WO2014141035A2 - Dérivés hétérocyclyles fusionnés en tant qu'inhibiteurs nampt - Google Patents

Dérivés hétérocyclyles fusionnés en tant qu'inhibiteurs nampt Download PDF

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WO2014141035A2
WO2014141035A2 PCT/IB2014/059582 IB2014059582W WO2014141035A2 WO 2014141035 A2 WO2014141035 A2 WO 2014141035A2 IB 2014059582 W IB2014059582 W IB 2014059582W WO 2014141035 A2 WO2014141035 A2 WO 2014141035A2
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carboxamide
pyridine
phenyl
dihydrothieno
methyl
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WO2014141035A3 (fr
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Dinesh Chikkanna
Vinayak Khairnar
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Aurigene Oncology Ltd
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Aurigene Discovery Technologies Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • 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.
  • 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
  • PBEF pre-B-cell-colony-enhancing factor
  • visfatin is an enzyme that catalyzes the phosphoribosylation of nicotinamide and is the rate- limiting enzyme in one of two pathways that salvage NAD + .
  • 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).
  • 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).
  • EAE experimental autoimmune encephalomyelitis
  • 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).
  • novel fused heterocyclyl derivatives and pharmaceutical compositions thereof which are useful as NAMPT inhibitors.
  • Xi and X 2 are independently selected from N or CH, provided that not more than one of Xi and X 2 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 *-(CH 2 ) m NHCO-, *-(CH 2 ) m CONH-, *-CH 2 -NH-S0 2 -, -NHCONH- or *-S0 2 NH-; wherein * indicates the point of attachment to Ri;
  • 'm' and 'n' are independently selected from 0 or 1 ;
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula (I), and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • the present invention relates to the preparation of the compounds of formula (I).
  • 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.
  • 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.
  • alkyl examples include but are not limited to methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, isopentyl or neopentyl and the like.
  • halo or halogen alone or in combination with other term(s) means fluorine, chlorine, bromine or iodine.
  • haloalkyl means alkyl substituted with one or more halogen atoms, where alkyl groups are as defined above.
  • halo is used herein interchangeably with the term “halogen” means F, CI, Br or I.
  • 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-.
  • 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, ind
  • a heterocyclyl group can be unsubstituted or substituted with one or more suitable groups.
  • cycloalkyl alone or in combination with other term(s) means C3-C 1 0 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.
  • fused means that the second ring is attached or formed by having two adjacent atoms in common with the first ring.
  • fused is equivalent to the term “condensed”.
  • Cyano refers to an -CN group.
  • heteroatom designates a sulfur, nitrogen, or oxygen atom.
  • the term 'compound(s)' comprises the compounds disclosed in the present invention.
  • 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.
  • 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.
  • treat refers to a method of alleviating or abrogating a disease and/or its attendant symptoms.
  • prevent refers to a method of preventing the onset of a disease and/or its attendant symptoms or barring a subject from acquiring a disease.
  • prevent also include delaying the onset of a disease and/or its attendant symptoms and reducing a subject's risk of acquiring a disease.
  • terapéuticaally 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.
  • 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.
  • 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.
  • the compounds of the present invention may exist as geometric isomers.
  • the present invention includes all cis, trans, syn, anti,
  • 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).
  • NAMPT nicotinamide phosphoribosyltransferase
  • the present invention further provides pharmaceutical compositions comprising the said substituted heterocyclyl compounds and their derivatives as therapeutic agents.
  • the first embodiment of the present invention provides the structure of compounds as set forth in formula (I);
  • Xi and X 2 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;
  • R 2 is selected from O, S or NCN
  • R3 is selected from hydrogen or alkyl
  • L is a linker selected from *-(CH 2 ) m NHCO-, *-(CH 2 ) m CONH-, *-CH 2 -NH-S0 2 -, -NHCONH- or *-S0 2 NH-; wherein * indicates the point of attachment to Ri;
  • 'm' and 'n' are independently selected from 0 or 1 ;
  • 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.
  • Another embodiment of the present invention provides a pharmaceutical composition
  • 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).
  • NAMPT nicotinamide phosphoribosyltransferase
  • NAMPT nicotinamide phosphoribosyltransferase
  • diseases and/or disorders associated with elevated level of nicotinamide phosphoribosyltransferase 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
  • 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.
  • parenteral administration include administration by injection, percutaneous, transmucosal, transnasal and transpulmonary administrations.
  • MS (Mass Spectral) data provided in the examples were obtained using the equipments- API 2000 LC/MS/MS Triplequad,
  • Method B H 2 ( i at m)/10 % Pd-C, MeOH, RT, 16 h.
  • Method E TFA, CH2CI2, RT, 16 h.
  • Method F EDCI.HCl, HOBt, DIPEA, DMF, RT, 16h.
  • Method B H 2 (i atm )/10 % Pd-C, MeOH, RT, 16 h.
  • Method C NaHC0 3 , THF, RT, 2 h.
  • Method D DMSO, RT, 16 h.
  • Method F EDCI.HC1, HOBt, DIPEA, DMF, RT, 16h.
  • Method A Reagents & conditions-i) Method A; ii) Method B; iii) Method C; iv) Method D; v) Method E; vi) Method F; vii) Et 3 N, CH2CI2, 0°C to RT, 2h; viii) Method A.
  • Method A THF, 0°C - RT, 2h.
  • Method B H 2 (i atm )/10 % Pd-C, MeOH, RT, 16 h;
  • Method E TFA, CH2CI2, RT, 16 h.
  • Method F EDCI.HC1, HOBt, DIPEA, DMF, RT, 16h.
  • Method E TFA, CH2CI2, RT, 16 h.
  • Method F EDCI.HC1, HOBt, DIPEA, DMF, RT, 16h.
  • 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 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.
  • 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.
  • Step-2 N-(4-aminophenyl)-5,6-dihydro-[l ,2,4]triazolo[4,3-a]pyrazine-7(8H)- carboxamide.
  • Step-3 N-(4-(2-cyclopentylacetamido)phenyl)-5 ,6-dihydro-[l ,2,4]triazolo[4,3- a]pyrazine-7(SH)-carboxamide.
  • 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 ⁇
  • Step-2 N-(4-aminophenyl)-3-(trifluoromethyl)-5,6-dihydro-[l ,2,4]triazolo[4,3- a]pyrazine-7(8H)-carboxamide
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • step-2 of example-4 N-(4-aminophenyl)-6J-dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide (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.
  • Example-5a N-(4-(2-(tetrahydrofuran-3-yl)acetamido)phenyl)-6,7-dihydrothieno
  • 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.
  • 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-
  • 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.
  • Example-7 N-(4-([l, l'-biphenyl]-2-ylsulfonamido) phenyl)-3, 4-dihydropyrrolo [1, 2-a] pyrazine-2(iH)-carboxamide.
  • step-2 of example-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.
  • Example-8 N-(4-(3-([l,l'-biphenyl]-2-yl)ureido)phenyl)-3,4-dihydropyrrolo[l,2- a]pyrazine-2(iH)-carboxamide.
  • step-2 of example-3 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.
  • Example-9 N-(4-([l,l'-biphenyl]-2-ylcarboxamido)phenyl)-3,4-dihydropyrrolo[l,2- a]pyrazine-2(iH)-carboxamide .
  • step-2 of example-3 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.
  • Step-1 Tert-butyl(4-(2-cyclopentylacetamido)phenyl) carbamate.
  • Step-2 N-(4-aminophenyl)-2-cyclopentylacetamide.
  • Step-3 N-(4-(N'-cyano-4,5,6 J-tetrahydrothieno[3,2-c]pyridine-5-carboximidamido) phenyl)-2-cyclopentyl acetamide.
  • 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%).
  • Example- 12 2-bromo-/V-(4-(2-cyclopentylacetamido)phenyl)-6,7-dihydrothieno[3,2- c] pyridine-5(4H)-carboxamide.
  • 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 (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 %).
  • Example- 14 N-(4-(2-cyclopentylacetamido)phenyl)-2-morpholino-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide.
  • step-2 of example- 10 (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)mo ⁇ holine as described in the synthesis of example- 12 to give title compound (0.050 g, 23.34%).
  • 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 %).
  • 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 %).
  • 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.
  • Step-2 Methyl5-((4-aminophenyl)carbamoyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- carboxylate.
  • 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.
  • Example- 18 5-((4-(2-cyclopentylacetamido)phenyl)carbamoyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid.
  • step-3 of example-17 methyl5-((4-(2-cyclopentylacetamido)phenyl)carbamoyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxylate (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.
  • Example- 19 N-(4-(2-(tetrahydro-2H-pyran-4-yl)acetamido)phenyl)-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-(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.
  • Example-20 N-(4-(2-cyclohexylacetamido)phenyl)-6,7-dihydrothieno[3,2- c] pyridine- 5 (4H) -carboxamide .
  • step-2 of example-4 N-(4-aminophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide (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.
  • Step-1 Tert-butyl4-(4,5,6J-tetrahydrothieno[3,2-c]pyridine-5-carboxamido) benzylcarbamate.
  • Step-2 N-(4-(aminomethyl)phenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)- carboxamide hydrochloride.
  • 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.
  • Example-22 N-(4-((2-(tetrahydro-2H-pyran-4-yl)acetamido)methyl)phenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide.
  • step-2 of example-21 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.
  • 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.
  • Step-2 4-(4,5,6J-tetrahydrothieno[3,2-c] ridine-5-carboxamido)benzoic acid.
  • Step-3 N-(4-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)phenyl)-6,7-dihydrothieno [3,2-c]pyridine-5(4H)-carboxamide .
  • Example-24 N-(4-((2-morpholinophenyl)carbamoyl)phenyl)-6,7-dihydrothieno[3,2- c]pyridine-5(4H)-carboxamide .
  • step-2 of example-23 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.
  • Example-25 N-(4-((tetrahydro-2H-pyran-4-yl)carbamoyl)phenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide .
  • step-2 of example-23 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.
  • Example-26 N-(4-(cyclohexylcarbamoyl) phenyl)-6,7-dihydrothieno[3,2-c]pyridine- 5 (4H) -carboxamide.
  • step-2 of example-23 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.
  • Example-27 N-(4-(cyclopropylcarbamoyl)phenyl)-6,7-dihydrothieno[3,2-c]pyridine- 5(4H)-carboxamide .
  • step-2 of example-23 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.
  • Example-28 N-(4-((furan-2-ylmethyl)carbamoyl)phenyl)-6,7-dihydrothieno[3,2- c] pyridine- 5 (4H) -carboxamide .
  • step-2 of example-23 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.
  • step-2 of example-23 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%).
  • 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.
  • Step-2 N-(4-(((tetrahydro-2H ⁇ yran-4-yl)methyl)carbamoyl)phenyl)-3,4-dihydropyrrolo [ 1 ,2-a]pyrazine-2(l H)-carboxamide.
  • 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 (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 %).
  • 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 (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% ).
  • 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%).
  • 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%).
  • 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.
  • 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.
  • Step-4 N-(5-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-2-yl)-6,7- dihydrothieno [3 ,2-c]pyridine-5 (4H)-carboxamide.
  • Example-36 N-(5-((tetrahydro-2H-pyran-4-yl)carbamoyl)pyridin-2-yl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide.
  • step-3 of example-35 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.
  • Example-37 N-(5-((cyclopentylmethyl)carbamoyl)pyridin-2-yl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide.
  • step-3 of example-35 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.
  • Example-38 N-(5-(((3-methyloxetan-3-yl)methyl)carbamoyl)pyridin-2-yl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide.
  • step-3 of example-35 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.
  • 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%).
  • 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.
  • 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.
  • Step-2 Phenyl (5-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-2-yl) carbamate.
  • 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%).
  • 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 (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%).
  • 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 (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%).
  • 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.
  • 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.
  • Step-2 Phenyl(6-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-3-yl)carbamate
  • 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%).
  • 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.
  • Step-2 4-amino-N-((tetrahydro-2H-pyran-4-yl)methyl)benzenesulfonamide.
  • Step-3 Phenyl (4-(N-((tetrahydro-2H-pyran-4-yl)methyl)sulfamoyl)phenyl)carbamate .
  • 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.
  • 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.
  • DMSO - Sigma Aldrich, D2650 dimethyl sulphoxide
  • 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 ⁇ , “B” refers to IC50 value in range of 4.001 to 10.0 ⁇ and “C” refers to IC50 value of greater than 10 ⁇ .
  • 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 ⁇ Nam (Km cone), 0.4 mM PRPP (Cat # P8296), 2 mM ATP (Cat # A7699), 0.02% BSA, 2 mM DTT, 12 mM MgCl 2 , 50 mM Tris HC1 pH-7.5, 2% DMSO (25 ⁇ . 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 Victor 3 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 ⁇ , “B” refers to IC50 value in range of 0.011 to 0.1 ⁇ and “C” refers to IC50 value in range of 0.11 to 0.2 ⁇ .

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Abstract

La présente invention concerne des dérivés à substitution hétérocyclyle de formule (I), qui peuvent être thérapeutiquement utiles, plus particulièrement en tant qu'inhibiteurs de NAMPT ‑ Ri, R2, Xi, X2, l'anneau A, L et 'n' possédant les significations figurant dans la description -, et leurs sels pharmaceutiquement acceptables utiles dans le traitement et la prévention de maladies ou de troubles provoqués par un niveau élevé de nicotinamide phosphoribosyltransférase (NAMPT) chez un mammifère. L'invention porte en outre sur la préparation desdits composés et desdites formulations pharmaceutiques comprenant au moins l'un des dérivés hétérocyclyles fusionnés substitués de formule (I) ou leurs sels pharmaceutiquement acceptables ou leurs stéréoisomères.
PCT/IB2014/059582 2013-03-11 2014-03-10 Dérivés hétérocyclyles fusionnés en tant qu'inhibiteurs nampt Ceased WO2014141035A2 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016049774A1 (fr) * 2014-10-03 2016-04-07 The Royal Institution For The Advancement Of Learning/Mcgill University Urée et composés à base de bis-urée et analogues de ceux-ci utiles dans le traitement de maladies ou trouble à médiation par récepteur des androgènes
EP3419612A4 (fr) * 2016-02-26 2019-11-06 The Regents of the University of California Inhibiteurs à petite molécule d'échange d'ions par la pendrine et compositions pharmaceutiques
WO2021050992A1 (fr) * 2019-09-11 2021-03-18 Vincere Biosciences, Inc. Inhibiteurs d'usp30 et utilisations de ceux-ci
CN113039187A (zh) * 2018-11-02 2021-06-25 艾库里斯有限及两合公司 抗乙型肝炎病毒HBV的脲6,7-二氢-4H-噻唑并[5,4-c]吡啶活性剂
WO2023187391A1 (fr) * 2022-03-31 2023-10-05 Pathios Therapeutics Limited Dérivés de 3,4,6,7-tétrahydro-2,7-naphtyridine-2(1h)-carboxamide utilisés en tant qu'inhibiteurs de gpr65 pour le traitement du cancer et de maladies auto-immunes
WO2025153715A1 (fr) 2024-01-19 2025-07-24 Scenic Biotech Bv Inhibiteurs hétérocycliques de pla2g15 et leur utilisation en thérapie, dans le traitement de maladies caractérisées par une dysrégulation lysosomale

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AR082886A1 (es) * 2010-09-03 2013-01-16 Forma Therapeutics Inc Compuestos y composiciones farmaceuticas que los contienen
MX2013005479A (es) * 2010-11-15 2013-06-12 Abbvie Inc Inhibidores de nampt.
AU2011329233A1 (en) * 2010-11-15 2013-05-23 Abbvie Deutschland Gmbh & Co Kg NAMPT and ROCK inhibitors

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016049774A1 (fr) * 2014-10-03 2016-04-07 The Royal Institution For The Advancement Of Learning/Mcgill University Urée et composés à base de bis-urée et analogues de ceux-ci utiles dans le traitement de maladies ou trouble à médiation par récepteur des androgènes
EP3419612A4 (fr) * 2016-02-26 2019-11-06 The Regents of the University of California Inhibiteurs à petite molécule d'échange d'ions par la pendrine et compositions pharmaceutiques
US10702506B2 (en) 2016-02-26 2020-07-07 The Regents Of The University Of California Small molecule inhibitors of pendrin ion exchange and pharmaceutical compositions
CN113039187A (zh) * 2018-11-02 2021-06-25 艾库里斯有限及两合公司 抗乙型肝炎病毒HBV的脲6,7-二氢-4H-噻唑并[5,4-c]吡啶活性剂
WO2021050992A1 (fr) * 2019-09-11 2021-03-18 Vincere Biosciences, Inc. Inhibiteurs d'usp30 et utilisations de ceux-ci
US11845724B2 (en) 2019-09-11 2023-12-19 Vincere Biosciences, Inc. USP30 inhibitors and uses thereof
WO2023187391A1 (fr) * 2022-03-31 2023-10-05 Pathios Therapeutics Limited Dérivés de 3,4,6,7-tétrahydro-2,7-naphtyridine-2(1h)-carboxamide utilisés en tant qu'inhibiteurs de gpr65 pour le traitement du cancer et de maladies auto-immunes
WO2025153715A1 (fr) 2024-01-19 2025-07-24 Scenic Biotech Bv Inhibiteurs hétérocycliques de pla2g15 et leur utilisation en thérapie, dans le traitement de maladies caractérisées par une dysrégulation lysosomale

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