WO2014141035A2

WO2014141035A2 - Fused heterocyclyl derivatives as nampt inhibitors

Info

Publication number: WO2014141035A2
Application number: PCT/IB2014/059582
Authority: WO
Inventors: Dinesh Chikkanna; Vinayak Khairnar
Original assignee: Aurigene Discovery Technologies Limited
Priority date: 2013-03-11
Filing date: 2014-03-10
Publication date: 2014-09-18
Also published as: WO2014141035A3

Abstract

The present invention provides substituted heterocyclyl derivatives of formula (I), which may be therapeutically useful, more particularly as NAMPT inhibitors; in which R₁, R₂, X₁, X₂, ring A, L and 'n' have the meanings given in the specification, and pharmaceutically acceptable salts thereof that are useful in the treatment and prevention of diseases or disorder caused by an elevated level of nicotinamide phosphoribosyltransferase (NAMPT) in a mammal. The present invention also provides preparation of the compounds and pharmaceutical formulations comprising at least one of the substituted fused heterocyclyl derivatives of formula (I) or pharmaceutically acceptable salts or stereoisomers thereof.

Description

FUSED HETEROCYCLYL DERIVATIVES AS NAMPT INHIBITORS

This application claims the benefit of Indian provisional application number 1024/CHE/2013, filed on March 11 , 2013; which hereby incorporated by reference.

TECHNICAL FIELD

This invention pertains to compounds which inhibit the activity of NAMPT, compositions containing the compounds, and methods of treating diseases during which NAMPT is expressed.

BACKGROUND OF THE INVENTION

NAD⁺ (nicotinamide adenine dinucleotide) is a coenzyme that plays a critical role in many physiologically essential processes (Ziegkel, M. Eur. J. Biochem. 267, 1550- 1564, 2000). NAD⁺ is necessary for several processes in signaling pathways including poly ADP-ribosylation in DNA repair, mono-ADP-ribosylation in both the immune system and G-protein-coupled signaling, deacylation mediated by sirtuins (Garten, A. et al Trends in Endocrinology and Metabolism, 20, 130-138, 2008).

NAMPT (also known as pre-B-cell-colony-enhancing factor (PBEF) and visfatin) is an enzyme that catalyzes the phosphoribosylation of nicotinamide and is the rate- limiting enzyme in one of two pathways that salvage NAD⁺.

Nicotinamide

NAD⁺ Synthetase D

(NAMN)

Increasing evidence suggests that NAMPT inhibitors have potential as anticancer agents. Cancer cells have a higher basal turnover of NAD⁺ and also display higher energy requirements compared with normal cells. Additionally, increased NAMPT expression has been reported in colorectal cancer (Van Beijnum, J. R. et al Int. J. Cancer 101, 118- 127, 2002) and NAMPT is involved in angiogenesis (Kim, S. R. et al. Biochem. Biophys. Res. Commun. 357, 150-156, 2007). Small-molecule inhibitors of NAMPT have been shown to cause depletion of intracellular NAD⁺ levels and ultimately induce tumor cell death (Hansen, C M et al. Anticancer Res. 20, 4211-4220, 2000) as well as inhibit tumor growth in xenograft models (Olesen, U. H. et al Mol Cancer Ther. 9, 1609-1617, 2010).

NAMPT inhibitors also have potential as therapeutic agents in inflammatory and metabolic disorders (Galli, M. et al Cancer Res. 70, 8-11, 2010). For example, NAMPT is the predominant enzyme in T and B lymphocytes. Selective inhibition of NAMPT leads to NAD⁺ depletion in lymphocytes blocking the expansion that accompanies autoimmune disease progression whereas cell types expressing the other NAD⁺ generating pathways might be spared. A small molecule NAMPT inhibitor (FK866) has been shown to selectively block proliferation and induce apoptosis of activated T cells and was efficacious in animal models of arthritis (collagen-induced arthritis) (Busso, N. et al. Plos One 3, e2267, 2008). FK866 ameliorated the manifestations of experimental autoimmune encephalomyelitis (EAE), a model of T-cell mediated autoimmune disorders (Bruzzone, S et al. Plos One 4, e7897, 2009). NAMPT activity increases NF-kB transcriptional activity in human vascular endothelial cell, resulting in MMP-2 and MMP-9 activation, suggesting a role for NAMPT inhibitors in the prevention of inflammatory mediated complications of obesity and type 2 diabetes (Adya, R. et. al. Diabetes Care, 31, 758-760, 2008).

SUMMARY OF INVENTION

Provided herein are novel fused heterocyclyl derivatives and pharmaceutical compositions thereof, which are useful as NAMPT inhibitors.

In one aspect of the present invention, it comprises compounds of formula (I):

wherein,

Xi and X₂ are independently selected from N or CH, provided that not more than one of Xi and X₂ is N; ring A is optionally substituted heterocyclyl; wherein the optional substituent is selected from alkyl, halo, haloalkyl, cyano, heterocyclyl or -COOR3;

Ri is selected from optionally substituted aryl, optionally substituted cycloalkyl or optionally substituted heterocyclyl; wherein the optional substituent is selected from alkyl, aryl or heterocyclyl;

R2 is selected from O, S or NCN;

R3 is selected from hydrogen or alkyl;

L is a linker selected from *-(CH₂)_mNHCO-, *-(CH₂)_mCONH-, *-CH₂-NH-S0₂-, -NHCONH- or *-S0₂NH-; wherein * indicates the point of attachment to Ri;

'm' and 'n' are independently selected from 0 or 1 ;

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

In yet another aspect, the present invention provides a pharmaceutical composition comprising the compound of formula (I), and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).

In yet another aspect, the present invention relates to the preparation of the compounds of formula (I).

In yet another aspect of the present invention, it provides novel fused heterocyclyl derivatives of formula (I), which are useful for the inhibition of the enzyme nicotinamide phosphoribosyltransferase (NAMPT) and to medical use of such heterocyclyl derivatives. DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in art to which the subject matter herein belongs. As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated in order to facilitate the understanding of the present invention.

As used herein, the term "optionally substituted" refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent including, but not limited to: halo, alkyl, aryl, heterocyclyl, alkoxy, haloalkyl, haloalkoxy, cyano, carboxyl and aliphatic. It is understood that the substituent may be further substituted. As used herein, unless otherwise defined the term "alkyl" alone or in combination with other term(s) means saturated aliphatic hydrocarbon chains, including Ci-Cio straight or Ci-Cio branched alkyl groups and Ci-Ce straight or Ci-Ce branched alkyl groups. Examples of "alkyl" include but are not limited to methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, isopentyl or neopentyl and the like.

As used herein, the term "halo" or "halogen" alone or in combination with other term(s) means fluorine, chlorine, bromine or iodine.

As used herein, the term "haloalkyl" means alkyl substituted with one or more halogen atoms, where alkyl groups are as defined above. The term "halo" is used herein interchangeably with the term "halogen" means F, CI, Br or I. Examples of "haloalkyl" include but are not limited to trifluoromethyl, difluoromethyl, 2, 2, 2-trifluoroethyl and the like.

"Aryl" refers to aromatic hydrocarbon ring system of about 5 to 7 carbon atoms; wherein the said aryl group can be fused with other non aromatic hydrocarbon ring system of about 3 to 5 carbon atoms. Examples of a aryl group include, but are not limited to phenyl, 2,3-dihydro-lH-indene, tetrahydronaphthyl and the like. Unless otherwise specified, all aryl groups described herein may be substituted or unsubstituted.

"Heterocyclyl" refers to a saturated (i.e., "heterocycloalkyl"), partially saturated (i.e., "heterocycloalkenyl"), or completely unsaturated (i.e., "heteroaryl") monocyclic or polycyclic ring (include bridged, fused, and spirocyclic) system of 3 to 14 member having at least one heteroatom or heterogroup selected from -0-, -N-, -S-, N-oxide, or - CO-. Exemplary heterocyclyl groups include pyridine, furan, pyrazole, isoxazole, pyrrole, piperidine, piperazine, morpholine, imidazole, imidazo[l ,2-a]pyridine, phenyl, 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, 1,2,3,4-tetrahydroisoquinoline, furan, pyridazine, pyrimidine, isoxazole, thiazole, pyrazole, thiophene, benzo[d]thiazole, pyrazine, benzo[b]thiophene, 1 ,3,4-thiadiazole, oxazole, imidazo[l ,2-a]pyridine, isoquinoline, 2,3- dihydrobenzo[b][l,4]dioxine, benzo[d]oxazole, quinoline, 2,3-dihydro-lH-indene, indazole, pyridine 1-oxide, l ,2,3,4-tetrahydropyrrolo[l,2-a]pyrazine, isoindoline, 2,3- dihydro-lH-pyrrolo[3,4-c]pyridine, lH-pyrrolo[3,2-c]pyridine, lH-benzo[d]imidazole, imidazo[l,2-a]pyrimidine, thieno[2,3-b]pyridine or furo[2,3-c]pyridine and the like. A heterocyclyl group can be unsubstituted or substituted with one or more suitable groups. As used herein the term "cycloalkyl" alone or in combination with other term(s) means C3-C₁0 saturated cyclic hydrocarbon ring. A cycloalkyl may be a single ring, which typically contains from 3 to 7 carbon ring atoms. Examples of single-ring cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. A cycloalkyl may alternatively be polycyclic or contain more than one ring. Examples of polycyclic cycloalkyls include bridged and fused carbocyclyls.

The term "fused" means that the second ring is attached or formed by having two adjacent atoms in common with the first ring. The term "fused" is equivalent to the term "condensed".

"Cyano" refers to an -CN group.

The term "heteroatom" as used herein designates a sulfur, nitrogen, or oxygen atom.

As used herein, the term 'compound(s)' comprises the compounds disclosed in the present invention.

As used herein, the term "comprise" or "comprising" is generally used in the sense of include, that is to say permitting the presence of one or more features or components.

As used herein, the term "or" means "and/or" unless stated otherwise.

As used herein, the term "including" as well as other forms, such as "include", "includes" and "included" is not limiting.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

As used herein, the term "treat", "treating" and "treatment" refer to a method of alleviating or abrogating a disease and/or its attendant symptoms.

As used herein, the term "prevent", "preventing" and "prevention" refer to a method of preventing the onset of a disease and/or its attendant symptoms or barring a subject from acquiring a disease. As used herein, "prevent", "preventing" and "prevention" also include delaying the onset of a disease and/or its attendant symptoms and reducing a subject's risk of acquiring a disease.

As used herein, the term "therapeutically effective amount" refers to that amount of the compound being administered sufficient to prevent development of or alleviate to some extent one or more of the symptoms of the condition or disorder being treated.

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

The term "stereoisomers" refers to any enantiomers, diastereoisomers, or geometrical isomers of the compounds of Formula (I), (IA), (IB) and (IC), wherever they are chiral or when they bear one or more double bond. When the compounds of the formula (I), (IA), (IB) and (IC), and related formulae are chiral, they can exist in racemic or in optically active form. It should be understood that the invention encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d-isomers and 1-isomers, and mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds of the present invention may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. Additionally, compounds may exist as tautomers, including keto-enol tautomers; all tautomeric isomers are provided by this invention.

The present invention provides substituted heterocyclyl derivatives of formula (I), which are useful for the inhibition of the enzyme nicotinamide phosphoribosyltransferase (NAMPT). The present invention further provides pharmaceutical compositions comprising the said substituted heterocyclyl compounds and their derivatives as therapeutic agents.

In our invention to provide substituted heterocyclyl compounds, the first embodiment of the present invention provides the structure of compounds as set forth in formula (I);

Xi and X₂ are independently selected from N or CH, provided that not more than one of Xi and X2 is N;

ring A is optionally substituted heterocyclyl; wherein the optional substituent is selected from alkyl, halo, haloalkyl, cyano, heterocyclyl or -COOR3;

R₂ is selected from O, S or NCN;

R3 is selected from hydrogen or alkyl;

'm' and 'n' are independently selected from 0 or 1 ;

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

In another embodiment of the present invention, it provides the structure of compounds as set forth in formula (IA):

wherein,

Xi, ring A, Ri and 'm' are same as defined in formula (I);

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

In yet another embodiment of the present invention, it provides the structure of compounds as set forth in formula (IB):

wherein,

ring A, Ri, 'm' and 'n' are same as defined in formula (I);

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

In yet another embodiment of the present invention, it provides the structure of compounds as set forth in formula (IC):

wherein,

Ri is selected from optionally substituted aryl, heterocyclyl or cycloalkyl, wherein the optional substituent is heterocyclyl and 'm' is as defined in formula (I); or a pharmaceutically acceptable salt thereof or a stereoisomer thereof. The embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified.

In one embodiment, specifically provided are compounds of the formula (I), (IA), (IB) and (IC) in which Ri is heterocyclyl.

In another embodiment, specifically provided are compounds of the formula (I),

(IA), (IB) and (IC) in which the above said heterocyclyl is selected from

In yet another embodiment, specifically provided are compounds of the formula (I), (IA), (IB) and (IC) in which Ri is cycloalkyl.

In yet another embodiment, specifically provided are compounds of the formula

(I), (IA), (IB) and (IC) in which the above said cycloalkyl is selected from cyclohexyl, cyclopentyl or cyclopropyl.

In yet ano ovided are compounds of the formula

(I) in which Ri is

In yet another embodiment, specifically provided are compounds of the formula

(I) in which R2 is O.

In yet another embodiment, specifically provided are compounds of the formula (I) in which R₂ is NCN.

In yet another embodiment, specifically provided are compounds of the formula (I) in which R₂ is S.

In yet another embodiment, specifically provided are compounds of the formula (I) in which Xi is N and X₂ is CH.

In yet another embodiment, specifically provided are compounds of the formula (I) in which Xi is CH and X₂ is CH.

In yet another embodiment, specifically provided are compounds of the formula

(I) in which Xi is CH and X₂ is N. In yet another embodiment, specifically provided are compounds of the formula (I), (IA) and (IB) in which ring A is selected from

In yet another embodiment, specifically provided are compounds of the formula (I) in which L is *-(CH₂)NHCO-.

In yet another embodiment, specifically provided are compounds of the formula

(I) in which L is *-NHCO-.

In yet another embodiment, specifically provided are compounds of the formula (I) in which L is *-(CH₂)CONH-.

In yet another embodiment, specifically provided are compounds of the formula (I) in which L is *-CONH-.

In yet another embodiment, specifically provided are compounds of the formula (I) in which L is *-CH₂-NH-S0₂-.

In yet another embodiment, specifically provided are compounds of the formula (I) in which L is -NHCONH-.

In yet another embodiment, specifically provided are compounds of the formula

(I) in which L is *-S0₂NH-.

In yet another embodiment, specifically provided are compounds of the formula (I) and (IB) in which 'n' is 0. In yet another embodiment, specifically provided are compounds of the formula (I) and (IB) in which 'n' is 1.

In yet another embodiment, specifically provided are compounds of the formula (IA) and (IB) in which 'm' is 0.

In yet another embodiment, specifically provided are compounds of the formula

(IA) and (IB) in which 'm' is 1.

In yet another embodiment, specifically provided are compounds of the formula (IA) in which Ri is tetrahydro-2H-pyran, Xi is N, ring A is 4,5,6J-tetrahydrothieno[3,2- c]pyridine and 'm' is 1.

Another embodiment of the present invention provides a pharmaceutical composition comprising the compound as disclosed, and a pharmaceutically acceptable salt or stereoisomer thereof.

The compounds as disclosed in the present invention are formulated for pharmaceutical administration.

Yet another embodiment of the present invention provides use of the compounds as disclosed in the present invention useful in the treatment and prevention of diseases or disorder, caused by an elevated level of nicotinamide phosphoribosyltransferase (NAMPT).

Diseases and/or disorders associated with elevated level of nicotinamide phosphoribosyltransferase (NAMPT) include, but are not limited to cancer, pancreatic cancer, ovarian cancer, lung cancer, prostate cancer, skin cancer, breast cancer, uterine cancer, colon cancer, cervical cancer, bladder cancer, leukemia, lymphoma, Hodgkin' s disease, viral infections including adult respiratory distress syndrome, ataxia telengiectasia, Human Immunodeficiency Virus, hepatitis virus, herpes virus, herpes simplex, inflammatory disorders, irritable bowel syndrome, inflammatory bowel disease, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, osteoarthritis, osteoporosis, fibrotic diseases, dermatitis, atoptic dermatitis, psoriasis, ultra-violet induced skin damage, systemic lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spodylitis, graft- versus-host disease, Alzheimer's disease, cerebrovascular accident, atherosclerosis, restenosis, diabetes, glomerulonephritis, metabolic syndrome, non-small cell lung cancer, small cell lung cancer, multiple myeloma, leukemias, lymphomas, cancers of the brain and central nervous system, squamous cell cancers, kidney cancer, uretral and bladder cancers, cancers of head and neck.

The compounds of the present invention may be used as single drug or as a pharmaceutical composition in which the compound is mixed with various pharmacologically acceptable materials.

The pharmaceutical composition can be administered by oral, parenteral or inhalation routes. Examples of the parenteral administration include administration by injection, percutaneous, transmucosal, transnasal and transpulmonary administrations.

The MS (Mass Spectral) data provided in the examples were obtained using the equipments- API 2000 LC/MS/MS Triplequad,

Agilent Technologies/LC/MS/DVL/Singlequad,

Shimadzu LCMS-2020/Singlequad.

The NMR data provided in the examples were obtained using the equipment - ^lH NMR: Varian -400 MHz and Varian 300 MHz

The HPLC performed forthe provided examples using the equipements- AgilentTechnologies 1200 Series,

AgilentTechnologies 1100 Series,

Shimadzu (UFLC) Prominance,

Shimadzu Nexera-UHPLC.

The following abbreviations refer respectively to the definitions below:

NCS - N-Chlorosuccinimide; BOP Reagent - (Benzotriazol-1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; DMSO - Dimethylsulfoxide; DIPEA - Ν,Ν-Diisopropylethylamine; HOBt - N- Hydroxybenzotriazole, NaHCCb - Sodium bicarbonate; NH₂OH.HCI - Hydroxylamine hydrochloride; EtOH - Ethanol; NaOCl - Sodium hypochlorite; Dioxane.HCl; - Hydrochloric acid in dioxane; K2CO3 - Potassium carbonate; Na2S04 - Sodium sulphate; Na2C03 - Sodium carbonate; DMP - Dess-Martin periodinane; Tetrakis - Tetrakis(triphenylphosphine)palladium(0); B(pin) - Bis(pinacolato)diboron, Pd(dppf)Ci2 - [1 ,1 '-Bis (diphenylphosphino) ferrocene] dichloropalladium(II); H₂O - water; br - Broad; A- Angstrom ; °C - Degree Celsius ; cone - Concentrated; CHCI3 - Chloroform; CDCLV/chloroform-d - Deuterated Chloroform; DMSO-d6- Deuterated dimethylsulfoxide; CH2CI2 - DCM - Dichloromethane; DMF- N, N- Dimethylformamide;; Et₂0 - Diethyl ether; g- Gram; h - Hours; ¾- Proton; HQ- Hydrochloric acid; Hz- Hertz; / - Coupling Constant; LC-MS - Liquid Chromatography- Mass Spectroscopy; HPLC - High-performance liquid chromatography; chiral HPLC - chiral high-performance liquid chromatography; MeOH - methanol; M - Molar; MHz - Mega Hertz (frequency); MS - Mass Spectroscopy; mmol - Milli Mole; mL - Milli Litre; min - Minutes; mol - Moles; M⁺- Molecular ion; Ν- Normality; NMR - Nuclear Magnetic Resonance; Et3N/TEA - Triethyl amine; ppm - Parts per million; rt/RT - Room temperature; s - Singlet; d - Doublet, t - Triplet; q - Quartet; m - Multiplet; dd - doublet of doublets; td - triplet of doublets; qd - quartet of doublets; ddd - doublet of doublet of doublets; dt - doublet of triplets; ddt - doublet of doublet of triplets; TLC - Thin Layer Chromatography; THF - Tetrahydrofuran; % - Percentage; μ - Micron; δ- Delta; anh. - anhydrous; PMS - Phenazine methosulfate; XTT - 2,3-Bis-(2-Methoxy-4- Nitro-5-Sulfophenyl)-2H-Tetrazolium-5-Carboxanilide; cDMEM - Dulbecco's Modified Eagle's Medium; FBS - Fetal bovine serum; NAM - Nam - Nicotinamide; NMN - Nmn - Nicotinamide mononucleotide; nm- nanometer; PRPP- Phosphoribosyl pyrophosphate; ATP - Adenosine triphosphate; BSA - Bovine serum albumin; DTT - Dithiothreitol; MgCb - Magnesium chloride; IC50 - Inhibitory concentration 50; RFU - relative fluorescence units and Tris - tris(hydroxymethyl)aminomethane.

General modes of preparation:

Compounds of this invention may be made by synthetic chemical processes, examples of which are shown herein. It is meant to be understood that the order of the steps in the processes may be varied, that reagents, solvents and reaction conditions may be substituted for those specifically mentioned, and that vulnerable moieties may be protected and deprotected, as necessary.

Schemes:

General procedure for examples:

Scheme-1:

Reagents & conditions-i) Method F; ii) Method B; iii) Method F; iv) Method E; v) Method C; vi) Et₃N, Method D.

Method B: H_{2 (}i_atm)/10 % Pd-C, MeOH, RT, 16 h.

Method C: NaHC0₃, THF, RT, 2 h.

Method D: DMSO, RT, 16 h.

Method E: TFA, CH2CI2, RT, 16 h.

Method F: EDCI.HCl, HOBt, DIPEA, DMF, RT, 16h.

Scheme-2

Reagents & conditions-i) Et₃N, CH2CI2, RT, 2h; ii) Method B; iii) Method C; iv) Et₃N, Method D.

Method B: H₂ (i_atm)/10 % Pd-C, MeOH, RT, 16 h.

Method C: NaHC0₃, THF, RT, 2 h. Method D: DMSO, RT, 16 h.

Scheme-3:

Reagents & conditions-i) Method H; ii) Method C; iii) EfaN, Method D iv); Method I; v) Method F.

Method C: NaHC0₃, THF, RT, 2 h.

Method D: DMSO, RT, 16 h.

Method F: EDCI.HC1, HOBt, DIPEA, DMF, RT, 16h.

Method H: Et₃N, THF, RT, 16 h.

Method I: 4N NaOH _(aq), MeOH:THF (1 :1), RT, 16 h.

Scheme-4:

Reagents & conditions-i) Method A; ii) Method B; iii) Method C; iv) Method D; v) Method E; vi) Method F; vii) Et₃N, CH2CI2, 0°C to RT, 2h; viii) Method A. Method A: THF, 0°C - RT, 2h.

Method B: H₂ (i_atm)/10 % Pd-C, MeOH, RT, 16 h;

Method C: NaHC0₃, THF, RT, 2 h.

Method D: DMSO, RT, 16 h.

Method E: TFA, CH2CI2, RT, 16 h.

Method F: EDCI.HC1, HOBt, DIPEA, DMF, RT, 16h.

Scheme-5:

Reagents & conditions-i) Method F; ii) Method E; iii) Method C or Method G ; iv) Method D; v) CH3CN, RT, 2h; vi) Acetonitrile, 80°C , 16 h.

Method C: NaHCOs, THF, RT, 2 h.

Method D: DMSO, RT, 16 h.

Method E: TFA, CH2CI2, RT, 16 h.

Method F: EDCI.HC1, HOBt, DIPEA, DMF, RT, 16h.

Method G: Et₃N, DMSO, RT, 2 h.

The specifics of the process for preparing compounds of the present invention are detailed in the experimental section.

In the following, the present invention shall be illustrated by means of some examples, which are not construed to be viewed as limiting the scope of the invention. EXPERIMENTAL

Unless otherwise stated, work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of layers and drying the organic layer over sodium sulphate, filtration and evaporation of the solvent. Purification, unless otherwise mentioned, includes purification by silica gel chromatographic techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase. Use of a different eluent system is indicated within parentheses.

Analysis for the compounds of the present invention unless mentioned, was conducted in the general methods well known to the person skilled in the art. Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples, describing in detail the analysis of the compounds of the invention.

It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLES

The present invention is further exemplified, but not limited, by the following examples that illustrate the preparation of compounds according to the invention.

Example-1: N-(4-(2-cyclopentylacetamido)phenyl)-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazine-7(8H)-carboxamide.

Step-1: 3-bromo-N-(4-nitrophenyl)-5,6-dihydro-[l ,2,4]triazolo[4,3-a]pyrazine-7fSH)- carboxamide.

To a stirred solution of 3-bromo-5,6,7,8-tetrahydro-[l ,2,4]triazolo[4,3-a]pyrazine (0.500 g, 2.40 mrnol) in THF (5 mL) was added l-isocyanato-4-nitrobenzene (0.403 g, 2.40 mmol) at 0° C. After being stirred at room temperature for 2h, the reaction mixture was evaporated off and the resulting foam was triturated with ether and filtered to give the title compound (0.300 g, 33.3%). LCMS : nt/z 366.95 [M+H] ⁺.

Step-2: N-(4-aminophenyl)-5,6-dihydro-[l ,2,4]triazolo[4,3-a]pyrazine-7(8H)- carboxamide.

To a solution of 3-bromo-N-(4-nitrophenyl)-5,6-dihydro-[l ,2,4]triazolo[4,3-a]pyrazine- 7(8H)-carboxarnide (0.100 g, 0.270 mmol ) in methanol (25 mL) was added 10% Pd/C (0.020 g). The reaction mixture was stirred at room temperature under H₂(_g> atmosphere (balloon pressure) for 16 h. The suspension was filtered through a pad of celite, and washed with methanol (3 x 10 mL). The resulting filtrate was concentrated in vaccuo to give the title compound (0.069 g, crude). The crude product obtained was taken to next step without further analysis.

Step-3: N-(4-(2-cyclopentylacetamido)phenyl)-5 ,6-dihydro-[l ,2,4]triazolo[4,3- a]pyrazine-7(SH)-carboxamide.

To a solution of N-(4-aminophenyl)-5,6-dihydro-[l ,2,4]triazolo[4,3-a]pyrazine-7(SH)- carboxamide (0.069 g, 0.270 mmol) in DMF (10 mL) was added cyclopentane acetic acid (0.034 g, 0.270 mmol), EDCI.HC1 (0.610 g, 0.320 mmol), HOBt (0.059 g, 0.440 mmol) followed by DIPEA (0.140 mL, 0.810 mmol) at 0°C. The homogeneous solution was stirred at ambient temperature for 16 h. The mixture was diluted with water, extracted with dichloromethane (2 x 25 mL). The combined organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (methanol/dichloromethane = 0/100 to 15/85) to give the title compound (0.012 g, 11.9 %) as white solid. LCMS: m/z 369.2 [M+H]⁺; HPLC: 99.7 %; ¾ NMR (400 MHz, DMSO-d₆) δ 9.74 (s, 1H), 8.77 (s, 1H), 8.49 (d, / = 0.9 Hz, 1H), 7.50 - 7.43 (m, 2H), 7.37 (dd, / = 9.0, 0.9 Hz, 2H), 4.84 (s, 2H), 4.12 (t, / = 5.4 Hz, 2H), 3.89 (t, / = 5.5 Hz, 2H), 2.32 - 2.15 (m, 3H), 1.81 - 1.68 (m, 2H), 1.68 - 1.44 (m, 4H), 1.18 (dd, / = 12.6, 6.8 Hz, 2H).

Example-2: N-(4-(2-cyclopentylacetamido) phenyl)-3-(trifluoromethyl)-5, 6-dihydro- [1, 2, 4] triazolo [4, 3-a] pyrazine-7(SH)-carboxamide. Step-1: N-(4-mtrophenyl)-3-(trifluoromem^

1(8H) carboxamide.

3-(trifluoromethyl)-5,6 ,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazine(5^,y«i ie5^,izeii as per procedure reported in J. Med. Chem., 48(1),141-151 ; 2005) (0.100 g, 0.520 mmol) was reacted with l-isocyanato-4-nitrobenzene (0.085 g, 0.520 mmol) as described in the synthesis of step-1 of example- 1 to give the title compound (0.150 g, 81 % ) as a yellow solid. LCMS: m/z 357.1 [M+H]; ^lU NMR (400 MHz, DMSO-d₆) δ 9.53 (s, 1H), 8.26 - 8.13 (m, 2H), 7.81 - 7.69 (m, 2H), 5.01 (s, 2H), 4.26 (t, / = 5.4 Hz, 2H), 4.02 (t, / = 5.4 Hz, 2H).

Step-2: N-(4-aminophenyl)-3-(trifluoromethyl)-5,6-dihydro-[l ,2,4]triazolo[4,3- a]pyrazine-7(8H)-carboxamide

N-(4-nitrophenyl)-3-(trifluoromemyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazine-7(SH)- carboxamide (0.150 g, 0.420 mmol) was reduced as described in the synthesis of step-2 of example- 1 to give the title compound (0.120 g, 87.3 % ) as a solid. LCMS: m/z 327.4 [Μ+Η] ⁺.

Step-3: N-(4-(2-cyclopentylacetamido) phenyl)-3-(trifluoromethyl)-5, 6-dihydro-[l , 2, 4] triazolo [4, 3-a] pyrazine-7(8H)-carboxamide.

N-(4-aminophenyl)-3-(trifluoromethyl)-5,6-dihydro-[l ,2,4]triazolo[4,3-a]pyrazine-7(SH)- carboxamide (0.120 g, 0.370 mmol) was reacted with cyclopentane acetic acid (0.047 g, 0.370 mmol) as described in the synthesis of step-3 of example- 1 to give the title compound (0.100 g, 62.3%) as a white solid. LCMS: mJz 437.15 [M+H]⁺; HPLC: 97.46%; ^lU NMR (400 MHz, DMSO-d₆) δ 9.74 (s, 1H), 8.81 (s, 1H), 7.52 - 7.43 (m, 2H), 7.40 - 7.32 (m, 2H), 4.94 (s, 2H), 4.22 (t, / = 5.4 Hz, 2H), 3.96 (t, / = 5.4 Hz, 2H), 2.31 - 2.16 (m, 3H), 1.74 (dq, / = 11.4, 6.3, 5.8 Hz, 2H), 1.65 - 1.44 (m, 4H), 1.18 (ddt, / = 14.4, 11.3, 6.6 Hz, 2H).

Example-3: N-(4-(2-cyclopentylacetamido) phenyl)-3, 4-dihydropyrrolo [1, 2-a] pyrazine-2( 1H) -carboxamide.

Step-1: N-(4-nitrophenyl)-3, 4-dihydropyrrolo [1, 2-a] pyrazine-2(7H)-carboxamide.

l,2,3,4-tetrahydropyrrolo[l ,2-a]pyrazine (synthesized as per procedure reported in WO2009090054A1 ) (0.100 g, 0.810 mmol) was reacted with l-isocyanato-4-nitrobenzene (0.134 g, 0.810 mmol) as described in the synthesis of step-1 of example-1 to give the title compound (0.234 g, crude). The crude product was taken to next step without further purification.

Step-2: N-(4-aminophenyl)-3,4-dihydropyrrolo[l ,2-a]pyrazine-2( iH)-carboxamide.

N-(4-nitrophenyl)-3,4-dihydropyrrolo[l,2-a]pyrazine-2(iH)-carboxamide (0.234 g, 0.810 mmol) was reduced as described in the synthesis of step-2 of example-1 to give the title compound (0.130 g, crude ) as a solid. The crude product was taken to next step without further purification.

Step-3: N-(4-(2-cyclopentylacetamido) phenyl)-3, 4-dihydropyrrolo [1, 2-a] pyrazine- 2( iH)-carboxamide.

N-(4-aminophenyl)-3 ,4-dihydropyrrolo[l ,2-a]pyrazine-2( iH)-carboxamide (0.100 g, 0.390 mmol) was reacted with cyclopentane acetic acid (0.049 g, 0.390 mmol) as described in the synthesis of step-3 of example- 1 to give the title compound (0.055 g, 38.4 %) as a white solid. LCMS: nt/z 367.3 [M+H]⁺; HPLC: 96.02 ; ¾ NMR (400 MHz, DMSO-d₆) δ 9.71 (s, 1H), 8.58 (s, 1H), 7.51 - 7.38 (m, 2H), 7.40 - 7.30 (m, 2H), 6.67 (dd, / = 2.7, 1.6 Hz, 1H), 6.00 (dd, / = 3.5, 2.7 Hz, 1H), 5.82 (dd, / = 3.4, 1.6 Hz, 1H), 4.62 (s, 2H), 3.97 (t, / = 5.5 Hz, 2H), 3.80 (t, / = 5.5 Hz, 2H), 2.30 - 2.13 (m, 3H), 1.73 (dd, / = 11.6, 5.3 Hz, 2H), 1.67 - 1.41 (m, 4H), 1.17 (dt, / = 12.1, 6.9 Hz, 2H).

Example-4: N-(4-(2-cyclopentylacetamido) phenyl)-6, 7-dihydrothieno [3, 2-c] pyridine-5(4H)-carboxamide.

Step-1: N-(4-nitrophenyl)-6, 7-dihydrothieno [3, 2-c] pyridine-5(4H)-carboxamide.

4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride (0.300 g, 1.82 mmol) was reacted with l -isocyanato-4-nitrobenzene (0.254 g, 1.82 mmol) as described in the synthesis of step-1 of example- 1 to give the title compound (0.440 g, 79.4% ) as a yellow solid. ¾ NMR (400 MHz, DMSO-d₆) δ 9.35 (s, lH), 8.21 - 8.10 (m, 2H), 7.78 - 7.66 (m, 2H), 7.42 - 7.30 (m, 1H), 6.90 (d, / = 5.1 Hz, 1H), 4.59 (d, / = 1.6 Hz, 2H), 3.80 (t, / = 5.7 Hz, 2H), 2.87 (t, /= 5.7 Hz, 2H).

Step-2: N-(4-aminophenyl)-6, 7-dihydrothieno [3, 2-c] pyridine-5(4H)-carboxamide.

N-(4-nitrophenyl)-6,7-dihydrothieno [3,2-c] pyridine-5(4H)-carboxamide (0.150 g, 0.490 mmol) was reduced as described in the synthesis of step-2 of example- 1 to give the title compound (0.135 g, crude) as a solid. The crude product was taken to next step without further purification.

Step-3: N-(4-(2-cyclopentylacetamido) phenyl)-6, 7-dihydrothieno [3, 2-c] pyridine- 5 (4H) -carboxamide .

N-(4-aminophenyl)-6, 7-dihydrothieno [3,2-c] pyridine-5(4H)-carboxamide (0.135 g, 0.490 mmol) was reacted with cyclopentane acetic acid (0.063 g, 0.490 mmol) as described in the synthesis of step-3 of example- 1 to give the title compound (0.050 g, 26.3% ) as a white solid. LCMS: nt/z 384.55 [M+H]⁺; HPLC: 92.07%; ¾ NMR (400 MHz, DMSO-d₆) δ 9.70 (s, 1H), 8.55 (s, 1H), 7.50 - 7.28 (m, 5H), 6.88 (d, / = 5.1 Hz, 1H), 4.53 (d, / = 1.7 Hz, 2H), 3.74 (t, / = 5.6 Hz, 2H), 2.82 (d, / = 5.7 Hz, 2H), 2.29 - 2.12 (m, 3H), 1.72 (dt, / = 11.5, 5.6 Hz, 2H), 1.67 - 1.43 (m, 4H), 1.17 (dt, / = 13.3, 7.0 Hz, 2H).

Example-5: N-(4-(2-(tetrahydrofuran-3-yl)acetamido)phenyl)-6,7-dihydrothieno

[3,2-c]pyridine-5(4H)-carboxamide ±).

N-(4-aminophenyl)-6J-dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide (step-2 of example-4) (0.150 g, 0.549 mmol) was reacted with 2-(tetrahydrofuran-3-yl) acetic acid (±) (JACS, V (115), P801, 1993.) (0.071 g, 0.549 mmol) as described in the synthesis of step-3 of example- 1 to give the title compound (0.015 g, 7 %) as a white solid. LCMS: nt/z 386.1 [M+H]⁺; HPLC: 97.8 %; ^lU NMR (400 MHz, DMSO-d₆) δ 9.79 (s, 1H), 8.56 (s, 1H), 7.49 - 7.39 (m, 2H), 7.39 - 7.28 (m, 3H), 6.88 (d, / = 5.1 Hz, 1H), 4.53 (d, / = 1.8 Hz, 2H), 3.86 - 3.68 (m, 4H), 3.63 (q, / = 7.6 Hz, 1H), 3.39 (s, 1H), 2.83 (s, 2H), 2.63 - 2.53 (m, 1H), 2.36 (dd, / = 7.4, 3.1 Hz, 2H), 2.1 1 - 1.89 (m, 1H), 1.54 - 1.49 (m, 1H). Further the enantiomeric mixture (0.010 g) was separated by Chiral Preparative HPLC to give two separated enantiomers (example 5a & 5b). Method: Column: LUX AMYLOSE-2 AXIA PACKED (21.2mm x 250mm x5u), Hexane: (Ethanol: IPA: 1 : 1): 50:50, Flow Rate: 20 mL/Min ), Isocratic.

Example-5a: N-(4-(2-(tetrahydrofuran-3-yl)acetamido)phenyl)-6,7-dihydrothieno

[3,2-c]pyridine-5(4H)-carboxamide (Enantiomer 1). Yield: 0.002 g; Retention Time: 10.65 min.; Chiral HPLC: 99.62 ; HPLC: 99.5 ; LCMS: m/z 386.1 [M+H] ⁺.

Example-5b: N-(4-(2-(tetrahydrofuran-3-yl)acetamido)phenyl)-6,7-dihydrothieno

[3,2-c]pyridine-5(4H)-carboxamide (Enantiomer 2).

Yield: 0.002 g; Retention Time: 13.53 min ; Chiral HPLC: 95.9 ; HPLC: 99.0 ; LCMS: m/z 386.1 [M+H] ⁺.

Example-6: N-(4-(2-cyclopentylacetamido)phenyl)-5,6-dihydroimidazo[l,2-a] pyrazine-7( 8H) -carboxamide.

Step-1: N-(4-nitrophenyl)-5,6-dihydroimidazo[l,2-a] pyrazine-7(8H)-carboxamide.

5,6,7,8-tetrahydroimidazo[l ,2-a]pyrazine (synthesized as per procedure reported in WO2008124083) (0.100 g, 0.880 mmol) was reacted with l-isocyanato-4-nitrobenzene (0.134 g, 0.880 mmol) as described in the synthesis of step-1 of example-1 to give the title compound (0.233 g, crude) as a yellow solid. The crude product was taken to next step without further purification.

Step-2: N-(4-aminophenyl)-5, 6-dihydroimidazo[l,2-a] pyrazine-7(SH)-carboxamide.

N-(4-nitrophenyl)-5,6-dihydroimidazo[l ,2-a] pyrazine-7(8H)-carboxamide (0.233 g, 0.880 mmol) was reduced as described in the synthesis of step-2 of example-1 to give the title compound (0.100 g, crude) as a solid. The crude product was taken to next step without further purification.

Step-3: N-(4-(2-cyclopentylacetamido)phenyl)-5,6-dihydroimidazo[l,2-a]pyrazine-

1( SH)-carboxamide.

N-(4-aminophenyl)-5 ,6-dihydroimidazo[l ,2-a]pyrazine-7( 8H)-carboxamide (0.100 g, 0.380 mmol) was reacted with cyclopentane acetic acid (0.050 g, 0.380 mmol) as described in the synthesis of step-3 of example- 1 to give the title compound (0.040 g, 28 % ) as a white solid. LCMS: nt/z 368.2 [M+H]⁺; HPLC: 97.49 %; ^lU NMR (400 MHz, DMSO-d₆) δ 9.73 (s, 1 H), 8.70 (s, 1H), 7.49 - 7.31 (m, 4H), 7.11 (d, / = 1.2 Hz, 1H), 6.89 (d, / = 1.3 Hz, 1H), 4.68 (s, 2H), 4.03 (t, / = 5.4 Hz, 2H), 3.87 (dd, / = 6.5, 4.3 Hz, 2H), 2.32 - 2.15 (m, 3H), 1.80 - 1.66 (m, 2H), 1.66 - 1.43 (m, 4H), 1.18 (tdd, / = 11.3, 9.3, 5.0 Hz, 2H).

Example-7: N-(4-([l, l'-biphenyl]-2-ylsulfonamido) phenyl)-3, 4-dihydropyrrolo [1, 2-a] pyrazine-2(iH)-carboxamide.

To a stirred solution of N-(4-aminophenyl)-3, 4-dihydropyrrolo [1 , 2-a] pyrazine-2(7H)- carboxamide (step-2 of example-3) (0.030 g, 0.110 mmol) in dichloromethane (10 mL) were added [l ,l ' -biphenyl]-2-sulfonyl chloride (0.029 g, 0.110 mmol) and triethylamine (0.046 mL, 0.330 mmol) at 0° C. After stirring at room temperature for 2h, the reaction mixture was diluted with dichloromethane (25 mL) and washed with saturated sodium bicarbonate solution and brine. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The resulting crude product was purified by column chromatography on silica gel (dichloromethane/methanol = 98/2) to give title compound (0.020 g, 36.1 %) as an off white solid. LCMS: nt/z 473.25 [M+H]⁺; HPLC: 95.23%: ¾ NMR (400 MHz, Chloroform-d) δ 8.21 - 8.13 (m, 1H), 7.56 (td, / = 7.5 , 1.4 Hz, 1H), 7.53 - 7.41 (m, 6H), 7.29 (d, / = 1.4 Hz, 1H), 7.18 - 7.14 (m, 2H), 6.75 - 6.65 (m, 2H), 6.63 (dd, / = 2.7, 1.6 Hz, 1H), 6.26 (s, 1H), 6.18 (dd, / = 3.5, 2.7 Hz, 1H), 5.97 (dt, / = 3.6, 1.3 Hz, 1H), 5.53 (s, 1H), 4.71 - 4.62 (m, 2H), 4.04 (dd, / = 6.4, 4.3 Hz, 2H), 3.89 (dd, / = 6.4, 4.3 Hz, 2H). Example-8: N-(4-(3-([l,l'-biphenyl]-2-yl)ureido)phenyl)-3,4-dihydropyrrolo[l,2- a]pyrazine-2(iH)-carboxamide.

N-(4-aminophenyl)-3 ,4-dihydropyrrolo[l ,2-a]pyrazine-2( iH)-carboxamide (step-2 of example-3) (0.050 g, 0.190 mmol) was reacted with 2-biphenyl isocyanate (0.038 g, 0.190 mmol) as described in the synthesis of step-1 of example-1 to give the title compound (0.050 g, 56.8% ) as an off white solid. LCMS: nt/z 452.6 [M+H]⁺; HPLC: 93.06%; ¾ NMR (400 MHz, DMSO-d₆) δ 8.88 (s, 1H), 8.55 (s, 1H), 7.93 (dd, / = 8.3, 1.2 Hz, 1H), 7.59 (s, 1H), 7.51 (dd, / = 8.0, 6.7 Hz, 2H), 7.46 - 7.37 (m, 3H), 7.37 - 7.30 (m, 3H), 7.30 - 7.24 (m, 2H), 7.20 (dd, / = 7.7, 1.7 Hz, 1H), 7.11 (td, / = 7.4, 1.3 Hz, 1H), 6.68 (dd, / = 2.7, 1.7 Hz, lH), 6.05 - 5.98 (m, 1H), 5.83 (dd, / = 3.4, 1.5 Hz, 1H), 4.63 (s, 2H), 3.98 (dd, / = 6.3, 4.6 Hz, 2H), 3.80 (t, / = 5.5 Hz, 2H).

Example-9: N-(4-([l,l'-biphenyl]-2-ylcarboxamido)phenyl)-3,4-dihydropyrrolo[l,2- a]pyrazine-2(iH)-carboxamide .

N-(4-aminophenyl)-3,4-dihydropyrrolo[l ,2-a] pyrazine-2(7H)-carboxamide (step-2 of example-3) (0.050 g, 0.190 mmol) was reacted with [l ,l '-biphenyl]-2-carboxylic acid (0.038 g, 0.190 mmol) as described in the synthesis of step-3 of example-1 to give the title compound (0.025 g, 29.3% ) as an off white solid. LCMS: nt/z 437.55 [Μ+Η] ⁺; HPLC: 95.12%; ¾ NMR (400 MHz, DMSO-d₆) δ 10.10 (s, 1H), 8.60 (s, 1H), 7.61 - 7.52 (m, 2H), 7.53 - 7.42 (m, 4H), 7.40 - 7.25 (m, 7H), 6.68 (dd, / = 2.6, 1.7 Hz, 1H), 6.01 (dd, / = 3.4, 2.7 Hz, 1H), 5.82 (dd, / = 3.4, 1.6 Hz, 1H), 4.63 (s, 2H), 4.03 - 3.93 (m, 2H), 3.80 (t, / = 5.5 Hz, 2H). Example- 10: N-(4-(N'-cyano-4,5,6,7-tetrahydrothieno[3,2-c] pyridine-5- carboximidamido)phenyl)-2-cyclopentyl acetamide.

Step-1: Tert-butyl(4-(2-cyclopentylacetamido)phenyl) carbamate.

Tert-butyl(4-aminophenyl)carbamate (0.650 g, 3.12 mmol) was reacted with cyclopentane acetic acid (0.400 g, 3.12 mmol) as described in the synthesis of step-3 of example-1 to give the title compound (0.993 g, crude). The crude product was taken to next step without further purification.

Step-2: N-(4-aminophenyl)-2-cyclopentylacetamide.

Tert-butyl(4-(2-cyclopentylacetamido)phenyl)carbamate (0.993 g. 3.120 mmol) was treated with 10% TFA in dichloromethane (50 mL) at room temperature for 16 h. The reaction was diluted with dichloromethane (100 mL) and washed with saturated sodium bicarbonate solution and brine. The organic layer was dried over sodium sulphate and evaporated under reduced pressure. The resulting crude product was purified by column chromatography on silica gel (hexanes/ethyl acetate = 60/40) to give the title compound (0.500 g, 73.4%). The product was takent to next step without further analysis.

Step-3: N-(4-(N'-cyano-4,5,6 J-tetrahydrothieno[3,2-c]pyridine-5-carboximidamido) phenyl)-2-cyclopentyl acetamide.

A solution of N-(4-aminophenyl)-2-cyclopentylacetamide (0.100 g, 0.450 mmol) and diphenyl cyanocarbonimidate (0.109 g, 0.450 mmol) in acetonitrile (10 mL) was stirred at room temperature for 2 h. The reaction mixture was evaporated off, resulting crude dissolved in ethyl acetate (25 mL) and washed with saturated sodium bicarbonate solution and brine and concentrated under reduced pressure. To a solution of crude (obtained above) in acetonitrile (5 mL) was added 4,5,6,7-tetrahydrothieno[3,2-c] pyridine (0.084 g, 0.045 mmol) and stirred at 80°c for 16 h. Then acetonitrile was evaporated, resulting crude purified by column chromatography on silica gel (dichloromethane/methanol= 98/2) to give title compound (0.020 g, 10.7%) as an off white solid. LCMS: nt/z 407.9 [M+H] ⁺; HPLC: 95.50%; ¾ NMR (400 MHz, DMSO-d₆) δ 9.84 (s, 1H), 9.35 (s, 1H), 7.59 - 7.47 (m, 2H), 7.35 (d, / = 5.1 Hz, 1H), 7.06 - 6.96 (m, 2H), 6.85 (d, / = 5.2 Hz, 1H), 4.52 (s, 2H), 3.79 (t, / = 5.6 Hz, 2H), 2.88 (t, 2H), 2.30 - 2.15 (m, 3H), 1.73 (dd, / = 11.7, 5.3 Hz, 2H), 1.65 - 1.43 (m, 4H), 1.28 - 1.1 1 (m, 2H).

Example-11: N-(4-(N'-cyano-l,2,3,4-tetrahydropyrrolo[l,2-a]pyrazine-2- carboximidamido)phenyl)-2-cyclopentyl acetamide.

N-(4-aminophenyl)-2-cyclopentylacetamide (step-2 of example- 10) (0.100 g, 0.450 mmol) was reacted with diphenyl cyanocarbonimidate (0.109 g, 0.450 mmol) followed by 1 ,2,3,4-tetrahydropyrrolo [1 ,2-a] pyrazine (0.056 g, 0.045 mmol) as described in the synthesis of step-3 of example- 10 to give title compound as an off white solid (0.010 g, 5.6%).LCMS: nt/z 391.35 [M+H] ⁺; HPLC: 89.30%; ^lU NMR (400 MHz, DMSO-d₆) δ 9.84 (s, 1H), 9.37 (s, 1H), 7.60 - 7.49 (m, 2H), 7.09 - 6.97 (m, 2H), 6.70 (dd, / = 2.7, 1.7 Hz, 1H), 6.00 (dd, / = 3.5, 2.7 Hz, 1H), 5.82 (dd, / = 3.4, 1.6 Hz, 1H), 4.62 (s, 2H), 4.03 (t, / = 5.4 Hz, 2H), 3.84 (t, / = 5.5 Hz, 2H), 2.30 - 2.14 (m, 3H), 1.73 (dt, / = 11.6, 5.4 Hz, 2H), 1.64 - 1.42 (m, 4H), 1.17 (dd, / = 13.1 , 6.7 Hz, 2H).

Example- 12: 2-bromo-/V-(4-(2-cyclopentylacetamido)phenyl)-6,7-dihydrothieno[3,2- c] pyridine-5(4H)-carboxamide.

To a stirred solution of N-(4-aminophenyl)-2-cyclopentylacetamide (step-2 of example-

10) (0.100 g, 0.450 mmol) in THF (15 mL) was added sodium bicarbonate (0.1 15 g, 1.370 mmol) followed by phenyl chloro formate (0.078 g, 0.50 mmol) at 0°C. After stirring at room temperature for 2 h, THF was evaporated. The crude obtained was dissolved in ethyl acetate (25 mL) and washed with saturated sodium bicarbonate solution. Ethyl acetate layer was dried over sodium sulphate and concentrated. The crude carbamate obtained was dissolved in DMSO (10 mL) and was added 2-bromo-4, 5, 6, 7- tetrahydrothieno [3, 2-c] pyridine {synthesis as per procedure reported in WO2011/110219) (0.106 g, 0.450 mmol) at room temperature. After stirring for 16 h at room temperature, reaction mixture poured into ice water, extracted with dichloromethane (2 x 25 mL) .The organic layer was washed with brine, dried over sodium sulphate and concentrated. The crude obtained was purified by column chromatography on silica gel (dichloromethane/methanol = 98/2) to give title compound (0.050 g, 23.5%) as a solid. LCMS: m/z 463.95 [M+H] ⁺; HPLC: 86.6%; ¾ NMR (400 MHz, DMSO-d₆) δ 9.70 (s, 1H), 8.57 (s, 1H), 7.48 - 7.39 (m, 2H), 7.39 - 7.27 (m, 2H), 7.02 (s, 1H), 4.46 (d, / = 1.8 Hz, 2H), 3.72 (t, / = 5.6 Hz, 2H), 2.76 (t, / = 5.7 Hz, 2H), 2.30 - 2.14 (m, 3H), 1.79 - 1.66 (m, 2H), 1.65 - 1.43 (m, 4H), 1.16 (dq, / = 15.0, 7.3 Hz, 2H).

Example- 13: 2-cyano-N-(4-(2-cyclopentylacetamido)phenyl)-6,7-dihydrothieno[3,2- c] p ridine- 5 (4H) -carboxamide .

N-(4-aminophenyl)-2-cyclopentylacetamide (step-2 of example-10) (0.100 g, 0.458 mmol) was reacted with phenyl chloroformate (0.079 g, 0.504 mmol) followed by 4,5, 6,7-tetrahydrothieno[3,2-c]pyridine-2-carbonitrile (Bioorganic Medicinal Chemistry Letters, 16(1 ),542-559,2008) (0.075 g, 0.458 mmol) as described in the synthesis of example-12 to give title compound (0.025 g, 13.8 %). LCMS: m/z 409.55 [M+H] ⁺; HPLC: 97.9 %; ¾ NMR (400 MHz, DMSO-d₆) δ 9.70 (s, 1H), 8.63 (s, 1H), 7.79 (s, 1H), 7.49 - 7.42 (m, 2H), 7.34 - 7.31 (m, 2H), 4.55 (d, / = 1.8 Hz, 2H), 3.77- 7.74 (m, 2H), 2.94 - 2.91 (m, 2H), 2.25 - 2.20 (m, 3H), 1.74 - 1.70 (m, 2H), 1.60 - 1.53 (m, 4H), 1.16 (dq, / = 15.0, 7.3 Hz, 2H).

Example- 14: N-(4-(2-cyclopentylacetamido)phenyl)-2-morpholino-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide.

ΤεΓί 3υΙγ12-ηιοφ1ιο1ίηο-6,7-(ϋ1ιγ(ΐΓθ11ιί6ηο[3,2-ο]ρντί(ϋη6-5(4Η)-ο^οχγ1 ΐ6 (WO2011/ 110219) (0.148 g,0.458 mmol) was dissolved in 10% TFA in dichloromethane (10 mL) and stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane (25 mL) and washed with sat. sodium bicarbonate solution. Dichloromethane layer dried over sodium sulphate and concentrated under reduced pressure to give 4-(4,5,6,7-tetrahydrothieno[3,2-c] pyridin-2-yl) morpholine (0.110 g) as crude. (4-aminophenyl)-2-cyclopentylacetamide (step-2 of example- 10) (0.100 g, 0.458 mmol) was reacted with phenyl chloroformate (0.078 g, 0.458 mmol) followed by above obtained crude 4-(4,5,6J-tetrahydrothieno[3,2-c]pyridin-2-yl)moφholine as described in the synthesis of example- 12 to give title compound (0.050 g, 23.34%). LCMS : m/z 469.3 [M+H] ⁺; HPLC: 98.55 %; ¾ NMR (400 MHz, DMSO-d₆) δ 9.70 (s, 1H), 8.51 (s, 1H), 7.44 _ 7.41 (_m, 2H), 7.34 - 7.31 (m, 2H), 5.92 (s, 1H), 4.36 (s, 2H), 3.79 - 3.62 (m, 6H), 3.03 - 2.90 (m, 4H), 2.73 - 2.61 (m, 2H), 2.36 - 2.11 (m, 3H), 1.81 - 1.66 (m, 2H), 1.66 - 1.40 (m, 4H), 1.27 - 1.03 (m, 2H).

Example- 15: 2-cyclopentyl-N-(4-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5- carbothioamido) phenyl)acetamide.

N-(4-aminophenyl)-2-cyclopentylacetamide (step-2 of example- 10) (0.100 g, 0.458 mmol) was reacted with phenylthienochloroformate (0.087 g, 0.504 mmol) followed by 4,5,6,7-tetrahydrothieno [3 , 2-c] pyridine hydrochloride (0.088 g,0.504 mmol) in DMSO in presence of triethylamine (0.190 mL, 1.374 mmol) as described in the synthesis of example-12 to give title compound (0.045 g, 24.5 %). LCMS: m/z 400.1 [M+H] ⁺; HPLC: 97.6 %; ¾ NMR (400 MHz, DMSO-d₆) δ 9.83 (s, 1H), 9.38 (s, 1H), 7.51 - 7.49 (m, 2H), 7.37 (d, / = 5.1 Hz, 1H), 7.25 - 7.09 (m, 2H), 6.89 (d, / = 5.2 Hz, 1H), 4.95 (d, / = 1.8 Hz, 2H), 4.19 (t, / = 5.6 Hz, 2H), 2.92 (t, / = 5.7 Hz, 2H), 2.35 - 2.10 (m, 3H), 1.84 - 1.68 (m, 2H), 1.68 - 1.40 (m, 4H), 1.32 - 1.14 (m, 2H).

Example- 16: N-(4-(2-cyclopentylacetamido)phenyl)-6,7-dihydrothiazolo[4,5-c] pyridine-5(4H)-carboxamide.

N-(4-aminophenyl)-2-cyclopentylacetamide (step-2 of example- 10) (0.030 g, 0.137 mmol) was treated with phenyl chloro formate (0.024 g, 0.151 mmol) as described in the synthesis of example- 12 to give the crude carbamate which was further treated with 4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine hydrochloride (0.020 g, 0.118 mmol) in DMSO (2 mL) in presence of triethylamine (0.032 mL, 0.236 mmol) to give title compound (0.005 g, 9.4 %). LCMS: mJz 385.5 [M+H] ⁺; HPLC: 97.9 ; ¾ NMR (400 MHz, DMSO-d₆) δ 9.73 (s, 1H), 8.98 (s, 1H), 8.64 (s, 1H), 7.52 - 7.42 (m, 2H), 7.42 - 7.31 (m, 2H), 4.69 (d, / = 1.8 Hz, 2H), 3.79 (t, / = 5.6 Hz, 2H), 2.91 (t, / = 5.6 Hz, 2H), 2.32 - 2.17 (m, 3H), 1.75 (d, / = 6.6 Hz, 2H), 1.67 - 1.41 (m, 4H), 1.32 - 1.10 (m, 2H).

Example- 17: Methyl5-((4-(2-cyclopentylacetamido)phenyl)carbamoyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxylate.

Step-1: Methyl 5-((4-nitrophenyl) carbamoyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- carboxylate.

Methyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate {synthesis as per procedure reported in WO2009037001 ) (0.230 g, 1.166 mmol) was reacted with l-isocyanato-4- nitrobenzene (0.191 g, 1.166 mmol) as described in the synthesis of step-1 of example- 1 to give the title compound (0.400 g, 95%) as a solid. LCMS: m/z 262.7 [M+H] ⁺.

Step-2: Methyl5-((4-aminophenyl)carbamoyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- carboxylate.

Methyl5 -((4-nitrophenyl)carbamoyl)-4 ,5 ,6 J -tetrahydrothieno [3 ,2-c]pyridine-2- carboxylate (0.400 g, 1.106 mmol) was reduced as described in the synthesis of step-2 of example-1 to give the title compound (0.300 g, 81.9 %) as a solid. LCMS: m/z 331.8 [M+H] ⁺

Step-3: Methyl5-((4-(2-cyclopentylacetamido)phenyl)carbamoyl)-4,5,6,7- tetrahydrothieno [3,2-c]pyridine-2-carboxylate.

Methyl5-((4-aminophenyl)carbamoyl)-4,5,6,7-tetrahydrothieno[3 ,2-c]pyridine-2- carboxylate (0.300 g, 0.905 mmol) was reacted with cyclopentane acetic acid (0.174 g, 1.357 mmol) as described in the synthesis of step-3 of example-1 to give the title compound (0.210 g,52.6 %) as a solid. LCMS: m/z 442.5 [M+H]⁺; HPLC: 90.86 ; ^lU NMR (400 MHz, DMSO-d₆) δ 9.70 (s, 1H), 8.60 (s, 1H), 7.61 (s, 1H), 7.50 - 7.38 (m, 2H), 7.38 - 7.26 (m, 2H), 4.54 (s, 2H), 3.79 (s, 3H), 3.75- 3.73 (m, 2H), 2.90 (t, / = 5.6 Hz, 2H), 2.30 - 2.08 (m, 3H), 1.73 (dq, / = 11.6, 6.0 Hz, 2H), 1.66 - 1.40 (m, 4H), 1.19 (ddq, / = 19.9, 14.1 , 7.2 Hz, 2H).

Example- 18: 5-((4-(2-cyclopentylacetamido)phenyl)carbamoyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid.

To a stirred solution of methyl5-((4-(2-cyclopentylacetamido)phenyl)carbamoyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxylate (step-3 of example-17) (0.120 g, 0.271 mmol) in THF:Methanol:Water (1 :1 :1, 6 mL) was added lithium hydroxide monohydrate (0.045 g, 1.087 mmol) at 0 °C and stirred at room temperature for 12 h. Reaction mixture was concentrated to dryness followed by addition of water, cooled to 0°C and pH was adjusted to 5-6 with IN HCl solution. The solid precipitated was filtered and dried under vacuum to give title compound (0.050 g, 43.1 %) as a solid. LCMS: m/z 428.1 [M+H]⁺; HPLC: 95.64 %; ¾ NMR (400 MHz, DMSO-d₆) δ 12.98 (s, 1H), 9.70 (s, 1H), 8.59 (s, 1H), 7.51 (s, lH), 7.48 - 7.42 (m, 2H), 7.34- 7.32 (m,2H), 4.53 (s, 2H), 3.75 (t, / = 5.6 Hz, 2H), 2.88 (t, / = 5.6 Hz, 2H), 2.29 - 2.10 (m, 3H), 1.72 (dt, / = 11.2, 5.8 Hz, 2H), 1.65 - 1.35 (m, 4H), 1.17 (dp, / = 13.7, 7.5, 7.0 Hz, 2H).

Example- 19: N-(4-(2-(tetrahydro-2H-pyran-4-yl)acetamido)phenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide.

N-(4-aminophenyl)-6J-dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide(step-2 of example-4) (0.150 g, 0.540 mmol) was reacted with 2-(tetrahydro-2H-pyran-4-yl)acetic acid (0.087 g, 0.600 mmol) as described in the synthesis of step-3 of example- 1 to give the title compound (0.100 g, 45.6% ) as a white solid. LCMS: m/z 400.1 [M+H]⁺; HPLC: 92.24%; ^lU NMR (400 MHz, DMSO-d₆) δ 9.76 (s, 1H), 8.56 (s, 1 H), 7.47 - 7.40 (m, 2H), 7.38 - 7.32 (m, 3H), 6.89 (d, / = 5.2 Hz, 1 H), 4.54 (d, / = 1.7 Hz, 2H), 3.86 - 3.80 (m, 2H), 3.75 (t, / = 5.6 Hz, 2H), 3.28 (dd, / = 11.7, 2.1 Hz, 2H), 2.84 (t, / = 5.6 Hz, 2H), 2.21 (d, / = 7.1 Hz, 2H), 2.01 - 1.94 (m, 1H), 1.58 (dd, / = 13.3, 3.2 Hz, 2H), 1.22 (tt, / = 12.4, 6.0 Hz, 2H).

Example-20: N-(4-(2-cyclohexylacetamido)phenyl)-6,7-dihydrothieno[3,2- c] pyridine- 5 (4H) -carboxamide .

N-(4-aminophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide (step-2 of example-4) (0.150 g, 0.540 mmol) was reacted with 2-cyclohexylacetic acid (0.078 g, 0.540 mmol) as described in the synthesis of step-3 of example- 1 to give the title compound (0.080 g, 36.6% ) as a white solid. LCMS: m/z 398.4 [M+H]⁺; HPLC: 99.38%; ¾ NMR (400 MHz, DMSO-d₆) δ 9.71 (s, 1H), 8.56 (s, 1H), 7.48 - 7.41 (m, 2H), 7.38 - 7.30 (m, 3H), 6.89 (d, / = 5.2 Hz, 1H), 4.55 (d, / = 1.8 Hz, 2H), 3.76 (t, / = 5.6 Hz, 2H), 2.84 (t, / = 5.7 Hz, 2H), 2.15 (d, / = 7.0 Hz, 2H), 1.69 (d, / = 12.9 Hz, 5H), 1.29 - 1.06 (m, 4H), 0.96 (q, / = 11.1 , 10.0 Hz, 2H).

Example-21 : N-(4-(nicotinamidomethyl)phenyl)-6,7-dihydrothieno[3,2-c]pyridine- 5 (4H) -carboxamide

Step-1: Tert-butyl4-(4,5,6J-tetrahydrothieno[3,2-c]pyridine-5-carboxamido) benzylcarbamate.

Tert-butyl-4-aminobenzylcarbamate {synthesis as per procedure reported WO2010020556) (2.5 g, 11.25 mmol) was reacted with phenyl chloroformate (1.760 g, 16.87 mmol) followed by 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (1.97 g, 11.25 mmol) as described in the synthesis of example- 12 to give title compound (2.0 g, 45.9%). ^lU NMR (400 MHz, Chloroform-d) δ 7.35 - 7.30 (m, 2H), 7.23 - 7.18 (m, 2H), 7.16 (d, / = 5.2 Hz, 1H), 6.81 (d, / = 5.2 Hz, 1H), 6.47 (s, 1H), 4.81 (s, 1H), 4.59 (d, / = 1.6 Hz, 2H), 4.26 (d, / = 5.9 Hz, 2H), 3.83 (t, / = 5.7 Hz, 2H), 2.94 (t, / = 5.7 Hz, 2H), 1.46 (s, 9H).

Step-2: N-(4-(aminomethyl)phenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)- carboxamide hydrochloride.

Tert-butyl 4-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carboxarnido)benzylcarbamate (0.500 g, 1.290 mmol) was treated with 10% TFA in dichloromethane (25mL) at room temperature for 16 h. The reaction mixture was diluted with dichloromethane (50 mL) and washed with saturated sodium bicarbonate solution and brine. The organic layer was dried over sodium sulphate and evaporated under reduced pressure. The residue obtained was treated with 0.5 M HCl (2 mL) methanol (2 mL) at room temperature for Ih.The reaction mixture was concentrated under reduced pressure to give title compound (0.300 g, 77.5%). The product was taken to the next step without further analysis.

Step-3: N-(4-(nicotinamidomethyl)phenyl)-6J-dihydrothieno[3,2-c]pyridine-5(4H)- carboxamide.

N-(4-(aminomethyl)phenyl)-6 J-dihydromieno[3,2-c]pyridine-5(4H)-carboxamide hydrochloride (0.150 g, 0.460 mmol) was reacted with nicotinic acid (0.057 g, 0.460 mol) as described in the synthesis of step-3 of example- 1 to give the title compound (0.080 g, 43.8 % ) as a white solid. LCMS: nt/z 393.35 [M+H]⁺; HPLC: 98.12%; ¾ NMR (400 MHz, DMSO-d₆) δ 9.18 (t, / = 5.9 Hz, 1H), 9.04 (dd, / = 2.2, 0.9 Hz, 1H), 8.70 (dd, / = 4.8, 1.7 Hz, 1 H), 8.62 (s, 1H), 8.22 (dt, / = 7.9, 2.0 Hz, 1H), 7.51 (ddd, / = 8.0, 4.8, 0.8 Hz, 1H), 7.45 - 7.38 (m, 2H), 7.35 (d, / = 5.1 Hz, 1H), 7.24 - 7.16 (m, 2H), 6.89 (d, / = 5.1 Hz, 1H), 4.55 (d, / = 1.7 Hz, 2H), 4.43 (d, / = 5.9 Hz, 2H), 3.76 (t, / = 5.6 Hz, 2H), 2.84 (t, / = 5.7 Hz, 2H).

Example-22: N-(4-((2-(tetrahydro-2H-pyran-4-yl)acetamido)methyl)phenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide.

N-(4-(aminomethyl)phenyl)-6,7-dihydromieno[3,2-c]pyridine-5(4H)-carboxamide hydrochloride (step-2 of example-21) (0.100 g, 0.300 mmol) was reacted with 2- (tetrahydro-2H-pyran-4-yl)acetic acid (0.045 g, 0.300 mmol) as described in the synthesis of step-3 of example- 1 to give the title compound (0.050 g, 39.1 % ) as a white solid. LCMS: nt/z 414.2 [M+H]⁺; HPLC: 93.10%; ^lU NMR (400 MHz, DMSO-d₆) δ 8.59 (s, 1H), 8.26 (t, / = 5.9 Hz, 1H), 7.43 - 7.32 (m, 3H), 7.13 - 7.07 (m, 2H), 6.89 (d, / = 5.1 Hz, 1H), 4.54 (s, 2H), 4.17 (d, / = 5.8 Hz, 2H), 3.78 (dt, / = 18.4, 4.8 Hz, 4H), 3.24 (dd, / = 11.7, 2.0 Hz, 2H), 2.84 (t, / = 5.7 Hz, 2H), 2.05 (d, / = 7.1 Hz, 2H), 1.94 - 1.88 (m, 1H), 1.55 - 1.48 (m, 2H), 1.16 (tt, / = 12.2, 6.0 Hz, 2H). Example-23: N-(4-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)phenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide.

Step-1: Methyl 4-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carboxamido)benzoate.

A solution of methyl-4-isocyanatobenzoate (1.6 g, 9.030 mmol), 4,5,6,7- tetrahydrothieno[3,2-c] pyridine hydrochloride (1.58 g, 9.030 mmol) and triethylamine (3.8 mL, 27.1 mmol) in THF (50 mL) was stirred at room temperature for 16 h. The solvent was evaporated off and the resulting residue was purified by column chromatography on silica gel (60-120 mesh) (hexanes /ethyl acetate =70/30) to give the title compound (2.2 g, 77.1 %) as solid. ¾ NMR (400 MHz, Chloroform-d) δ 8.00 - 7.92 (m, 2H), 7.51 - 7.43 (m, 2H), 7.15 (d, / = 5.1 Hz, 1H), 6.87 - 6.76 (m, 2H), 4.61 (t, / = 1.6 Hz, 2H), 3.96 - 3.77 (m, 5H), 2.93 (t, / = 5.6 Hz, 2H).

Step-2: 4-(4,5,6J-tetrahydrothieno[3,2-c] ridine-5-carboxamido)benzoic acid.

To a stirred solution of methyl-4-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5- carboxamido) benzoate (2.2 g, 6.95 mmol) in methanol:THF (1 :1) (40 mL) was added 4N aqueous solution of sodium hydroxide (8.6 mL, 1.39 g, 34.7 mmol ) at room temperature and further stirred for 16 h. The reaction mixture was diluted with water and evaporated off .The residual aqueous solution was acidified to pH~3 using 3N HCl. The resulting solid was filtered and washed with water and dried to give the title compound (1.5 g, 71.4%) as a white solid. The product obtained was taken to next step without further analysis.

Step-3: N-(4-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)phenyl)-6,7-dihydrothieno [3,2-c]pyridine-5(4H)-carboxamide .

To a solution of 4-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carboxamido)benzoic acid (0.150 g, 0.496 mmol ) and (tetrahydro-2H-pyran-4-yl)methanamine (0.068 g, 0.593 mmol) in DMF (10 mL) were added EDCI.HC1 (0.114 g, 0.593 mmol), HOBt (0.120 g, 0.873 mmol) and DIPEA (0.259 mL, 1.488 mmol) at room temperature and the reaction mixture was stirred for 16 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (2 x 50 mL) and washed with water. The organic phase was dried over sodium sulphate and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (60-120 mesh) (dichloromethane/ methanol= 97/3) to give the title compound (0.050 g, 25.2%) as a white solid. LCMS: m/z 400.40 [M+H] ⁺; HPLC: 96.5%; ¾ NMR (400 MHz, Chloroform-d) δ 7.75 - 7.67 (m, 2H), 7.50 - 7.42 (m, 2H), 7.17 (d, / = 5.1 Hz, 1H), 6.82 (d, / = 5.1 Hz, 1H), 6.60 (s, 1H), 6.18 (s, 1H), 4.62 (d, / = 1.7 Hz, 2H), 4.04 - 3.92 (m, 2H), 3.85 (t, / = 5.7 Hz, 2H), 3.48 - 3.29 (m, 4H), 2.96 (t, / = 5.8 Hz, 2H), 1.97 - 1.81 (m, 1H), 1.68 (d, / = 13.2 Hz, 2H), 1.46 - 1.18 (m, 2H).

Example-24: N-(4-((2-morpholinophenyl)carbamoyl)phenyl)-6,7-dihydrothieno[3,2- c]pyridine-5(4H)-carboxamide .

4-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carboxamido)benzoic acid (step-2 of example-23) (0.150g, 0.496 mmol) was reacted with 2-morpholinoaniline {synthesized as per procedure reported in WO20090548) (0.105 g, 0.593 mmol) in presence of EDCI.HC1 (0.114 g, 0.593 mmol ), HOBt (0.120 g, 0.873 mmol) and DIPEA (0.259 mL, 1.488 mmol) in DMF (10 mL) as described in the synthesis of step-3 of example-23 to give the title compound (0.045 g, 19.61 %) as a solid. LCMS: m/z 463.1 [M+H] ⁺; HPLC: 97.85 %; ¾ NMR (400 MHz, Chloroform-d) δ 9.47 (s, 1H), 8.56 (dd, / = 8.4, 1.5 Hz, 1H), 7.95 - 7.86 (m, 2H), 7.64 - 7.52 (m, 2H), 7.31 - 7.07 (m, 4H), 6.85 (d, / = 5.2 Hz, 1H), 6.66 (s, 1H), 4.66 (d, / = 1.6 Hz, 2H), 3.97 - 3.83 (m, 6H), 2.96 (dt, / = 19.1 , 5.1 Hz, 6H).

Example-25: N-(4-((tetrahydro-2H-pyran-4-yl)carbamoyl)phenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide .

4-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carboxamido)benzoic acid (step-2 of example-23) (0.150 g,0.496 mmol) was reacted with tetrahydro-2H-pyran-4-amine (0.060 g,0.593 mmol) in presence of EDCI.HC1 (0.114 g, 0.593 mmol), HOBt (0.120 g, 0.873 mmol ) and DIPEA (0.259 mL ,1.488 mmol ) in DMF (10 mL) as described in the synthesis of step-3 of example-23 to give the title compound (0.060 g, 31.3%) as a solid. LCMS: m/z 386.0 [M+H] ⁺; HPLC: 98.0 %; ¾ NMR (400 MHz, DMSO-d₆) δ 8.91 (s, 1H), 8.14 (d, / = 7.7 Hz, 1H), 7.84 - 7.74 (m, 2H), 7.63 - 7.54 (m, 2H), 7.39 (d, / = 5.2 Hz, 1H), 6.93 (d, / = 5.2 Hz, 1H), 4.61 (d, / = 1.8 Hz, 2H), 4.09 - 3.75 (m, 4H), 3.51 - 3.40 (m, 2H), 2.89 (t, / = 5.8 Hz, 2H), 1.76 (dd, / = 13.2, 4.0 Hz, 2H), 1.59 (qd, / = 12.2, 4.5 Hz, 2H).

Example-26: N-(4-(cyclohexylcarbamoyl) phenyl)-6,7-dihydrothieno[3,2-c]pyridine- 5 (4H) -carboxamide.

4-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carboxamido)benzoic acid (step-2 of example-23) (0.150 g, 0.496 mmol ) was reacted with cyclohexanamine (0.058 g, 0.593 mmol) in presence of EDCI.HC1 (0.114 g, 0.593 mmol ), HOBt (0.120 g, 0.873 mmol) and DIPEA (0.259 mL, 1.488 mmol) in DMF (10 mL) as described in the synthesis of step-3 of example-23 to give the title compound (0.040 g, 21 %) as a solid. LCMS: m/z 384.1 [M+H] ⁺; HPLC: 98.1 %; ¾ NMR (400 MHz, Chloroform-d) δ 7.75 - 7.67 (m, 2H), 7.50 - 7.42 (m, 2H), 7.18 (d, / = 5.2 Hz, 1H), 6.83 (d, / = 5.2 Hz, 1H), 6.58 (s, 1H), 5.91 (d, / = 8.1 Hz, 1H), 4.04 - 3.91 (m, 2H), 4.63 (d, / = 1.6 Hz, lH), 3.86 (t, / = 5.6 Hz, 2H), 2.97 (t, / = 5.7 Hz, 2H), 2.04 (d, / = 11.9 Hz, 2H), 1.76 (s, 2H), 1.52 - 1.14 (m, 6H).

Example-27: N-(4-(cyclopropylcarbamoyl)phenyl)-6,7-dihydrothieno[3,2-c]pyridine- 5(4H)-carboxamide .

4-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carboxamido)benzoic acid (step-2 of example-23) (0.150 g, 0.496 mmol) was reacted with cyclopropanamine (0.340 g, 0.593 mmol) in presence of EDCI.HC1 (0.114 g, 0.593 mmol ), HOBt (0.120 g, 0.873 mmol) and DIPEA (0.259 mL, 1.488 mmol) in DMF (10 mL) as described in the synthesis of step-3 of example-23 to give the title compound (0.070 g, 41.3%) as a solid. LCMS: m/z 341.43 [M+H] ⁺; HPLC: 91.99 %; ¾ NMR (400 MHz, Chloroform-d) δ 7.72 - 7.65 (m, 2H), 7.48 - 7.42 (m, 2H), 7.18 (dd, / = 5.2, 0.7 Hz, 1H), 6.83 (d, / = 5.2 Hz, 1H), 6.66 (s, 1H), 6.21 (s, 1H), 4.63 (d, / = 1.6 Hz, 2H), 3.86 (t, / = 5.7 Hz, 2H), 3.13 - 2.83 (m, 3H), 0.87 (td, /= 7.0, 5.2 Hz, 2H), 0.62 (ddd, / = 6.9, 5.3, 3.9 Hz, 2H).

Example-28: N-(4-((furan-2-ylmethyl)carbamoyl)phenyl)-6,7-dihydrothieno[3,2- c] pyridine- 5 (4H) -carboxamide .

4-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carboxamido)benzoic acid (step-2 of example-23) (0.150 g, 0.496 mmol) was reacted with furan-2-ylmethanamine (0.048 g, 0.496 mmol) as described in the synthesis of step-3 of example-23 to give the title compound (0.060 g, 31.7%) as a solid. LCMS: m/z 382 [M+H] ⁺; HPLC: 95.75 %; ¾ NMR (400 MHz, Chloroform-d) δ 7.74 (d, / = 8.6 Hz, 2H), 7.47 (d, / = 8.6 Hz, 2H), 7.39 (d, / = 1.7 Hz, 1H), 7.17 (d, / = 5.2 Hz, lH), 6.83 (d, / = 5.2 Hz, 1H), 6.60 (s, 1H), 6.40 - 6.33 (m, 2H), 6.31 (d, / = 3.2 Hz, 1H), 4.68 - 4.59 (m, 4H), 3.86 (t, / = 5.6 Hz, 2H), 2.96 (t, /= 5.8 Hz, 2H). Example-29: N-(4-(((tetrahydrofuran-2-yl)methyl)carbamoyl)phi dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide (±) .

4-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carboxamido)benzoic acid (step-2 of example-23) (0.150 g, 0.496 mmol ) was reacted with (tetrahydrofuran-2-yl)methanamine (±) (0.050 g, 0.496 mmol) as described in the synthesis of step-3 of example-23 to give the title compound (0.100 g, 52.29%). LCMS: nt/z 386.4 [M+H] ⁺; HPLC: 92.24%; ¾ NMR (400 MHz, Chloroform-d) δ 7.77 - 7.71 (m, 2H), 7.50 - 7.43 (m, 2H), 7.17 (d, / = 5.2 Hz, 1H), 6.83 (d, / = 5.2 Hz, 1H), 6.61 (s, 1H), 6.47 (s, 1H), 4.63 (d, / = 1.7 Hz, 2H), 4.07 (qd, / = 7.2, 3.3 Hz, l H), 3.94 - 3.73 (m, 5H), 3.34 (ddd, / = 13.8, 7.4, 4.9 Hz, 1H), 2.96 (t, / = 5.7 Hz, 3H), 2.12 - 1.86 (m, 3H).

Example-30: N-(4-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)phenyl)-3,4- dihydropyrrolo[ 1 ,2-a] pyrazine-2(l H)-carboxamide.

Step-1: Phenyl (4-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)phenyl)carbamate.

To a solution of 4-nitrobenzoic acid (0.200g, 1.196 mmol), (tetrahydro-2H-pyran-4-yl) methanamine (0.137 g, 1.196 mmol), EDCI.HC1 (0.231 g, 1.436 mmol ) and HOBt (0.242 g, 1.795 mmol ) in DMF (5 mL) was added DIPEA (0.624 mL, 3.59 mmol ) at room temperature under N2 atmosphere. After being stirred at room temperature for 16 h, the reaction mixture was poured into ice-water (20 mL) and extracted with ethyl acetate (2 x 20 mL). Ethyl acetate layer was dried over sodium sulphate and concentrated under reduced pressure. The crude compound obtained was hydrogenated under ¾ gas balloon with 10 % Pd on carbon (50 mg) in ethanol (25 mL) at room temperature for 16 h. The reaction mixture was filtered through celite pad and the filtrate obtained was concentrated under reduced pressure to give 4-amino-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide as a crude solid. The solid obtained was dissolved in THF (10 mL) and was added sodium bicarbonate (0.301 g, 3.590 mmol) followed by phenylchloroformate (0.187 g, 1.436 mmol) and stirred at room temperature for 3h. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with saturated aqueous solution of sodium bicarbonate (20 mL). The ethyl acetate layer was dried over sodium sulphate and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (hexanes/ethyl acetate = 80/20) to give the title compound (0.150 g, 35.3 %) as a solid. The product obtained was taken to next step without further analysis.

Step-2: N-(4-(((tetrahydro-2H^yran-4-yl)methyl)carbamoyl)phenyl)-3,4-dihydropyrrolo [ 1 ,2-a]pyrazine-2(l H)-carboxamide.

To a solution of phenyl(4-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)phenyl) carbamate (0.100 g, 0.280 mmol) in DMSO (5 mL) was added 1,2,3,4- tetrahydropyrrolo[l ,2-a]pyrazine (0.035 g, 0.280 mmol), triethylamine (0.117 mL, 0.840 mmol) and resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into ice-water (20 mL) and extracted with ethyl acetate (2 x 20 mL). Ethyl acetate layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product obtained was purified by column chromatography on silica gel (dichloromethane/methanol = 100/0 to 97/3) to give the title compound (0.055 g, 50.9%). LCMS: nt/z 383.2 [M+H] ⁺; HPLC: 98.01 %; ¾ NMR (400 MHz, Chloroform-d) δ 7.71 (d, / = 8.4 Hz, 2H), 7.46 (d, / = 8.4 Hz, 2H), 6.62 (d, / = 15.6 Hz, 2H), 6.20-6.18 (m, 2H), 5.99 (s, 1H), 4.74 (s, 2H), 4.07 (t, / = 10.8 Hz, 2H), 4.01 -3.92 (m, 4H), 3.42-3.34 (m, 4H), 1.94 - 1.84 (m, 1H), 1.68 (d, / = 13.2 Hz, 2H), 1.38 (m, 2H).

Example-31: N-(4-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)phenyl)-3- (trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxamide.

Phenyl(4-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)phenyl)carbamate (step- 1 of example-30) (0.100 g, 0.280 mmol) was reacted with 3-(trifluoromethyl)-5,6,7,8- tetrahydro-[l ,2,4]triazolo[4,3-a]pyrazine (0.054 g, 0.280 mmol) and triethylamine (0.117 mL, 0.840 mmol) as described in the synthesis of step-2 of example-30 to give the title compound (0.055 g, 43.1 %). LCMS: nt/z 453.2 [M+H] ⁺; HPLC: 98.13 %; ¾ NMR (400 MHz, DMSO-d₆) δ 9.09 (s, 1H), 8.32 (t, / = 5.9 Hz, 1H), 7.81 - 7.73 (m, 2H), 7.59 - 7.50 (m, 2H), 4.98 (s, 2H), 4.25 (t, / = 5.4 Hz, 2H), 3.99 (t, / = 5.4 Hz, 2H), 3.90 - 3.78 (m, 2H), 3.26 (td, / = 11.6, 1.9 Hz, 2H), 3.14 (q, / = 6.1 Hz, 2H), 1.78 (ddd, / = 11.1 , 7.3, 3.7 Hz, 1H), 1.58 (d, / = 13.0 Hz, 2H), 1.18 (qd, / = 12.1 , 4.4 Hz, 2H).

Example-32: N-(4-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)phenyl)-5,6- dihydroimidazo[l,2-a]pyrazine-7(8H)-carboxamide.

Phenyl (4-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)phenyl)carbamate (step- 1 of example-30) (0.100 g, 0.280 mmol) was reacted with 5,6,7,8-tetrahydroimidazo[l ,2- a]pyrazine (0.035 g, 0.280 mmol) and triethylamine (0.117 mL, 0.840 mmol) as described in the synthesis of step-2 of example-30 to give the title compound (0.030 g, 27.7% ). LCMS: nt/z 384.2 [M+H] ⁺; HPLC: 97.70 %; ¾ NMR (400 MHz, DMSO-d₆) δ 9.01 (d, / = 2.8 Hz, 1H), 8.33 (d, / = 6.7 Hz, 1H), 7.75 (dt, / = 9.0, 2.4 Hz, 2H), 7.63 - 7.46 (m, 2H), 7.12 (d, / = 2.9 Hz, 1H), 6.89 (d, / = 3.2 Hz, 1H), 4.76 - 4.66 (m, 2H), 4.04 (t, / = 4.9 Hz, 2H), 3.98 - 3.72 (m, 4H), 3.29 - 3.18 (m, 2H), 3.12 (q, / = 4.8 Hz, 2H), 1.78 (d, / = 10.9 Hz, 1H), 1.57 (d, / = 13.3 Hz, 2H), 1.18 (q, / = 13.3 Hz, 2H).

Example-33: N-(4-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)phenyl)-4,5- dihydrofuro[2,3-c]pyridine-6(7H)-carboxamide.

Phenyl(4-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)phenyl)carbamate (step- 1 of example-30) (0.100 g, 0.280 mmol) was reacted with 4,5,6,7-tetrahydrofuro[2,3- c]pyridine hydrochloride {synthesis as per procedure reported in WO2008124083) (0.045 g ,0.280 mmol) and triethylamine (0.117 mL, 0.840 mmol) as described in the synthesis of step-2 of example-30 to give the title compound (0.020 g, 18.5%). LCMS: m/z 384.2 [M+H]⁺; HPLC: 98.57%; ¾ NMR (400 MHz, Chloroform-d) δ 7.73 - 7.67 (m, 2H), 7.44 (d, / = 8.7 Hz, 2H), 7.32 (dd, / = 1.8, 1.0 Hz, 1H), 6.57 (s, 1H), 6.28 (d, / = 2.0 Hz, 1H), 6.19-6.11 (m, 1H), 4.56 (d, / = 1.7 Hz, 2H), 3.98 (dd, / = 11.6, 4.3 Hz, 2H), 3.74 (t, / = 5.6 Hz, 2H), 3.43 - 3.31 (m, 4H), 2.63 (q, / = 5.2 Hz, 2H), 1.67 (d, / = 13.0 Hz, 2H), 1.37 (qd, / = 12.3, 4.5 Hz, 2H), 1.92 - 1.82 (m, 1H).

Example-34: N-(4-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)phenyl)-6,7- dihydrofuro[3,2-c]pyridine-5(4H)-carboxamide.

Phenyl(4-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)phenyl)carbamate (step-1 of example-30) (0.158 g, 0.440 mmol) was reacted with 4,5,6,7-tetrahydrofuro[3,2- c]pyridine hydrochloride (synthesis as per procedure reported in WO2012054535) (0.070 g, 0.440 mmol) and triethylamine (0.187 mL, 1.340 mmol) as described in the synthesis of step-2 of example-30 to give the title compound (0.030 g, 17.4%). LCMS: m/z 384.2 [M+H]⁺; HPLC:95.88%; ^lU NMR (400 MHz, Chloroform-d) δ 7.74 - 7.67 (m, 2H), 7.48 - 7.42 (m, 2H), 7.33 (d, / = 1.9 Hz, 1H), 6.61 (s, 1H), 6.27 (d, / = 1.9 Hz, 1H), 6.19 (t, / = 6.3 Hz, 1H), 4.45 (d, / = 1.8 Hz, 2H), 4.03 - 3.95 (m, 2H), 3.85 (t, / = 5.7 Hz, 2H), 3.42 - 3.32 (m, 4H), 2.81 (t, / = 5.7 Hz, 2H), 1.89 (ddd, / = 11.4, 7.6, 4.3 Hz, 1H), 1.68 (d, / = 13.3 Hz, 2H), 1.44 - 1.33 (m, 2H).

Example-35: N-(5-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-2-yl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide. Step-1 : Methyl-6-((phenoxycarbonyl)amino)nicotinate.

To a stirred solution of methyl-6-aminonicotinate (0.200 g, 1.31 mmol) in THF (15 mL) was added sodium bicarbonate (0.552 g, 6.570 mmol) followed by phenyl chloroformate (0.308 g, 1.970 mmol) at 0°C. After being stirred at room temperature for 3h, THF was evaporated off. The crude dissolved in ethyl acetate (25 mL) and washed with saturated sodium bicarbonate solution. Ethyl acetate layer dried over sodium sulphate, evaporated and the crude product obtained was purified by column chromatography on silica gel (methanol/dichloromethane = 1/99) to give title compound (0.150 g, 42 ). The product obtained was taken to next step without further analysis.

Step-2: Methyl 6-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carboxamido)nicotinate.

Methyl 6-((phenoxycarbonyl) amino)nicotinate (0.150 g, 0.550 mmol) was reacted with 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (0.097 g, 0.550 mmol) and triethylamine (0.230 mL, 1.650 mmol) as described in the synthesis of step-2 of example-30 to give the title compound (0.125 g, 71.8 ). The product obtained was taken to next step without further analysis.

Step-3: 6-(4,5,6J-tetrahydrothieno[3,2-c]pyridine-5-carboxamido)nicotinic acid.

To a stirred solution of methyl 6-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5- carboxamido)nicotinate (0.125 g, 0.39 mmol) in mixture of solvents methanol:THF (1 : 1, 5 mL) was added 4N aq. sodium hydroxide solution (0.4 mL) and further stirred at room temperature for 16 h. The organic solvents were evaporated and aqueous solution was acidified to pH~6 using 3N HCl. The resulting solid was filtered and washed with water and dried to give the title compound (0.110 g, 92.4%) as a white solid. The product obtained was taken to next step without further analysis.

Step-4: N-(5-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-2-yl)-6,7- dihydrothieno [3 ,2-c]pyridine-5 (4H)-carboxamide.

6-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carboxamido)nicotinic acid (0.100 g, 0.331 mmol) was reacted with (tetrahydro-2H-pyran-4-yl)methanamine (0.052 g, 0.331 mmol) as described in the synthesis of step-3 of example-23 to give the title compound (0.040 g, 30.3%) as a solid. LCMS: nt/z 401.4 [M+H] ⁺; HPLC: 98.44 %; ¾ NMR (400 MHz, Chloroform-d) δ 8.68 - 8.63 (m, 1H), 8.13 (dd, / = 8.8, 0.9 Hz, 1H), 8.01 (dd, / = 8.8, 2.5 Hz, lH), 7.45 (s, 1 H), 7.18 (d, / = 5.1 Hz, 1H), 6.83 (d, / = 5.2 Hz, 1H), 6.13 (s, 1H), 4.66 (d, / = 1.7 Hz, 2H), 4.00 (dd, / = 1 1.4, 4.3 Hz, 2H), 3.88 (t, / = 5.7 Hz, 2H), 3.46 - 3.32 (m, 4H), 2.97 (t, / = 5.7 Hz, 2H), 1.94 - 1.84 (m, 1H), 1.69 (d, / = 12.9 Hz, 2H), 1.39 (qd, / = 12.1 , 4.5 Hz, 2H).

Example-36: N-(5-((tetrahydro-2H-pyran-4-yl)carbamoyl)pyridin-2-yl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide.

6-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carboxamido)nicotinic acid (step-3 of example-35) (0.100 g, 0.331 mmol) was reacted with tetrahydro-2H-pyran-4-amine (0.040 g, 0.331 mmol) as described in the synthesis of step-3 of example-23 to give the title compound (0.030 g, 23.5%) as a solid. LCMS: nt/z 387.1 [M+H] ⁺; HPLC: 91.27 %; ¾ NMR (400 MHz, Chloroform-d) δ 8.64 (d, / = 2.4 Hz, 1H), 8.12 (d, / = 8.8 Hz, 1H), 8.00 (dd, / = 8.8, 2.4 Hz, 1H), 7.50 (s, 1H), 7.17 (d, / = 5.2 Hz, 1H), 6.82 (d, / = 5.1 Hz, 1H), 5.91 (d, / = 7.8 Hz, 1H), 4.65 (d, / = 1.6 Hz, 2H), 4.20 (dtt, / = 11.8, 8.5, 4.3 Hz, 1H), 4.04 - 3.95 (m, 2H), 3.87 (t, / = 5.7 Hz, 2H), 3.54 (td, / = 11.8, 2.1 Hz, 2H), 2.97 (t, / = 4.8 Hz, 2H), 2.01 (dd, / = 12.9, 3.1 Hz, 2H), 1.55 (dd, / = 11.9, 4.5 Hz, 2H).

Example-37: N-(5-((cyclopentylmethyl)carbamoyl)pyridin-2-yl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide.

6-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carboxamido)nicotinic acid (step-3 of example-35) (0.100 g, 0.331 mmol) was reacted with cyclopentylmethanamine (0.039 g, 0.390 mmol) as described in the synthesis of step-3 of example-23 to give the title compound (0.035 g, 27.52%) as a solid. LCMS: m/z 385.5 [M+H] ⁺; HPLC: 91.00 %; ¾ NMR (400 MHz, Chloroform-d) δ 8.66 - 8.61 (m, 1H), 8.11 (d, / = 8.8 Hz, 1H), 8.03 - 7.96 (m, 1H), 7.49 (s, 1H), 7.17 (d, / = 5.2 Hz, 1H), 6.82 (d, / = 5.3 Hz, 1H), 6.05 (t, / = 5.7 Hz, 1H), 4.65 (d, / = 1.5 Hz, 2H), 3.92 - 3.80 (m, 2H), 3.43 - 3.35 (m, 2H), 2.96 (t, / = 5.7 Hz, 2H), 2.19 - 2.11 (m, 1H), 1.88 - 1.73 (m, 2H), 1.70 - 1.64 (m, 2H), 1.26 (q, / = 9.4, 8.2 Hz, 4H).

Example-38: N-(5-(((3-methyloxetan-3-yl)methyl)carbamoyl)pyridin-2-yl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide.

6-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carboxamido)nicotinic acid (step-3 of example-35) (0.150g, 0.496 mmol) was reacted with (3-methyloxetan-3-yl)methanamine (synthesis as per procedure reported in US20090076062 ) (0.075 g, 0.744 mmol) as described in the synthesis of step-3 of example-23 to give the title compound (0.030 g, 15.6%) as a solid. LCMS: m/z 387.1 [M+H] ⁺; HPLC: 97.75 %; ¾ NMR (300 MHz, Chloroform-d) δ 8.76 - 8.62 (m, 1H), 8.14 (d, / = 8.8 Hz, 1H), 8.03 (dd, / = 8.8, 2.4 Hz, 1H), 7.50 (s, lH), 7.18 (d, / = 5.2 Hz, 1H), 6.83 (d, / = 5.2 Hz, 1H), 6.45 (t, / = 6.2 Hz, 1H), 4.65 (d, / = 1.7 Hz, 2H), 4.56 (d, / = 6.2 Hz, 2H), 4.48 (d, / = 6.1 Hz, 2H), 3.88 (t, / = 5.7 Hz, 2H), 3.65 (d, / = 6.0 Hz, 2H), 2.97 (t, / = 5.7 Hz, 2H), 1.37 (s, 3H). Example-39: 2-methyl-N-(5-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin -2-yl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide.

Step-1: Methyl 6-(2-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carboxamido) nicotinate.

Methyl 6-((phenoxycarbonyl)amino)nicotinate (0.100 g, 0.360 mmol) was reacted with 2- methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (synthesis as per procedure reported in Bioorganic & Medicinal chemistry, 16(1 ),542-559;2008) (0.056 g, 0.360 mmol) and triethylamine (0.153 mL, 1.10 mmol) as described in the synthesis of step-2 of example- 30 to give the title compound (0.050 g, 41.0%). ¾ NMR (400 MHz, Chloroform-d) δ 8.86 (dd, / = 2.3, 0.8 Hz, 1H), 8.27 (dd, / = 8.9, 2.3 Hz, 1H), 8.15 (dd, / = 8.8, 0.8 Hz, 1H), 7.51 (s, 1H), 6.51 - 6.45 (m, 1H), 4.56 (d, / = 1.7 Hz, 2H), 3.94 (s, 3H), 3.86 (t, / = 5.6 Hz, 2H), 2.89 (t, /= 5.7 Hz, 2H), 2.48 (s, 3H).

Step-2: 6-(2-memyl-4,5,6,7-tetrahydromieno[3,2-c]pyridine-5-carboxamido)nicotinic

Methyl-6-(2-memyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carboxamido)nicotinate (0.050 g, 0.150 mmol) was treated with 4N sodium hydroxide aq. solution (0.18 mL) as described in the synthesis of step-2 of example-23 to give the title compound (0.030 g, 62.6%) as a solid. The product obtained was taken to next step without further analysis.

Step-3: 2-methyl-N-(5-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-2-yl)-6,7- dihydrothieno [3 ,2-c]pyridine-5 (4H)-carboxamide.

6-(2-memyl-4,5,6J-tetrahydrothieno[3,2-c]pyridm^ acid

(0.030 g, 0.094 mmol) was reacted with (tetrahydro-2H-pyran-4-yl)methanamine (0.011 g, 0.094 mmol) as described in the synthesis of step-3 of example-23 to give the title compound (0.015 g, 38.3%) as a solid. LCMS: nt/z 415.1 [M+H] ⁺; HPLC: 97.50 %; ^lU NMR (400 MHz, Chloroform-d) δ 8.66 (d, / = 2.4 Hz, 1H), 8.14 (d, / = 8.8 Hz, 1H), 8.01 (dd, / = 8.8, 2.4 Hz, 1H), 7.47 (s, 1H), 6.48 (s, 1H), 6.16 (t, / = 6.1 Hz, 1H), 4.56 (s, 2H), 4.06 - 3.95 (m, 2H), 3.86 (t, / = 5.7 Hz, 2H), 3.46 - 3.33 (m, 4H), 2.89 (t, / = 5.7 Hz, 2H), 2.45 (s, 3H), 1.96 - 1.85 (m, 1H), 1.71 (m, 2H), 1.40 (qd, / = 12.1 , 4.4 Hz, 2H). Example-40: N-(5-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-2-yl)-4,5- dihydrothieno[2,3-c]pyridine-6(7H)-carboxamide.

Step-1: Tert-butyl(5-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-2- yl)carbamate.

6-((tert-butoxycarbonyl)amino)nicotinic acid (synthesis as per procedure reported in WO2010144345) (1.40 g, 5.870 mmol) was reacted with (tetrahydro-2H-pyran-4- yl)methanamine (0.677 g, 5.870 mmol) as described in the synthesis of step-3 of example-23 to give the title compound (1.00 g, 50.7%) as a solid. ^lU NMR (400 MHz, DMSO-d₆) δ 10.10 (s, 1H), 8.69 (d, / = 2.2 Hz, 1H), 8.51 (t, / = 6.0 Hz, 1H), 8.15 (dt, / = 8.8, 2.0 Hz, 1H), 7.85 (d, / = 8.8 Hz, 1H), 3.88 - 3.80 (m, 2H), 3.25 (t, / = 11.6 Hz, 2H), 3.15 (t, / = 6.4 Hz, 2H), 1.84 - 1.72 (m, 1H), 1.65 - 1.54 (m, 2H), 1.47 (d, / = 1.6 Hz, 9H), 1.18 (qd, / = 12.3, 4.1 Hz, 2H).

Step-2: Phenyl (5-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-2-yl) carbamate.

Tert-butyl (5-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-2-yl)carbamate (1.0 g, 2.980 mmol) was treated with 10% TFA in dichloromethane (25 mL) at room temperature for 16 h.The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. Dichloromethane layer dried over sodium sulphate, concentrated to give 6-amino-N-((tetrahydro-2H-pyran-4-yl) methyl) nicotinamide as crude. To a stirred solution of the obtained 6-amino-N-((tetrahydro-2H- pyran-4-yl)methyl)nicotinamide (crude) in THF (25 mL) was added sodium bicarbonate (0.750 g, 8.940 mmol) followed by phenyl chloroformate (0.560 g, 3.580 mmol) at 0°C and stirred at room temperature for 3h. Evaporated off THF from reaction mixture under reduced pressure and the crude product obtained was dissolved in ethyl acetate (50 mL) and washed with saturated sodium bicarbonate solution. Ethyl acetate layer dried over sodium sulphate, concentrated to give title compound (0.600 g, 57.1%). ¾ NMR (400 MHz, DMSO-d₆) δ 8.43 (d, / = 2.3 Hz, 1H), 8.19 - 8.12 (m, 1H), 7.79 (dd, / = 8.8, 2.4 Hz, 1H), 7.15 (t, / = 7.8 Hz, 2H), 6.75 (d, / = 7.7 Hz, 2H), 6.47 - 6.37 (m, 3H), 3.83 (dd, / = 11.1, 4.3 Hz, 2H), 3.24 (ddd, / = 11.7, 7.8, 4.1 Hz, 2H), 3.10 (t, / = 6.4 Hz, 2H), 1.75 (tp, / = 10.9, 4.2, 3.3 Hz, 1H), 1.57 (dt, / = 13.5, 6.7 Hz, 2H), 1.18 (dtd, / = 24.7, 13.2, 12.2, 5.6 Hz, 2H).

Step-3: N-(5-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-2-yl)-4,5- dihydrothieno [2,3-c]pyridine-6(7H)-carboxamide.

Phenyl (5-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-2-yl)carbamate (0.150 g, 0.420 mmol) was reacted with 4,5,6,7-tettahydrothieno[2,3-c]pyridine hydrochloride {synthesis as per procedure reported in WO2005095387) (0.074 g, 0.420 mmol) and triethylamine (0.175 mL, 1.260 mmol) as described in the synthesis of step-2 of example-30 to give the title compound (0.070 g, 41.4%). LCMS: m/z 400.8 [M+H] ⁺; HPLC: 91.2 %; ¾ NMR (400 MHz, Chloroform-d) δ 8.72 - 8.63 (m, 1H), 8.18 - 8.10 (m, 1H), 8.02 (dd, / = 8.7, 2.4 Hz, 1H), 7.53 (s, 1H), 7.20 (d, / = 5.1 Hz, 1H), 6.84 (d, / = 5.1 Hz, 1H), 6.17 (t, / = 6.1 Hz, 1H), 4.81 (s, 2H), 4.06 - 3.96 (m, 2H), 3.87 - 3.79 (m, 2H), 3.47 - 3.33 (m, 4H), 2.86 (t, / = 5.8 Hz, 2H), 1.89 (m, 1H), 1.71 - 1.66 (m, 2H), 1.41 (tt, / = 12.2, 6.2 Hz, 2H).

Example-41: N-(5-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-2-yl)-4,5- dihydrofuro[2,3-c]pyridine-6(7H)-carboxamide.

Phenyl (5-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-2-yl)carbamate (step-2 of example-40) (0.100 g, 0.280 mmol) was reacted with 4,5,6,7-tetrahydrofuro[2,3- c]pyridine hydrochloride (0.045 g, 0.280 mmol) and triethylamine (0.117 mL , 0.840 mmol) as described in the synthesis of step-2 of example-30 to give the title compound (0.015 g, 13.8%). LCMS: nt/z 385.5 [M+H] ⁺; HPLC: 93.70 %; ^lU NMR (400 MHz, Chloroform-d) δ 8.68 - 8.63 (m, 1H), 8.11 (dd, / = 8.8, 0.8 Hz, 1H), 8.01 (dd, / = 8.8, 2.4 Hz, 1H), 7.44 (s, 1H), 7.34 - 7.30 (m, 1H), 6.29 (d, / = 1.9 Hz, 1H), 6.14 (s, 1H), 4.60 (q, / = 1.5 Hz, 2H), 4.00 (dd, / = 11.6, 4.3 Hz, 2H), 3.77 (t, / = 5.6 Hz, 2H), 3.45 - 3.33 (m, 4H), 2.68 - 2.62 (m, 2H), 1.96 - 1.82 (m, 1H), 1.68 (d, / = 13.1 Hz, 2H), 1.39 (qd, / = 12.2, 4.6 Hz, 2H).

Example-42: N-(5-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-2-yl)-6,7- dihydrofuro[3,2-c]pyridine-5(4H)-carboxamide.

Phenyl(5-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-2-yl)carbamate (step-2 of example-40) (0.100 g, 0.280 mmol) was reacted with 4,5,6,7-tetrahydrofuro[3,2- c]pyridine hydrochloride (synthesis as per procedure reported in WO2012054535) (0.045 g, 0.280 mmol) and triethylamine (0.117 mL, 0.840 mmol) as described in the synthesis of step-2 of example-30 to give the title compound (0.010 g, 9.2%). LCMS: nt/z 385.1 [M+H] ⁺; HPLC: 97.65 %; ¾ NMR (400 MHz, Chloroform-d) δ 8.69 - 8.61 (m, 1H), 8.10 (d, / = 8.7 Hz, 1H), 7.99 (d, / = 9.2 Hz, lH), 7.44 (s, 1H), 7.33 (s, 1H), 6.31 - 6.22 (m, 1H), 6.13 (s, 1H), 4.56 - 4.41 (m, 2H), 4.00 (d, / = 11.0 Hz, 2H), 3.92 - 3.80 (m, 2H), 3.39 (t, / = 11.4 Hz, 4H), 2.82 (s, 2H), 1.96 - 1.83 (m, 1H), 1.72 - 1.62 (m, 2H), 1.38 (d, / = 12.2 Hz, 2H).

Example-43: l-methyl-N-(5-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl) pyridin-2-yl)-6,7-dihydro-lH-pyrrolo[3,2-c]pyridine-5(4H)-carboxamide.

Step-1: Methyl-6-(l-methyl-4,5,6,7-tetrahydro-lH-pyrrolo[3,2-c]pyridine-5- carboxamido) nicotinate.

Methyl-6-((phenoxycarbonyl)amino)nicotinate (0.050 g, 0.180 mmol) was reacted with l-methyl-4,5,6,7-tetrahydro-lH-pyrrolo[3,2-c]pyridine (synthesis as per procedure reported in J. Med. Chem. 46{18), 3930-3937 ; 2003) (0.025 g, 0.180 mmol) and triethylamine (0.077 mL, 0.500 mmol) as described in the synthesis of step-2 of example-30 to give the title compound (0.025 g, 43.3%). LCMS: m/z 315.1 [M+H] ⁺. Step-2: 6-(l-methyl-4,5,6,7-tetrahydro-lH-pyrrolo[3,2-c]pyridine-5-carboxamido) nicotinic acid.

Methyl-6-(l -methyl-4,5,6,7-tetrahydro-lH-pyrrolo[3,2-c]pyridine-5-carboxamido) nicotinate (0.025 g, 0.079 mmol) was treated with 4N aqueous sodium hydroxide solution (0.1 mL) as described in the synthesis of step-2 of example-23 to give the title compound (0.024 g, 99 %) as a solid. The product obtained was taken to next step without further analysis.

Step-3: l-methyl-N-(5-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-2-yl)-6,7- dmydro-lH-pyrrolo[3,2-c]pyridine-5(4H)-carboxarnide.

6-(l-memyl-4,5,6J etrahydro-lH^yrrolo[3,2-c]pyridine-5-carboxamido)nicotinic acid (0.024 g, 0.079 mmol) was reacted with (tetrahydro-2H-pyran-4-yl)methanamine (0.009 g, 0.079 mmol) as described in the synthesis of step-3 of example-23 to give the title compound (0.005 g, 8.6%) as a solid. LCMS: m/z 398.7 [M+H] ⁺; HPLC: 92.3 %; ¾ NMR (300 MHz, Chloroform-d) δ 8.65 (s, 1H), 8.12 (d, / = 8.9 Hz, 1H), 7.99 (d, / = 8.9 Hz, 1H), 7.45 (s, 1H), 6.56 (s, 1H), 6.11 (d, / = 6.7 Hz, 1H), 5.97 (s, 1H), 4.55 (s, 2H), 4.01 (d, / = 11.7 Hz, 2H), 3.90 (d, / = 6.4 Hz, 2H), 3.52 (s, 3H), 3.46 - 3.31 (m, 4H), 2.73 (s, 2H), 1.96 (d, / = 29.0 Hz, 1H), 1.69 (d, / = 14.9 Hz, 2H), 1.42 (t, / = 12.3 Hz, 2H).

Example-44: N-(6-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-3-yl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide.

Step-1: 5-amino-N-((tetrahydro-2H-pyran-4-yl)methyl)picolinamide.

5-aminopicolinic acid (0.300 g, 1.97 mmol) was reacted with (tetrahydro-2H-pyran-4-yl) methanamine (0.227 g, 1.970 mmol) as described in the synthesis of step-3 of example- 23 to give the title compound (0.300 g, crude). The crude product was taken to next step without further purification.

Step-2: Phenyl(6-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-3-yl)carbamate

5-amino-N-((tetrahydro-2H-pyran-4-yl)methyl)picolinamide (0.300 g, 1.270 mmol) in THF (25 mL) was added sodium bicarbonate (0.535 g, 6.380 mmol) followed by phenyl chloroformate (0.300 g, 1.91 mmol) at 0°C and stirred at room temperature for 3h. Evaporated off THF from the reaction mixture under reduced pressure to get the crude. The crude dissolved in ethyl acetate (50 mL) and washed with saturated sodium bicarbonate solution. Ethyl acetate layer dried over sodium sulphate and concentrated to give title compound (0.350 g, crude). The crude product was taken to next step without further purification.

Step-3: N-(6-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-3-yl)-6,7- dihydrothieno [3 ,2-c]pyridine-5 (4H)-carboxamide.

Phenyl-(6-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-3-yl)carbamate (0.350 g, 0.980 mmol) was reacted with 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (0.173 g, 0.980 mmol) and triethylamine (0.410 mL, 2.95 mmol) as described in the synthesis of step-2 of example-30 to give the title compound(0.210 g, 53.3%). LCMS: m/z 401.6 [M+H] ⁺; HPLC: 97.12 %; ¾ NMR (400 MHz, Chloroform-d) δ 8.58 (d, / = 2.5 Hz, 1H), 8.14 (d, / = 8.6 Hz, lH), 8.07 - 7.96 (m, 2H), 7.20 (d, / = 5.1 Hz, 1H), 6.87 - 6.78 (m, 2H), 4.67 (d, / = 1.7 Hz, 2H), 4.07 - 3.97 (m, 2H), 3.89 (t, / = 5.7 Hz, 2H), 3.46 - 3.32 (m, 4H), 2.99 (t, / = 5.7 Hz, 2H), 1.90 (ttt, / = 10.8, 6.8, 3.8 Hz, 1H), 1.75 - 1.68 (m, 2H), 1.47 - 1.36 (m, 2H).

Example-45: N-(4-(N-((tetrahydro-2H-pyran-4-yl)methyl)sulfamoyl)phenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide.

Step-1: 4-nitro-N-((tetrahydro-2H-pyran-4-yl)methyl)benzenesulfonamide.

A mixture of 4-nitrobenzene-l-sulfonyl chloride (0.500 g, 2.26 mmol), (tetrahydro-2H- pyran-4-yl)methanamine (0.260 g, 2.26 mmol) and triethylamine (0.942 mL, 6.780 mmol) in dichloromethane (25 mL) was stirred at room temperature for 2 h. The reaction mixture was diluted with dichloromethane and washed with sat. sodium bicarbonate solution and brine. Dichloromethane layer dried and concentrated to give title compound (0.300 g, 44.7%). The product obtained was taken to next step without further analysis.

Step-2: 4-amino-N-((tetrahydro-2H-pyran-4-yl)methyl)benzenesulfonamide.

To a solution of 4-nitro-N-((tetrahydro-2H-pyran-4-yl)methyl)benzenesulfonamide

(0.300 g, 0.810 mmol) in ethanol (25 mL) was added 10% Pd/C (0.050 g). The reaction mixture was stirred under ¾ atmosphere (balloon pressure). After stirring for 16 h, the reaction mixture was filtered through a pad of celite, and washed with ethanol (3 x 10 mL). The resulting filtrate was concentrated in vaccuo to give the title compound (0.220 g, crude). The crude product was taken to next step without further purification.

Step-3: Phenyl (4-(N-((tetrahydro-2H-pyran-4-yl)methyl)sulfamoyl)phenyl)carbamate .

4-amino-N-((tetrahydro-2H-pyran-4-yl)methyl)benzene sulfonamide (0.220 g, 0.813 mmol) was treated with phenyl chloro formate (0.153 g, 0.976 mmol) as described in the synthesis of step-1 of example-35 to give the title compound (0.317 g, 99%). The product obtained was taken to next step without further analysis.

Step-4: N-(4-(N-((tetrahydro-2H-pyran-4-yl)methyl)sulfamoyl)phenyl)-6J- dihydrothieno [3 ,2-c]pyridine-5 (4H)-carboxamide.

Phenyl-(4-(N-((tetrahydro-2H-pyran-4-yl)methyl)sulfamoyl)phenyl)carbamate (0.317 g, 0.813 mmol) was reacted with 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (0.142 g, 0.813 mmol) and triethylamine (0.339 mL, 2.439 mmol) as described in the synthesis of step-2 of example-30 to give the title compound (0.110 g, 31 %) as a solid. LCMS: m/z 435.95 [M+H] ⁺; HPLC: 99.53 %; ^lU NMR (400 MHz, DMSO-d₆) δ 9.05 (s, 1H), 7.66 (s, 4H), 7.44 (t, / = 6.1 Hz, 1H), 7.37 (d, / = 5.1 Hz, 1H), 6.91 (d, / = 5.1 Hz, 1H), 4.58 (d, / = 1.8 Hz, 2H), 3.84 - 3.73 (m, 4H), 3.19 (td, / = 11.7, 1.9 Hz, 2H), 2.87 (t, / = 5.7 Hz, 2H), 2.57 (d, / = 6.3 Hz, 2H), 1.62 - 1.47 (m, 3H), 1.14 - 1.00 (m, 2H).

Biology:

Cytotoxicity Assay in MiaPaCa-2:

MiaPaCa-2 Cells (ATCC) were seeded in 96 well plates (Costar clear flat bottom) at a density of 3000 cells/well and allowed to settle overnight. Test compounds were dissolved in dimethyl sulphoxide (DMSO - Sigma Aldrich, D2650) and incubated with MiaPaCa-2 cells for 72 h. Post 72h, 50μ1 XTT (lmg/mL; Invitrogen, X 6493) and PMS (8 μΜ; Sigma Aldrich, P9625) reagents were added to the cells in 100 μΐ of cDMEM (Sigma Aldrich-D5648) + 10% FBS (Hyclone-5430088-03) + IX Pen Strep (Sigma Aldrich-P0781). After 1 hour incubation with XTT and PMS absorbance was monitored with Spectramax M3 (Molecular Device). IC50 values were plotted using Graphppad prism software (Graphpad Inc, La Jola, CA, USA).

IC50 values of the compounds are indicated in Table 1 wherein "A" refers to an IC50 value in range of 0.0001 to 4.00 μΜ, "B" refers to IC50 value in range of 4.001 to 10.0 μΜ and "C" refers to IC50 value of greater than 10 μΜ.

NAMPT Fluorescence Assay:

The enzymatic assay was standardized using in-house recombinant NAMPT wild type protein from E.coli expression & NAM (Cat # 47865-U) as a substrate. The product NMN formed after enzymatic reaction was derivatized to a fluorescent derivative through sequentially reacting with acetophenone/KOH and formic acid. The derivatized fluorescent NMN derivative was detected at 382 nm excitation wavelength and a 445 nm emission wavelength. The final assay conditions were 50 ng NAMPT, 2 μΜ Nam (Km cone), 0.4 mM PRPP (Cat # P8296), 2 mM ATP (Cat # A7699), 0.02% BSA, 2 mM DTT, 12 mM MgCl₂, 50 mM Tris HC1 pH-7.5, 2% DMSO (25 μΐ. reaction volume: 15 minutes pre-incubation of enzyme with compound & 15 minutes incubation for the complete reaction) in 96 well Black plate. The florescence was measured (Excitation at 382 nm & Emission at 445 nm) using Victor³ V fluorimeter. The data is calculated using the RFU values. The final concentration of DMSO was 2 % in the assay. Each individual IC50 was determined using 10 point dose response curve generated by GraphPad Prism software Version 4 (San Diego, California, USA) using non linear regression curve fit for sigmoidal dose response (variable slope).

IC50 values of the compounds are indicated in Table 1 wherein "A" refers to an IC50 value in range of 0.0001 to 0.01 μΜ, "B" refers to IC50 value in range of 0.011 to 0.1 μΜ and "C" refers to IC50 value in range of 0.11 to 0.2 μΜ.

Table 1: Biochemical assay and cell proliferation assay result

Cell Cell

Biochemical Biochemical

Example Proliferation Example Proliferation

Assay Assay

No. Assay No. Assay

( ICso ) ( ICso )

1 B C 23 A A

2 B c 24 A A

3 A A 25 A A

4 A A 26 A A

5 A A 27 A A

5a A A 28 A A

5b A A 29 A A

6 B B 30 A A

7 B C 31 B C

8 B C 32 A C

9 B C 33 A A

10 A A 34 A A

11 C B 35 A A

12 ND C 36 A B

13 ND C 37 A A

14 ND C 38 A A

15 A A 39 ND C

16 A A 40 A A NA C 41 A A

NA C 42 A A

A A 43 B C

A A 44 A A

A A 45 A A

A C - - -

Claims

We claim:

1. A compound of formula (I),

wherein,

R₂ is selected from O, S or NCN;

R3 is selected from hydrogen or alkyl;

L is a linker selected from *-(CH₂)_mNHCO-, *-(CH₂)_mCONH-, *-CH₂-NH-S0₂-, -NHCONH- or *-SC NH-; wherein * indicates the point of attachment to Ri;

'm' and 'n' are independently selected from 0 or 1 ;

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

2. The compound according to Claim 1 , having the formula (IA):

wherein,

Xi, ring A, Ri and 'm' are same as defined in Claim 1 ;

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

3. The compound according to Claim 1 , wherein ring A is selected from the group

The compound according to Claim 1 , wherein Ri is heterocyclyl.

erocyclyl is

6. The compound according to Claim 1 , wherein ring Ri is cycloalkyl.

7. The compound according to Claim 6, wherein cycloalkyl is cyclohexyl,

cyclopentyl or cyclopropyl.

8. according to Claim 1 , wherein Ri is

The compound according to Claim 1 , having the formula (IB)

wherein,

ring A, Ri, 'm' and 'n' are same as defined in Claim 1 ;

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof

10. The compound according to Claim 1 , having the formula (IC):

wherein,

Ri is selected from optionally substituted aryl, heterocyclyl or cycloalkyl, wherein the optional substituent is heterocyclyl and 'm' is as defined in Claim 1 ;

or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

11. A compound selected from the group consisting of:

Example

IUPAC NAME

No.

N-(4-(2-cyclopentylacetamido)phenyl)-5,6-dihydro-[l ,2,4]triazolo[4,3-

1

a]pyrazine-7(8H)-carboxamide;

N-(4-(2-cyclopentylacetamido) phenyl)-3-(trifluoromethyl)-5, 6-dihydro-[l, 2,

2

4] triazolo [4, 3-a] pyrazine-7(8H)-carboxamide;

N-(4-(2-cyclopentylacetamido) phenyl)-3, 4-dihydropyrrolo [1, 2-a] pyrazine-

3

2( 1 H)-carboxamide ;

N-(4-(2-cyclopentylacetamido) phenyl)-6, 7-dihydrothieno [3, 2-c] pyridine-

4

5(4H)-carboxamide;

N-(4-(2-(tetrahydrofuran-3-yl)acetamido)phenyl)-6,7-dihydrothieno[3,2-

5

c]pyridine-5(4H)-carboxamide(±);

N-(4-(2-(tetrahydrofuran-3-yl)acetamido)phenyl)-6,7-dihydrothieno[3,2-

5a

c]pyridine-5(4H)-carboxamide; (Enantiomer-1)

5b N-(4-(2-(tetrahydrofuran-3-yl)acetamido)phenyl)-6,7-dihydrothieno[3,2- c]pyridine-5(4H)-carboxamide; (Enantiomer-2)

N-(4-(2-cyclopentylacetamido) phenyl)-5, 6-dihydroimidazo [1, 2-a] pyrazine- 7(8H)-carboxamide;

N-(4-([l , l '-biphenyl]-2-ylsulfonamido) phenyl)-3, 4-dihydropyrrolo [1, 2-a] pyrazine-2( 1 H)-carboxamide ;

N-(4-(3-([l,l'-biphenyl]-2-yl)ureido)phenyl)-3,4-dihydropyrrolo[l ,2- a]pyrazine-2(lH)-carboxamide;

N-(4-([l, -biphenyl]-2-ylcarboxamido)phenyl)-3,4-dihydropyrrolo[l,2- a]pyrazine-2(lH)-carboxamide;

N-(4-(N'-cyano-4, 5, 6, 7-tetrahydrothieno [3, 2-c] pyridine-5- carboximidamido) phenyl)-2-cyclopentyl acetamide;

N-(4-(N'-cyano-l , 2, 3, 4-tetrahydropyrrolo [1, 2-a] pyrazine-2- carboximidamido) phenyl)-2-cyclopentyl acetamide;

2-bromo-N-(4-(2-cyclopentylacetamido) phenyl)-6, 7-dihydrothieno [3, 2-c] pyridine-5 (4H)-carboxamide ;

2-cyano-N-(4-(2-cyclopentylacetamido) phenyl)-6,7-dihydrothieno[3,2- c]pyridine-5(4H)-carboxamide;

N-(4-(2-cyclopentylacetamido)phenyl)-2-mo holino-6,7-dihydrothieno[3,2- c]pyridine-5(4H)-carboxamide;

2-cyclopentyl-N-(4-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5- carbothioamido)phenyl)acetamide;

N-(4-(2-cyclopentylacetamido)phenyl)-6,7-dihydrothiazolo[4,5-c]pyridine- 5(4H)-carboxamide;

methyl 5 - ((4- (2-cyclopentylacetamido)phenyl)carbamoyl) -4 ,5 ,6 ,1 - tetrahydrothieno[3,2-c]pyridine-2-carboxylate;

5-((4-(2-cyclopentylacetamido)phenyl)carbamoyl)-4,5,6J- tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid;

N-(4-(2-(tetrahydro-2H-pyran-4-yl)acetamido)phenyl)-6,7-dihydrothieno[3,2- c]pyridine-5(4H)-carboxamide;

N-(4-(2-cyclohexylacetamido)phenyl)-6,7-dihydrothieno[3,2-c]pyridine- 5(4H)-carboxamide;

N-(4-(nicotinamidomethyl)phenyl)-6J-dihydrothieno[3,2-c]pyridine-5(4H)- carboxamide;

N-(4-((2-(tetrahydro-2H-pyran-4-yl)acetamido)methyl)phenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide;

N-(4-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)phenyl)-6,7-dihydro thieno [3 ,2-c]pyridine-5 (4H)-carboxamide;

N-(4-((2-mo holinophenyl)carbamoyl)phenyl)-6,7-dihydrothieno[3,2- c]pyridine-5(4H)-carboxamide;

N-(4-((tetrahydro-2H-pyran-4-yl)carbamoyl)phenyl)-6,7-dihydrothieno[3,2- c]pyridine-5(4H)-carboxamide;

N-(4-(cyclohexylcarbamoyl)phenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)- carboxamide;

N-(4-(cyclopropylcarbamoyl)phenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)- carboxamide;

N-(4-((furan-2-ylmethyl)carbamoyl)phenyl)-6J-dihydrothieno[3,2-c]pyridine- 5(4H)-carboxamide;

N-(4-(((tetrahydrofuran-2-yl)methyl)carbamoyl)phenyl)-6,7- dihydrothieno [3 ,2-c]pyridine-5 (4H)-carboxamide(±) ;

N-(4-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)phenyl)-3,4- dihydropyrrolo[l ,2-a]pyrazine-2(lH)-carboxamide;

N-(4-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)phenyl)-3-

(trifluoromethyl)-5,6-dihydro-[l ,2,4]triazolo[4,3-a]pyrazine-7(8H)- carboxamide;

N-(4-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)phenyl)-5,6- dihydroimidazo[l ,2-a]pyrazine-7(8H)-carboxamide; N-(4-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)phenyl)-4,5- dihydrofuro[2,3-c]pyridine-6(7H)-carboxamide;

N-(4-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)phenyl)-6,7- dihydrofuro[3 ,2-c]pyridine-5(4H)-carboxamide;

N-(5-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-2-yl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide;

N-(5 -((tetrahydro-2H-pyran-4-yl)carbamoyl)pyridin-2-yl)-6 ,7- dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide;

N-(5-((cyclopentylmethyl)carbamoyl)pyridin-2-yl)-6,7-dihydrothieno[3,2- c]pyridine-5(4H)-carboxamide;

N-(5-(((3-methyloxetan-3-yl)methyl)carbamoyl)pyridin-2-yl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide;

2-methyl-N-(5-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-2-yl)- 6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide;

N-(5-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-2-yl)-4,5- dihydrothieno[2,3-c]pyridine-6(7H)-carboxamide;

N-(5-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-2-yl)-4,5- dihydrofuro[2,3-c]pyridine-6(7H)-carboxamide;

N-(5-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-2-yl)-6,7- dihydrofuro[3 ,2-c]pyridine-5(4H)-carboxamide;

l-methyl-N-(5-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-2-yl)- 6,7-dihydro-lH-pyrrolo[3,2-c]pyridine-5(4H)-carboxamide;

N-(6-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-3-yl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide; and

N-(4-(N-((tetrahydro-2H-pyran-4-yl)methyl)sulfamoyl)phenyl)-6,7- dihydrothieno [3 ,2-c]pyridine-5 (4H)-carboxamide,

pharmaceutically acceptable salt thereof or a stereoisomer thereof.

12. A pharmaceutical composition comprising at least one compound according to any one of Claims 1 to 11 or a pharmaceutically acceptable salt or a stereoisomer thereof, and a pharmaceutically acceptable carrier.

13. The pharmaceutical composition of Claim 12 further comprising at least one additional pharmaceutical agent wherein the said additional pharmaceutical agent is an anticancer agent, chemotherapy agent or antiproliferative compound.

14. A compound according to any one of the Claims 1 to 11 or a pharmaceutically acceptable salt or a stereoisomer thereof, for use as a medicament.

15. The compound according to any one of the Claims 1 to 11 for use as a medicament for the treatment of a disease or a condition caused by an elevated level of nicotinamide.

16. A method of inhibiting Nicotinamide phosphoribosyltransferase in a patient by administering therapeutically effective amount of at least one compound of any one of Claims 1 to 11.

17. A method of treating, preventing, inhibiting or eliminating a disease or condition in a patient by inhibiting NAMPT in said patient by administering a therapeutically effective amount of at least one compound of any one of Claims 1 to 11 , wherein said disease or condition is selected from the group consisting of cancer, pancreatic cancer, ovarian cancer, lung cancer, prostate cancer, skin cancer, breast cancer, uterine cancer, colon cancer, cervical cancer, bladder cancer, leukemia, lymphoma, Hodgkin' s disease, viral infections including adult respiratory distress syndrome, ataxia telengiectasia, Human Immunodeficiency Virus, hepatitis virus, herpes virus, herpes simplex, inflammatory disorders, irritable bowel syndrome, inflammatory bowel disease, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, osteoarthritis, osteoporosis, fibrotic diseases, dermatitis, atoptic dermatitis, psoriasis, ultra-violet induced skin damage, systemic lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spodylitis, graft- versus-host disease, Alzheimer's disease, cerebrovascular accident, atherosclerosis, restenosis, diabetes, glomerulonephiritis, metabolic syndrome, non-small cell lung cancer, small cell lung cancer, multiple myeloma, leukemias, lymphomas, cancers of the brain and central nervous system, squamous cell cancers, kidney cancer, uretral and bladder cancers, cancers of head and neck.