythema multiforme, StevensJohnson syndrome, atopie keratoconjunctivitis, venereal keratoconjunctivitis, giant papillary conjunctivitis, and mastocytosis;

inflammatory bowel diseases, induding Crohn's disease, ulcerative colitis, ileitis.enteritis, and necrotizing enterocolitis;

vasculitis, and Behcet's syndrome;

psoriasis and inflammatory dermatoses, induding dermatitis, eczema, , allergie contact dermatitis, , viral cutaneous pathologies induding those derived from human papillomavirus, HIV or RLV infection, bacterial, flugal, and other parasitai cutaneous pathologies, and cutaneous lupus erythematosus;

asthma and respiratory allergie diseases, induding allergie asthma, exercise induced asthma, allergie rhinitis, otitis media, hypersensitivity lung diseases, chronic obstructive pulmonary disease and other respiratory problems;

autoimmune diseases and inflammatory conditions, induding but are not limited to acute disseminated encephalomyelitis (ADEM), Addison's disease, antiphospholipid antibody syndrome (APS), aplastic anémia, autoimmune hepatitis, coeliac disease, Crohn's disease, Diabètes mellitus (type 1), Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome (GBS), Reynaud’s syndrome, Hashimoto’s disease, lupus erythematosus, systemic lupus erythematosus (SLE), multiple sderosis, myasthenia gravis, opsodonus myodonus syndrome (OMS), optic neuritis, Ord's thyroiditis, oemphigus, polyarthritis, primary bîliary drrhosis, 64 psoriasis, rheumatoid arthritis, psoriatic arthritis, gouty arthritis, spondylitis, reactive arthritis, chronic or acute glomerulonephritis, lupus nephritis, Reiteris syndrome, Takayasu’s arteritis, temporal arteritis (also known as giant cell arteritis), warm autoimmune hemolytic anémia, Wegener’s granulomatosis, alopeda universalis, Chagas' disease, chronic fatigue syndrome, dysautonomia, endometriosis, hidradenitis suppurativa, interstitiel cystitis, neuromyotonia, sarcoidosis, sderoderma, ulcerative colitis, connective tissue disease, autoimmune pulmonary inflammation, autoimmune thyroiditis, autoimmune inflammatory eye disease, vitiligo, and vulvodynîa. Other disorders indude bone-resorption disorders and thromobsis;

tissue or organ transplant rejection disorders induding but not limited to graft rejection (induding allograft rejection and graft-v-host disease (GVHD)), e.g., skin graft rejection, solid organ transplant rejection, bone marrow transplant rejection;

fever;

cardiovascular disorders, induding acute heart failure, hypotension, hypertension, angina pectoris, myocardial infarction, cardiomyopathy, congestive heart failure, atherosderosis, coronary artery disease, restenosis, and vascular stenosis;

cerebrovascular disorders, induding traumatic brain injury, stroke, ischémie reperfusion injury and aneurysm;

cancers of the breast, skin, prostate, cervix, utérus, ovary, testes, bladder, lung, liver, larynx, oral cavity, colon and gastrointestîna! tract (e.g., esophagus, stomach, pancréas), brain, thyroid, blood, and lymphatic system;

fibrosis, connective tissue disease, and sarcoidosis;

génital and reproductive conditions, induding erectile dysfunction;

gastrointestinal disorders, induding gastritis, ulcers, nausea, pancreatitis, and vomiting; neurologie disorders, induding Alzheimer’s disease;

sleep disorders, induding insomnia, narcolepsy, sleep apnea syndrome, and Pickwick Syndrome;

pain, myalgias due to infection;

rénal disorders;

ocular disorders, induding glaucoma;

infectious diseases, induding HIV;

sepsis; septic shock; endotoxic shock; gram négative sepsis; gram positive sepsis; toxic shock syndrome; multiple organ injury syndrome secondary to septicemia, trauma, or hemorrhage;

pulmonary or respiratory conditions including but not Iimited to asthma, chronic bronchitis, allergie rhinitis, adult respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), chronic pulmonary inflammatory diseases (e.g., chronic obstructive pulmonary disease), silicosis, pulmonary sarcoidosis, pleurisy, alveolitis, vasculitis, pneumonia, bronchiectasis, hereditary emphysema, and pulmonary oxygen toxidty;

Ischemic-reperfusion injury, e.g., ofthe myocardium, brain, or extremities;

fibrosis including but not Iimited to cystic fibrosis; keloid formation or scar tissue formation; central or peripheral nervous system inflammatory conditions including but not Iimited to meningitis (e.g., acute purulent meningitis), encephalitis, and brain or spinal cord injury due to minor trauma;

Sjorgren's syndrome; diseases involving leukocyte diapedesis; alcoholic hepatitis; bacterial pneumonia; community acquired pneumonia (CAP); Pneumocystis carinii pneumonia (PCP); antigen-antibody complex mediated diseases; hypovolémie shock; acute and defayed hypersensitivity; disease states due to leukocyte dyscrasia and metastasis; thermal injury; granulocyte transfusion associated syndromes; cytokine-induced toxidty; stroke; pancreatitis; myocardial infarction, respiratory syncytial virus (RSV) Infection; and spinal cord injury.

In certain embodiments, the cancer or cancers treatable with the methods provided herein indudes, but is or are not Iimited to, leukemias, induding, but not Iimited to, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemias such as myeloblasts, promyélocyte, myelomonocytic, monocytic, erythroleukemia leukemias and myelodysplastic syndrome or a symptom thereof (such as anémia, thrombocytopénie, neutropenia, bicytopenia or pancytopenia), refractory anémia (RA), RA with ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB in transformation (RAEB-T), preleukemia, and chronic myelomonocytic leukemia (CMML);

chronic leukemias, induding, but not Iimited to, chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, and hairy cell leukemia;

polycythemia vera;

lymphomas, induding, but not Iimited to, Hodgkin's disease and non-Hodgkin’s disease;

multiple myelomas, induding, but not Iimited to, smoldering multiple myeloma, nonsecretory myeloma, osteosderotic myeloma, plasma cell leukemia, solitary plasmacytoma, and extramedullary plasmacytoma;

Waldenstrom's macroglobulinémie;

monodonal gammopathy of undetermined significance;

benign monodonal gammopathy, heavy chain disease;

bone and connective tissue sarcomas, induding, but not limited to, bone sarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissue sarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, metastatic cancers, neurilemmoma, rhabdomyosarcome, and synovial sarcoma;

brain tumors, induding, but not limited to, glioma, astrocytoma, brain stem glioma, ependymoma, oligodendroglioma, nonglial tumor, acoustic neurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma, pineoblastoma, and primary brain lymphoma; breast cancer, induding, but not limited to, adenocardnoma, lobular (small cell) cardnoma, intraductal cardnoma, medullary breast cancer, mudnous breast cancer, tubular breast cancer, papillary breast cancer, primary cancers, Paget’ s disease, and Inflammatory breast cancer; adrenal cancer, Induding, but not limited to, pheochromocytom and adrenocortical cardnoma; thyroid cancer, induding, but not limited to, papillary or follicular thyroid cancer, medullary thyroid cancer, and anaplastic thyroid cancer;

pancreatic cancer, induding, but not limited to.insullnoma, gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor, and cardnoid or islet cell tumor;

pituitary cancer, induding, but limited to, Cushing's disease, prolactîn-secreting tumor, acromegaly, and diabètes Insipidus;

eye cancer, inciuding, but not limited, to ocular melanoma such as iris melanoma, choroidal melanoma, and dllîary body melanoma, and retinoblastoma;

vaginal cancer, induding, but not limited to, squamous cell cardnoma, adenocardnoma, and melanoma;

vulvar cancer, induding, but not limited to, squamous cell cardnoma, melanoma, adenocardnoma, basal cell cardnoma, sarcoma, and Paget* s disease;

cervical cancers, induding, but not limited to, squamous cell cardnoma, and adenocardnoma; uterine cancer, induding, but not limited to, endométrial cardnoma and uterine sarcoma; ovarian cancer, induding, but not limited to, ovarian épithélial cardnoma, borderiine tumor, germ cell tumor, and stromal tumor;

esophageal cancer, induding, but not limited to, squamous cancer, adenocardnoma, adenoid cystic cardnoma, mucoepidermoid cardnoma, adenosquamous cardnoma, sarcoma, melanoma, plasmacytoma, verrucous cardnoma, and oat cell (small cell) cardnoma;

stomach cancer, including, but not limited to, adenocarcinoma, fungating (polypoid), ulcerating, superfiaal spreading, diffusely spreading, malignant lymphoma, liposarcoma, fibrosarcoma, and cardnosarcoma;

colon cancer;

rectal cancer;

liver cancer, induding, but not limited to, hepatocellular cardnoma and hepatoblastoma; gallbladder cancer, Induding, but not limited to, adenocardnoma;

cholangiocardnomas, induding, but not limited to, pappillary, nodular, and diffuse;

lung cancer, induding, but not limited to, non-small cell lung cancer, squamous cell cardnoma (epidermoid cardnoma), adenocardnoma, large-cell cardnoma, and small-cell lung cancer;

testicular cancer, induding, but not limited to, germinal tumor, seminoma, anaplastic, dassic (typical), spermatocytic, nonseminoma, embryona! cardnoma, teratoma cardnoma, and choriocardnoma (yolk-sac tumor);

prostate cancer, induding, but not limited to, adenocardnoma, leiomyosarcoma, and rhabdomyosa rcoma ;

penal cancer;

oral cancer, induding, but not limited to, squamous cell cardnoma;

basal cancer;

salivary gland cancer, induding. but not limited to, adenocardnoma, mucoepidermotd cardnoma, and adenoidcystic cardnoma;

pharynx cancer, induding, but not limited to, squamous cell cancer and verrucous;

skin cancer, induding, but not limited to, basal cell cardnoma, squamous cell cardnoma and melanoma, superfiaal spreading melanoma, nodular melanoma, lentigo malignant melanoma, and acral lentiginous melanoma;

kidney cancer, induding, but not limited to, rénal cell cancer, adenocardnoma, hypemephroma, fibrosarcoma, and transitional cell cancer (rénal pelvis and/or uterer); Wîlms' tumor;

bladder cancer, induding, but not limited to, transitional cell cardnoma, squamous cell cancer, adenocardnoma, and cardnosarcoma; and other cancer, induding, not limited to, myxosarcoma, ostéogénie sarcoma, endotheliosarcoma, lymphangio· endotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, épithélial cardnoma, cystadenocardnoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, and papillary adenocarcinomas

See Fishman et al., 1985, Medidne, 2d Ed., J.B. Lippincott Co., Philadelphia and Murphy et al., 1997, Informed Dedsions: The Complété Book of Cancer Diagnosîs, Treatment, and Recovery, Viking Penguin, Penguin Books U.S A, Inc., United States of America.

It will be appredated that the treatment methods of the invention are usefui in the fields of human medidne and veterinary medidne. Thus, the individual to be treated may be a mammal, preferably human, or other animais. For veterinary purposes, individu al s indude but are not limited to farm animais înduding cows, sheep, pîgs, horses, and goats; companion animais such as dogs and cats; exotic and/or zoo animais; laboratory animais induding mice, rats, rabbits, guinea pîgs, and hamsters; and poultry such as chickens, turkeys, ducks, and geese.

ln another embodiment, the compounds described herein are used for the treatment of cancer such as acute myeloid leukemia, thymus, brain, lung, squamous cell, skin, eye, retinoblastoma, intraocular melanoma, oral cavity and oropharyngeal, bladder, gastric, stomach, pancreatic, bladder, breast, cervical, head, neck, rénal, kidney, liver, ovarian, prostate, colorectal, esophageal, testicular, gynecological, thyroid, CNS, PNS, AlDS-related (e.g. Lymphoma and Kaposi’s Sarcoma) or viral-induced cancer, ln some embodiments, said method relates to the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e. g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).

The invention also relates to a method of treating diseases related to vasculogenesis or angiogenesis in a mammal that comprises administering to said mammal a therapeuticaiiy effective amount of a compound of the présent invention, ln some embodiments, said method is for treating a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosderosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and sderoderma, diabètes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.

Patients that can be treated with compounds of the présent invention, according to the methods of this invention indude, for example, patients that hâve been diagnosed as having psoriasis; restenosis; atherosderosis; BPH; breast cancer such as a dudal cardnoma in duct tissue in a mammary gland, medullary cardnomas, colloid cardnomas, tubular cardnomas, and inflammatory breast cancer, ovarian cancer, induding épithélial ovarian tumors such as adenocarcinoma in the ovary and an adenocarcinoma that has migrated from the ovary into the abdominal cavity; uterine cancer; cervical cancer such as adenocarcinoma in the cervix 69

épithélial including squamous cell carcinoma and adenocarcinomas; prostate cancer, such as a prostate cancer selected from the following: an adenocarcinoma or an adenocarinoma that has migrated to the bone; pancreatic cancer such as epitheliod carcinoma in the pancreatic duct tissue and an adenocarcinoma in a pancreatic duct; bladder cancer such as a transitional cell carcinoma in urinary bladder, urothélial cardnomas (transitional cell carcinomes), tumors in the urothélial cells that line the bladder, squamous cell cardnomas, adenocardnomas, and small cell cancers; leukemia such as acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and myelodysplastic syndrome (MDS); bone cancer; lung cancer such as non-small cell lung cancer (NSCLC), which is divided into squamous cell cardnomas, adenocardnomas, and large cell undifferentiated cardnomas, and small cell lung cancer; skin cancer such as basal cell cardnoma, melanoma, squamous cell carcinoma and actinie keratosis, which is a skin condition that sometimes develops into squamous cell carcinoma; eye retinoblastoma; cutaneous or intraocular (eye) melanoma; primary liver cancer (cancer that begins in the liver); kidney cancer; thyroid cancer such as papillary, follicular, medullary and anaplastic; AIDS-related lymphoma such as diffuse large B-cell lymphoma, B-cell immunoblastic lymphoma and small non-cleaved cell lymphoma; Kaposi’s Sarcoma; viral-induced cancers induding hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatocellular carcinoma; human lymphotropic virus-type 1 (HTLV-I) and adult T-cell leukemia/lymphoma; and human papilloma virus (HPV) and cervical cancer, central nervous System cancers (CNS) such as primary brain tumor, which indudes gliomas (astrocytoma, anaplastic astrocytoma, or glioblastoma multiforme), Oligodendrogliome, Ependymoma, Meningîoma, Lymphoma, Schwannoma, and Medulloblastoma; peripheral nervous system (PNS) cancers such as acoustic neuromas and malignant peripheral nerve sheath tumor (MPNST) induding neurofibromas and schwannomas, malignant fibrous cytoma, malignant fibrous histiocytoma, malignant meningîoma, malignant mesothelioma, and malignant mixed MOilerian tumor oral cavity and oropharyngeal cancer such as, hypopharyngeal cancer, laryngeal cancer, nasopharyngeal cancer, and oropharyngeal cancer; stomach cancer such as lymphomas, gastric stromal tumors, and cardnoid tumors; testicular cancer such as germ cell tumors (GCTs), which indude seminomas and nonseminomas, and gonadal stromal tumors, which indude Leydig cell tumors and Sertoli cell tumors; thymus cancer such as to thymomas, thymie cardnomas, Hodgkin disease, non-Hodgkin lymphomas cardnoids or cardnoid tumors; rectal cancer; and colon cancer.

The invention also relates to a method of treating diabètes in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the présent invention.

In addition, the compounds described herein may be used to treat acné.

In addition, the compounds described herein may be used for the treatment of arteriosclerosis, induding atherosderosis. Arteriosderosis is a general term describing any hardening of medium or large arteries. Atherosderosis is a hardening of an artery specifically due to an atheromatous plaque.

Further the compounds described herein may be used for the treatment of glomerulonephritis. Glomerulonephritis is a primary or secondary autoimmune rénal disease characterized by inflammation of the glomeruli. It may be asymptomatic, or présent with hematuria and/or proteinuria. There are many recognîzed types, divided In acute, subacute or chronic glomerulonephritis. Causes are infectious (bacterial, viral or parasitic pathogens), autoimmune or paraneoplastic.

Additionally, the compounds described herein may be used for the treatment of bursitis, lupus, acute disseminated encephalomyelitis (ADEM), addison’s disease, antiphospholipid antibody syndrome (APS), aplastic anémia, autoimmune hepatitis, coeliac disease, Crohrïs disease, diabètes mellitus (type 1), goodpasture’s syndrome, graves' disease, guîllain-barre syndrome (GBS), hashimoto's disease, inflammatory bowel disease, lupus erythematosus, myasthenia gravis, opsoclonus myoclonus syndrome (OMS), optic neuritis, ord's thyroiditiSjOstheoarthritis, uveoretinitis, pemphigus, polyarthritis, primary biliary dnrhosis, reiter*s syndrome, takayasu's arteritis, temporal arteritis, warm autoimmune hemolytîc anémia, Wegener*s granulomatosis, alopeda uni versa lis, chagas¹ disease, chronic fatigue syndrome, dysautonomia, endometriosis, hîdradenitis suppurativa, interstitiel cystitis, neuromyotonia, sarcoidosis, sderoderma, ulcerative colitis, vitiligo, vulvodynia, appendidtis, arteritis, arthritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, cholecystitis, chorioamnionitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondyiitis, epididymitis, fasditis, fibrositis, gastritis, gastroenteritis, gingivitis, hepatitis, hîdradenitis, ileitis, iritis, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.

The invention also relates to a method of treating a cardiovascular disease in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the présent invention. Examples of cardiovascular conditions include, but are not limited to, atherosderosis, restenosis, vascular ocdusion and carotid obstructive disease.

In another asped, the présent invention provides methods of disrupting the fundion of a leukocyte or disrupting a function of an osteodast. The method indudes contacting the leukocyte or the osteodast with a fundion disrupting amount of a compound of the invention.

In another aspect of the présent invention, methods are provided for treating ophthalmic disease by administering one or more of the subjed compounds or pharmaceutical compositions to the eye of a subject

The invention further provides methods of modulating kinase activity by contacting a kinase with an amount of a compound of the invention suffident to modulate the activity of the kinase. Modulate can be inhibiting or adivating kinase activity. In some embodiments, the invention provides methods of inhibiting kinase activity by contacting a kinase with an amount of a compound of the invention suffident to inhibit the activity of the kinase. In some embodiments, the invention provides methods of inhibiting kinase adivity in a solution by contading said solution with an amount of a compound of the invention suffident to inhibit the activity of the kinase in said solution. In some embodiments, the invention provides methods of inhibiting kinase adivity in a cell by contading said cell with an amount of a compound of the invention suffident to inhibit the activity of the kinase in said cell. In some embodiments, the invention provides methods of inhibiting kinase activity in a tissue by contacting said tissue with an amount of a compound of the invention suffident to inhibit the activity of the kinase in said tissue. In some embodiments, the invention provides methods of inhibiting kinase adivity in an organîsm by contacting said organism with an amount of a compound of the invention suffident to inhibit the activity of the kinase in said organism. In some embodiments, the invention provides methods of inhibiting kinase activity in an animal by contacting said animal with an amount of a compound of the invention suffident to inhibit the activity of the kinase in said animal. In some embodiments, the invention provides methods of inhibiting kinase activity in a mammal by contacting said mammal with an amount of a compound of the invention suffident to Inhibit the adivity of the kinase in said mammal. In some embodiments, the Invention provides methods of inhibiting kinase activity in a human by contacting said human with an amount of a compound of the Invention suffident to inhibit the activity of the kinase in said human. In some embodiments, the % of kinase activity after contading a kinase with a compound of the invention is less than 1, 5,10, 20, 30,40, 50,60,70, 80, 90, 95, or 99% of the kinase activity in the absence of said contading step.

In some embodiments, the kinase is a pretein kinase , more particularly a non-receptor or receptor tyrosine protein kinase. In some embodiments, the kinase is selected from the group consisting of C-met including mutants if any; Abl, VEGFR, Ephrin receptor B4 (EphB4); TEK receptor tyrosine kinase (HE2); FMS-related tyrosine kinase 3 (FLT-3); Platelet derived growth factor receptor (PDGFR); RET; ATM; ATR; hSmg-1; Hck; Src; Epidermal growth factor receptor (EGFR); KIT; Inulsin Receptor (IR) and IGFR.

The invention further provides methods of modulating c-met kinase activity by contacting a cmet kinase with an amount of a compound of the invention suffident to modulate the activity of the c-met kinase. Modulate can be inhibiting or activating c-met kinase activity. ln some embodiments, the invention provides methods of inhibiting c-met kinase activity by contacting a c-met kinase with an amount of a compound of the invention suffident to inhibit the activity of the c-met kinase, ln some embodiments, the invention provides methods of inhibiting c-met kinase activity. Such inhibition can take place In solution, in a cell expressing one or more c-met kinase, in a tissue comprising a cell expressing one or more c-met kinases, or in an organism expressing one or more c-met kinase, ln some embodiments, the invention provides methods of inhibiting c-met kinase activity in an animal (induding mammal such as humans) by contacting said animal with an amount of a compound of the invention suffident to inhibit the activity of the c-met kinase in said animal.

COMBINATION TREATMENT

The présent invention also provides methods for combination thérapies in which an agent known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes are used in combination with a compound of the présent invention. In one aspect, such therapy indudes but is not limited to the combination of the subject compound with chemotherapeutic agents, therapeutic antibodies, and radiation treatment, to provide a synergistic or additive therapeutic effect.

For treatment of autoimmune diseases, the subject compounds or pharmaceutical compositions can be used in combination with commonly prescribed drugs induding but not limited to Enbrel®, Remicade®, Humira®, Avonex®, and Rebif®. For treatment of respiratory diseaseses, the subject compounds or pharmaceutical compositions can be adminîstered in combination with commonly prescribed drugs induding but not limited to Xolair®, Advair®, Singulair®, and Spiriva*.

The compounds of the invention may be formulated or adminîstered in conjunction with other agents that act to relieve the symptoms of inflammatory conditions such as encephalomyelitis, asthma, and the other diseases described herein. These agents indude non-steroidal antiinflammatory drugs (NSAIDs), e.g. acetylsalicylic add; ibuprofen; naproxen; indomethadn; nabumetone; tolmetin; etc. Corticosteroids are used to reduce inflammation and suppress activity of the immune system. The most commonly prescribed drug of this type is Prednisone.

Chloroquine (Aralen) or hydroxychloroquine (Plaquenil) may also be very useful in some individuals with lupus. They are most often prescribed for skin and joint symptoms of lupus. Azathioprine (Imuran) and cyclophosphamide (Cytoxan) suppress inflammation and tend to suppress the immune system. Other agents, e.g. methotrexate and cyclosporin are used to control the symptoms of lupus. Anticoagulants are employed to prevent blood from dotting rapidly. They range from aspirin at very low dose which prevents platelets from sticking, to hepa rin/coumadi n.

In another one aspect, this invention also relates to a pharmaceutical composition for inhibiting abnormal cell growth in a mammal which comprises an amount of a compound of the présent invention, in combination with an amount of an anti-cancer agent (e.g. a chemotherapeutic agent). Many chemotherapeutics are presently known in the art and can be used in combination with the compounds ofthe invention.

In some embodiments, the chemotherapeutic is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cyde inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and anti-androgens. Non-limiting examples are chemotherapeutic agents, cytotoxic agents, and non-peptide small molécules such as Gleevec (lmatinib Mesylate), Velcade (bortezomib), tressa (gefitinib), Sprycel (Dasatinib), and Adriamydn as well as a host of chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents indude alkylating agents such as thiotepa and cydosphosphamide (CYTOXAN™); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethyienimines and methylamelamines including altretamine, triethylenemelamine, trietyienephosphoramide, triethylenethiophosphaonamide and trimethylolomelamine; nitrogen mustards such as chlorambudl, chlomaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uradl mustard; nitrosureas such as carmustine, chlorozotodn, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as adadnomysins, adinomydn, authramydn, azaserine, bleomycins, cactinomyan, caficheamidn, carabidn, carminomydn, carzinophilin, Casodex™ , chromomydns, dactinomydn, daunorubidn, detorubidn, 6-diazo-5oxo-L-norieudne, doxorubidn, epirubidn, esorubidn, idarubidn, marcellomycin, mitomycins, mycophenolic add, nogalamydn, olivomydns, peplomycin, px)tfiromydn, puromydn, quelamydn, rodorubidn, streptonigrin, streptozodn, tuberddin, ubenimex, zinostatin, zorubidn; anti-metabolites such as methotrexate and 5-fluorouradl (5-FU); folie add analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 674 mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as andtabîne, azacitidine, 6azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enodtabine, floxuridine, androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutéthimide, mitotane, trilostane; folie acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic add; amsacrine; bestrabudl; bisantrene; edatraxate; defofamine; demecoldne; diaziquone; elfomithine; elliptinium acetate; etogludd; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopldamol; nitracrine; pentostatin; phenamet; pirarubidn; podophyüinic add; 2-ethylhydrazide; procarbazine; PSK.R™-; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2’,2-trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxanes, e.g. paditaxel (TAXOL™, Bristol-Myers Squibb Oncology, Princeton, NJ.) and docetaxel (TAXOTERE™, Rhône- Poulenc Rorer, Antony, France); retinoic add; esperamidns; capecitabine; and pharmaceuticaily acceptable salts, adds or dérivatives of any of the above. Also induded as suîtable chemotherapeutic cell conditioners are anti- hormonal agents that act to regulate or inhibit hormone action on tumors such as antiestrogens including for example tamoxifen (Nolvadex™), raloxifene, aromatase Inhiblting 4(5)imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and toremifene (Fareston); and anti-androgens such as flutamide, nilutamide, bicalutamide (Casodex), leuprolide, and goserelin (Zoladex); chlorambudl; gemdtabine; 6-throguanine; mercaptopurine; methotrexate; platinum analogs such as dsplatin and carboplatin; Vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomydn C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomydn; aminopterin; xeloda; ibandronate; camptothedn-11 (CPT11); topoîsomerase inhibitor RFS 2000; difluoromethyfomithlne (DMFO), 17a-Ethiny!estradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Megestrolacetate, Méthylprednisolone, Methyl-testosterone, Prednisolone, Triamdnolone, chlorotrianisene, Hydroxyprogesterone, Aminoglutéthimide, Medroxyprogesteroneacetate, matrix metalloproteinase inhibitors, EGFR inhibitors, Pan Her inhibitors, VEGF inhibitors, including as anti-VEGF antibodies such as Avastin, and small molécules such as ZD6474 and SU6668, vatalanib, BAY-43-9006, SU11248, CP-547632, and CEP-7055. Anti-Her2 antibodies (such as Herceptin from Genentech) may also be utilized. Suîtable EGFR Inhibitors indude gefîtinib, eriotinib, and cetuximab. Pan Her inhibitors indude canertinib, EKB-569, and GW-572016. Further suîtable anticancer agents indude, but areTiot limited to, Src inhibitors, MEK-1 kinase inhibitors, MAPK kinase inhibitors, PI3 kinase inhibitors, and PDGF inhibitors, such as imatinib. Also induded are anti-angiogenic and antivascular agents which, by interrupting blood flow to solid tumors, render cancer cells quiescent by depriving them of nutrition. Castration which also renders androgen dépendent cardnomas non-prolrferative, may also be utilized. Also Included are IGF1R inhibitors, inhibitors of non-receptor and receptor tyrosine kinases, and inhibitors of integrin signalling. Additional anticancer agents indude microtubule-stabilizing agents 7-0methylthiomethylpaditaxel (disdosed in U.S. Pat No. 5,646,176), 4-desacetyl-4methylcarbonatepaditaxel, 3'-tert-butyl-3’-N-tert-butyloxycarbony1-4-desacetyl-3'-dephenyl-3^,-Ndebenzoyl-4-O-methoxycarbonyl-paditaxel (disdosed in U.S. Ser. No. 09/712,352 filed on Nov. 14,2000), C-4 methyl carbonate paditaxel, epothilone A, epothilone B, epothilone C, epothilone D, desoxyepothilone A, desoxyepothîlone B, [1S-[1R*l3R*(E),7R*,10S^e,11R*,12R‘l16S*]]-7-11di hyd roxy-6,8,10,12,16-pentamethyl-3-[1-m ethyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17 oxabicydo [14.1.0]heptadecane-5,9-dione (disdosed in WO 99/02514), (1S-[1R*,3R* (E) ,7R*,10S*,11R*,12R*,16S*]}-3-{2-{2-(aminomethyl)-4-thiazolyl]-1-methyl ethenyl]-7,11dihydroxy-8,8,10,12,16-pentamethyl-4-17-dioxabicyclo[14.1.0}-heptadecane-5,-9-dione ( as disdosed in U.S. Pat No. 6,262,094) and dérivatives thereof; and microtubule-disruptor agents. Also suitable are CDK inhibitors, an antiproliférative cell cyde inhibitor, epidophyUotoxin; an antineoplastic enzyme; biological response modifiera; growth inhibitors; antihormonal therapeutic agents; leucovorin; tegafun and haematopoietic growth factors.

Additional cytotoxic agents indude, hexamethyl melamine, idatrexate, L-asparaginase, camptothean, topotecan, pyridobenzoindole dérivatives, interferons, and interieukins.Where desired, the compounds or pharmaceutical composition of the présent invention can be used in combination with commonly prescribed anti-cancer drugs such as Herceptin*, Avastin* Erbitux·, Rituxan·, Taxol®, Arimidex*, Taxotere®, and Velcade®

This invention further relates to a method for using the compounds or pharmaceutical composition in combination with radiation therapy in inhibiting abnormal cell growth or treating the hyperproliferative disorder in the mammal. Techniques for administering radiation therapy are known in the art, and these techniques can be used In the combination therapy described herein. The administration of the compound of the invention in this combination therapy can be determined as described herein.

Radiation therapy can be administered through one of several methods, or a combination of methods, including without limitation extemal-beam therapy, internai radiation therapy, implant radiation, stereotactic radiosurgery, systemic radiation therapy, radiotherapy and permanent or temporary interstitial brachytherapy. The term ’brachytherapy, as used herein, refera to radiation therapy delivered by a spatially confined radioactive material inserted into the body at or near a tumor or other proliférative tissue disease site. The term is intended without limitation to include exposure to radioactive isotopes (e.g. At-211, 1-131, 1-125, Y-90, Re-186, Re-188, 76

Sm-153, Bi-212, P-32, and radioactive isotopes of Lu). Suitable radiation sources for use as a cell conditioner of the présent invention Include both solids and liquids. By way of non-limiting example, the radiation source can be a radionuclide, such as 1-125,1-131, Yb-169, Ir-192 as a solid source, 1-125 as a solid source, or other radionuclides that émit photons, beta particles, gamma radiation, or other therapeutic rays. The radioactive material can also be a fluld made from any 5 solution of radionuclides), e.g., a solution of 1-125 or 1-131, or a radioactive fluid can be produced using a slurry of a suitable fluid containing small particles of solid radionuclides, such as Au-198, Y-90. Moreover, the radionudide(s) can be embodied in a gel or radioactive micro sphères.

Without being limited by any theory, the compounds of the présent invention can render abnormal cells more sensitive to treatment with radiation for purposes of killing and/or inhibtting the growth of such cells. Accordingly, this invention further relates to a method for sensitizing abnormal cells in a mammal to treatment with radiation which comprises administering to the mammal an amount of a compound of the présent invention, which amount is effective is sensitizing abnormal cells to treatment with radiation.

The compounds or pharmaceutical compositions of the présent invention can be used in combination with an amount of one or more substances selected from anti-angiogenesis agents, signal transduction inhibitors, and antiproliférative agents.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloprotienase 2) inhibitors, MMP-9 (matrix- metalloprotienase 9) inhibitors, and COX-H (cyclooxygenase 11) inhibitors, can be used in conjunction with a compound of the présent invention and pharmaceutical compositions described herein. Examples of useful COX-II inhibitors include CELEBREX™ (alecoxib), valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO 96/33172 (published October 24,1996), WO 96/27583 (published March 7,1996), Européen Patent Application No. 97304971.1 (filed July 8,1997), Européen Patent Application No. 99308617.2 (filed October 29, 1999), WO 98/07697 (published February 26,1998), WO 98/03516 (published January 29,1998), WO 98/34918 (published August 13,1998), WO 98/34915 (published August 13,1998), WO 98/33768 (published August 6,1998), WO 98/30566 (published July 16, 1998), Européen Patent Publication 606,046 (published July 13,1994), European Patent Publication 931, 788 (published July 28,1999), WO 90/05719 (published May 31,1990), WO 99/52910 (published October 21,1999), WO 99/52889 (published October 21, 1999), WO 99/29667 (published June 17,1999), PCT International Application No. PCT/IB98/01113 (filed July 21,1998), European Patent Application No. 99302232.1 (filed March 25,1999), Great Britain Patent Application No. 9912961.1 (filed June 3, 1999), United States Provisional Application No. 60/148,464 (filed August 12,1999), United States Patent 5,863, 949 (issued January 26,1999), United States Patent 5,861, 510 (issued January 19,1999), and European Patent Publication 780,386 (published June 25, 1997), ail of which are Incorporated herein in their entireties by reference. Preferred MMP-2 and MMP-9 inhibitors are those that hâve little or no activity inhibiting MMP-I. More preferred, are those that selectively inhibit MMP2 and/or AMP-9 relative to the other matrix-metalloproteinases (i. e„ MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP- 7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some spécifie examples of MMP inhibitors useful in the présent invention are AG-3340, RO 32-3555, and RS 13-0830.

The Invention also relates to a method of and to a pharmaceutical composition of treating a cardiovascular disease in a mammal which comprises an amount of a compound of the présent invention, or an isotopicatly-labeled dérivative thereof, and an amount of one or more therapeutic agents use for the treatment of cardiovascular diseases.

Examples for use in cardiovascular disease applications are anti-thrombotic agents, e.g., prostacyclin and salicylates, thrombolytic agents, e.g., streptokinase, urokinase, tissue plasminogen activator (TPA) and anisoylated plasminogen-streptokinase activator complex (APSAC), anti-platelets agents, e.g., acetyl-salicylic add (ASA) and dopidrogel, vasodilating agents, e.g., nitrates, caldum channel blocking drugs, antiproliférative agents, e.g., colchîdne and alkylating agents, intercalating agents, growth modulating factors such as interleukins, transformation growth factor-beta and congeners of platelet derived growth factor, monodonal antibodies directed against growth factors, anti-inflammatory agents, both steroida! and nonsteroidal, and other agents that can modulate vessel tone, function, arteriosderosis, and the healing response to vessel or organ injury post intervention. Antibiotics can also be induded in combinations or coatings comprised by the invention. Moreover, a coating can be used to effect therapeutic delivery focally within the vessel wall. By incorporation of the active agent in a swellable polymer, the active agent will be released upon swelling of the polymer.

Other exemplary therapeutic agents useful for a combination therapy indude but are not limited to agents as described above, radiation therapy, hormone antagonists, hormones and their releasing factors, thyroid and antithyroid drugs, estrogens and progestins, androgens, adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs; inhibitors of the synthesis and actions of adrenocortical hormones, insulin, oral hypoglycémie agents, and the pharmacology of the endocrine pancréas, agents affecting calcification and bone turnover: caldum, phosphate, parathyroid hormone, vitamln D, calcitonin, vitamins such as water-soluble vitamins, vitamin B complex, ascorbic add, fat-soluble vitamins, vitamins A, K, and E, growth factors, cytokines, chemokines, muscarinic receptor agonists and antagonists; anticholinesterase agents; agents acting at the neuromuscular junction and/or autonomie ganglia; catecholamines, sympathomimetic drugs, and adrenergic receptor agonists or antagoniste; and 5-hydroxytryptamine (5-HT, serotonin) receptor agonists and antagonists. Therapeutic agents can also include agents for pain and Inflammation such as histamine and histamine antagonists, bradykïnin and bradykinin antagonists, 5-hydroxytryptamine (serotonin), lipid substances that are generated by biotransformation of the products of the sélective hydrolysis of membrane phospholipids, eicosanoids, prostaglandins, thromboxanes, leukotrienes, aspirin, nonsteroîdal anti-inflammatory agents, analgesic-antipyretic agents, agents that inhibit the synthesis of prostaglandins and thromboxanes, sélective inhibitors of the Indudble cydooxygenase, sélective inhibitors of the indudble cydooxygenase-2, autacoids, paracrine hormones, somatostatin, gastrin, cytokines that médiate interactions involved in humoral and cellular immune responses, lipid-derived autacoids, eicosanoids, β-adrenergic agonists, ipratropium, glucocorticoids, methylxanthines, sodium channel blockers, opioid receptor agonists, caldum channel blockers, membrane stabilizers and leukotriene Inhibitors.

Additional therapeutic agents contemplated herein indude diuretics, vasopressin, agents affecting the rénal conservation of water, rennin, angiotensin, agents useful in the treatment of myocardial ischemia, anti-hypertensive agents, angiotensin converting enzyme inhibitors, βadrenergic receptor antagonists, agents for the treatment of hypercholesterolemia, and agents for the treatment of dyslipidemia.

Other therapeutic agents contemplated indude drugs used for control of gastric addity, agents for the treatment of peptic ulcers, agents for the treatment of gastroesophageal reflux disease, prokinetic agents, antiemetics, agents used in irritable bowel syndrome, agents used for diarrhea, agents used for constipation, agents used for inflammatory bowel disease, agents used for bîliary disease, agents used for pancreatic disease. Therapeutic agents used to treat protozoan infections, drugs used to treat Malaria, Amebiasis, Giardiasis, Tri ch om onia si s, Trypanosomîasis, and/or Leishmaniasis, and/or drugs used in the chemotherapy of helminthiasis. Other therapeutic agents indude antimicrobial agents, sulfonamides, trimethoprim-sulfamethoxazole quinolones, and agents for urinary tract Infections, penîdllins, cephalosporins, and other, β-Lactam antibiotics, an agent comprising an aminoglycoside, protein synthesis Inhibitors, drugs used in the chemotherapy of tuberculosis, mycobacterium avium complex disease, and leprosy, antifungal agents, antiviral agents induding nonretroviral agents and antirétroviral agents.

Examples of therapeutic antibodies that can be combined with a subject compound indude but are not limited to anti-receptor tyrosine kinase antibodies (cetuximab, panitumumab, trastuzumab), anti CD20 antibodies (rituximab, tositumomab), and other antibodies such as alemtuzumab, bevadzumab, and gemtuzumab.

Moreover, therapeutic agents used for immunomodulation, such as immunomodulators, immunosuppressive agents, tolerogens, and immunostimulants are contemplated by the methods herein. In addition, therapeutic agents acting on the blood and the blood-forming organs, hematopoietic agents, growth factors, minerais, and vitamîns, anticoagulant, thrombolytic, and antiplatelet drugs.

Further therapeutic agents that can be combined with a subject compound may be found in Goodman and Gilman’s The Pharmacological Basis of Therapeutics Tenth Edition edited by Hardman, Umbird and Gilman or the Physidan’s Desk Reference, both of which are incorporated herein by reference in their entirety.

The compounds described herein can be used in combination with the agents disdosed herein or other suitable agents, depending on the condition being treated. Hence, in some embodiments the compounds of the invention will be co-administered with other agents as described above. When used In combination therapy, the compounds described herein may be administered with the second agent simuitaneously or separately. This administration in combination can indude simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, a compound described herein and any of the agents described above can be formulated together in the same dosage form and administered simuitaneously. Aitematively, a compound of the présent invention and any of the agents described above can be simuitaneously administered, wherein both the agents are présent in separate formulations. In another alternative, a compound of the présent invention can be administered just followed by and any of the agents described above, or vice versa. In the separate administration protocol, a compound of the présent invention and any of the agents described above may be administered a few minutes apart, or a few hours apart, or a few days apart.

The methods in accordance with the invention may include administering a c-met kinase sélective inhibitor with one or more other agents that either enhance the activity of the inhibitor or compliment its activity or use in treatment. Such additional factors and/or agents may produce an augmented or even synergistic effect when administered with a c-met kinase sélective inhibitor, or minimize side effects.

In one embodiment, the methods of the invention may include administering formulations comprising a c-met kinase sélective inhibitor of the invention with a particular cytokine, lymphokine, other hematopoietic factor, thrombolytic or anti-thrombotic factor, or antiinflammatory agent before, during, or after administration of the c-met kinase inhibitor. One of ordinary skill can easiîy détermine if a particular cytokine, lymphokine, hematopoietic factor, thrombolytic of anti-thrombotic factor, and/or anti-inflammatory agent enhances or compliments the activity or use of the c-met kinase inhibitors in treatment.

More specifically, and without limitation, the methods of the invention may comprise administering a omet kinase sélective inhibitor with one or more of TNF, IL-1, IL-2, IL-3, IL4, IL5, IL-6, IL-7, IL-8, IL-9, IL-10. IL-11. IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IFN, G-CSF, Meg-CSF, GM-CSF, thrombopoietin, stem cell factor, and erythropoietin. Compositions in accordance with the invention may also indude other known angiopoietins such as Ang-2, Ang4, and Ang-Y, growth fadors such as bone morphogenic protein-1, bone morphogenic protein-2, bone morphogenic protein-3, bone morphogenic protein-4, bone morphogenic protein-5, bone morphogenic protein-6, bone morphogenic protein-7, bone morphogenic protein-8, bone morphogenic protein-9, bone morphogenic protein-10, bone morphogenic protein-11, bone morphogenic protein-12, bone morphogenic protein-13, bone morphogenic protein-14, bone morphogenic protein-15, bone morphogenic protein receptor IA, bone morphogenic protein receptor IB, brain derived neurotrophic fador, dliary neutrophic fador, dliary neutrophic fador receptor a, cytokine-induced neutrophil chemotadic fador 1, cytokineInduced neutrophil chemotadic fador 2 alpha, cytokine-induced neutrophil chemotadic fador 2 beta, beta endothélial cell growth fador, endothelin 1, epidermal growth fador, epithelialderived neutrophil attradant, fibroblast growth fador 4, fibroblast growth fador 5, fibroblast growth fador 6, fibroblast growth fador 7, fibroblast growth fador 8, fibroblast growth fador 8b, fibroblast growth fador 8c, fibroblast growth fador 9, fibroblast growth fador 10, fibroblast growth fador addic, fibroblast growth fador basic, glial cell line-derived neutrophic fador receptor al, glial cell line-derived neutrophic fador receptor a2, growth related protein, growth related protein a, growth related protein .beta., growth related protein .gamma., heparin binding epidermal growth fador, hépatocyte growth fador, hépatocyte growth fador receptor, insulinlîke growth fador I, insulin-like growth fador receptor, insulin-like growth fador II, insulin-like growth fador binding protein, kératinocyte growth fador, leukemia inhibitory fador, leukemia inhibitory fador receptor alpha, nerve growth fador, nerve growth fador receptor, neurotrophin3, neurptrophin-4, placenta growth fador, placenta growth fador 2, platelet derived endothélial cell growth fador, platelet derived growth fador, platelet derived growth fador A chain, platelet derived growth fador AA, platelet derived growth fador AB, platelet derived growth fador B chain, platelet derived growth fador BB, platelet derived growth fador receptor a, platelet derived growth fador receptor beta, pre-B cell growth stimulating fador, stem cell fador, stem cell fador receptor, transforming growth fador alpha, transforming growth fador beta, transforming growth fador beta 1, transforming growth fador beta 1.2, transforming growth fador beta 2, transforming growth fador beta 3, transforming growth fador beta 5, latent transforming growth factor beta 1, transforming growth factor beta binding protein I, transforming growth factor beta binding protein II, transforming growth factor beta binding protein lll, tumor necrosis factor receptor type I, tumor necrosis factor receptor type II, urokinase-type plasminogen activator receptor, and chimeric proteins and biologically or immunologically active fragments thereof.

The following general methodology described herein provides the manner and process of makîng and using the compound of the présent invention and are illustrative rather than limiting. Further modification of provided methodology and additionally new methods may also be devised in order to achieve and serve the purpose of the invention. Accordingly, it should be understood that there may be other embodiments which fall within the spirit and scope of the invention as defined by the spécification hereto.

Représentative compounds of the présent invention include those spedfied above in Table 1 and pharmaceutically acceptable salts thereof. The présent invention also indudes the intermediate compounds discussed in the examples and elsewhere in the spedfication as well as their salts. The présent invention should not be construed to be limited to them.

GENERAL METHODS OF PREPARATION OF COMPOUNDS OF THE INVENTION

The compounds of the présent invention may be prepared by the following processes. Unless otherwise indicated, the variables (e.g. Cy¹, R², L,, L₂, X, and Cy²) when used in the below formulae are to be understood to présent those groups described above in relation to formula (I)

Scheme 1: This scheme provides a method for the préparation of the compound of formula (IA) wherein L₂ is -CR*R^b-, X is CR¹ or N and the other variables such as Cy¹, R², and C/are the same as described above in relation to formula (I).

Scheme 1

6 (ΙΑ) (a) C^-Lj-NHj; base; (b) réduction; (c) HN0₂ (X=N); RCOOH, D [for X = CR¹] ; (d) Cy1-B(OR)₂, base, transition metat catalyst

The compound of formula (1) wherein Hal represents a halogen and R² is the same as described above in relation to formula (1) can be coupled with a compound of formula Cy^Lr NH2 in the presence of a suitable base, such as sodium or potassium carbonate, to give a compound of formula (2) wherein L2 is -CR*R^b-. The compound of formula (2) can then be converted to a compound of formula (3) by reducing with a métal such as iron, or a métal halide such as stannous chloride and an add (such as acetic add, hydrochloric add or ammonium chloride). The compound of formula (3) can then be cyclised to form a compound of formula (4) wherein X=N using nitrous add, generated in situ by reacting an alkali métal nitrite such as sodium nitrite with an add such as acetic acid or hydrochloric add. The compound of formula (3) can be cydised to form a compound of formula (4) wherein X=CR¹, by heating or irradiatîng with microwaves in the presence of R’COOH wherein R¹ is H or a C1-C4 alkyl group. The compound of formula (4) can be coupled with a boronic add of formula Cy’-BfORk (wherein R = H) or its ester (wherein R = alkyl) in the presence of a transition métal catalyst such as tetrakis(triphenyiphosphine)palladium(0) and a suitable base such as potassium carbonate to give the desired compounds of formula (IA) wherein L2 is -CR’R^b-, X is CR¹ or N and the other variables such as Cy¹, R² and Cy² are the same as described above in relation to formula (I)

Altematively, the compound of formula (2) may be coupled with a boronic add of formula Cy¹B(OR)₂ (wherein R = H) or its ester (wherein R - alkyl) in the presence of a catalyst such as tetrakis(triphenytphosphine)palladium(0) and a suitable base such as potassium carbonate to give a compound of formula (5). The compound of formula (5) can then be converted to a compound of formula (6) by redudng with a métal such as iron, or a métal halide such as stannous chloride and an acid such as acetic acid, hydrochloric add or ammonium chloride. The compound of formula (6) can then be cydised to a compound of formula (IA) wherein X=N, using nitrous add, generated in situ by reacting an alkali métal nitrite such as sodium nitrite with an add such as acetic add or hydrochloric add. The compound of formula (6) can then be cydised to form a compound of formula (IA) wherein X=CR’, by heating or irradiating with microwaves in the presence of R’COOH wherein R¹ is H or a C1-C4 alkyl group.

Scheme 1A: This scheme provides a method for the préparation of the compound of formula (IA) wherein L₂ is -CR*R^b-, X is CR¹ or N and the other variables such as Cy¹, R², and C/are the same as described above in relation to formula (I).

Scheme 1A

(a) Cy’-Lj-NHj; base; (b) réduction, (c) HNOj (X=N),R1COOH, Δ [for X = CR¹] (d) Cy¹-B(OR)2. base, transition métal catafyst:(e) i. Ammonia or NHPg( wherein Pg is protecting group) ii. Deprotection; (f) Cy’-Lï; base

The compound of formula (1) wherein Hal represents a halogen and R² is the same as described above in relation to formula (I) can be coupled with a boronic add of formula Cy¹B{OR)î (wherein R ~ H) or its ester (wherein R - alkyl) in the presence of a transition métal catalyst such as tetrakis(tripheny1phosphine)pa!ladium(0) and a suitable base such as potassium carbonate to give compound of formula (1a). Compound of formula (1a) can be converted to compound of formula (1b) using Ammonia or rectinf compound of formula (1a) with a compound of formula -NHPg (wherein Pg is protecting group) under suitable conditions. Compound of formula (1a) can then be coupled with a compound of formula Ο/Ί-ζ-ΝΚΐ or orcompound of formula (1b) can be coupled LrNHJn the presence of a suitable base, such as sodium or potassium carbonate, to give a compound of formula (5) wherein L₂ is -CR^aR^b-. The compound of formula (5) can then be converted to a compound of formula (6) by redudng with a métal such as iron, or a métal halide such as stannous chloride and an add such as acetic add, hydrochloric add or ammonium chloride. The compound of formula (6) can then be cyclised to provide desired compound of formula (IA) wherein X=N, using nitrous add, generated in situ by reading an alkali métal nitrite such as sodium nitrite with an add such as acetic add or hydrochloric add. The compound of formula (6) can then be cydised to provide desired compound of formula (IA) wherein X=CR’, by heating or irradiating with microwaves in the presence of R’COOH wherein R¹ is H or a C,-C4 alkyl group.

Illustration 1 :

(·) C^-Ly-NH}. baie. (b) réduction; (c) HNOy ; (d) Cy1-B(ORh. bue. tranwbon meüi catatyit ;(e) L Anvnoraa or NHPgf wherein pg b protecbng group) I Deprotecbon, (f) Cy^î-L_}; base. (g) SOO, & NHrCttCONHj

Illustration 2:

Example>1007 (a) C^-LrNHj; base; (b) réduction; (c) HNOj ; (d) Cyl-fiiOR^. baie, tanalbon métal catatyst^e) L Ammonia or NHPg( wherein Pg la protecting group) I DeprotecISon; (f) Cy²-!.}: base; (g) SOCt} & NH,

Illustration 3:

(a) C^-Lj-NHj; base; (b) réduction; (c) HCOOH ; (d) Cy1-B(OR)2. base, transition métal catatysL;(e) i. Ammorda or NHPg( wherein Pg Is protecting group) il. Deprotection; (f) Cy^-Lj; base; (g) SOCI2 & NH₃

Scheme 2: This scheme provides a method for the préparation of a compound of formula (IA-1) wherein D is substituted or unsubstituted monocyclic aryl or substituted or unsubstituted 5 monocydic heteroaryl and the other variables such as Lî, R², X, and Cy² are the same as described above in relation to formula (IA-I):

(·) bue, Tmsrtwn mai! eniiyit

A compound of formula (4) can be coupled with a boronic add of formula (7) (wherein R = H or 10 its ester (i.e. R = alkyl)) in the presence of a transition métal catalyst such as tetrakis(triphenylphosphine)palladium(0) and a suitable base such as potassium carbonate to give compound of formula (IA-1).

Scheme 2A: This scheme provides an alternative method for the préparation of a compound of formula (ΙΑ-t) wherein D is substituted or unsubstituted monocyclic aryl or substituted or unsubstituted monocyclic heteroaryl and the other variables such as L₂, R², X, and Cy² are the same as described above ln relation to formula (IA-I):

Scheme 2A

4a 7a (a)

(IA-1) (a) Base, transition Métal catalyst

A compound of formula formula (7a) wherein Lg is leaving group (preferably Halogen or Triflate) can be coupled with a boronic add of formula (4a) wherein R = H or its ester (i.e. R = alkyl) in the presence of a transition métal catalyst such as tetrakis(triphenylphosphine)palladium(0) and a suitabie base such as potassium carbonate to give compound of formula (IA-I).

Scheme 3: This scheme provides a method for the préparation of a compound of formula (IA-I) wherein D is phenyl substituted with -CONH-O-iCR’RVOR*, -CONH-ÎCR’ROp-OR’. -CONH(CR’R^p-NHR*. Optionally the phenyl ring is further substituted with one or more R’ wherein each R is independently hydrogen, halogen or substituted or unsubstituted alkyl.

Scheme 3

(a) base, transition métal catalyst; (b) Hydrolysis, (c) arrxde coupling

The compound of formula (4) can be coupled with a boronic add of formula (8) (wherein R = H) or its ester (wherein R = alkyl) in the presence of a transition métal catalyst such as tetrakis(triphenylphosphine)palladîum(0) and a suitabie base such as potassium carbonate to give the compound of formula (9). The compound of formula (9) can be hydrolysed in the presence of an alkali métal hydroxide such as lithium hydroxide to give the compound of formula (10). The compound of formula (10) can be converted into a compound of formula (IA*I) by reacting it with an amine of the formula R’FTNH in the presence of an amide coupling reagent such as N-(3-dimethylaminopropyl)-//-ethylcarbodiimide hydrochloride (EDC.HCI), (benzotriazol-1yl)oxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) or any other amide coupling reagent known in the art. Altematively the conversion can be effected by reacting the compound of formula (10) with with a halogenating agent such as thionyl chloride and subsequently reacting the résultant add halide with an amine of the formula NH2-O(CR’ROp-OR’ , NH₂4CR’^,R^ï)p-OR^,t or NH₂-(CR’'R^ï)p-NHR^¥ in the presence of a suitable base such as a trialkylamine. The compounds of formula (IA-1) can also be obtained by reading the compound of formula (4) with a boronic add of formula (11) (wherein R = H) or its ester (wherein R = alkyl).

ILLUSTRATIVE EXAMPLE FOR SCHEME 3

(a) base, transition métal catalyst: (b) Hydrolysis:

Additionally, the compounds of the présent invention may be prepared by the following processes as disdosed în International Patent Application No. PCT/IB2011/052120, filed 13* May 2011, and U.S. Patent Application No. 13/108,642 filed 16” May 2011. These methods can similarly be applied to other compounds of formula as provided herein above with or without modification.

Similar méthodologies with certain modifications as known to those skilled in the art can be used to synthesize compounds of formula (I), (IA) and (IA-Ι) wherein ail the variables are to be understood to présent those groups described above in relation to formula (I), (IA) and (IA-1) using suitable intermediates and reagents.

EXPERIMENTAL DATA

Intermediates

Intermediate 1: Quinolin-6-ylmethanamlne:

Stepl: Quinoline-6-carboxvlic add: To a mixture of 4-aminobenzoic add: (175 g, 1.28 mol), 4nitrophenol (88.75 g, 0.64 mol) and sulphuric add (1.2 lit), glycerol (234.8 g, 2.55 mol) was added drop wise at 135°C. After 48h, the reaction mixture was cooled to 0°C and the pH adjusted to 3-5 with 10% sodium hydroxide solution. The resulting predpitate was collected by filtration and washed with water and dried under vacuum to afford the title compound as a black solid (125 g, 56%).

Step 2: Methyl Quinoline-6-carboxylate: To a solution of quinoline-6-carboxylic add (183 g, 1.06 mol) in methanol (1 lit.), thionyl chloride (150.7 g, 1.2 mol) was added drop wise at 0°C and then stirred at 65°C for 12h. The reaction mixture was concentrated and to the residue dichloromethane and aqueous sodium carbonate solutions were added. The organic layer was dried with sodium sulphate and concentrated to afford the title compound as a brown solid (150 g. 75%).

Step 3: Quinoline-6-carboxamide: To a solution of methyl quinolîne-6-carboxylate (148 g, 0.79 mol) in methanol (600 ml), aqueous ammonia (800 ml) was added and then stirred at 45°C for 12h. The reaction mixture was concentrated to afford the title compound as a dark red solid (120 g, 88%).

Step 4: Quinoline-6-carbonitrile: To a solution of quinoline-6-carboxamide (177 g, 1.03 mol) in chloroform (1.5 lit) triethylamine (520.15 g, 5.15 moljand trifluoroacetic anhydride (540.34 g,

2.57 mol) was added drop wise below 10°C. After 1.5h, the pH was adjusted to 7 with sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried with sodium sulphate and concentrated to afford the title compound as a brown solid (96 g, 59%).

Step 5: Quinolîn-6-vlmethanamtne: To a solution of quinoline-6-carbonitrile (96 g, 0.62 mol) in saturated ammonia in methanol (1 lit.), Raney-Ni (10g) was added and the mixture was stirred at 1 atm of H₂ at RT for 16h. The reaction mixture was filtered and the filtrate was concentrated under vacuum to afford the title compound as a brown oil (80 g, 82%). ’H-NMR (δ ppm, DMSOd₆,400 MHz): δ 8.83 (dd, J= 4.2,1.7 Hz, 1H), 8.29 (d, J- 8.3 Hz, 1H), 7.95 (d, J= 8.6 Hz, 1H),

7.85 (s, 1H), 7.75 (dd J = 8.7,1.8 Hz, 1H), 7.49 (dd, J - 8.2,4.2 Hz, 1H), 3.90 (s, 2H).

Intermediate 2: (7-fluoroquinolin-6-yl)methanamine

Step 1: 6-Bromo-7-fluoroquinoline: To a mixture of 4-bromo-2-fluoroaniline (10 g, 52.62 mmol), ferrous sulphate (3.33 g, 11.97 mmol) and glycerol (15.78 ml) con. sulphuric add (9.15 ml) was added slowly and the reaction mixture was heated to 140°C. After 12h, the reaction mixture was cooled to 0°C and the pH adjusted to 10-12 with 10% sodium hydroxide solution. The reaction mixture was filtered through celite, washed with ethyl acetate and layers were separated. The organic layer was washed with brine solution, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as a white solid (4.9 g, 44%). ’H-NMR (δ ppm, CDCI₃.400 MHz): δ

8.96 (dd, J = 4.3, 2.7 Hz, 1H), 8.15 (m, 2H), 7.81 (d, J - 9.5 Hz, 1H), 7.42 (dd. J = 8.3,4.3 Hz, 1H).

Step 2: 7-FluoroQuinolîne-6-carbonitrile: To a solution of 6-bromo-7-fluoroquinoline (4.90 g,

22.12 mmol) in dimethylacetamide (38 ml), potassium ferrocyanide (2.65 g, 4.86 mmol) and sodium carbonate (2.34 g, 22.12 mmol). The system was purged with nitrogen for 15 min. Palladium acetate (0.248 g, 1.10 mmol) was added under nitrogen and heated to 120°C. After 3h, the reaction mixture was filtered through celite, washed with ethyl acetate. The organic layer was washed with brine solution, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as a white solid (3.2g g. 86%). ¹H-NMR (δ ppm, CDCI₃, 400 MHz): δ □□□□ (dd, J= 4.1,2.9 Hz, 1H), 8.25 (m, 2H), 7.90 (d, J- 10.0 Hz, 1H), 7.53 (dd, J- 8.3,4.3 Hz, 1H).

Step 3: (7-Fluoroquinolin-6-vDmethanamine: To 7-fluoroquinoline-6-carbonitrile (1.00 g, 5.813 mmol), methanol saturated with ammonia (13.5 ml) and Raney-Ni (1.27 g) were added and hydrogenated at 50-60 psi for 4h. The reaction mixture was filtered and concentrated to afford the title compound as a brown oil (0.80 g, 78%). ¹H-NMR (δ ppm, DMSO-d₆,400 MHz):ü δ 8.85 (d, J = 2.3 Hz, 1H), 8.35 {d.J- 8.0 Hz, 1H), 8.06 (d, J= 9.5 Hz, 1H), 7.68 (d, J= 11.8 Hz, 1H),

7.49 (t, J- 3.8 Hz. 1H), 3.92 (s, 2H). 1.90 (br s. 2H).

Intermediate 3: 6-ChIoro-3-nitro-N-(qulnolin-6-ylmethyl)pyridin-2-amine: To a solution of

2,6-Dichloro-3-nitropyridine (1.62 g, 8.42 mmol) in ethano! (30 ml), sodium carbonate (2.34 g,

22.12 mmol) was added at RT and cooled to 0°C followed by the addition of intermediate 1 (2g, 12.64 mmol) in éthanol (20 ml) the mixture was stirred at RT for 12h. The reaction mixture was poured into 25 ml of water and extracted with ethyl acetate, washed with brine solution, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with dichlomethane: methanol to afford the title compound as a yellow solid (2.0g, 50%). Ή-NMR (δ ppm, DMSO-d_e, 400 MHz): 009.35 (t, J - 6.0Hz, 1H), 8.85 (dd, J = 4.0,1.4Hz, 1H), 8.46 (d, J = 8.5Hz, 1H), 8.31 (d, J = 7.8Hz, 1H), 7.98 (d J = 8.7Hz, 1H), 7.88 (s, 1 H), 7.79 (dd, J = 8.7,1.6Hz, 1H), 7.50 (dd, J = 8.3,4.2Hz. 1H), 6.80 (d. J ~ 8.6Hz. 1H). 4.92 (d. J = 6.1Hz, 2H).

Intermediate 4: 6-Chloro-N-((7-fluoroqulnolin-6-yi)methy1)-3-nitropyrldin-2-amine: The title compound was obtained as a yellow solid (0.750 g, 50%) by using a procedure that is similar to the one described for intermediate 3 from 2,6-dichloro-3-nitropyridine (1.31 g, 6.81 mmol),

Intermediate 2 (0.80 g, 4.54 mmol), éthanol (15 ml) and sodium carbonate (0.838 g, 7.90 mmol). ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): δ 9.27 (t, J - 5.7 Hz, 1H), 8.87 (d, J = 2.8 Hz,

H). 8.49 (d, J = 8.5 Hz, 1H), 8.34 (d, J = 8.0 Hz, 1H), 7.96 (d J- 8.4 Hz, 1H), 7.78 (d, J = 7.7

Hz, 1H). 7.49 (dd, J - 8.3,4.2 Hz, 1H), 6.83 (d, J - 8.6 Hz, 1H), 4.95 (d. J = 5.9 Hz, 2H).

Intermediate 5: 6-chloro-N^z-(qulnolin-6-ylmethyl)pyridine-2,3-diamlne: Stannous chloride (0.258 g, 1.143 mmol) and conc.HCI (3 ml) were added intermediate 3 (0.180 g, 0.571 mmol) at RT and stirred for 1h. After 1h stannous chloride (0.258g, 1.143 mmol) and conc.HCI (2 ml) were added and maintained for 1h. The reaction mixture was poured into ice water and the pH was adjusted to ca. 8 with sodium bicarbonate solution, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulphate and concentrated to afford the title compound as a yellow solid (0.150g, 92%). ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): 008.85 (dd, J - 4.2,

I. 6Hz, 1H), 8.32 (d, J = 7.9Hz, 1H), 7.98 (d, J = 8.7Hz, 1H), 7.86 (s, 1H), 7.76 (dd, J = 8.7,1.8Hz, 1H), 7.51 (dd, J - 8.3,4.2Hz, 1H), 6.73 (d, J = 7.8Hz, 1H), 6.59(t, J = 5.6Hz, 1H),

6.38 (d, J- 7.7Hz, 1H), 4.92(s, 2H), 4.70 (s, 2H).

Intermediate 6: 6-Chloro-N2-((7-fluoroqulnolin-6-yl)methyl)pyridine-2,3-dlamine: The title compound was obtained as a yellow solid (0.550 g, 74%) by using a procedure that is similar to the one described for intermediate 5 from intermediate 4 (0.750 g, 2.25 mmol), stannous chloride (2.28 g, 10.14 mmol) and conc. HCl (13 ml). ’H-NMR (δ ppm, DMSO-d_e, 400 ΜΗζ):δ8.87 (d, J - 3.0 Hz, 1H), 8.36 (d, J = 8.2 Hz, 1H). 7.97 (d, J = 8.3 Hz, 1H), 7.77 (d, J =

II. 6 Hz, 1H), 7.50 (dd, J = 8.2, 4.1 Hz. 1H), 6.74 (d, J - 8.5 Hz, 1H), 6.54 (t, J = 5.0 Hz, 1H),

6.39 (d, J = 7.8 Hz, 1 H), 4.94 ( s, 2H), 4.72 (d, J - 5.3 Hz, 2H).

Intermediate 7: 6-((5-chlorc>>3H-[1_l2,3]trlazolo[4,5-b]pyridln-3-yl)methyl)quInoline:

Intermediate 5 (0.220 g, 0.772 mmol) was dissolved in acetic acid (1.3 ml) and cooled to 5°C. Sodium nitrite (0.063 g, 0.927 mmol) in 0.35 m! water was added slowly followed by sulphuric add (0.09 ml). The reaction mixture was warmed to RT and stirred for 30 min. The reaction mixture was poured into ice water and pH adjusted to ca. 8 with sodium bicarbonate solution, extracted with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated to afford the title compound as a brown solid (0.220 g, 96%). ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): 008.88 (s, 1H). 8.69 (d, J= 8.6Hz, 1H), 8.35 (d, J = 8.1Hz, 1H), 8.01 (d, J = 8.6Hz, 1H),

7.90 (s, 1H), 7.74 (d. J~ 8.5Hz, 1H), 7.61 (d, J = 8.5Hz, 1 H), 7.53 (dd, J = 8.0,4.0Hz. 1H). 6.12 (s, 2H).

Intermediate 8: 6-((5-Chloro-3H-(1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)-7fluoroqulnoline: The title compound was obtained as a brown solid (0.345 g, 62%) by using a procedure that is similar to the one described for intermediate 7 from intermediate 6 (0.540 g,

1.78 mmol), acetic add (3.1 ml), sodium nitrite (0.148 g, 2.13 mmol), water (0.8 ml) and sulphuric add (0.2 ml). ’H-NMR (δ ppm, CDCI₃,400 MHz): δ 8.91 (d, J= 2.9 Hz, 1H), 8.36 (d,

J - 8.6 Hz, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.80 (d, J = 11.0 Hz, 1H), 7.70 (d, J - 7.8 Hz, 1H),

7.40 (m,2H), 6.11 (s, 2H).

Intermediate 9: 2-chloro-4-(4,4_l5,5-tetramethyl-1,3,2-dioxaboro!an-2-y1)benzamide:

Potassium acetate (0.627 g, 6.39 mmol) and bis(pinacolato)diboron (0.595 g, 2.34 mmol) were added to a solution of 4-bromo-2-chlorobenzamide (0.500 g, 2.13 mmol) In dioxane 3.6 ml), and the solution was degassed for 30 min. To this solution [1,1bis(diphenylphosphino)ferrocene]dichloro palladium(ll).CH₂CI₂ (0.052 g, 0.063 mmol) was added under nitrogen atmosphère and heated to 80°C. After 12h, the reaction mixture was fîltered through celite and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleumDether to afford the title compound as a brown solid (0.75 g, 69%). Ή-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 7.91 (s, 1H), 7.89 (m, 1H), 7.61 (m. 2Η),Π 7.44 (d, J= 7.6 Hz, 1H), 1.14 (s,12H).

Intermediate 10: 3-(qulnolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridine-5· carbonltrile:The title compound was obtained as a brown solid (0.400 g, 83%) by using the procedure described for intermediate 9 from intermediate 7 (0.700 g, 2.92 mmol), zinc cyanide (0.159 g, 1.35 mmol), DMF (8 ml) and ) and tetrakis(triphenylphosphine)palladium(0) (0.156 g, 0.135 mmol) under microwave irradiation (microwave power = 100W, température =127 °C) for 45 min. Ή-NMR (δ ppm, DMSO-d_e, 400 MHz): δ 8.91 (dd, J= 4.2,1.6 Hz, 1H). 8.53 (d, J =

8.4 Hz, 1H), 8.16 (d, J = 8.3 Hz, 1H). 8.09 (d, J = 8.8 Hz, 1H), 7.93 (s, 1H), 7.82 (dd, J = 8.7,2.0 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1 H). 7.42 (dd, J = 8.3,4.2 Hz, 1H), 6.10 (s,2H).

Intermediate 11: 4-(3-(qulnolin-6-y1methy1)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-y1)benzolc acid:

Step:1 Methyl 4-(3-(auinolin-6-vlmethvl)-3H-ri .2.31triazolor4.5-blDvridin-5-vl)benzoate: To a solution of intermediate 7 (0.130 g, 0.439 mmol) and 4-methoxycarbonyiphenylboronic acid (0.100 g, 0.562 mmol) in dioxane (2.6 ml), potassium carbonate (0.202 g, 1.46 mmol) and water (0.5 ml) were added and degassed for 30 min. Tetrakis(tripheny!phosphine)palladium(0) (0.040 g, 0.035 mmol) was added under nitrogen at RT and the reaction mixture was refluxed for 12h. The solvent was evaporated completely and water was added to the residue and extracted with ethyl acetate, dried over sodium suiphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as an off-white solid (0.100 g, 57%). ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): 8.88 (dd, J = 4.2,1.8 Hz, 1H), 8.72 (d, J = 8.7 Hz. 1H). 8.39 (m, 3H), 8.21 (d, J = 8.8 Hz, 1H), 8.12 (d, J= 8.6 Hz, 2H), 8.02 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.84 (dd, J = 8.6,2.0 Hz, 1H), 7.53 (dd. J = 8.3,4.2 Hz, 1H), 6.23 (s, 2H), 3.89 (s, 3H).

Step:2 443-fQuinolin-6-ylmethv1Î-3H-f1 2,3'|Îriazolor4.5-b1pvridin-5-vl)benzoic add: To a solution of intermediate 11 (0.095 g, 0.240 mmol) in methanol (1.4 ml), lithium hydroxide (0.028 g, 1.20 mmol) in water (0.36 ml) was added and stirred at RT. After 12h, the pH was adjusted to ca. 7.5 using 0.5N HCl and the solid predpitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as an off-white solid (0.070 g, 76%). M.P.: 245-247°C. Ή-NMR (δ ppm, DMSO-d_e, 400 MHz): 13.18 (s, 1H), 8.88 (dd, J- 4.1,1.7 Hz, 1H), 8.71 (d, J = 8.7 Hz, 1H), 8.39 (d, J = 1.1 Hz, 1H), 8.36 (d, J - 8.5 Hz, 2H), 8.21 (d, J= 8.7 Hz, 1H), 8.10 (d, J = 8.5 Hz, 2H), 8.03 (d, J = 9.2 Hz, 2H), 7.84 (dd, J = 8.7,2.0 Hz, 1H), 7.53 (dd, J ~ 8.4,4.2 Hz, 1H), 6.22 (s, 2H). MS (m/z): 381.88 (m*).

Intermediate 12: 2-Chloro-4-(3-(quinolln-6-ylmethyl}-3H-[1,2,3]triazolo[4,5-b]pyridin-5y1)benzolc acid:

Step:1 Methyl 2-chloro-4-(3-(quinolin-6-v!methvlÎ-3H-T1.2.3]triazolof4.5-blpvridin-5-vDbenzoate: The title compound was prepared by following the procedure described for step 1 of Intermediate 11 using intermediate 7 (1.00 g, 3.07 mmol), 3-chloro-4methoxycarbonylphenylboronic add (0.825 g, 3.84 mmol), potassium acetate (0.976 g, 9.945 mmol), dioxan (20 ml) and tetrakis (triphenylphosphine)palladium(O) (0.284 g, 0.246 mmol). Reddish brown solid (1.00 g, 71%). ¹H-NMR (δ ppm, DMSO-d_e, 400 MHz ): C8.92 (dd, J = 4.2,1.6 Hz, 1H), 8.48 (d, J~ 8.6 Hz, 1H). 8.24 (d, J= 1.3 Hz, 1H), 8.17 (d, J = 8.3 Hz, 1H), 8.10 (d, J= 11.8 Hz, 1H), 78.04 (m, 3H), 7.87 (m, 2H), 7.43 (q, J = 4.2 Hz, 1H), 6.15 (s, 2H), 3.98 (s, 3H).

Step:2 2-Chloro-4-(3-fquinolin-6-vlmethvlÎ-3H-ri .2.31triazolof4.5-b1pvridin-5-vl)benzoic acid: The title compound was prepared by following the procedure described for step 2 of Intermediate 11 using step 1 of Intermediate 12 (1.00 g, 2.18 mmol) in methanol (5 ml), lithium hydroxide (0.856 g, 20.40 mmol), water(5 ml), THF(19 ml). Off-white solid (0.900 g, 93%). The add was used without further purification in the next step.

Intermediate 13: (2-methylquinotln-6-yl)methanamine

Stepl: 2-methylquinoline-6-carboxylic add: To 4-aminobenzoic add (5 g, 36.45 mmol) , 6N HCl (73 ml) was added and refluxed for 2h. Crotonaldehyde (3.06 g, 43.75 mmol) was added dropwise over 45 min.. After 12h, the reaction mixture was cooled to 0°C and the pH adjusted to

3-5 with aqueous ammonia solution. The aqueous layer containing solid was washed with dichloromethane and addified with 2N HCl, filtered and dried under vacuum to afford the title compound as brown solid (3.0 g, 44%).

Step 2: methyl 2-methylquinoline-O-carboxviate: To a solution of 2-methvfquinoline-6-carboxvtic add (3.0 g, 16.20 mmol) in methanol (30 ml.), sulphuric add ( 3ml) was added dropwise at 0°C

and then stirred at 65°C for 12h. The reaction mixture was concentrated and to the residue dichloromethane and aqueous sodium carbonate solutions were added. The organic layer was dried with sodium sulphate and concentrated to afford the title compound as a brown solid (1.9 g, 59%).

Step 3: 2-methvlqutnoline-6-carboxamide: To a solution of methyl 2-methylquinoline-6carboxvlate (1.9 g, 9.44 mmol) in methanol (7.6 ml.), aqueous ammonia (10 ml) was added and then stirred at 45°C for 12h. The reaction mixture was concentrated to afford the title compound as a off-white red solid (1.0 g, 56%).

Step 4: 2-methvlquinoline-6-carbonitrile: To a solution of 2-methylquinoline-6-carboxamide (1.0 g, 5.36 mmol) in chloroform (5 ml.) and triethylamine (2.71 g, 26.84 mmol), trifluoroacetic anhydride (2.81 g, 13.42 mmol) was added dropwise below 10°C. After 1.5h, the pH was adjusted to 7 with sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried with sodium sulphate and concentrated to afford the title compound as a yellow solid (0.70 g, 77%).

Step 5: (2-methvlquinolin-6-vl)methanamine: To a solution of 2-methylquinoIine-6-carbonitrile (0.700 g, 4.16 mmol) in saturated ammonia in methanol (10 ml ), Raney-Ni (1.4g) was added and the mixture was stirred at 1 atm of H₂ at RT for 16h. The reaction mixture was filtered and the filtrate was concentrated under vacuum to afford the title compound as a brown oil (0.700 g, 97%). ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): 8.83 (dd, J = 4.2,1.7 Hz, 1H), 8.29 (d, J = 8.3 Hz, 1 H), 7.95 (d, J - 8.6 Hz, 1H), 7.85 (s, 1H), 7.75 (dd J = 8.7,1.8 Hz, 1H), 7.49 (dd. J = 8.2,4.2 Hz, 1H). 3.90 (s, 2H).

Intermediate 14: 6-{(5-chloro-3H-[1,2,3]triazoloI4,5-b]pyridln-3-yl)methyl)-2methylqulnoline:

Step-1: 6-chloro-N-ff2-methvlquinolin-6-vl)methvl)-3-nitropyridin-2-amine: The title compound was obtained as a yellow solid (0.500 g, 38%) by using a procedure that is similar to the one described for intermediate 3 from 2,6-dichloro-3-nitropyridine (1.17 g, 6.09 mmol), Intermediate 13 (0.700 g, 4.06 mmol), éthanol (10 ml) and sodium carbonate (0.749 g, 7.07 mmol). ’H-NMR (δ ppm, CDCI₃, 400 MHz): □□□□□ (br s, 1H), 8.38 (d, J ~ 8.6 Hz, 1H), 8.03 (m, 2H), 7.75 (s, 1 H). 7.69 (dd, J ~ 8.7,2.0 Hz, 1 H), 7.30 (d J - 8.4 Hz, 1H), 6.67 (d, J = 8.6 Hz, 1 H), 4.99 (d, J = 5.8 Hz, 2H), 2.74 (s, 3H).

Step-2: 6-chloro-N2-ff2-methvlquinolin-6-vl)methvl)pvridine-2.3-dîamine: The title compound was obtained as a off-white solid (0.500 g, 95%) by using a procedure that is similar to the one described for intermediate 5 from Step-1 (0.500 g, 1.52 mmol), stannous chloride (1.54 g, 6.85 mmol) and conc. HCl (5.2 ml) which is used as such in next step.

Step-3: The title compound was obtained as a brown solid (0.400 g, 77%) by using a procedure that is simiiar to the one described for intermediate 7 from Step-2 (0.500 g, 1.67 mmol), acetic add (2.94 ml), sodium nitrite (0.138 g, 2.03 mmol), water (0.8 ml) and sulphuric add (0.2 ml) which is used as such in next step.

Intermediate 15: 6-((5-chloro-3H-(1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl) benzo[d]thlazo1e:

Stepl: tert-butyl benzordlthiazol-6-vlmeÎhvlcarbamate: Triethylamine (2.92 ml, 20.82 mmol) and diphenylphosphoryl azide (5.72 g, 20.82 mmol) were added to a solution of benzothiazole-

6-acetic add (4.0 g, 20.82 mmol) in tert-butano! (80 ml) and refluxed for 18h. The excess tert~ butanol was distiîted out. Aq. 10% dtric add solution (20 ml) was added to the residue, extraded with ethyl acetate, dried over sodium sufphate and concentrated under reduced pressure to afford the title compound as a brown gummy liquid (3.3 g, 59%) which was used as such for next step.

Step 2: benzofdlthÎazol-6-vlmeÎhanamine: To a solution of tert-butyl benzo[d]thiazol-6ylmethylcarbamate (3.3 g, 12.48 mmol) in dioxane (33 ml), trifluoroacetic add (8.25 ml) was added and stirred at RT for 3h. The reaction mixture was concentrated, basified with sodium hydroxide solution, extracted with ethyl acetate, the organic layers dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as yellow solid (2.7 g) which was used as such for next step.

Step 3: N-fbenzofdlthÎazol-6-vlmethvl)-6-chloro-3-niÎropvridin-2-amÎne: The title compound was obtained as a yellow solid (0.460 g, 9%) by using a procedure that is simiiar to the one described for intermediate 3 from 2,6-Dichloro-3-nitropyridine (4.75 g, 24.66 mmol), benzo[d]thiazol-6-ylmethanamine (2.70 g, 16.44 mmol), éthanol (50 ml) and sodium carbonate (3.03 g, 28.60 mmol) which was used as such for next step.

Step:4 : N2-(benzofd1thîazol-6-vlmethvlÎ-6-chloropvridine-2.3-diamine: The title compound was obtained as a yellow solid (0.360 g, 88%) by using a procedure that is simiiar to the one described for intermediate 5 from N-(benzo[dJthiazol-6-ylmethyl)-6-chloro-3-rirtropyridin-2-amine (0.450 g, 1.40 mmol), stannous chloride (1.42 g, 6.31 mmol) and conc.HCI (7.5 ml) which is used as such for next step.

Step:5 6-f(5-chloro-3H-H ,2.3]triazoloT4.5-blDvridin-3-v0methvn benzoldlthiazole: The title compound was obtained as a brown solid (0.068 g, 83%) by using a procedure that is simiiar to the one described for Intermediate 7 from N2-(benzo[d]thiazol-6-ylmethyl)-6-chloropyridine-2,3diamine (0.350 g, 0.249 mmol), acetic acid (1.75 ml), sodium nitrite (0.099 g, 1.44 mmol), water (0.8 ml) and sulphuric acid (0.4 ml). ’H-NMR (δ ppm, CDCI₃, 400 MHz): □ δ 8.99 (s, 1H), 8.32 (d, J - 8.5 Hz, 1H), 8.11 (d, J = 8.4 Hz. 1H), 8.07 (s, 1H). 7.66 (d, J = 8.4 Hz. 1H), 7.36 (d, J 8.5 Hz, 1 H), 6.00 (s, 2H).

Intermediate 16: 2-Chloro-4-(3-((7-fluoroqulnolln-6-y1)methy!)-3H-[1,2,3]triazolo[4,5b]pyridin-5-yl)benzolc acid

Step-1 : Methyl 2-chloro-4-(3-((7-fluoroQutnolin-6-vl)methvl)-3H41.2.31triazoloî4.5-blpvridin-5vObenzoate: The title compound was prepared by following the procedure described for example 1 using intermediate 8 (0.345 g, 1.091 mmol). 3-chloro-4methoxycarbonylphenylboronic acid (0.295 g, 1.37 mmol), potassium acetate (0.359 g, 3.65 mmol), dioxane (8 ml) and tetrakis(triphenyiphosphine)pailadium(0) (0.101 g, 0.087 mmol). Off-* white solid (0.277 g, 56%). ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): 8.91 (d, J = 3.3 Hz, 1H),

8.50 (d, J = 8.6 Hz, 1H), 8.23 (s,1H), 8.10 (d, J = 8.2 Hz, 1H), 8.03 (d, J = 6.9 Hz. 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.87 (m,3H). 7.38 (dd, J= 8.3.4.2 Hz. 1H), 6.22 (s.2H), 3.97 (s,3H).

Step-2 : 2-Chloro-4-(3-((7-f1uoroQuinolin-6-vl)methv!)-3H-f1.2.31triazolof4,5-bÎpyridin-5vhbenzoic add: To a solution of Step-1 (0.185 g, 0.412 mmol) în methanol (2 ml), lithium hydroxide (0.161 g, 3.84 mmol) in water (2 ml) and THF (4 ml) were added and stirred at RT. After 12h, pH was adjusted to ca. 7 using 0.5N HCl and the solid predpitated was fïltered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as a pale brown solid (0.150 g, 84%). The add was used as such for further steps.

Intermediate 17: 2,6-Difluoro-4-{3-(quInolIn-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin*5yl)benzolc acid

Step-1 : Methyl 2.6-difluoro-4-(3-fauinolîn-6-vlmethvl)-3H-f1,2,31triazolor4,5-blpvridin-5vDbenzoate: To a solution of Intermediate 7 (1.15 g, 3.91 mmol) and 3,5-dîfluoro-4methoxycarbonylphenylboronic add (prepared according to et al in Eur. J. Org. Chem. 2009, 4325-4332,1.10 g, 5.09 mmol) in dioxan (20 ml), potassium acetate (1.276 g, 13.03 mmol) was added and degassed for 30 min. Tetrakis (triphenylphosphine)palladium(O) (0.361 g, 0.31346 mmol) was added under nitrogen at RT and the reaction mixture was refluxed for 12h. The solvent was evaporated completely and water was added to the residue and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as a brown solid (0.620 g, 37%). ’H-NMR (δ ppm, DMSO-de, 400 MHz):C8.91 (d. J = 2.9 Hz, 1H), 8.49 (d, J - 8.6 Hz, 1H), 8.17 (d. J = 8.2 Hz, 1H), 8.10 (d, J = 8.7 Hz. 1H),

7.97 (s,1H), 7.86 (dd, J = 8.8,1.4 Hz, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.74 (d, J ~ 9.1 Hz, 2H),

7.43 (dd, J = 8.4,4.2 Hz, 1H), 6.15 (s, 2H). 3.99 (s. 3H).

Step-2: 2,6-Difluoro-4-(3-(quinolin-6-ylmethvl)-3H-i1.2,3ltriazolor4.5-blDvridin-5-vl) benzoic add: To a solution of Step-1 (0.70 g, 1.62 mmol) in methanol (3.8 ml), lithium hydroxide (0.635 g,

15.13 mmol) in water (3.8 ml) and THF (14.3 ml) were added and stirred at RT. After 12h, pH was adjusted to ca. 7 using 0.5N HCl and the solid preapitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as pale brown solid (0.500 g, 74%). The add was used as such for further steps.

Intermediate 18 : 2,6-difluoro-4-(3-{(7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazoIo[4,5b]pyridin-5-yl)benzolc acid:

Stet>-1 : methvl 2.6-difluoro-4-(3-((7-fluoroquinolin-6-vlÎnnethvl)-3H41,2.31triazolor4.5-blpvridin-5vDbenzoate: The title compound was prepared by following the procedure described for example 1 using Intermediate 8 (0.750 g, 2.39 mmol), 3,5-difluoro-4methoxycarbonylphenylboronic add (0.569 g, 2.63 mmol), potassium acetate (0.783 g, 7.97 mmol), dioxane (17.2 ml) and tetrakls(triphenylphosphine)palladium(0) (0.221 g, 0.191 mmol). Brown solid (0.78 g, 76%) which is used as such in next step.

Step-2: To a solution of Step 2 (0.780 g, 1.73 mmol) in methanol (8.4 ml), lithium hydroxide (0.678 g, 16.17 mmol) in water (8.4 ml) and THF (17 ml) were added and stirred at RT. After 12h, pH was adjusted to ca. 7 using 0.5N HCl and the solid preapitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as a pale brown solid (0.600 g, 80%). The aa*d was used as such for further steps.

Intermediate 19 :2-Fluoro-4-(3-(qulnolin-6-ylmethyl)-3H-[1,2,3]triazo!o[4,5-b]pyrldin-5yl)benzolc acid

Step-1 : Methvl 2-fluoro-4434quinolin-6-vlmethylÎ-3H41.2.31triazolor4.5-blpvridin-5-ylÎbenzoate: The title compound was prepared by following the procedure described for example 1 using intermediate 7 (0.300 g, 1.01 mmol), 3-fluoro-4-methoxycarbonylphenylboronÎc aa'd (0.257 g, 1.29 mmol), potassium carbonate (0.466 g, 13.37 mmol), dioxan (6 ml), water (1.2 ml) and tetrakis (triphenylphosphine)palladium(O) (0.093 g, 0.081 mmol). Brown colour solid (0.300 g, 71%). ¹H-NMR (δ ppm, DMSO-d_e, 400 MHz): 8.88 (dd, J = 4.2,1.8 Hz, 1H), 8.74 (d, J = 8.7 Hz, 1 H). 8.38 (dd, J = 8.4,1.0 Hz, 1 H), 8.27 (d, J = 8.8 Hz, 1 H), 8.24 (s, 1 H), 8.22 (m, 1 H), 8.07-8.00 (m, 3H), 7.83 (dd, J = 8.7,2.0 Hz, 1H), 7.63 (m, 1H), 6.24 (s, 2H). 3.89 (s. 3H).

Step-2: To a solution of Step-1 (0.230 g, 0.556 mmol) in methanol (3.5 ml), lithium hydroxide (0.132 g, 5.56 mmol) In water(0.9 ml) was added and stirred at RT. After 12h, the pH was adjusted to 7-7.5 using 0.5N HCl and the solid preapitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as pale brown solid (0.130 g, 61%).M.P.: 254-257°C ’H-NMR (δ ppm. DMSO-d_e, 400 MHz ): □ 13.43 (s,

1H), 8.88 (dd, J = 4.2,1.7 Hz, 1H), 8.73 (d, J= 8.8 Hz, 1H), 8.38 (d, J= 7.5 Hz. 1H), 8.25 (d, J =

8.8 Hz, 1H), 8.19 (m, 2H), 8.04 (m, 3H), 7.83 (dd, J = 8.8,2.0 Hz, 1H), 7.53 (dd. J = 8.4,4.2 Hz,

1H), 6.23 (s, 2H). MS (m/z): 400.01 (m*+1).

Intermediate 20 : 2-chloro-4-(3-((2-methylquinolln-6-yl)methyl)-3H-[1,2,3]triazolo[4,5b]pyridln-5-yl)benzoic acid:

Steo-1 : methyl 2-chloro-4434(2-methylauino1in-6-vl)methvl)-3H41,2,31triazolor4,5-bTpvridin-5vDbenzoate: The title compound was prepared by following the procedure described for Step-1 of Intermediate 17 using intermediate 14 (0.400 g, 1.29 mmol), 3-chloro-4methoxycarbonyiphenylboronic acid (0.304 g, 1.42 mmol), potassium acetate (0.422 g, 4.30 mmol), dioxan (8 ml) and tetrakis (triphenylphosphine)palladium(O) (0.119 g, 0.103 mmol). Brown colour solid (0.237 g, 41%) which is used as such in next step.

Steo-2__________:2-chloro-4434(2-methvlQUÎnolin-6-vl)methvl)-3H41.2,3)triazoloî4.5-blpYridin-5vDbenzoic add: To a solution of Step-1 (0.237 g, 0.556 mmol) in methanol (0.5 ml), THF (2.7 ml), lithium hydroxide (0.209 g, 4.98 mmol) in water(0.5 ml) was added and stirred at RT. After 12h, the pH was adjusted to 7-7.5 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as black solid (0.200 g, 87%).which is used as such in next step.

Intermediate 21: 4-(3-(benzo[d]thîazol-6-ylmethyl)-3H-[1,2,3]triazolo[4₍5-b]pyridin-5-yl)-2chlorobenzoic acid:

Step-1 : methyl 4434benzordlthiazol-6-vlmethvl)-3H41.2.31triazolor4,5-b|pvridin-5-vl)-2chlorobenzoate: The title compound was prepared by following the procedure described for Step-1 of intermediate 17 using intermediate 15 (0.400 g, 1.32 mmol), 3-chloro-4methoxycarbonylphenylboronic acid (0.312 g, 1.45 mmol), potassium acetate (0.433 g, 4.41 mmol), dioxan (9.5 ml) and tetrakis (triphenylphosphine)palladium(O) (0.122 g, 0.106 mmol). Brown colour solid (0.400 g, 69%) which is used as such in next step.

Step-2: To a solution of Step-1 (0.400 g, 0.917 mmol) In methanol (2.1 ml), THF (8.1 ml), lithium hydroxide (0.359 g, 8.56 mmol) in water(2.1 ml) was added and stirred at RT. After 12h, the pH was adjusted to 7-7.5 using 2N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as brown solid (0.370 g. 95%). MS (m/z): 422.1 (m*).

Intermediate 22 : 4-(3-(benzo[d]thlazol-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrldIn-5-yl)-

2,6-difluorobenzolc acid:

Step-1 : methyl 4434benzordlthÎazol-6-vlmethvl)-3H-[1.2.3'ltriazolor4.5-blpvridin-5-vl)-2,6difluorobenzoate: The title compound was prepared by following the procedure described for 98

Step-1 of intermediate 17 using intermediate 15 (0.400 g, 1.32 mmol), 3,5-difluoro-4methoxycarbonylphenylboronic add (0.314 g, 1.45 mmol), potassium acetate (0.433 g, 4.41 mmol), dioxan (9.5 ml) and tetrakis (triphenylphosphine)palIadium(O) (0.122 g, 0.106 mmol).

Brown colour solid (0.380 g, 65%) which is used as such in next step.

Steo-2: To a solution of Step-1 (0.380 g, 0.868 mmol) in methanol (1.9 ml), THF (7.6 ml), lithium hydroxide (0.340 g, 8.10mmol) in water (1.9 ml) was added and stirred at RT. After 12h, the pH was adjusted to 7-7.5 using 2N HCl and the solid predpitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as brown solid (0.340 g, 92%). MS (m/z): 424.2 (m*+1).

Intermediate 23 : 4-(3-(beno[d]thlazol-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2fluorobenzoic acid

Step-1: methyl 443-(benzo[dlthiazol-6-vlmethvlÎ-3H-ri 2.31triazolof4.5-b)pyridin-5-vlÎ-2fluorobenzoate: The title compound was prepared by following the procedure described for Step-1 of intermediate 17 using intermediate 15 (0.300 g, 0.994 mmol), 3-fluoro-4methoxycarbonylphenylboronic add (0.197 g, 1.09 mmol), potassium acetate (0.324 g, 3.31 mmol), dioxan (7.1 ml) and tetrakis (triphenylphosphine)palladium(O) (0.091 g, 0.079 mmol). Brown colour solid (0.400 g, 95%) which is used as such in next step.

Step-2: To a solution of Step-1 (0.400 g, 0.952 mmol) in methanol (2.0 ml), THF (8.3 ml), lithium hydroxide (0.372 g, 8.88 mmol) in water (2.0 ml) was added and stirred at RT. After 12h, the pH was adjusted to 7-7.5 using 2N HCl and the solid predpitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as oof-white solid (0.300 g, 77%) which is used as such in next step.

Intermediate 24 : 2,6-dlluoro-4-(3-((2-methylquinolin-6-yl)methyl)-3H-[1,2,3]trlazolo[4,5b]pyrldln-5-y1)benzoic acid

Step-1 : methyl 2,6-difîuoro-4-f3-f(2-methvlquînolin-6-vlÎmethvl)-3H41,2.3Ttriazolor4.5-b1pyridin-

5-vBbenzoate: The title compound was prepared by following the procedure described for step1 of intermediate 17 using intermediate 14 (0.500 g, 1.61 mmol), 3,5-difluoro-4methoxycarbonylphenylboronic add (0.383 g, 1.77 mmol), potassium acetate (0.527 g, 5.37 mmol), dioxan (11.5 m!) and tetrakis (triphenylphosphine)palladium(O) (0.149 g, 0.129 mmol). Brown colour solid (0.500 g, 69%) which is used as such in next step.

Step-2: To a solution of Step-1 (0.400 g, 0.898 mmol) in methanol (1.9 ml), THF (7.8 ml), lithium hydroxide (0.351 g, 8.37 mmol) in water (1.9 ml) was added and stirred at RT. After 12h, the pH was adjusted to 7-7.5 using 2N HCl and the solid predpitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as off-white solid (0.200 g, 51%) which is used as such in next step.

Intermediate 25 : 4-(3-(qulnolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoIc acid:

Steo-1 : Methyl 4-(3-fguinolin~6-ylmethvl)-3H-ri ,2,3~|triazoloÎ4,5-blovridin-5-vl')benzoate:The title compound was prepared by following the procedure described Step-1 for intermediate 17 using intermediate 7 (0.130 g, 0.439 mmol), 4-methoxycarbonylphenylboronic add (0.100 g, 0.562 mmol), potassium carbonate (0.202 g, 1.46 mmol), dioxan (2.6 ml), water (0.5 ml) and tetrakis (triphenylphosphine)palladium(O) (0.040 g, 0.035 mmol). Off-white solid (0.100 g, 57%). ¹HNMR (δ ppm, DMSO-d_e, 400 MHz): 8.88 (dd, J = 4.2,1.8 Hz, 1H). 8.72 (d. J= 8.7 Hz, 1H), 8.39 (m, 3H), 8.21 (d, J = 8.8 Hz, 1H), 8.12 (d, J = 8.6 Hz, 2H), 8.02 (s, 1H), 8.02 (d, J = 8.8 Hz. 1H),

7.84 (dd, J = 8.6,2.0 Hz, 1H). 7.53 (dd. J = 8.3,4.2 Hz, 1H), 6.23 (s, 2H), 3.89 (s, 3H).

Step-2: To a solution of Step-1 (0.095 g, 0.240 mmol) in methanol (1.4 ml), lithium hydroxide (0.028 g, 1.20 mmol) in water (0.36 ml) was added and stirred at RT. After 12h, the pH was adjusted to ca. 7.5 using 0.5N HCl and the solid predpitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as an offwhite solid (0.070 g. 76%). M.P.: 245-247°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): 13.18 (s, 1H), 8.88 (dd, J = 4.1,1.7 Hz, 1H), 8.71 (d, J = 8.7 Hz, 1H). 8.39 (d, J= 1.1 Hz, 1H), 8.36 (d, J =

8.5 Hz, 2H), 8.21 (d, J = 8.7 Hz, 1 H). 8.10 (d, J = 8.5 Hz, 2H), 8.03 (d, J = 9.2 Hz, 2H), 7.84 (dd, J= 8.7,2.0 Hz, 1H), 7.53 (dd, J = 8.4,4.2 Hz, 1H), 6.22 (s. 2H). MS (m/z): 381.88 (m*).

Intermediate 26 : 4-(3-(quinolin-6-yimethyI)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-y1)-2(trifluoro methyl) benzoic acid:

Step-1 :_________methyl_________4-(3-(quinolin-6-vlmethvl)-3H41.2.3^,|triazolor4.5-b|pvridin-5-vf)-2(trifluoromethvDbenzoate: The title compound was prepared by following the procedure described for step-1 of intermediate 17 using intermediate 7 (0.400 g, 1.35 mmol), 3methy1 4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y!)-2-(trifluoromethyl)benzoate (0.491 g, 1.48 mmol), potassium acetate (0.441 g, 4.50 mmol), dioxan (9.6 ml) and tetrakis (triphenylphosphine)patladium(O) (0.124 g, 0.108 mmol). Brown colour solid (0.400 g, 68%) which is used as such in next step.

Step-2: To a solution of Step-1 (0.400 g, 0.863 mmol) in methanol (4 ml), THF (8.2 ml), lithium hydroxide (0.327 g, 8.05 mmol) ln water (4 ml) was added and stirred at RT. After 12h, the pH was adjusted to 7-7.5 using 2N HCl and the solid predpitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as off-white solid (0.250 g, 64%) which is used as such in next step.

100

Intermediate 27 :4-(3-((7-fIuoroquinolln-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)2-(trifluoromethyl)benzolc acid:

Step-1 : methyl 4-(3-f(7-fluoroquinolin-6-yl)methyl)-3H-ri ,2.31triazolo[4.5-b1pyridin-5-vl)-2(trifluoromethvl)benzoate: The title compound was prepared by following the procedure described for step-1 of intermediate 17 using intermediate 8 (0.400 g, 1.27 mmol), 3methyl 4(4,4,5,5-tetramethy!-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)benzoate (0.464 g, 1,40 mmol), potassium acetate (0.417 g, 4.25 mmol), dioxan (9.6 ml) and tetrakis (triphenylphosphine)palladium(O) (0.118 g, 0.102 mmol). Brown colour solid (0.380 g, 62%) which ls used as such In next step.

Step-2: To a solution of step-1 (0.400 g, 0.830 mmol) in methanol (1.8 ml), THF (7.2 ml), lithium hydroxide (0.325 g, 7.75 mmol) in water (1.8 ml) was added and stirred at RT. After 12h, the pH was adjusted to 7-7.5 using 2N HCl and the solid predpîtated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as off-white solid (0.300 g, 77%) which is used as such in next step.

Intermediate 28: 2-methyl-4-(3-(quinolin-6-yimethy1}-3H-[1_>2,3jtriazolo[4,5-b]pyridin-5yl)benzolc acid

Step-1 :_______methyl_______2-methv1-4-f3-fQuinolin-6-vlmethvl)-3H41.2.3lÎriazolor4.5-b1pvridin-5vDbenzoate: The title compound was prepared by following the procedure described for step-1 of intermediate 17 using intermediate 7 (0.290 g, 0.869 mmol), methyl 2-methyl-4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.300 g, 1.08 mmol), potassium acetate (0.320 g,

3.26 mmol), dioxan (7.0 ml) and tetrakis (triphenylphosphine)palladium(O) (0.090 g, 0.078 mmol). Brown colour solid (0.250 g, 65%). which îs used as such In next step.

Step-2: To a solution of Step-1 (0.250 g, 0.640 mmol) in methanol (5.5 ml), THF (2.5 ml), lithium hydroxide (0.250 g, 5.97 mmol) in water (2.5 ml) was added and stirred at RT. After 12h, the pH was adjusted to 7-7.5 using 2N HCl and the solid predpîtated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as off-white solid (0.120 g, 48%) which is used as such in next step.

Intermediate 29: 4-(3-((7-fluoroqulnolin-6-yl)methyl)-3H-[1,2,3Jtrlazolo[4,5-b]pyridin-5-y1)2-methylbenzoic acid:

Step-1 : methyl 4-(3-((7-fluoroquinolin-6-vl)meÎhvl)-3H-f1.2.31triazolor4.5-b1pvridin-5-vl)-2methylbenzoate: The title compound was prepared by following the procedure described for step-1 of intermediate 17 using intermediate 8 (0.303 g, 0.968 mmol), methyl 2-methyl-4(4,4,5,5-tetramethy!-1,3,2-dioxaborolan-2-yl)benzoate (0.300 g, 1.08 mmol), potassium acetate

101 (0.322 g, 3.28 mmol), dioxan (7.0 ml) and tetrakis (triphenylphosphine)palladium(O) (0.088 g,

0.077 mmol). Brown colour solid (0.250 g, 63%). which is used as such in next step.

Step-2: To a solution of step-1 (0.250 g, 0.610 mmol) in methanol (1.5 ml), THF (5.3 ml), lithium hydroxide (0.239 g, 5.69 mmol) in water (1.5 ml) was added and stirred at RT. After 12h, the pH was adjusted to 7-7.5 using 2N HCl and the solid predpitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as off-white solid (0.150 g, 59%) which is used as such In next step.

Intermediate 30: 2-Fluoro-4-{3-((7-fluoroqu1nolin-6-yI)methy1)-3H-[1,2,3]triazolo[4,5b]pyridin-5-y1)benzoic acid:

Step-1 Methyl 2-fluoro-4-(3-{(7-fluoroouinolÎn-6-vl)methvl)-3H41.2.31triazolof4,5-b1pyridin-5vDbenzoate: The title compound was prepared by following the procedure described for step-1 of intermediate 17 using intermediate 8 (0.350 g, 1.15 mmol), 3-fluoro-4methoxycarbonylphenylboronic acid (0.276 g, 1.39 mmol), potassium acetate (0.365 g, 3.71 mmol), dioxane (8 ml) and tetrakis(triphenylphosphine)palladium(0) (0.103 g, 0.089 mmol). Pale brown solid (0.350 g, 70%). M.P.: 213-215°C.

Step-2: To a solution of step-1 (0.240 g, 0.605 mmol) în methanol (3 ml), lithium hydroxide (0.237 g, 5.64 mmol) in water (3 ml) and THF (6 ml) were added and stirred at RT. After 12h, pH was adjusted to ca. 7 using 0.5N HCl and the solid predpitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as pale brown solid (0.110 g, 44%). The add was used as such for further steps.

Intermediate 31: 6-((5-chloro-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)qulnoline 1oxide:

Intermediate 7 (0.300 g, 1.01 mmol) was dîssolved in dichloromethane (3.8 ml) and metachloroperbenzoic add (0.350 g, 2.02 mmol) was added at RT and stirred for 12h. Sodium sulphite solution (10 ml) and saturated potassium carbonate solution (10 ml) were added to the reaction mixture, extracted with dichloromethane, washed with brine, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as a pale green solid (0.140 g, 44%). Ή-NMR (δ ppm, DMSO-d_e, 400 MHz): δ 8.70 (d. J = 8.6 Hz, 1H), 8.56 (d. J~ 6.0 Hz, 1H), 8.51 (d, J- 9.0 Hz, 1H), 7.98 (s, 1H), 7.91 (d, J- 8.5 Hz, 1H), 7.77 (dd, J - 9.0,1.5 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.47 (dd. J= 8.4,1.6 Hz, 1H). 6.14 (s, 2H).

Intermediate 32: 6-((5-chloro-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)qulnolin-2(1H)one : Intermediate 31 (0.100 g, 0.321 mmol) was dîssolved in DMF (1 ml) and trifluoacetic

102 anhydride (0.486 g, 2.31 mmol) was added at RT and stirred for 12h. To the reaction mixture, sat. sodium bicarbonate solution (10 ml) was added and the obtained solid was fîltered and washed with ethyl acetate and dried under vacuum to afford the title compound as an off-white solid (0.060 g, 60%). ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): δ C11.74 (s, 1H), 8.66 (d. J= 8.7 Hz, 1H), 7.88 (d, J- 9.6 Hz, 1H), 7.65 (d, J- 1.7 Hz, 1H), 7.60 (d, J- 8.6 Hz, 1H), 7.52 (dd, J = 8.5,1.9 Hz, 1H), 7.28 (d, J= 8.4 Hz, 1H), 6.48 (d, J= 9.5 Hz, 1H). 5.93 (s, 2H).

Intermediate33: 2,6-difluoro-4-(4,4,5,Î>-tetramethy1-1,3,2-dioxaborolan-2-yl)benzamide

Step:1 4-bromo-2.6-difluorobenza1dehvde: n-BuU (1.6M in hexane, 38 ml, 62.16 mmol) was added drop wise to a solution of diisopropylamine (10 ml, 77.7 mmol) in THF (28 ml) at 0°C, maintained for 15 min. and cooled to -78’C. To this 3,5-dîfluorobromobenzene (10 g, 51.80 mmol) in THF (56 ml) was added, stirred at -78°C for 1 h, and N.N-dimethylformamide (7.6 ml) was added and stirred for further 1h. The reaction mixture was quenched with NH₄CI solution and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as an off-white solid (5.2 g. 46%) which was used without characterisation in the next step.

Step:2 4-bromo-2.6-difluorobenzoic add: To 4-bromo-2,6-difluorobenzaldehyde (4.0 g, 18.07 mmol) In DMF (80 ml), oxone (11.07 g, 18.07 mmol) was added and stirred at RT for 12h. The reaction mixture was quenched with 2N HCl solution and extracted with ethyl acetate, The organic layer was dried over sodium sulphate and concentrated under vacuum to afford the title compound as an off-white solid (3.5 g , 83 %) which was used without characterisation in the next step.

Step:3 4-bromo-2.6-difluorobenzamide: To 4-bromo-2,6-difluorobenzoic add (0.900 g, 3.81 mmol), thionyl chloride (9 ml) was added and refluxed for 3h. The excess thionyl chloride was removed under reduced pressure and the residue was cooled to 0°C. Aqueous 25% ammonia (7 ml) was added and stirred for 15 min. The predpitate formed was fîltered and vacuum dried to afford title compound as an off-white solid (0.700 g, 78%) which was used without characterisation in the next step.

Step:4 2.6-difluoro-4-(4.4.5.5-tetramethvl-1.3.2-dioxaboro1an-2-vhbenzamîde: The title compound was obtained as a brown solid (0.500 g, 61%) by using the procedure described for intermediate 9 from 4-bromo-2,6-difluorobenzamide___(0.700 g, 2.92 mmol), bis(pinacolato)diboron (0.825 g, 3.22 mmol), potassium acetate (0.862 g, 8.75 mmol), dioxane (5 ml) and [1,T-bis(diphenylphosphino)ferrocene]dichloro palladiumillJ.CHïCb (0.071 g, 0.087 mmol). ’H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 8.12 (s, 1H), 7.86 (s, 1H), 7.26 (d, J = 7.2 Hz,

1H), 1.29 (s, 12H).

103

Intermediate 34: 6-((5-chloro-3H-lmidazo[4,5-b]pyridin-3-yl)methy1)quinollne::

Intermediate 5 (0.200 g, 0.702 mmol) was dissolved in formic add (1.0 ml), heated to 100 ’C and stirred for 12h. The reaction mixture was poured into ice water and pH adjusted to 7-8 with sodium bicarbonate solution, extraded with ethyl acetate , washed with brine, dried over sodium sulphate and concentrated to afford the title compound as yellowish brown solid (0.200 g, 97%). ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): δ 8.88 (dd, J - 4.0,1.3Hz, 1H), 8.70 (s, 1H).

8.33 (d, J = 8.2Hz, 1H). 8.19 (d, J = 8.3Hz, 1H), 8.01 (d, J- 8.8Hz, 1H), 7.81 (s, 1H). 7.73 (dd, J = 8.7,1.7Hz, 1H), 7.52 (dd, J = 8.3,2.2Hz, IH), 7.37 (d, J = 8.4Hz, 1H), 5.69 (s, 2H).

Intermediate 35: 6-((5-ch!oro-3H-1mldazo[4,5-b]pyrldin-3-yl)methyl)-7-fluoroquinollne: The title compound was obtained as a brown solid (0.400 g, 78%) by using a procedure that is simiiar to the one described for intermediate 34 from intermediate 6 (0.500 g, 1.65 mmol), and formic add (2.5 ml). ’H-NMR (δ ppm. DMSO-d_e, 400 MHz): δΠ8.92 (dd, J - 4.3,1.7 Hz, 1 H),

8.16 (d, J - 0.8 Hz, 1H), 8.12 (d, J = 8.3 Hz, 1H), 8.04 (d, J - 8.3 Hz, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.78 (d, J = 5.5 Hz, 1H), 7.40 (dd, J = 8.4,4.3 Hz, 1H), 7.29 (d, J - 8.3 Hz, 1 H), 5.68 (s. 2H).

Intermediate 36: 6-{(5-chloro-2-methyl-3H-1midazo[4_l5-b]pyridin-3-yl)methyl)qulnollne: : The title compound was obtained as a brown solid (0.400 g, 62%) by using a procedure that is simiiar to the one described for intermediate 34 from intermediate 5 (0.600 g, 2.10 mmol), and acetic add (3 ml). ’H-NMR (δ ppm. DMSO-d₆, 400 ΜΗζ):δα8.91 (dd, J - 4.2,1.3Hz, 1H), 8.09 (d, J ~ 9.3 Hz, 1H). 8.06 (d, J - 7.5 Hz, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.57 (dd, J = 8.7,2.0 Hz, 1H), 7.47 (d, J = 1.2 Hz, 1H), 7.40 (dd, J = 8.3,4.0 Hz, 1H), 7.27 (d, J = 8.3 Hz. 1H), 5.62 (s. 2H), 2.53 (s,3H).

Intermediate 37: 2-chloro-N-methyl-4-[4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2yl)benzamlde: :

Step:1 4-bromo-2-chloro-N-methylbenzamide: To 4-bromo-2-chlorobenzoic add (1.00 g, 4.24 mmol), thionyl chloride (10 ml) was added and refluxed for 3h. Excess thionyl chloride was removed under reduced pressure and the residue was cooled to 0°C. Methyl amine solution (25% in MeOH, 15 ml) was added and stirred for 15 min. The predpitate formed was filtered and vacuum dried to afford title compound as an off-white solid (0.900 g, 85%) which was used in the next step.

Step:2: 2-chloro-N-methvl-4-(4,4.5.5-tetramethvl-1.3.2-dioxaborolan-2-vl)benzamide: The title compound was obtained as a brown solid (0.500 g, 46%) by using the procedure described for

104 intermediate 9 from 4-bromo-2-chloro-N-methylbenzamide (0.900 g, 3.62 mmol), bis(pinacolato)diboron (1.01 g, 3.99 mmol), potassium acetate (1.18 g, 12.08 mmol), dioxane (10 ml) and [1,T-bis(diphenylphosphino}ferTOcene]dichloro palladium(ll).CH₂CI₂ (0.088 g, 0.108 mmol) which was used without characterisation in the next step.

Intermediate 38: 2-Methyl-4-(4,4,5,5-tetramethyl-1_t3,2-dioxaborolan-2-yl)benzamlde: The title compound was obtained as a brown solid (0.600 g, 70%) by using the procedure described intermediate 9 from 4-bromo-2-methy!benzamide (0.700 g, 3.27 mmol), bis(pinacolato)diboron (0.913 g, 3.59 mmol), potassium acetate (0.96 g, 9.81 mmol), dioxane (12 ml) and [1,1bis(dîphenylphosphino)fenOcene]dichloropalladium(ll).CH₂CI₂ (0.080 g, 0.098 mmol) which was used without characterisation in the next step.

Intermediate 39: 6-('143-chIoro-3H-lmldazo[4₎5-b]pyridin-3-yl)ethy1)quinollne

Step:1 6-Chloro-3-nitro-N-(1-(quinolin-6-vl)ethvlÎPvridin-2-amine: The title compound was obtained as a yellow solid (0.785 g, 50%) by using a procedure that is similar to the one described for intermediate 4 from 2,6-Dichloro-3-nitropyridine (0.924g, 4.78 mmol), 1-(quinolin6-yl)ethanamine (1.25.g, 7.25 mmol), éthanol (7 ml) and sodium carbonate (1.32g, 12.54 mmol). ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): δ D8.86 (dd, J = 4.2, 1.7Hz, 1H). 8.78 (d, J = 7.5Hz, 1H), 8.44 (d, J = 8.6Hz, 1H), 8.33 (dd, J ~ 8.3, 1.0Hz, 1H), 7.99 (m,2H), 7.89 (dd J = 8.8,1.9Hz, 1H), 7.51 (q. J = 4.2Hz, 1H), 6.80 (d. J = 7.5Hz, 1H), 5.57(q, J-7.1Hz, 1H). 1.69 (d, J = 7.0Hz, 3H).

Step:2 6-chloro-N2-(1-fquinolin-6-vl)ethvl)pvridine-2,3-diamine: The title compound was obtained as a pale brown solid (0.600 g, 74%) by using a procedure that is similar to the one described for intermediate 5 from 6-Chloro-3-nitro-N-(1-(quinolin-6-yl)ethyl)pyridin-2-amine (0.900 g, 2.72 mmol), stannous chloride ( 2.77 g, 12.28 mmol) and conc.HCI (1.5 ml) which is used as such for next step.

Step: 3 6-(1-(5-chloro-3H-imidazor4.5-b1pvridin-3-vl)ethvl)Quinoline: The title compound was obtained as a brown solid (0.410 g, 80%) by using a procedure that is similar to the one described for intermediate 34 from 6-chloro-N2-(1-(quinolin-6-yl)ethy1)pyridine-2,3-diamine (0.500 g, 1,67 mmol), and formic acid (2.5ml). Ή-NMR (δ ppm, CDCI₃,400 MHz): δ 8.93 (dd, J = 4.2,1.7 Hz, 1H), 8.15 (dd, J =8.3,0.9 Hz, 1H), 8.11 (d. J =8.8 Hz, 1H), 8.08 (s, 1H), 8.03 (d. J - 8.4 Hz, 1H), 7.77 (d, J = 1.9 Hz, 1H), 7.68 (dd, J - 8.8,2.1 Hz, 1 H). 7.44 (dd. J = 8.3,4.2 Hz, 1H), 7.28 (d, J = 8.4 Hz. 1 H), 6.29 (q, J = 7.2 Hz, 1 H), 2.11 (d, J = 7.2 Hz, 3H).

Intermediate 40: 6-((5-chloro-3H-lmidazo[4,5-b]pyrldin-3-yl)methyl)-5,7-difluoroqulnoline:

105

Step: 1 6-chloro-N4(5.7-dîfluoroquinolin-6-yl)methvD-3-nitropvridin-2-aniÎne: The title compound was obtained as a yellow solid (0.050 g, 5%) by using a procedure that is similar to the one described for intermediate 3 from 2,6-Dichloro-3-nitropyridine (1.40 g, 7.73 mmol), (5,7difluoroquinolin-6-yl)methanamine (1.00 g, 5.15 mmol), éthanol (10 ml) and sodium carbonate (0.97 g, 9.22 mmol). ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): δ 9.09 (t, J = 5.1 Hz, 1H), 8.96 (d. J = 3.7 Hz, 1H), 8.49 (d, J = 8.4 Hz, 1H), 8.41 (d, J - 8.5 Hz, 1H), 7.68 (d, J - 11.0 Hz, 1H),

7.61 (dd, J = 8.4,4.2 Hz, 1H), 6.79 (d, J= 8.5Hz, 1H). 4.97 (d, J =5.5 Hz, 2H).

Step: 2: 6-chloro-N2-((5,7-difluoroquinolin-6-y1)methyl)pyridine-2,3-diamine: The title compound was obtained as a brown solid (0.080 g, 73%) by using a procedure that is similar to the one described for intermediate 5 from 6-ch1oro-N-((5,7-difluoroquinolin-6-yl}methyl)-3nitropyridîn-2-amine (0.12 g, 0.342 mmol), stannous chloride (0.347 g, 1.54 mmol) and conc.HCI (2 ml) which is used as such for next step.

Step 3: 6-((5-chloro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5,7-difluoroquinoline: The title compound was obtained as a brown solid (0.150 g, 81%) by using a procedure that is similar to the one described for intermediate 34 from 6-chloro-N2- ((5,7-difluoroquinolin-6-y!) methyl) pyridine-2,3-diamine (0.180 g, 0.562 mmol), and formic add (0.9 ml). ’H-NMR (δ ppm, DMSOde, 400 MHz): δ 8.98 (dd, J= 4.3,1.6 Hz. 1H), 8.44 (dd, J = 8.5,1.1 Hz, 1H),8.10 (s,1H), 8.00 (d, J= 8.3 Hz. 1H), 7.67 (d, J~ 10.6 Hz, 1H), 7.49 (dd, J- 8.5,4.3 Hz, 1H), 7.27 (d, J= 8.4 Hz, 1H) . 5.71 (s, 2H).

Intermediate 41:1-(3-(qulnolin-6-ylmethyi)-3H-[1,2,3]trlazolo[4,5-b]pyrldin-5-yl)ethanone:

To a solution of Intermediate 7 (0.200 g, 0.676 mmol) and 1-ethoxyvinyl tri(n-butyl)stannane (0.244 g, 0.676 mmol) in triphenylphosphine (0.0284 g, 0.054 mmol) , toluene (3.8 ml), was degassed for 30 min. To this tris(dibenzilidineacetone) palladium(O) (0.028 g, 0.027 mmol) was added under nitrogen at RT and the reaction mixture was refluxed for 12h. The solvent was evaporated completely and water was added to the residue and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. Then followed by add hydrolysis to afford the title compound as a brown solid (0.080 g, 39%). M.P.: 165-167°C. ’HNMR (δ ppm, CDCI₃, 400 MHz ): δ 8.92 (d, J = 3.0 Hz, 1H), 8.49 (d, J = 8.5 Hz, 1H). 8.15 (m, 1H), 7.94 (s, 1H). 7.87 (d, J = 8.6 Hz, 1H), 7.43 (dd, J - 8.3,4.2 Hz, 1H), 6.15 (s, 2H). 2.82 (s, 1H).

Intermediate 42: 6-((5-chloro-3H-(1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)-7fluoroquinoline 1-oxide:

106

The title compound was obtained as a brown solid (0.800 g, 76%) by using a procedure that is similar to the one described for intermediate 31 from intermediate 8 (1.00 g, 3.18 mmolj.dichloromethane (13 ml) and metachloroperbenzoic add (1.10 g, 6.37 mmol) which was used as such in next step.

Intermediate 43: 6-((5-chloro-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)-7-f1uoroquinolin2(1H)-one:

Intermediate 43: The title compound was obtained as off-white solid (0.600 g, 79%) by using a procedure that is similar to the one described for intermediate 32 from intermediate 42 (0.800 g,

2.43 mmol), DMF (8 ml) and trifluoacetic anhydride (1.20 ml, 8.78 mmol). ’H-NMR (δ ppm, DMSO-d_e. 400 MHz): δ 011.54 (s. 1H), 8.65 (d, J = 8.76Hz, 1H), 7.87 (d, J = 9.6 Hz, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.60 (d, J~ 8.6 Hz. 1H), 7.08 (d, J = 11.3 Hz, 1H), 6.44 (d, J~ 9.6 Hz, 1H),

5.93 (s, 2H).

Intermediate 44: 2-chloro-4-(3-((7-fluoro-2-oxo-1,2-dihydroquinolin-6-yi)methyl)-3H- [1.2.3] trlazolo[4,5-b]pyridin-5-yt)benzolc add:

The title compound was prepared by following the procedure described for step 1 of Intermediate 11 using intermediate 43 (0.100 g, 0.317 mmol), 4-borono-2-chlorobenzoic add (0.069 g, 0.349 mmol), potassium acetate (0.103 g, 1.058 mmol), dioxan (2.30 ml), water (1.0 ml) and tetrakis (triphenytphosphîne)palladium(O) (0.029 g, 0.0254 mmol) and in microwave oven (microwave power = 100W, température = 110 °C) for 45 min. Brown solid (0.100 g, 62%). Mass : 449.6 (M⁺).

Intermediate 45: 2-methyl-4-(3-((2-oxo-1,2-dihydroquInolln-6-yl)methyl)-3H- [1.2.3] triazolo[4,5-b]pyridin-5-yl)benzolc acid:

The title compound was prepared by following the procedure described for step 1 of Intermediate 11 using intermediate 32 (0.100 g, 0.320 mmol), 4-borono-2-methylbenzoic add (0.062 g, 0.362 mmol), potassium acetate (0.104 g, 1.068 mmol), dioxan (2.30 ml), water (1.0 ml) and tetrakis (triphenylphosphine)palladium(O) (0.029 g, 0.0254 mmol) and in microwave oven (mïcrowave power = 100W, température = 110 °C) for 45 min. Brown solid (0.100 g, 75%) which was used as such in next step.

Intermediate 46: 2-fluoro-4-(3-(qulnolin-6-y1methyl)-3H-lmldazo[4,5-b]pyridln-5-yl)benzolc acid:

StepQl: methyl 2-fluoro-4-(3-(quinolin-6-vlmethvD-3H-imidazor4.5-b1pvridin-5-vllbenzoate: The title compound was prepared by following the procedure described for step-1 of intermediate 17 using intermediate 34 (1.00 g, 3.36 mmol), 3-fluoro-4-methoxycarbonylphenylboronic add

107 (0.734 g, 3.70 mmol), potassium acetate (1.11 g, 11.22 mmol), dioxane (24 ml) and tetrakis(triphenylphosphine)palladium(0) (0.311 g, 0.269 mmol). Pale brown solid (1.00 g, 76%). Step-2: To a solution of step-1 (1.00 g, 2.42 mmol) in methanol (12 ml), lithium hydroxîde (0.940 g, 22.62 mmol) In water (12 ml) and THF (24 ml) were added and stirred at RT. After 12h, pH was adjusted to ca. 7 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as off-white solid (0.600 g, 62%). The add was used as such for further steps.

Intermediate 47: 2-methyl-4-(3-(quinolin-6-ylmethy1)-3H-lmidazo[4,5-b]pyridin-5yl)benzoic acid:

Step-1: methyl 2-methyl-4-(3-(quinolin-6-v!methvi)-3H-Îmidazof4,5-blpvridin-5-vl)benzoate : The title compound was prepared by following the procedure described for step-1 of intermediate 17 using intermediate 34 (1.00 g, 3.39 mmol), 3-methy!-4-methoxycarbonylphenylboronic add (0.716 g, 3.73 mmol), potassium acetate (1.11 g, 11.29 mmol), dioxane (24 ml) and tetrakis(triphenylphosphine)pal1adium(0) (0.313 g, 0.271 mmol). Pale brown solid (0.800 g, 61%).

Step-2: To a solution of step-1 (0.800 g, 1.95 mmol) in methanol (9 ml), lithium hydroxîde (0.766 g, 18.27 mmol) in water (9 ml) and THF (18 m!) were added and stirred at RT. After 12h, pH was adjusted to ca. 7 using 0.5N HCl and the solid predpitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as pale brown solid (0.600 g, 83%). The acid was used as such for further steps.

Intermediate 48: 2-chloro-4-(3-(quinolin-6-ylmethyl)-3H-imidazo[4,5-b]pyridin-5yl)benzoic acid:

Step-1 : methyl 2-chloro-4-(3-fquinolin-6-vlmethvl)-3H-lmidazor4.5-b1pvridin-5-vl)benzoate: The title compound was prepared by following the procedure described for step-1 of intermediate 17 using intermediate 34 (1.00 g, 3.39 mmol), 3-chloro-4-methoxycarbonylphenylboronic add (0.715 g, 3.37 mmol), potassium acetate (1.11 g, 11.29 mmol), dioxane (24 ml) and tetrakis(triphenylphosphÎne)palladium(0) (0.313 g, 0.271 mmol). Pale brown solid (0.500 g, 35%).

Step-2: To a solution of step-1 (0.500 g, 1.16 mmol) in methanol (5.3 ml), lithium hydroxîde (0.456 g, 10.86 mmol) In water (5.3 ml) and THF (10.7 ml) were added and stirred at RT. After 12h, pH was adjusted to ca. 7 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as pale brown solid (0.400 g, 82%). The add was used as such for further steps.

Intermediate 49:4-bromo-2-(trifluoromethyl)benzamlde

108

To 4-bromo-3-(trifluoromethy1)benzoic add¹ (1.0 g, 3.71 mmol), thionyl chloride (10 ml) was added and refluxed for 3h. The excess thionyl chloride was removed under reduced pressure and the residue was cooled to 0°C. Aqueous 25% ammonia (7 ml) was added and stirred for 15 min. The predpitate formed was washed with sodium bicarbonate solution and vacuum dried to afford title compound as a brown solid (0.500 g, 50%) which is used as such for next step. Bioorg. Med. Chem. 2007,15,2198.

Intermediate 50: 4-{4,4,5,5-tetramethyM,3,2-dioxaborolan-2-y1)-2(trifluoromethyl)benzamlde

The title compound was obtained as a brown solid (0.30 g, 50%) by using the procedure described in step 4 for intermediate 19 from intermediate 41 (0.500 g, 1.86 mmol), bis(pînacolato)diboron (0.705 g, 2.77 mmol), potassium acetate (0.743 g, 7.57 mmol), dioxane (4.6 ml) and [1,r-bis(diphenylphosphino)ferrocene]dichloro palladium(ll).CH₂Cl2 (0.061 g, 0.067 mmol) which is used as such for next step.

Intermediate 51: N-methy!-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboroIan-2-y1)plcolinamlde:

The title compound was obtained as a black solid (0.500 g, 53%) by using the procedure described intermediate 9 from 5-bromo-N-methylpîcolinamide (0.900 g, 4.47 mmol), bis(pinacolato)diboron (1.25 g, 4.92 mmol), potassium acetate (1.31 g, 13.43 mmol), dioxane (13 ml) and [1,r-bis(diphenyiphosphino)ferrocene]dichloropafladium(ll).CH₂CI₂ (0.109 g, 0.134 mmol) which was used without characterisation in the next step.

Intermediate 52: 5-(4,4_>5,5-tetramethyl-1,3,2-dioxaboro!an-2-yi)isoindolin-1-one:

The title compound was obtained as a off-white solid (0.410 g, 84%) by using a procedure that is similar to the one described for intermediate 9 from 5-bromoisoindolin-1-one (0.400 g, 1.88 mmol), potassium acetate (0.645 g, 6.58 mmol), bis(pinacofato)diboron (0.520 g, 2.07 mmol) dioxane (7 ml) and [1,T-Bis(diphenylphosphino)ferrocene]dichloro palladium(ll).CH₂CI₂ (0.076 g, 0.094 mmol). ¹H-NMR (δ ppm, CDCI₃, 400 MHz): δ 7.93 (m, 2H), 7.87 (d. J = 7.8 Hz. 1H),

7.16 (s, 1H), 1 H). 4.45 (s, 2H), 1.36 (s, 12H).

amples

Example 1

N-(2-amIno-2-oxoethyl)-4-(3-(quinolin-7-yïmethy1)-3H-[1,2,3]triazolo[4_l5-b]pyridin-5y!)benzamide

To a solution of intermediate 11 (0.100 g, 0.262 mmol) in DMF (1 ml) N-ethyldiisopropylamine (0.033 g, 0.262 mmol) and HATU (0.099 g, 0.262 mmol) were added and stirred for 5 min. 2aminoacetamide (0.038 g, 0.524 mmol) was added at RT and the reaction mixture was stirred

109 for 12h. To the reaction mixture water was added and extracted with ethyl acetate, dried over sodium suiphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as an Offwhite solid (0.030 g, 26 %). M.P.: 264-266°C. ¹H-NMR (δ ppm, DMSO-d_e, 400 MHz): δ 8.88

S (dd, J = 4.1,1.6 Hz, 1H), 8.80 (t, J = 5.8 Hz, 1H), 8.69 (d, J= 8.8 Hz, 1H), 8.38(s, 1H), 8.36 (d, J = 8.5 Hz, 2H), 8.22 (d, J = 8.8 Hz, 1H). 8.05 (m, 4H), 7.82 (dd, J = 8.7.1.9 Hz, 1H), 7.53 (dd, J-

8.4,4.2 Hz, 1H), 7.39 (s,1H), 7.04 (s,1H), 6.23 (s,2H), 3.85 (d, J = 5.8 Hz, 2H).

Example 2

N-(2-(methylamino)-2-oxoethyl)-4-(3-(quinolin-6-ylmethy1)-3H-[1,2,3]triazolo[4,5-b]pyridîn5-yl) benzamlde:

The title compound was prepared by following the procedure described for example 1 using intermediate 11 (0.100 g, 0.262 mmol), DMF (1 ml), N-ethyldiisopropylamine (0.033 g, 0.262 mmol), HATU (0.099 g, 0.262 mmol) and 3-amino-N-methylpropanamide (0.047 g, 0.524 15 mmol). Off-white solid (0.030 g, 25%). M.P.: 232-234°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz):

6d8.89(m,2H), 8.70 (d, J = 8.7 Hz. 1H), ), 8.39 (d. J = 7.6 Hz, 1H), 8.36 (d, J = 8.5 Hz, 2H),

8.22 (d. J = 8.8 Hz, 1H), 8.06 -8.01 (m, 4H), 7.85 (m, 2H), 7.55 (dd, J = 8.3,4.2 Hz, 1H). 6.23 (s,2H), 3.86 (d, J =5.9 Hz. 2H), 2.61 (d, J = 4.6 Hz, 3H).

Example 3

N-(3-amino-3-oxopropyl)-4-(3-(qulnolin-6-yimethyl)-3H-[1,2,3]trlazolo[4,5-b]pyridin-5yl)benzamlde:

The title compound was prepared by following the procedure described for example 1 using intermediate 11 (0.100 g, 0.262 mmol), DMF (1 ml), N-ethyldiisopropylamine (0.033 g, 0.262 mmol), HATU (0.099 g, 0.262 mmol) and 3-aminopropanamide (0.046 g, 0.524 mmol). Off25 white solid (0.030 g, 25 %). M.P.: 256-258°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): δΠ8.88 (dd, J = 4.1,1.6 Hz, 1H). ). 8.69 (d. J = 8.7 Hz. 1H), 8.64 (t, J = 5.4 Hz, 1H), 8.37 (d, J = 7.7 Hz, 1H), 8.33 (d, J = 8.4 Hz, 2H), 8.20 (d, J = 8.8 Hz, 1H), 8.03 (m, 4H). 7.84 (dd, J = 8.7,1.9 Hz, 1H), 7.53 (dd, J = 8.3,4.2 Hz, 1H), 7.35 (s,1H), 6.82 (s,1H), 6.22 (s,2H), 3.49 (m,2H), 2.39 (t, J = 7.2 Hz, 2H).

Example 4

N-O-fmethylamlnoï-S-oxopropylH-ÎS-tquinolln-e-ylmethylJ-SH-II^.SJtriazolo^.Sb]pyridin-5-yl)benzamIde:

The title compound was prepared by following the procedure described for example 1 using intermediate 11 (0.100 g, 0.262 mmol), DMF (1 ml), N-ethyldiisopropylamine (0.033 g, 0.262

110 mmol), HATU (0.099 g, 0.262 mmol) and 3-amino-N-methylpropanamide (0.055 g, 0.524 mmol). Off-white solid (0.040 g, 33 %). M.P.: 226-228°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): δ08.88 (dd, J ~ 4.2.1.7 Hz, 1H), ). 8.69 (m, 2H), 8.38 (d, J = 7.3 Hz, 1H), 8.33 (d, J = 8.5 Hz, 2H), 8.20 (d, J = 8.8 Hz, 1H). 8.03 -7.97(m, 4H). 7.84 (dd, J ~ 8.8,2.0 Hz, 2H), 7.53 (dd, J =

8.3,4.2 Hz. 1 H), 6.22 (s,2H), 3.50 (m, 2H), 2.57 (d, J - 4.6 Hz, 3H), 2.39 (t, J - 7.2 Hz, 2H).

Example 5

2-chloro-N-(2-(pyrrolidin-1-yi)ethyl)-4-(3-(qulnolin-7-ylmethy1)-3H-{1_l2_l3]triazolo[4,5b]pyridin-5-yl)benzamide:

The title compound was prepared by following the procedure described for example 1 using intermediate 12 (0.150 g, 0.359 mmol), DMF (1.05 ml) N-ethyfdiisopropyfamine (0.046 g, 0.359 mmol), HATU (0.136 g, 0.359 mmol) and 2-{ pyrrolidin -1-yl)ethanamine (0.040 g, 0.359 mmol). Yellow solid (0.040 g, 22%). M.P.: 143-145°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): δ 8.88 (dd, J = 4.1,1.7 Hz, 1H). 8.70 (d, J = 8.7 Hz, 1H), 8.49 (t, J - 5.6 Hz, 1H). 8.37 (d. J = 5.4 Hz. 1H), 8.31 (d, J= 1.6 Hz, 1H), 8.25 (dd, J - 8.1,1.7 Hz, 1H), 8.21 (d, J= 8.8 Hz, 1H). 8.04 (d, J =

1.6 Hz, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.83 (dd, J = 8.7,2.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.53 (dd, J ~ 8.3,4.2 Hz, 1H), 6.23 (s, 2H), 3.38 (m, 2H), 2.54 (m,6H), 1.68 (m, 4H).

Example 6 2-chloro-N-(2-hydroxyethoxy)-4-(3-(qulnolin-6-ylmethy1)-3H-[1,2,3]triazolo(4₎5-b] pyridin5-y1)benzamide:

The title compound was prepared by following the procedure described for example 1 using intermediate 12 (0.150 g, 0.360 mmol), DMF (1 ml), N-ethyldiisopropylamÎne (0.046 g, 0.360 mmol), HATU (0.136 g, 0.360 mmol) and 2-hydroxyethylhydroxylamine (0.027 g, 0.360 mmol). Yellow solid (0.049 g, 29 %). M.P.: 189-191°C. ’H-NMR (δ ppm, DMSO-d₆₁400 MHz): δ 10.56 (s, 1H), 8.88 (dd, J-4.1,1.5 Hz, 1H). 8.42 (d, J= 8.7 Hz, 1H), 8.16(d, J= 1.6 Hz, 1H), 8.12 (d, J - 7.9 Hz, 1 H). 8.04 (d, J = 8.8 Hz. 1 H), 8.00 (dd, J = 8.1,1.7 Hz, 1 H), 7.92 (d, J ~ 1.6 Hz, 1 H),

7.81 (m,2H), 7.60 (d, J= 8.0 Hz, 1H), 7.38 (dd. J = 8.3,4.2 Hz, 1H), 6.10 (s,2H), 4.32 (t, J= 4.2 Hz, 1H), 4.08 (t, J= 4.2 Hz, 2H), 3.80 (m, 2H).

Example 6a

2-chloro-N-(2-hydroxyethoxy)-4-(3-(qulnolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrtdin-5yl) benzamïde hydrochloride:

The title compound was prepared by following the procedure described for example 1 using example 6 (0.025 g, 0.052 mmol), THF (0.5 ml) and ether-HCI (0.2 ml). Pale yellow solid (0.013 g, 49 %). M.P.: 218-220°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): δα 11.69 (s. 1H), 9.08 (d, J111

4.3 Hz, 1H), 8.75 (d, J = 7.7 Hz, 1 H), 8.72 (d, J = 8.7 Hz, 1 H), 8.33 (d, J - 1.3 Hz, 1H), 8.268.17 (m, 4H), 8.02 (d, J - 8.7 Hz, 1H), 7.79 (d, J = 4.4 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 6.29 (s,2H), 3.96 (t, J- 5.0 Hz, 2H), 3.66 (t, J- 5.1 Hz, 2H).

Example 6b

2-chIoro-N-(2-hydroxyethoxy)-4-{3-(quInolIn-6-ylmethyl)-3H-[1,2,3]trlazolo[4_l5-b]pyridin-5y!)benzamtde 4-methylbenzenesulfonate:

The example 6 (0.070 g. 0.147 mmol) was dissolved in THF (2 ml), para-toluenesulphonic acid( 0.028 g, 0.147 mmol) was added at 0°C and stirred for 30 min. The solvent was concentrated and dried under vacuum to afford the title compound as a yellow solid (0.050 g, 52%). M.P.: 226-228°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): 11.68 (s, 1H), 9.07 (d, J= 1.2 Hz, 1H), 8.73 (d, J = 8.7 Hz, 2H), 8.34 (d, J = 1.4 Hz, 1H), 8.27-8.19 (m, 3H), 8.13 (d, J - 8.7 Hz, 1H), 8.00 (d, J - 8.7 Hz, 1H), 7.78 (dd, J = 8.3, 3.7 Hz, 1H), 7.64 (d, J= 8.1 Hz, 1H), 7.47 (d, J- 8.0 Hz, 2H), 7.10 (d, J = 7.9 Hz, 2H), 6.28 (s,2H), 3.96 (t, J - 4.9 Hz. 2H), 3.66 (t. J = 4.9 Hz, 2H). 2.27 (s, 3H).

Example 6c

2-chloro-N-(2-hydroxyethoxy)-4-(3-(quinolln-6-ylmethy1)-3H-[1_l2,3]triazolo[4_l5-b]pyridin-5yljbenzamlde hydrobromide:

The example 6 (0.070 g. 0.147 mmol) was dissolved in THF (2 ml), HBr in ether (1.5 ml) was added at 0°C and stirred for 30 min. The precipitate was filtered and washed with ether and dried under vacuum to afford the title compound as a yellow solid (0.050 g, 61%). M.P.: 222224°C. ’H-NMR (δ ppm. DMSO-d_e, 400 MHz): 11.68 (s, 1H), 9.07 (dd, J ~ 4.6,1.2 Hz, 1H). 8.73 (d, J= 8.7 Hz, 2H), 8.34 (d, J= 1.6 Hz, 1H), 8.27-8.19 (m, 3H), 8.13 (d, J-8.8 Hz, 1H), 8.00 (dd, J = 8.7,1.7 Hz. 1H), 7.79 (dd, J - 8.4, 4.7 Hz, 1H), 7.64 (d, J - 8.0 Hz, 1H), 6.29 (s,2H),

3.96 (t, J = 4.9 Hz, 2H), 3.65 (t, J- 5.1 Hz, 2H).

Example 6d sodium (2-chloro-4-(3-(quinolin-6-y1inethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5yl)benzoyi)(2-hydroxyethoxy)amlde:

To example 6 (0.100 g, 0.210 mmol) in isopropanol (2 ml) , 3N sodium hydroxide solution (0.076 ml) was added and stirred for 30 min. The reaction mixture was concentrated under reduced pressure. To the residue 1 ml isopropanol was added, filtered, washed with isopropanol, diethyf ether and dried under vacuum to afford the title compound as a yellow solid (0.080 g, 79 %). M.P.: 256-258°C. Ή-NMR (δ ppm, DMSO-d_e, 400 MHz): 8.88 (dd, J = 4.2,1.7 Hz, 1H), 8.63 (d. J~ 8.8 Hz, 1H), 8.38 (dd, J = 8.5,0.9 Hz, 1H), 8.15 (d, J = 1.7 Hz, 1H). 8.14 (d,

112

J - 8.8 Hz, 1H), 8.07-8.00 (m. 3H), 7.83 (dd, J = 8.7.2.0 Hz, 1H), 7.53 (dd, J - 8.3,4.2 Hz, 1H),

7.48 (d, J= 8.0 Hz, 1H), 6.21 (s, 2H), 5.83 (s, 1H), 3.67 (t. J- 4.2 Hz, 2H), 3.54 (m, 2H).

Example 7 2-ch1oro-4-(3-((7-fIuoroqulnolln-6-yl)methyl)-3H-[1|2,3]trlazolo[4,5-b]pyrîdin-5-y!)-N-(2hydroxyethoxy)benzamide:

The title compound was prepared by following the procedure described for example 6 using Intermediate 16 (0.150 g, 0.345 mmol), DMF (1.1 ml), N-ethyldiisopropy!amine (0.044 g, 0.345 mmol), HATU (0.131 g, 0.345 mmol) and 2-hydroxyethylhydroxylamine (0.053 g, 0.691 mmol).Pale green solid (0.040 g, 23 %). M.P.: 195-198°C. Ή-NMR (δ ppm, DMSO-d_e, 400 MHz): 11.67 (s, 1H), 8.92 (dd, J-4.2,1.6 Hz, 1H), 8.71 (d, J = 8.7 Hz, 1 H), 8.43 (d, 7.2 Hz,

1H), 8.31 (d, J- 1.5 Hz, 1H), 8.24 (m, 3H), 7.83 (d, J~ 11.5 Hz, 1H). 7.62 (d, J = 7.9 Hz, 1H), 7.55 (dd, J = 8.5,4.2 Hz, 1H), 6.26 (s,2H), 4.72 (t, J - 5.5 Hz, 1H), 3.96 (t, J = 4.9 Hz, 2H). 3.66 (m, 2H).

Example 7a

2-chloro-4-(3-((7'fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyrîdin-5-yl)-N-(2hydroxyethoxy)benzamlde hydrochloride:

The title compound was prepared by following the procedure described for example 6a using example 7 (0.050 g, 0.101 mmol), THF (1.0 ml) and ether-HCI (0.2 ml). Pale yellow solid (0.045 g, 84 %). M.P.: 189-191 °C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): 11.69 (s, 1H), 8.97 (dd, J =

4.4,1.4 Hz, 1 H), 8.71 (d, J = 8.7 Hz, 1 H), 8.54 (d. J = 8.0 Hz, 1 H). 8.31 (d, J = 1.5 Hz, 1 H), 8.27 (m, 3H), 7.87 (d, J= 11.3 Hz, 1H), 7.62 (m, 2H), 6.27 (s, 2H), 3.92 (t, J = 4.9 Hz, 2H), 3.64 (m, 2H).

Example 7b sodium (2-chloro-4-(3-((7-fluoroquInonn-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5yl)benzoyl)(2-hydroxyethoxy)amide:

To example 7 (0.050 g, 0.101 mmol) in isopropanol (1.0 ml) , 3N sodium hydroxide solution (0.036 ml) was added and stirred for 30 min. The réaction mixture was concentrated under reduced pressure. To the residue 0.5 ml isopropanol was added, filtered and washed with water (1 ml), dried under v acuum to afford the title compound as a yellow solid (0.020 g, 37 %). M.P.: 222-224°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): 8.91 (dd, J - 4.2,1.6 Hz. 1H), 8.63 (d, J = 8.8 Hz, 1H), 8.44 (dd, J = 8.4,1.0 Hz, 1H), 8.22 (d, J = 8.2 Hz, 1H), 8.14 (d, J - 8.6 Hz, 1H),

8.12 (s, 1H), 8.03 (dd, J = 8.0,1.7 Hz. 1H). 7.82 (d. J - 11.4 Hz, 1H). 7.54 (dd. J = 8.4,4.3 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1 H),6.24 (s, 2H), 5.79 (s, 1H). 3.67 (t, J-4.1 Hz, 2H), 3.54 (m. 2H).

113

Example 7c

2-chloro-4-(3-((7-f1uoro-2-oxo-1,2-dihydroqulnolln-6-yl}methy1)-3H-[1,2,3]triazo!o[4,5b]pyridln-5-yi)-N-(2-hydroxyethoxy)benzamide

The title compound was prepared by following the procedure described for example 6 using intermediate 44 (0.100 g, 0.222 mmol), DMF (2.0 ml), N-ethyldiisopropylamine (0.028 g, 0.222 mmol), HATU (0.084 g, 0.222 mmol) and 2-hydroxyethylhydroxylamine (0.034 g, 0.444 mmol). Pale green solid (0.035 g, 20 %). M.P.: 211-214°C. ’H-NMR (δ ppm, DMSO-d₆, 400 MHz): 11.82 (s, 1H), 11.69 (s, 1H), 8.68 (d, J = 8.8 Hz, 1 H), 8.32 (d, J = 1.5 Hz, 1H), 8.25 (dd, J 8.1,1.7 Hz, 1H), 8.22 (d, J = 8.8 Hz, 1H), 7.94 (m, 2H), 7.64 (d, J - 8.0 Hz, IH), 7.08 (d, J -

11.1 Hz, 1H), 6.46 (d. J =9.5 Hz, 1H), 6.06 (s,2H), 4.73 {LJ~5.7 Hz. 1H). 3.95 (t, J-4.9 Hz, 2H), 3.67 (m, 2H).

Example 8

2.6- difluoro-N-(2-hyd roxyeth oxy)-4-(3-(quinol i n-6-ylmeth yl )-3 H -f! ,2,3] tri azolo[4,5-

b]pyridin-5-yf)benzamlde:

The title compound was prepared by following the procedure described for example 6 using intermediate 17 (0.150 g, 0.359 mmol), DMF (1.1 ml), N-ethyldiisopropylamine (0.046 g, 0.359 mmol), HATU (0.136 g, 0.359 mmol) and 2-hydroxyethylhydroxylamine (0.055 g, 0.718 mmol).Off-white solid (0.035 g, 20 %). M.P.: 187-190°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): 11.91 (s, 1H), 8.89 (dd. J = 4.2,1.7 Hz, 1H), 8.75 (d, J = 8.7 Hz, 1H), 8.37 (d, J ~ 7.6 Hz, 1H),

8.27 (d, J= 8.7 Hz, 1H), 8.12-7.99 (m, 4H). 7.83 (dd, J = 8.8,6.8 Hz, 1H). 7.54 (dd, J - 8.3,4.2 Hz, 1H), 6.24 (s,2H), 4.74 (t, J = 5.7 Hz, 1H), 3.95 (t, J= 4.9 Hz, 2H), 3.65 (m, 2H).

Example 8a

2.6- difluoro-N-(2-hydroxyethoxy)-4-(3-(quinolin-6-ylmethyl)-3H-[1_l2,3]triazolo[4_l5-

b]pyridin-5-yl)benzamide hydrochloride:

The title compound was prepared by following the procedure described for example 6a using example 8 (0.040 g, 0.083 mmol), THF (1.0 ml) and ether-HCI (0.2 ml). Pale yellow solid (0.040 g. 95 %). M.P.: 208-210°C. ’H-NMR (5 ppm. DMSO-d₆, 400 MHz): 11.95 (s. 1H), 9.05 (s,1H),

8.76 (d, J ~ 8.7 Hz, 1 H), 8.69 (br s, 1 H). 8.28 (d, J = 8.8 Hz, 1 H), 8.19-8.09 (m, 5H), 8.00 (d, J =

8.6 Hz, 1H), 7.76 (d, J = 3.2 Hz. 1H), 6.29 (s, 2H), 3.95 (t. J= 5.0 Hz, 2H), 3.68 (m, 2H).

Example 8b

114 sodium (2,6-difluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazo!o[4,5-b]pyr1din-5yl)benzoy1)(2-hydroxyethoxy)amide:

To example 8 (0.080 g, 0.167 mmol) in isopropanol (2.0 ml) , 3N sodium hydroxide solution (0.06 ml) was added and stirred for 30 min. The reaction mixture was concentrated under reduced pressure. To the residue 0.5 ml isopropanol was added, fïltered and washed with water (1 ml), dried under vacuum to afford the title compound as a off-white solid (0.060 g, 72 %). M.P.: 240-242°C. ’H-NMR (5 ppm, DMSO-d_e, 400 MHz): 8.88 (dd. J = 4.2,1.7 Hz. 1H), 8.66 (d. J = 8.7Hz. 1H), 8.37 (d, J= 8.3 Hz. 1H). 8.19(d, J= 8.8Hz. 1H). 8.05(d. J~ 1.2 Hz, 1H). 8.02 (d. J = 8.6 Hz. 1H), 7.83 (m. 3H). 7.53 (dd. J = 8.4,4.2 Hz, 1H). 6.22 (s, 2H). 5.49 (s, 1H). 3.64 (t. J = 4.1 Hz, 2H), 3.51 (m. 2H).

Example 9

2.6- difluoro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(2- hyd roxyeth oxy)benzam Ide:

The title compound was prepared by following the procedure described for example 6 using intermediate 18 (0.150 g, 0.344 mmol), DMF (1.1 ml), N-ethyldiisopropylamine (0.044 g, 0.344 mmol), HATU (0.131 g, 0.344 mmol) and 2-hydroxyethylhydroxylamine (0.053 g, 0.689 mmol).Off-white solid (0.050 g. 29 %). M.P.: 206-209°C. ’H-NMR (δ ppm, DMSO-d_e> 400 MHz): 11.92 (s, 1H), 8.92 (dd, J = 4.2,1.6 Hz, 1H), 8.75 (d, J = 8.7 Hz, 1H), 8.43 (d, J = 7.5 Hz, 1H),

8.27 (d, J - 8.8 Hz, 1 H), 8.23 (d. J = 8.3 Hz. 1 H), 8.07 (d, J = 8.9 Hz. 2H). 7.83 (d. J - 11.4 Hz, 1H). 7.55 (dd. J = 8.2.4.2 Hz, 1H), 6.27 (s,2H), 4.74 (t, J= 5.6 Hz, 1H), 3.95 (t, J= 5.0 Hz, 2H), 3.65 (m, 2H).

Example 9a

2.6- difIuoro-4-(3-((7*fluoroqulnolln-6-yl)methyl)-3H-[1,2,3]triazoIo[4,5-b]pyridin-5-yl)-N-(2- hydroxyethoxy)benzamlde hydrochloride:

The title compound was prepared by following the procedure described for example 6a using example 9 (0.030 g, 0.060 mmol), THF (1.0 ml) and ether-HCI (0.2 ml). Off-white solid (0.025 g, 78 %). M.P.: 193-195°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): 11.95 (s, 1H), 9.01 (dd, J = 4.4,1.4Hz, 1H), 8.77 (d, J = 8.7 Hz, 1H), 8.58(d, J = 7.8 Hz, 1H), 8.27(m, 2H), 8.07(d, J- 8.9 Hz, 2H), 7.90 (d, J = 11.2 Hz. 1H), 7.66 (dd, J = 8.4,4.5 Hz, 1H), 6.29 (s, 2H), 3.95 (t. J = 4.9 Hz, 2H), 3.64 (t, J = 5.1 Hz, 2H).

Example 9b sodium (2,6-difluoro-4-(3-{(7-fluoroquinolin-6-yl)methy1)-3H-[1,2,3]triazolo[4,5-b]pyrldin-5yl)benzoy1)(2-hydroxyethoxy)amide:

115

To example 9 (0.050 g, 0.182 mmol) in isopropanol (1 ml), 3N sodium hydroxide solution (0.06 ml) was added and stirred for 30 min. The reaction mixture was concentrated under reduced pressure. To the residue 0.5 ml isopropanol was added, fîltered, dried under vacuum to afford the title compound as a off-white solid (0.020 g, 21 %). M.P.: 238-240°C. ¹H-NMR (δ ppm, DMSO-d_e, 400 MHz): 8.91 (d, J = 2.9 Hz, 1H), 8.62 (d, J - 8.8 Hz, 1H), 8.42 (d, J ~ 8.0 Hz, 1H), 8.22 (d, J = 8.3 Hz, 1H), 8.18 (d, J - 8.8 Hz, 1H), 7.82 (m, 3H), 7.54 (dd, J = 8.4,4.2 Hz, 1H), 6.25 (s, 2H), 5.58 (s, 1H), 3.62 (t, J- 5.2 Hz, 2H), 3.50 (m. 2H).

Example 10

2-fluoro-N-(2-hydroxyethoxy)-4-(3-(quInolln-6-ylmethy1)-3H-[1,2,3]triazolo[4_l5-b]pyridln-5yl)benzamlde:

The title compound was prepared by following the procedure described for example 6 using intermediate 19 (0.200 g, 0.500 mmol), DMF (2.0 ml), N-ethyldiisopropylamine (0.064 g, 0.500 mmol), HATU (0.190 g, 0.500 mmol) and 2-hydroxyethylhydroxylamine (0.077 g, 1.00 mmol).Off-white solid (0.040 g, 17 %). M.P.: 200-203°C. MS (m/z): 459.0 (m*+1).

Example 11

2-(2-chloro-4-(3-(qulnolin-6-yimethyl)-3H-[1_>2,3]triazolo[4,5-b]pyridin-5yl)benzamldooxy)ethyl acetate:

The title compound was prepared by following the procedure described for example 6 using example 6 (0.100 g, 0.210 mmol), DMF (1.0 ml), triethylamine (0.063 g, 0.630 mmol), HOBT (0.034 g. 0.252 mmol), EDC-HCI (0.100 g, 0.525 mmol) and acetic add (0.012 g, 0.210 mmol).Off-white solid (0.030 g, 27 %). M.P.: 168-170°C MS (m/z): 517.2 (m*).

Example 12 (S)-2-(2-chloro4-(3-(qulnotin-6-y1methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5yl)benzamldooxy)ethy12-(tert-butoxycarbonylamlno)propanoate:

The title compound was prepared by following the procedure described for example 6 using example 6 (0.200 g, 0.421 mmol), DMF (2.0 ml), triethylamine (0.128 g, 1.26 mmol), HOBT (0.068 g, 0.505 mmol), EDC-HCI (0.201 g, 1.153 mmol) and N-Boc-L-alanine (0.079 g, 0.421 mmol).Yellow solid (0.100 g, 36 %) which is used as such in next step.

Example 13 (S)-2-(2-chloro-4-(3-(qulnolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-bJpyridin-5y1)benzamldooxy)ethy1 2-aminopropanoate:

116

To example 12 (0.100 g, 0.154 mmol) in dichloromethane (2 ml), trifluoroacetic add (1 ml) was added at o C and stirred at room température for 12h. The reaction mass was basified to pH 910 using sodium carbonate solution, extracted with dichlromethane, dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as a off-white solid (0.025 g, 9 %). M.P.: 175-177°C MS (m/z): 546.1 (m*).

Example 14

2-(2-chloro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5yl)benzamidooxy)ethyl pivalate:

The title compound was prepared by following the procedure described for example 6 using example 6 (0.100 g, 0.210 mmol), DMF (1.0 ml), triethylamine (0.063 g, 0.630 mmol), HOBT (0.034 g, 0.252 mmol), EDC-HCI (0.100 g, 0.525 mmol) and pivolicc acid (0.021 g, 0.210 mmol).Off-white solid (0.060 g, 51 %). M.P.: 130-133°C MS (m/z): 558.9 (m*).

Example 15

2-(2-chloro-4-(3-(quinolln-6-ylmethy1)-3H-[1,2_l3]triazolo[4,5-b]pyrldln-5yi)benzamldooxy)ethyl Isobutyrate:

The title compound was prepared by following tire procedure described for example 6 using example 6 (0.100 g, 0.210 mmol), DMF (1.0 ml), triethylamine (0.063 g, 0.630 mmol), HOBT (0.034 g, 0.252 mmol), EDC-HCI (0.100 g, 0.525 mmol) and isobutyric add (0.018 g, 0.210 mmol).Pale yellow solid (0.030 g, 26 %). M.P.: 115-118°C MS (m/z): 545.1 (m*).

Example 16

2-(2-chloro-4-{3-(quinoHn-6-y1methy1)-3H-[1,2,3]triazolo[4,5-b]pyridin-5yl)benzamidooxy)ethyi 2-benzamldoacetate:

The title compound was prepared by following the procedure described for example 6 using example 6 (0.100 g, 0.210 mmol), DMF (1.0 ml), triethylamine (0.063 g, 0.630 mmol), HOBT (0.034 g, 0.252 mmol), EDC-HCI (0.100 g, 0.525 mmol) and hippuric add (0.037 g, 0.210 mmol).Off-white solid (0.060 g, 44 %). M.P.: 110-112°C MS (m/z): 636.0 (m*).

Example 17

2-chloro-N-(2-hydroxyethoxy)-4-(3-((2-methylquinolln-6-yl)methyl)-3H-[1,2,3]triazolo[4,5b]pyridin-5-yl)benzamide:

The title compound was prepared by following the procedure described for example 7 using

Intermediate 20 (0.140 g, 0.326 mmol), DMF (2.0 ml), N-ethyldiisopropylamine (0.084 g, 0.652

117 mmol), HATU (0.123 g, 0.326 mmol) and 2-hydroxyethylhydroxylamine (0.050 g, 0.652 mmol). Off-white solid (0.045 g, 28 %). M.P.: 219-222°C. MS (m/z): 489.2 (m*).

Example 18

4-(3-{benzo[d]thlazol-6-ylmethy1)-3H-[1,2,3]triazolo[4,5-b]pyrîdin-5-yl)-2-chloro-N-(2hydroxyethoxy)benzamide:

The title compound was prepared by following the procedure described for example 6 using Intermediate 21 (0.150 g, 0.355 mmol), DMF (2.0 ml), N-ethyldiisopropylamine (0.092 g, 0.711 mmol), HATU (0.135 g, 0.355 mmol) and 2-hydroxyethy!hydroxylamine (0.054 g, 0.711 mmol).Brown solid (0.014 g, 8 %). M.P.: 194-196°C. MS (m/z): 481.1 (m*).

Example 19

4-{3-(benzo[d]thiazol-6-ylmethy1)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-y1)-2,6-dîfluoro-N-{2hydroxyethoxy)benzamlde:

The title compound was prepared by following the procedure described for example 6 using Intermediate 22 (0.150 g, 0.354 mmol), DMF (2.0 ml), N-ethyldiisopropylamine (0.092 g, 0.708 mmol), HATU (0.136 g, 0.354 mmol) and 2-hydroxyethylhydroxylaniine (0.054 g, 0.708 mmol).Off-white solid (0.026 g, 15 %). M.P.: 202-205°C. MS (m/z): 483.1 (m* + 1).

Example 19a sodium (4-(3-(benzo[d]thlazol-6-ylmethyl)-3H-[1,2_l3]triazolo[4,5-b]pyrldin-5-yl)-2,6difluorobenzoyl)(2-hydroxyethoxy)amide:

To example 19 (0.050 g, 0.124 mmol) in isopropanol (2 ml) , 3N sodium hydroxide solution (0.067 ml) was added and stirred for 30 min. The reaction mixture was concentrated under reduced pressure. To the residue 0.5 ml isopropanol was added, filtered, washed with isopropanol, diethyl ether and dried under vacuum to afford the title compound as a off-white solid (0.035 g, 67 %). M.P.: 242-244°C. ’H-NMR (δ ppm. DMSO-d_e, 400 MHz): 9.35 (s, 1H), 8.65 (d, J = 8.7 Hz, 1H), 8.29 (d, J = 0.9 Hz, 1H), 8.19 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.88 (d, J = 8.0 Hz, 2H). 7.65 (dd, J = 8.4,1.6 Hz, 1 H). 6.17 (s, 2H), 5.52 (s, 1H), 3.63 (t, J = 5.3 Hz, 2H). 3.52 (m, 2H).

Example 20

4-(3-(benzo[d]thlazol-6-ylmethyl)-3H-[1,2,3]triazolo[4_l5-b]pyridin-5-yl)-2-fluoro-N-{2hydroxyethoxy)benzamlde:

The title compound was prepared by following the procedure described for example 6 using

Intermediate 23 (0.200 g, 0.490 mmol), DMF (2.0 ml), N-ethyldiisopropylamine (0.063 g, 0.490

118 mmol), HATU (0.186 g, 0.490 mmol) and 2-hydroxyethylhydroxylamine (0.075 g, 0.980 mmol).Off-white solid (0.030 g, 13 %). M.P.: 164-166°C. MS (m/z): 465.1 (m* +1).

Example 21

2.6- difIuoro«N-(2-hydroxyethoxy)-4-(3-((2-methylquinolin-6-yl)methyl)-3H- [1,2,3]triazolo[4,5-b]pyrl d I n*5-yl)benzaml de:

The title compound was prepared by following the procedure described for example 6 using intermediate 24 (0.150 g, 0.346 mmol), DMF (1.5 ml), N-ethyldiisopropylamine (0.089 g, 0.693 mmol), HATU (0.131 g, 0.346 mmol) and 2-hydroxyethylhydroxy!amine (0.054 g, 0.693 mmol).Off-white solid (0.040 g, 23 %). M.P.: 208-210°C. MS (m/z): 491.0 (m* + 1).

Example 21a

2.6- dlfl uoro-N-(2-hydroxyethoxy)-4-{3-((2-methy!qul n ol I n-6-yl Jmethyl )-3H- [1,2,3]triazolo[4,5-b]pyridln-5-yl)benzamlde hydrochloride:

The title compound was prepared by following the procedure described for example 6a using example 21 (0.030 g, 0.061 mmol), THF (2.0 ml) and ether-HCI (0.3 ml). Pale green solid (0.022 g, 68 %). M.P.: 211-213°C. ’H-NMR (δ ppm. DMSO-d_e, 400 MHz): 11.95 (s, 1H). 8.76 (s,1H), 8.74 (d, J= 8.7 Hz. 1H), 8.28 (d. J= 8.8 Hz, 1H), 8.22 (s, 1H), 8.17 (d, J = 8.8 Hz, 1H).

8.12 (d, J= 8.9 Hz, 1H), 8.06 (d, J= 8.7 Hz, 1H). 7.79 (d, J~ 7.9 Hz, 1H), 6.30 (s, 2H), 3.95 (t, J =4.9 Hz, 2H), 3.64 (m, 2H), 2.83 (s, 3H).

Example 22 N-(2-hydroxyethoxy)-4-{3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5yl)benzamlde:

The title compound was prepared by following the procedure described for example 6 using intermediate 25 (0.150 g, 0.393 mmol), DMF (2.0 ml), N-ethyldiisopropylamine (0.050 g, 0.393 mmol), HATU (0.149 g, 0.393 mmol) and 2-hydroxyethylhydroxylamÎne (0.060 g, 0.786 mmol).Yellow solid (0.045 g, 26 %). M.P.: 210-212°C. Ή-NMR (δ ppm, DMSO-d_e, 400 MHz): 11.88(s, 1H), 8.88 (dd, J = 4.2,1.7 Hz, 1H), 8.70 (d, J= 8.7 Hz, 1H). 8.38 (m, 3H), 8.20 (d, J =

8.7 Hz, 1H), 8.03 (m. 2H), 7.93 (d, J = 8.4 Hz, 2H), 7.84 (dd, J = 8.7,2.0 Hz, 1H), 7.53 (dd, J =

8.4,4.2 Hz, 1H), 6.22 (s, 2H). 4.78 (t, J= 5.7 Hz, 1H), 3.96 (t, J- 4.8 Hz, 2H), 3.64 (m, 2H).

Example 23

N-(2-hydroxyethoxy)-4-(3-(qulnolin-6-yimethyl)-3H-[1,2,3]triazolo[4,5-b]pyrldin-5-yl)-2(trifluoromethyl)benzamide:

The title compound was prepared by following the procedure described for example 6 using intermediate 26 (0.150 g, 0.333 mmol), DMF (2.0 ml), N-ethyldiisopropylamîne (0.043 g, 0.393

119 mmol), HATU (0.126 g, 0.333 mmol) and 2-hydroxyethy!hydroxylamine (0.051 g, 0.667 mmol).Yellow solid (0.055 g, 32 %). M.P.: 24O-242°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz):

11.73 (s, 1H), 8.88 (dd, J = 4.1,1.7 Hz, 1H), 8.74 (d, J ~ 8.8 Hz, 1H), 8.58 (s, 1H), 8.56 (d, J =

6.2 Hz, 1H), 8.35 (dd, J - 8.4,1.0 Hz, 1H), 8.30 (d, J = 8..0 Hz, 1H), 8.05 (d, J = 1.5 Hz. 1H), 8.01 (d, J - 8..7 Hz. 1H), 7.84 (dd, J - 8.7,1.9 Hz, 1H), 7.75 (d, J = 8..4 Hz, 1H), 7.54 (dd, J =

8.3.4.2 Hz. 1H), 6.24 (s, 2H), 4.75 (t, J= 5.7 Hz, 1H). 3.95 (t, J~ 4.9 Hz, 2H), 3.65 (m, 2H).

Example 24

4-(3-({7-fluoroqulnolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,!>-b]pyridin-!>-yl)-N-(2hydroxyethoxy)-2-(trifluoromethyl)benzamide:

The title compound was prepared by following the procedure described for example 6 using Intermediate 27 (0.150 g, 0.320 mmol), DMF (2.0 ml), N-ethyldiisopropylamine (0.041 g, 0.320 mmol), HATU (0.121 g, 0.320 mmol) and 2-hydroxyethylhydroxy!amine (0.049 g, 0.640 mmol).Yellow solid (0.060 g, 35 %). M.P.: 227-229°C. ¹H-NMR (δ ppm, DMSO-d_e, 400 MHz):

11.72 (s. 1H), 8.91 (dd, J - 4.2,1.6 Hz, 1H), 8.74 (d, J = 8.7 Hz, 1H). 8.56 (m, 1H), 8.41 (dd, J = 8.4,1.0 Hz. 1H), 8.30 (d. J - 8.8 Hz. 1H), 8.23 (d, J= 8..2 Hz, 1H), 7.81 (d, J= 11.4 Hz, 1H), 7.74 (d, J = 8..7 Hz, 1H). 7.84 (dd, J - 8.7,1.9 Hz. 1H), 7.75 (d. J - 8..4 Hz. 1H), 7.54 (dd, J =

8.3,4.2 Hz, 1H), 6.24 (s, 2H), 4.75 (t, J~ 5.7 Hz, 1H), 3.95 (t, J= 4.9 Hz, 2H), 3.65 (m, 2H).

Example 24a

4-(3-((7-fluoroqulnolin-6-yl)methy1)-3H-[1_l2,3]triazolo[4_l5-bJpyrtdin-5-y1)-N-(2hydroxyethoxy)-2-(trifluoromethy1)benzamide hydrochloride:

The title compound was prepared by following the procedure described for example 6 using example 24 (0.033 g, 0.062 mmol), THF (1.0 ml) and ether-HCi (0.1 ml). Off-white solid (0.028 g, 80 %). M.P.: 166-170°C. ¹H-NMR (δ ppm, DMSO-d_e, 400 MHz): 11.72 (s, 1H). 8.96 (dd, J~

4.3,1.5 Hz, 1H), 8.74 (d, J = 8.7 Hz. 1H). 8.56 (s. 1H), 8.53 (d, J= 8.7 Hz, 1H), 8.49 (d, J = 8.3 Hz. 1H), 8.30 (d, J = 8..8 Hz. 1H), 8.26 (d, J = 8.2 Hz, 1H), 7.85 (d, J= 11.3 Hz, 1 H). 7.74 (d, J = 7.9 Hz, 1H), 7.60 (dd, J - 8.4,4.4 Hz, 1H), 6.28 (s, 2H). 3.95 (t, J - 4.9 Hz, 1H), 3.59 (m, 2H).

Example 25

N-(2-hydroxyethoxy)-2-methyl-4-(3-(qulnolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5yl)benzamlde:

The title compound was prepared by following the procedure described for example 6 using intermediate 28 (0.120 g, 0.303 mmol), DMF (1.5 ml), N-ethyldiisopropylamine (0.039 g, 0.303 mmol), HATU (0.115 g, 0.303 mmol) and 2-hydroxyethylhydroxyîamîne (0.046 g, 0.607 mmol).Yellow solid (0.025 g, 18 %). M.P.: 196-198°C. Ή-NMR (δ ppm. DMSO-d_e. 400 MHz):

11.50 (s, 1H), 8.88 (dd, J = 4.2,1.6 Hz, 1H), 8.67 (d, J = 8.7 Hz, 1H), 8.37 (d, J = 7.6 Hz, 1H),

120

8.15 (d, J= 8.8 Hz, 1H), 8.10 (s, 1H), 8.08 (d, J= 9..2 Hz, 1H), 8.04 (d, J= 1.5 Hz, 1H), 8.02 (d,

J = 8..8 Hz, 1H), 7.83 (dd, J = 8.7,2.0 Hz, 1H), 7.54 (dd, J = 8.3,4.2 Hz, 1 H), 7.48 (d, J = 7..8

Hz, 1H), 6.21 (s. 2H), 4.75 (t, J = 5.3 Hz, 1H), 3.95 (t, J = 4.8 Hz, 2H), 3.65 (m, 2H), 2.43 (s,

3H).

Example 25a

N-(2-hydroxyethoxy)-2-methyl-4-(3-(qulnolln-6-ylniethy1)-3H-[1,2,3]triazolo[4,5-b]pyridln-5yl)benzamlde hydrochloride:

The title compound was prepared by following the procedure described for example 6 using example 25 (0.080 g, 0.176 mmol), THF (2.0 ml) and ether-HCI (0.4 ml). Off-white solid (0.080 g, 93 %). M.P.: 220-222°C. ¹H-NMR (δ ppm, DMSO-d_e, 400 MHz): 11.51 (s, 1H), 8.99 (d, J =

3.1 Hz, 1H), 8.68 (d. J = 8.7 Hz, 1H). 8.59 (d, J = 7.6 Hz, 1H), 8.16-8.08 (m, 5H), 7.93 (d, J =

8.7 Hz, 1H), 7.68 (dd, J = 8.4,4.0 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 6.24 (s, 2H), 3.95 (t, J = 5.0 Hz, 2H),. 3.38 (t, J = 7.0 Hz, 2H), 2.43 (s, 3H).

Example 25b

N-(2-hydroxyethoxy)-2-methyl-4-{3-(^tl^u^^no^^ⁿ6·y^,methy^l·^3H·I‘^·²·³]^tria2O^^ot4ι5-b]pyridin-5yl)benzamlde hydrobromide:

The example 25 (0.070 g. 0.154 mmol) was dissolved in THF (2 ml), HBr in ether (1.5 ml) was added at 0°C and stirred for 30 min. The precipitate was filtered and washed with ether and dried under vacuum to afford the title compound as a off-white solid (0.049 g, 59%). M.P.: 173175°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): 11.51 (s, 1H), 8.99 (dd, J = 4.4,1.3 Hz, 1H), 8.68 (d, J = 8.7 Hz, 1H), 8.57 (d, J = 7.8 Hz, 1H), 8.16-8.06(m, 5H), 7.92 (dd. J = 8.7,1.9 Hz, 1H),

7.67 (dd, J = 8.3,4.4 Hz, 1H). 7.48 (d, J = 7..8 Hz, 1H), 6.24 (s, 2H), 3.95 (t, J = 4.8 Hz, 2H).

3.64 (t, J = 5.0 Hz, 2H), 2.43 (s, 3H).

Example 25c

N-(2-hydroxyethoxy)-2-methyl-4-(3-(quinolln-6-ylmethyl)-3H-[1,2,3]tiiazolo[4,5-b]pyridin-5yl)benzamlde 4-methylbenzenesulfonate:

The example 25 (0.070 g. 0.154 mmol) was dissolved in THF (2 ml), para-toluenesulphonîc add( 0.029 g, 0.154 mmol) was added at 0°C and stirred for 30 min. The solvent was concentrated and dried under vacuum to afford the title compound as a yellow solid (0.070 g, 70%). M.P.: 1246-126°C. ¹H-NMR (δ ppm, DMSO-d_e, 400 MHz): 11.51 (s. 1H), 9.09 (d, J =4.6 Hz, 1H), 8.77 (d, J = 8.4 Hz, 1H), 8.69 (d. J = 8.7 Hz, 1H), 8.20-8.08 (m, 5H), 8.02 (d, J = 8.8 Hz, 1H), 7.81 (dd. J = 8.1, 4.6 Hz, 1H), 7.48 (m, 3H), 7.10 (d, J = 7.9 Hz, 2H). 6.27 (s,2H), 3.95 (t, J= 4.7 Hz, 2H), 3.64 (t, J = 4.9 Hz, 2H). 2.43 (s, 3H), 2.27 (s, 3H).

Example 25d

121

N-(2-hydroxyethoxy)-2-methyl-4-(3-((2-oxo-1,2-<iihydroquinolin-6-yl)methyl)-3H[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described for example 6 using intermediate 45 (0.100 g, 0.242 mmol), DMF (2.0 ml), N-ethyldiisopropylamine (0.062 g, 0.484 mmol), HATU (0.092 g, 0.242 mmol) and 2-hydroxyethylhydroxylamine (0.037 g, 0.484 mmol). Brown solid (0.007 g, 6 %). M.P.: 207-209°C.¹H-NMR (δ ppm. DMSO-d_e, 400 MHz): 11.75 (s, 1H), 11.52 (s, 1H), 8.65 (d, J = 8.8 Hz, 1H), 8.14 (m, 3H), 7.90 (d, J = 9.6 Hz, 1H), 7.78 (s. 1H),

7.63 (dd, J = 8.5,1.9 Hz, 1H), 7.49 (d, J = 7.9 Hz, 1H). 7.28 (d, J = 8.5 Hz, 1H), 6.48 (dd, J =

9.6,1.9 Hz, 1H), 6.02 (s, 2H), 4.76 (t, J = 5.8 Hz, 1H), 3.96 (t, J = 4.9 Hz, 2H). 3.65 (m, 2H), 2.45 (s. 3H).

Example 25e

6-((5-{4-(2-hydroxyethoxycarbamoyl)-3-methylpheny1)-3H-[1,2,3]triazolo[4,5-b]pyridin-3yl)methyl)quinoline 1-oxide

The title compound was obtained as a pale green solid (0.020 g, 19%) by using a procedure that is similar to the one described for intermediate 31 from example 25 (0.100 g, 0.220 mmol),DMF (2.0 ml) and metachloroperbenzoic acid (0.189 g, 1.10 mmol). M.P.: 160-162°C. ’H-NMR (δ ppm, DMSO-d_ei 400 MHz): 11.52 (s, 1H), 8.68 (d, J = 8.8 Hz. 1H). 8.56 (d, J = 5.6 Hz, 1H), 8.52 (d, J = 9.0 Hz, 1H), 8.16 (m, 4H), 7.94 (d, J = 8.6 Hz, 1H), 7.86 (dd, J = 8.9,1.8 Hz, 1H), 7.47 (m, 2H), 6.23 (s, 2H), 4.76 (t, J = 5.7 Hz, 1H), 3.95 (t, J = 4.8 Hz, 2H), 3.65 (m, 2H), 2.43 (s, 3H).

Example 26

4-(3-((7-fluoroqulnolin-6-yi)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(2hydroxyethoxy)-2-methylbenzamide:

The title compound was prepared by following the procedure described for example 6 using intermediate 29 (0.120 g, 0.361 mmol), DMF (1.5 ml), N-ethyldiisopropylamine (0.046 g, 0.361 mmol), HATU (0.137 g, 0.361 mmol) and 2-hydroxyethylhydroxylamine (0.055 g, 0.723 mmol).Yelïow solid (0.060 g, 35 %). M.P.: 200-203°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): 11.51 (s, 1H), 8.92 (dd, J - 4.2,1.6 Hz. 1H), 8.67 (d, J = 8.8 Hz, 1H), 8.44 (dd, J = 8.4,1.0 Hz, 1H), 8.21 (d, J = 8.2 Hz, 1H), 8.15 (d, J = 8.7 Hz, 1H), 8.06 (s. 1H), 8.05 (d, J = 6.3 Hz, 1H). 7.83 (d, J = 11.4 Hz, 1H). 7.55 (dd, J = 8.3,4.2 Hz, 1 H), 7.46 (d, J = 8.4 Hz, 1H), 6.24 (s, 2H),

4.76 (t, J = 5.7 Hz, 1H), 3.95 (t, J = 4.9 Hz, 2H), 3.65 (m. 2H), 2.41 (s, 3H).

Example 26a

122

4-(3-((7-fIuoroquinolin-6-y1)methyl)-3H-[1_l2,3]triazolo[4,5-b]pyridin-5-yI)-N-(2hydroxyethoxy)-2-methylbenzamide hydrochloride:

The title compound was prepared by following the procedure described for example 6 using example 26 (0.040 g, 0.084 mmol), THF (1.0 ml) and ether-HCI (0.1 ml). Off-white solid (0.030 g, 70 %). M.P.: 146-149°C. ’H-NMR (δ ppm, DMSO-d_e. 400 MHz): 11.51 (s, 1H), 8.96 (dd, J =

4.4,1.6 Hz, 1H). 8.67 (d, J= 8.8 Hz, 1H). 8.52 (d, J = 8.3 Hz, 1H), 8.25 (d, J- 8.2 Hz, 1H), 8.16 (d, J = 8..7 Hz, 1 H). 8.07 (m, 2H), 7.86 (d, J = 11.3 Hz, 1 H). 7.60 (dd, J - 8.3,4.3 Hz, 1 H), 7.47 (d, J= 8.5 Hz, 1H), 6.25 (s, 2H). 3.95 (t, J = 4.9 Hz, 2H), 3.64 (t, J - 5.1 Hz, 2H),2.41 (s, 3H).

Example 27 2-fluoro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyrldin-5-y1)-N-(2hydroxyethoxy)benzamlde:

The title compound was prepared by following the procedure described for example 6 using intermediate 30 (0.150 g, 0.359 mmol), DMF (1.5 ml), N-ethyldiisopropylamine (0.046 g, 0.359 mmol), HATU (0.136 g, 0.359 mmol) and 2-hydroxyethylhydroxylamine (0.055 g, 0.718 mmol).Off-white solid (0.100 g, 58 %). M.P.: 208-211°C. ¹H-NMR (δ ppm, DMSO-d_e, 400 MHz): 11.65 (s, 1H), 8.92 (dd, J = 4.3,1.6 Hz, 1H), 8.72 (d, J= 8.7 Hz, 1H), 8.43 (dd, J = 8.5,1.0 Hz, 1H), 8.23-8.11 (m. 4H), 7.83 (d, J= 11.5 Hz, 1H), 7.76 (t, J =7.7 Hz, 1H). 7.54 (dd, J = 8.4,4.3 Hz, 1H), 6.26 (s, 2H), 4.75 (t, J= 5.6 Hz, 1H), 3.95 (t. J~ 4.8 Hz, 2H), 3.65 (m, 2H).

Example 27a 2-fluoro-4-(3-((7-fluoroqulnolin-6-yl)methy1)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-y1)-N-(2hydroxyethoxy)benzamlde hydrochloride:

The title compound was prepared by following the procedure described for example 6 using example 27 (0.050 g, 0.120 mmol), THF (1.0 ml) and ether-HCI (0.3 ml). Off-white solid (0.045 g. 83 %). M.P.: 175-178°C. ¹H-NMR (δ ppm, DMSO-d_fl, 400 MHz): 11.65 (s, IH), 8.97 (dd, J =

4.4,1.4 Hz, 1H), 8.72 (d, J = 8.7 Hz, 1H), 8.52 (d, J = 7.9 Hz. 1 H). 8.25 (m, 2H), 8.16 (m, 2H), 7.87 (d, J = 11.3 Hz. 1H), 7.76 (t, J = 7.5 Hz, 1H). 7.61 (dd, J = 8.3,4.3 Hz, 1H), 6.27 (s, 2H),

3.94 (t, J = 4.8 Hz, 2H), 3.65 (m, 2H).

Example 28

2-chloro-N-(2-hydroxypropoxy)-4-(3-(quinolin-6-y!methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-

5-yi)benzamlde:

The title compound was prepared by following the procedure described for example 6 using intermediate 12 (0.165 g, 0.399 mmol), DMF (1.5 ml), N-ethyldiisopropylamine (0.154 g, 1.190

123 mmol), HATU (0.151 g, 0.399 mmol) and 1-(aminooxy)propan-2-ol hydrochloride (0.100 g, 0.786 mmol). Pale yellow solid (0.040 g, 20 %). M.P.: 150-152°C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 11.71 (s, 1H), 8.88 (dd, J ~ 4.1,1.6 Hz, 1H), 8.71 (d, J= 8.7 Hz, 1H), 8.37 (d, J= 8.4 Hz, 1H), 8.35 (s, 1H), 8.27 (dd, J = 8.0,1.4 Hz, 1H), 8.23 (d, J - 8.8 Hz, 1H). 8.04 (d, J - 1.2 Hz, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.83 (dd, J = 8.7,1.9 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.54 (dd. J ~ 8.4,4.2 Hz, 1H), 6.23 (s, 2H), 4.81 (s, 1H), 3.94 (q, J= 6.0 Hz, 1H). 3.76 (d, J = 5.5 Hz, 2H), 1.10 (d, J = 6.3 Hz, 3H).

Example 29 ethyl 2-(2-chloro-4-(3-(qulnolln-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5yl)benzamldooxy)acetate:

The title compound was prepared by following the procedure described for example 6 using intermediate 12 (0.300 g, 0.722 mmol), DMF (2.2 ml), N-ethy!diisopropy!amine (0.094 g. 0.722 mmol), HATU (0.274 g, 0.722 mmol) and ethyl 2-(aminooxy)acetate (0.173 g, 1.445 mmol). Offwhite solid (0.090 g, 24 %). M.P.: 140-142°C. Ή-NMR (δ ppm, DMSO-d_e, 400 MHz): 11.98 (s, 1H), 8.88 (d, J - 2.8 Hz, 1H), 8.71 (d, J = 8.7 Hz, 1H), 8.37 (d, J = 7.9 Hz, 1H), 8.33 (s, 1H),

8.26 (m, 2H), 8.05(s. 1H). 8.02 (d, J= 8.6 Hz, 1H), 7.83 (d, J- 8.6 Hz, 1H), 7.61 (d, J= 7.9 Hz, 1H). 7.54 (dd, J = 8.2,4.1 Hz, 1H), 6.23 (s, 2H), 4.60 (s, 2H), 4.20 (q. J= 6.9 Hz, 2H). 1.24 (t, J = 7.1 Hz, 3H).

Example 30

2-chloro-N-{2-hydroxy-2-methylpropoxy)-4-(3-(qulnolin-6-ylmethyl)-3H-[1,2_f3]triazolo[4,5b]pyrldin-5-yi)benzamide:

The title compound was prepared by following the procedure described for example 6 using Intermediate 12 (0.152 g, 0.366 mmol), DMF (1.0 ml), N-ethyidiisopropylamine (0.047 g, 0.366 mmol), HATU (0.139 g, 0.366 mmol) and 1-(aminooxy)-2-methylpropan-2-ol (0.050 g, 0.549 mmol).Pale green solid (0.040 g, 22 %). M.P.: 104-107°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): 11.70 (s, 1H), 8.88 (dd, J - 4.3,1.6 Hz, 1H), 8.71 (d, J = 8.8 Hz, 1H). 8.37 (m, 2H), 8.27(dd, J = 8.0,1.5 Hz, 1H). 8.23 (d, J~ 8.7 Hz, 1H), 8.07 (d, J= 8.7 Hz, 1H), 8.05 (d, J= 1.4 Hz, 1H), 7.83 (dd, J = 8.7,1.5 Hz, 1H), 7.63 (d, J - 8.0 Hz, 1H), 7.53 (dd, J - 8.3,4.2 Hz, 1H),

6.23 (s, 2H), 4.61 (s, 1H), 3.75(s, 2H), 1.17 (s, 6H).

Example 31 (S)-2-chloro-N-(2-hydroxypropoxy}-4-(3-(q^ui^noliⁿ‘S'yl^rnethy1)^_3H-[1,2_l3]triazolo[4,5· b]pyridin-5-yl)benzamide:

124 mmol), HATU (0.151 g, 0.399 mmol) and (S)-1-(aminooxy)propan-2-ol hydrochloride (0.100 g,

0.786 mmol). Pale green solid (0.040 g, 21 %). M.P.: 138-140°C. Ή-NMR (δ ppm, DMSO-d_e,

400 MHz): 11.70 (s, 1H), 8.88 (dd, J = 4.1,1.6 Hz, 1H), 8.71 (d, 8.8 Hz. 1H), 8.37 (d, J= 8.0

Hz, 1H), 8.35 (s, 1 H). 8.27 (dd, J - 8.1,1.6 Hz, 1H), 8.23 (d, J = 8.7 Hz, 1H), 8.04 (d, J = 1.5 Hz. 1H), 8.02 (d, J - 8.7 Hz. 1H), 7.83 (dd, J = 8.7,2.0 Hz, 1H), 7.64 (d, J - 8.0 Hz, 1H), 7.54 (dd, J = 8.3,4.2 Hz, 1H), 6.23 (s. 2H), 4.80 (m, 1H),), 3.93 (q, J - 5.9 Hz. 1H), 3.77 (d, J = 4.8 Hz, 2H), 1.11 (d, J = 6.3 Hz. 3H).

Example 32 (R)-2-chloro-N-(2-hydroxypropoxy)-4-(3-(quinonn-6-ylmethyl)-3H-[1_l2,3]triazolo[4,5b]pyridin-5-y1)benzamIde:

The title compound was prepared by following the procedure described for example 6 using intermediate 12 (0.1645 g, 0.393 mmol), DMF (1.5 ml), N-ethyldiisopropylamine (0.154 g, 1.190 mmol), HATU (0.151 g, 0.399 mmol) and (R)-1-(aminooxy)propan-2-ol hydrochloride (0.100 g, 0.786 mmol). Pale green solid (0.050 g, 26 %). M.P.: 158-160°C. ¹H-NMR (5 ppm, DMSO-d_e, 400 MHz): 11.72 (s, 1H), 8.88 (dd, J = 4.2,1.7 Hz, 1H), 8.71 (d, J~ 8.7 Hz, 1H), 8.37 (d, J= 7.6 Hz, 1H). 8.35 (s, 1H), 8.27 (dd, J = 8.0,1.6 Hz, 1H), 8.23 (d, J - 8.8 Hz, 1H), 8.04 (d, J = 1.5 Hz, 1 H). 8.02 (d, J = 8.7 Hz, 1H), 7.83 (dd, J ~ 8.7,2.0 Hz, 1H). 7.64 (d, J = 8.0 Hz, 1H), 7.54 (dd, J = 8.3,4.2 Hz, 1H), 6.23 (s, 2H), 4.80 (m, 1 H).). 3.92 (q, J = 4.3 Hz. 1H), 3.76 (d, J - 4.8 Hz. 2H). 1.11 (d, J = 6.2 Hz. 3H).

Example 33

N-(2-hydroxy-2-methylpropoxy)-2-methyl-4-(3-(qulnolin-6-y1methy1)-3H-[1,2,3]triazolo[4,5b]pyridin-5-yi)benzamide:

The title compound was prepared by following the procedure described for example 6 using Intermediate 28 (0.144 g, 0.366 mmol), DMF (1.0 ml), N-ethyldiisopropylamine (0.047 g, 0.366 mmol), HATU (0.139 g, 0.366 mmol) and 1-(aminooxy)-2-methylpropan-2-ol (0.050 g, 0.549 mmol).Off-white solid (0.088 g, 50 %). M.P.: 145-148°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): 11.54 (s, 1H), 8.88 (dd, J - 4.2,1.7 Hz, 1H), 8.67 (d, J = 8.7 Hz, 1H), 8.38(d, J = 7.5 Hz, 1H), 8.15(d, J = 8.8 Hz. 1H). 8.13-8.00(m. 4H). 7.83 (dd, J - 8.7,2.0 Hz. 1H), 7.54 (dd, J = 8.4,4.2 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H). 6.21 (s, 2H), 4.64 (s, 1H), 3.74 (s. 2H), 2.43 (s, 3H), 1.17 (s, 6H). .

Example 34

2,6-difluoro-N-(2-hydroxy-2-methylpropoxy)-4-(3-(quinolin-6-y1methyl)-3H- [1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide:

125

The title compound was prepared by following the procedure described for example 6 using intermediate 17 (0.159 g, 0.366 mmol), DMF (1.0 ml), N-ethyldiisopropylamine (0.047 g, 0.366 mmol), HATU (0.139 g, 0.366 mmol) and 1-(aminooxy)-2-methylpropan-2-ol (0.040 g, 0.549 mmol).Off-white solid (0.040 g, 21 %). M.P.: 171-174°C. Ή-NMR (δ ppm, DMSO-d_e, 400 MHz):

11.94 (s, 1H), 8.89 (dd, J - 4.2,1.7 Hz, 1H), 8.74 (d, J = 8.7 Hz, 1H), 8.37(d, J = 8.5 Hz, 1H). 8.26(d, J - 8.8 Hz, 1H), 8.10 (m, 3H), 8.01 (d, J ~ 8.7 Hz. 1H), 7.84 (dd, J = 8.2,2.0 Hz, 1H), 7.54 (dd, J - 8.3,4.2 Hz, 1H), 6.24 (s. 2H). 4.63 (s. 1H), 3.72 (s, 2H). 1.17 (s, 6H).

Example 35

2-fluoro-N-(2-hydroxy-2-methylpropoxy)-4-(3-(qulnolin-6-y1methyl)-3H-[1,2,3]triazolo[4,5b]pyridin-5-yl)benzamide:

The title compound was prepared by following the procedure described for example 6 using intermediate 19 (0.152 g, 0.366 mmol), DMF (1.0 ml), N-ethyldiisopropylamine (0.047 g, 0.366 mmol), HATU (0.139 g, 0.366 mmol) and 1-(aminooxy)-2-methylpropan-2-ol (0.040 g, 0.549 mmol).Off-white solid (0.080 g, 44 %). M.P.: 148-151°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz):

11.67 (s, 1H), 8.88 (dd, J = 4.2,1.7 Hz, 1H), 8.72 (d, J - 8.7 Hz, 1H), 8.37(d, J = 7.5 Hz, 1H), 8.21(d, J = 7.9 Hz, 1H), 8.18 (m, 2H), 8.05 (d, J = 1.6 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.84 (dd. J = 8.8,2.0 Hz, 1H). 7.77 (t, J = 8.0 Hz, 1H), 7.53 (dd, J - 8.3,4.2 Hz, 1H), 6.23 (s, 2H),

4.65 (s, 1H), 3.73 (s, 2H), 1.17 (s, 6H).

Example 36 (S)-N-(2-hydroxypropoxy)-2-methy1-4-(3-(quïnolin-6-ylmethyl}-3H-[1,2,3]trlazolo[4,5b]pyrldin-5-yl)benzamlde

The title compound was prepared by following the procedure described for example 6 using intermediate 28 (0.200 g, 0.506 mmol), DMF (1.5 ml), N-ethyldiisopropylamine (0.196 g, 1.51 mmol), HATU (0.192 g, 0.506 mmol) and (S)-1-(aminooxy)propan-2-ol hydrochloride (0.128 g, 1.01 mmol). Off-white solid (0.100 g, 42 %). M.P.: 230-232°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): 11.53 (s, 1H), 8.88 (dd, J= 4.0,1.3 Hz, 1H), 8.67 (d, J = 8.7 Hz, 1H), 8.38(d, J = 8.1 Hz, 1H), 8.15(d, J=8.7 Hz, 1H), 8.10 (m, 4H), 7.83 (dd, J = 8.7,1.5 Hz. 1 H), 7.53 (dd. J = 8.3,4.1 Hz, 1H), 7.48 (d, J - 7.8 Hz, 1H), 6.21 (s, 2H). 4.85 (s, 1H), 3.92 (m, 1H), 3.75 (m, 2H), 2.43 (s, 3H), 1.10 (d, J= 6.2 Hz, 3H).

Example 37

N-(2-hydroxy-2-methylpropoxy)-2-methyl-4-(3-((2-oxo-1,2-dihydroqulnolin-6-yl)methy1)3H-[1,2,3]triazolo[4,5-b]pyridin-5-y1)benzamIde

The title compound was prepared by following the procedure described for example 6 using intermediate 45 (0.150 g, 0.363 mmol), DMF (1.5 ml), N-ethyldiisopropylamine (0.094 g, 0.727

126 mmol), HATU (0.138 g, 0.363 mmol) and 1-{aminooxy)-2-methylpropan-2-ol (0.076 g, 0.727 mmol).Off-whîte solid (0.035 g, 19 %). M.P.: 209-212°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): 11.74 (s, 1H), 11.55{s, 1H), 8.65 (d, J= 8.7 Hz, 1H), 8.14 (m, 3H), 7.89 (d. J~ 9.6 Hz, 1H), 7.78 (d, J- 1.7 Hz, 1H), 7.63 (dd, J = 8.5,1.9 Hz, 1H), 7.48 (d, J= 7.8 Hz, 1H), 7.28 (d, J= 8.5 Hz, 1H), 6.48 (dd, J = 9.5,1.6 Hz, 1H), 6.02 (s, 2H). 4.65 (s. 1H), 3.74 (s, 2H), 2.45 (s, 3H), 1.18 (s, 6H).

Example 38 (R)-N-(2-hydroxypropoxy)-2-niethyl-4-(3-{qulnolin-6-ylmethyt)-3H-[1,2,3]triazolo[4,5b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described for example 6 using intermediate 28 (0.200 g, 0.506 mmol), DMF (1.5 ml), N-ethyldiisopropylamine (0.196 g, 1.51 mmol), HATU (0.192 g, 0.506 mmol) and (R)-1-(aminooxy)propan-2-ol hydrochloride (0.128 g,

I. 01 mmol). Off-white solid (0.034 g, 14 %). M.P.: 200-202°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): 8.88 (dd, J = 4.1,1.5 Hz, 1H), 8.62 (d, J= 8.8 Hz, 1H), 8.37(d, J- 7.8 Hz, 1H), 8.10 (d, J = 8.7 Hz, 1H), 8.04 (m, 4H), 7.83 (dd, J - 8.7,1.9 Hz, 1H), 7.53 (dd, J = 8.3,4.2 Hz, 1H). 7.46 (d, J = 7.8 Hz, 1H), 6.20 (s, 2H), 3.89 (m. 1H), 3.69 (dd, J = 10.6,3.7 Hz, 1H), 3.57 (dd, J =

II. 5,7.8 Hz, 1H), 2.44 (s, 3H), 1.03 (d, J- 6.4 Hz, 3H).

Example 39

N-(1-hydroxy-2-methy1propan-2-yloxy)-2-methyl-4-(3-(qulnolin-6-ylmethyl)-3H- [1.2.3] triazo1o[4,5-b]pyridin-5-y!)benzamlde

The title compound was prepared by following the procedure described for example 6 using intermediate 28 (0.200 g, 0.506 mmol), DMF (1.5 ml), N-ethyldiisopropylamine (0.196 g, 1.51 mmol), HATU (0.192 g, 0.506 mmol) and 2-(aminooxy)-2-methylpropan-1-ol hydrochloride (0.142 g, 1.01 mmol). Pale yellow solid (0.034 g, 13 %). M.P.: 193-195°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz):11.12 (s, 1H), 8.88 (dd, J = 4.2,1.7 Hz. 1H), 8.62 (d. J = 8.8 Hz, 1H), 8.38 (dd, J ~ 8.4,1.9 Hz, 1H), 8.16 (m, 3H), 8.05 (d, J - 1.7 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.83 (dd, J - 8.7,4.7 Hz, 1H), 7.54 (m, 2H), 6.21 (s, 2H), 4.83 (t, J = 6.8 Hz, 1H), 3.38 (m, 2H), 2.44 (s, 3H), 1.19 (s. 6H).

Example 40

2-chloro-N-(1-hydroxy-2-methylpropan-2-y1oxy)-4-(3-(qulnolln-6-ylmethyl)-3H- [1.2.3] triazolo[4,5-b]pyrldin-5-yl)benzamlde

The title compound was prepared by following the procedure described for example 6 using intermediate 12 (0.200 g, 0.480 mmol), DMF (1.5 ml), N-ethyldiisopropylamine (0.186 g, 1.44

127 mmol), HATU (0.182 g, 0.480 mmol) and 2-(aminooxy)-2-methylpropan-1-ol hydrochloride (0.135 g, 0.961 mmol). Pale green solid (0.040 g, 17 %). M.P.: 148-150°C. Mass : 502.8(M⁺).

Example 41

N-(2-Hydroxy-2-methyl-propoxy)-2-methyl-4-[3-(1-oxy-qulnolîn-6-ylmethyl)-3H- [1,2,3]trlazo!o[4,5-b] pyrldi n-5-yl]-benzaml de

The title compound was obtained as a off-white solid (0.040 g, 38%) by using a procedure that is similar to the one described for intermediate 31 from example 33 (0.100 g, 0.213 mmol), DMF (2.0 ml) and metachloroperbenzoic acid (0.184 g, 1.06 mmol). M.P.: 160-162°C. Mass : 498.9(M*).

Example 42

N-Hydroxy-2-methyl-4-{3-qulnoHn-6-ylmethyl-3H-[1_l2,3]trlazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described for example 6 using intermediate 28 (0.200 g, 0.505 mmol), DMF (2.5 ml), triethyfamine (0.352 ml, 2.52 mmol), HBTU (0.287 g, 0.758 mmol) and hydroxylamine hydrochloride (0.069 g, 1.01 mmol). Brown solid (0.005 g, 3 %). M.P.: 200-203°C. ’H-NMR (δ ppm. DMSO-d_e, 400 MHz):9.16 s, 1H). 9.07 (s, 1H), 8.88 (dd, J = 4.2,1.7 Hz, 1H), 8.58 (d. J = 8.8 Hz, 1H). 8.38 (dd, J = 8.5,1.0 Hz, 1H),

8.15 (s, 1H), 8.08 (m, 4H), 7.95 (d, J = 8.3 Hz, 1H), 7.83 (dd, J = 8.8,2.0 Hz, 1H), 7.53 (dd, J =

8.3,4.2 Hz, 1H), 6.18 (s, 2H), 2.31 (s, 3H).

Example 43

2-{2-methyl-4-(3-(qu!nolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5y!)benzamïdooxy)ethyl acetate \The title compound was prepared by following the procedure described for example 6 using example 25 (0.200 g, 0.440 mmol), DMF (2.0 ml), triethyîamine (0.184 ml, 1.32 mmol), EDCHCI (0.210 g, 1.10 mmol), HOBt (0.071 g, 0.528 mmol) and acetic acid (0.030g, 0.440 mmol). Off-white solid (0.065 g. 29 %). M.P.: 145-147°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): 11.56 (s, 1H), 8.88 (dd, J = 4.2,1.7 Hz, 1H), 8.67 (d, J = 8.7 Hz. 1H), 8.38 (dd, J = 8.3,0.9 Hz, 1H),

8.15 (d, J= 8.7 Hz, 1H), 8.10(m, 2H), 8.04 (m, 2H), 7.83 (dd, J = 8.7,2.0 Hz, 1H), 7.54 (dd, J =

8.3,4.2 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 6.21 (s, 2H), 4.26 (t, J = 4.7 Hz. 2H), 4.13 (t, J = 4.6 Hz, 2H), 2.43 (s, 3H), 2.04 (s, 3H).

Example 44

2-(2-methyi-4-(3-(quInolln-6-ylmethyl)-3H-[1,2,3]trlazolo[4,5-b]pyridin-5yl)benzamldooxy)ethyl isobutyrate

128

The title compound was prepared by following the procedure described for example 6 using example 25 (0.200 g, 0.440 mmol), DMF (2.0 ml), triethylamine (0.184 ml, 1.32 mmol), EDO HCl (0.210 g. 1.10 mmol), HOBt (0.071 g, 0.528 mmol) and isobutyric add (0.038g, 0.440 mmol). Off-white solid (0.080 g, 34 %). M.P.: 157-159°C. ’H-NMR (δ ppm, DMSO-d₆,400 MHz):

11.42 (s, 1H), 8.88 (dd, J = 4.2,1.6 Hz. 1H). 8.64 (d, J = 8.8 Hz, 1H), 8.37 (d, J= 7.9 Hz, 1H),

8.12 (d, J = 8.8 Hz, 1H), 8.04 (m, 4H), 7.83 (dd, J - 8.7,1.8 Hz, 1H), 7.53 (dd, J - 8.3,4.2 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H). 6.20 (s, 2H), 4.26 (t, J - 4.3 Hz, 2H), 4.02 (t, J - 4.2 Hz, 2H), 2.53 (m, 1H), 2.42 (s, 3H), 1.10 (d, J = 7.0Hz, 6H).

Example 45

2-(2-methyl-4-(3-(quino!ln-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5yl)benzamldooxy)ethy1 plvalate

The title compound was prepared by following the procedure described for example 6 using example 25 (0.200 g, 0.440 mmol), DMF (2.0 ml), triethylamine (0.184 ml, 1.32 mmol), EDCHCI (0.210 g, 1.10 mmol), HOBt (0.071 g, 0.528 mmol) and pivalic add (0.044 g, 0.440 mmol). Off-white solid (0.070 g, 29 %). M.P.: 128-130°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): 11.57 (s, 1H), 8.91 (dd, J = 4.0,1.4 Hz, 1H), 8.68 (d. J ~ 8.8 Hz, 1H), 8.43 (d, J = 7.9 Hz, 1H), 8.16 (d, J= 8.8 Hz, 1H), 8.11 (m, 4H), 7.85 (d, J= 8.8 Hz, 1H), 7.57 (dd, J= 8.3,4.2 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 6.22 (s, 2H), 4.26 (t, J = 4.5 Hz, 2H), 4.11 (t, J~ 4.5 Hz, 2H), 2.43 (s, 3H), 1.16 (s, 9H),

Example 46

2-(2-methy1-4-(3-(qulnolin-6-y1methyl)-3H-[1,2_l3]triazolo[4,5-b]pyrldln-5yl)benzamldooxy)ethyl benzoate

The title compound was prepared by following the procedure described for example 6 using example 25 (0.200 g, 0.440 mmol), DMF (2.0 ml), triethylamine (0.184 ml, 1.32 mmol), EDCHCI (0.210 g, 1.10 mmol), HOBt (0.071 g, 0.528 mmol) and benzoic add (0.053 g, 0.440 mmol). Off-white solid (0.020 g. 9 %). M.P.: 128-130°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): 11.62 (s, 1H), 8.88 (d, J- 2.8 Hz, 1H), 8.66 (d, J= 8.6 Hz. 1H), 8.37 (d. J ~ 8.4 Hz, 1H), 8.14-8.00 (m, 7H), 7.83 (d, J= 8.0 Hz, 1H), 7.65 (t, J = 7.0 Hz, 1H), 7.53 (m, 4H), 6.21 (s, 2H), 4.53 (t, J = 4.5 Hz, 2H), 4.26 (t, J = 4.5 Hz, 2H), 2.43 (s, 3H).

Example 47

242-methy!-4-(3-(quinolln-6-ylnriethyl)-3H-[1,2,3]trIazolo[4,5-b]pyiidin-5yi)benzamldooxy)ethy1 furan-2-carboxylate

The title compound was prepared by following the procedure described for example 6 using example 25 (0.200 g, 0.440 mmol), DMF (2.0 ml), triethylamine (0.184 ml, 1.32 mmol), EDC129

HCl (0.210 g, 1.10 mmol), HOBt (0.071 g, 0.528 mmol) and 2-furoîc add (0.049 g, 0,440 mmol). Off-white solid (0.070g, 29 %). M.P.: 146-148°C. Ή-NMR (δ ppm, DMSO-d_e, 400 MHz): 11.61 (s, 1H), 8.88 (dd, J = 4.2,1.7 Hz, 1H), 8.67 (d, J= 8.8 Hz, 1H), 8.38 (d, J~ 8.4 Hz, 1H), 8.15-

7.98 (m, 6H), 7.83 (dd, J - 8.8.2.0 Hz, 1H), 7.54 (dd, J = 8.3,4.2 Hz, 1H), 7.49 (d, J - 8.0 Hz. 1H), 7.33 (d, J= 3.3 Hz, 1H), 6.70 (d, J= 1.8 Hz, 1H), 6.21 (s, 2H), 4.50 (t, J = 4.8 Hz, 2H),

4.23 (t, J = 4.8 Hz, 2H), 2.43 (s, 3H).

Example 48 1-(3-((7-fluoroqulnolin-6-yÎ)methyl)-3H-[1,2,3]triazolo[4,5-b]pyrïdin-5-yl)ethanone:

The title compound was prepared by following the procedure described for Intermediate 41 using intermediate 8 (2.0 g, 6.33 mmol), 1-ethoxyvinyf tri(n-butyl)stannane (2.12 g, 6.70 mmol), DMF (20ml ml) and [1,r-bis(diphenylphosphino)ferroceneldichloro palladium(ll).CH₂CI₂(0.417 g, 0.511 mmol) in a microwave oven (microwave power = 100W, température = 100 °C) for 45 min and followed by add hydrolysis .Yellow solid (1.00 g, 39%). ’H-NMR (δ ppm, CDCh, 400 MHz ): δ 8.92 (dd, J = 4.2,1.6 Hz, 1H), 8.50 (d, J= 8.6 Hz, 1H), 8.16 (d, J= 8.6 Hz, 1H), 8.09 (dd, J = 8.4,0.9 Hz, 1H), 7.83 (d, J = 3.3 Hz, 1 H), 7.81 (d, J= 5.5 Hz, 1H), 7.39 (dd, J = 8.4,4.3 Hz, 1H), 6.21 (s, 2H), 2.78 (s, 3H).

Example 49

2-(1-(3-(quinolin-6-ylmethyl)-3H-[1_l2,3]triazolo[4,5-b]pyTidin-5-yl)ethy1idene) hydrazlnecarboxamide hydrochloride:

Steo-1:2-(1-{3-(ouinolin-6-vlmethvl)-3H-T1,2,3ltriazolor4.5-b|pvridin-5-vDethylidene) hvdrazinecarboxamide: to a solution of intermediate 41 (0.070 g, 0.230 mmol) In ethnol (2 ml), sodium acetate (0.018 g, 0.230 mmol) and semicarbazide hydrochloride (0.026 g, 0.230 mmol) were added and stirred at RT for 12h. The reaction mixture was concentrated and the residue was washed with bicarbonate solution, dichlorométhane and dried under vacuum.

Step-2:2-(1-f3-fquinolin-6-vlmethvl)-3H-ri.2,3'|triazolor4.5-b1pvridin-5-vltethviidene) hvdrazinecarboxamide hydrochloride: the product of step-1 (0.050g, 0.138 mmol) was dissolved in THF (1 ml), eather saturated with HCl (0.15ml) was added at 0°C and stirred for 15 min. The precipitate formed was washed with eather and dried under vacuum to afford the title compound as an off-white solid (0.045 g, 82%).

M.P.: 241-243°C. Ή-NMR (δ ppm, DMSO-d_e, 400 MHz): δ 9.70 ($□□□□□□□□□□□ (dd, J =

4.7,1.2 Hz, 1H), 8.85 (d. J ~ 8.3 Hz, 1H), 8.53 (d, J ~ 8.9 Hz, 1H), 8.46 (d, J - 8.9 Hz, 1H). 8.23 (d, J = 9.0 Hz, 1H), 8.20 ( s,1H), 8.05 (dd, J = 8.8,1.7 Hz, 1H), 7.86 (dd, J = 8.4,4.9 Hz, 1H),

6.73 (br s, 2H), 6.20 (s, 2H), 2.34 (s, 3H).

130

Example 50

2-(1-(3-(qulnolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridÎn-5-yl)ethylldene) hydrazinecarbothioamlde:

The title compound was prepared by following the procedure described for step-1 of Example 49using Intermediate 41 (0.100 g, 0.329 mmol), éthanol (1.5 ml) and thiosemicarbazide (0.030 g, 0.329 mmol). Yellow solid (0.050 g, 40 %). M.P.: 233-235°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): □ δ 10.43 (s,1H), 8.88 (dd, J - 4.1,1.5 Hz, 1H), 8.65 (d, J - 8.9 Hz, 2H), 8.51 (s, 1H), 8.48 (d, J- 8.9 Hz, 1H), 8.36 (d, J - 7.8 Hz, 1H), 8.30 (s,1H), 8.01 (s,1H), 7.99 (d, J = 8.9 Hz, 1H), 7.82 (dd, J= 8.7,1.9 Hz, 1H), 7.53 (dd, J = 8.3,4.2 Hz, 1H), 6.15 (s, 2H), 2.48 (s,3H).

Example 51

6-((5-(1-(2-(pyridln-2-yl)hydrazono)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyrldin-3-yl)methy1) qulnoline:

The title compound was prepared by following the procedure described for step-1 of Example 49 using Intermediate 41 (0.100 g, 0.329 mmol), éthanol (2 ml) and 2-hydrazinopyridine (0.036 g. 0.329 mmol), heating at 80°C for 12h. Yellow solid (0.050 g, 39 %). M.P.: 221-223°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): δ 10.23 (s,1H), 8.89 (dd, J = 4.2,1.7 Hz, 1H), 8.48 (d, J ~ 8.9 Hz, 1H), 8.37 (dd, J = 8.3,1.3 Hz, 1H), 8.33 (d, J = 8.9 Hz, 1H), 8.20 (dd, J = 4.8,1.0 Hz, 1H). 8.02 (s,1H), 8.00 (d, J= 9.0 Hz, 1H), 7.83 (dd, J= 8.6,2.0 Hz, 1H), 7.74 (dt, J = 8.6,1.8 Hz, 1H), 7.53 (dd, J = 8.3,4.2 Hz, 1H), 7.45 (d, J - 8.4 Hz, 1H), 6.90 (dt, J - 6.5,1.5 Hz, 1H), 6.10 (s, 2H). 2.48 (s,3H).

Example 52

2-{amino(3-(qulnolin-6-ylmethy1)-3H-[1,2,3]triazolo[4,5-b]pyridln-5-yl)methylene) hyd razl n ecarboxamide:

The title compound was prepared by following the procedure described for step-1 of Example 49 using intermediate 10 (0.100 g, 0.348 mmol), éthanol (3 ml), semicarbazide hydrochloride (0.050 g, 0.452 mmol), sodium acetate (0.028 mg, 0.348 mmol) and sodium bicarbonate (0.029 mg. 0.348 mmol) heating at 80°C for 12h. Yellow solid (0.050 g, 20 %). M.P.: 194-196°C. ’HNMR (δ ppm, DMSO-d_e, 400 MHz): 0Π8.91 (dd, J = 4.2,1.6 Hz, 1H), 8.73 (d, J~ 8.6 Hz, 1H), 8.46(s,1H), 8.35 (d, J = 7.9 Hz. 1H), 8.15 (d, J ~ 8.4 Hz, 1H), 8.06 (s,1H), 8.01 (d, J - 8.7 Hz, 1H), 7.89 (s, 1H), 7.86 (dd, J = 8.8,2.0 Hz, 1H), 7.53 (dd, J= 8.3,4.2 Hz, 1H), 6.23 (s, 2H).

Example 53 tert-butyl 2-(1-(3-(qulnolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,&-b]pyr1din-5-y1)ethylldene) hyd razl n e carboxylate :

131

The title compound was prepared by following the procedure described for step-1 of Example 49 using Intermedlate 41 (0.200 g, 0.659 mmol), éthanol (5 ml) and tert-butyi carbazate (0.131 g, 0.989 mmol), heating at 60°C for 12h. Off-white solid (0.150g, 55 %). M.P.: 193196°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): δ 10.22 (s, 1H). 8.88 (dd, J = 4.1,1.5 Hz, 1H),

8.52 (d, J = 8.9 Hz, 1H), 8.36 (d, J = 7.2 Hz, 1H), 8.16 (d, J - 8.9 Hz. 1H), 8.01 (m,2H), 7.81 (dd, J = 8.8,1.8 Hz, 1H), 7.53 (dd, J= 8.4,4.2 Hz, 1H), 6.14 (s, 2H), 2.36 (s, 3H), 1.49 (s, 9H).

Example 54 (E/Z)-1-(1-(3-(quinolln-6-ylmethy1)-3H-[1,2,3]triazolo[4,5-b]pyridin-5yi)ethyiideneamino)imidazolldine-2,4-dione:

The title compound was prepared by following the procedure described for step-1 of Example 49 using Intermediate 41 (0.100 g, 0.659 mmol), éthanol (2.2 ml), triethylamine (0.1 ml) and 1-aminohytantoin hydrochloride (0.074 g, 0.494 mmol), heating at 60°C for 12h. Off-white solid (0.090 g, 68 %). M.P.: 260-264°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): δ 11.36 (s,1H), 8.89 (dd, J = 4.1,1.6 Hz, 1H), 8.61 (d, J = 8.8 Hz, 1H). 8.37 (d, J = 7.4 Hz, 1H), 8.18 (d, J - 8.8 Hz, 1H), 8.03 (d, J= 1.5 Hz, 1H), 8.02 (d, J= 8.8 Hz, 1H), 7.82 (dd, J = 8.7,1.9 Hz, 1H), 7.53 (dd. J = 8.3,4.1 Hz, 1H), 6.19 (s,2H), 4.49(s,2H), 2.51 (s,3H).

Example 55

N-ethyl-2-(1-(3-(qulnolin-6-y1methy1)-3H-[1,2,3]trlazolo[4,5-b]pyridin-5-yl)ethy1idene) hydrazinecarbothioamide:

The title compound was prepared by following the procedure described for step-1 of Example 49 using intermedlate 41 (0.100 g, 0.329 mmol), éthanol (2 ml), Nethylhydrazinecarbothîoamide (0.078 g, 0.659 mmol) heating at 60°C for 12h. Yellow solid (0.050 g, 20 %). M.P.: 194-196°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): δ 10.39 (s, 1H), 8.89 (dd, J = 4.2,1.7 Hz, 1H). 8.85 (t, J - 5.6 Hz, 1H), 8.62 (d, J = 8.9 Hz, 1H), 8.54 (d, J = 8.9 Hz.

1H), 8.36 (d, J - 7.4 Hz, 1 H). 8.02 (t, J - 1.7 Hz, 1H), 7.99 (d. J = 9.0 Hz, 1H), 7.82 (dd, J = 8.7,2.0 Hz, 1H), 7.53 (dd, J = 8.3,4.1 Hz, 1H), 6.16 (s, 2H), 3.67 (m, 2H), 2.47 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H).

Example 56

2-(1-(3-(qulnolin-6-ylmethyl)-3H-[1_I2,3]triazolo[4,5-b]pyrldIn-5-yl)ethylidene) hydrazinecarbothioamide hydrochloride:

The title compound was prepared by following the procedure described for example 49 using example 50 (0.030 g, 0.119 mmol), THF (1.0 ml) and ether-HCI (0.5 ml). Pale yellow solid (0.030 g, 91 %). M.P.: 201-2036°C. Ή-NMR (δ ppm. DMSO-d_e. 400 MHz): δΠ 10.44 (s, 1H).

132

9.05 (s,1 H), 8.70 (s,1H), 8.66 (d, J = 8.9 Hz, 1H), 8.51 (s, 1 H), 8.50 (d. J = 8.9 Hz, 1H), 8.31 (s,1 H), 8.15 (m, 2H), 7.98 (m,1H), 7.76 (m,1H), 6.20 (s, 2H), 2.46 (s,3H).

Example 57 2-(1-(3-((7-fIuoroquinolln-6-yl)methy1)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)ethylidene) hydrazlnecarbothloamide:

The title compound was prepared by following the procedure described for step-1 of Example 49 using example 48 (0.100 g, 0.311 mmol), éthanol (2 ml) and thiosemicarbazide (0.079 g, 0.623 mmol), heating at 60°C for 48h. Pale yellow solid (0.090 g, 73 %). M.P.: 249-253°C. ’HNMR (δ ppm, DMSO-de, 400 MHz): δα10.42 (s,1H), 8.92 (dd, J - 4.2,1.6 Hz, 1H), 8.65 (d, J~

8.9 Hz, 1H), 8.51 (s,1H), 8.48 (d, J= 8.9 Hz, 1H), 8.42 (dd, J = 8.3,1.1 Hz, 1H), 8.30 (s,1H),

8.16 (d, J - 8.2 Hz, 1H). 7.82 (d, J- 11.4 Hz, 1H), 7.53 (dd, J - 8.3,4.3 Hz, 1H), 6.18 (s,2H),

2.42 (s,3H).

Example 58

Methyl 2-(1-(3^9^uï^noliⁿ*6’y’^meffⁱyl)-3H-[1,2_t3]triazolo[4,5-b]pyridin-5-yl)ethy!ldene) hydrazlnecarboxylate:

The title compound was prepared by following the procedure described for step-1 of Example 49 using Intermediate 41 (0.100 g, 0.329 mmol), methanol (2 ml) and methyl hydrazinecarboxylate(0.059 g, 0.65930 mmol), heating at 80°C for 48h. Off-white solid (0.080 g, 65 %). M.P.: 206-208°C. ’H-NMR (δ ppm, DMSO-d₆, 400 MHz): 6010.55 (s, 1H), 8.88 (dd. J = 4.0,1.4 Hz, 1H), 8.53 (d, J = 8.9 Hz, 1H), 8.36 (d, J= 7.5 Hz, 1H), 8.16 (d, J= 8.8 Hz, 1H), 8.01 (m, 2H), 7.81 (dd, J = 8.8,1.8 Hz, 1H), 7.53 (dd, J = 8.3,4.2 Hz, 1H), 6.15 (s, 2H), 3.75 (s,3H), 2.38 (s,3H).

Example 59 1-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b)pyridin-5-yl)ethanone oxime:

To a solution of example 48 (0.100 g, 0.311 mmol) in éthanol (2.1 ml), sodium acetate (0.025 g, 0.315 mmol) and hydroxylamine hydrochloride (0.021 g, 0.315 mmol) were added and stined at 60°C for 12h. The reaction mixture was concentrated and the residue was washed with water, dichloromethane, ethyl acetate and dried under vacuum to afford the title compound as an off-white solid as a mixture of two diastereomers (approx. 9:1) (0.070 g, 67%). M.P.: 244247°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz ): δ 11.92 (s, 0.9H), 11.27 (s,0.1H), 8.92 (dd, J =

4.2,1.6 Hz, 1H), 8.75 (d, J = 8.6 Hz, 0.1 H), 8.60 (d, J - 8.7 Hz, 0.1 H), 8.52 (d, J = 8.8 Hz, 0.9H), 8.41 (d, J~ 7.3 Hz, 0.9H), 8.16 (d, J- 8.3 Hz, 1H), 8.02 (d. J= 8.6 Hz, 1H), 7.82 (d, J = 11.5 Hz, 1H), 7.53 (dd, J = 8.3,4.2 Hz, 1H), 6.27( s, 0.2H), 6.18 (s, 1.8H), 2.25( s, 2.7H), 2.19 (s, 0.3H).

133

Example 60

1-(3-((7-fluoroquinolin-6-yi)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)ethanone Omethyl oxime:

To a solution of example 48 (0.100 g, 0.311 mmol) in éthanol (2.1 ml), sodium acetate (0.025 g, 0.315 mmol) and methoxylamine hydrochloride (0.026 g, 0.315 mmol) were added and stirred at 60°C for 12h. The reaction mixture was concentrated and the residue was washed with water, dichloromethane, ethyl acetate and dried under vacuum to afford the title compound as an off-white solid as a mixture of two diastereomers (approx. 9:1) (0.050 g, 45%). M.P.: 169172°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz ): δ 8.90 (dd, J - 4.2,1,6 Hz, 1H), 8.38 (d, J = 8.8 Hz. 0.1 H), 8.31 (d, J = 8.8 Hz, 0.9H), 8.12 (d. J = 8.8 Hz. 1H), 8.06 (dd, J - 8.4,1.0 Hz, 1H), 7.80 (d, J = 11.1 Hz, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.37 (dd, J- 8.3,4.3 Hz, 1H), 6.15 (s, 2H),

2.36 (s, 2.7H), 2.33 (s, 0.3H).

Example 61 1-(3-((7-f1uoroqulnolIn-6-yl)methyl)-3H-[1,2_t3]triazolo[4,5-b]pyridin-5-yl)ethanone O-2hydroxyethyi oxime:

The title compound was prepared by following the procedure described for step-1 of Example using example 48 (0.100 g, 0.311 mmol), éthanol (2 ml) and 2-hydroxyethylhydroxylamine (0.047 g, 0.623 mmol) heating at 60°C for 12h. Pale green solid (0.055 g, 46 %). M.P.: 142145°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): δΠ8.92 (dd, J= 4.2,1.7 Hz, 1H), 8.54 (d, J = 8.8 Hz, 1H), 8.42 (dd, J= 8.4,1.0 Hz, 1H), 8.16 (d, J= 8.3 Hz, 1H), 8.02 (d, J- 8.8 Hz, 1H), 7.82 (d, J - 11.4 Hz, 1 H), 7.53 (dd, J = 8.3,4.2 Hz, 1H). 6.19 (s, 2H), 4.74 (t, J ~ 5.6 Hz, 1 H), 4.25 (t, J = 5.0 Hz, 2H), 3.69 (t, J ~ 5.0 Hz, 2H), 2.29 (s,3H).

Example 62

1- ^quinolin-e-yimethylJ-SH-ll^.SJtriazolo^S-bjpyridln-S-ynethanone O-2-hydroxyethyl oxime:

2- Hydroxyethylhydroxy!amine was prepared according to Shiow-Jyi et al. J. Med. Chem. 2007, (25), 6367-6382. The title compound was prepared by following the procedure described for step-1 of Example 49 using Intermediate 41 (0.196 g, 0.646 mmol), éthanol (5 m!) and 2hydroxyethylhydroxylamine (0.100 g, 1.29 mmol) heating at 60°C for 12h. Pale green solid (0.090 g, 38 %). M.P.: 165-168°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): δ 8.88 (dd, J =

4.1.1.9 Hz, 1H), 8.55 (d, J = 8.8 Hz, 1H), 8.36 (d, J= 7.4 Hz, 1H), 8.02 (m,3H), 7.81 (dd, J~

8.7.1.9 Hz, 1H), 7.53 (dd, J = 8.3,4.2 Hz, 1H), 6.16 (s,2H), 4.75 (t, J = 5.6 Hz, 1H), 4.26 (t, J -

5.3 Hz, 2H), 3.71 (m, 2H). 2.35 (s, 3H).

Example 63

134

1-{3’(^tî^ul^no'lⁿ*6’yl^meffⁱyi)'3FI’[1>2,3]triazolo[4_l5-b]pyridln-5-yl)ethanone O-2-aminoethyl oxl me:

To example 62 (0.300 g, 0.827 mmol) in dichloromethane (3 ml), triethylamine (0.251g, 2.41 mmol) was added and cooled to 0°C. Methenesulphonyl chloride (0.189 g, 1.65 mmol) was added and stirred at RT for 2h. The reaction mixture was basified with sodium bicarbonate solution, extracted with dichloromethane, dried and concentrated to afford brown coloured mesylate (0.350 g). The mesylate was dissolved In DMF (1.7 ml) and sodium azide (0.103 g, 1.584 mmol) was added and heated at 80°C for 12h. The reaction mixture was quenched with water, extracted with ethyl acetate, dried with sodium sulphate and concentrated to afford brown coloured azide (0.260 g). To the azide dissolved in THF (4.7 ml), triphenylphosphine (0.108 g, 0.413 mmol) and aqueous ammonia solution (0.23 ml) were added and refluxed for 3h. .The reaction mixture was quenched with water, extracted with ethyl acetate, dried with sodium sulphate and concentrated. The crude product was column chromatographed with methanol: dichloromethane to afford the title compound as a pale green solid (0.110 g, 37%). M.P.: 122-125°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): δΠ8.88 (dd, J = 4.2,1.7 Hz, 1H). 8.54 (d, J = 8.8 Hz, 1H), 8.36 (dd, J = 7.9,1.3 Hz, 1H), 8.02 (m, 3H), 7.81 (dd, J = 8.8,2.0 Hz, 1H),

7.53 (dd, J = 8.3,4.2 Hz, 1H), 6.16 (s, 2H), 4.20 (t, J ~ 5.8 Hz, 2H). 2.86 (t, J = 5.9 Hz, 2H), 2.31 (s, 3H), 1.58 (s, 2H).

Example 64

1-(2-(1-(3-(qulnolin-6-y!methyt)-3H-[1,2,3]triazolo[4,5-b)pyridln-5-yl) ethy1ideneamlnooxy)ethy!)urea:

To example 63 (0.050 g, 0.137 mmol) in dichloromethane (17 ml), trimethylsilylisocyanate (0.064 g, 0.556 mmol) was added and stirred at RT for 12h. The reaction mixture was concentrated completely under vacuum, the residue was washed with water, filtered and dried under vacuum to afford the title compound as an off-white solid (0.030 g, 54%). M.P.: 207210°C. ’H-NMR (δ ppm, DMSO-d₆,400 MHz): δΠ8.89 (dd, J = 4.2.1.7 Hz, 1H), 8.55 (d. J= 8.8 Hz, 1H), 8.36 (d, J = 8.3 Hz, 1H), 8.04 (m,3H), 7.81 (dd, J = 8.8,1.8 Hz, 1H), 7.53 (dd, J =

8.3,4.2 Hz, 1H), 6.16 (s,2H), 6.04 (t, J =5.6 Hz, 1H), 5.47 (s, 2H), 4.22 (t, J= 5.6 Hz, 2H), 3.34 (m, 2H), 2.35 (s, 3H).

Example 65

1-(3-((7-fluoroqulnolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridIn-5-yl)ethanone Om ethyl oxlme hydrochloride:

The title compound was prepared by following the procedure described for example 49 using example 60 (0.030 g, 0.085 mmol), THF (1.0 ml) and ether-HCI (0.2 ml). Off-white solid (0.030

135 g, 90 %). M.P.: 200-204°C. ¹ H-NMR (δ ppm, DMSO-d₆₁ 400 MHz): δΠ8.99 (d, J= 4.3 Hz, 1H),

8.55 (d, J = 8.8 Hz, 2H), 8.23 (d, J = 8.1 Hz, 1H). 8.01 (d, J =8.7 Hz. 1H), 7.88 (d, J= 11.2 Hz.

1H). 7.63 (dd, J= 8.3,4.4 Hz, 1H), 6.20 (s, 2H), 4.01 (s, 3H), 2.27 (s, 3H).

Example 66

1-(3-({7-fluoroquinolln-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyîidin-5-yl)ethanone oxime hydrochloride:

The title compound was prepared by following the procedure described for example 49 using example 59 (0.025 g, 0.074 mmol), THF (1.0 ml) and ether-HCI (0.3 ml). Off-white solid (0.025 g, 90 %). M.P.: 243-246°C. ¹H-NMR (δ ppm, DMSO-d_e, 400 MHz): δΟ11.93 (s,1H), 8.99 (dd. J = 4.3,1.4 Hz. 1H), 8.76 (d. J = 8.6 Hz, 0.1H), 8.61 (d, J = 8.3 Hz, 0.1H), 8.55 (d, J = 8.3 Hz. 0.9H), 8.52 (d, J = 8.8 Hz. 0.9H), 8.23 (d, J = 8.1 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1 H), 7.88 (d, J =

11.2 Hz, 1H), 7.63 (dd, J = 8.4,4.5 Hz, 1H), 6.28 (s. 0.2H), 6.20 (s, 2.7H), 2.25 (s, 2.7H), 2.21 (s, 0.3H).

Example 67 1-(3-((7-fluoroquinolin-6-yt)methyl)-3H-[1,2,3]triazolo(4,5-b]pyridin-5-yl)ethanone 0-2hydroxyethyl oxime hydrochloride:

The title compound was prepared by following the procedure described for example 49 using example 61 (0.020 g, 0.052 mmol), THF (0.5 ml) and ether-HCI (0.2 ml). Pale green solid (0.020 g, 91%). M.P.: 193-196°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): δαβ.97 (dd. J =

4.3,1.5 Hz. 1H). 8.55 (d, J = 8.8 Hz. 1H), 8.52 (d, J= 8.4 Hz, 1H), 8.21 (d. J= 8.1 Hz. 1H), 8.02 (d, J= 8.8 Hz, 1H), 7.86 (d, J= 11.3 Hz. 1H). 7.61 (dd, J = 8.3,4.4 Hz, 1H). 6.20 (s. 2H), 4.25 (t, J = 5.0 Hz, 2H), 3.69 (t, J= 5.2 Hz, 2H), 2.29 (s, 3H).

Example 68

N-(3-Dimethylamino-propyl)-4-(3-qulnolin-6-ylmethyl-3H-[1,2,3]trlazolo[4_l5-b]pyridin-5-yl)benzamide dlhdrochloride

The title compound was prepared by following the procedure described for example 49 using N-(2-(dimethylamino)ethyl)-4-(3-(quinolin-7-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5yl)benzamtdeyl)pheny!)methanone (0.100 g, 0.215 mmol), THF (2.0 ml) and ether-HCI (2 ml). Yellow solid (0.100 g, 92%). M.P.: 110-112°C. Ή-NMR (δ ppm, DMSO-d_e, 400 MHz): 10.06 (br s, 1H), 9.05 (brs, 1H), 8.81 (brs, 1H). 8.71 (d, J= 8.8 Hz. 2H), 8.34 (d, J= 8.4 Hz, 2H), 8.22 (m, 3H), 8.04 (m, 3H), 7.76 (br s, 1H), 6.27 (s. 2H), 3.39 (m, 2H), 3.12 (m, 2H), 2.75 (s, 3H), 2.74 (s,3H), 1.95 (m, 2H).

Example 101

136

2-chloro-N-(2-(dimethy1amino)ethyl)-4-(3-{quinolin-6-y1meth^)-3H-lmidazo[4,5-b]pyridÎn5-yl)benzamlde:

To a solution of example 1012 ( (0.100 g, 0.250 mmol) in DMF (0.7 ml) Nethyldiisopropylamine (0.032g, 0.250 mmol) and HATU (0.095 g, 0.250 mmol) were added and stirred for 5 min. (2-dimethylaminoethylamine (0.033 g, 0.375 mmo was added at RT and the reaction mixture was stirred for 12h. To the reaction mixture water was added and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as a Grey solid (0.023 g, 16 %). M.P.: 11O-112°O.1’H-NMR (δ ppm, DMSO-de, 400 MHz): δα 400 MHz):J = 4.1,1.6 Hz, 1H), 8.72 (s, 1H), 8.41 (s,1H), 8.34 (d, J =

8.2 Hz, 1H), 8.20(s,1H), 8.18 (d, J = 8.3 Hz, 1H), 8.14 (dd, J = 8.0,1.6 Hz, 1H), 8.01 (s,1H),

7.98 (d, J = 2.8 Hz, 1H), 7.96 (s,1H), 7.84 (dd, J = 8.7,1.9 Hz, 1H), 7.53 (m, 2H), 5.78 (s, 2H),

3.36 (m, 2H), 2.52 (m, 2H), 2.27 (s. 6H).

Example 102 2-chloro-N-(3-(di'nethy!amlno)propyl)-4-(3-(qulnolin-6*ylmethyt)-3H-lmidazo[4,5-b] pyridln-5-y!)benzamlde:

The title compound was prepared by following the procedure described for example 101 using example 1012 (0.100 g, 0.250 mmol), DMF (0.7 ml), N-ethyldiisopropylamine (0.032g, 0.250 mmol), HATU (0.095 g, 0.250 mmol) and 3-dimethyiaminopropylamine (0.038 g, 0.375 mmol). Grey solid (0.011 g, 9 %). M.P.: 80-84°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): δα8.87 (dd, J = 4.1,1.5 Hz, 1H), 8.72 (s, 1H), 8.45 (t, J = 5.6 Hz, 1H), 8.34 (d, J = 8.1 Hz, 1 H), 8.20(s,1H),

8.18 (d, J = 8.3 Hz, 1H), 8.14 (dd, J = 8.1,1.4 Hz, 1H), 8.01 (s,1H), 7.98 (d, J - 3.5 Hz, 1H). 7.95 (s,1H), 7.84 (dd, J = 8.7,1.8 Hz, 1H), 7.53 (m, 2H), 5.78 (s, 2H), 3.27 (m, 2H), 2.29 (t, J = 7.0 Hz, 2H), 2.13 (s, 6H), 1.65(m, 2H).

Example 103

2-chloro-N-methoxy-4-(3-(qulnolin-6-ylmethyl)-3H-lmidazo[4,5-b]pyridin-5-yl)benzamlde:

The title compound was prepared by following the procedure described for example 101 using example 1012 (0.100 g, 0.250 mmol), DMF (0.7 ml), N-ethyldiisopropylamine (0.097g, 0.750 mmol), HATU (0.095 g, 0.250 mmol) and methoxylamine hydrochloride (0.041 g, 0.500 mmol). Grey solid (0.025 g, 23 %). M.P.: 72-75°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): δ 11.63 (s, 1H),OOGDD (dd, J = 4.2,1.7 Hz, 1H), 8.73 (s,1H), 8.34 (d, J = 7.2 Hz, 1H), 8.24 (d, J= 1.5 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H), 8.19 (dd, J = 8.7.1.7 Hz, 1H), 8.01 (m,3H), 7.84 (dd, J = 8.7,1.9 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H). 7.53 (dd, J = 8.3,4.2 Hz, 1H), 5.78 (s, 2H), 3.73 (s,3H).

Example 104

137

N-(2-(dimethy1amlno)ethyl)-2,6-<!ifluoro-4-(3-(qulnolin-6-ylmethyl)-3H-imidazo[4,5b]pyridln-5-yl)benzamlde:

The title compound was prepared by following the procedure described for example 101 using example 1015 (0.100 g, 0.239 mmol), DMF (1 ml), N-ethyldiisopropylamine (0.062g, 0.478 mmol), HATU (0.090 g, 0.239 mmol) and 2-dimethylaminoethylamine (0.021 g, 0.239 mmol). Pale green solid (0.030 g, 26 %). M.P.: 145-147°0.ΓH-NMR (δ ppm, DMSO-d_e, 400 MHz): □ □ □ 400 MHz): J = 4.2,1.7 Hz, 1 H), 8.75 (s, 1 H), 8.74 (t, J = 5.6 Hz, 1 H), 8.33 (d, J = 7.4 Hz, 1 H),

8.22 (d, J = 8.4 Hz, 1H), 8.03 (m, 3H). 7.94 (d, J = 9.1 Hz, 2H). 7.83 (dd, J = 8.7,2.0 Hz, 1 H),

7.53 (dd, J = 8.3,4.2 Hz, 1H), 5.79 (s, 2H), 3.40 (m, 2H), 2.53 (m, 2H), 2.29 (s, 6H).

Example 105

2,6-difluoro-N-methoxy-4-(3-(qulnolin-6-ylmethyl)-3H-lmldazo[4,5-b]pyridln-5-y!) benzamide:

The title compound was prepared by following the procedure described for example 101 using example 1015 (0.100 g, 0.239 mmol), DMF (1 ml), N-ethyldiisopropylamine (0.092 g, 0.717 mmol), HATU (0.090 g. 0.239 mmol) and methoxylamine hydrochloride (0.039 g, 0.478 mmol). Pale green solid (0.040 g, 38 %). M.P.: 158-160°0.1’H-NMR (δ ppm, DMSO-d_e, 400 MHz): δΠ 400 MHz): □□□□□□□□□□□□□□J = 4.2,1.7 Hz, 1H), 8.76 (s, 1H), 8.33 (d, J = 8.4 Hz, 1H),

8.23 (d, J= 8.4 Hz, 1H), 8.05-7.96 (m, 5H), 7.83 (dd, J = 8.7,2.0 Hz, 1H), 7.53 (dd. J = 8.3,4.2 Hz, 1H), 5.79 (s, 2H), 3.73 (s, 3H).

Example 106 1-(3-(quinolin-6-ylmethyl)-3H-lmldazo[4,5-b]pyridin-5-yl)ethanone:

The title compound was prepared by following the procedure described for example 1008 using intermediate 34 (1.0 g, 3.39 mmol), 1-ethoxyvinyl tri(n-butyl)stannane (1.12 g, 3.56 mmol), DMF (10 ml) and [1,r-bis(diphenyfphosphino)ferrocene]dichloro palladium(ll).CH₂Cl2 (0.221 g, 0.271 mmol) in a microwave oven (microwave power = 100W, température = 100 °C) for 45 min. and followed by add hydrolysis .Off-white solid (0.500 g, 49%). Ή-NMR (δ ppm, CDCI₃, 400 MHz ): δ 8.94 (dd, J = 4.2,1.7 Hz, 1H), 8.27 (s, 1H). 8.19 (d, J= 8.4 Hz, 1H), 8.12 (m, 3H),

7.78 (d, J = 1.8 Hz, 1H). 7.73 (dd, J = 8.7,2.0 Hz, 1H), 7.45 (dd, J = 8.2,4.2 Hz, 1H), 5.72 (s, 2H), 2.79 (s, 3H).

Example 107 2-(1-(3-(quinolin-6-ylmethyl)-3H4mldazo[4,5-b]pyr1din-5-yl)ethytidene) hydrazlnecarboxamlde:

To a solution of example 106 (0.100 g, 0.330 mmol) in éthanol (2 ml), sodium acetate (0.027 g,

0.330 mmol) and semicarbazide hydrochloride (0.036 g, 0.330 mmol) were added and stirred at

138

RT for 12h. The reaction mixture was concentrated and the residue was washed with bicarbonate solution, dichloromethane and dried under vacuum to afford the title compound as an off white solid (0.060 g, 51 %). M.P.: 228-231°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): 6D9.40 (s, 1H), 8.88 (dd, J = 4.2,1.7 Hz, 1H), 8.66 (s,1H), 8.34 (d, J= 7.4 Hz, 1H), 8.26 (d, J-

8.6 Hz, 1H), 8.02 (d. J = 8.5 Hz, 1H), 7.98 (s, 2H), 7.84 (dd, J = 8.7,2.0 Hz, 1H), 7.53 (dd, J =

8.2,4.2 Hz, 1 H). 6.58 (s, 2H), 5.71 (s,2H), 2.32 (s,3H).

Example 108

2-(1-(3-{qulnolin-6-y!methyl)-3H-lmldazo[4,5-b]pyrldin-5-yl)ethy1ldene) hydrazlnecarbothloamlde:

The title compound was prepared by following the procedure described for example 107 using example 106 (0.100 g, 0.330 mmol), éthanol (2 m!) and thiosemicarbazide (0.042 g, 0.330 mmol), heating at 60°C for 12h. Off-white solid (0.075 g, 59 %). M.P.: 218-221° fo’H-NMR (δ ppm, DMSO-d_ei 400 MHz): δΠ 400 MHz): □□□□□□□□□□□□□J = 4.1,1.6 Hz, 1H), 8.69 (s, 1H), 8.40 (d, J = 8.5 Hz, 1H), 8.37 (s, 1H), 8.33 (d, J - 8.8 Hz, 1H), 8.10 (s,1H), 8.04-7.98 (m,3H), 7.83 (dd, J - 8.7,1.9 Hz, 1H), 7.52 (dd, J = 8.3,4.1 Hz, 1H), 5.72 (s, 2H), 2.45 (s,3H).

Example 109 (R) -2-fluoro-N-(2-hydroxypropy1)-4-(3-(quInolin-6-y!methyl)-3H-lmldazo[4,5-b]pyrldin-5yl)benzamlde

The titîe compound was prepared by following the procedure described for example 6 using intermediate 46 (0.200 g, 0.503 mmol), DMF (1.5 ml), N-ethyldiisopropy!amine (0.130 g, 1.00 mmol), HATU (0.191 g, 0.503 mmol) and (R)-1-aminopropan-2-ol (0.056 g, 0.755 mmol). Offwhite solid (0.080 g, 35 %). M.P.: 151-158°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): D8.87 (dd, J = 4.2,1.6 Hz, 1H), 8.73 (s, 1H), 8.34 (dd, J = 8.4,1.1 Hz, 1H), 8.21 (m, 2H), 8.07 (m. 5H),

7.84 (dd, J = 8.8,1.9 Hz, 1H), 7.76 (t, J = 7.9 Hz, 1H), 7.52 (dd, J = 8.3,4.2 Hz, 1H), 5.78 (s, 2H), 4.76 (d, J = 4.8 Hz, 1H). 3.79 (m, 1H), 3.23 (m, 2H). 1.09 (d, J = 6.2 Hz, 3H). Mass : 456.4 (M*+1).

Example 110 (S) -2-fluoro-N-(2-hydroxypropyi)-4-(3-(qulnolin-6-ylmethyl)-3H-lmldazo[4,5-b]pyridln-5· yl)benzamlde

The title compound was prepared by following the procedure described for example 6 using intermediate 46 (0.200 g, 0.503 mmol), DMF (1.5 ml), N-ethyldiisopropylamine (0.130 g, 1.00 mmol), HATU (0.191 g, 0.503 mmol) and (S)-1-aminopropan-2-ol (0.056 g, 0.755 mmol). Offwhite solid (0.050 g. 22 %). M.P.: 166-169°C. ’H-NMR (δ ppm, DMSO-d_fl, 400 MHz): D8.87 (dd, J = 4.2,1.7 Hz, 1H), 8.73 (s, 1H), 8.35 (dd, J= 8.4,1.3 Hz, 1H). 8.21 (m, 2H), 8.07 (m, 5H).

139

7.85 (dd, J - 8.8,1.9 Hz, 1H), 7.76 (t, J - 7.9 Hz, 1H), 7.52 (dd, J = 8.3,4.2 Hz, 1H), 5.74 (s,

2H), 4.49 (br s, 1H). 3.79 (m, 1 H). 3.23 (m, 2H), 1.09 (d, J =6.2 Hz, 3H). Mass : 456.4 (M*+1).

Example 111

N-(2-Hydroxy-ethoxy)-2-methyl-4-(3-qulnolln-6-ylmethyl-3H-imldazoI4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described for example 6 using intermediate 47 (0.200 g, 0.507 mmol), DMF (1.5 ml), N-ethyldiisopropylamine (0.131 g, 1.01 mmol), HATU (0.192 g, 0.507 mmol) and 2-hydroxyethylhydroxylamine (0.078 g, 1.01 mmol). Off-white solid (0.075 g, 32 %). M.P.: 223-225°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): 11.45 (s, 1H), 8.87 (dd, J = 4.2,1.7 Hz, 1H). 8.70 (s, 1H), 8.35 (d, J = 8.2 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.01 (m, 4H), 7.92 (d, J = 8.4 Hz, 1H), 7.84 (dd, J = 8.7,2.0 Hz, 1H), 7.53 (dd. J = 8.3,4.2 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 5.77 (s, 2H), 4.76 (t, J = 5.6 Hz, 1H), 3.98(t, J= 4.7 Hz, 2H),

3.64 (m, 2H), 2.41 (s, 3H).

Example 112

N-(2-Hydroxy-2-methyl-propoxy)-2-methyl-4-(3-qulnolin-6-ylmethyl-3H-lmidazo[4,5b]pyridin-5-y1)-benzamlde

The title compound was prepared by following the procedure described for example 6 using intermediate 47 (0.200 g, 0.507 mmol), DMF (1.5 ml), N-ethyldiisopropylamine (0.131 g, 1.01 mmol), HATU (0.192 g, 0.507 mmol) and 1-(aminooxy)-2-methylpropan-2-ol (0.106 g, 1.01 mmol). Off-white solid (0.053 g, 21 %). M.P.: 176-178°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): 11.48 (s, 1H), 8.87 (d, J = 2.7 Hz, 1H). 8.69 (s, 1H). 8.34 (d, J = 8.1 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.01 (m, 4H), 7.91 (d, J = 8.5 Hz, 1H), 7.84 (d, J= 8.5 Hz, 1H), 7.53 (dd, J = 8.2,4.3 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 5.77 (s. 2H), 4.64 (s, 1H), 3.73 (s,2H), 2.41 (s, 3H), 1.17 (s,6H).

Example 113 2-Chloro-N-(2-hydroxy-ethoxy)-4-(3-qulnolln-6-ylmethyl-3H-lmldazo[4,5-b]pyrldin-5-yi)benzamide

The title compound was prepared by following the procedure described for example 6 using intermediate 48 (0.150 g, 0.361 mmol), DMF (1.5 ml), N-ethyldiisopropylamine (0.093 g, 0.722 mmol), HATU (0.137 g, 0.361 mmol) and 2-hydroxyethylhydroxylamine (0.055 g, 0.722 mmol). Pale green solid (0.035 g, 20 %). M.P.: 198-200°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): 11.63 (s. 1H), 8.87 (dd, J = 4.2,1.7 Hz, 1H), 8.73 (s, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.23-8.14 (m. 3H), 8.00(m,3H), 7.84 (dd, J = 8.6,1.9 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H). 7.53 (dd, J = 8.3,4.2 Hz, 1H), 5.78 (s. 2H), 4.73 (d, J =5.7 Hz, 1H), 3.95 (t, J =5.0 Hz, 2H), 3.66 (m, 2H).

140

Example 114

2-Chloro-N-(2-hydroxy-2-methyl-propoxy)-4-(3-qulnolin-6-y1methyi-3H-lmldazo[4,5b]pyridln-5-yl)-benzamide

The title compound was prepared by following the procedure described for example 6 using intermediate 48 (0.150 g, 0.361 mmol), DMF (1.5 ml), N-ethyldiisopropylamine (0.093 g, 0.722 mmol), HATU (0.137 g, 0.361 mmol) and 1-(aminooxy)-2-methylpropan-2-ol (0.075 g, 0.722 mmol). Pale yellown solid (0.050 g, 27 %). M.P.: 146-148°C. ’H-NMR (5 ppm, DMSO-d_e, 400 MHz): 11.65 (s, 1H), 8.87 (dd, J = 4.1,1.6 Hz, 1H), 8.73 (s, 1H), 8.34 (d, J= 7.5 Hz, 1H), 8.23 (d, J ~ 1.4 Hz. 1H), 8.21 (d, J - 8.4 Hz, 1H), 8.16 (dd, J = 8.4,1.4 Hz, 1H), 8.01 (m, 3H), 7.84 (dd, J = 8.7,1.9 Hz, 1H), 7.56 (d. J = 8.1 Hz, 1H), 7.53 (dd, J - 8.4,4.2 Hz, 1H), 5.78 (s. 2H),

4.62 (s,1H), 3.74 (s, 2H), 1.17 (s, 6H).

Example 1001

6-((5-( 4-carbamoyl-3_l5-difluorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methy1) qulnollne 1-oxide

Step-1: Methyl 2,6-difluoro-4-(3-(qulnolln-6-yimethyt)-3H-[1_t2,3]triazolo[4,5-b]pyridin-5yl)benzoate: To a solution of Intermediate 7 (1.15 g, 3.91 mmol) and and 3,5-difluoro-4methoxycarbonylphenyfboronic acid (1.10 g, 5.09 mmol) in dioxane (20 ml), potassium acetate (1.276 g, 13.03 mmol) was added and degassed for 30 min. To this tetrakis (triphenylphosphine)palladium(O) (0.361 g, 0.31346 mmol) was added under nitrogen at RT and the reaction mixture was refluxed for 12h. The solvent was evaporated completely and water was added to the residue and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as an brown solid (0.620 g, 37%). ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): δ 8.91 (d, J = 2.9 Hz, 1H), 8.49 (d, J = 8.6 Hz, 1H), 8.17 (d, J- 8.2 Hz, 1H), 8.10 (d, J= 8.7 Hz, 1H), 7.97(s,1 H), 7.86 (dd, J = 8.8,1.4 Hz, 1H).

7.81 (d, J = 8.6 Hz, 1H), 7,74 (d, J = 9.1 Hz, 2H), 7.43 (dd, J = 8.4,4.2 Hz, 1H), 6.15 (s, 2H),

3.99 (s, 3H).

Step-2: 2,6-Difluoro-4-(3-(qulnolin-6-ytmethyi)-3H-[1_>2,3]triazolo[4,5-b]pyridIn-5-y1)benzDlc acid: To a solution of step-1 of example 1001 (0.70 g, 1.62 mmol) in methanol (3.8 ml), lithium hydroxide (0.635 g, 15.13 mmol) in water (3.8 ml) and THF (14.3 ml) were added and stirred at RT. After 12h, pH was adjusted to ca. 7 using 0.5N HCl and the solid predpitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as pale brown solid (0.500 g, 74%). The add was used as such for further steps.

Step-3: 2,6-Difluoro-4-(3-(qulnolin-6-ylmethyl)-3K-(1,2_I3]triazolo[4,5-b]pyridin-5yl)benzamide:To step-2 of example 1001 (0.500 g, 1.19 mmol), thionyl chloride (10 m!) was

141 added and refluxed for 3h. The excess thionyl chloride was removed under reduced pressure and the residue was cooled to 0°C. Aqueous 25% ammonia (7 ml) was added and stirred for 15 min. The precipitate formed was washed with sodium bicarbonate solution and vacuum dried to afford title compound as an off-white solid (0.400 g, 81%). M.P.: 272-275°C. ¹H-NMR (δ ppm, DMSO-d_6t 400 MHz): □ δ 8.88 (dd. J = 3.9 Hz, 1H), 8.74 (d, J - 8.8 Hz, 1H), 8.37 (d. J = 7.8 Hz, 1H). 8.25 (d, J - 8.9 Hz, 1H), 8.20 (s,1H), 8.07 (m,3H), 8.01 (d, J - 8.5 Hz, 1H), 7.93 (s,1 H),7.83 (d, J- 6.8 Hz, 1H), 7.53 (dd. J= 8.6,4.4 Hz, 1H), 6.24 (s, 2H).

Step-4: 6-((5-(4-carbamoyl-3,5-difluoropheny!)-3H-[1,2,3]triazolo[4,5-b]pyrfdin-3-yl)methyl) quinoline 1-oxide:To step-3 of example 1001 (0.100 g, 0.240 mmol) in acetone (1.5 ml) and water (1.5 ml), oxone (1.47g, 2.40 mmol) was added and stirred at RT for 12h. To the reaction mixture sodium bicarbonate solution (5 ml) was added and extracted with dichloromethane, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as a pale-yellow solid (0.010 g, 10%). M.P.: 234-236°C. ¹H-NMR (δ ppm, DMSO-d_e>400 MHz): □ δ 8.74 (d, J = 8.8 Hz, 1H), 8.55 (d, J - 7.9 Hz, 1H), 8.52 (d, J - 9.0 Hz, 1H), 8.26 (d, J- 8.8 Hz, IH), 8.19 (s,1H), 8.14 (s,1H), 8.05 (d, J= 8.8 Hz, 2H). 7.92 (d, 8.2 Hz, 2H),

7.87 (dd, J ~ 9.0,1.6 Hz, 1H). 7.47 (dd, J = 8.5,4.1 Hz, 1H), 6.25(s, 2H).

Example 1002

6-((5-(4-carbamoyl-3-chlorophenyl)-3H-(1,2,3]triazolo[4,5-b]pyrldin-3-yl)methy1)-7fluoroqulnollne 1-oxide:

Step-1 : Methyl 2-chloro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5b]pyridln-5-yl)benzoate: The title compound was prepared by following the procedure described for step-1 of example 1001 using intermediate 8 (0.345 g, 1.091 mmol), 3-chloro-4methoxycarbonylphenyfboronic acid (0.295 g, 1.37 mmol), potassium acetate (0.359 g, 3.65 mmol), dioxane (8 ml) and tetrakis{triphenylphosphtne)palladium(0) (0.101 g, 0.087 mmol). Offwhite solid (0.277 g, 56%). Ή-NMR (δ ppm, DMSO-d_e, 400 MHz): δ Π8.91 (d, J = 3.3 Hz, 1H),

8.50 (d, J= 8.6 Hz, 1H), 8.23 (s,1H), 8.10 (d, J= 8.2 Hz, 1H), 8.03 (d, J- 6.9 Hz, 1H), 7.98 (d, J= 8.1 Hz, 1H), 7.87 (m,3H), 7.38 (dd, J= 8.3,4.2 Hz, 1H), 6.22 (s,2H), 3.97 (s,3H).

Step-2: 2-Chloro-4-(3-((7-fluoroquinolin-6-y1)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5yl)benzolc add: To a solution of step-1 of example 1002 (0.185 g, 0.412 mmol) in methanol (2 ml), lithium hydroxîde (0.161 g, 3.84 mmol) in water (2 ml) and THF (4 ml) were added and stirred at RT. After 12h, pH was adjusted to ca. 7 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the

142 title compound as a pale brown solid (0.150 g, 84%). The add was used as such for further steps.

Step-3: 2-Chloro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridln-5yl)benzamlde: The title compound was prepared by following the procedure described for step3 of example 1001 using step-2 of example 2 (0.050 g. 0.115 mmol), thionyl chloride (2 ml) and aqueous 25% ammonia (2 ml). Brown solid (0.015 g, 30%). M.P.: 202-204°C. ¹H-NMR (Q ppm, DMSO-de, 400 MHz): δ 8.92 (d, J = 4.1 Hz, 1H), 8.70 (d, J = 8.6 Hz, 1H), 8.44 (d, J - 8.0 Hz, 1H). 8.27(s, 1H), 8.22 (m, 3H), 7.96 (s, 1 H). 7.83 (d, J- 11.5 Hz, 1 H), 7.68(s, 1H), 7.60 (d, J8.0 Hz, 1H), 7.55 (dd, J = 8.4,4.3 Hz, 1H), 6.26 (s, 2H).

Step-4:6-((5-(4-carbamoy1-3-chlorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl}-7fluoroquinoline 1-oxide: The title compound was prepared by following the procedure described for step-4 of example 1001 using step-3 of Example 1002 (0.100 g, 0.231 mmol), acetone (1.5 ml), water (1.5 ml) and oxone (1.42g, 2.31 mmol). Pale yellow solid (0.010 g, 9%). M.P.: 176-178°C. Ή-NMR (δ ppm, DMSO-d_e, 400 MHz): □ 5C8.71 (d, J =8.7 Hz, 1H), 8.62 (d, J = 6.0 Hz, 1H), 8.34 (d, J = 7.6 Hz, 1H), 8.27-8.19 (m, 4H), 8.00 (d, J = 8.7 Hz, 1H), 7.95 (s,1H), 7.67 (s,1H), 7.60 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 8.5,6.1 Hz, 1H), 6.20 (s, 2H).

Example 1003

2,6-difluoro-4-(3-{qulnolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridln-5-yl)benzamlde

2,2,2-trifl uoroacetate:

To step-3 of Example 1001 (0.100 g, 0.240 mmol), 2 ml of 2% Trifluoroacetic acid in acetonitrile: water (1:1) was added and stirred for 10 min. The clear solution obtained, was concentrated under reduced pressure to afford the title compound as a brown solid (0.57 g, 44%). M.P.: 203-206°C. Ή-NMR (δ ppm, DMSO-d_e, 400 MHz): δ 8.98 (d, J = 4.2 Hz, 1H), 8.74 (d, J = 8.7 Hz. 1H), 8.56 (d, J = 8.1 Hz, 1H). 8.25 (d, J = 8.7 Hz. 1H), 8.18 (s,1H), 8.13 (s,1H), 8.07 (m,3H), 7.92 (s,1H), 7.91 (d, J = 6.7 Hz, 1H), 7.67 (dd, J = 8.0,4.3 Hz, 1H), 6.27 (s, 2H).

Example 1004

2-chloro-4-(3-((2-oxo-1,2-dihydroqulnolln-6-yl)methyt)-3H-[1_l2,3]triazolo[4,5-b]pyrldin-5yljbenzamide:

To a solution of Intermediate 32 (0.060 g, 0.202 mmol) and intermediate 9 (0.072 g, 0.253 mmol) in dioxane (1.8 ml), potassium carbonate (0.093 g, 0.675 mmol) was added and degassed for 30 min. To this tetrakis (triphenylphosphine)palladium(O) (0.018 g, 0.016 mmol) was added under nitrogen at RT and the reaction mixture was refluxed for 12h. The solvent was evaporated completely and water was added to the residue and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. The crude product was 143 purified by column chromatography with methanol: dichloromethane to afford the title compound as an off-white solid (0.040 g, 46%). M.P.: >300°C. ’H-NMR (δ ppm, DMSO-de, 400

MHz): δ 11.74 (saODDDDO8.67 (d, J = 8.7 Hz, 1H), 8.31 (d, J = 1.5 Hz, 1H), 8.25 (dd, J =

8.0,1.5 Hz, 1H). 8.20 (d, J = 8.8 Hz, 1H). 7.95 (s,1H), 7.89 (d, J = 9.5 Hz, 1H), 7.78 (s,1H), 7.68 (s,1H), 7.62 (d. J = 8.1 Hz. 2H), 7.28 (d. J= 8.4 Hz, 1H), 6.48 (d, J = 8.2 Hz, 1H), 6.03 (s, 2H).

Example 1005

2.6- difluoro-4-(3-((2-oxo-1,2-dihydroqulnolln-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-

5-yl)benzamlde:

The title compound was prepared by following the procedure described for example 1004 using Intermediate 32 (0.150 g, 0.507 mmol), intermediate 33 (0.176 g, 0.634 mmol), potassium carbonate (0.233 g, 1.689 mmol), dioxane (4 ml), water (2 ml) and tetrakis(triphenylphosphine)palladium(0) (0.046 g, 0.040 mmol) under microwave irradiation (microwave power = 100W, température = 100 °C) for 30 min. Off-white solid (0.050 g, 23 %). M.P.: 275-278°C. ’H-NMR (δ ppm. DMSO-d_e, 400 MHz):D611.74 (s,1H), 8.70 (d, J = 8.6 Hz, 1H), 8.23 (m,2H), 8.07 (d, J = 8.6 Hz, 2H), 7.93 (s, 1H), 7.88 (d, J = 9.6 Hz, 1H), 7.79(s,1H),

7.64 (d, J= 8.5 Hz, 1H), 7.28 (d, J = 8.3 Hz, 1H), 6.48 (d, J =9.5 Hz, 1H), 6.04 (s, 2H).

Example 1006

4-(3-(benzo[d]thlazol-6-ylmethy1)-3H-[1,2,3]triazolo[4,5-b]pyrldin-5-yl )-2,6difluorobenzamlde:

The title compound was prepared by following the procedure described for example 1004 using intermediate 15 (0.120 g, 0.397 mmol), intermediate 33 (0.110 g, 0.496 mmol), potassium carbonate (0.182 g, 1.32 mmol), dioxane (2.5 ml), water (1 ml) and tetrakis (triphenylphosphine)palladium(O) (0.036 g, 0.031 mmol) under microwave irradiation (microwave power = 100W, température = 100 °C) for 45 min. Yellow solid (0.050 g, 30%). M.P.: 255-258°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): δ 9.37 (s, 1H), 8.72 (d, J = 8.7 Hz, 1H), 8.30 (d, J= 1.2 Hz, 1H), 8.25 (d, J= 8.8 Hz, 1H), 8.20 (s,1H), 8.07 (d. J =8.7 Hz, 2H), 8.05 (s,1H), 7.92 (s, 1H). 7.65 (dd, J = 8.4,1.6 Hz, 1H), 6.19 (s,2H).

Example 1007

2.6- difluoro-4-(3-((7-fluoroqulnolin-6-yl)methy1)-3H-[1,2_l3]trlazolo[4,5-b]pyridin-5-yl) benzamlde:

The title compound was prepared by following the procedure described for example 4 using intermediate 8 (0.100 g, 0.319 mmol), intermediate 33 (0.111 g, 0.399 mmol), potassium carbonate (0.147 g, 1.06 mmol), dioxane (2 ml), water (0.8 ml) and tetrakis (triphenylphosphine)patladium(O) (0.029 g, 0.025 mmol) under microwave irradiation

144 (microwave power = 100W, température = 100 *C) for 45 min. Off-white solid (0.075 g, 54%).

M.P.: 244-247°C. Ή-NMR (δ ppm. DMSO-d₆, 400 MHz): 0Π8.92 (dd, J = 4.3,1.6 Hz, 1H), 8.73 (d, J = 8.8 Hz, 1H), 8.42 (d, J = 7.4 Hz, 1H), 8.25 (d, J - 8.8 Hz, 1H), 8.21 (s,1H), 8.19 (s, 1H),

8.01 (d. J = 8.8 Hz, 2H), 7.92 (s, 1H), 7.82 (d, J = 11.4 Hz, 1H), 7.55 (dd, J - 8.3,4.2 Hz. 1H),

6.27 (s,2H).

Example 1008 2-Chloro-4-(3-(qulnolin-6-ylmethyl)-3H4mldazo[4_l5-b]pyrldin-5-yl)benzamlde:

To a solution of Intermediate 34 (0.150 g, 0.508 mmol) and intermediate 9 (0.179 g, 0.636 mmol), in dioxane (3 ml), potassium carbonate (1.276 g, 13.03 mmol), water (1 ml) and tetrakis (triphenylphosphîne)palladium(O) (0.047 g, 0.040 mmol) was added under nitrogen at RT and the reaction mixture was kept under microwave irradiation (microwave power = 100W, température = 100 °C) for 45 min The solvent was evaporated completely and water was added to the residue and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as an off-white solid (0.095 g, 45%). M.P.: 212-214°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz ): δ 8.87 (dd, J = 4.1,2.8 Hz, 1H), 8.73 (s. 1H). 8.35 (d, J= 8.5 Hz. 1H), 8.20 (s, 1H), 8.18 (d, J= 7.6 Hz, 1H), 8.13 (d, J- 8.1 Hz. 1H), 8.01 (m, 3H), 7.90 (s, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.62(s, 1H), 7.55 (d, J~ 8.0 Hz, 1H), 7.53 (dd, J = 8.6,4.5 Hz, 1H), 5.78 (s, 2H).

Example 1009 Z-chloro^S-fquInolin-e-ylmethylJ-SH-imldazo^.S-blpyridin-S-yiJbenzamlde hydrochloride:

The example 1008 (0.050 g, 0.119 mmol), was dissolved in THF (1.5 ml), ether saturated with HCl (0.15 ml) was added at 0°C and stirred for 15 min. The precipitate formed was washed with ether and dried under vacuum to afford the title compound as an off-white solid (0.040 g, 75 %). M.P.: 244-246°C. ¹H-NMR (δ ppm, DMSO-d_e, 400 MHz): δ 9.19 (d, J = 4.0 Hz, 1H). 9.11 (s, 1H), 8.99 (d, J = 8.2 Hz, 1H), 8.34-8.27 (m, 3H). 8.19-8.06 (m, 4H), 7.97 (dd, J = 8.3,5.0 Hz, 1H), 7.90 (s,1H), 7.62 (s, 1H), 7.55 (d, J- 8.0 Hz, 1H), 5.92 (s, 2H).

Example 1010

2,6-difluoro-4-(3-(qulnolin-6-y!methyl)-3H4mldazo[4,5-b]pyridIn-5-yl)benzamide:

The title compound was prepared by following the procedure described for example 1008 using intermediate 34 (0.100 g, 0.339 mmol), intermediate 33 (0.117 g, 0.424 mmol), potassium carbonate (0.156 g, 1.12 mmol), dioxane (2 ml), water (0.8 ml) and tetrakis 145

(triphenylphosphine)palladium(O) (0.032 g, 0.027 mmol) under microwave irradiation (microwave power = 100W, température = 100 *C) for 45 min. Off-white solid (0.080 g, 57%). M.P.: 242-245°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): 6D8.87 (dd, J = 4.1,1.6 Hz, 1H), 8.75 (s. 1H). 8.33 (d. J= 7.6 Hz, 1H), 8.22 (d, J-8.4 Hz, 1H), 8.13 (s,1H), 8.03 (m,3H), 7.93 (d, J = 9.0 Hz. 2H), 7.86 (s,1H), 7.83 (dd, J - 8.7,1.8 Hz, 1H). 7.53 (dd, J = 8.3,4.1 Hz, 1H), 5.79 (s,2H).

Example 1011

Methyt 2-chloro-4-(3-(quinolin-6-y1methyl)-3H-lmidazo[4_I5-b]pyridin-5-yl)benzoate:

The title compound was prepared by following the procedure described for example 1008 using intermediate 34 (2.5 g, 8.48 mmol), 3-chloro-4-methoxycarbonylphenylboronic add (2.0 g, 9.32 mmol), potassium acetate (2.77 g, 28.24 mmol), dioxane (50 ml) and tetrakis (triphenylphosphine)palladium(O) (0.784 g, 0.678 mmol). Brown solid (crude) (4.0 g) which is used as such for next step.

Example 1012 2-chloro-4-(3-(qulnolin-6-ylmethyl)-3H-lmidazo[4,5-b]pyrldin-5-yl)benzoic acid:

To a solution of Example 1011 (4.00 g, 9.38 mmol) in methanol (43 ml), lithium hydroxide (3.65 g. 87.12 mmol) in water (43 ml) and THF (86 ml) were added and stirred at RT. After 12h, pH was adjusted to 7-7.5 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as an black solid (1.2 g, 31%). ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): δ 8.87 (dd, J - 4.1,1.4 Hz, 1H), 8.71 (s, 1H), 8.34 (d. J= 7.4 Hz, 1H), 8.18 (d, J = 8.3 Hz, 1H), 8.16 (s,1H), 8.09 (d, J = 8.0 Hz, 1H), 8.02 (s, 1 H), 8.01 (d, J - 8.1 Hz, 1 H). 7.96 (d, J = 8.4 Hz, 1H), 7.84 (dd, J - 8.8,1.7 Hz, 1H),

7.72 (d, J- 8.3 Hz, 1H), 7.52 (d, J = 8.3,4.1 Hz, 1H), 5.78 (s,2H).

Example 1013 2-chloro-N-ethyl-4-(3-(quinolin-6-ylmethyl)-3H-lmidazo[4,5-b]pyridin-5-yl)benzamtde:

The title compound was prepared by following the procedure described for example 101 using example 1012 (0.100 g, 0.251 mmol), DMF (0.7 ml), N-ethyldiisopropylamine (0.064 g, 0.500 mmol), HATU (0.095 g, 0.250 mmol) and ethylamine hydrochloride (0.040 g, 0.500 mmol). Pale green solid (0.035 g, 32 %). M.P.: 185-187°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): δ 8.87 (dd, J = 4.2,1.6 Hz, 1 H), 8.73 (s,1H), 8.44 (t. J - 5.5 Hz, 1H), 8.34 (d, J - 8.3 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 8.18 (s,1H), 8.14 (dd, J = 8.0,1.6 Hz, 1H), 8.01 (d, J = 9.4 Hz, 2H), 7.96 (s, 1H). 7.84 (dd, J - 8.7,1.6 Hz, 1H), 7.53 (m, 2H), 5.78 (s, 2H), 3.29 (m,2H), 1.09 (t. J = 7.0 Hz, 3H).

Example 1014

146 r

Methyl 2,6-difluoro-4-(3-(qulnolin-6-ylmethy1)-3H-lmldazo(4,5-b]pyridin-5-yl)benzoate:

The title compound was prepared by following the procedure described for example 1008 using intermediate 34 (1.5 g, 5.08 mmol), 3,5-difluoro-4-methoxycarbonylphenylborontc acid (1.20 g, 5.59 mmol), potassium acetate (1.66 g, 16.94 mmol), dioxane (30 m!) and tetrakis (triphenylphosphine)palladium(O) (0.470 g, 0.407 mmol). Brown solid (1.7g, 77%). ’H-NMR (δ ppm. CDCI₃,400 MHz): δ 8.93 (dd. J - 4.3,1.7 Hz, 1H). 8.19 (d. J = 8.4 Hz. 1H), 8.18 (s, 1H). 8.14 (m, 2H), 7.80 (d. J= 1.5 Hz. 1H), 7.75 (m, 4H). 7.44 (dd, J= 8.3,4.2 Hz, 1H), 5.72 (s, 2H),

3.97 (s, 3H).

Example 1015

2,6-difluoro-4-(3-(qulnolin-6-ylmethyl)-3H-imtdazo[4_l5-b]pyridin-5-yl)benzolcacid:

To a solution of Example 1014 (1.7 g, 3.94 mmol) in methanol (18 ml), lithium hydroxide (1.54 g, 36.81 mmol) in water (18 ml) and THF (36 ml) were added and stirred at RT. After 12h, pH was adjusted to 7-7.5 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as an offwhite solid (1.0 g, 61%) which is used as such for next step.

Example 1016

N-ethyl-2,6-difluoro-4-(3-(quinolin-6-ylmethyl)-3H-lmidazo[4,5-b]pyridin-5-yl) benzamlde:

The title compound was prepared by following the procedure described for example 101 using example 1015 (0.100 g, 0.239 mmol), DMF (1 ml), N-ethyldiisopropylamine (0.092 g, 0.717 mmol). HATU (0.090 g, 0.239 mmol) and ethylamine hydrochloride (0.038 g, 0.478 mmol).Pale green solid (0.020 g, 19 %). M.P.: 174-176°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): 8.87 (dd, J = 4.1.1.6 Hz, 1H), 8.75 (s, 1H), 8.71 (t, J= 5.5 Hz, 1H), 8.33 (d, J = 7.4 Hz. 1H), 8.22 (d. J =

8.4 Hz, 1H), 8.03 (d, J = 8.5 Hz, 2H), 8.00 (d. J - 8.7 Hz. 1H), 7.93 (d. J = 9.1 Hz, 2H), 7.83 (dd, J= 8.7,1.9 Hz, 1H), 7.53 (dd, J= 8.3,4.2 Hz. 1H), 5.79 (s, 2H). 3.28 (m, 2H), 1.12 (t, J= 7.2 Hz, 3H).

Example 1017

2-chloro-N-methyl-4-(3-(quinolin-6-ylmethyl)-3H-lmidazo[4,5-b]pyrldin-5-yl) benzamlde:

The title compound was prepared by following the procedure described for example 1008 using intermediate 34 (0.100 g, 0.339 mmol), intermediate 37 (0.175 g, 0.424 mmol), potassium carbonate (0.156 g, 1.12 mmol), dioxane (2 ml), water (0.5 ml) and tetrakis (triphenylphosphine)palladium(O) (0.031 g, 0.027 mmol) under microwave irradiation (microwave power = 100W, température = 100 *C) for 45 min. Pale green solid (0.030 g, 21 %). M.P.: 169-171°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): δ 8.87 (d, J = 2.8 Hz, 1H), 8.72 (s,

147

H), 8.37 (m, 2H), 8.20 (s, 1H), 8.18 (d. J- 8.0 Hz, 1H), 8.14 (dd, J = 8.0,1.2 Hz, 1H), 8.01 (m,

3H), 7.84 (d, J- 8.3 Hz, 1 H), 7.53 (m, 2H), 5.78 (s, 2H), 2.77 (d, J = 4.6 Hz, 3H).

Example 1018 2-methyl-4-(3-(quinolin-6-y!methy!)-3H-lmldazo[4_l5-b]pyridin-5-yI)benzamlde:

The title compound was prepared by following the procedure described for example 1008 using intermediate 34 (0.100 g, 0.339 mmol), intermediate 38 (0.110 g, 0.424 mmol), potassium carbonate (0.156 g, 1.12 mmol), dioxane (2 ml), water (0.8 ml) and tetrakis (triphenylphosphine)palladium(O) (0.031 g, 0.027 mmol) under microwave irradiation (microwave power = 100W, température = 100 ’C) for 45 min.. Pale green solid (0.070 g, 52%). M.P.: 135-138°C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): δ08.87 (dd, J = 4.1,1.6 Hz, 1H), 8.68 (s, 1H), 8.34 (d, J= 7.0 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H), 8.01-7.95 (m, 4H), 7.90 (d, J~ 8.4 Hz, 1H), 7.84 (dd, J = 8.6,1.9 Hz, 1H), 7.72 (s, 1H). 7.53 (dd. J = 8.3,4.2 Hz, 1H), 7.47 (d, J = 8.5 Hz. 1H), 7.36 (s, 1H), 5.77 (s, 2H), 2.44 (s, 3H).

Example 1019 2-chloro-4-(3-(qulnolln-6-ylmethyl)-3H-lmldazo[4,5-b]pyridin-5-yl)benzamide 2,2,2trifluoroacetate:

To Example 1008 (0.060 g, 0.144 mmol), 1 ml of 2% Trifluoroacetic acid in acetonitrile: water (1:1) was added and stirred for 20 min. The dear solution obtained was concentrated under reduced pressure to afford the title compound as a brown solid (0.50 g, 65%). M.P.: 158160°(0.’H-NMR (δ ppm, DMSO-d_e, 400 MHz): □ □□ 400 MHz):J = 4.6.1.6 Hz, 1H), 8.86 (s. 1H), 8.69 (d. J = 8.3 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.17 (d, J= 1.5 Hz, 2H), 8.12 (m,2H), 8.01 (m, 2H), 7.89 (s,1H), 7.70 (dd, J = 8.4,4.7 Hz, 1H), 7.62 (s,1H), 7.56 (d, J = 8.0 Hz, 1H), 5.85 (s, 2H).

Example 1020 2-chloro-4-(2-methyl-3-(quinolin-6-ylmethyl)-3H-lmldazo[4,5-b]pyridin-5-yl) benzamlde:

The title compound was prepared by following the procedure described for example 1008 using intermediate 36 (0.100 g, 0.323 mmol), intermediate 9 (0.113 g, 0.404 mmol), potassium carbonate (0.149 g, 1.078 mmol), dioxane (2.0 ml), water (0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.029 g, 0.025 mmol) under microwave irradiation (microwave power = 100W, température = 100 ’C) for 45 min. Off-white solid (0.030 g, 22%). M.P.: 207-209°) f H-NMR (δ ppm, DMSO-d₆, 400 MHz): □□□ 400 MHz):J = 4.2,1.7 Hz, 1H),

8.33 (d, J= 7.4 Hz, 1H), 8.20 (d, J= 1.6 Hz, 1H), □□□□□□□□□DJ» 8.1.1.7 Hz, 1H), 8.08 (d, J = 8.3 Hz, 1H), 8.00 (d, J= 8.8 Hz, 1H), 7.95 (d, J = 8.3 Hz, 1H). 7.87 (s, 1H), 7.83 (s,1H), 7.71

148 (dd, J = 8.7,1.9 Hz, 1H), 7.60 (s,1H), 7.54 (d, J = 8.0 Hz, 1H), 7.51 (dd, J = 8.3,4.2 Hz, 1H),

5.77 (s, 2H), 2.59 (s, 3H).

Example 1021 2-chloro-4-(3-(1'{^tl^ul^noliⁿ’^^_y’)^eriⁱyl)-3H-lmidazo[4_I5-b]pyridin-5-yl}benzamlde:

The title compound was prepared by following the procedure described for example 1008 using intermediate 39 (0.100 g, 0.323 mmol), intermediate 9 (0.113 g, 0.404 mmol), potassium carbonate (0.149 g, 1.078 mmol), dioxane (2.0 ml), water ( 0.5 ml) and tetrakis(triphenylphosphine)pa1ladium(0) (0.029 g, 0.025 mmol) under microwave irradiation (microwave power = 100W, température =100 °C) for 45 min. Grey solid (0.060 g, 43%). M.P.: 157-159°C. ’H-NMR (Ô ppm, DMSO-d_e, 400 MHz): δΠ8.86 (dd, J = 4.2,1.6 Hz, 1H), 8.84 (s,1H),

8.36 (d, J - 7.4 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 1.6 Hz, 1H), 8.09 (m, 2H). 7.99 (d, J = 8.8 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.88 (s, 1H), 7,85 (dd, J = 8.9,1.8 Hz, 1H), 7.61 (s,1H), 7.54 (d, J- 7.9 Hz, 1H), 7.52 (dd, J = 7.5,4.2 Hz, 1H), 6.32 (q, J =7.0 Hz, 1H), 2.14 (d, J = 7.1 Hz, 3H).

Example 1022 2-chloro-4-(3-((7-fluoroqulnolin-6-yf)methyl)-3H-lmldazo[4,5-b]pyridin-5-yl)benzamlde:

The title compound was prepared by following the procedure described for example 1008 using intermediate 35 (0.100 g, 0.319 mmol), intermediate 9 (0.112 g, 0.399 mmol), potassium carbonate (0.146 g, 1.062 mmol), dioxane (2.0 ml), water (0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.029 g, 0.025 mmol) under microwave Irradiation (microwave power = 100W, température = 100 ’C) for 45 min. Off-white solid (0.100 g, 73%). M.P.: 230-232 °C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): δΠ8.89 (d. J = 2.8 Hz, 1H). 8.68 (s,1H), 8.40 (d, J = 8.0 Hz, 1H), 8.20 (m, 2H), 8.13 (d, J = 8.1 Hz, 1H), 8.10 (dd, J = 8.0,1.6 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.88 (s, 1H), 7.82 (d, J = 11.6 Hz, 1H), 7.60 (s,1H), 7.53 (d. J =

8.4 Hz, 1H), 7.51 (dd, J = 7.7,4.2 Hz, 1H), 5.83 (s, 2H).

Example 1023 2-ch!oro-4-(3-((5,7-difIuoroqulnolin-6-yl)methyl)-3H-lmtdazo[4,5-b]pyridin-5-yl) benzamide:

The title compound was prepared by following the procedure described for example 1008 using intermediate 40 (0.100 g, 0.303 mmol), intermediate 9 (0.106 g, 0.378 mmol), potassium carbonate (0.139 g, 1.008 mmol), dioxane (2.0 ml), water (0.8 ml) and tetrakis(triphenylphosphine)palladium(0) (0.028 g, 0.024 mmol) under microwave irradiation (microwave power = 100W, température = 100 ’C) for 45 min. Off-white solid (0.100 g, 73%). M.P.: 220-224 °C.’H-NMR (δ ppm, DMSO-d_e, 400 MHz): δΠ8.98 (dd, J = 4.1,2.7 Hz, 1H). 8.71

149

8.58 (d, J- 8.0 Hz, 1H), 8.19 (d, J = 1.4 Hz, 1H), 8.15 (d, J= 8.4 Hz, 1H), 8.06 (dd, J = 8.0,1.5 Hz, 1H), 7.95 (d, J - 8.4 Hz, 1H), 7.89 (s, 1H), 7.73 (d, J = 11.1 Hz, 1H), 7.66 (dd, J =

8.5,4.3 Hz, 1H). 7.61 (s,1H), 7.52 (d, J= 8.0 Hz, 1 H), 5.83 (s, 2H).

Example 1024

4-(3-Qulnolin-6-ylmethyl-3H-lmldazo[4,5-b]pyridin-5-yl)-2-trifluoromethyl-benzamide

The title compound was prepared by following the procedure described for example 1008 using intermediate 34 (0.150 g, 0.508 mmol), intermediate 50 (0.208 g, 0.661 mmol), potassium carbonate (0.234 g, 1.69 mmol), dioxane (2.9 ml), water (0.8 ml) and tetrakis(triphenylphosphine)palladium(0) (0.047 g, 0.040 mmol) at 100°C for 12h. Off-white solid (0.017 g. 7%). M.P.: 243-245 °C.Mass : 448.9(M*+1).

Example 1025

4-[3-(7-Fluoro-quinot1n-6-ylmethy!)-3H-lmldazo[4,5-b]pyrldin-5-ylJ-2-methyl-benzamlde

The title compound was prepared by following the procedure described for example 1008 using intermediate 35 (0.150 g, 0.479 mmol), intermediate 38 (0.162 g, 0.623 mmol), potassium carbonate (0.220 g, 1.59 mmol), dioxane (2.8 ml), water (0.7 ml) and tetrakis(triphenylphosphine)palladium(0) (0.044 g, 0.038 mmol) under microwave irradiation (microwave power = 100W, température - 100 *C) for 50 min. Off-white solid (0.020 g, 10%). M.P.: 206-208 °C. Mass : 448.9(M*+1).

Example 1026

4-[3-(7-Fluoro-qulnolin-6-y!methyl)-3H-imldazo[4,5-b]pyridIn-5-yl]-2-trifluoromethy1benzamide

The title compound was prepared by following the procedure described for example 1008 using intermediate 35 (0.100 g, 0.319 mmol), intermediate 50 (0.139 g, 0.415 mmol), potassium carbonate (0.156 g, 1.12 mmol), dioxane (2.0 ml), water (0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol) under mtcrowave irradiation (mtcrowave power = 100W, température = 100 *C) for 50 min. Off-white solid (0.040 g, 27%). M.P.: 239-241 °C. Mass : 465.9(M*).

Example 1027

4-(3-(5,7-Difluoro-quinotln-6-ylmethyl)-3H4midazo[4,5-b]pyridin-5-yl]-2-methy1-benzamlde

The title compound was prepared by following the procedure described for example 1008 using intermediate 40 (0.100 g, 0.303 mmol), intermediate 38 (0.102 g, 0.393 mmol), potassium carbonate (0.139 g, 1.00 mmol), dioxane (2.0 ml), water (0.8 ml) and

150 tetrakis(triphenylphosphine)palladium(0) (0.028 g, 0.024 mmol) at 100°C for 12h. Pale green solid (0.017 g, 10%). M.P.: 158-160 °C. Mass : 430.1(M*+1).

Example 1028

4-(3-(5,7-Difluoro-quinolin-6-ylmethyl)-3H-lmidazo[4,5-b]pyridln-5-yl]-2-trifluoromethylbenzamide

The title compound was prepared by following the procedure described for example 1008 using intermediate 40 (0.150 g, 0.454 mmol), intermediate 50 (0.186 g, 0.596 mmol), potassium carbonate (0.209 g, 1.51 mmol), dioxane (2.9 ml), water (1.2 ml) and tetrakîs(tripheny1phosphine)palladium(0) (0.041 g, 0.036 mmol) at 100°C for 12h. Off-white solid (0.017 g, 7%). M.P.: 252-254 °C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): D8.97 (d, J = 3.2 Hz, 1H), 8.74 (s,1H), 8.56 (s,1H), 8.50 (d, J = 8.6 Hz, 1H), 8.36 (d, J = 7.7 Hz, 1H), 8.18 (d, J =

8.4 Hz, 1H), 8.01 (d, J = 8.4 Hz. 1H), 7.97 (s,1H), 7.70-7.59 (m, 4H), 5.84 (s, 2H).

Example 1029

4-[3-(7-Fluoro-qulnolin-6-ylmethyl)-3H-lmldazo[4,5-bIpyridin-5-yl]-2-methyl-benzamlde hydrochloride

The example 1025 (0.060 g, 0.145 mmol), was dissolved in THF (2.0 ml), ether saturated with HCl (0.50 ml) was added at 0°C and stirred for 15 min. The precipitate formed was washed with ether and dried under vacuum to afford the title compound as pale green solid (0.050 g, 76 %). M.P.: 250-252°C.’H-NMR (δ ppm, DMSO-d_e, 400 MHz): 9.19(s, 1H0, 9.07 (dd, J = 4.6,1.4 Hz, 1H), 8.71 (d, J= 8.1 Hz, 1H), 8.35 (d, J= 8.0 Hz, 1H), 8.28 (d, J= 8.5 Hz, 1H), 8.05 (d. J = 8.5 Hz, 1H), 8.01 (d, J = 11.0 Hz, 1H). 7.98 (m, 2H), 7.75 (m, 2H). 7.47 (d, J = 8.5 Hz, 1H), 7.40(s,1H), 5.93 (s, 2H), 2.43 (s,3H).

Example 1030 2,N-Dimethyl-443-qulnolin-6-ylmethyl-3H-lmIdazo[4,5-b]pyrldin-5-yl)-benzamlde

The title compound was prepared by following the procedure described for example 1008 using intermediate 34 (0.100 g, 0.339 mmol), intermediate 37 (0.121 g, 0.441 mmol), potassium carbonate (0.156 g, 1.12 mmol), dioxane (2.0 ml), water (0.5 ml) and tetrakis(tn'phenylphosphine)palladium(0) (0.031 g, 0.027 mmol) under microwave irradiation (microwave power = 100W, température =100 ’C) for 45 min. Off-white solid (0.012 g, 9%). M.P.: 118-120 °C. Mass : 408.4(M*+1).

Example 1031

151

5-(3-Quinolin-6-ylmethyl-3H-Imidazo[4,5-b]pyr1din-5-yl)-pyrldine-2-carboxylic acid methylamlde

The title compound was prepared by following the procedure described for example 1008 using intermediate 34 (0.100 g, 0.339 mmol), intermediate 51 (0.115 g, 0.441 mmol), potassium carbonate (0.156 g, 1.12 mmol), dioxane (2.0 ml), water (0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol) at 100°C for 12h. Off-white solid (0.070 g. 52%). M.P.: 219-221 °C. Mass : 395.4(M*+1).

Example 1032

S-fS-QuInolin-e-ytmethyl-SH-fl^.SltriazolopLS-bJpyridin-S-yO-Z.S-dihydro-isoIndol-l-one The title compound was prepared by following the procedure described for example 1008 using intermediate 7 (0.150 g, 0.507 mmol), intermediate 52 (0.163 g, 0.634 mmol), potassium carbonate (0.233 g, 1.68 mmol), dioxane (2.0 ml), water (0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.046 g, 0.040 mmol) under microwave irradiation (microwave power = 100W, température = 100 ’C) for 45 min. Off-white solid (0.010 g, 5%). M.P.: 237-239 °C. ’H-NMR (δ ppm, DMSO-d_e, 400 MHz): 8.88 (dd, J = 4.2,1.7 Hz, 1H), 8.71(d, J =8.7 Hz, 1H), 8.69 (s, 1H), 8.41 (m, 3H). 8.21 (d, J= 8.7 Hz, 1H). 8.01 (m, 2H), 7.83 (d, J-

7.6 Hz, 2H), 7.54 (dd, J= 8.3,4.1 Hz, 1H), 6.23 (s, 2H), 4.48 (s,2H).

Example 1033

5-{3-Qulnolin-6-ylmethyl-3H-imidazo[4,5-b]pyridin-5-yl)-2₍3-dlhydro-lsolndol-1-one

The title compound was prepared by following the procedure described for example 1008 using intermediate 34 (0.150 g, 0.508 mmol), intermediate 52 (0.164 g, 0.636 mmol), potassium carbonate (0.234 g, 1.69 mmol), dioxane (2.5 ml), water (1.0 ml) and tetrakis(triphenylphosphine)palladium(0) (0.047 g, 0.040 mmol) at 100°C for 12h. Off-white solid (0.080 g,40%). M.P.: 267-269 °C.’H-NMR (δ ppm, DMSO-d_e, 400 MHz): 8.87 (dd, J =

4.2,1.7 Hz, 1H), 8.71(s,1H), 8.59 (s, 1H), 8.36 (dd, J = 8.5,1.2 Hz, 1H), 8.30 (s. 1H), 8.26 (dd. J = 8.1,1.3 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H), 8.01 (m, 3H), 7.84 (dd, J = 8.7,2.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.53 (dd, J = 8.3,4.1 Hz, 1H), 5.79 (s, 2H), 4.45 (s,2H).

BIOLOGICAL ASSAY

The pharmacological properties of the compounds of this invention may be confirmed by a number of pharmacological assays. The pharmacological assays which can be been carried out with the compounds according to the invention and/or their pharmaceutically acceptable salts are exemplified below.

152

MET Kinase Assay Protocol:

Colorimétrie détermination of c-Met Kinase activity

The receptor tyrosine kinase c-Met is a heterodimeric transmembrane glycoprotein involved in several cellular processes that aid in tumor progression. Phosphorylation of the tyrosine residues in the c-Met kinase domain is critical for its activity and the resulting down-stream effects. The colorimétrie assay allows détection of the phosphorylated form of a biotinylated peptide upon activation of human recombinant Met kinase.

MET Kinase Assay Protocol:

c-Met Kinase activity shal! be determined using an HTScan® Met Kinase Assay Kit (Cell Signalling Technology, Beverly, MA) with modifications. Ail incubations are carried out at room température. Briefly, 12.5 pl of a 4X reaction cocktail (DTT/Kinase buffer containing appropriate quantity of human Met kinase) is added to each well of a 96-well plate containing 12.5 μΙ prediluted compound of interest and incubated for 5 minutes. After the initial incubation, 25 μΙ/well of 2X ATP/biotinylated peptide is added and incubated for an additional 30 minutes. The reaction is terminated by the addition of 50 μΙ/well stop buffer (50 mM EDTA, pH 8.0). The reaction mixture (25 μΙ/well) is then transferred to a streptavidin coated plate (Perkin Elmer, Cat# 4009-0010) containing 75 μΙ dH₂O and incubated for 60 minutes. The plate is washed with 200 μΙ/well wash buffer (1X PBS, 0.05% Tween-20). After washing, 100 μΙ/well phosphotyrosine mAb (1:1000 in wash buffer containing 1% BSA) is added and incubated for 60 minutes. After another round of washes, 100 μΙ/well europium labelled anti-mouse IgG (1:500 in wash buffer containing 1% BSA) is added and Incubated for an additional 30 minutes. Following additional washes, 100 μΙ/well Delfia^<R) enhancement solution (Perkin Elmer, Cat#1244-105) is added and Incubated for 45 minutes. Florescence is measured on a microplate reader (BMG Labtech., Germany) at 340 nm (excitation) and 615 nm (émission) for calculating % inhibition. Data generated can be analyzed further using Graphpad Prism (Graphpad software, San Diego CA) for détermination of IC».

Results: The results are as given below in Table 4A, 4B and 4C as % Inhibition or IC50 of cMet

TABLE 4A

Example No	c-Met Enzyme	MKN45
% inhibition @ 100nM	IC50nM	% Inhibition @ 100nM	G150nM
Example	A	-	0	-

153

Exampie No	c*Met Enzyme	MKN45
% inhibition @ 100nM	IC50nM	% Inhibition @ 100nM	GISOnM
1
Example 2	A*			++
Example 3	B*			++
Example 4	A*			+
Example 5	A*	++++	A	++++
Example 6	A*	++++	A	++++
Example 6a	-	-	-	-
Example 6b	-	-	-	-
Example 6c	-	-	-	-
Example 6d	-	-	-	-
Example 7	A	++++	A	++++
Example 7a			A	++++
Example 7b	-	-	-	-
Example 7c	-	-	-	-

154

Example No	c*Met Enzyme	MKN45
% Inhibition @ 100nM	ICSOnM	% Inhibition @ 100nM	GISOnM
Example 8	A	++++	C	+++
Example 8a			C	+++
Example 8b	-	-	-	-
Example 9	A	++++	A	+++
Example 9a			A	++++
Example 9b	-	-	-	-
Example 10	A	++++	A	++++
Example 11	A	-	-	-
Example 12	-	-	-	-
Example 13	A	-	-	-
Example 14	A	-	-	-
Example 15	A	-	-	-
Example 16	A	-	-	-
Example	D	-	-	-

155

Example No	c-Met Enzyme	MKN45
% Inhibition @ 100nM	IC50nM	% Inhibition @ 100nM	GI50nM
17
Example 18	B	++++	C	+++
Example 19	A	++++	C	+++
Exampie 19a	-	-	-	-
Example 20	A	++++	A	+++
Example 21	A	++++	D
Example 21a	A
Example 22	A		B	+++
Example 23	A		A	+++
Example 24	A		A	++++
Example 24a	-	-	-	-
Example 25	A	++++	A	++++
Example 25a			B	++++
Example 25b	-	-	-	-

156

Example No	c>Met Enzyme	MKN45
% Inhibition @ 100nM	ICSOnM	% Inhibition @ 100nM	GISOnM
Example 25c	-	-	-	-
Example 25d	D	-	-	-
Example 25e	-	-	-	-
Example 26	A		A	++++
Example 26a	-		-
Example 27	A		A	++++
Example 27a	-		-
Example 28	A		A	++++
Example 29	A		D	++
Example 30	A	++++	A	++++
Example 31	B		B	++++
Example 32	A	++++	A	++++
Example 33	A	-	-	-
Example	A	-	A	++++

157

Example No	c-Met Enzyme	MKN45
% Inhibition @ 100nM	IC50nM	% inhibition @ 100nM	G150nM
34
Example 35	A		A	++++
Example 36	A	-	-	-
Example 37	B	-	-	-
Example 38	A	-	A	-
Example 39	A	-	A	-
Example 40	A	-	-	-
Example 41	-	-	-	-
Example 42	A	-	-	-
Example 43	A	-	-	-
Example 44	A	-	-	-
Example 45	A		-	-
Example 46	A	-	-	-
Example 47	A	-	-	-

158

Example No	c*Met Enzyme	MKN45
% Inhibition @ 100nM	ICSOnM	% Inhibition @ 100nM	GISOnM
Example 48	-	-	-	-
Example 49	-	-	-	-
Example 50	A*	++++	A	++++
Example 51	D*		D
Example 52	D*
Example 53	D*		D
Example 54	C*
Example 55	D*
Example 56	-	-	-	-
Example 57	A*	++++	B	++++
Example 58	D*		C
Example 59	A*	++++		++++
Example 60	A*	++++		+++
Example	A*	++++	-	+++

159

Example No	c-Met Enzyme	MKN45
% inhibition @ 100nM	ICSOnM	% inhibition @ 100nM	GI50nM
61
Example 62	D*		D
Example 63	A*	++++	D	+
Example 64	B	-	-	-
Example 65	-	-	-	-
Example 66	-	-	-	-
Example 67	-	-	-	-
Example 68	A	-	-	-

TABLE 4B

Example No	c-Met Enzyme	MKN45
% Inhibition @ 100nM	ICSOnM	% inhibition @ 100nM	GI50nM
Example 101	D*	-	-	-
Example 102	D*	-	-	-
Example 103	C*	-	-	-
Example	B*	++	D	-

160

104
Example 105	c·	-	D	-
Example 106	-	-	-	-
Example 107	A*	++	D	+
Example 108	D*	-	D	-
Example 109	A	-	-	-
Example 110	A	-	-	-
Example 111	A	-	D	-
Example 112	A	-	D	-
Example 113	A	-	-	-
Example 114	A	-	-	-
	D = < 25 %, C = £25-<50%,B = £50-<75%, A= S75 to 100 %
+++++= < 25 nM ;++++= 25 to s 50 Mm; +++ — >50 to £100 nM; ++ =>100-£250 nM and += >251-£1000 nM
tested @ 300nM

TABLE 4C

Example No	c-Met Enzyme	MKN45
% Inhibition @ 100nM	ICSOnM	% Inhibition @ 100nM	GISOnM

161

Example 1001	D	*
Example 1002	D
Example 1003	A*	+++++
Example 1004	D*
Example 1005	D
Example 1006	A*	++++	A	++++
Example 1007	A*	+++++	A	+++++
Example 1008	A*	+++	C	++
Example 1009
Example 1010	D*	-	-	-
Example 1011	-	-	-	-
Example 1012	-	-	-	-
Example 1013	D*	-	-	-
Example 1014	-	-	-	-
Example 1015	-	-	-	-

162

Example 1016	C*	-	D	-
Example 1017	C*	-	D	-
Example 1018	B*	-	C	-
Example 1019
Example 1020	D*	-	B	-
Example 1021	D*	-	C	-
Example 1022	A*	+++++	B	+++
Example 1023	A*	+++++	B	+++++
Example 1024	A	+++++	-	++
Example 1025	A	+++++	-	+++
Example 1026	C	-	-	-
Example 1027	A	-	A	-
Example 1028	A	-	A	-
Example 1029	-	-	-	-
Example 1030	D	-	-	-

163

Example 1031	D	-	-	-
Example 1032	A	-	-	-
Example 1033	D	-	-	-
D = < 25 % , C = £25-<50%,B = S50-<75%, A= £75 to 100 % +++++= < 25 nM ;++++= 25 to 2 50 Mm; +++ - >50 to 5100 nM; ++ =>100-5250 nM and += >251-51000 nM ‘tested @ 300nM

Inhibition of MKN-45 prolifération:

Cell prolifération assays were carried out using the high Met expressing human gastric adenocardnoma cell line, MKN-45, according to the following schedule:

Day 1: Cells were plated in 96-well plates in complété growth medium.

Day 2: Compounds at desired concentrations were added.

Day 5: Cell viability was determined using the 3-[4,5-dÎmethylthiazol-2-yll-2,5diphenyltetrazolium bromide (MTT) dye réduction test.

Results: The results are as given as % Inhibition of MKN-45 prolifération at 100 nM and GI50 values in Table 4A to 4C above.

Inhibition of c-Met kinase phosphorylation In MKN-45 cells:

MKN45 cells are a prototype of “c-Met addicted’ cells having constitutively activated c-Met kinase similar to that observed in sub-sects of gastric or hepatocellular cancer patients with dysregulated c-Met kinase activity. Inhibition of Met phosphorylation was determined using a cell based ELISA assay according to the following schedule:

Day 1: MKN-45 cells were plated in 96-well plates in complété growth medium.

Day 2: Inhibitors at the desired concentration were added to the plates and incubated for 1 h and lysed subsequently.

Lysâtes were transferred to NUNC Maxisorp plates coated with anti-cMet receptor antibody.

Phopho-tyrosîne mAb and HRP-lined anti-mouse IgG were used as primary and secondary antibodies respectively. Optical density was measured on a microplate reader (BMG Labtech.,

Germany) at 450 nM. Inhibition of c-Met phosphorylation in this cell line indicates a therapeutic

164 potential for test compounds in patients diagnosed with cancers caused by aberrant c-Met kinase signalling.

Results: The results are provided above în Table 4D as IC50 values.

Table 4D
Example No	IC 50
Example 6	+++
Example 7	+
Example 8	++++
Example 9	+++
Example 25	+++
Example 30	+++
Example 31	+
Example 32	+
Example 33	++
Example 1006	+++
+ = S 10 ;++*=> 10 to £25; +++ = >25-550 and +++ = >50-£500 in nM

Inhibition of c-Met kinase phosphorylation In NCI-H441 cells:.

Inhibition of Met phosphorylation was determined using a cell based ELISA assay according to the following schedule:

Day 1: NCI-H441 cells were plated in 96-well plates in complété growth medium.

Day 2: Inhibitors at the desired concentration were added to the plates, incubated for 1 h and lysed subsequently. Lysâtes were transferred to NUNC Maxisorp plates coated with anti-cMet 10 receptor antibody. Phopho-tyrosine mAb and HRP-lined anti-mouse IgG were used as primary and secondary antibodies respectively. Optical density was measured on a microplate reader

(BMG Labtech., Germany) at 450 nM. The compounds potently inhibit ed c-Met kinase phosphorylation in NCI-H441, a non-small cell lung cancer derived cell line indicating a therapeutic potential in lung cancer patients with mutant kras.

Results: The results are given below in Table 5 as IC50 values.

Table 5
Example No	IC 50
Exampie 6	+
Example 7	+
Example 8	+++
Example 9	++
Example 25	+
Example 30	++
Example 33	+
Example 1006	+
+ = S 10;++'= > 10 to S25; +++ = >25-s50 and +++ = >50-s500 in nM

Inhibition of Akt phosphorylation In MKN-45 or NCI-H441 cells:

Akt is a serine-threonine kinase and a downstream marker regulated by c-Met kinase via the

PI3K pathway. Once phosphorylated, Akt régulâtes several end processes including cell 10 survival and growth. Cells were treated with 0 -1000 nM of test compounds, lysed, and the proteins separated on a 10% SDS-PAGE. Following séparation, proteins were transie rred onto a nitrocellulose membrane and detected by chemîluminescence after incubation with pAkt S473 mAb (primary) and rabbit anti-mouse Ab (secondary). Intensity of the bands was determined using ImageJ 1.42q (NIH, USA) and normalized to Actin (loading control).

Results: The results are provided below as IC50 values in Table 6.

166

Table 6
Example No	MKN- 45	NCI- H441
Example 6	♦+	♦
Example 7	+	+
Example 8	++++	+
Example 9	++♦+	++
Example 25	++	+
Example 30	+++	+
Example 33	+++	+
Example 1006	+++	+
+ = 510; = >25-550	++'= > 10 to S25; +++ and +++ = >50-5250 in nM

Induction of apoptosls In MKN-45 cells: I

Induction of Caspase 3 was measured fluorimetrically. Cells were incubated with desired concentrations of the compound for 24 h. After incubation, cells were harvested and counted. 5 An equal number of viable cells per well (0.3 x 10^e cells) were used for détermination of caspase-3 activity. Increase in apoptosis manifested by an élévation in caspase-3 levels was determined using a Caspase-3 kit from Millipore. Data are expressed as a percent of the maximum response (100%). Compounds of the invention dose-dependently induced apoptosis in MKN-45 cells manifested by an increase in caspase-3 activity.

Results: The results are provided below as percentage induction @ 3 μΜ in Table 7.

Table 5

167

Example No	% Inhibition
Example 6	B
Example 7	A
Example 8	C
Example 9	A
Example 25	B
Example 30	B
Example 33	A
Example 1006	B
A is fc 75 ; B îs < 75 and z 50; C is < 50 and Z 25 and Dis<25. in%

Inhibition of HGF-induced Met phosphorylation In MDA-MB-231 cells:

MDA-MB-231 is a breast cancer cell line having a high level of c-Met expression. Activation of Met kinase in these cells occurs only after the addition of its naturel ligand, Hépatocyte Growth

Factor (HGF). Upon binding to the extracellular domain of the enzyme, it triggers phosphorylation of tyrosine residues and régulâtes several downstream events such as cell prolifération. Cell prolifération assays were carried out using the high Met expressing cell line (MDA-MB-231) according to the following schedule:

Day 1: Cells were plated In 96-well plates in complété growth medium.

Day 2: Media was replaced with starvation medium containing 0.04% BSA.

Day 3: Inhibitors at the desired concentrations and HGF (50 ng/ml) were added.

Day 5: Cell viability was determined using the 3-[4,5-dimethylthiazo1-2-yl]-2,5diphenyltetrazolium bromide (MTT) dye réduction test.

The compounds of the présent invention tested potently inhtbîted HGF-induced Met 15 phosphorylation in MDA-MB-231 cells thereby implicating their rôle in the modulation of the HGF/Met axis in breast cancer.

168

Results: The results are provided below in Table 8 as IC50 values.

Table 8
Example No	IC 50
Example 6	+
Example 25	+
Example 30	+
Example 33	++
Example 1006	++
+ = S 10 ; ++= > 10 to £50;in nM

Hépatocyte Growth Factor (HGF) Induced Cell Scatter:

Human prostate cancer (PC3), human breast cancer (MDAMB231), Human lung 5 adenocarcinoma (NCIH-441) cells were individually allowed to grow in small colonies by plating them in low density (20,000cel1s/well) in growth media supplemented with 10% foetal bovine sérum and incubated ovemight at 37° C and 5% CO2. The next day each of these cells were placed în starvation media, i.e. serum-free growth media and incubated ovemight at 37° C and 5% CO₂. Test compounds were added at required concentrations in complété growth media 10 supplemented with foetal bovine sérum and allowed an incubation of 2 hours. Cells were stimulated by repladng the test compounds with complété growth media containing 40ng/ml HGF and incubated for 48 hrs. Cell scatter was observed as dissémination of the cells under effect of HGF in comparison to unstimulated cells growing in small colonies.

Results: Exemplary compounds of the invention potently inhibited HGF-induced PC3, 15 MDAMB231 and NCIH-441 cell scatter when tested @ 1 to 1000 nM thereby indicating their potential effect and therapeutic utility in metastasis.

Hépatocyte Growth Factor (HGF) Induced Scratch Wound Assay for Cell Motility:

Individually 60,000ceIls/well each of Human prostate cancer (PC3), human breast cancer (MDAMB231), Human lung adenocarcinoma (NCIH-441) were plated in growth media

169 r

supplemented with 10% foetal bovine sérum and incubated at 37° C and 5% CO₂. grown to confluency. A channel was introduced between cells using a 200μ! tip and fresh sérum containing media was added along with inhibitors and HGF (50ng/ml). Cells were incubated ovemight at 37° C and 5% CO₂ and cell motîlity was observed under microscope as migration of cells into the artifidally created space.

Results : Exemplary compounds of the invention potently inhibited HGF-induced PC3, MDAMB231 and NCIH-441 cell migration when tested @ 1 to 1000 nM thereby indicating their potential effect and therapeutic utilîty in metastasis.

Although the invention herein has been described with reference to particular embodiments, it is 10 to be understood that these embodiments are merely illustrative of the prindples and applications of the présent invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the présent invention as described above and the daims.

Ail publications and patent and/or patent applications ated in this application are herein incorporated by reference to the same extent as if each individual publication or patent application was speafically and individually indicated to be incorporated herein by reference.

Claims

1. A compound of formula (IA-I) (1A-I) or a tautomer, stereoisomer, enantiomer, diastereomer, a prodrug, a pharmaceutically acceptable sait, or N-oxide thereof; wherein

Xis CR¹ or N;

D is substituted or unsubstituted monocyclic aryl or substituted or unsubstituted monocyclic heteroaryl; wherein D is substituted with a group E which is seiected from -CONH-O-(CR^xR^y)p-OR^x, -CONH-tCR’ROp-OR’. -CONH-(CR'R^y)p-NR’'R^y. -CONH-fCR’ROp-StO)^’. -CONH-O-tCR’R^p[cycloalkyl]-(CR^KR^y)p-OR^x,-CONH-{CR^MR^y)p-[cycloalkyll-(CR^IR^y)p-OR^x.-CONH-(CR’'R^y)p-[cycloalkyl](CR^xR^y)p-NR^llR^v,and -CONH-(CR^xR^y)p-[cycloalkyl]-(CR^xR^y)p-S(O)_qR^x; and further D can optionally be substituted with one or more of R¹;

L₂is seiected from -O-, -S(=O)_q-, -NR‘-, -(CR*R^b)n-, -C(=Y)-, -C(=Y)-C(=Y)-, -CR’R^b-C(=Y)CR^aR^b-, -CR’R^b-Y-CR^aR^b-, -C(=Y)-NR^a-, -NR^a-C(=Y)-NR^a-, -S(=O)q-NR^a-, -NR^a-S(=O)q-NR’-, -NR^aNR^a-, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl;

Cy² is independently seiected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

each occurrence of R’ and R² may be same or different and is independently seiected from hydrogen, nitro, hydroxy, cyano, halogen, -OR^a, -S(=O)q-R‘, -NR’R^b, -C(=Y)-R^a, -CR*R^b-C(=Y)-R^a, -CR^aR^b-Y-CR’R^bR^b, -C(=Y)-NR^aR^b, -NR^aR^b-C(=Y)-NR^aR^b, -S(=O)q-NR^aR^b-, -NR^aR^b-S(=O)q-NR’R^b, NR^aR^b-NR*R^b, substituted or unsubstituted C14l alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Cî-β alkynyl, substituted or unsubstituted Cj« cycloalkyl, substituted or unsubstituted C^cycloalkylalkyl, and substituted or unsubstituted cycloalkenyl;

each occurrence of Y is independently seiected from O, S, and NR^a;

171 each occurrence of R* and R^b may be same or different and are independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted C3. t cycloalkyl, substituted or unsubstituted C^e cydoalkylalkyl, and substituted or unsubstituted Cye cycloalkenyl, or when two R* and/or R^b substituents are directly bound to a common atom, they may be joîned to form a substituted or unsubstituted, saturated or unsaturated 3-10 member ring, which may optionally include one or more heteroatoms which may be same or different and are selected from O, NR^e or S;

each occurrence of R^c is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted C24 alkynyl, substituted or unsubstituted Cm cycloalkyl, substituted or unsubstituted Cm cydoalkylalkyl, and substituted or unsubstituted cydoalkenyl:

each occurrence of R’ and R* is independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thîo (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cydoalkenyl, substituted or unsubstituted cydoalkylalkyl, substituted or unsubstituted cydoalkenylalkyl, substituted or unsubstituted heterocycyl, substituted or unsubstituted heterocydylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, -COOR¹, -C(O)R^Z, -C(S)R^Z, -C(O)NR^ZR^Z, C(O)ONR^ZR^Z, -NR^ZR^Z, -NR^ZCONR^ZR^Z, -N(R^Z)SOR^Z, -N(R^Z)SO2R^Z, -(=N-N(R^I)R^I). -NR^ZC{O)OR^Z, , NR^ZC(O)R^Z-, -NR^xC(S)R^y -NR^IC(S)NR^ZR^I, -SONR^IR^I-, -SO2NR^ÏR^I-, -OR¹, -OR^ZC(O)NR^ZR^Z, OR^ZC(O)OR^Z-, -OC(0)R^Z, -OC(O)NR^ZR^Z, -R^ZNR^ZC(O)R^Z, -ROR^Z, -R^ZC(O)OR^Z, -R^ZC(O)NR^ZR^Z, R^ZC(O)R^Z, -ROC(O)R^Z, -SR¹, -SOR¹, -SO2R^t, and -ONO2, or any two of R^x and R* which are diredly bound to a common atom may be joined to form (i) a substituted or unsubstituted, saturated or unsaturated 3-14 membered ring, which may optionally indude one or more heteroatoms which may be the same or different and are selected from O, NR^l or S, or (ii) an oxo (=0), thîo (=S) or imino (=NR^Z); wherein each occurrence of R¹ is independently hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=O), thîo (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cydoalkyl, substituted or unsubstituted cydoalkenyl, substituted or unsubstituted cydoalkylalkyl, substituted or unsubstituted cydoalkenylalkyl, substituted or unsubstituted heterocycyl, substituted or unsubstituted heterocydcyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or

172 unsubstituted heteroaryialkyl, and -ONO₂, or any two of R¹ which are directly bound to a common atom may be joined to form (i) a substituted or unsubstituted, saturated or unsaturated 3-14 membered ring, which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NR (where R' is H or alkyl) or S, or (ii) an oxo (=0), thio (=S) or imino (=NR²);

each occurrence of n independently represents 0,1,2,3 or 4;

each occurrence of p independently represents 0,1-7 or 8; and each occurrence of q independently represents 0,1 or 2.

2. A compound of daim 1, wherein

Dis E ;

E is selected from -CONH-O-iCR’RVOR¹, -CONH-(CR^MR^ï)p-OR’^t. -CONH-(CR^xR^¥)p-NR^xR^¥( -CONH-(CR^xR^¥)p-S(O)qR^x. -CONH-0-(CR^xR^¥)p-[cydoalkyl]-(CR^xR^¥)p-OR^x, -CONH-(CR^XR^¥)P[cycloalkyl]-(CR^KR^y)p-OR^x, -CONH-(CR^xR^¥)P-[cycloa’ky1]-(CR^xR^¥)p-NR^xR^¥. and -CONH-fCR’RV [cydoalkyl]-(CR^IR^¥)p-S(O)qR^x; and

X’, X² and X³ are independently selected from -CR¹, -CR^CR¹, -CR^Z=N, -N=CR^Z, -N=N-, O-, -S- or -N-.

3. A compound of any one of daims 1 and 2, wherein Cy² is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

4. A compound of any one of daims 1-3, wherein Cy² is selected from

Ό, x Λ, ΧχΆ JCO -CO XQ’ XX? XX

JCÙ Xû XÛJC0 X» Xq XQ> XX? ’XQÀ) L XQ-Ç3 jÇQ -ÇQ jÇO jÇQ· ’JÇO 'xp 'JÇQ 'V?

xq 'άλΛχ'ά? cLo xqxq XQ XQ XQ

173

5. A compound of any one of claims 3 and 4, wherein Cy² is selected from

Ό, XÔ XÛ '^ÜXÛ XQ jçq XQ XG

XQ Χ^ΧΦ

6. A compound of any one of daims 1 -5, wherein L₂ is -CR^,R^b-.

7. A compound of claim 6, wherein L₂ is -CH2-, -CH(OH)-, -CHF-, -CF_r, -CH (CH₃)- or -C(CH₃)_r

8. A compound of any one of daims 1-7, wherein L₂ is -CH₂.

9. A compound of formula (IA-I):

(IA-I) or a tautomer, stereoisomer, enantiomer, diastereomer, a prodrug, a pharmaceutically acceptable sait, or N-oxide thereof, wherein

-LrCy² is

R^c (where the squiggly line represents the bond to

174 the bicydic core in formula (IA-I);

each occurrence of R* and R⁶ are independently selected from hydrogen, halogen, and substituted or unsubstituted (C^) alkyl, or both together with the carbon atom to which they are attached form a saturated 3 to 6 member cydic ring which may optionally indude one or more heteroatoms which may be same or different and are seleded from O, NR® and S (where R® îs R¹);

Z is selected from CR®, S, O, NR', R'C=CR', -N=CR'-, and -R'ON-;

Zi is selected from N, NR^C and CR^C;

Z₂ and Z₃ are independently selected from C or N;

R^c 1s absent or selected from hydrogen, hydroxy and halogen;

XisCR¹ or N;

D is substituted or unsubstituted monocyclic aryl or substituted or unsubstituted monocyclic heteroaryi; wherein D is substituted with a group E which is selected from -CONH-O-(CR^XR^¥)P-OR^X, -CONH-(CR^XR^¥)P-OR^X -CONH-(CR^xR^y)p-NR^xR^¥, -CONH-(CR^xR^¥)p-S(O)_qR^x, -CONH-O-(CR^xR^y)p[cycloalkyl]-{CR^xR^y)p-OR^x,-CONH-(CR^xR^¥)p-[cycloalkyl]-(CR^xR^y)p-OR^x,-CONH-(CR^xR^y)p-[cycloalkyl](CR^XR^¥)P-NR^XR^¥. and -CONH-CCR’R^p-tcycloalkylHCR'ROp-StOJqR’; and further D can optionally be substituted with one or more of R¹;

each occurrence of R¹ and R² may be same or different and is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, -OR”, -S(=O)q-R^a, -NR^aR^b, -C(=Y)*R’, -CR^aR^b-C(=Y)-R^a, -CR^aR^b-Y-CR^aR^bR^b, -C(=Y)-NR^aR^b, -NR^eR^b-C(=Y)-NR^aR^b, -S(=O),-NR^aR^b-, -NR’R^b-S(=O)q-NR^aR^b, NR^aR^b-NR^aR^b, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Qw cycloalkylalkyl, and substituted or unsubstituted cycloalkenyl;

each occurrence of Y is independently selected from O, S, and NR^a;

each occurrence of R^x and R^¥ is independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocycyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryi, substituted or unsubstituted heteroarylalkyl, -COOR¹, -C(O)R^Z, -C(S)R^Z, -C(O)NR^ZR^Z, C(O)ONR^ZR^Z, -NR^ZR^Z, -NR²CONR²R^Z, -N(R^Z)SOR^Z, -N(R^Z)SO2R^Z, -(=N-N(R^t)R¹), -NR²C(O)OR², , NR^ZC(O)R^Z-, -NR^xC(S)R^y -NR^zCtS)NR^zR^z, -SONR^ZR^Z-, -SO2NR^ZR^Z-, -OR¹, -OR^ZC(O)NR^ZR^Z, OR^ZC(O)OR^Z-, -OC(0)R^Z, -OC(O)NR^ZR^Z, -R^ZNR^ZC(O)R^Z, -ROR^Z, -R^zC(0)0R^z, -R^ZC(O)NR^ZR^Z, R²C(0)R², -ROC(O)R^Z, -SR^Z, -SOR¹, -SO2R^Z, and -ONO2, or any two of R^x and R^¥ which are directly bound to a common atom may be joined to form (i) a substituted or unsubstituted, saturated or unsaturated 3-14 membered ring, which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NR^Z or S, or (ii) an oxo (=O), thio (=S) or imîno (=NR^Z), wherein

175 each occurrence of R¹ is independently hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cydoalkenyl, substituted or unsubstituted cydoalkylalkyl, substituted or unsubstituted cydoalkenylalkyl, substituted or unsubstituted heterocycyl, substituted or unsubstituted heterocydcyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, and -0N0₂, or any two of R¹ which are directly bound to a common atom may be joined to form (i) a substituted or unsubstituted, saturated or unsaturated 3-14 membered ring, which may optionally indude one or more heteroatoms which may be the same or different and are seleded from O, NR’ (where R' is H or alkyl) or S, or (H) an oxo (=0), thio (=S) or imino (=NR^I);

each occurrence of q independently represents 0,1 or 2; and each occurrence of p independently represents 0,1-7 or 8.

10. A compound of formula (IA-I):

D is

176

LrCy² is R^c (where the squiggly line represents the bond to the bicydic core in formula (IA-l);

Xis CR¹ or N;

X¹, X² and X³ are independently selected from -CR¹, -CR^CR¹, -CR^N, -N=CR^Z, -N=N-, O-, -S- or -N-;

Z is selected from CR^e, S, O, NR^C, R^cC=CR^c. -N=CR^C-, and -R'C=N-;

Ζ_Ί is selected from N, NR^C and CR^C;

Z₂ and Z₃ are independently selected from C or N;

E is -CONH-O-fCR’R^p-OR’, -CONH^CR’R^p-OR’, -CONH-(CR’R^y)p-NR'R^y. -CONH(CR^xR^y)p-S(O)qR^x< -CONH-O-(CR^xR^ï)p-[cydoalkylHCR^I,R^v)p-OR^x, -CONH-fCRTVMcycloalky!](CR^ïR^y)p-OR\ -CONH-(CR'R^Y)p-[cycloalkyl}-{CR’R^y)p-NR’^tR^y or -CONH-(CR^xR^y)P4cycloalkyl}(CR^xR^y)p-S(O)qR^M each occurrence of R¹ and R² may be same or different and is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, -OR, -S(=O)q-R^a, -NR*R^b, -C(=Y)-R’t -CR*R^b-C(=Y)-R’, -CR*R^b-Y-CR’R^bR^b, -C(=Y)-NR^aR^b, -NR’R^b-C(=Y)-NR^,R^b, -S(=O)q-NR^aR^b-, -NR^aR^b-S(=O)q-NR^aR^b, NR^aR^b-NR^aR^b, substituted or unsubstituted Cm alkyl, substituted or unsubstituted Cm alkenyl, substituted or unsubstituted Cm alkynyl, substituted or unsubstituted Q» cycloalkyl, substituted or unsubstituted Cm cydoalkylalkyl, and substituted or unsubstituted Cm cydoalkenyl;

each occurrence of Y is independently selected from O, S, and NR^a;

each occurrence of R^a and R^b may be same or different and are independently seleded from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted Cm alkyl, substituted or unsubstituted Cm alkenyl, substituted or unsubstituted Cm alkynyl, substituted or unsubstituted C3. _e cydoalkyl, substituted or unsubstituted Cm cydoalkylalkyl, and substituted or unsubstituted Cm cydoalkenyl, or when two R^a and/or R^b substituents are directly bound to a common atom, they may be joined to form a substituted or unsubstituted, saturated or unsaturated 3-10 member ring, which may optionally indude one or more heteroatoms which may be same or different and are selected from O, NR^e or S, preferably each occurrence of R^a and R^b are independently seleded from hydrogen, halogen, and substituted or unsubstituted (Cm) alkyl, or both together with the carbon atom to which they are attached form a saturated 3 to 6 member cydic ring which may

177 optionally include one or more heteroatoms which may be same or different and are selected from

O, NR* and S (where R* is R¹);

each occurrence of R^e is independently selected from hydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted Cî-e alkenyl, substituted or unsubstituted C^ alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Cm cydoalkylalkyl, and substituted or unsubstituted Cm cydoalkenyl, preferably R^cis absent or selected from hydrogen, hydroxy and halogen;

each occurrence of R* and R^y is independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cydoalkyl, substituted or unsubstituted cydoalkenyl, substituted or unsubstituted cydoalkylalkyl, substituted or unsubstituted cydoalkenylalkyl, substituted or unsubstituted heterocycyl, substituted or unsubstituted heterocydylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, -COOR¹, -CfOJR¹, -C(S)R^l, -C(O)NR^ZR^Z, C(O)ONR^ZR^Z, -NR^ZR^Z, -NR^ZCONR^ZR^Z, -NfR^SOR¹, -N(R^Z)SO2R^Z, -<=N-N(R^Z)R^Z), -NR^ZC(O)OR^Z, , NR^IC(O)R^I-, -NR^<C(S)R^y -NRHXSJNR'R*, -SONR^IR^I-, -SO2NR^lR^l-, -OR¹, -OR^ZC(O)NR^ZR^Z, OR^IC(O)OR^Ï-, -OC(O)R^Z, -OC(O)NR^ZR^Z, -R^rNR^IC(O)R^I, -ROR^Z, -R^ZC(O)OR^Z, -R^ïC(O)NR^zRⁱ, R^ZC(O)R^Z, -ROC(0)R\ -SR¹, -SOR¹, -SO2R^Z, and -ONO2, or any two of R and R^y which are diredly bound to a common atom may be joined to form (i) a substituted or unsubstituted, saturated or unsaturated 3-14 membered ring, which may optionally indude one or more heteroatoms which may be the same or different and are selected from O, NR* or S, or (ii) an oxo (=0), thio (=S) or imino (=NR^Z); wherein each occurrence of R¹ Is Independently hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cydoalkyl, substituted or unsubstituted cydoalkenyl, substituted or unsubstituted cydoalkylalkyl, substituted or unsubstituted cydoalkenylalkyl, substituted or unsubstituted heterocycyl, substituted or unsubstituted heterocydcyalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, and -0N0₂, or any two of R¹ which are dîrectly bound to a common atom may be joined to form (i) a substituted or unsubstituted, saturated or unsaturated 3-14 membered ring, which may optionally indude one or more heteroatoms which may be the same or different and are selected from O, NR' (where R’ is H or alkyl) or S, or (ii) an oxo (=0), thio (=S) or imino (=NR^I);

178 each occurrence of q independentiy represents 0,1 or 2:

each occurrence of p independentiy represents 0,1-7 or 8.

11. A compound of daim 2 or daim 10, wherein X¹ and X² are CR¹ and X³ is independentiy seleded from -CR^CR¹ and -S-.

5

12. A compound of daim 11, wherein X¹ is CH, X² is CR¹ and X³ is -CR^CR¹, wherein R¹ is hydrogen, haiogen or substituted or unsubstituted alkyl.

13. A compound of any one of daims 1-12, wherein D is seleded from

HjN

ΉγΫ” AV?, ό-’ϊ?'. b Xf?. fi.

-,ΝΗ O „.NH CF, „.NH CH, _.NH O „.NH a NH a F „NH F „NH ÔF, i y y y y y .

x Λ .c Λ Λ Λ Λ Λ A .

b? J? b? χφ

F _ΝΜ f CF. ^ΝΗ » _ΝΗ Ο _ΝΗ F ^ΝΗ F _ΝΗ CF· _ΝΗ <

ί .¥ ϊ ,ϊ t t t t .t

179

180

181 tS2

14.

J νΧ νΑ νΑ νΑ η s %A/^s °γψ vV °rV °yV Yl AlHF σ'™ ^α ο-ΝΠ CFj Τη CK₃ Ο / f ? / V £_η OH ΟΗ οη οη î^c ρΧ. Ν=Ζ ΐ⁴^ ^ΝΑ °γ^γ VV ‘VS'’⁵

Ο-^ΝΗ α θ,ΝΗ α ^ΝΗ i JlH I _ο/νη I '/ ν’ ψ Ψ * Ψ ΟΗ ΟΗ ΟΗ ΟΗ ΟΗ

A compound of daim 13, wherein D is selected from hAA# 'H-O/T ’vA^ jçUyO /γΑίΤ ο ο οο ο ο \_j ο ά θγ(Ζ ’ / Y^rÇ^

P ° ° ₍ ϊΨ\ /<vⁿ/F, °w °yÇ^ °yÇ^ °yÇ^ ^oyÇ^ ^ούΌ^ θγΟ^ °yU u ^FW o-*^{1 7} O-*¹ * <y^NH « o-”” *· o-^Ο-* °

-V .AVi l ,i ,i ,-i.

·& ·& ·& -F -8 *8 ·& ·& X Y X x x x Y ,Ê?.

183 t

15.

A compound of any one of daims 1-12, wherein D is selected from

5

16.

17.

10

18.

A compound of daim 15, wherein E is selected from

HN^O _HN^₀

J°. YHO^X HCT

A compound of daim 15 or daim 16, wherein E is selected from HN'^O HN'^O H A HN'^O HN'^O / r / ? è

WS . , HOr . HC/S ^OT HO^X

A compound of daim 15, wherein each occurrence of R¹ is selected from hydrogen, halogen or substituted or unsubstituted alkyl.

19. A compound of daim 18, wherein each occurrence of R¹ is selected from hydrogen, fluoro, chlore, methyl or CF₃.

20. A compound of daims 9-19, wherein each of R* and R^b is hydrogen, alkyl or halogen.

184

21. A compound of any one of daims 9-20, wherein

a) both R“ and R^b are hydrogen;

b) R“ is methyl and R^b is hydrogen;

c) R* is fluoro and R^b is hydrogen;

d) R* and R^b both are fluoro; or

e) R and R^b both are methyl.

22. A compound of any one of daims 9-21, wherein

Z is CR^C, N, S, O, HC=CH- or-N=CH-;

Z, is CH or N;

Z₂ is C; and

Z3 is C or N.

23. A compound of any one of daims 9-22, wherein

a) Z is -HC=CH-, -S- or -O- ; Z, is CH ; Z₂ is C and Z₃ is C or N;

b) Zis-HC=CH-, Z, Is CH ; Z₂ is C; and Z3 is C;

c) Z is CH. Z, is CH, Z₂ is C and Z₃ is N;

d) Z is -S-, Z1 is CH, Z₂ is C and Z₃ is C;

e) Z is -O-, Z, is CH, Z₂ is C and Z₃ is C; or

f) Z is -CH-, Z, is NH, Z₂ is C and Z₃ is C.

24. A compound of any one of daims 9-23, wherein each occurrence of R^c Is hydrogen or fluoro.

25. A compound of any one of daims 1-24, wherein X Is N or CR¹ and R¹ is H, substituted or unsubstituted C,^ alkyl, NH₂, OH, CN or CONH₂.

26. A compound of any one of daims 1-25, wherein X is N.

27. A compound of any one of daims 1-26, wherein each R² is H.

28. A compound selected from:

N-(2-amino-2-oxoethyl)-4-(3-{quinolin-7-y1methyl)-3H-(1,2,3]triazolo[4,5-b]pyridin-5yl)benzamide:

N-(2-( m ethyla mino}-2-oxoethyl )-4-( 3-(qui nolin-6-ylmethyl }-3H -[ 1,2,3]triazolo[4,5-b] pyridi n-5yl) benzamide:

N-(3-amino-3-oxopropyiy4-(3-{quinolin-6-ylmethyl)-3H-[1,2_f3]triazo!o[4,5-b]pyridin-5yl)benzamide:

N-{3-(methy1amino)-3-oxopropyl)-4-(3-(quinolin-6-ylmethyl)-3H41.2_l3]triazolo[4_l5-b]pyridin5-yl)benzamide

2-chloro-N-{2-(pyrrolidin-1 -ylJethylJ^S-fquinolin^-ylmethylJ-SH’Il _t2,3]triazolo[4,5b]pyridin-5-ylJbenzamide:

2-chloro-N-(2-hydroxyethoxy)-4-(3-{quinoIin-6-ylmethy!)-3H-{1,2,3]triazolo[4,5-bl pyridin-5yljbenzamide:

2-diloro-N-(2-hydroxyethoxyJ-4-(3-(qutnolin-6-ylmethylJ-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl) benzamide hydrochloride:

2-chloro-N-(2-hydroxyethoxyJ-4-(3-(quinolin-6-y!methylJ-3H-[1,2_l3]triazolo[4,5-b]pyridin-5yljbenzamide 4-methylbenzenesulfonate

2-chloro-N-(2-hydroxyethoxy)-4-(3-(quinolîn-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin’5yljbenzamide hydrobromide:

sodium (2-chloro-4-(3-(quinolin-6-ylmethylJ-3H-[1.2_l3]triazolo[4,5-b]pyridin-5-ylJbenzoy1)(2hydroxyethoxyjamide:

2-chloro-4-(3-{(7-fluoroquinolin-6-y1)methyl)-3H-{1,2,3]triazolo[4,5-b]pyridin-5-y1)-N-(2hydroxyethoxyjbenzamide:

2-ch!oro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl}-N-(2hydroxyethoxyjbenzamide hydrochloride:

sodium (2-chloro-4-(3-{(7-f!uoroquinolin-e-yl)methy!)-3H-i1,2,3]triazo!o[4,5-b]pyridin-5yl)benzoyl)(2-hydroxyethoxy)amtde:

2-chloro-4-(3-{(7-fluoro-2-oxO'1,2’<lihydroquino!in-6-y1)methyl)-3H-[1_t2,3]triazolo[4,5b]pyridîn-5-ylJ-N-(2-hydroxyethoxy)benzamide

2.6- difluoro-N-(2-hydroxyethoxy)-4-(3-(quinolin-6-ylmethyl)-3H-i1.2,3]triazolo[4,5-b]pyridin-

5-yl)benzamide:

2_l6-difluoro-N-(2-hydroxyethoxy)-4-(3-(quinolin-6-ylmethyl)-3H’{1,2,3]triazo!o[4_l5-b]pyridin-

5-ylJbenzamide hydrochloride:

sodium (2,6-difluoro-4-(3-(quinolin-6-y!methy1J-3H-[1_I2,3]triazolo[4,5-b]pyridin-5yl)benzoy1)(2-hydroxyethoxy)amide:

2.6- difluoro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-{1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(2hydroxyethoxyjbenzamide

2.6- difluoro-4-(3-{(7-fluoroqurnolin-6-ylJmethylJ-3H-{1,2,3]triazolo[4,5-b]pyridin-5-y!)-N-(2- hydroxyethoxyjbenzamide hydrochloride

186 sodium (2,6-dîfluoro-4-(34(7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5yl)benzoyl)(2-hydroxyethoxy)amide:

2-fluoro-N-(2-hydroxyethoxy)-4-(3-(quÎnolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5yljbenzamide:

2-(2-chloro-4-(3-{quinolin-6-ytmethyf)-3H-{1,2,3Jtriazolo[4,5-bJpyridin-5yt)benzamîdooxy)ethyl acetate:

(S)-2-(2-chloro-4-(3-(quinolin-6-ylmethyl)-3H-[1.2,3]triazolo[4,5-b]pyridin-5yl)benzamidooxy)ethyl 2-(tert-butoxycarbonylamino)propanoate:

(S)-2-(2-chloro-4-{3-(quinolin-6-y!methy1)-3H-[1,2,3]triazolo[4,5-b]pyridin-5yl)benzamidooxy)ethyl 2-aminopropanoate:

2-(2-ch!oro-4-(3-(quino!in-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5yl)benzamidooxy)ethyl pivalate:

2-(2-chloro-4-(3-(quinolin-6-yfmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5yf}benzamidooxy)ethyf isobutyrate:

2-(2-chloro-4-(3-(quinolin-6-yl methyl )-3H-{1,2,3]triazolo[4,5-b]pyridÎn-5y!)benzamidooxy)ethyl 2-benzamidoacetate:

2-chloro-N-(2-hydroxyethoxy)-4-(3-((2-methylquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5b]pyridin-5-yl)benzamide:

4-(3-{benzo[d]thiazol-6-ylmethyt)-3H-{1_l2,3]triazolo[4,5'b]pyridin-5-yl)-2-chloro-N-{2hydroxyethoxy)benzamide:

4-(3-(benzo[d]thiazol-6-ylmethyl)-3H-{1.2,3Jtriazolo[4,5-b]pyridin-5-yl)-2,6-difluoro-N-(2hydroxyethoxy)benzamide:

sodium (4-(3-(benzo[d]thiazol-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2,6difluorobenzoyl)(2-hydroxyethoxy)amide:

4-(3-(benzo[d]thiazol-6-ylmethyl)-3H-[1,2_l3ltriazolo[4_I5-b]pyridin-5-yl)-2-fluoro-N-(2hydroxyethoxyjbenzamide:

2.6- difluoro-N-(2-hydroxyethoxy)-4-(3-((2-methy!quinolin-6-yl)methyl)-3H-{1,2,3]triazolo[4,5b]pyridin-5-yl)benzamide

2.6- difluoro-N-{2-hydroxyethoxy)-4-{3-{(2-methy1quinolin-6-yl)methyl)-3H-[1_t2.3]triazolo[4,5b]pyridin-5-yl)benzamide hydrochloride:

N-(2-hydroxyethoxy)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3ltriazolo[4,5-b]pyridin-5yljbenzamide:

187

N-(2-hydroxyethoxy)-4-(3-(quinolin-6-y1methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2(trifluoromethyl)benzamide:

4-{3-((7-fluoroquinolin-6-yl)methyl}-3H-[1,2_I3]triazolo[4,5-b]pyridin-5-yl)-N-(2hydroxyethoxy)-2-(trifluoromethyl)benzamide:

4-(3-((7-fl uoroqui noli n-6-yl )methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl )-N-(2hydroxyethoxy)-2-(trifluoromethyl)benzamide hydrochloride:

N-(2-hydroxyethoxy)-2-niethyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5yl)benzamide:

N-(2-hydroxyethoxy)-2-methyt-4-(3-(quinolin-6-yimethyl)-3H-[1,2,3]triazofo[4_l5-b]pyridin-5yljbenzamide hydrochloride:

N-(2-hydroxyethoxy)-2-methyl-4-(3-(quinolin-6-y1methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5yl)benzamide hydrobromîde:

N42-hydroxyethoxy)-2-methyl-4-(3-(quinolin-6-ylmethy!)-3H-[1,2,3]triazolo[4,5-b]pyridin-5yljbenzamide 4-methylbenzenesulfonate:

N-(2-hydroxyethoxy)-2-methyl-4-(3-((2-oxo-1,2-dihydroquinolin-6-yl)methyl)-3H[I^.SJtriazolo^.S-bJpyridin-S-ylJbenzamide

6-((5-(4-(2-hydroxyethoxycarbamoyl)-3-methy!phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3- yl)methyl)quinoline 1-oxide

4-(3-{(7-fluoroquinolin-6-yl)methyl}-3H-[1_t2,3]triazolo[4_l5-b]pyridin-5-yl)-N-(2hydroxyethoxy)-2-methyibenzamÎde:

4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2_l3]triazoloi4,5-b]pyridin-5-y1)-N-(2hydroxyethoxy>2-niethy1benzamide hydrochloride:

2-fluoro-4-(3-((7-fluoroquinolin-e-yl)methyt)-3H-(1.2,3]triazolo[4,5-b]pyridin-5-yl)-N-(2hydroxyethoxyjbenzamide:

2-fl uoro-4-(3-((7’fl uoroquinoli n-6-yl )methyl }-3H-[1,2,3]triazo!o[4,5-b]pyridi n-5-yl)-N-(2hydroxyethoxyjbenzamide hydrochloride:

2-chloro-N-(2-hydroxypropoxy)-4-(3-(quÎnolin-6-ylmethyl)-3H-[1,2_l3]triazolo[4,5-b]pyridin-5yljbenzamide:

ethyl 2-(2-chloro-4-(3-(quÎnolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5yl)benzamidooxy)acetate:

2-chloro-N-(2-hydroxy-2-methyfpropoxy)-4-(3-(quinofin-6-yfmethyt)-3H-[1.2,3]triazolo[4,5b]pyridin-5-yl)benzamide:

188 (S)-2-chloro-N-(2-hydroxypropoxy)-4-(3-(quinoîin-6-y!methyl .2,3]triazolo[4,5b]pyridin-5-yl)benzamide:

(R) -2-ch!oro-N-(2-hyd roxypropoxy)-4-(3-{quinoli n-6-y!methyl)-3H-[1,2 ,3]triazolo[4, 5b]pyridin-5-yl)benzamide:

N-(2-hydroxy-2-methy!propoxy)-2-methy1-4-(3-{quinolin-6-yîmethyl}-3H-[1,2,3]triazolo[4_l5b]pyridin-5-y1)benzamide:

2,6-difluoro-N-(2-hyd roxy-2-methylpro poxy)-4-(3-(q ui noli n-6-ylm ethyl )-3 H-[1,2,3]triazolo[4,5b]pyridin-5-yl)benzamide:

2-fluoro-N-(2-hydiOxy-2-methylpropoxy)-4-{3-(quino!in-6-ylmethyl)-3H-[1,2,3]triazolo[4_l5b]pyridin-5-yl)benzamide:

(S) -N-(2-hydroxypropoxy)-2-methyl-4-(3-{quinolin-6-ylmethyl)-3H-[1_l2,3]triazolo[4,5bjpyridi n-5-y1)benzam ide

N-(2-hydroxy-2-methylpropoxy)-2-methyl-4-{3-((2-oxo-1,2-dihydroquinolin-6-yl)methyl)-3H- [1.2.3] triazolo[4,5-b]pyridin-5-y1)benzamide (R)-N-(2-hydroxypropoxy)-2-methyt-4-(3-(quinolin-6-ylmethyl)-3H-[1.2,3]triazolo[4,5b]pyridin-5-yl)benzamide

N-( 1 -hydroxy-2-methylpropan-2-yloxy)-2-methyl-4-(3-(quinolin-6-ylmethyl)-3H[ 1,2,3]triazolo[4,5-b]pyridi n-5-yl)be nza mide

2-ch!oro-N-(1-hydroxy’2-methylpropan-2-yloxy)-4-(3-{quinolin-6-ylmethyl)-3H- [1.2.3] triazolo[4,5-b]pyridin-5-yl)benzamide

N-(2-Hydroxy-2-methyl-propoxy}-2-methyl-4-[3-(1-oxy-quinoîin-6-ylmethyl)-3H- [1.2.3] triazolo[4,5-b]pyridin-5-yl]-be nza mide

N-H ydroxy-2-methyl-4-(3-q ui nolin-6-ylm ethyl-3 H-[1,2,3]triazolo[4,5-b] pyridin-5-yl)benzamide

2-(2-methyl-4-(3-(quinolin-6-y!methyl}-3H-[1,2,3]triazolo[4,5-b]pyridin-5yl)benzamidooxy)ethyl acetate

2-(2-methyl-4-(3-(quinolin-6-ylmethy1)-3H-[1_t2_l3]triazolo[4,5-b]pyridin-5yl)benzamidooxy)ethyl isobutyrate

2-(2-methy!-4-(3-(quinolin-6-ylmethyl)-3H’{1,2,3]triazolo[4,5-b]pyridin-5yl)benzamidooxy)ethyl pivalate

2-(2-methyl-4-(3-{quinolin-6-y!methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5yl)benzamidooxy)ethyl benzoate

1S9

2-(2-methy1-4-(3-{quinolin-6-ylmethyl)-3H-{1,2,3Jtriazofo[4_l5-b]pyridin-5y1)benzamidooxy)ethy! furan-2-carboxytate

1 -(3-((7-fiuoroquinolin-6-yl)methy!)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yi)ethanone

2-(1-{3-{quÎnolin-6-ylmethyl)-3H-(1,2_l3]triazolo[4,5-b]pyridin-5-yl)ethy1idene) hydrazinecarboxamide hydrochloride

2-(1 -<3-(quinolÎn-6-ylmethyl)-3H-[1 ^.Sltriazolo^.S-bJpyridin-B-ylJethylidene) hydrazinecarbothioamide

6-((5-(1-(2-(pyridîn-2-yl)hydrazono)ethyl)-3H-[1.2,3]triazoloI4,5-b]pyridin-3-yl)methyl) quinotine

2-(amino(3-(quinolin-6-ylmethyl)-3H-[1_>2,3]triazolo[4_l5-b]pyridin-5-yl)methylene) hydrazinecarboxamide:

tert-butyl 2-(1-(3-(quinolin-6-ylmethyl)-3H-[1_t2,3]triazolo[4,5-b]pyridin-5-yl)ethylidene) hydrazinecarboxylate:

(E/ZJ-1 -{1 -(3-(quinolin-6-y!methy!)-3H-[1,2,3]triazolo[4,5-b]pyridin-5yl)ethyiideneamino)imidazolidine-2,4-dione:

N-ethy1-2-(1-(3-(quinolin-6-y1methy1)-3H-[1_l2,3]triazolo[4,5-b]pyridin-5-y1)ethylidene) hydrazinecarbothioamide:

2-(1-(3-(quinolin-6-y!methyl)-3H-{1,2,3]triazolo[4_l5-b]pyridin-5-yl)ethylidene) hydrazinecarbothioamide hydrochloride:

2-(1-(3-{(7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-y1)ethylÎdene) hydrazinecarbothioamide:

Methyl 2-( 1 -(3-(quinolin-6-y!methyl)-3H-[1 ,2,3]triazolo[4,5-b]pyridin-5-yl)ethytidene) hydrazinecarboxylate:

1-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2_l3]triazolo[4_l5-b]pyridin-5-yl)ethanone oxime:

1-(3-((7-fluoroquînolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl}ethanone O-methyl oxime:

1 -(3-{(7-fluoroquinolin-6-y1)methyl)-3H-[1,2,3]triazo!o[4,5-b]pyridin-5-yl)ethanone 0-2hydroxyethyl oxime:

1 -(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazo!o[4₁5-b]pyridin-5-yl)ethanone 0-2-hydroxyethyl oxime:

1 -<3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)ethanone O-2-aminoethyl oxime:

190

1 -(2-(1 -(3-(quinolîn-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl) ethyfideneam inooxyjethyl) urea :

1- (3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2_l3]triazolo[4,5-b]pyridin-5-yt)ethanone O-methyl oxime hydrochloride:

1 -(3-((7-fluoroquinolin-6-yl}methyl}-3H-(1 _t2,3]triazolo[4,5-bÎpyridin-5-yl)ethanone oxime hydrochloride:

1 -(3-{(7-fluorüquino!in-6-y!)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)ethanone 0-2hydroxyethy! oxime hydrochloride:

N-ÎS-Dimethylamino-propylJ-i-ÎS-quinolin-e-ylmethyl-SH-ll^.Sltriazolo^.S-bJpyridin-S-yl)benzamide dihydrochloride:

or a pharmaceutically acceptable salts thereof.

29. A compound selected from:

2- chloro-N-(2-(dimethy!amino)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-irnidazo[4,5-b]pyridin-5yl)benzamide:

2-chloro-N-(3-(dimethylamino}propyl)-4-(3-{quinolin-6-ylmethyl)-3H-Îmidazo[4,5’b] pyridïn-5yljbenzamide:

2-chloro-N-methoxy-4-(3-(qui noli n-6-ylmethyi)-3H-imidazo[4,5-b]pyridin-5-yl ) benzam ide:

N-(2-(dimethylamino)ethyl)-2,6-difluoro-4-(3-(quinolin-6-ylmethyl)-3H-imidazo[4₁5-b]pyridin-

5-y1)benzamide:

2,6-difluoro-N-methoxy-4-(3-(quinolÎn-6-ylmethy1)-3H-imidazo[4,5-b]pyridin-5-y1) benzamide:

1- (3-(quinolin-6-ylmethyl)-3H-imidazo[4,5-b]pyridin-5-y1)ethanone:

2- (1-(3-(quinolÎn-6-ylmethy1)-3H-imidazo[4_l5-b]pyridin-5-yl)ethylidene) hydrazinecarboxamide:

2-(1-(3-(quinolin-6-ylmethyl)-3H-imidazo[4_l5-b]pyridin-5-yl)ethylidene) hydrazinecarbothîoamide:

(R) -2-fluoro-N-(2-hydroxypropyl)-4-(3-(quinolin-6-ylmethyl)-3H-imidazo[4,5-b]pyridin-5yl)benzamide (S) -2-fluoro-N-(2-hydroxypropyl)-4-(3-(quinolin-6-yîmethyl)-3H-Îmidazo[4,5-b]pyridin-5yl)benzamide

N-(2-Hydroxy-ethoxy)-2-methyl-4-(3-quinolin-6-ylmethyl-3H-imidazo[4,5-b]pyridin-5-yl)benzamide

191

N-(2-Hydroxy-2-methyl-propoxy)-2-methyl-4-(3-quinolin-6-y1methyl-3H-imidazo[4,5b]pyridin-5-yl)-benza mide

2-Chloro-N-(2-hydroxy-ethoxy)-4-(3-quinonn-6-ylmethyl-3H-imidazo[4,5-b]pyridin-5-yl)benzamide

2-Chlorc>N42-hydroxy-2-methy1-piOpoxy)-4-(3-quinolin-6-ylmethy1-3H-imidazo[4,5-b]pyridin-

5-yl)-benzamide:

or a pharmaceutically acceptable salts thereof

30. A compound selected from:

6-((5-{4-carbamoy1-3_l5-difluorophenyl)-3H-[1,2,3]triazolo[4,5-bJpyridin-3-yl)methyl)quinoline

1-oxide:

6-((5-(4-carbamoyl-3-chlorophenyl)-3H41,2_l3]triazolo[4,5-b]pyridin-3-y1)methy1)-7fluoroquinoline 1-oxide:

2.6- difluoro-4-(3-(quinolin-6-yfmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide 2,2,2trifluoroacetate:

2-chloro-4-(3-{(2-oxo-1,2-dÎhydroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5yljbenzamide:

2.6- difluoro-4-(3-((2-oxo-1 ^-dihydroquinolin-O-ylîmethylJ-SH-II^.Sltriazolo^.S-bjpyridin-Syljbenzamide:

4-(3-(benzo[d]thiazol-6-y1methyl)-3H-{1,2,3]triazolo[4,5-b]pyridin-5-yl)-2,6difluorobenzamide:

2.6- difluoro-4-(3-((7-fluoroquinolin-6-y!)methy!)-3H-[1_l2,3]triazolo[4,5-b]pyridin-5-yl) benzamide:

2-Ch!oro-4-(3-(quinolin-6-ylmethyl)-3H-imidazo[4,5-b]pyridin-5-yl)benzamide:

2-chloro-4-(3-(quinolin-6-y1methyl)-3H-imidazo[4,5-b]pyridin-5-y1)benzamide hydrochloride:

2.6- difluoro-4-{3-{quinolin-6-y!methyl}-3H-imidazo[4,5-b]pyridÎn-5-y!)benzamide:

Methyl 2-chloro-4-(3-(quinolin-6-ylmethyl)-3H-imidazo[4,5-b]pyridin-5-yl)benzoate:

2-chloro-4-(3-(quinolin-6-ylmethyl)-3H-imidazo[4,5-bJpyridin-5-yl)benzoicacid: 2-chloro-N-ethy1-4-(3-(quinolin-ô-ylmethy1)-3H-imidazo[4,5-b]pyridin-5-y1)benzamide:

Methyl 2,6-difluoro-4-{3-(quinolin-6-y!methyl)-3H-imidazo[4,5-b]pyridin-5-y!)benzoate:

2.6- difluoro-4-(3-{quinonn-6-y1methy1)-3H-imÎdazo[4,5-b]pyridin-5-yl)benzoic add:

N-ethy1-2,6-difluoro-4-(3-(quinolin-6-ylmethy1)-3H-imidazo[4,5-b]pyridin-5-yl) benzamide: 2-chloro-N-methyl-4-(3-(quinolin-6-ylmethyl)-3H-imidazo[4,5-b]pyridin-5-yl) benzamide:

192

2-methyl-4-(3-(quinolin-6-ylmethyl)-3H-imidazo[4,5-b]pyridin-5-yl)benzamide:

2-chloro-4-(3-(quinol in-6-ylm ethyl)-3H-i mid azo[4,5-b] pyridin-5-yl)benzamide 2,2,2trifluoroacetate:

2-chloro-4-(2-methyl-3-(quinolin-6-y1methy!)-3H-lmidazo[4,5-b]pyridin-5-yl) benzamide:

2-chloro-4-(3-(1-(qutnotin-6-yl)ethyl)-3H-lmidazo[4,5-b]pyridin-5-yl)benzamide:

2-ch1oro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-imidazo[4,5-bJpyridin-5-yl)benzamide:

2-chloro-4-(3-((5,7-difluoroquinolin-6-yl)methyl)-3H4midazo[4,5-b]pyridin-5-yl) benzamide:

4-(3-Quinolin-6-y1methyf-3H4midazo[4,5-b]pyridin-5-y1)-2-trifluoromethyl-benzamide

4-(3-(7-Fluoro-quinolin-6-y!methyl)-3H4midazo[4,5-b]pyridin-5-ylI-2-methy!-benzamide

4-{3-(7-Ruoro-quinolin-6-ylmethyl)-3H4midazo[4,5-b]pyridin-5-y1]-2-trifluoromethy1benzamide

4-(3-(5,7-Difluoro-quinolin-6-y1methyl)-3H4nnidazo[4,5-b]pyridin-5-yl]-2-methyl-benzamide

4-(3-(5₁7-Difluoro-qutnolin-6-ylmethyl)-3H4midazo[4,5-b]pyridin-5-yl]-2-trifluoromethylbenzamide

4- [3-(7-Fluoro-quinolin-6-ylmethyl)-3H4midazo[4,5-b]pyridin-5-yl]-2-methyl-benzamide hydrochloride

2,N-Dimethyl-4-(3-quinolin-6-y1methyl-3H-imidazo[4₁5-b]pyridin-5-yl)-benzamide

5- (3-Quinolin-6-ylmethyl-3H4midazo[4,5-b]pyridÎn-5-yl)-pyridine-2-carboxylic add methytamide

5-(3-Quinolin-6-ylmethy!-3H-{1,2,3]triazolo[4,5-b]pyridin-5-yl)-2_t3-dihydro4soindol-1-one

5-(3-Quinolin-e-ylmethy1-3H-imidazo[4,5-b]pyridin-5-yl)-2,3-dihydro-isoindol-1-onQ or a pharmaceutically acceptable salts thereof

31. A pharmaceutical composition comprising a compound of any one of claims 1-30 and a pharmaceutically acceptable carrier.

32. The pharmaceutical composition of daim 31, further comprising one or more additional therapeutic agents and mixtures thereof.

33. The pharmaceutical composition of claim 32, wherein the one or more additional therapeutic agent is an anti-cancer agent, anti-inflammatory agent, immunosuppressive agent, steroid, nonsteroidal anti-inflammatory agent, antihistamine, analgésie, or a mixture thereof.

34. Use of a compound of any one of daims 1-30 in the manufacture of a médicament for the treatment of a disease, disorder, or condition that would benefit from inhibiting catalytic activity of a kinase.

193

35. Use of a compound of claim 34, wherein the kinase is c-Met kinase.

36. A method of Inhibiting the HGF/c-Met kinase signaling pathway in a cell comprising contacting said cell with a compound of any one of claims 1-30.

37. A method of Inhibiting the proliférative activity of a cell comprising contacting said cell with a compound of any one of claims 1-30.

38. A method of înhibiting tumor growth in a patient comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1-30.

39. A method of înhibiting tumor metastasîs in a patient comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1-30.

40. A method for the treatment of a c-Met associated disease or disorder, comprising the step of administering to a subject in need thereof an effective amount of compound of any one of claims 1-30.

41. The method of claim 40, further comprising the step of administering simultaneously or sequentialiy to a subject in need thereof at least one other anti-cancer agent, anti-inflammatory agent, immunosuppressive agent, steroid, non-steroidal anti-inflammatory agent, antihistamine, analgésie, or a mixture thereof.

42. The method of daim 40 or daim 41, wherein the c-Met assodated disease, disorder or condition is an immune system-related disease, a disease or disorder involving inflammation, cancer or other proliférative disease, a hepatic disease or disorder, or a rénal disease or disorder.

43. A method of treating a cancer in a patient comprising administering to said patient a therapeutically effective amount of a compound of any one of daims 1-30.

44. The method of daim 43, wherein said cancer is a cardnoma, musculoskeletal sarcoma, soft tissue sarcoma, or hematopoietic malignancy.

45. The method of daim 44, wherein said cancer îs cardnoma of the bladder, cardnoma of the breast, cardnoma of the colon, cardnoma of the kidney, cardnoma of the liver, cardnoma of the lung, small cell lung cancer, esophageal cancer, gall bladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, skin cancer, squamous cell cardnoma; cholangiocardnoma cancer .tumors of mesenchyma! origin, fîbrosarcoma, rhabdomyosarcoma; tumors of the central and peripheral nervous system, astrocytoma, neuroblastoma, glioma, schwannoma; melanoma, seminoma, teratocardnoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma, synovial sarcoma, rhabdomyosarcoma, MFH/fibrosarcoma, leiomyosarcoma, multiple myeloma, lymphoma, glioblastoma, astrocytoma, melanoma, mesothelioma, Wilm's tumor , hematopoietic tumors of lymphoid lineage, leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia,

B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma and Burkett’s lymphoma; hematopoietic tumors of myeloîd lineage, acute myelogenous leukemias, chronic myelogenous leukemias, myelodysplastic syndrome, or promyelocytic leukemia.