WO2005115986A1 - Therapeutic compounds: pyridine as scaffold - Google Patents

Therapeutic compounds: pyridine as scaffold Download PDF

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Publication number
WO2005115986A1
WO2005115986A1 PCT/SE2005/000753 SE2005000753W WO2005115986A1 WO 2005115986 A1 WO2005115986 A1 WO 2005115986A1 SE 2005000753 W SE2005000753 W SE 2005000753W WO 2005115986 A1 WO2005115986 A1 WO 2005115986A1
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WIPO (PCT)
Prior art keywords
alkyl
amino
alkoxy
carboxamide
aryl
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PCT/SE2005/000753
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French (fr)
Inventor
Kosrat Amin
Johan Broddefalk
Helene Desfosses
Emma Evertsson
Ziping Liu
Claire Milburn
Karolina Nilsson
Maxime Tremblay
Christopher Walpole
Zhong-Yong Wei
Hua Yang
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Astrazeneca Ab
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Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=32589804&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2005115986(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to US11/569,315 priority Critical patent/US20070225292A1/en
Priority to EP05745177A priority patent/EP1756060A1/en
Priority to MXPA06013538A priority patent/MXPA06013538A/en
Priority to AU2005247834A priority patent/AU2005247834A1/en
Priority to BRPI0511531-0A priority patent/BRPI0511531A/en
Priority to JP2007514980A priority patent/JP2008500336A/en
Priority to CA002565065A priority patent/CA2565065A1/en
Publication of WO2005115986A1 publication Critical patent/WO2005115986A1/en
Priority to IL179149A priority patent/IL179149A0/en
Priority to NO20065878A priority patent/NO20065878L/en

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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
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    • A61P25/16—Anti-Parkinson drugs
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    • A61P25/00—Drugs for disorders of the nervous system
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
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    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the invention is related to therapeutic compounds, pharmaceutical compositions containing these compounds, manufacturing processes thereof and uses thereof.
  • the present invention is related to compounds that may be effective in treating pain, cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, anxiety disorders, gastrointestinal disorders and/or cardiavascular disorders.
  • CBi receptor e.g., CBi receptor, CB 2 receptor
  • ligands including agonists, antagonists and inverse agonists produce relief of pain in a variety of animal models by interacting with CBi and/or CB receptors.
  • CBi receptors are located predominately in the central nervous system
  • CB 2 receptors are located primarily in the periphery and are primarily restricted to the cells and tissues derived from the immune system.
  • CBi receptor agonists such as ⁇ 9 -tetrahydrocannabinol ( ⁇ 9 -THC) and anadamide
  • CNS side effects e.g., psychoactive side effects, the abuse potential, drug dependence and tolerance, etc.
  • CBi receptors located in CNS There are lines of evidence, however, suggesting that CBI agonists acting at peripheral sites or with limited CNS exposure can manage pain in humans or animals with much improved overall in vivo profile. Therefore, there is a need for new CBi receptor ligands such as agonists that may be useful in managing pain or treating other related symptoms or diseases with reduced or minimal undesirable CNS side effects.
  • CBi receptor ligands which may be useful in treating pain and/or other related symptoms or diseases.
  • nomenclature used in this specification generally follows the examples and rules stated in Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F, andH, Pergamon Press, Oxford, 1979, which is incorporated by references herein for its exemplary chemical structure names and rules on naming chemical structures.
  • CB 1 /CB 2 receptors means CBi and/or CB 2 receptors
  • C m-n or "C m-n group” used alone or as a prefix, refers to any group having m to n carbon atoms.
  • hydrocarbon used alone or as a suffix or prefix, refers to any structure comprising only carbon and hydrogen atoms up to 14 carbon atoms.
  • hydrocarbon radical or “hydrocarbyl” used alone or as a suffix or prefix, refers to any structure as a result of removing one or more hydrogens from a hydrocarbon.
  • alkyl used alone or as a suffix or prefix, refers to monovalent straight or branched chain hydrocarbon radicals comprising 1 to about 12 carbon atoms. Unless otherwise specified, "alkyl” general includes both saturated alkyl and unsaturated alkyl.
  • alkylene used alone or as suffix or prefix, refers to divalent straight or branched chain hydrocarbon radicals comprising 1 to about 12 carbon atoms, which serves to links two structures together.
  • alkenyl used alone or as suffix or prefix, refers to a monovalent straight or branched chain hydrocarbon radical having at least one carbon-carbon double bond and comprising at least 2 up to about 12 carbon atoms.
  • alkynyl used alone or as suffix or prefix, refers to a monovalent straight or branched chain hydrocarbon radical having at least one carbon-carbon triple bond and comprising at least 2 up to about 12 carbon atoms.
  • cycloalkyl used alone or as suffix or prefix, refers to a monovalent ring-containing hydrocarbon radical comprising at least 3 up to about 12 carbon atoms.
  • cycloalkenyl used alone or as suffix or prefix, refers to a monovalent ring-containing hydrocarbon radical having at least one carbon-carbon double bond and comprising at least 3 up to about 12 carbon atoms.
  • cycloalkynyl used alone or as suffix or prefix, refers to a monovalent ring-containing hydrocarbon radical having at least one carbon-carbon triple bond and comprising about 7 up to about 12 carbon atoms.
  • aryl used alone or as suffix or prefix, refers to a hydrocarbon radical having one or more polyunsaturated carbon rings having aromatic character, ⁇ e.g., 4n + 2 delocalized electrons) and comprising 5 up to about 14 carbon atoms, wherein the radical is located on a carbon of the aromatic ring.
  • non-aromatic group or “non-aromatic” used alone, as suffix or as prefix, refers to a chemical group or radical that does not contain a ring having aromatic character ⁇ e.g., 4n + 2 delocalized electrons).
  • arylene used alone or as suffix or prefix, refers to a divalent hydrocarbon radical having one or more polyunsaturated carbon rings having aromatic character, ⁇ e.g., 4n + 2 delocalized electrons) and comprising 5 up to about 14 carbon atoms, which serves to link two structures together.
  • heterocycle used alone or as a suffix or prefix, refers to a ring- containing structure or molecule having one or more multivalent heteroatoms, independently selected from N, O, P and S, as a part of the ring structure and including at least 3 and up to about 20 atoms in the ring(s).
  • Heterocycle may be saturated or unsaturated, containing one or more double bonds, and heterocycle may contain more than one ring. When a heterocycle contains more than one ring, the rings may be fused or unfused. Fused rings generally refer to at least two rings share two atoms therebetween. Heterocycle may have aromatic character or may not have aromatic character.
  • heteroalkyl used alone or as a suffix or prefix, refers to a radical formed as a result of replacing one or more carbon atom of an alkyl with one or more heteroatoms selected from N, O, P and S.
  • heterocyclic used alone or as a suffix or prefix, refers to a ring- containing structure or molecule having one or more multivalent heteroatoms, independently selected from N, O, P and S, as a part of the ring structure and including at least 3 and up to about 20 atoms in the ring(s), wherein the ring-containing structure or molecule has an aromatic character (e.g., 4n + 2 delocalized electrons).
  • heterocyclic group “heterocyclic moiety,” “heterocyclic,” or “heterocyclo” used alone or as a suffix or prefix, refers to a radical derived from a heterocycle by removing one or more hydrogens therefrom.
  • heterocyclyl used alone or as a suffix or prefix, refers a radical derived from a heterocycle by removing at least one hydrogen from a carbon of a ring of the heterocycle.
  • heterocyclylene used alone or as a suffix or prefix, refers to a divalent radical derived from a heterocycle by removing two hydrogens therefrom, which serves to link two structures together.
  • heteroaryl used alone or as a suffix or prefix, refers to a heterocyclyl having aromatic character, wherein the radical of the heterocyclyl is located on a carbon of an aromatic ring of the heterocyclyl.
  • heterocycloalkyl used alone or as a suffix or prefix, refers to a heterocyclyl that does not have aromatic character.
  • heteroarylene used alone or as a suffix or prefix, refers to a heterocyclylene having aromatic character.
  • heterocycloalkylene used alone or as a suffix or prefix, refers to a heterocyclylene that does not have aromatic character.
  • six-membered used as prefix refers to a group having a ring that contains six ring atoms.
  • five-membered used as prefix refers to a group having a ring that contains five ring atoms.
  • a five-membered ring heteroaryl is a heteroaryl with a ring having five ring atoms wherein 1, 2 or 3 ring atoms are independently selected fromN, O and S.
  • Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3- thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4- triazolyl, 1,3,4-thiadiazolyl, and 1,3,4- oxadiazolyl.
  • a six-membered ring heteroaryl is a heteroaryl with a ring having six ring atoms wherein 1, 2 or 3 ring atoms are independently selected fromN, O and S.
  • Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.
  • substituted used as a prefix refers to a structure, molecule or group, wherein one or more hydrogens are replaced with one or more C 1-12 hydrocarbon groups, or one or more chemical groups containing one or more heteroatoms selected from N, O, S, F, CI, Br, I, and P.
  • substituted phenyl may refer to nitrophenyl, pyridylphenyl, methoxyphenyl, chlorophenyl, aminophenyl, etc., wherein the nitro, pyridyl, methoxy, chloro, and amino groups may replace any suitable hydrogen on the phenyl ring.
  • substituted used as a suffix of a first structure, molecule or group, followed by one or more names of chemical groups refers to a second structure, molecule or group, which is a result of replacing one or more hydrogens of the first structure, molecule or group with the one or more named chemical groups.
  • a "phenyl substituted by nitro" refers to nitrophenyl.
  • Heterocycle includes, for example, monocyclic heterocycles such as: aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazoline, dioxolane, sulfolane 2,3-dihydrofuran, 2,5-dihydrofuran tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydro-pyridine, piperazine, morpholine, thiomorpholine, pyran, thiopyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dihydropyridine, 1,4-dioxane, 1,3-dioxane, dioxane
  • heterocycle includes aromatic heterocycles, for example, pyridine, pyrazine, pyrimidine, pyridazine, thiophene, furan, furazan, pyrrole, imidazole, thiazole, oxazole, pyrazole, isothiazole, isoxazole, 1,2,3-triazole, tetrazole, 1,2,3-thiadiazole, 1,2,3- oxadiazole, 1,2,4-triazole, 1,2,4-thiadiazole, 1,2,4-oxadiazole, 1,3,4-triazole, 1,3,4- thiadiazole, and 1,3,4- oxadiazole.
  • aromatic heterocycles for example, pyridine, pyrazine, pyrimidine, pyridazine, thiophene, furan, furazan, pyrrole, imidazole, thiazole, oxazole, pyrazole, isothiazole,
  • heterocycle encompass polycyclic heterocycles, for example, indole, indoline, isoindoline, quinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, 1,4-benzodioxan, coumarin, dihydrocoumarin, benzofuran, 2,3-dihydrobenzofuran, isobenzofuran, chromene, chroman, isochroman, xanthene, phenoxathiin, thianthrene, indolizine, isoindole, indazole, purine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, phenanthridine, perimidine, phenanthroline, phenazine, phenothiazine, phenoxazine, 1,2-benzisoxazole, benzothiophene, benzoxazole
  • heterocycle includes polycyclic heterocycles wherein the ring fusion between two or more rings includes more than one bond common to both rings and more than two atoms common to both rings.
  • bridged heterocycles include quinuclidine, diazabicyclo[2.2.1]heptane and 7-oxabicyclo[2.2.1]heptane.
  • Heterocyclyl includes, for example, monocyclic heterocyclyls, such as: aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, dioxolanyl, sulfolanyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, tetrahydrofuranyl, thiophanyl, piperidinyl, 1,2,3,6-tetrahydro-pyridinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, 2,3-dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyridinyl, 1,4-di
  • heterocyclyl includes aromatic heterocyclyls or heteroaryl, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, furazanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4- oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4 oxadiazolyl.
  • heterocyclyl encompasses polycyclic heterocyclyls (including both aromatic or non-aromatic), for example, indolyl, indolinyl, isoindolinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, 1,4-benzodioxanyl, coumarinyl, dihydrocoumarinyl, benzofuranyl, 2,3-dihydrobenzofuranyl, isobenzofuranyl, chromenyl, chromanyl, isochromanyl, xanthenyl, phenoxathiinyl, thianthrenyl, indolizinyl, isoindolyl, indazolyl, purinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteri
  • heterocyclyl includes polycyclic heterocyclyls wherein the ring fusion between two or more rings includes more than one bond common to both rings and more than two atoms common to both rings.
  • bridged heterocycles include quinuclidinyl, diazabicyclo[2.2.1]heptyl; and 7-oxabicyclo[2.2.1]heptyl.
  • alkoxy used alone or as a suffix or prefix, refers to radicals of the general formula -O-R, wherein -R is selected from a hydrocarbon radical.
  • Exemplary alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy, cyclopropylmethoxy, allyloxy, and propargyloxy.
  • aryloxy used alone or as suffix or prefix, refers to radicals of the general formula -O-Ar, wherein -Ar is an aryl.
  • heteroaryloxy used alone or as suffix or prefix, refers to radicals of the general formula -O-Ar', wherein -Ar' is a heteroaryl.
  • amine or “amino” used alone or as a suffix or prefix, refers to radicals of the general formula -NRR', wherein R and R' are independently selected from hydrogen or a hydrocarbon radical.
  • "Acyl” used alone, as a prefix or suffix, means -C( O)-R, wherein -R is an optionally substituted hydrocarbyl, hydrogen, amino or alkoxy.
  • Acyl groups include, for example, acetyl, propionyl, benzoyl, phenyl acetyl, carboethoxy, and dimethylcarbamoyl.
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • Halogenated used as a prefix of a group, means one or more hydrogens on the group is replaced with one or more halogens.
  • RT or “rt” means room temperature.
  • a first ring group being “fused” with a second ring group means the first ring and the second ring share at least two atoms therebetween.
  • Link means covalently linked or bonded.
  • “Saturated carbon” means a carbon atom in a structure, molecule or group wherein all the bonds connected to this carbon atom are single bond. In other words, there is no double or triple bonds connected to this carbon atom and this carbon atom generally adopts an sp atomic orbital hybridization.
  • "Unsaturated carbon” means a carbon atom in a structure, molecule or group wherein at least one bond connected to this carbon atom is not a single bond. In other words, there is at least one double or triple bond connected to this carbon atom and this carbon atom generally adopts a sp or sp 2 atomic orbital hybridization.
  • RT means room temperature.
  • “DMF” refers to dimethyl formamide.
  • DIPEA N,N-diisopropylethylamine.
  • HATU 2-(7-Aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate.
  • One aspect of the invention is a compound of formula IC, a pharmaceutically acceptable salt thereof, diastereomers, enantiomers, or mixtures thereof:
  • A is selected from N and CR 1 ; and R 1 is independently selected from hydrogen, halogen, cyano, amino, acetylamino, hydroxyl, alkoxy, alkyl, haloalkoxy, alkylene, haloalkyl, haloalkenyl and NR 5 R 6 ; each of R 5 and R 6 is independently selected from hydrogen, C 1-6 alkyl, C 2-
  • the compounds of the present invention are those of formula IC, wherein R 1 is independently selected from halogen, hydroxyl, cyano, C 1-6 alkoxy, C 1-6 alkyl, amino, C 1- haloalkoxy, C 2-6 alkylene, C 1-4 haloalkyl, C 2-6 haloalkenyl and NR 5 R 6 ; each of R 5 and R 6 is independently selected from hydrogen, C 1-6 alkyl, C 2- 6 alkenyl, C 1-6 alkylalkoxy; C 1-6 alkylhydroxy, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyl- C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-4 alkylcarbonyl, C 3-6 heterocyclyl and C 3-6 heterocylcyl-C ⁇ .
  • the compounds of the present invention are those of formula IC, wherein R 1 is independently selected from halogen, hydroxyl, C 1-6 alkoxy, C 1-6 alkyl, C 2-6 alkylene, NH 2 , and NR 5 R 6 ; each of R 5 and R 6 is independently selected from hydrogen, C 1-6 alkyl, C 2- 6 alkenyl, C 1-6 alkylalkoxy; C 1-6 alkylhydroxy, C 1-4 alkylcarbonyl, C 1-4 alkoxy, C 3- 6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 3-6 heterocyclyl and C 3-6 heterocylcyl-C 1-6 alkyl; wherein said C 1-6 alkyl, C -6 alkenyl, C 1-6 alkylalkoxy; C 1-6 alkylhydroxy, C 1-4 alkylcarbonyl, C 1- alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C
  • the compounds of the present invention are those of formula IC, wherein R 1 is independently selected from halogen, hydroxyl, C 1-3 alkoxy, C 1-6 alkyl, NH 2 , C 2-6 alkylene and NR 5 R 6 ; each of R 5 and R 6 is independently selected from hydrogen, C 1-4 alkyl, C 2- alkenyl, C 1-4 alkylalkoxy; C 1-4 alkylhydroxy, alkoxy, C 3-6 cycloalkyl, alkyl, methylcarbonyl, ethylcarbonyl, C 3-6 heterocyclyl and C 3-6 heterocylcyl-C 1-6 alkyl; wherein said C 1-4 alkyl, C 2-4 alkenyl, C 1- alkylalkoxy; C 1-4 alkylhydroxy, alkoxy, C 3- 6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl, methylcarbonyl, ethylcarbonyl, C -6 heterocycl
  • R 5 and R 6 alkyl used in defining R 5 and R 6 are optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, and hydroxy; and A is selected from N and CR 1 ; and R 2 is selected from
  • R 4 alkenyl, hydroxy, C 1-6 alkoxy, -CR 5 R 6 ; and -NR 5 R 6 ; wherein the groups used in defining R 4 are optionally substituted by one or more groups selected from halogen, hydroxy, C 1-4 alkoxy, halo substituted alkyl, C 1- alkyl, cyano, nitro, -NR 5 R 6 , and phenyl optionally substituted by one or more selected from methyl and ethyl; and n is selected from 0, 1, 2 and 3; and R 3 and R 4 together with the nitrogen atom to which they are attached may form a group selected from
  • Another aspect of the invention is a compound of formula I, a pharmaceutically acceptable salt thereof, diastereomers, enantiomers, or mixtures thereof:
  • a 1 , A 2 , A 3 or A 4 is N and the remaining are each and independently CR 1 ; and R 1 is independently selected from hydrogen, halogen, cyano, amino, acetylamino, hydroxyl, alkoxy, alkyl, halogenated alkoxy, alkylene, halogenated alkyl, halogenated alkenyl and NR 5 R 6 ; R 2 is selected from
  • R 2 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, halogenated alkoxy, cyano, nitro, alkoxy, hydroxy, hydroxy-alkyl, amino, alkyl-aryl, alkoxy, alkoxy-alkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, amino-alkyl, alkyl-amino-carbonyl, heteroaryl-carbonyl, heterocyclyl-carbonyl, arylcarbonyl, heterocyclyl, cycloalkyl, heteroaryl, heteroarylalkyl-, aryl, aryl-alkyl and-NR 5 R 6 ;
  • R 3 is selected from hydrogen and alkyl;
  • R 4 is selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl; wherein said alky
  • certain compounds of the present invention are those of fonnula I as defined above, wherein R 1 is independently selected from hydrogen, halogen, hydroxyl, alkoxy, alkyl, halogenated alkoxy, and halogenated alkyl; and R 2 is selected from
  • R 2 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, halogenated alkoxy, cyano, nitro, alkylalkoxy, hydroxy- alkyl, alkoxy, alkoxyalkyl, alkylamino, amino-alkyl, alkyl-amino- carbonyl, heterocyclyl, heteroaryl, -heteroarylalkyl-, aryl-alkyl and- ⁇ R 5 R 6 ;
  • R 3 is selected from hydrogen and alkyl;
  • R 4 is selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl used in defining R 4 is optionally substituted by one or more groups
  • certain compounds of the present invention are those of formula I, wherein R 1 is independently selected from hydrogen, fluoro, chloro, hydroxyl, alkoxy, alkyl, halogenated alkoxy, and halogenated alkyl; and R 2 is selected from
  • R 2 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, halogenated alkoxy, alkyl-alkoxy, hydroxy- alkyl, alkoxy, alkoxyalkyl, alkylamino, amino-alkyl, alkyl-amino-carbonyl, heterocyclyl, heteroaryl, -heteroarylalkyl- and-NR 5 R 6 ;
  • R 3 is selected from hydrogen and alkyl;
  • R 4 is selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl used in defining R 4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl,
  • a 1 , A 2 or A 3 is N and the remaining are each and independently CR 1 ; and R 1 is independently selected from hydrogen, halogen, cyano, amino, acetylamino, hydroxyl, alkoxy, alkyl, halogenated alkoxy, alkylene, halogenated alkyl, halogenated alkenyl and NR 5 R 6 ; R 2 is selected from
  • R 2 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, halogenated alkoxy, cyano, nitro, alkoxy, hydroxy, hydroxy-alkyl, amino, alkyl-aryl, alkoxy, alkoxy-alkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, amino-alkyl, alkyl-amino-carbonyl, heteroaryl-carbonyl, heterocyclyl-carbonyl, arylcarbonyl, heterocyclyl, cycloalkyl, heteroaryl, heteroarylalkyl-, aryl, aryl-alkyl and-NR 5 R 6 ;
  • R 3 is selected from hydrogen and alkyl;
  • R 4 is selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl; wherein said alky
  • certain compounds of the present invention are those of formula IA as defined above, wherein R 1 is independently selected from hydrogen, halogen, hydroxyl, alkoxy, alkyl, halogenated alkoxy, and halogenated alkyl; and R 2 is selected from
  • R 2 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, halogenated alkoxy, cyano, nitro, alkylalkoxy, hydroxy- alkyl, alkoxy, alkoxyalkyl, alkylamino, amino-alkyl, alkyl-amino- carbonyl, heterocyclyl, heteroaryl, -heteroarylalkyl-, aryl-alkyl and- ⁇ R 5 R 6 ;
  • R 3 is selected from hydrogen and alkyl;
  • R 4 is selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl used in defining R 4 is optionally substituted by one or more groups
  • certain compounds of the present invention are those of formula IA, wherein R 1 is independently selected from hydrogen, fluoro, chloro, hydroxyl, alkoxy, alkyl, halogenated alkoxy, and halogenated alkyl; and R 2 is selected from
  • R 2 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, halogenated alkoxy, alkyl-alkoxy, hydroxy- alkyl, alkoxy, alkoxyalkyl, alkylamino, amino-alkyl, alkyl-amino-carbonyl, heterocyclyl, heteroaryl, -heteroarylalkyl- and-NR 5 R 6 ;
  • R 3 is selected from hydrogen and alkyl;
  • R 4 is selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl used in defining R 4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl,
  • certain compounds of the present invention are those of formula IB or a pharmaceutically acceptable salt thereof, diastereomers, enantiomers, or mixtures thereof:
  • A is each and independently CR 1 ; and R 1 is independently selected from hydrogen, halogen, cyano, amino, acetylamino, hydroxyl, alkoxy, alkyl, halogenated alkoxy, alkylene, halogenated alkyl, halogenated alkenyl and NR 5 R 6 ; R 2 is selected from
  • R 2 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, halogenated alkoxy, cyano, nitro, alkoxy, hydroxy, hydroxy-alkyl, amino, alkyl-aryl, alkoxy, alkoxy-alkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, amino-alkyl, alkyl-amino-carbonyl, heteroaryl-carbonyl, heterocyclyl-carbonyl, arylcarbonyl, heterocyclyl, cycloalkyl, heteroaryl, heteroarylalkyl-, aryl, aryl-alkyl and-NR 5 R 6 ;
  • R 3 is selected from hydrogen and alkyl;
  • R 4 is selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl; wherein said alky
  • certain compounds of the invention are those formula IB, or a pharmaceutically acceptable salt thereof, diastereomers, enantiomers, or mixtures thereof, wherein A is each and individually CR 1 ; R 1 is independently selected from hydrogen, halogen, hydroxyl, alkoxy, alkyl, halogenated alkoxy, and halogenated alkyl; R 2 is selected from
  • R 2 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, halogenated alkoxy, cyano, nitro, alkylalkoxy, hydroxy- alkyl, alkoxy, alkoxyalkyl, alkylamino, amino-alkyl, alkyl-amino- carbonyl, heterocyclyl, heteroaryl, -heteroarylalkyl-, aryl-alkyl and-NR 5 R 6 ;
  • R is selected from hydrogen and alkyl;
  • R 4 is selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl used in defining R 4 is optionally substituted by one or more groups selected from
  • certain compounds of the invention are those of formula IB, or a pharmaceutically acceptable salt thereof, diastereomers, enantiomers, or mixtures thereof, wherein A is each and individually CR 1 ; R 1 is independently selected from hydrogen, fluoro, chloro, hydroxyl, alkoxy, alkyl, halogenated alkoxy, and halogenated alkyl; R 2 is selected from
  • R 2 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, halogenated alkoxy, alkyl-alkoxy, hydroxy- alkyl, alkoxy, alkoxyalkyl, alkylamino, amino-alkyl, alkyl-amino-carbonyl, heterocyclyl, heteroaryl, -heteroarylalkyl- and-NR 5 R 6 ;
  • R 3 is selected from hydrogen and alkyl;
  • R 4 is selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl used in defining R 4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl,
  • the compounds of the invention may exist in, and be isolated as, enantiomeric or diastereomeric forms, or as a racemic mixture.
  • the present invention includes any possible enantiomers, diastereomers, racemates or mixtures thereof, of a compound of Formula I, IA, IB or IC.
  • the optically active forms of the compound of the invention may be prepared, for example, by chiral chromatographic separation of a racemate, by synthesis from optically active starting materials or by asymmetric synthesis based on the procedures described thereafter. It will also be appreciated that certain compounds of the present invention may exist as geometrical isomers, for example E and Z isomers of alkenes.
  • the present invention includes any geometrical isomer of a compound of Formula I, IA, IB or IC. It will further be understood that the present invention encompasses tautomers of the compounds of the Formula I, IA, IB or IC. It will also be understood that certain compounds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms. It will further be understood that the present invention encompasses all such solvated forms of the compounds of the Formula I, IA, IB or IC. Within the scope of the invention are also salts of the compounds of the Formula I, IA, IB or IC.
  • pharmaceutically acceptable salts of compounds of the present invention may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound, for example an alkyl amine with a suitable acid, for example, HCl or acetic acid, to afford a physiologically acceptable anion.
  • a sufficiently basic compound for example an alkyl amine
  • a suitable acid for example, HCl or acetic acid
  • a corresponding alkali metal such as sodium, potassium, or lithium
  • an alkaline earth metal such as a calcium
  • a compound of the present invention having a suitably acidic proton, such as a carboxylic acid or a phenol with one equivalent of an alkali metal or alkaline earth metal hydroxide or alkoxide (such as the ethoxide or methoxide), or a suitably basic organic amine (such as choline or meglumine) in an aqueous medium, followed by conventional purification techniques.
  • a suitably acidic proton such as a carboxylic acid or a phenol
  • an alkali metal or alkaline earth metal hydroxide or alkoxide such as the ethoxide or methoxide
  • a suitably basic organic amine such as choline or meglumine
  • the compound of Formula I, IA, IB or IC above may be converted to a pharmaceutically acceptable salt or solvate thereof, particularly, an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulphonate orp-toluenesulphonate.
  • an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulphonate orp-toluenesulphonate.
  • the compounds of the invention exhibit activity as agonist of the CBi receptors and are useful in therapy, especially for relief of various pain conditions such as chronic pain, neuropathic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain etc. This list should however not be interpreted as exhaustive. Additionally, compounds of the present invention are useful in other disease states in which dysfunction of CBi receptors is present or implicated. Furthermore, the compounds of the invention may be used to treat cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, anxiety disorders, gastrointestinal disorders and cardiovascular disorders.
  • Compounds of the invention are useful as immunomodulators, especially for autoimmune diseases, such as arthritis, for skin grafts, organ transplants and similar surgical needs, for collagen diseases, various allergies, for use as anti-tumour agents and anti viral agents.
  • Compounds of the invention are useful in disease states where degeneration or dysfunction of cannabinoid receptors is present or implicated in that paradigm. This may involve the use of isotopically labelled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET).
  • PET positron emission tomography
  • Compounds of the invention are useful for the treatment of diarrhoea, depression, anxiety and stress-related disorders such as post-traumatic stress disorders, panic disorder, generalized anxiety disorder, social phobia, and obsessive compulsive disorder, urinary incontinence, premature ejaculation, various mental illnesses, cough, lung oedema, various gastrointestinal disorders, e.g.
  • gastroesophageal reflux disease constipation
  • functional gastrointestinal disorders such as Irritable Bowel Syndrome and Functional Dyspepsia
  • Parkinson's disease and other motor disorders traumatic brain injury, stroke, cardioprotection following miocardial infarction, spinal injury and drug addiction, including the treatment of alcohol, nicotine, opioid and other drug abuse and for disorders of the sympathetic nervous system for example hypertension.
  • Compounds of the invention are useful as an analgesic agent for use during general anaesthesia and monitored anaesthesia care. Combinations of agents with different properties are often used to achieve a balance of effects needed to maintain the anaesthetic state (e.g. amnesia, analgesia, muscle relaxation and sedation).
  • inhaled anaesthetics include hypnotics, anxiolytics, neuromuscular blockers and opioids.
  • a compound according to Formula I, IA, IB or IC for inhibition of transient lower esophageal sphincter relaxations (TLESRs) and thus for treatment or prevention of gastroesophageal reflux disorder (GERD).
  • TLESRs transient lower esophageal sphincter relaxations
  • GERD gastroesophageal reflux disorder
  • the major mechanism behind reflux has been considered to depend on a hypotonic lower esophageal sphincter.
  • the compounds according to the present invention are useful for the prevention of reflux, treatment or prevention of regurgitation, treatment or prevention of asthma, treatment or prevention of laryngitis, treatment or prevention of lung disease and for the management of failure to thrive.
  • a further aspect of the invention is the use of a compound according to Formula I, IA, IB or IC, for the manufacture of a medicament for the inhibition of transient lower esophageal sphincter relaxations, for the treatment or prevention of GERD, for the prevention of reflux, for the treatment or prevention of regurgitation, treatment or prevention of asthma, treatment or prevention of laryngitis, treatment or prevention of lung disease and for the management of failure to thrive.
  • Another aspect of the invention is the use of a compound according to Formula I, IA, IB or IC for the manufacture of a medicament for the treatment or prevention of functional gastrointestinal disorders, such as functional dyspepsia (FD).
  • Yet another aspect of the invention is the use of a compound according to Formula I, I A, IB or IC for the manufacture of a medicament for the treatment or prevention of irritable bowel syndrome (IBS), such as constipation predominant IBS, diarrhea predominant IBS or alternating bowel movement predominant LBS.
  • IBS irritable bowel syndrome
  • IBS irritable bowel syndrome
  • functional gastrointestinal disorders such as functional dyspepsia
  • Thompson WG Longstreth GF
  • Drossman DA Heaton KW
  • Irvine EJ Irvine EJ
  • Mueller-Lissner SA a Functional Bowel Disorders and Functional Abdominal Pain.
  • Drossman DA Talley NJ
  • Thompson WG Whitehead WE
  • Coraziarri E Coraziarri E, eds.
  • a further aspect of the invention is a method for the treatment of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the Formula I, IA, IB or IC above, is administered to a patient in need of such treatment.
  • the invention provides a compound of Formula I, IA, IB or IC, or pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.
  • the present invention provides the use of a compound of Formula I, IA, IB or IC, or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the term “therapeutic” and “therapeutically” should be contrued accordingly.
  • the term “therapy” within the context of the present invention further encompasses to administer an effective amount of a compound of the present invention, to mitigate either a pre-existing disease state, acute or chronic, or a recurring condition.
  • This definition also encompasses prophylactic therapies for prevention of recurring conditions and continued therapy for chronic disorders.
  • the compounds of the present invention are useful in therapy, especially for the therapy of various pain conditions including, but not limited to: acute pain, chronic pain, neuropathic pain, back pain, cancer pain, and visceral pain.
  • the compound of the invention may be administered in the form of a conventional pharmaceutical composition by any route including orally, intramuscularly, subcutaneously, topically, intranasally, inrraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints.
  • the route of administration may be oral, intravenous or intramuscular. The dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen and dosage level at the most appropriate for a particular patient.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • a solid carrier can be one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or table disintegrating agents; it can also be an encapsulating material.
  • the carrier is a finely divided solid, which is in a mixture with the finely divided compound of the invention, or the active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture in then poured into convenient sized moulds and allowed to cool and solidify.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like.
  • composition is also intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it.
  • cachets are included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
  • Liquid form compositions include solutions, suspensions, and emulsions. For example, sterile water or water propylene glycol solutions of the active compounds may be liquid preparations suitable for parenteral administration. Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired.
  • Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
  • the pharmaceutical composition will preferably include from 0.05% to 99%w (per cent by weight), more preferably from 0.10 to 50%w, of the compound of the invention, all percentages by weight being based on total composition.
  • a therapeutically effective amount for the practice of the present invention may be determined, by the use of known criteria including the age, weight and response of the individual patient, and interpreted within the context of the disease which is being treated or which is being prevented, by one of ordinary skills in the art.
  • any compound of Formula I, I A, IB or IC as defined above for the manufacture of a medicament.
  • any compound of Formula I, I A, IB or IC for the manufacture of a medicament for the therapy of pain.
  • any compound according to Formula I, IA, IB or IC for the manufacture of a medicament for the therapy of various pain conditions including, but not limited to: acute pain, chronic pain, neuropathic pain, back pain, cancer pain, and visceral pain.
  • a further aspect of the invention is a method for therapy of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the Formula I, IA, IB or IC above, is administered to a patient in need of such therapy.
  • a pharmaceutical composition comprising a compound of Formula I, IA, IB or IC, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a compound of Formula I, I A, LB or IC, or a pha ⁇ naceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier for therapy, more particularly for therapy of pain.
  • a pharmaceutical composition comprising a compound of Formula I, IA, IB or IC, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier use in any of the conditions discussed above.
  • Another aspect of the invention is a method of preparing the compounds of the present invention.
  • One embodiment of the invention provides a method for preparing a compound of formula I,
  • Another embodiment of the invention provides a method for preparing a compound of formula IA,
  • IA comprising the step of reacting a compound of formula IIA, IIA with a compound of R 3 (CH 2 ) n R NH, in the presence of a base, such as an DIPEA, a solvent such as DMF, wherein A , A , A , R , R , R and n are as defined above.
  • Another embodiment of the invention provides a method for preparing a compound of formula IB,
  • R 3 (CH2)nR 4 NH solvent e.g. DMF
  • DIPEA solvent e.g. CH 2 CI 2
  • hCBi and hCB 2 receptor binding Human CBi receptor from Receptor Biology (hCBi) or human CB 2 receptor from BioSignal (hCB 2 ) membranes are thawed at 37 °C, passed 3 times through a 25-gauge blunt-end needle, diluted in the cannabinoid binding buffer (50 mM Tris, 2.5 mM EDTA, 5 mM MgCl 2 , and 0.5 mg/mL BSA fatty acid free, pH 7.4) and aliquots containing the appropriate amount of protein are distributed in 96-well plates.
  • cannabinoid binding buffer 50 mM Tris, 2.5 mM EDTA, 5 mM MgCl 2 , and 0.5 mg/mL BSA fatty acid free, pH 7.4
  • the IC 5 o of the compounds of the invention at hCBi and hCB 2 are evaluated from 10-point dose-response curves done with 3 H-CP55,940 at 20000 to 25000 dpm per well (0.17-0.21 nM) in a final volume of 300 ⁇ l.
  • the total and non-specific binding are determined in the absence and presence of 0.2 ⁇ M of HU210 respectively.
  • the plates are vortexed and incubated for 60 minutes at room temperature, filtered through Unifilters GF/B (presoaked in 0.1% polyethyleneimine) with the Tomtec or Packard harvester using 3 mL of wash buffer (50 mM Tris, 5 mM MgCl 2 , 0.5 mg BSA pH 7.0). The filters are dried for 1 hour at 55 °C.
  • the radioactivity (cpm) is counted in a TopCount (Packard) after adding 65 ⁇ l/well of MS-20 scintillation liquid.
  • GTP ⁇ S binding Human CBi receptor from Receptor Biology (hCBi) or human CB 2 receptor membranes (BioSignal) are thawed at 37 °C, passed 3 times through a 25-gauge blunt-end needle and diluted in the GTP ⁇ S binding buffer (50 mM Hepes, 20 mM NaOH, 100 mM NaCl, 1 mM EDTA, 5 mM MgCl 2 , pH 7.4, 0.1% BSA).
  • the EC 50 and E max of the compounds of the invention are evaluated from 10-point dose-response curves done in 300 ⁇ l with the appropriate amount of membrane protein and 100000-130000 dpm of GTPg 35 S per well (0.11 -0.14 nM).
  • the basal and maximal stimulated binding is determined in absence and presence of 1 ⁇ M (hCB 2 ) or 10 ⁇ M (hCBi;) Win 55,212-2 respectively.
  • the membranes are pre-incubated for 5 minutes with 56.25 ⁇ M (hCB2) or 112.5 ⁇ M (hCBi) GDP prior to distribution in plates (15 ⁇ M (hCB 2 ) or 30 ⁇ M (hCBi) GDP final).
  • the plates are vortexed and incubated for 60 minutes at room temperature, filtered on Unifilters GF/B (presoaked in water) with the Tomtec or Packard harvester using 3 ml of wash buffer (50 mM Tris, 5 mM MgCl 2 , 50 mM NaCl, pH 7.0). The filters are dried for 1 hour at 55 °C. The radioactivity (cpm) is counted in a TopCount (Packard) after adding 65 ⁇ l/well of MS-20 scintillation liquid.
  • wash buffer 50 mM Tris, 5 mM MgCl 2 , 50 mM NaCl, pH 7.0.
  • the filters are dried for 1 hour at 55 °C.
  • the radioactivity (cpm) is counted in a TopCount (Packard) after adding 65 ⁇ l/well of MS-20 scintillation liquid.
  • Antagonist reversal studies are done in the same way except that (a) an agonist dose-response curve is done in the presence of a constant concentration of antagonist, or (b) an antagonist dose-response curve is done in the presence of a constant concentration of agonist.
  • the Ki towards human CBi receptors for certain compounds of the invention is measured to be in the range of 0.2-5000 nM.
  • the Ki towards human CB 2 receptors for certain compounds of the invention is measured to be in the range of about 4.5-4970 nM.
  • the EC 5 o towards human CBi receptors for certain compounds of the invention is measured to be in the range of about 1.5-2220 nM.
  • the E max towards human CBi receptors for certain compounds of the invention is measured to be in the range of about 20 -130 %.
  • the following table shows certain biological activities for some of the exemplified compounds.
  • Step A N-(Cyclobutylmethyl)-3-[(l-naphthalenylcarbonyl)amino]-2- pyridinecarboxamide
  • Step B 2-(l-naphthalenyl)-fl r -pyrido[3,2- ⁇
  • Step A N-(Cyclobutylmethyl)-3-[[(4-methyl-l-naphthalenyl)carbonyl]amino]-2- pyridinecarboxamide
  • Step A iV-(Cyclobutylmethyl)-3-[[(4-methoxy-l-naphthalenyl)carbonyl]amino]-2- pyridinecarboxamide
  • Step B in Example 18 Following the procedure for Step B in Example 18, using 3-amino-2-pyridinecarboxylic acid (690 mg , 5.0 mmol), DIPEA (780 mg, 6.0 mmol), 4-methoxy-l-naphthalenecarbonyl chloride, prepared from 4-methoxy-l-naphthoic acid (1.0 g, 5.0 mmol) and oxalyl chloride (5 mL, 2.0 M in CH 2 C1 2 , 10 mmol), and then HATU (2.28 g, 6.0 mmol) provided the title compound which was directly used in Step A.
  • 3-amino-2-pyridinecarboxylic acid 690 mg , 5.0 mmol
  • DIPEA 780 mg, 6.0 mmol
  • 4-methoxy-l-naphthalenecarbonyl chloride prepared from 4-methoxy-l-naphthoic acid (1.0 g, 5.0 mmol) and oxalyl chloride (5 m
  • Step A N-(Cyclohexylmethyl)-3-[[[4-(dimethylamino)-l- naphthalenyl] carbonyl] amino]-2-pyridinecarboxamide
  • Step B in Example 18 Following the procedure for Step B in Example 18, using 3-amino-2-pyridinecarboxylic acid (672 mg, 4.87 mmol), DIPEA (780 mg, 6.0 mmol), 4-dimethylamino-l- naphthalenecarbonyl chloride prepared from 4-dimethylamino-l-naphthoic acid (1.0 g, 4.64 mmol) and oxalyl chloride (3 mL, 2.0 M in CH 2 C1 2 , 6 mmol), and then HATU (1.9 g, 5.0 mmol) provided the title compound which was directly used in Step A.
  • 3-amino-2-pyridinecarboxylic acid 672 mg, 4.87 mmol
  • DIPEA 780 mg, 6.0 mmol
  • 4-dimethylamino-l- naphthalenecarbonyl chloride prepared from 4-dimethylamino-l-naphthoic acid (1.0 g, 4.64 mmol) and
  • Step A iV-(cyclopentyloxy)-3-[(l-naphthalenylcarbonyl)amino]-2- pyridinecarboxamide
  • HATU (3.03 g, 7.96 mmol) was added to a solution of 3-aminopyridine-2-carboxylic acid (1.0 g, 7.24 mmol), cyclobutanemethylamme (2.7 mL, 5.3 M in MeOH, 14.5 mmol), and DIPEA (3.8 g, 30 mmol) in DMF (50 ml) at room temperature. After 24 hr, the reaction mixture was quenched with H 2 O (100 mL), and extracted with EtOAc (2 x 100 mL). The combined organic phases were washed with brine, and condensed in vacuo to provide the title compound (1.22 g, 82 %).
  • Step A N- ⁇ 2- ⁇ [(Tetrahydro-2i ⁇ -pyran-4-ylmethyl)amino] carbonyl ⁇ pyridin-3- yl)quinoline-4-carboxamide
  • Step A in Example 30 Following the procedure for Step A in Example 30, using DIPEA (65 mg, 0.5 mmol), 3- amino-N-(tetrahydro-2H-pyran-4-ylmethyl)pyridine-2-carboxamide (50 mg, 0.21 mmol, see Step B for its preparation), and quinoline-4-carboxylic acid (52 mg, 0.3 mmol), and ⁇ ATU (114 mg, 0.3 mmol) provided the title compound as its TFA salt after purification by reversed-phase ⁇ PLC (24 mg, 23 %).
  • DIPEA 65 mg, 0.5 mmol
  • 3- amino-N-(tetrahydro-2H-pyran-4-ylmethyl)pyridine-2-carboxamide 50 mg, 0.21 mmol, see Step B for its preparation
  • quinoline-4-carboxylic acid 52 mg, 0.3 mmol
  • ⁇ ATU 114 mg, 0.3 mmol
  • Step A 3-(l-Naphthoylamino)-iV-(tetrahydro-2fl-pyran-4-yl-methyl)pyrazine-2- carboxamide
  • Step A 3-[(4-Methyl-l-naphthoyl)amino]-N-pentylpyrazine-2-carboxamide
  • Step A N-(Cyclobutylmethyl)-3-[(4-ethyl-l-naphthoyl)amino]pyrazine-2- carboxamide
  • Step A N-(Cyclobutylmethyl)- 3- ⁇ [4-(l#-l,2,3-triazol-l-ylmethyl)-l- naphthoyl]amino ⁇ pyrazine-2-carboxamide
  • Step A N-(Cyclohexylmethyl)-3-[(4-methoxy-l-naphthoyl)amino]pyrazine-2- carboxamide
  • Step B Methyl 3-[(4-Methoxy-l-naphthoyl)amino]pyrazine-2-carboxylate
  • Step A 3-[(4-Methoxy-l-naphthoyl)amino]-iV-(morpholin-3-ylmethyl)pyridine-2- carboxamide
  • Step B tart-Butyl 3- ⁇ [( ⁇ 3-[(4-methoxy-l-naphthoyl)amino]pyridin ⁇ 2- yl ⁇ carbonyl)amino] methyl ⁇ morpholine-4-carboxylate
  • Step A N-(Cyclohexylmethyl)-3-[(4-ethoxy-l-naphthoyl)amino]pyridine-2- carboxamide
  • Step B Methyl 3-[(4-ethoxy-l-naphthoyl)amino]pyridine-2-carboxylate
  • Step A 3-(l-Naphthoylamino)-iV-[(2R)-piperidin-2-ylmethyl]pyridine-2-carboxamide
  • HATU (5.60 g, 14.7 mmol) was added to a mixture of the (2R)-l-(tert- butoxycarbonyl) ⁇ iperidine-2-carboxylic acid (2.29 g, 10 mmol), ammonium chloride (3.21 g, 60 mmol) and DIPEA (3.88 g, 30 mmol) in DMF (70 mL) at 0 °C.
  • the mixture was stirred for 18 h at room temperature, diluted with H 2 O (100 mL) and extracted with EtOAc (3x100 mL). The combined organic phases were washed with 10% Na 2 CO 3 solution (2x30 mL), brine (2x30 mL) and dried with Na2SO .
  • Step A 3-(l-Naphthoylamino)-N-[(2S)-piperidin-2-ylmethyl]pyridine-2-carboxamide
  • Step A 3-[(4-Amino-l-naphthoyl)amino]-iV-(cyclohexylmethyl)pyridine-2- carboxamide tert-Butyl (4- ⁇ [(2- ⁇ [(cyclohexylmethyl)amino]carbonyl ⁇ pyridin-3-yl)amino]carbonyl ⁇ -l- naphthyl)carbamate (14.2 mg, 0.028 mmol) in CH 2 CI 2 (1.5 mL) was treated with trifluoroacetic acid (1.5 mL). The reaction mixture was stirred for 3 h at room temperature. After concentration and lyophihzation, the title compound was obtained as TFA salt (14.0 mg, 97 %).
  • Oxalyl chloride (0.28 mL, 2.0M, 0.56 mmol) in CH 2 C1 2 was added to a solution of A-[(tert- butoxycarbonyl)amino]-l-naphthoic acid (72.7 mg, 0.25 mmol) in CH 2 C1 2 (5 mL). Stirring for 4.5 h at room temperature and evaporation of the solvent, the residue was dissolved in CH 2 C1 (5 mL). 3-Amino-2-pyridinecarboxylic acid (34.5 mg , 0.25 mmol) and DIPEA (105 uL, 77.8 mg, 0.60 mmol) were added at 0 °C.
  • Step A N-(Cyclohexylmethyl)-3-[(4-methyl-l-naphthalenylcarbonyl)amino]-2- pyridinecarboxamide
  • 3-Aminopyridine-2-carboxylic acid (138 mg, 1.0 mmol) was added to a solution of cyclohexane methylamine (226 mg, 2. 0 mmol) and DIPEA (259 mg, 0.35 mmol) in DMF (5 mL). After sti ⁇ ing for 30 min, HATU (456 mg, 1.2 mmol) was added at 0 °C. The resulting mixture was stirred overnight at room temperature, quenched with water (50 ml), and extracted with EtOAc (3x40 mL). The combined organic phases were washed with water (2x5 mL), brine (5 mL), and dried with Na 2 SO 4 .
  • Step A 3-[(4-Amino-l-naphthoyl)amino]-iV-(tetrahydro-2J ⁇ -pyran-4- ylmethyl)pyridine-2-carboxamide
  • Oxalyl chloride (3.8 lnL, 2.0M, 7.6 mmol) in CH 2 C1 2 was added to a solution of A-[ ⁇ tert- butoxycarbonyl)amino]-l-naphthoic acid (985.8 mg, 3.42 mmol) and DMAP (459.6 mg, 3.76 mmol) in CH 2 C1 2 (70 mL) at 0 °C. Stirring for 2 h at room temperature and evaporation of the solvent and excess oxalyl chloride, the residue was dissolved in CH C1 2 (70 mL).
  • Acetyl chloride (7.7 mg, 0.099 mmol) was added to a solution of 3 -[(4- Amino- 1- naphthoyl)amino]-N-(tetrahydro-2H-pyran-4-ylmethyl)pyridine-2-carboxamide hydrochloride (33.4 mg, 0.076 mmol) and DMAP (23.2 mg, 0.19mmol) in C ⁇ 2 C1 2 (5 mL). The reaction mixture was stirred overnight at room temperature, diluted with CH 2 C1 2 (100 mL), washed with saturated ⁇ aHCO 3 solution (2x10 mL) and dried over Na 2 SO 4 .
  • Step A iV-(Cyclohexyloxy)-3-[(4-methyl-l-naphthoyl)amino]pyridine-2-carboxamide
  • Step D tart-Butyl 2-( ⁇ [(3- ⁇ [4-(methoxymethyl)-l-naphthoyI]amino ⁇ pyridin-2- yl)carbonyl] amino ⁇ methyl)piperidine-l-carboxylate
  • Step B tart-Butyl 2-( ⁇ [(3- ⁇ [4-(ethoxymethyl)-l-naphthoyl]amino ⁇ pyridin-2- yl)carbonyl]amino ⁇ methyl)piperidine-l-carboxylate
  • Step A N-(piperidin-2-ylmethyl)-3- ⁇ [4-(lfl-l,2,4-triazol-l-ylmethyl)-l- naphthoyl] amino ⁇ pyridine-2-carboxamide
  • Step B tart-Butyl 2-( ⁇ [(3- ⁇ [4-(lJ ⁇ -l,2,4-triazol-l-ylmethyl)-l- naphthoyl]amino ⁇ pyridin-2-yl)carbonyl]amino ⁇ methyl)piperidine-l-carboxylate
  • Step A iV-(Piperidin-2-ylmethyl)-3- ⁇ [4-(l J H r -l,2,3-triazol-l-ylmethyl)-l- naphthoyl]amino ⁇ pyridine-2-carboxamide AndN-(Piperidin-2-ylmethyl)-3- ⁇ [4-(2 J r7-l,2,3-triazol-2-ylmethyl)-l- naphthoyl]amino ⁇ pyridine-2-carboxamide
  • Step A 3- ⁇ [4-(Methoxymethyl)-l-naphthoyl]amino ⁇ -iV-[2-(tetrahydro-2H-pyran-4- yl)ethyl]pyridine-2-carboxamide
  • Step A 3-[(4-MethyI-l-naphthoyI)amino]-N-(morpholin-3-ylmethyl)pyridine-2- carboxamide
  • Step B tart-Butyl 3- ⁇ [( ⁇ 3-[(4-methyl-l-naphthoyl)amino]pyridin-2- yl ⁇ carbonyl)amino]methyl ⁇ morpholine-4-carboxylate
  • Step A N-butyl-3-[[[4-(lj9 r -l,2,3-triazol-l-ylmethyl)-l-naphthalenyl]carbonyl]amino]- 2-pyridinecarboxamide
  • Step B Methyl 3- ⁇ [4-(bromomethyl)-l-naphthoyl] amino ⁇ pyridine-2-carboxylate
  • Step A N-(Cyclohexylmethyl)-3- ⁇ [4-(lH-l,2,3-triazol-l-ylmethyl)-l- naphthoyl] amino ⁇ pyridine-2-carboxamide and N-(cyclohexylmethyl)-3- ⁇ [4 ⁇ (2H-l,2,3- triazol-2-ylmethyl)-l-naphthoyl]amino ⁇ pyridine-2-carboxamide
  • Step D 3- ⁇ [4-(li?-l,2,3-triazoI-l-ylmethyl)-l-naphthoyl]amino ⁇ pyridine-2-carboxylic acid
  • Step A iV-[(tetrahydro-2 J H-pyran-4-yl)methyl]-3-[[[4-(4fl-l,2,4-triazol-4-ylmethyl)-l- naphthalenyl] carbonyl] amino]-2-pyridinecarboxamide and N-[(tetrahydro-2H-pyran-4-yl)methyl]-3-[[[4-(lir-l,2,4-triazol-l-ylmethyl)-l- naphthalenyl] carbonyl] amino]-2-pyridinecarboxamide
  • Step B 3- ⁇ [4-(bromomethyl)-l-naphthoyl] amino ⁇ -iV-(tetrahydro-2i ⁇ -pyran-4- ylmethyl)pyridine-2-carboxamide
  • Step A iV-(Tetrahydro-2 J r7-pyran-4-yl)-3-[[[4-(l J r7-l,2,3-triazol-l-ylmethyl)-l- naphthalenyl] carbonyl] amino]-2-pyridinecarboxamide
  • Step A 3-(l-Naphthoylammo)-iV-(pyrrolidin-2-ylmethyl)pyridine-2-carboxamide
  • Step B tart-Butyl 2-[( ⁇ [3-(l-naphthoylamino)pyridin-2- yl]carbonyl ⁇ amino)methyl]pyrrolidine-l-carboxylate
  • Oxalyl chloride (0.011 mL, 0.115 mmol) was added to a mixture of 4- ⁇ [(2- ⁇ [(Tetrahydro- 2H-pyran-4-ylmethyl)amino]carbonyl ⁇ pyridin-3-yl)amino]carbonyl ⁇ -l-naphthoic acid (50 mg, 0.11 mmol) and DCE (20 mL) at 0°C.
  • the reaction mixture was allowed to warm to ambient temperature and oxalyl chloride (0.005 mL, 0.057 mmol) was added.
  • the reaction mixture was heated to 70°C, stirred for 1 hr and cooled to 0°C.
  • Step B S-Amino-iV- ⁇ etrahydro ⁇ H-pyran ⁇ -ylmethy ⁇ pyridine ⁇ -carboxamide
  • HATU (2.63 g, 6.93 mmol) and 4-aminomethyltetrahydropyran (0.80 g, 6.94 mmol) were added to a solution of 3-amino-2-pyridine carboxylic acid (0.91 g, 6.60 mmol) and DIPEA (1.26 mL, 7.26 mmol) in DMF (120 mL) at 0°C.
  • the reaction mixture was allowed to warm to ambient temperature and heated to 50°C for 3 hrs.
  • the solvent was concentrated and the residue was recovered in EtOAc (300 mL).
  • the solution was washed with water, saturated NaHCO 3 solution, brine and dried over anhydrous Na 2 SO 4 .
  • the solvent was concentrated and the product was purified on silica gel by flash chromatography using Et 3 N 0.1%, MeOH 3% and Acetone 5% in DCM to provide the title compound as white solid (1.40 g, 90 %).
  • Step D 4- ⁇ [(2- ⁇ [(Tetrahydro-2H-pyran-4-ylmethyl)amino]carbonyl ⁇ pyridin-3- yl)amino] carbonyl ⁇ -l-naphthoic acid
  • Methane sulfonyl chloride (0.011 mL, 0.14 mmol) was added to a solution of 3- ⁇ [4- (Hydroxymethyl)- 1 -naphthoyl]amino ⁇ -N-(tetrahydro-2H-pyran-4-ylmethyl)pyridine-2- carboxamide (50 mg, 0.11 mmol) and Et 3 ⁇ (0.032 mL, 0.17 mmol) in DCM (20 mL) at 0°C. The reaction mixture was allowed to warm to ambient temperature and stirred for 4 hrs. The solvent was concentrated and the product was recovered in DMF (10 mL).
  • Example 160 Following the procedure in Example 160, using azetidine (68 mg, 1.19 mmol, after azetidine addition, the reaction mixture was heated to 80°C and sti ⁇ ed overnight) provided the title compound as its TFA salt after purification by reversed-phase HPLC (42 mg, 61 %).

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Abstract

Compounds of formulas I, IA, and IB or IC or pharmaceutically acceptable salts thereof: wherein A, A1, A2, A3, A4, R2, R3, R4 and n are as defined in the specifications well as salts and pharmaceutical compositions including the compounds are prepared. They are useful in therapy, in particular in the management of pain.

Description

THERAPEUTIC COMPOUNDS: PYRIDINE AS SCAFFOLD
BACKGROUND OF THE INVENTION 1. Field of the invention The invention is related to therapeutic compounds, pharmaceutical compositions containing these compounds, manufacturing processes thereof and uses thereof.
Particularly, the present invention is related to compounds that may be effective in treating pain, cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, anxiety disorders, gastrointestinal disorders and/or cardiavascular disorders.
2. Discussion of Relevant Technology Pain management has been an important field of study for many years. It has been well known that cannabinoid receptor (e.g., CBi receptor, CB2 receptor) ligands including agonists, antagonists and inverse agonists produce relief of pain in a variety of animal models by interacting with CBi and/or CB receptors. Generally, CBi receptors are located predominately in the central nervous system, whereas CB2 receptors are located primarily in the periphery and are primarily restricted to the cells and tissues derived from the immune system. While CBi receptor agonists, such as Δ9-tetrahydrocannabinol (Δ9-THC) and anadamide, are useful in anti-nociception models in animals, they tend to exert undesired CNS side effects, e.g., psychoactive side effects, the abuse potential, drug dependence and tolerance, etc. These undesired side effects are known to be mediated by the CBi receptors located in CNS. There are lines of evidence, however, suggesting that CBI agonists acting at peripheral sites or with limited CNS exposure can manage pain in humans or animals with much improved overall in vivo profile. Therefore, there is a need for new CBi receptor ligands such as agonists that may be useful in managing pain or treating other related symptoms or diseases with reduced or minimal undesirable CNS side effects. DESCRIPTION OF THE EMBODIMENTS
The present invention provides CBi receptor ligands which may be useful in treating pain and/or other related symptoms or diseases. Unless specified otherwise within this specification, the nomenclature used in this specification generally follows the examples and rules stated in Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F, andH, Pergamon Press, Oxford, 1979, which is incorporated by references herein for its exemplary chemical structure names and rules on naming chemical structures. "CB1/CB2 receptors" means CBi and/or CB2 receptors, The term "Cm-n" or "Cm-n group" used alone or as a prefix, refers to any group having m to n carbon atoms. The term "hydrocarbon" used alone or as a suffix or prefix, refers to any structure comprising only carbon and hydrogen atoms up to 14 carbon atoms. The term "hydrocarbon radical" or "hydrocarbyl" used alone or as a suffix or prefix, refers to any structure as a result of removing one or more hydrogens from a hydrocarbon. The term "alkyl" used alone or as a suffix or prefix, refers to monovalent straight or branched chain hydrocarbon radicals comprising 1 to about 12 carbon atoms. Unless otherwise specified, "alkyl" general includes both saturated alkyl and unsaturated alkyl. The term "alkylene" used alone or as suffix or prefix, refers to divalent straight or branched chain hydrocarbon radicals comprising 1 to about 12 carbon atoms, which serves to links two structures together. The term "alkenyl" used alone or as suffix or prefix, refers to a monovalent straight or branched chain hydrocarbon radical having at least one carbon-carbon double bond and comprising at least 2 up to about 12 carbon atoms. The term "alkynyl" used alone or as suffix or prefix, refers to a monovalent straight or branched chain hydrocarbon radical having at least one carbon-carbon triple bond and comprising at least 2 up to about 12 carbon atoms. The term "cycloalkyl," used alone or as suffix or prefix, refers to a monovalent ring-containing hydrocarbon radical comprising at least 3 up to about 12 carbon atoms. The term "cycloalkenyl" used alone or as suffix or prefix, refers to a monovalent ring-containing hydrocarbon radical having at least one carbon-carbon double bond and comprising at least 3 up to about 12 carbon atoms. The term "cycloalkynyl" used alone or as suffix or prefix, refers to a monovalent ring-containing hydrocarbon radical having at least one carbon-carbon triple bond and comprising about 7 up to about 12 carbon atoms. The term "aryl" used alone or as suffix or prefix, refers to a hydrocarbon radical having one or more polyunsaturated carbon rings having aromatic character, {e.g., 4n + 2 delocalized electrons) and comprising 5 up to about 14 carbon atoms, wherein the radical is located on a carbon of the aromatic ring. The term "non-aromatic group" or "non-aromatic" used alone, as suffix or as prefix, refers to a chemical group or radical that does not contain a ring having aromatic character {e.g., 4n + 2 delocalized electrons). The term "arylene" used alone or as suffix or prefix, refers to a divalent hydrocarbon radical having one or more polyunsaturated carbon rings having aromatic character, {e.g., 4n + 2 delocalized electrons) and comprising 5 up to about 14 carbon atoms, which serves to link two structures together. The term "heterocycle" used alone or as a suffix or prefix, refers to a ring- containing structure or molecule having one or more multivalent heteroatoms, independently selected from N, O, P and S, as a part of the ring structure and including at least 3 and up to about 20 atoms in the ring(s). Heterocycle may be saturated or unsaturated, containing one or more double bonds, and heterocycle may contain more than one ring. When a heterocycle contains more than one ring, the rings may be fused or unfused. Fused rings generally refer to at least two rings share two atoms therebetween. Heterocycle may have aromatic character or may not have aromatic character. The term "heteroalkyl" used alone or as a suffix or prefix, refers to a radical formed as a result of replacing one or more carbon atom of an alkyl with one or more heteroatoms selected from N, O, P and S. The term "heteroaromatic" used alone or as a suffix or prefix, refers to a ring- containing structure or molecule having one or more multivalent heteroatoms, independently selected from N, O, P and S, as a part of the ring structure and including at least 3 and up to about 20 atoms in the ring(s), wherein the ring-containing structure or molecule has an aromatic character (e.g., 4n + 2 delocalized electrons). The term "heterocyclic group," "heterocyclic moiety," "heterocyclic," or "heterocyclo" used alone or as a suffix or prefix, refers to a radical derived from a heterocycle by removing one or more hydrogens therefrom. The term "heterocyclyl" used alone or as a suffix or prefix, refers a radical derived from a heterocycle by removing at least one hydrogen from a carbon of a ring of the heterocycle. The term "heterocyclylene" used alone or as a suffix or prefix, refers to a divalent radical derived from a heterocycle by removing two hydrogens therefrom, which serves to link two structures together. The term "heteroaryl" used alone or as a suffix or prefix, refers to a heterocyclyl having aromatic character, wherein the radical of the heterocyclyl is located on a carbon of an aromatic ring of the heterocyclyl. The term "heterocycloalkyl" used alone or as a suffix or prefix, refers to a heterocyclyl that does not have aromatic character. The term "heteroarylene" used alone or as a suffix or prefix, refers to a heterocyclylene having aromatic character. The term "heterocycloalkylene" used alone or as a suffix or prefix, refers to a heterocyclylene that does not have aromatic character. The term "six-membered" used as prefix refers to a group having a ring that contains six ring atoms. The term "five-membered" used as prefix refers to a group having a ring that contains five ring atoms. A five-membered ring heteroaryl is a heteroaryl with a ring having five ring atoms wherein 1, 2 or 3 ring atoms are independently selected fromN, O and S. Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3- thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4- triazolyl, 1,3,4-thiadiazolyl, and 1,3,4- oxadiazolyl. A six-membered ring heteroaryl is a heteroaryl with a ring having six ring atoms wherein 1, 2 or 3 ring atoms are independently selected fromN, O and S. Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl. The term "substituted" used as a prefix refers to a structure, molecule or group, wherein one or more hydrogens are replaced with one or more C1-12hydrocarbon groups, or one or more chemical groups containing one or more heteroatoms selected from N, O, S, F, CI, Br, I, and P. Exemplary chemical groups containing one or more heteroatoms include heterocyclyl, -NO2, -OR, -CI, -Br, -I, -F, -CF3, -C(=O)R, -C(=O)OH, -NH2, -SH, -NHR, - NR2, -SR, -SO3H, -SO2R, -S(=O)R, -CN, -OH, -C(=O)OR, -C(=O)NR2) -NRC(=O)R, oxo (=O), imino (=NR), thio (=S), and oximino (=N-OR), wherein each "R" is a Ci-i2hydrocarbyl. For example, substituted phenyl may refer to nitrophenyl, pyridylphenyl, methoxyphenyl, chlorophenyl, aminophenyl, etc., wherein the nitro, pyridyl, methoxy, chloro, and amino groups may replace any suitable hydrogen on the phenyl ring. The term "substituted" used as a suffix of a first structure, molecule or group, followed by one or more names of chemical groups refers to a second structure, molecule or group, which is a result of replacing one or more hydrogens of the first structure, molecule or group with the one or more named chemical groups. For example, a "phenyl substituted by nitro" refers to nitrophenyl. The term "optionally substituted" refers to both groups, structures, or molecules that are substituted and those that are not substituted. Heterocycle includes, for example, monocyclic heterocycles such as: aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazoline, dioxolane, sulfolane 2,3-dihydrofuran, 2,5-dihydrofuran tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydro-pyridine, piperazine, morpholine, thiomorpholine, pyran, thiopyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dihydropyridine, 1,4-dioxane, 1,3-dioxane, dioxane, homopiperidine, 2,3,4,7-tetrahydro-lH-azepine homopiperazine, 1,3-dioxepane, 4,7-dihydro-l,3-dioxepin, and hexamethylene oxide. In addition, heterocycle includes aromatic heterocycles, for example, pyridine, pyrazine, pyrimidine, pyridazine, thiophene, furan, furazan, pyrrole, imidazole, thiazole, oxazole, pyrazole, isothiazole, isoxazole, 1,2,3-triazole, tetrazole, 1,2,3-thiadiazole, 1,2,3- oxadiazole, 1,2,4-triazole, 1,2,4-thiadiazole, 1,2,4-oxadiazole, 1,3,4-triazole, 1,3,4- thiadiazole, and 1,3,4- oxadiazole. Additionally, heterocycle encompass polycyclic heterocycles, for example, indole, indoline, isoindoline, quinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, 1,4-benzodioxan, coumarin, dihydrocoumarin, benzofuran, 2,3-dihydrobenzofuran, isobenzofuran, chromene, chroman, isochroman, xanthene, phenoxathiin, thianthrene, indolizine, isoindole, indazole, purine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, phenanthridine, perimidine, phenanthroline, phenazine, phenothiazine, phenoxazine, 1,2-benzisoxazole, benzothiophene, benzoxazole, benzthiazole, benzimidazole, benztriazole, thioxanthine, carbazole, carboline, acridine, pyrolizidine, and quinolizidine. In addition to the polycyclic heterocycles described above, heterocycle includes polycyclic heterocycles wherein the ring fusion between two or more rings includes more than one bond common to both rings and more than two atoms common to both rings. Examples of such bridged heterocycles include quinuclidine, diazabicyclo[2.2.1]heptane and 7-oxabicyclo[2.2.1]heptane. Heterocyclyl includes, for example, monocyclic heterocyclyls, such as: aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, dioxolanyl, sulfolanyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, tetrahydrofuranyl, thiophanyl, piperidinyl, 1,2,3,6-tetrahydro-pyridinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, 2,3-dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyridinyl, 1,4-dioxanyl, 1,3-dioxanyl, dioxanyl, homopiperidinyl, 2,3,4,7-tetrahydro-lH-azepinyl, homopiperazinyl, 1,3-dioxepanyl, 4,7- dihydro-l,3-dioxepinyl, and hexamethylene oxidyl.
In addition, heterocyclyl includes aromatic heterocyclyls or heteroaryl, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, furazanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4- oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4 oxadiazolyl. Additionally, heterocyclyl encompasses polycyclic heterocyclyls (including both aromatic or non-aromatic), for example, indolyl, indolinyl, isoindolinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, 1,4-benzodioxanyl, coumarinyl, dihydrocoumarinyl, benzofuranyl, 2,3-dihydrobenzofuranyl, isobenzofuranyl, chromenyl, chromanyl, isochromanyl, xanthenyl, phenoxathiinyl, thianthrenyl, indolizinyl, isoindolyl, indazolyl, purinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, phenanthridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, 1,2-benzisoxazolyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, benztriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrolizidinyl, and quinolizidinyl. In addition to the polycyclic heterocyclyls described above, heterocyclyl includes polycyclic heterocyclyls wherein the ring fusion between two or more rings includes more than one bond common to both rings and more than two atoms common to both rings. Examples of such bridged heterocycles include quinuclidinyl, diazabicyclo[2.2.1]heptyl; and 7-oxabicyclo[2.2.1]heptyl. The term "alkoxy" used alone or as a suffix or prefix, refers to radicals of the general formula -O-R, wherein -R is selected from a hydrocarbon radical. Exemplary alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy, cyclopropylmethoxy, allyloxy, and propargyloxy. The term "aryloxy" used alone or as suffix or prefix, refers to radicals of the general formula -O-Ar, wherein -Ar is an aryl. The term "heteroaryloxy" used alone or as suffix or prefix, refers to radicals of the general formula -O-Ar', wherein -Ar' is a heteroaryl. The term "amine" or "amino" used alone or as a suffix or prefix, refers to radicals of the general formula -NRR', wherein R and R' are independently selected from hydrogen or a hydrocarbon radical. "Acyl" used alone, as a prefix or suffix, means -C(=O)-R, wherein -R is an optionally substituted hydrocarbyl, hydrogen, amino or alkoxy. Acyl groups include, for example, acetyl, propionyl, benzoyl, phenyl acetyl, carboethoxy, and dimethylcarbamoyl. Halogen includes fluorine, chlorine, bromine and iodine. "Halogenated," used as a prefix of a group, means one or more hydrogens on the group is replaced with one or more halogens. "RT" or "rt" means room temperature. A first ring group being "fused" with a second ring group means the first ring and the second ring share at least two atoms therebetween. "Link," "linked," or "linking," unless otherwise specified, means covalently linked or bonded. When a first group, structure, or atom is "directly connected" to a second group, structure or atom, at least one atom of the first group, structure or atom forms a chemical bond with at least one atom of the second group, structure or atom. "Saturated carbon" means a carbon atom in a structure, molecule or group wherein all the bonds connected to this carbon atom are single bond. In other words, there is no double or triple bonds connected to this carbon atom and this carbon atom generally adopts an sp atomic orbital hybridization. "Unsaturated carbon" means a carbon atom in a structure, molecule or group wherein at least one bond connected to this carbon atom is not a single bond. In other words, there is at least one double or triple bond connected to this carbon atom and this carbon atom generally adopts a sp or sp2 atomic orbital hybridization. "RT", "r.t." or "rt" means room temperature. "DMF" refers to dimethyl formamide. "DIPEA" refers to N,N-diisopropylethylamine. "HATU" refers to 2-(7-Aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate. One aspect of the invention is a compound of formula IC, a pharmaceutically acceptable salt thereof, diastereomers, enantiomers, or mixtures thereof:
Figure imgf000010_0001
IC wherein: A is selected from N and CR1; and R1 is independently selected from hydrogen, halogen, cyano, amino, acetylamino, hydroxyl, alkoxy, alkyl, haloalkoxy, alkylene, haloalkyl, haloalkenyl and NR5R6; each of R5 and R6 is independently selected from hydrogen, C1-6alkyl, C2-
6alkenyl, alkoxyC1-6 alkyl; Cι-6 alkylcarbonyl, hydroxyC1-6 alkyl, alkoxy, C3-6cycloalkyl, C3-6cycloalkyl-C1-6alkyl, Cι-6alkylcarbonyl, C3-6heterocyclyl and -eheterocylcyl- . 6alkyl; wherein said ^alkyl, C -6alkenyl, alkoxyCι-6 alkyl; C1-6 alkylcarbonyl, hydroxyC1-6 alkyl, alkoxy, C3-6cycloalkyl, C3-6cycloalkyl-C1-6alkyl, C1-6alkylcarbonyl, C3- sheterocyclyl and C3-6heterocylcyl-Cι-6alkyl used in defining R5 and R6 are optionally substituted by one or more groups selected from halogen, cyano, nitro, C1-6 alkoxy, Cι-6 alkyl and hydroxy; and and R2 is selected from aryl and heterocyclyl; wherein said aryl and heterocyclyl used in defining R2 is optionally substituted by one or more groups selected from halogen, halo substituted alkyl, alkyl, cyano, nitro, alkoxy, hydroxy, hydroxy-alkyl, carbonyl, amino, alkyl-aryl, alkoxy, alkoxy-alkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, amino-alkyl, cycloalkyl, heteroaryl, heteroarylalkyl, aryl, aryl-alkyl and-NR5R6; R3 is selected from hydrogen and alkyl; R4 is selected from alkyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl; wherein said alkyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl used in defining R4 is optionally substituted by one or more groups selected from halogen, halo substituted alkyl, carbonyl, alkyl, cyano, nitro, amino, amino-alkyl, alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxy-carbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, aryl-alkyl and -NR5R6; and n is selected from 0, 1, 2, 3, 4 and 5; R3 and R4 together with the nitrogen atom to which they are attached may form a group selected from heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms; wherein said heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms used in defining R3 and R4 is optionally substituted by one or more groups selected from halogen, halo substituted alkyl, carbonyl, alkyl, cyano, nitro, amino, amino-alkyl, alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxy-carbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, aryl-C1-6alkyl and -NR5R6.
Particularly, the compounds of the present invention are those of formula IC, wherein R1 is independently selected from halogen, hydroxyl, cyano, C1-6 alkoxy, C1-6 alkyl, amino, C1- haloalkoxy, C2-6 alkylene, C1-4 haloalkyl, C2-6 haloalkenyl and NR5R6; each of R5 and R6 is independently selected from hydrogen, C1-6alkyl, C2- 6alkenyl, C1-6 alkylalkoxy; C1-6 alkylhydroxy, C1-6 alkoxy, C3-6cycloalkyl, C3-6cycloalkyl- C1-6alkyl, C1-6alkylcarbonyl, C1-4alkylcarbonyl, C3-6heterocyclyl and C3-6heterocylcyl-Cι. 6alkyl; wherein said C1-6alkyl, C2-6alkenyl, C1-6 alkylalkoxy; Cι-6 alkylhydroxy, C1-6 alkoxy, C3-6cycloalkyl, C3-6cycloalkyl-C1-6alkyl, C1-6alkylcarbonyl, C1-4alkylcarbonyl, C3- 6heterocyclyl and C3-6heterocylcyl-C1-6alkyl used in defining R5 and R6 are optionally substituted by one or more groups selected from halogen, cyano, nitro, C1-3 alkoxy, C1-3 alkyl, and hydroxy; and A is selected from N and CR1; and R2 is selected from aryl and C2-6 heterocyclyl; wherein said aryl and C2-6 heterocyclyl used in defining R2 is optionally substituted by one or more groups selected from halogen, halo substituted C1-6 alkyl, alkyl, cyano, nitro, C1-6 alkoxy, hydroxy, hydroxy-Cι-6 alkyl, carbonyl, amino, C1-6 alkoxy-alkyl, C1-6 alkyl-carbonyl, aryl, aryl-C1-6 alkyl and -NR5R6; and R3 is selected from hydrogen and C1-6 alkyl; and R4 is selected from aryl and C2-10 heterocyclyl; wherein said aryl and C2-10 heterocyclyl used in defining R2 is optionally substituted by one or more groups selected from halogen, halo substituted C1-10 alkyl, carbonyl, alkyl, cyano, nitro, amino, aminoalkyl, alkoxy, hydroxy, alkoxy-alkyl, C1-10 alkoxy-aryl, C1-10 alkoxy-carbonyl, heterocyclic moiety, C3-10 aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl- heteroaryl, aryl-alkyl and -NR5R6; and n is selected from 0, 1, 2, 3 and 4; and R3 and R4 together with the nitrogen atom to which they are attached may form a group selected from selected from azepanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, isoxazolidinyl, oxadiazolyl, trazolyl, thiadiaxolyl, morpholinyl, piperidinyl, pyridinyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, triazinyl, tetrahydrofuranyl, tetrahydrofuranyl-methyl, tefrahydrofuranyl-ethyl, tetrahydropyranyl, tetrahydropyranylmethyl, tetrahydropyranylethyl or l,4-dioxa-8-azaspiro[4.5]decan-8-yl; wherein said azepanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, isoxazolidinyl, oxadiazolyl, trazolyl, thiadiaxolyl, morpholinyl, piperidinyl, pyridinyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, triazinyl, tetrahydrofuranyl, tetrahydrofuranyl-methyl, tetrahydrofuranyl-ethyl, tetrahydropyranyl, tetrahydropyranylmethyl, tetrahydropyranylethyl or l,4-dioxa-8-azaspiro[4.5]decan-8-yl used in defining R3 and R4 are optionally substituted by one or more groups selected from halogen, fiuoro substituted alkyl, C1-6alkyl, cyano, nitro, hydroxy, amino, amino-C1-4alkyl, hydroxy-C1-4alkyl, Ci. 4alkoxy, C1-4alkoxy-C1-4alkyl, C1-4alkoxy-aryl, ^alkoxycarbonyl, heterocyclic moiety, heterocyclic-C1-4alkyl, aryl and aryl-C1-4alkyl, and -NR5R6.
More particularly, the compounds of the present invention are those of formula IC, wherein R1 is independently selected from halogen, hydroxyl, C1-6 alkoxy, C1-6 alkyl, C2-6 alkylene, NH2, and NR5R6; each of R5 and R6 is independently selected from hydrogen, C1-6alkyl, C2- 6alkenyl, C1-6 alkylalkoxy; C1-6 alkylhydroxy, C1-4alkylcarbonyl, C1-4 alkoxy, C3- 6cycloalkyl, C3-6cycloalkyl-C1-6alkyl, C3-6heterocyclyl and C3-6heterocylcyl-C1-6alkyl; wherein said C1-6alkyl, C -6alkenyl, C1-6 alkylalkoxy; C1-6 alkylhydroxy, C1-4alkylcarbonyl, C1- alkoxy, C3-6cycloalkyl, C3-6cycloalkyl-C1-6alkyl, C3-6heterocyclyl and C3-6heterocylcyl-C1-6alkyl used in defining R5 and R6 are optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, and hydroxy; A is selected from N and CR1; and R2 is selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, pyrrolyl, imidazolyl, fhiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3- triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4- thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4 oxadiazolyl, indolyl, indolinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, 1,4-benzodioxanyl, coumarin, dihydrocoumarinyl, 2,3-dihydrobenzofuranyl, 1,2- benzisoxazolyl, 1,3-benzodioxolyl, 2,3-dihydro-l,4-benzodioxinyl, 3,4-dihydro-2H-l,5- benzodioxepinyl, 4H-l,3-benzodioxinyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, benztriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrolizidinyl, naphthalenyl or quinolizidinyl; wherein said phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, pyrrolyl, imidazolyl, fhiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3- oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4- thiadiazolyl, and 1,3,4 oxadiazolyl, indolyl, indolinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, 1,4-benzodioxanyl, coumarin, dihydrocoumarinyl, 2,3-dihydrobenzofuranyl, 1,2-benzisoxazolyl, 1,3-benzodioxolyl, 2,3-dihydro-l,4- benzodioxinyl, 3,4-dihydro-2H-l,5-benzodioxepinyl, 4H-l,3-benzodioxinyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, benztriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrolizidinyl, naphthalenyl or quinolizidinyl used in defining R2 is optionally substituted by one or more groups selected from hydrogen, halogen, hydroxy, Cι-4alkyl, amino, trifluoromethyl, C1- alkyl-aryl, . 4alkyl-heteroaryl, C1-4alkoxy, C1-6alkoxy-C1-4alkyl, C1-6alkamino, amino-C1-4alkyl, C3-8 aryl and heteroaryl, N,N-dimethylmethylamino, methylmethoxy, methyl-diazolyl, methyl- triazolyl, methyl-tetrazolyl, and -NR5R6; and R is selected from hydrogen and C1-6 alkyl; and R4 is selected from amino, amino-C1-6alkyl, hydroxy, hydroxy-C1-6alkyl, C1-6 alkyl,
C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkoxy-C1-6alkyl, C1-6alkoxy-aryl, Ci. 6alkoxycarbonyl, C1-6alkcarbonyl, C3-1ocycloalkyl, C3-10cycloalkyl-C1-6alkyl, C4- 8cycloalkenyl-C1-6alkyl, C4-8cycloalkenyl, C3-10cycloalkoxy, C3-1o aryl, aryl-C1-6alkyl, amino-carbonyl-C1-6alkyl, heterocyclic moiety, heterocyclic-C1-6alkyl or heterocyclic- carbonyl-C1-6alkyl wherein said amino, amino-C1-6alkyl, hydroxy, hydroxy-C1-6alkyl, Cι. 10alkyl, C2-1oalkenyl, C2-1oalkynyl, C1-10alkoxy, C1-1oalkoxy-C1-6alkyl, C1-10alkoxy-aryl, Ci. ioalkoxycarbonyl, C1-10alkcarbonyl, C -1ocycloalkyl, C3-1ocycloalkyl-C1-6alkyl, C - 8cycloalkenyl-C1-6alkyl, C4-8cycloalkenyl, C3-1ocycloalkoxy, C3-1o aryl, aryl-C1-6alkyl, amino-carbonyl-C1-6alkyl, heterocyclic moiety, heterocyclic-C1-6alkyl or heterocyclic- carbonyl-C1-6alkyl used in defining R4 is optionally substituted with one or more substituents selected from halogen, hydroxy, hydroxy-C1-6alkyl, cyano, carbonyl, nitro, amino, C1-6alkyl, C1-6alkoxy, C1-6alkoxy-C1-6alkyl, C1-6alkcarbonyl, C1-6alkoxycarbonyl, C1-6alkamino, amino-C1-6alkyl, C3-6cycloalkyl, C3-6 aryl-C1-4 alkyl, C3-6 aryl and -NR5R6; and n is selected from 0, 1, 2, and 3; and R3 and R4 together with the nitrogen atom to which they are attached may form a group selected from azepanyl, isoxazolidinyl, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrofuranyl-methyl, tetrahydrofuranyl-ethyl, tetrahydropyranyl, tetrahydropyranylmethyl, tetrahydropyranylethyl or l,4-dioxa-8- azaspiro[4.5]decan-8-yl with one or more substituents selected from halogen, cyano, nitro, methyl, ethyl, hydroxy, hydroxy-methyl, hydroxy-ethyl, amino-methyl, amino-ethyl, methoxy-methyl, methoxy-phenyl, ethoxycarbonyl, tert-butoxycarbonyl, diphenyl-methyl, morpholinyl-eth-2-yl, piperidinyl-methyl and pyridinyl.
Most particularly, the compounds of the present invention are those of formula IC, wherein R1 is independently selected from halogen, hydroxyl, C1-3 alkoxy, C1-6 alkyl, NH2, C2-6 alkylene and NR5R6; each of R5 and R6 is independently selected from hydrogen, C1-4alkyl, C2- alkenyl, C1-4 alkylalkoxy; C1-4 alkylhydroxy, alkoxy, C3-6cycloalkyl,
Figure imgf000015_0001
alkyl, methylcarbonyl, ethylcarbonyl, C3-6heterocyclyl and C3-6heterocylcyl-C1-6alkyl; wherein said C1-4alkyl, C2-4alkenyl, C1- alkylalkoxy; C1-4 alkylhydroxy, alkoxy, C3- 6cycloalkyl, C3-6cycloalkyl-C1-4alkyl, methylcarbonyl, ethylcarbonyl, C -6heterocyclyl and C -6heterocylcyl-C1.6alkyl used in defining R5 and R6 are optionally substituted by one or more groups selected from halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, and hydroxy; and A is selected from N and CR1; and R2 is selected from
Figure imgf000016_0001
wherein above-identified groups are optionally substituted by one or more groups selected from CI, Br, F, hydroxy, ethoxy, methoxy, trifluoromethyl, Cι-6 alkyl, cyano, nitro, and phenyl optionally substituted by one or more groups selected from methyl and ethyl; and R3 is selected from hydrogen, methyl and ethyl; and R4 is selected from
Figure imgf000017_0001
alkenyl, hydroxy, C1-6 alkoxy, -CR5R6; and -NR5R6; wherein the groups used in defining R4 are optionally substituted by one or more groups selected from halogen, hydroxy, C1-4 alkoxy, halo substituted alkyl, C1- alkyl, cyano, nitro, -NR5R6, and phenyl optionally substituted by one or more selected from methyl and ethyl; and n is selected from 0, 1, 2 and 3; and R3 and R4 together with the nitrogen atom to which they are attached may form a group selected from
Figure imgf000018_0001
Another aspect of the invention is a compound of formula I, a pharmaceutically acceptable salt thereof, diastereomers, enantiomers, or mixtures thereof:
Figure imgf000018_0002
I wherein: one of A1, A2, A3 or A4 is N and the remaining are each and independently CR1; and R1 is independently selected from hydrogen, halogen, cyano, amino, acetylamino, hydroxyl, alkoxy, alkyl, halogenated alkoxy, alkylene, halogenated alkyl, halogenated alkenyl and NR5R6; R2 is selected from
Figure imgf000019_0001
wherein said group used in defining R2 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, halogenated alkoxy, cyano, nitro, alkoxy, hydroxy, hydroxy-alkyl, amino, alkyl-aryl, alkoxy, alkoxy-alkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, amino-alkyl, alkyl-amino-carbonyl, heteroaryl-carbonyl, heterocyclyl-carbonyl, arylcarbonyl, heterocyclyl, cycloalkyl, heteroaryl, heteroarylalkyl-, aryl, aryl-alkyl and-NR5R6; R3 is selected from hydrogen and alkyl; R4 is selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl used in defining R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, alkylcarbonyl, cyano, nitro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxy- carbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, aryl-alkyl and -NR5R6; and n is selected from 0, 1, 2, 3, 4 and 5; or R3 and R4 together with the nitrogen atom to which they are attached may form a group selected from heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms; wherein said heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms used in defining R and R is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, cyano, nitro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxy-carbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, aryl-C1-6alkyl and -NR5R6, wherein each of R5 and R6 is independently selected from hydrogen, C1-6alkyl, C2-
6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyC1-6 alkyl, alkoxy, C3-6cycloalkyl, C3-6cycloalkyl-C1-6alkyl, Cι-6alkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-Cι.6alkyl; wherein said C1-6alkyl, C2-6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyC1-6 alkyl, alkoxy, C3-6cycloalkyl, C3-
6cycloalkyl-C1-6alkyl, C1-6alkylcarbonyl, C3-6heterocyclyl and
Figure imgf000020_0001
used in defining R and R are optionally substituted by one or more groups selected from halogen, cyano, nitro, C1-6 alkoxy, C1-6 alkyl and hydroxy; with a proviso that when n=0 then R4 is not thiazolyl or 5-chloropyridinyl; with a further proviso that when R2 is phenyl then n=0 and R4 is not unsubstituted methyl, C3 alkyl or unsubstituted C4 alkyl; and with a further proviso that said compound of formula I is not any one of
3-(benzoylamino)-N-benzylpyridine-2-carboxamide; 3-(benzoylamino)-N-pyridin-3-ylpyridine-2-carboxamide;
3-(benzoylamino)-N-phenylpyridine-2-carboxamide;
3-(benzoylamino)-N-(3-nitrophenyl)pyridine-2-carboxamide;
3-(benzoylamino)-N-(4-methoxyphenyl)pyridine-2-carboxamide;
3-(benzoylamino)-N-[4-(dimethylamino)phenyl]pyridine-2-carboxamide; N-(2-hydroxyethyl)-4-(2-naphthoylamino)nicotinamide;
4-(benzoylamino)-N-(2-hydroxyethyl)nicotinamide;
3-(benzoylamino)-2,6-dimethyl-N-phenylisonicotinamide; 3-(benzoylamino)-2,6-dimethyl-N-(3-nitrophenyl)isonicotinamide; 2-(benzoylamino)-N- [cyano(2-thienyl)methyl]nicotinamide; and 2-(benzoylamino)-N-[cyano(phenyl)methyl]nicotinamide. In another embodiment, certain compounds of the present invention are those of fonnula I as defined above, wherein R1 is independently selected from hydrogen, halogen, hydroxyl, alkoxy, alkyl, halogenated alkoxy, and halogenated alkyl; and R2 is selected from
Figure imgf000021_0001
wherein said group used in defining R2 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, halogenated alkoxy, cyano, nitro, alkylalkoxy, hydroxy- alkyl, alkoxy, alkoxyalkyl, alkylamino, amino-alkyl, alkyl-amino- carbonyl, heterocyclyl, heteroaryl, -heteroarylalkyl-, aryl-alkyl and-ΝR5R6; R3 is selected from hydrogen and alkyl; R4 is selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl used in defining R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, alkyl-carbonyl, cyano, nitro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxy-carbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, and -NR5R6; and n is selected from 0, 1, 2, 3, 4 and 5; or R3 and R4 together with the nitrogen atom to which they are attached may form a group selected from heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms; wherein said heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms used in defining R3 and R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, cyano, nitro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxy-carbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, aryl-C1-6alkyl and -NR5R6, wherein each of R5 and R6 is independently selected from hydrogen, C1-6alkyl, C2. 6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyCι.6 alkyl, alkoxy, C3-6cycloalkyl, C3-6cycloalkyl-C1-6alkyl, C1-6alkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-C1-6alkyl; wherein said C1-6alkyl, C2-6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyCι-6 alkyl, alkoxy, C3-6cycloalkyl, C3- 6cycloalkyl-C1-6alkyl, C1-6alkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-C1-6alkyl used in defining R5 and R6 are optionally substituted by one or more groups selected from halogen, cyano, nitro, C1-6 alkoxy, C1-6 alkyl and hydroxy. In a further embodiment, certain compounds of the present invention are those of formula I, wherein R1 is independently selected from hydrogen, fluoro, chloro, hydroxyl, alkoxy, alkyl, halogenated alkoxy, and halogenated alkyl; and R2 is selected from
Figure imgf000022_0001
wherein said group used in defining R2 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, halogenated alkoxy, alkyl-alkoxy, hydroxy- alkyl, alkoxy, alkoxyalkyl, alkylamino, amino-alkyl, alkyl-amino-carbonyl, heterocyclyl, heteroaryl, -heteroarylalkyl- and-NR5R6; R3 is selected from hydrogen and alkyl; R4 is selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl used in defining R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, alkyl-carbonyl, cyano, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxycarbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, and -NR5R6; and n is selected from 0, 1, 2, 3, 4 and 5; or R3 and R4 together with the nitrogen atom to which they are attached may form a group selected from heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms; wherein said heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms used in defining R3 and R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, cyano, nitro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxy-carbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, aryl-C1-6alkyl and -NR5R6, wherein each of R5 and R6 is independently selected from hydrogen, C1-6alkyl, C2- 6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, Cι_6 alkoxycarbonyl, hydroxyCι-6 alkyl, alkoxy, C3-6cycloalkyl, C3-6cycloalkyl-C1-6alkyl, C1-6alkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-C1-6alkyl; wherein said C1-6alkyl, C2-6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyC1-6 alkyl, alkoxy, C3-6cycloalkyl, C3- 6cycloalkyl-C1-6alkyl, C1-6alkylcarbonyl, C3-6heterocyclyl and Cs-eheterocyclyl-C^ealkyl used in defining R5 and R are optionally substituted by one or more groups selected from halogen, C1-6 alkoxy, C1-6 alkyl and hydroxy. In another embodiment, certain compounds of the present invention are those of formula IA or a pharmaceutically acceptable salt thereof, diastereomers, enantiomers, or mixtures thereof:
Figure imgf000023_0001
IA wherein: one of A1, A2 or A3 is N and the remaining are each and independently CR1; and R1 is independently selected from hydrogen, halogen, cyano, amino, acetylamino, hydroxyl, alkoxy, alkyl, halogenated alkoxy, alkylene, halogenated alkyl, halogenated alkenyl and NR5R6; R2 is selected from
Figure imgf000024_0001
wherein said group used in defining R2 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, halogenated alkoxy, cyano, nitro, alkoxy, hydroxy, hydroxy-alkyl, amino, alkyl-aryl, alkoxy, alkoxy-alkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, amino-alkyl, alkyl-amino-carbonyl, heteroaryl-carbonyl, heterocyclyl-carbonyl, arylcarbonyl, heterocyclyl, cycloalkyl, heteroaryl, heteroarylalkyl-, aryl, aryl-alkyl and-NR5R6; R3 is selected from hydrogen and alkyl; R4 is selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl used in defining R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, alkylcarbonyl, cyano, nitro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxycarbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, aryl-alkyl and -NR5R6; and n is selected from 0, 1, 2, 3, 4 and 5; or R3 and R4 together with the nitrogen atom to which they are attached may form a group selected from heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms; wherein said heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms used in defining R3 and R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, cyano, nitro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxy-carbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, aryl-C1-6alkyl and -NR5R6, wherein each of R5 and R6 is independently selected from hydrogen, C1-6alkyl, C2- 6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyC1-6 alkyl, alkoxy, C3-6cycloalkyl, C3-6cycloalkyl-C1-6alkyl, C1-6alkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-C1-6alkyl; wherein said C1-6alkyl, C2-6alkenyl, alkoxyC1-6 alkyl, Cι-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyC1-6 alkyl, alkoxy, C3-6cycloalkyl, C3- 6cycloalkyl-C1-6alkyl, C1-6alkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-C1-6alkyl used in defining R and R are optionally substituted by one or more groups selected from halogen, cyano, nitro, C1-6 alkoxy, C1-6 alkyl and hydroxy; with a proviso that when n=0 then R4 is not thiazolyl or 5-chloropyridinyl; with a further proviso that when R2 is phenyl then n=0 and R4 is not unsubstituted methyl, C3 alkyl or unsubstituted C4 alkyl; and with a further proviso that said compound of formula IA is not any one of 3 -(benzoylamino)-N-benzylpyridine-2-carboxamide;
3-(benzoylamino)-N-pyridin-3-ylpyridine-2-carboxamide; 3-(benzoylamino)-N-phenylpyridine-2-carboxamide; 3-(benzoylamino)-N-(3-nitrophenyl)pyridine-2-carboxamide; 3-(benzoylamino)-N-(4-methoxyphenyl)pyridine-2-carboxamide; 3-(her^oylanrhno)-N-[4-(dimethylamino)phenyl]pyridine-2-carboxamide; N-(2-hydroxyethyl)-4-(2-naphthoylamino)nicotinamide; 4-(benzoylamino)-N-(2-hydroxyethyl)nicotinamide; 3-(benzoylamino)-2,6-dimethyl-N-phenylisonicotinamide; and 3-(benzoylamino)-2,6-dimethyl-N-(3-nitrophenyl)isonicotinamide
In another embodiment, certain compounds of the present invention are those of formula IA as defined above, wherein R1 is independently selected from hydrogen, halogen, hydroxyl, alkoxy, alkyl, halogenated alkoxy, and halogenated alkyl; and R2 is selected from
Figure imgf000026_0001
wherein said group used in defining R2 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, halogenated alkoxy, cyano, nitro, alkylalkoxy, hydroxy- alkyl, alkoxy, alkoxyalkyl, alkylamino, amino-alkyl, alkyl-amino- carbonyl, heterocyclyl, heteroaryl, -heteroarylalkyl-, aryl-alkyl and-ΝR5R6; R3 is selected from hydrogen and alkyl; R4 is selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl used in defining R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, alkyl-carbonyl, cyano, nitro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxy-carbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, and -NR5R6; and n is selected from 0, 1, 2, 3, 4 and 5; or R3 and R4 together with the nitrogen atom to which they are attached may form a group selected from heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms; wherein said heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms used in defining R3 and R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, cyano, nitro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxy-carbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, aryl-C1-6alkyl and -NR5R6, wherein each of R5 and R6 is independently selected from hydrogen, C1-6alkyl, C2- 6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyC1-6 alkyl, alkoxy, C3-6cycloalkyl, C3-6cycloalkyl-Cι.6alkyl, C1-6alkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-C1-6alkyl; wherein said Cι.6alkyl, C2-6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyC1-6 alkyl, alkoxy, C3-6cycloalkyl, C3- 6cycloalkyl-C1-6alkyl, C1-6alkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-C1-6alkyl used in defining R5 and R6 are optionally substituted by one or more groups selected from halogen, cyano, nitro, C1-6 alkoxy, C1-6 alkyl and hydroxy. In a further embodiment, certain compounds of the present invention are those of formula IA, wherein R1 is independently selected from hydrogen, fluoro, chloro, hydroxyl, alkoxy, alkyl, halogenated alkoxy, and halogenated alkyl; and R2 is selected from
Figure imgf000027_0001
wherein said group used in defining R2 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, halogenated alkoxy, alkyl-alkoxy, hydroxy- alkyl, alkoxy, alkoxyalkyl, alkylamino, amino-alkyl, alkyl-amino-carbonyl, heterocyclyl, heteroaryl, -heteroarylalkyl- and-NR5R6; R3 is selected from hydrogen and alkyl; R4 is selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl used in defining R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, alkyl-carbonyl, cyano, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxycarbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, and -NR5R6; and n is selected from 0, 1, 2, 3, 4 and 5; or R3 and R4 together with the nitrogen atom to which they are attached may form a group selected from heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms; wherein said heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms used in defining R3 and R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, cyano, nitro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxy-carbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, aryl-C1-6alkyl and -NR5R6, wherein each of R5 and R6 is independently selected from hydrogen, C1-6alkyl, C2- 6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyCι.6 alkyl, alkoxy, C3-6cycloalkyl, C3-6cycloalkyl-C1-6alkyl, C1-6alkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-C1-6alkyl; wherein said C1-6alkyl, C2-6alkenyl, alkoxyCι-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyC1-6 alkyl, alkoxy, C3-6cycloalkyl, C3- 6cycloalkyl-C1-6alkyl, C1-6alkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-C1-6alkyl used in defining R5 and R6 are optionally substituted by one or more groups selected from halogen, C1-6 alkoxy, C1-6 alkyl and hydroxy.
In another embodiment, certain compounds of the present invention are those of formula IB or a pharmaceutically acceptable salt thereof, diastereomers, enantiomers, or mixtures thereof:
Figure imgf000028_0001
wherein: A is each and independently CR1; and R1 is independently selected from hydrogen, halogen, cyano, amino, acetylamino, hydroxyl, alkoxy, alkyl, halogenated alkoxy, alkylene, halogenated alkyl, halogenated alkenyl and NR5R6; R2 is selected from
Figure imgf000029_0001
wherein said group used in defining R2 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, halogenated alkoxy, cyano, nitro, alkoxy, hydroxy, hydroxy-alkyl, amino, alkyl-aryl, alkoxy, alkoxy-alkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, amino-alkyl, alkyl-amino-carbonyl, heteroaryl-carbonyl, heterocyclyl-carbonyl, arylcarbonyl, heterocyclyl, cycloalkyl, heteroaryl, heteroarylalkyl-, aryl, aryl-alkyl and-NR5R6; R3 is selected from hydrogen and alkyl; R4 is selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl used in defining R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, alkylcarbonyl, cyano, nitro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxycarbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, aryl-alkyl and -NR5R6; and n is selected from 0, 1, 2, 3, 4 and 5; or R3 and R4 together with the nitrogen atom to which they are attached may form a group selected from heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms; wherein said heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms used in defining R3 and R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, cyano, nitro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxy-carbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, aryl-Cι-6alkyl and -NR5R6, wherein each of R5 and R6 is independently selected from hydrogen, C1-6alkyl, C2-
6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyC1-6 alkyl, alkoxy, C3-6cycloalkyl, C3-6cycloalkyl-C1-6alkyl, C1-6alkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-C1-6alkyl; wherein said C1-6alkyl, C2-6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyC1-6 alkyl, alkoxy, C3-6cycloalkyl, C3- 6cycloalkyl-C1-6alkyl, C1-6alkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-C1-6alkyl used in defining R5 and R6 are optionally substituted by one or more groups selected from halogen, cyano, nitro, C1-6 alkoxy, C1-6 alkyl and hydroxy; with a proviso that said compound of formula IB is not any one of 3-[(4-tert- butylbenzoyl)amino]-N-(5-chloro-pyridin-2-yl)pyrazine-2-carboxamide; N-[2-(lH- imidazol-2-yl)ethyl]-3-[[4-(l,l-dimethylethyl)benzoyl]amino]-2-pyrazinecarboxamide and 3-(benzoylamino)-N-(methoxycarbonylmethyl)pyrazine-2-carboxamide.
In a further embodiment, certain compounds of the invention are those formula IB, or a pharmaceutically acceptable salt thereof, diastereomers, enantiomers, or mixtures thereof, wherein A is each and individually CR1; R1 is independently selected from hydrogen, halogen, hydroxyl, alkoxy, alkyl, halogenated alkoxy, and halogenated alkyl; R2 is selected from
Figure imgf000031_0001
wherein said group used in defining R2 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, halogenated alkoxy, cyano, nitro, alkylalkoxy, hydroxy- alkyl, alkoxy, alkoxyalkyl, alkylamino, amino-alkyl, alkyl-amino- carbonyl, heterocyclyl, heteroaryl, -heteroarylalkyl-, aryl-alkyl and-NR5R6; R is selected from hydrogen and alkyl; R4 is selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl used in defining R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, alkyl-carbonyl, cyano, nitro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxy-carbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, and -NR5R6; and n is selected from 0, 1, 2, 3, 4 and 5; or R3 and R4 together with the nitrogen atom to which they are attached may form a group selected from heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms; wherein said heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms used in defining R3 and R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, cyano, nitro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxy-carbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, aryl-C1-6alkyl and -NR5R6, wherein each of R5 and R6 is independently selected from hydrogen, C1-6alkyl, C2- 6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyC1-6 alkyl, alkoxy, C3-6cycloalkyl, C3-6cycloalkyl-Cι-6alkyl, C1-6alkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-C1-6alkyl; wherein said Cι-6alkyl, C2-6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyC1-6 alkyl, alkoxy, C3-6cycloalkyl, C3- 6cycloalkyl-C1-6alkyl, C1-6alkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-C1-6alkyl used in defining R5 and R6 are optionally substituted by one or more groups selected from halogen, cyano, nitro, C1-6 alkoxy, C1-6 alkyl and hydroxy. In an even further embodiment, certain compounds of the invention are those of formula IB, or a pharmaceutically acceptable salt thereof, diastereomers, enantiomers, or mixtures thereof, wherein A is each and individually CR1; R1 is independently selected from hydrogen, fluoro, chloro, hydroxyl, alkoxy, alkyl, halogenated alkoxy, and halogenated alkyl; R2 is selected from
Figure imgf000032_0001
wherein said group used in defining R2 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, halogenated alkoxy, alkyl-alkoxy, hydroxy- alkyl, alkoxy, alkoxyalkyl, alkylamino, amino-alkyl, alkyl-amino-carbonyl, heterocyclyl, heteroaryl, -heteroarylalkyl- and-NR5R6; R3 is selected from hydrogen and alkyl; R4 is selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl used in defining R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, alkyl-carbonyl, cyano, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxycarbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, and -NR5R6; and n is selected from 0, 1, 2, 3, 4 and 5; or R3 and R4 together with the nitrogen atom to which they are attached may form a group selected from heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms; wherein said heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms used in defining R3 and R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, cyano, nitro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxy-carbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, aryl-C1-6alkyl and -NR5R6, wherein each of R5 and R6 is independently selected from hydrogen, C1-6alkyl, C2- 6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyC1-6 alkyl, alkoxy, C3-6cycloalkyl, C3-6cycloalkyl-C1-6alkyl, C1-6alkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-C1-6alkyl; wherein said C1-6alkyl, C2-6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyC1-6 alkyl, alkoxy, C3-6cycloalkyl, C3- 6cycloalkyl-C1-6alkyl, C1-6alkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-C1-6alkyl used in defining R5 and R6 are optionally substituted by one or more groups selected from halogen, C1-6 alkoxy, C1-6 alkyl and hydroxy. It will be understood that when compounds of the present invention contain one or more chiral centers, the compounds of the invention may exist in, and be isolated as, enantiomeric or diastereomeric forms, or as a racemic mixture. The present invention includes any possible enantiomers, diastereomers, racemates or mixtures thereof, of a compound of Formula I, IA, IB or IC. The optically active forms of the compound of the invention may be prepared, for example, by chiral chromatographic separation of a racemate, by synthesis from optically active starting materials or by asymmetric synthesis based on the procedures described thereafter. It will also be appreciated that certain compounds of the present invention may exist as geometrical isomers, for example E and Z isomers of alkenes. The present invention includes any geometrical isomer of a compound of Formula I, IA, IB or IC. It will further be understood that the present invention encompasses tautomers of the compounds of the Formula I, IA, IB or IC. It will also be understood that certain compounds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms. It will further be understood that the present invention encompasses all such solvated forms of the compounds of the Formula I, IA, IB or IC. Within the scope of the invention are also salts of the compounds of the Formula I, IA, IB or IC. Generally, pharmaceutically acceptable salts of compounds of the present invention may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound, for example an alkyl amine with a suitable acid, for example, HCl or acetic acid, to afford a physiologically acceptable anion. It may also be possible to make a corresponding alkali metal (such as sodium, potassium, or lithium) or an alkaline earth metal (such as a calcium) salt by treating a compound of the present invention having a suitably acidic proton, such as a carboxylic acid or a phenol with one equivalent of an alkali metal or alkaline earth metal hydroxide or alkoxide (such as the ethoxide or methoxide), or a suitably basic organic amine (such as choline or meglumine) in an aqueous medium, followed by conventional purification techniques. In one embodiment, the compound of Formula I, IA, IB or IC above may be converted to a pharmaceutically acceptable salt or solvate thereof, particularly, an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulphonate orp-toluenesulphonate. We have now found that the compounds of the invention have activity as pharmaceuticals, in particular as modulators or ligands such as agonists, partial agonists, inverse agonist or antagonists of CBi receptors. More particularly, the compounds of the invention exhibit activity as agonist of the CBi receptors and are useful in therapy, especially for relief of various pain conditions such as chronic pain, neuropathic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain etc. This list should however not be interpreted as exhaustive. Additionally, compounds of the present invention are useful in other disease states in which dysfunction of CBi receptors is present or implicated. Furthermore, the compounds of the invention may be used to treat cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, anxiety disorders, gastrointestinal disorders and cardiovascular disorders. Compounds of the invention are useful as immunomodulators, especially for autoimmune diseases, such as arthritis, for skin grafts, organ transplants and similar surgical needs, for collagen diseases, various allergies, for use as anti-tumour agents and anti viral agents. Compounds of the invention are useful in disease states where degeneration or dysfunction of cannabinoid receptors is present or implicated in that paradigm. This may involve the use of isotopically labelled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET). Compounds of the invention are useful for the treatment of diarrhoea, depression, anxiety and stress-related disorders such as post-traumatic stress disorders, panic disorder, generalized anxiety disorder, social phobia, and obsessive compulsive disorder, urinary incontinence, premature ejaculation, various mental illnesses, cough, lung oedema, various gastrointestinal disorders, e.g. gastroesophageal reflux disease, constipation, functional gastrointestinal disorders such as Irritable Bowel Syndrome and Functional Dyspepsia, Parkinson's disease and other motor disorders, traumatic brain injury, stroke, cardioprotection following miocardial infarction, spinal injury and drug addiction, including the treatment of alcohol, nicotine, opioid and other drug abuse and for disorders of the sympathetic nervous system for example hypertension. Compounds of the invention are useful as an analgesic agent for use during general anaesthesia and monitored anaesthesia care. Combinations of agents with different properties are often used to achieve a balance of effects needed to maintain the anaesthetic state (e.g. amnesia, analgesia, muscle relaxation and sedation). Included in this combination are inhaled anaesthetics, hypnotics, anxiolytics, neuromuscular blockers and opioids. In another aspect of the invention is the use of a compound according to Formula I, IA, IB or IC for inhibition of transient lower esophageal sphincter relaxations (TLESRs) and thus for treatment or prevention of gastroesophageal reflux disorder (GERD). The major mechanism behind reflux has been considered to depend on a hypotonic lower esophageal sphincter. However, e.g. Holloway & Dent (1990) Gastroenterol. Clin. N. Amer. 19, pp. 517-535, has shown that most reflux episodes occur during transient lower esophageal sphincter relaxations (TLESRs), i.e. relaxations not triggered by swallows. In further embodiments, the compounds according to the present invention are useful for the prevention of reflux, treatment or prevention of regurgitation, treatment or prevention of asthma, treatment or prevention of laryngitis, treatment or prevention of lung disease and for the management of failure to thrive.
A further aspect of the invention is the use of a compound according to Formula I, IA, IB or IC, for the manufacture of a medicament for the inhibition of transient lower esophageal sphincter relaxations, for the treatment or prevention of GERD, for the prevention of reflux, for the treatment or prevention of regurgitation, treatment or prevention of asthma, treatment or prevention of laryngitis, treatment or prevention of lung disease and for the management of failure to thrive. Another aspect of the invention is the use of a compound according to Formula I, IA, IB or IC for the manufacture of a medicament for the treatment or prevention of functional gastrointestinal disorders, such as functional dyspepsia (FD). Yet another aspect of the invention is the use of a compound according to Formula I, I A, IB or IC for the manufacture of a medicament for the treatment or prevention of irritable bowel syndrome (IBS), such as constipation predominant IBS, diarrhea predominant IBS or alternating bowel movement predominant LBS. Exemplary irritable bowel syndrome (IBS) and functional gastrointestinal disorders, such as functional dyspepsia, are illustrated in Thompson WG, Longstreth GF, Drossman DA, Heaton KW, Irvine EJ, Mueller-Lissner SA. C. Functional Bowel Disorders and Functional Abdominal Pain. In: Drossman DA, Talley NJ, Thompson WG, Whitehead WE, Coraziarri E, eds. Rome II: Functional Gastrointestinal Disorders: Diagnosis, Pathophysiology and Treatment. 2 ed. McLean, VA: Degnon Associates, Inc.; 2000:351-432 and Drossman DA, Corazziari E, Talley NJ, Thompson WG and Whitehead WE. Rome II: A multinational consensus document on Functional Gastrointestinal Disorders. Gut 45(Suρρl.2), 111-1181.9-1-1999. Also within the scope of the invention is the use of any of the compounds according to the Formula I, IA, IB or IC above, for the manufacture of a medicament for the treatment of any of the conditions discussed above. A further aspect of the invention is a method for the treatment of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the Formula I, IA, IB or IC above, is administered to a patient in need of such treatment. Thus, the invention provides a compound of Formula I, IA, IB or IC, or pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined for use in therapy. In a further aspect, the present invention provides the use of a compound of Formula I, IA, IB or IC, or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy. In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The term "therapeutic" and "therapeutically" should be contrued accordingly. The term "therapy" within the context of the present invention further encompasses to administer an effective amount of a compound of the present invention, to mitigate either a pre-existing disease state, acute or chronic, or a recurring condition. This definition also encompasses prophylactic therapies for prevention of recurring conditions and continued therapy for chronic disorders. The compounds of the present invention are useful in therapy, especially for the therapy of various pain conditions including, but not limited to: acute pain, chronic pain, neuropathic pain, back pain, cancer pain, and visceral pain. In use for therapy in a warm-blooded animal such as a human, the compound of the invention may be administered in the form of a conventional pharmaceutical composition by any route including orally, intramuscularly, subcutaneously, topically, intranasally, inrraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints. In one embodiment of the invention, the route of administration may be oral, intravenous or intramuscular. The dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen and dosage level at the most appropriate for a particular patient. For preparing pharmaceutical compositions from the compounds of this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or table disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided compound of the invention, or the active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. For preparing suppository compositions, a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture in then poured into convenient sized moulds and allowed to cool and solidify. Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like. The term composition is also intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it. Similarly, cachets are included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration. Liquid form compositions include solutions, suspensions, and emulsions. For example, sterile water or water propylene glycol solutions of the active compounds may be liquid preparations suitable for parenteral administration. Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art. Depending on the mode of administration, the pharmaceutical composition will preferably include from 0.05% to 99%w (per cent by weight), more preferably from 0.10 to 50%w, of the compound of the invention, all percentages by weight being based on total composition. A therapeutically effective amount for the practice of the present invention may be determined, by the use of known criteria including the age, weight and response of the individual patient, and interpreted within the context of the disease which is being treated or which is being prevented, by one of ordinary skills in the art. Within the scope of the invention is the use of any compound of Formula I, I A, IB or IC as defined above for the manufacture of a medicament. Also within the scope of the invention is the use of any compound of Formula I, I A, IB or IC for the manufacture of a medicament for the therapy of pain. Additionally provided is the use of any compound according to Formula I, IA, IB or IC for the manufacture of a medicament for the therapy of various pain conditions including, but not limited to: acute pain, chronic pain, neuropathic pain, back pain, cancer pain, and visceral pain. A further aspect of the invention is a method for therapy of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the Formula I, IA, IB or IC above, is administered to a patient in need of such therapy. Additionally, there is provided a pharmaceutical composition comprising a compound of Formula I, IA, IB or IC, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier. Particularly, there is provided a pharmaceutical composition comprising a compound of Formula I, I A, LB or IC, or a phaπnaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier for therapy, more particularly for therapy of pain. Further, there is provided a pharmaceutical composition comprising a compound of Formula I, IA, IB or IC, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier use in any of the conditions discussed above. Another aspect of the invention is a method of preparing the compounds of the present invention. One embodiment of the invention provides a method for preparing a compound of formula I,
Figure imgf000040_0001
I comprising the step of reacting a compound of formula II,
Figure imgf000040_0002
II with a compound of R3(CH )nR4NH, in the presence of a base, such as an DIPEA, a solvent such as DMF, wherein A1, A2, A3, A4, R2, R3, R4 and n are as defined above. Another embodiment of the invention provides a method for preparing a compound of formula IA,
Figure imgf000040_0003
IA comprising the step of reacting a compound of formula IIA,
Figure imgf000041_0001
IIA with a compound of R3(CH2)nR NH, in the presence of a base, such as an DIPEA, a solvent such as DMF, wherein A , A , A , R , R , R and n are as defined above.
Another embodiment of the invention provides a method for preparing a compound of formula IB,
Figure imgf000041_0002
IB comprising the step of reacting a compound of foπnula IIB,
Figure imgf000041_0003
IIB with a compound of R3(CH2)nR4NH, in the presence of a base, such as an DIPEA, a solvent such as DMF, wherein A, R , R , R and n are as defined above. Compounds of the present invention may also be prepared according to the synthetic routes as depicted in Schemes 1-5. Scheme 1. A synthetic route used for the synthesis of examples
Figure imgf000042_0001
Scheme 2. A synthetic route used for the synthesis of examples
Figure imgf000042_0002
when Y=OH base, e.g. DIPEA solvent, e.g. DMF coupling reagent, e.g. HATU
Figure imgf000042_0003
Scheme 3. A synthetic route used for the synthesis of examples
1. ArCOY
Figure imgf000043_0001
R3(CH2)nR4NH solvent, e.g. DMF
Figure imgf000043_0002
Scheme 4. A synthetic route used for the synthesis of examples
Figure imgf000044_0001
NHR5R6 NBS or R5OH or ArB(OH)2
Figure imgf000044_0002
NHR5R6 R3(CH2)nR4NH or R5OH or ArB(OH)2 solvent, e.g. DMF
Figure imgf000044_0003
A = N or CR1; B = NR5R6, OR5, or Ar Scheme 5. A synthetic route used for the synthesis of examples
Figure imgf000045_0001
base, e.g. DIPEA solvent, e.g. CH2CI2
Figure imgf000045_0002
A = N or CR1; B = OR5 or NR5R6
Biological Evaluation hCBi and hCB2 receptor binding Human CBi receptor from Receptor Biology (hCBi) or human CB2 receptor from BioSignal (hCB2) membranes are thawed at 37 °C, passed 3 times through a 25-gauge blunt-end needle, diluted in the cannabinoid binding buffer (50 mM Tris, 2.5 mM EDTA, 5 mM MgCl2, and 0.5 mg/mL BSA fatty acid free, pH 7.4) and aliquots containing the appropriate amount of protein are distributed in 96-well plates. The IC5o of the compounds of the invention at hCBi and hCB2 are evaluated from 10-point dose-response curves done with 3H-CP55,940 at 20000 to 25000 dpm per well (0.17-0.21 nM) in a final volume of 300 μl. The total and non-specific binding are determined in the absence and presence of 0.2 μM of HU210 respectively. The plates are vortexed and incubated for 60 minutes at room temperature, filtered through Unifilters GF/B (presoaked in 0.1% polyethyleneimine) with the Tomtec or Packard harvester using 3 mL of wash buffer (50 mM Tris, 5 mM MgCl2, 0.5 mg BSA pH 7.0). The filters are dried for 1 hour at 55 °C. The radioactivity (cpm) is counted in a TopCount (Packard) after adding 65 μl/well of MS-20 scintillation liquid.
hCBi and hCB? GTPγS binding Human CBi receptor from Receptor Biology (hCBi) or human CB2 receptor membranes (BioSignal) are thawed at 37 °C, passed 3 times through a 25-gauge blunt-end needle and diluted in the GTPγS binding buffer (50 mM Hepes, 20 mM NaOH, 100 mM NaCl, 1 mM EDTA, 5 mM MgCl2, pH 7.4, 0.1% BSA). The EC50 and Emax of the compounds of the invention are evaluated from 10-point dose-response curves done in 300μl with the appropriate amount of membrane protein and 100000-130000 dpm of GTPg35S per well (0.11 -0.14 nM). The basal and maximal stimulated binding is determined in absence and presence of 1 μM (hCB2) or 10 μM (hCBi;) Win 55,212-2 respectively. The membranes are pre-incubated for 5 minutes with 56.25 μM (hCB2) or 112.5 μM (hCBi) GDP prior to distribution in plates (15 μM (hCB2) or 30 μM (hCBi) GDP final). The plates are vortexed and incubated for 60 minutes at room temperature, filtered on Unifilters GF/B (presoaked in water) with the Tomtec or Packard harvester using 3 ml of wash buffer (50 mM Tris, 5 mM MgCl2, 50 mM NaCl, pH 7.0). The filters are dried for 1 hour at 55 °C. The radioactivity (cpm) is counted in a TopCount (Packard) after adding 65 μl/well of MS-20 scintillation liquid. Antagonist reversal studies are done in the same way except that (a) an agonist dose-response curve is done in the presence of a constant concentration of antagonist, or (b) an antagonist dose-response curve is done in the presence of a constant concentration of agonist. Based on the above assays, the dissociation constant (Ki) for a particular compound of the invention towards a particular receptor is determined using the following equation: Ki = IC50/(l+[rad]/Kd), Wherein IC50 is the concentration of the compound of the invention at which 50% displacement has been observed; [rad] is a standard or reference radioactive ligand concentration at that moment; and Kd is the dissociation constant of the radioactive ligand towards the particular receptor. Using the above-mentioned assays, the Ki towards human CBi receptors for certain compounds of the invention is measured to be in the range of 0.2-5000 nM. The Ki towards human CB2 receptors for certain compounds of the invention is measured to be in the range of about 4.5-4970 nM. The EC5o towards human CBi receptors for certain compounds of the invention is measured to be in the range of about 1.5-2220 nM. The Emax towards human CBi receptors for certain compounds of the invention is measured to be in the range of about 20 -130 %. The following table shows certain biological activities for some of the exemplified compounds.
Figure imgf000047_0001
EXAMPLES
The invention will further be described in more detail by the following Examples which describe methods whereby compounds of the present invention may be prepared, purified, analyzed and biologically tested, and which are not to be construed as limiting the invention.
Example 1 iV-(Cyclobutylmethyl)-3-[(l-naphthalenylcarbonyl)amino]-2-pyridinecarboxamide
Figure imgf000048_0001
Step A. N-(Cyclobutylmethyl)-3-[(l-naphthalenylcarbonyl)amino]-2- pyridinecarboxamide
Figure imgf000048_0002
A solution of 2-(l-naphthalenyl)-H-pyrido[3,2-< ][l,3]oxazin-4-one (100 mg, 0.365 mmol, see Step B for its preparation) in DMF (2 mL) was treated with cyclobutane methylamine (0.1 mL, 5.3 Min MeOΗ, 0.53 mmol) at 0 °C. The mixture was stirred for 18 h at room temperature. After evaporation of the solvents, the residue was purified by MPLC using Ηex/EtOAc (9:1) to provide the title compound (156 mg, 83%). 1H NMR (400 MHz, CDC13) δ 1.69-1.78 (m, 2 H), 1.81-1.91 (m, 2 H), 1.99-2.07 (m, 2 H), 2.51-2.62 (m, 1 H), 3.34 (d, J=7.03 Hz, 2 H), 7.52-7.59 (m, 4 H), 7.87-7.89 (m, 1 H), 7.92-7.96 (m, 1 H), 8.03- 8.05 (m, 1 H), 8.30-8.35 (m, 1 H), 8.42-8.45 (m, 1 H), 9.27 (dd, J=8.59, 1.17 Hz, 1 H). MS (ESI) (M+H)+ 360.0. Anal. (C, H, N) calcd for C22H21N3O2+0.30CH3OH: C 72.58, H 6.06, N 11.39; found C 72.58, H 5.86, N 11.30.
Step B. 2-(l-naphthalenyl)-flr-pyrido[3,2-< |[l,3]oxazin-4-one
Figure imgf000049_0001
1-Naphthalenecarbonyl chloride (400 mg, 2.1 mmol) in CH2C12 (2 mL) was added into a solution of 3-amino-2-pyridinecarboxylic acid (277 mg, 2.0 mmol) and DIPEA (284 mg, 2.2 mmol) in DMF (10 mL) at 0 °C. The reaction mixture was allowed to stir overnight at room temperature, and was then treated with DIPEA (284 mg, 2.2 mmol) and HATU (837 g, 2.2 mmol). After stirring for 1 h at room temperature, the reaction mixture was heated at 50 °C to provide the title compound which was used in Step A. MS (ESI) (M+H)+ 274.79.
Example 2 iV-[2-(4-MorphoUnyl)ethyl]-3-[(l-naphthalenylcarbonyl)amino]-2- pyridinecarboxamide
Figure imgf000049_0002
Following the procedure for Step A in Example 1, using DIPEA (0.67 mL, 3.8 mmol), 2- (l-naphthalenyl)-4H-pyrido[3,2-t ][l,3]oxazin-4-one (100 mg, 0.36 mmol), and 4- morpholineethanamine (0.15 mL, 1.17 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (68 mg, 47 %). 1H NMR (400 MHz, CDC13) δ 2.47-2.54 (m, 4 H), 2.60 (t, J=6.15 Hz, 2 H), 3.46-3.55 (m, 2 H), 3.73-3.75 (m, 4 H), 7.51- 7.60 (m, 4 H), 7.89-7.92 (m, 2 H), 7.97-7.99 (m, 1 H), 8.31 (dd, J=4.39, 1.51 Hz, 1 H), 8.53-8.55 (m, 1 H), 8.72-8.78 (m, 1 H), 9.41 (dd, J=8.59, 1.51 Hz, 1 H), 12.80-12.86 (br s, 1 H); MS (ESI) (M+H)+ 405.0; Anal. Calcd for C23H24N4O3 + 0.2 CH3CN + 0.6 CF3CO2H + 0.7 H2O: C, 59.85; H, 5.43; N, 11.92. Found: C, 59.75; H, 5.35; N, 11.90.
Example 3 iV-4-morpholinyl-3-[(l-naphthalenylcarbonyl)amino]-2-pyridinecarboxamide
Figure imgf000050_0001
Following the procedure for Step A in Example 1, using DIPEA (0.67 mL, 3.8 mmol), 2- (l-naphthalenyl)-4H-pyrido[3,2- ][l,3]oxazin-4-one (100 mg, 0.36 mmol), and 4- morpholine amine (0.12 mL, 1.17 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (37 mg, 21 %). 1H NMR (400 MHz, CD3OD) δ 2.87- 2.89 (m, 4 H), 3.74-3.77 (m, 4 H), 7.54-7.64 (m, 4 H), 7.90-7.92 (m, 1 H), 7.95-7.97 (m, 1 H), 8.05-8.07 (m, 1 H), 8.37 (dd, J= .49, 1.37 Hz, 1 H), 8.42-8.44 (m, 1 H), 9.28 (dd, J=8.59, 1.37 Hz, 1 H), 12.65 (br s, 1 H); MS (ESI) (M+H)+ 377.0; Anal. Calcd for C21H20N4O3 + 0.2 H2O: C, 66.37; H, 5.41; N, 14.74. Found: C, 66.46; H, 5.35; N, 14.63.
Example 4
3- [(l-Naphthalenylcarbonyl)amino] -N- [(tetrahy dro~2H-pyran-4-yl)methyl] -2- pyridinecarb oxamide
Figure imgf000050_0002
Following the procedure for Step A in Example 1, using 2-(l-naphthalenyl)-4H- ρyrido[3,2-d][l,3]oxazin-4-one (122 mg, 0.446 mmol) and tetrahydro-2H-pyran-4- methanamine (62 mg, 0.535 mmol) provided the title compound (139 mg, 90 %). 1Η MR (400 MHz, CDC13) δ 0.98 (m, 2H), 1.23 (m, 3H), 1.56 (m, IH), 1.76 (m, 5H), 3.25 (t, J = 6.4 Hz, 2H), 7.54 (m, 4H), 7.90 (m, 2H), 7.98 (d, J = 8.0 Hz, IH), 8.28 (dd, J = 8.4, 1.6 Hz, IH), 8.53 (m, 2H), 9.41 (dd, J = 8.4, 0.8 Hz, IH), 12.87 (s, IH); MS (ESI) (M+H)+ = 390.2; Anal. Calcd for C23H23N3O3: C, 70.93; H, 5.95; N, 10.79. Found: C, 70.82; H, 5.92; N, 10.64.
Example 5 iV-CycIohexyl-3-[(l-naphthalenylcarbonyl)amino]-2-pyridinecarboxamide
Figure imgf000051_0001
Following the procedure for Step A in Example 1, using DIPEA (1.02 mL, 5.8 mmol), 2- (l-naphthalenyl)-4H-pyrido[3,2-( |[l,3]oxazin-4-one (150 mg, 0.55 mmol), and cyclohexylamine (0.19 mL, 1.65 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (68 mg, 33 %). 1H NMR (400 MHz, CD3OD) δ 1.18- 1.43 (m, 5 H), 1.59-1.66 (m, 1 H), 1.74-1.90 (m, 4 H), 3.74-3.81 (m, 1 H), 7.54-7.61 (m, 4 H), 7.89-7.91 (m, 1 H), 7.94-7.97 (m, 1 H), 8.05-8.07 (m, 1 H), 8.35 (dd, J=4.49, 1.46 Hz, 1 H), 8.43-8.45 (m, 1 H), 9.29 (dd, J=8.59, 1.46 Hz, 1 H); MS (ESI) (M+H)+ 374.0; Anal. Calcd for C23H23N3O2: C, 73.97; H, 6.21; N, 11.25. Found: C, 74.14; H, 6.30; N, 11.33.
Example 6 N-(3-Methylcyclohexyl)-3-[(l-naphthalenylcarbonyl)amino]-2-pyridinecarboxamide
Figure imgf000052_0001
Following the procedure for Step A in Example 1, using 2-(l-naphthalenyl)-4H- pyrido[3,2-d][l,3]oxazin-4-one (100 mg, 0.36 mmol), and 3-methylcyclohexylamine (0.3 mL, 2.2 mmol) provided the title compound as its TFA salt after purification by reversed- phase ΗPLC (24 mg, 13 %). 1H NMR (400 MHz, CD3OD) δ 0.82-1.04 (m, 5 H), 1.19-1.79 (m, 6 H), 1.87-1.92 (m, 1 H), 3.74-3.81 (m, 1 H), 7.54-7.63 (m, 4 H), 7.91 (dd, J-7.03, 1.17 Hz, 1 H), 7.94-7.98 (m, 1 H), 8.05-8.08 (m, 1 H), 8.34-8.37 (m, 1 H), 8.43-8.45 (m, 1 H), 9.27-9.31 (m, 1 H); MS (ESI) (M+H)+ 388.0; Anal. Calcd for C24H25N3O2 + 0.2 CH3OH + 0.1 H2O: C, 73.46; H, 6.62; N, 10.62. Found: C, 73.47; H, 6.46; N, 10.48.
Example 7 7Λr-Cyclobutyl-3-[(l-naphthalenylcarbonyl)amino]-2-pyridinecarboxamide
Figure imgf000052_0002
Following the procedure for Step A in Example 1, using 2-(l-naphthalenyl)-4H- pyrido[3,2-i/][l,3]oxazin-4-one (100 mg, 0.36 mmol), and cyclobutylamine (0.2 mL, 2.16 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (20 mg, 12 %). 1H NMR (400 MHz, CD3OD) δ 1.71-1.80 (m, 2 H), 2.07-2.18 (m, 2 H), 2.27-2.34 (m, 2 H), 4.38-4.47 (m, 1 H), 7.54-7.63 (m, 4 H), 7.89-7.91 (m, 1 H), 7.94- 7.98 (m, 1 H), 8.06-8.08 (m, 1 H), 8.38 (dd, J=4.49, 1.32 Hz, 1 H), 8.42-8.44 (m, 1 H), 9.29 (dd, J=8.49, 1.32 Hz, 1 H); MS (ESI) (M+H)+ 346.0; Anal. Calcd for C2iH19N3O2 + 0.1 H2O: C, 72.65; H, 5.57; N, 12.10. Found: C, 72.63; H, 5.65; N, 12.02. Example 8 N-(Cyclohexylmethyl)-3-[(l-naphthalenylcarbonyl)amino]-2-pyridinecarboxamide
Figure imgf000053_0001
Following the procedure for Step A in Example 1, using 2-(l-naphthalenyl)-4H- pyrido[3,2-rf][l,3]oxazin-4-one (129 mg, 0.47 mmol), and cyclohexanemethylamine (261 mg, 2.3 mmol) provided the title compound (172 mg, 95 %). 1H NMR (400 MHz, CD3OD) δ 0.90-1.00 (m, 2 H), 1.13-1.28 (m, 3 H), 1.52-1.75 (m, 6 H), 3.16 (d, J=6.83 Hz, 2 H), 7.55-7.61 (m, 4 H), 7.88-7.90 (m, 1 H), 7.94-7.96 (m, 1 H), 8.05-8.07 (m, 1 H), 8.36 (dd, J=4.49, 1.56 Hz, 1 H), 8.41-8.43 (m, 1 H), 9.29 (dd, J=8.59, 1.37 Hz, 1 H). MS (ESI) (M+H)+ = 388.0
Example 9
3-[(l-Naphthalenylcarbonyl)amino]-iV-(tetrahydro-2H-pyran-4-yl)-2- pyridinecarboxamide
Figure imgf000053_0002
Following the procedure for Step A in Example 1, using DIPEA (0.2 mL, 1.08 mmol), 2- (l-naphthalenyl)-4H-pyrido[3,2-^[l,3]oxazin-4-one (100 mg, 0.36 mmol), and 4- tetrahydropyranamine (109 mg, 1.08 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (33 mg, 18 %). 1H NMR (400 MHz, CD3OD) δ 1.63-1.73 (m, 2 H), 1.81-1.88 (m, 2 H), 3.44-3.50 (m, 2 H), 3.90-3.96 (m, 2 H), 3.98-4.07 (m, 1 H), 7.56-7.62 (m, 3 H), 7.88-7.90 (m, 1 H), 7.93-7.97 (m, 1 H), 8.05-8.07 (m, 1 H), 8.36 (dd, J-4.49, 1.17 Hz, 1 H), 8.40-8.45 (m, 1 H), 9.28 (dd, J=8.59, 1.17 Hz, 1 H); MS (ESI) (M+H)+ 376.3; Anal. Calcd for C22H2ιN3O3 + 0.2 CH3OH: C, 69.83; H, 5.75; N, 11.00. Found: C, 69.87; H, 5.57; N, 10.93.
Example 10
3-[(l-Naphthalenylcarbonyl)amino]-iV-[2-(l-piperidinyl)ethyl]-2- pyridinecarboxamide
Figure imgf000054_0001
Following the procedure for Step A in Example 1, using DIPEA (0.4 mL, 2.2 mmol), 2-(l- naphthalenyl)-4H-pyrido[3,2-^[l,3]oxazin-4-one (200 mg, 0.73 mmol), and l-(2- aminoethyl)piperidine (0.32 mL, 2.2 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (122 mg, 38 %). 1H NMR (400 MHz, CDC13) δ 1.22-1.85 (m, 7 H), 2.81-2.96 (m, 2 H), 3.53-3.78 (m, 5 H), 7.49-7.66 (m, 4 H), 7.86-7.94 (m, 2 H), 8.04 (d, J=7.22 Hz, 1 H), 8.34-8.41 (m, 2 H), 9.20 (d, J=7.62 Hz, 1 H); MS (ESI) (M+H)+ 403.3.
Example 11 iV-(2-Hydroxypropyl)-3-[(l-naphthalenylcarbonyl)amino]-2-pyridinecarboxamide
Figure imgf000054_0002
Following the procedure for Step A in Example 1, using DIPEA (0.1 mL, 1.1 mmol), 2-(l- naphthalenyl)-4H-pyrido[3,2-d][l,3]oxazin-4-one (100 mg, 0.36 mmol), and l-amino-2- propanol (0.2 mL, 2.2 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (78 mg, 47 %). 1H NMR (400 MHz, CD3OD) δ 1.14 (d, J=6.25 Hz, 3 H), 3.23 (dd, J=13.57, 7.32 Hz, 1 H), 3.40 (dd, J=13.57, 4.20 Hz, 1 H), 3.86-3.92 (m, 1 H), 7.52-7.61 (m, 4 H), 7.89 (dd, J=7.03, 1.17 Hz, 1 H), 7.92-7.96 (m, 1 H), 8.05 (d, J=8.40 Hz, 1 H), 8.35 (dd, J=4.49, 1.56 Hz, 1 H), 8.41-8.43 (m, 1 H), 9.28 (dd, J=8.59, 1.56 Hz, 1 H), 12.90 (d, J=9.96 Hz, 1 H); MS (ESI) (M+H)+ 350.3; Anal. Calcd for C20H19N3O3 + 0.1 CF3COOH: C, 67.25; H, 5.34; N, 11.65. Found: C, 67.39; H, 5.45; N, 11.52.
Example 12 N-(2-Hydroxybutyl)-3-[(l-naphthalenylcarbonyl)amino]-2-pyridinecarboxamide
Figure imgf000055_0001
Following the procedure for Step A in Example 1, using DIPEA (0.1 mL, 1.1 mmol), 2-(l- naphthalenyl)-4H-pyrido[3,2- ][l,3]oxazin-4-one (100 mg, 0.36 mmol), and l-amino-2- butanol (96 mg, 1.1 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (38 mg, 22 %). 1H NMR (400 MHz, CD3OD) δ 0.93 (t, J=7.42 Hz, 3 H), 1.38-1.53 (m, 2 H), 3.22 (dd, J=13.67, 7.62 Hz, 1 H), 3.46 (dd, J=13.67, 3.91 Hz, 1 H), 3.58-3.64 (m, 1 H), 7.52-7.61 (m, 4 H), 7.88 (dd, J=7.03, 1.17 Hz, 1 H), 7.92-7.95 (m, 1 H), 8.04-8.06 (m, 1 H), 8.35 (dd, J=4.49, 1.56 Hz, 1 H), 8.40-8.43 (m, 1 H), 9.28 (dd, J=8.59, 1.56 Hz, 1 H); MS (ESI) (M+H)+ 364.2; Anal. Calcd for C2ιH21N3O3 + 0.4 CF3COOH + 0.1 H2O: C, 63.73; H, 5.30; N, 10.23. Found: C, 63.75; H, 5.25; N, 9.99.
Example 13 iV-(Cyclopentylmethyl)-3-[(l-naphthalenylcarbonyl)amino]-2-pyridinecarboxamide
Figure imgf000056_0001
Following the procedure for Step A in Example 1, using DIPEA (0.2 mL, 1.1 mmol), 2-(l- naphthalenyl)-4H-pyrido[3,2-cT|[l,3]oxazin-4-one (100 mg, 0.36 mmol), and cyclopentanemethylamine (0.33 mL, 1.1 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (52 mg, 29 %). 1H NMR (400 MHz, CD3OD) δ 1.16-1.24 (m, 2 H), 1.45-1.63 (m, 4 H), 1.66-1.74 (m, 2 H), 2.05-2.17 (m, 1 H), 3.20-3.23 (m, 2 H), 7.49-7.56 (m, 4 H), 7.86 (dd, J=7.03, 0.98 Hz, 1 H), 7.89-7.93 (m, 1 H), 8.00-8.02 (m, 1 H), 8.29 (dd, J=4.49, 1.46 Hz, 1 H), 8.40-8.44 (m, 1 H), 9.01-9.07 (m, 1 H), 9.23 (dd, J-8.59, 1.46 Hz, 1 H), 12.89-12.93 (br.s, 1 H); MS (ESI) (M+H)+ 374.2; Anal. Calcd for C23H23N3O2+ 0.2 H2O: C, 73.27; H, 6.26; N, 11.14. Found: C, 74.10; H, 6.19; N, 11.08.
Example 14 3-[(l-Naphthalenylcarbonyl)amino]-iV-(2-piperidinylmethyl)-2-pyridinecarboxamide
Figure imgf000056_0002
Following the procedure for Step A in Example 1, using 2-(l-naphthalenyl)-4H- pyrido[3,2-d][l,3]oxazin-4-one (100 mg, 0.36 mmol), and 2-(aminomethyl)piperidine (250 mg, 2.2 mmol) provided the title compound as its TFA salt after purification by reversed- phase ΗPLC (14 mg, 8 %). 1H NMR (400 MHz, CD3OD) δ 1.43-1.64 (m, 3 H), 1.73-1.95 (m, 3 H), 2.80-2.86 (m, 1 H), 3.20-3.22 (m, 2 H), 3.48-3.67 (m, 2 H), 7.53-7.58 (m, 3 H), 7.63 (dd, J=8.59, 4.49 Hz, 1 H), 7.88 (dd, J=7.23, 1.17 Hz, 1 H), 7.93-7.97 (m, 1 H), 8.04- 8.06 (m, 1 H), 8.39 (dd, J=4.49, 1.37 Hz, 1 H), 8.40-8.43 (d, 1 H), 9.27 (dd, J=8.59, 1.37 Hz, 1 H); MS (ESI) (M+H)+ 389.2.
Example 15
N-(2,2-Dimethylpropyl)-3-(l-naphthoylamino)pyridine-2-carboxamide
Figure imgf000057_0001
Following the procedure for Step A in Example 1, using 2-(l-naphthalenyl)-4H- pyrido[3,2-ι ][l,3]oxazin-4-one (100 mg, 0.36 mmol), and (2,2-dimethylpropyl)amine (174 mg, 2.0 mmol) provided the title compound as its TFA salt after purification by reversed- phase ΗPLC (49 mg, 29 %). 1HNMR (400 MHz, CD3OD) δ 0.95 (s, 9H), 3.18 (s, 2H), 7.58 (m, 4H), 7.90 (d, J - 7.2 Hz, IH), 7.97 (m, IH), 8.07 (d, J = 8.4 Hz, IH), 8.39 (m, IH), 8.44 (m, IH), 9.31 (d, J = 8.8 Hz, IH); MS (ESI) (M+H)+ 362.0.
Example 16 iV-(2-Methoxy-l-methylethyl)-3-(l-naphthoylamino)pyridine-2-carboxamide
Figure imgf000057_0002
Following the procedure for Step A in Example 1, using 2-(l-naphthalenyl)-4H- pyrido[3,2-cT][l,3]oxazin-4-one (100 mg, 0.36 mmol), and (2-methoxy-l- methylethyl)amine (178 mg, 2.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (56 mg, 33 %). 1H NMR (400 MHz, CDC13) δ 1.28 (d, J = 6.8 Hz, 3H), 3.39 (s, 3H), 3.45 (m, 2H), 4.24 (m, IH), 7.54 (m, 4H), 7.89 (m, 2H), 7.98 (d, J = 8.4 Hz, IH), 8.29 (m, IH), 8.53 (m, 2H), 9.40 (dd, J = 8.4, 1.2 Hz, IH), 12.84 (s, IH); MS (ESI) (M+H)+ 364.0.
Example 17 Λ'-[(l-Hydroxycyclohexyl)methyl]-3-(l-naphthoylamino)pyridine-2-carboxamide
Figure imgf000058_0001
Following the procedure for Step A in Example 1, using DIPEA (129 mg, 1.0 mmol), 2-(l- naphthalenyl)-4H-pyrido[3,2- ][l,3]oxazin-4-one (100 mg, 0.36 mmol), and 1- (aminomethyl)cyclohexanol (129 mg, 1.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (29 mg, 16 %).1H NMR (400 MHz, CD3OD) δ 1.13 - 1.30 (m, 1 H), 1.37 (d, J=10.15 Hz, 9 H), 3.28 (s, 2 H), 7.39 - 7.61 (m, 4 H), 7.78 - 7.85 (m, 1 H), 7.85 - 7.93 (m, 1 H), 7.98 (d, J=8.20 Hz, 1 H), 8.29 (dd, J=4.49, 1.37 Hz, 1 H), 8.32 - 8.39 (m, 1 H), 9.22 (dd, J-8.59, 1.37 Hz, 1 H); MS (ESI) (M+H)+ 404.0.
Example 18
N-(Cyclobutylmethyl)-3-[[(4-methyl-l-naphthalenyl)carbonyl]amino]-2- pyridinecarboxamide
Figure imgf000058_0002
Step A. N-(Cyclobutylmethyl)-3-[[(4-methyl-l-naphthalenyl)carbonyl]amino]-2- pyridinecarboxamide
Figure imgf000059_0001
Following the procedure for Step A in Example 1, using 2-(4-methyl-l-naphthalenyl)-4H- pyrido[3,2-cT][l,3]oxazm-4-one (130 mg, 0.45 mmol, see Step B for its preparation) and cyclobutylmethylamine (0.5 mL, 5.3 Min MeOΗ, 2.5 mmol) provided the title compound (105 mg, 72%). 1H NMR (400 MHz, CD3OD) δ 1.77 (m, 2 H), 1.87 (m, 2 H), 2.05 (m, 2 H), 2.60 (m, 1 H), 2.76 (s, 3 H), 3.37 (d, J=7.03 Hz, 2 H), 7.46 (d, J=7.23 Hz, 1 H), 7.59 (m, 3 H), 7.80 (d, J=7.23 Hz, 1 H), 8.14 (m, 1 H), 8.36 (dd, J=4.49, 1.37 Hz, 1 H), 8.46 (m, 1 H), 9.29 (dd, J=8.59, 1.37 Hz, 1 H). MS (ESI) (M+H)+ = 374.0. Step B. 2-(4-Methyl-l-naphthalenyl)-4JJ-pyrido[3,2-<fl [l,3]oxazin-4-one
Figure imgf000059_0002
Following the procedure for Step B in Example 1, a suspension of 3-amino-2- pyridinecarboxylic acid (414 mg, 3.0 mmol) in CH2C12 (10 mL) and DIPEA (1.25 mL, 7.2 mmol) was treated with 4-methyl-l-naphthalenecarbonyl chloride, prepared from 4- methyl-1-naphthalenecarbonylic acid (590 mg, 3.17 mmol) with thionyl chloride (4.11 g, 35 mmol), and then with HATU (1.25 g, 3.3 mmol) in DMF (10 mL). The title compound was formed and directly used in Step A.
Example 19 3-[[(4-Methyl-l-naphthalenyl)carbonyl]amino]-N-[(tetrahydro-2H-pyran-4- yl)methyl]-2-pyridinecarboxamide
Figure imgf000060_0001
Following the procedure for Step A in Example 1, using 2-(4-methyl-l-naphthalenyl)-4H- pyrido[3,2- ][l,3]oxazin-4-one (108 mg, 0.375 mmol) and tetrahydro-2H-pyran-4- methanamine (122 mg, 1.06 mmol) provided the title compound (75 mg, 49%). 1H NMR (400 MHz, CD3OD) δ 1.26 (dd, J=11.91, 4.49 Hz, 1 H), 1.33 (dd, J= 11.9, 4.5 Hz, 1 H), 1.63 (m, 2 H), 1.85 (m, 1 H), 2.76 (s, 3 H), 3.24 (d, J-7.03 Hz, 2 H), 3.36 (m, 2 H), 3.90 (dd, J=11.03, 3.22 Hz, 2 H), 7.45 (m, 1 H), 7.60 (m, 3 H), 7.79 (d, J=7.23 Hz, 1 H), 8.13 (m, 1 H), 8.36 (dd, J=4.49, 1.37 Hz, 1 H), 8.46 (m, 1 H), 9.28 (dd, J=8.59, 1.37 Hz, 1 H). MS (ESI) (M+H)+ = 404.0. Anal. (C, H, N) calcd for C24H25N3O3+0.1 H2O: C 71.13, H 6.27, N 10.37; found C 71.03, H 6.04, N 10.26.
Example 20 3-[(4-Methyl-l-naphthoyl)amino]-N-(piperidin-2-ylmethyl)pyridine-2-carboxamide
Figure imgf000060_0002
Following the procedure for Step A in Example 1, using 2-(4-methyl-l-naphthyl)-4H- pyrido[3,2-cf][l,3]oxazin-4-one (288 mg, 1.0 mmol) and (piperidin-2-yl-methyl)amine (340 mg, 3.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (195 mg, 38 %). 1H NMR (400 MHz, CD3OD) δ 1.58 (m, 3H), 1.88 (m, 3H), 2.77 (s, 3H), 2.86 (m, IH), 3.29 (m, 2H), 3.58 (m, 2H), 7.43 (d, J=7.6 Hz, 1 H), 7.61 (m, 3 H), 7.80 (d, J=7.6 Hz, 1 H), 8.15 (d, J=8.0 Hz, 1 H), 8.41 (dd, J=4.4, 1.2 Hz, 1 H), 8.46 (dd, J-8.0, 0.8 Hz, 1 H), 9.28 (dd, J=8.8, 0.8 Hz, 1 H); MS (ESI) (M+H)+ 403.3.
Example 21 iV-(Cyclobutylmethyl)-3-[[(4-methoxy-l-naphthalenyl)carbonyl]amino]-2- pyridinecarboxamide
Figure imgf000061_0001
Step A. iV-(Cyclobutylmethyl)-3-[[(4-methoxy-l-naphthalenyl)carbonyl]amino]-2- pyridinecarboxamide
Figure imgf000061_0002
Following the procedure for Step A in Example 1, using 2-(4-methoxy-l-naphthalenyl)- 4H-pyrido[3,2-c ][l,3]oxazin-4-one (120 mg, 0.40 mmol, see Step B for its preparation) and cyclobutylmethylamine (0.5 mL, 5.3 Min MeOΗ, 2.5 mmol) provided the title compound (87 mg, 56 %). 1H NMR (400 MHz, CD3OD) δ 1.77 (m, 2 H), 1.88 (m, 2 H), 2.06 (m, 2 H), 2.61 (m, 1 H), 3.38 (d, J=7.23 Hz, 2 H), 4.08 (s, 3 H), 7.02 (d, J=8.20 Hz, 1 H), 7.56 (m, 3 H), 7.93 (d, J=8.01 Hz, 1 H), 8.32 (m, 2 H), 8.52 (m, 1 H), 9.27 (dd, J=8.59, 1.37 Hz, 1 H). MS (ESI) (M+H)+ = 390.0. Step B. 2-(4-Methoxy-l-naphthalenyl)-4jg-pyrido[3,2-//] [l,3]oxazin-4-one
Figure imgf000062_0001
Following the procedure for Step B in Example 18, using 3-amino-2-pyridinecarboxylic acid (690 mg , 5.0 mmol), DIPEA (780 mg, 6.0 mmol), 4-methoxy-l-naphthalenecarbonyl chloride, prepared from 4-methoxy-l-naphthoic acid (1.0 g, 5.0 mmol) and oxalyl chloride (5 mL, 2.0 M in CH2C12, 10 mmol), and then HATU (2.28 g, 6.0 mmol) provided the title compound which was directly used in Step A.
Example 22
3-[(4-Methoxy-l-naphthoyl)amino]-iV-(tetrahydro-2iϊ-pyran-4-ylmethyl)pyridine-2- carboxamide
Figure imgf000062_0002
Following the procedure for Step A in Example 1, using 2-(4-methoxy-l-naphthyl)-4H- pyrido[3,2-ci][l,3]oxazin-4-one (120 mg, 0.4 mmol), and tetrahydro-2H-pyran-4- methanamine (210 mg, 1.8 mmol) provided the title compound (81 mg, 48 %). !Η NMR (400 MHz, CD3OD) δ 1.31 (m, 2 H), 1.64 (dd, J=13.08, 1.17 Hz, 2 H), 1.87 (m, J=7.62, 3.51 Hz, 1 H), 3.26 (m, J=6.83 Hz, 2 H), 3.36 (m, 2 H), 3.91 (dd, J=11.72, 3.51 Hz, 2 H), 4.08 (s, 3 H), 7.01 (d, J=8.20 Hz, 1 H), 7.56 (m, 3 H), 7.93 (d, J=8.01 Hz, 1 H), 8.33 (m, 2 H), 8.51 (d, J=8.59 Hz, 1 H), 9.26 (m, 1 H). MS (ESI) (M+H)+ = 420.0.
Example 23 iV-(CycIohexylmethyl)-3-[[[4-(dimethylammo)-l-naphthalenyl]carbonyl]amino]-2- pyridinecarboxamide
Figure imgf000063_0001
Step A. N-(Cyclohexylmethyl)-3-[[[4-(dimethylamino)-l- naphthalenyl] carbonyl] amino]-2-pyridinecarboxamide
Figure imgf000063_0002
Following the procedure for Step A in Example 1, using 2-[4-(dimethylamino)-l- naphthalenyl]-4H-pyrido[3,2- ][l,3]oxazin-4-one (1.47 g, 4.64 mmol, see Step B for its preparation) and cyclohexanemethylamine (174 mmol, 1.54 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (15 mg, 2 %). 1H NMR (400 MHz, CDC13) δ 1.00 (m, 2 H), 1.21 (m, 4 H), 1.75 (m, 4 H), 3.03 (s, 6 H), 3.25 (t, J=6.64 Hz, 2 H), 7.18 (d, J=7.81 Hz, 1 H), 7.51 (m, 1 H), 7.57 (m, 2 H), 7.89 (d, J=7.81 Hz, 1 H), 8.27 (m, 2 H), 8.54 (t, J=5.86 Hz, 1 H), 8.61 (m, 1 H), 9.39 (dd, J=8.59, 1.37 Hz, 1 H), 12.83 (s, 1 H); MS (ESI) (M+H)+ 431.0. Step B. 2-[4-(Dimethylamino)-l-naphthalenyl]-4j9r-pyrido[3,2-</][l,3]oxazin-4-one
Figure imgf000063_0003
Following the procedure for Step B in Example 18, using 3-amino-2-pyridinecarboxylic acid (672 mg, 4.87 mmol), DIPEA (780 mg, 6.0 mmol), 4-dimethylamino-l- naphthalenecarbonyl chloride prepared from 4-dimethylamino-l-naphthoic acid (1.0 g, 4.64 mmol) and oxalyl chloride (3 mL, 2.0 M in CH2C12, 6 mmol), and then HATU (1.9 g, 5.0 mmol) provided the title compound which was directly used in Step A.
Example 24
3-[[[4-(Dimethylamino)-l-naphthalenyl]carbonyl]amino]-iV-[(tetrahydro-2JHr-pyran-4- yl)methyl]-2-pyridinecarboxamide
Figure imgf000064_0001
Following the procedure for Step A in Example 1, using 2-[4-(Dimethylamino)-l- naphthalenyl]-4H-pyrido[3,2-c |[l,3]oxazin-4-one (1.47 g, 4.64 mmol) and 4- aminomethyltetrahydropyran (177 mg, 1.54 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (30 mg, 4 %). 1H NMR (400 MHz, CDC13) δ 1.40 (m, 1 H), 1.68 (dd, J=12.79, 1.46 Hz, 2 H), 3.00 (s, 6 H), 3.32 (t, J=6.64 Hz, 2 H), 3.38 (m, 2 H), 3.99 (dd, J-11.42, 3.61 Hz, 2 H), 7.13 (d, J=7.81 Hz, 1 H), 7.54 (m, 3 H), 7.88 (d, J=7.81 Hz, 1 H), 8.26 (m, 2 H), 8.60 (m, 2 H), 9.40 (dd, J=8.49, 1.27 Hz, 1 H), 12.73 (s, 1 H); MS (ESI) (M+H)+ 433.0.
Example 25 _V-(Cy clobutylmethyl)-3- [ [ [4-(dimethylamino)-l-naphthalenyl] carbonyl] amino] -2- pyridinecarboxamide
Figure imgf000065_0001
Following the procedure for Step A in Example 1, using 2-[4-(Dimethylamino)-l- naphthalenyl]-4H-pyrido[3,2-ci][l,3]oxazin-4-one (1.47 g, 4.64 mmol) and cyclobutanemethylamme (393 mg, 4.62 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (18 mg, 2 %). 1H NMR (400 MHz, CDC13) δ 1.75 (m, 2 H), 1.90 (m, 2 H), 2.10 (m, 2 H), 2.59 (m, 1 H), 3.10 (s, 6 H), 3.43 (dd, J=7.23, 6.25 Hz, 2 H), 7.27 (d, J=2.73 Hz, 1 H), 7.51 (m, 1 H), 7.60 (m, 2 H), 7.90 (d, J=8.01 Hz, 1 H), 8.27 (dd, J=4.49, 1.56 Hz, 1 H), 8.30 (m, 1 H), 8.46 (t, J=5.57 Hz, 1 H), 8.61 (m, 1 H), 9.38 (dd, J=8.59, 1.37 Hz, 1 H), 12.86 (s, 1 H); MS (ESI) (M+H)+ 403.3.
Example 26 N-(Cyclobutyloxy)-3-[(l-naphthalenylcarbonyl)amino]-2-pyridinecarboxamide
Figure imgf000065_0002
Following the procedure for Step A in Example 1, using 2-(l-naphthalenyl)-4H- pyrido[3,2-£t][l,3]oxazin-4-one (55 mg, 0.2 mmol) and O-cyclobutylhydroxylamine (prepared as ref. A. Miyake et alJ. Antibiot. 53 (10), 1071-1085, 2000) (38 mg, 0.44 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (41 mg, 43 %). 1HΝMR (400 MHz, CD3OD) δ 1.53 (m, 1 H), 1.75 (m, 1 H), 2.17 (m, 4 H), 4.51 (m, 1 H), 7.59 (m, 4 H), 7.91 (dd, J=7.03, 0.98 Hz, 1 H), 7.96 (m, 1 H), 8.07 (d, J=8.20 Hz, 1 H), 8.36 (dd, J=4.49, 1.37 Hz, 1 H) ,8.43 (m, 1 H), 9.27 (dd, J=8.59, 1.37 Hz, 1 H). MS (ESI) (M+H)+ = 362.0. Anal. Calcd for C2ιH19N3O3 + 3.0 TFA+5.2 MeCN+7.1 H2O: C, 42.99; H, 5.00; N, 10.99. Found: C, 43.01; H, 5.00; N, 11.00.
Example 27 N-(Cyclopentyloxy)-3-[(l-naphthalenylcarbonyl)amino]-2-pyridinecarboxamid
Figure imgf000066_0001
Step A. iV-(cyclopentyloxy)-3-[(l-naphthalenylcarbonyl)amino]-2- pyridinecarboxamide
Figure imgf000066_0002
Following the procedure for Step A in Example 1, using 2-(l-naphthalenyl)-4H- pyrido[3,2-d][l,3]oxazin-4-one (55 mg, 0.2 mmol), O-cyclopentylhydroxylamine hydrochloride (66 mg, 0.48 mmol, see Step B & C for its preparation) and DIPEA (67 mg, 0.52 mmol) provided the title compound as its TFA salt after purification by reversed- phase ΗPLC (52 mg, 67 %). 1H NMR (400 MHz, CD3OD) δ 1.57 (m, 2 H), 1.74 (m, 4 H), 1.89 (m, 2 H), 4.58 (m, 1 H), 7.59 (m, 4 H), 7.91 (dd, J=7.13, 1.07 Hz, 1 H), 7.96 (m, 1 H), 8.07 (d, J=8.40 Hz, 1 H), 8.36 (dd, J=4.49, 1.56 Hz, 1 H), 8.43 (m, 1 H) 9.27 (dd, J=8.59, 1.37 Hz, 1 H). MS (ESI) (M+H)+ = 376.0. Anal. Calcd for C22H21N3O3 +0.1 TFA+ 0.1 H2O: C, 68.61; H, 5.52; N, 10.81. Found: C, 68.51; H, 5.45; N, 10.68. Step B. tert-Butyl (cyclopentyloxy)carbamate
Figure imgf000067_0001
Sodium hydride (0.88 g, 23 mmol) was added to a solution of the N-Boc hydroxylamine (1.33 g, 10 mmol) in THF (60 mL) at 0 °C. Stirring for 30 min., cyclopentyl bromide (1.49 g, 10 mmol) was added. The mixture was heated at reflux for 8 h, quenched with aqueous sodium biscarbonate, washed with brine, and dried over sodium sulphate. After evaporation of the solvent, the residue was purified by MPLC using hexane/EtOAc (4:1) on SiO2 to give the title compound as a colorless oil (0.43 g, 21%). 1H NMR (400 MHz, CDC13) δ 1.48 (s, 9 H), 1.56 (m, 2 H), 1.70 (m, 4 H), 1.82 (m, 2 H), 4.40 (m, 1 H), 7.01 (s, I H).
Step C. 0-Cyclopentylhydroxylamine
Figure imgf000067_0002
Hydrogen chloride in dioxane (3 mL, M, 12 mmol) was added to a solution of the tert- butyl (cyclopentyloxy)carbamate (0.43 g, 2.14 mmol) in CH2C12 (1 mL) at room temperature. After stirring for 2 h, removal of solvents provided the title compound as its HCl salt ( 0.29 g, 100%). 1H NMR (400 MHz, DMSO-D6) δ 1.56 (m, 4 H), 1.74 (m, 4 H), 4.64 (m, 1 H), 10.87 (s, 3 H).
Example 28 N-(Cyclohexyloxy)-3-[(l-naphthalenylcarbonyl)amino]-2-pyridinecarboxamide
Figure imgf000067_0003
Following the procedure for Step A in Example 1, using 2-(l-naphthalenyl)-4H- pyrido[3,2-d][l,3]oxazm-4-one (55 mg, 0.2 mmol) and O-cyclohexylhydroxylamine (prepared as ref. A. Miyake et alJ. Antibiot. 53 (10), 1071-1085, 2000) (51 mg, 0.44 mmol) provided the title compound as its TFA salt after purification by reversed-phase HPLC (64 mg, 78 %). 1H NMR (400 MHz, CD3OD) δ 1.26 (m, 3 H), 1.42 (m, 2 H), 1.54 (m, 1 H), 1.77 (m, 2 H), 1.98 (m, 2 H), 3.90 (m, 1 H), 7.59 (m, 4 H), 7.91 (dd, J=7.13, 1.07 Hz, 1 H), 7.97 (m, 1 H), 8.07 (d, J=8.40 Hz, 1 H), 8.36 (dd, J=4.49, 1.56 Hz, 1 H) 8.43 (m, 1 H) 9.27 (dd, J=8.59, 1.37 Hz, 1 H). MS (ESI) (M+H)+ = 390.0. Anal. Calcd for C23H23N3O3 + 0.2 TFA: C, 68.18; H, 5.67; N, 10.19. Found: C, 68.41; H, 5.72; N, 10.18.
Example 29 iV-(Cyclohexyloxy)-3-[(4-methoxy-l-naphthalenylcarbonyl)amino]-2- pyridinecarb oxamide
Figure imgf000068_0001
Following the procedure for Step A in Example 1, using 2-(4-methoxyl-naphthalenyl)-H- pyrido[3,2-fi ][l,3]oxazin-4-one (120 mg, 0.4 mmol) and O-cyclohexylhydroxylamine (prepared as ref. A. Miyake et alJ. Antibiot. 53 (10), 1071-1085, 2000) (205 mg, 1.8 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (91 mg, 54 %). 1H NMR (400 MHz, CD3OD) δ 1.28 (m, 3 H), 1.48 (m, 3 H), 1.79 (m, 2 H), 1.99 (m, 2 H), 3.92 (m, 1 H), 4.08 (s, 3 H), 7.01 (d, J=8.20 Hz, 1 H), 7.56 (m, 3 H), 7.93 (d, J=8.01 Hz, 1 H), 8.32 (m, 2 H), 8.51 (d, J=8.20 Hz, 1 H), 9.25 (dd, J=8.59, 1.37 Hz, 1 H). MS (ESI) (M+H)+ = 420.0.
Example 30 iV-(Cyclobutylmethyl)-3-[(2-methoxybenzoyl)amino]-2-pyridinecarboxamide
Figure imgf000069_0001
Step A. N-(Cyclobutylmethyl)-3-[(2-methoxybenzoyl)amino]-2-pyridinecarboxamide
Figure imgf000069_0002
DIPEA (0.13 mL, 0.73 mmol) was added into a solution of 3-amino-N-(cyclobutylmethyl)- 2-pyridinecarboxamide (87 mg, 0.43 mmol, see Step B for its preparation) and 2-methoxy- benzoic acid (79 mg, 0.52 mmol) in DMF (10 mL) at 0 °C. After stiπing for 20 min. HATU (179 mg, 0.47 mmol) was added. The reaction mixture was stiπed for 24 h at room temperature, and was then quenched with H2O (50 mL) and extracted with EtOAc (2 x 50 mL). The crude product was purified by reversed-phase HPLC to provide the title compound as its TFA salt (51 mg, 26 %). 1H MR (400 MHz, CD3OD) δ 1.77-1.97 (m, 4 H), 2.06-2.14 (m, 2 H), 2.59-2.70 (m, 1 H), 3.43-3.47 (m, 2 H), 4.07 (s, 3 H), 7.06-7.10 (m, 1 H), 7.19 (d, J=8.40 Hz, 1 H), 7.51-7.57 (m, 2 H), 8.00 (dd, J=7.81, 1.76 Hz, 1 H), 8.30 (dd, J=4.39, 1.46 Hz, 1 H), 8.89-8.96 (br. s., 1 H), 9.24 (dd, J=8.59, 1.46 Hz, 1 H), 12.93- 13.02 (br. s., 1 H); MS (ESI) (M+H)+ 340.3.
Step B. 3-Amino-iV-(cyclobutylmethyl)-2-pyridinecarboxamide
Figure imgf000069_0003
HATU (3.03 g, 7.96 mmol) was added to a solution of 3-aminopyridine-2-carboxylic acid (1.0 g, 7.24 mmol), cyclobutanemethylamme (2.7 mL, 5.3 M in MeOH, 14.5 mmol), and DIPEA (3.8 g, 30 mmol) in DMF (50 ml) at room temperature. After 24 hr, the reaction mixture was quenched with H2O (100 mL), and extracted with EtOAc (2 x 100 mL). The combined organic phases were washed with brine, and condensed in vacuo to provide the title compound (1.22 g, 82 %).
Example 31 N-[2-[[(Cyclobutylmethyl)amino]carbonyl]-3-pyridinyl]-4-quinolinecarboxamide
Figure imgf000070_0001
Following the procedure for Step A in Example 30, using DIPEA (0.07 mL, 0.42), 3- amino-N-(cyclobutylmethyl)-2-pyridinecarboxamide (50 mg, 0.24 mmol), quinoline-4- carboxylic acid (50 mg, 0.29 mmol), and HATU (110 mg, 0.29 mmol) provided the title compound as its TFA salt after purification by reversed-phase HPLC (9 mg, 8 %). 1H ΝMR (400 MHz, CD3OD) δ 1.71-1.93 (m, 4 H), 2.02-2.10 (m, 2 H), 2.57-2.64 (m, 1 H), 3.38 (d, J=7.23 Hz, 2 H), 7.64 (m, 1 H), 7.76-7.78 (m, 1 H), 7.82-7.96 (m, 2 H), 8.17-8.19 (d, 1 H), 8.41 (dd, J=4.59, 1.51 Hz, 1 H), 8.50-8.52 (m, 1 H), 9.10 (d, J=4.69 Hz, 1 H), 9.27 (dd, J=8.59, 1.51 Hz, 1 H); MS (ESI) (M+H)+ 361.2.
Example 32 iV-[2-[[(Cyclobutylmethyl)amino]carbonyl]-3-pyridinyl]-5-isoquinolinecarboxamide
Figure imgf000071_0001
Following the procedure for Step A in Example 30, using DIPEA (0.17 mL, 0.97), 3- amino-N-(cyclobutylmethyl)-2-pyridinecarboxamide (100 mg, 0.49 mmol), isoquinoline-5 - carboxylic acid (168 mg, 0.97 mmol), and HATU (369 mg, 0.97 mmol) provided the title compound as its TFA salt after purification by reversed-phase HPLC (97 mg, 42 %). 1H ΝMR (400 MHz, CD3OD) δ 1.47-1.96 (m, 4 H), 2.02-2.10 (m, 2 H), 2.58-2.65 (m, 1 H), 3.39 (d, J=7.23 Hz, 2 H), 7.62 (dd, J=8.59, 4.59 Hz, 1 H), 8.10 (dd, J=8.30, 7.32 Hz, 1 H), 8.39 (dd, J=4.59, 1.41 Hz, 1 H), 8.59-8.64 (m, 3 H), 8.98-8.90 (m, 1 H) 9.26 (dd, J=8.59, 1.41 Hz, 1 H), 9.73-9.80 (br. s., 1 H); MS (ESI) (M+H)+ 361.2.
Example 33
N-(Cyclobutylmethyl)-3-[[(2,3-dihydro-l,4-benzodioxin-5-yl)carbonyl]amino]-2- pyridinecarboxamide
Figure imgf000071_0002
Following the procedure for Step A in Example 30, using DIPEA (0.17 mL, 0.97), 3- amino-N-(cyclobutylmethyl)-2-pyridinecarboxamide (100 mg, 0.49 mmol), 1,4- benzodioxan-5-carboxylic acid (175 mg, 0.97 mmol), and HATU (369 mg, 0.97 mmol) provided the title compound as its TFA salt after purification by reversed-phase HPLC (90 mg, 50 %). 1HΝMR (400 MHz, DMSO-D6) δ 1.70-1.85 (m, 4 H), 1.93-2.01 (m, 2 H), 2.53-2.62 (m, 1 H), 3.32-3.36 (m, 2 H), 4.33-3.45 (m, 4 H), 6.95 (t, J=7.91 Hz, 1 H), 7.07- 7.10 (m, 1 H), 7.42 (dd, J=7.81, 1.56 Hz, 1 H), 7.62 (dd, J=8.59, 4.41 Hz, 1 H), 8.34 (dd, J= .41, 1.51 Hz, 1 H), 9.04-9.07 (m, 1 H), 9.17 (dd, J=8.59, 1.51 Hz, 1 H), 12.87-12.91 (br. s., 1 H); MS (ESI) (M+H)+ 368.3.
Example 34
N-(Cyclobutylmethyl)-3-[[(2,3-dihydro-7-benzofuranyl)carbonyl]amino]-2- pyridinecarboxamide
Figure imgf000072_0001
Following the procedure for Step A in Example 30, using DIPEA (0.17 mL, 0.97), 3- amino-N-(cyclobutylmefhyl)-2-pyridinecarboxamide (100 mg, 0.49 mmol), 2,3- dihydrofuran-7-carboxylic acid (159 mg, 0.97 mmol), and HATU (369 mg, 0.97 mmol) provided the title compound as its TFA salt after purification by reversed-phase HPLC (92 mg, 38 %). 1H ΝMR (400 MHz, DMSO-D6) δ 1.68-1.85 (m, 4 H), 1.93-2.01 (m, 2 H), 2.52-2.60 (m, 1 H), 3.26-3.37 (m, 4 H), 4.73 (t, J=8.79 Hz, 2 H), 6.96-6.99 (m, 1 H), 7.46 (dd, J=7.23, 1.17 Hz, 1 H), 7.61 (dd, J=8.59, 4.49 Hz, 1 H), 7.65 (dd, J=7.81, 1.17 Hz, 1 H), 8.34 (dd, J=4.49, 1.46 Hz, 1 H), 8.99-9.02 (m, 1 H), 9.06 (dd, J=8.59, 1.46 Hz, 1 H), 12.62 (s, 1 H); MS (ESI) (M+H)+ 352.3.
Example 35 iV-(Cyclobutylmethyl)-3-[(3-methoxy-2-methylbenzoyl)amino]-2- pyridinecarboxamide
Figure imgf000073_0001
Following the procedure for Step A in Example 30, using DIPEA (0.17 mL, 0.97), 3- amino-N-(cyclobutylmethyl)-2-pyridinecarboxamide (100 mg, 0.49 mmol), 3-methoxy-2- methylbenzoic acid (161 mg, 0.97 mmol), and HATU (369 mg, 0.97 mmol) provided the title compound as its TFA salt after purification by reversed-phase HPLC (44 mg, 19 %). 1H ΝMR (400 MHz, CD3OD) δ 1.72-1.97 (m, 4 H), 2.01-2.10 (m, 2 H), 2.31 (s, 3 H), 2.55- 2.64 (m, 1 H), 3.37 (d, J=7.23 Hz, 2 H), 3.87 (s, 3 H), 7.09 (d, J=8.20 Hz, 1 H), 7.14-7.16 (m, 1 H), 7.28-7.32 (m, 1 H), 7.56 (dd, J=8.59, 4.49 Hz, 1 H), 8.33 (dd, J=4.49, 1.31 Hz, 1 H), 9.18 (dd, J=8.59, 1.31 Hz, 1 H); MS (ESI) (M+H)+ 354.2.
Example 36
N-(2-{[(Tetrahydro-2j5r-pyran-4-ylmethyl)amino]carbonyl}pyridin-3-yl)quinoline-4- carboxamide
Figure imgf000073_0002
Step A. N-{2-{ [(Tetrahydro-2iϊ-pyran-4-ylmethyl)amino] carbonyl} pyridin-3- yl)quinoline-4-carboxamide
Figure imgf000074_0001
Following the procedure for Step A in Example 30, using DIPEA (65 mg, 0.5 mmol), 3- amino-N-(tetrahydro-2H-pyran-4-ylmethyl)pyridine-2-carboxamide (50 mg, 0.21 mmol, see Step B for its preparation), and quinoline-4-carboxylic acid (52 mg, 0.3 mmol), and ΗATU (114 mg, 0.3 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (24 mg, 23 %). 1H ΝMR (400 MHz, CD3OD) δ 1.31 (m, 2 H), 1.61 (m, 2 H), 1.82 (m, 1 H), 3.26 (m, 2 H), 3.35 (m, 2 H), 3.90 (m, 2 H), 7.64 (m, 1 H), 7.90 (m, IH), 8.06 (m, 1 H), 8.13 (m, 1 H), 8.24 (d, J=8.8 Hz, 1 H), 8.43 (dd, J=4.4, 1.6 Hz, 1 H), 8.58 (d, J=8.0 Hz, IH), 9.24 (dd, J=8.4, 1.6 Hz, 2H); MS (ESI) (M+H)+ 391.2. Step B. 3-Amino-iV-(tetrahydro-2fι -pyran-4-ylmethyl)pyridine-2-carboxamide
Figure imgf000074_0002
Following the procedure for Step B in Example 30, using HATU (1.52 g, 4.0 mmol), 3- aminopyridine-2-carboxylic acid (387 mg, 3.0 mmol), tetrahydro-2H-pyran-4- methanamine (456 mg, 4.0 mmol), and DIPEA (520 mg, 4.0 mmol) provided the title compound (650 mg, 92 %).
Example 37 N-(2-{[(Tetrahydro-2fl-pyran-4-ylmethyl)amino]carbonyl}pyridin-3-yl)isoquinoline- 5-carboxamide
Figure imgf000075_0001
Following the procedure for Step A in Example 30, using DIPEA (65 mg, 0.5 mmol), 3- amino-N-(tetrahydro-2H-pyran-4-ylmethyl)pyridine-2-carboxamide (50 mg, 0.21 mmol), and isoquinoline-5-carboxylic acid (52 mg, 0.3 mmol), and ΗATU (114 mg, 0.3 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (25 mg, 24 %). 1H ΝMR (400 MHz, CD3OD) δ 1.32 (m, 2 H), 1.65 (m, 2 H), 1.88 (m, 1 H), 3.29 (m, 2 H), 3.38 (m, 2 H), 3.93 (m, 2 H), 7.65 (m, IH), 8.13 (m, 1 H), 8.42 (d, J=4.4 Hz, 1 H), 8.63 (m, 3 H), 9.05 (m, IH), 9.29 (d, J=4.4 Hz, IH), 9.45 (m, IH); MS (ESI) (M+H)+ 391.0.
Example 38
N-(2-{[(Tetrahydro-2jET-pyran-4-ylmethyl)amino]carbonyl}pyridin-3-yl)quiιιoline-5- carboxamide
Figure imgf000075_0002
Following the procedure for Step A in Example 30, using DIPEA (65 mg, 0.5 mmol), 3- amino-N-(tetrahydro-2H-pyran-4-yl-methyl)pyridine-2-carboxamide (50 mg, 0.21 mmol), and quinoline-5 -carboxylic acid (52 mg, 0.3 mmol), and ΗATU (114 mg, 0.3 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (30 mg, 28 %). 1HNMR (400 MHz, CD3OD) δ 1.31 (m, 2 H), 1.67 (m, 2 H), 1.88 (m, 1 H), 3.29 (m, 2 H), 3.38 (m, 2 H), 3.92 (m, 2 H), 7.63 (dd, J=8.4, 4.4 Hz, 1 H), 7.86 (dd, J=8.8, 4.8 Hz, IH), 8.09 (m, 1 H), 8.24 (d, J=7.6 Hz, 1 H), 8.31 (d, J=8.8 Hz, 1 H), 8.41 (d, J= .4 Hz, 1 H), 9.10 (m, IH), 9.28 (dd, J=8.8, 1.6 Hz, IH), 9.37 (d, J=8.0 Hz, IH); MS (ESI) (M+H)+ 391.2.
Example 39 Λ?-(Cyclohexylmethyl)-4-(l-naphthoylamino)nicotinamide
Figure imgf000076_0001
Step A.7Y-(Cyclohexylmethyl)-4-(l-naphthoylamino)nicotinamide
Figure imgf000076_0002
Following the procedure for Step A in Example 1, using 2-(l-naphthyl)-4H-pyrido[4,3- < |[l,3]oxazin-4-one (137 mg, 0.5 mmol, see Step B for its preparation) and cyclohexylmethylamine (226 mg, 2.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (39 mg, 16 %). 1H NMR (400 MHz, CDC13) δ 0.99 (m, 2H), 1.23 (m, 3H), 1.63 (m, IH), 1.76 (m, 5H), 3.22 (d, J = 6.8 Hz, 2H), 7.61 (m, 3H), 7.98 (m, 2H), 8.14 (d, J = 8.4 Hz, IH), 8.53 (m, IH), 8.72 (m, IH), 9.05 (s, IH), 9.22 (d, J = 6.8 Hz, IH); MS (ESI) (M+H)+ 388.0. Step B. 2-(l-Naphthyl)-4JHr-pyrido[4,3-f |[l,3]oxazin-4-one
Figure imgf000077_0001
Following the procedure for Step B in Example 1, using 4-aminonicotinic acid (138 mg, 1.0 mmol), 1-naphthalenecarbonyl chloride (191 mg, 1.0 mmol), DIPEA (284 mg, 2.2 mmol), and then HATU (419 mg, 1.1 mmol) provided the title compound as a DMF (6 mL) solution which was used directly in Step A. MS (ESI) (M+H)+ 274.79.
Example 40 iV-(Cyclobutylmethyl)-4-(l-naphthoylamino)nicotinamide
Figure imgf000077_0002
Following the procedure for Step A in Example 1, using 2-(l-naphthyl)-4H-pyrido[4,3- ][l,3]oxazin-4-one (137 mg, 0.5 mmol) and cyclobutylmethylamine (170 mg, 2.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (45 mg, 19 %). 1H NMR (400 MHz, CDC13) δ 1.74 (m, 2H), 1.88 (m, 2H), 2.08 (m, 2H), 2.61 (m, IH), 3.46 (m, 2H), 7.62 (m, 3H), 7.94 (m, 2H), 8.09 (d, J = 8.4 Hz, IH), 8.39 (s, IH), 8.55 (m, 2H), 9.34 (d, J = 6.4 Hz, IH), 9.39 (s, IH), 13.10 (s, IH); MS (ESI) (M+H)+ 360.0.
Example 41 N-(Cyclohexylmethyl)-3-(l-naphthoylamino)isonicotinamide
Figure imgf000078_0001
Step A. N-(Cyclohexylmethyl)-3-(l-naphthoylamino)isonicotinamide
Figure imgf000078_0002
Following the procedure for Step A in Example 1, using 2-(l-naphthyl)-4H-pyrido[3,4- ][l,3]oxazin-4-one (137 mg, 0.5 mmol, see Step B for its preparation) and cyclohexylmethylamine (226 mg, 2.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (55 mg, 22 %). 1H NMR (400 MHz, CD3OD) δ 0.99 (m, 2H), 1.22 (m, 3H), 1.70 (m, 6H), 3.22 (d, J = 7.2 Hz, 2H), 7.59 (m, 3H), 7.90 (dd, J= 7.2, 1.2 Hz, IH), 7.96 (m, IH), 7.99 (brs, IH), 8.08 (d, J = 8.4 Hz, IH), 8.47 (m, IH), 8.64 (brs, IH), 10.08 (brs, IH); MS (ESI) (M+H)+ 388.1. Step B. 2-(l-Naphthyl)-4#-pyrido[3,4-< ][l,3]oxazin-4-one
Figure imgf000078_0003
Following the procedure for Step B in Example 1, using 3-aminoisonicotinic acid (138 mg, 1.0 mmol), 1-naphthalenecarbonyl chloride (191 mg, 1.0 mmol), DIPEA (284 mg, 2.2 mmol), and then HATU (419 mg, 1.1 mmol) provided the title compound as a DMF (6 mL) solution which was used directly in Step A. MS (ESI) (M+H)+ 274.79. Example 42 N-Cyclobutyl-3-(l-naphthoylamino)isonicotinamide
Following the procedure for Step A in Example 1, using 2-(l-naphthyl)-4H-pyrido[3,4- <f][l,3]oxazin-4-one (137 mg, 0.5 mmol) and cyclobutylamine (142 mg, 2.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (43 mg, 19 %). 1H MR (400 MHz, CD3OD) δ 1.73 (m, 2H), 2.07 (m, 2H), 2.28 (m, 2H), 4.24 (m, IH), 7.53 (m, 3H), 7.84 (dd, J= 7.2, 1.2 Hz, IH), 7.88 (m, IH), 8.0 (d, J = 8.0 Hz, IH), 8.04 (m, IH), 8.40 (m, IH), 8.54 (brs, IH), 9.90 (brs, IH); MS (ESI) (M+H)+ 346.1.
Example 43 3-(l-Naphthoylamino)-iV-(tetrahydro-2i?-pyran-4-ylmethyl)pyrazine-2-carboxamide
Figure imgf000079_0002
Step A.3-(l-Naphthoylamino)-iV-(tetrahydro-2fl-pyran-4-yl-methyl)pyrazine-2- carboxamide
Figure imgf000080_0001
Following the procedure for Step A in Example 1, using 2-(l-naphthyl)-4H-pyrazino[2,3- d][l,3]oxazin-4-one (69 mg, 0.25 mmol, see Step B for its preparation), and tetrahydro- 2H-pyran-4-methanamine (115 mg, 1.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (12 mg, 10 %). 1H NMR (400 MHz, CD3OD) δ 1.27 (m, 2 H), 1.62 (m, 2 H), 1.88 (m, 1 H), 3.29 (m, 4 H), 3.91 (m, 2 H), 7.59 (m, 3H), 7.95 (m, 2H), 8.10 (m, IH), 8.43 (m, IH), 8.48 (m, IH), 8.59 (m, IH); MS (ESI) (M+H)+ 391.0. Step B. 2-(l~Naphthyl)-4 -pyrazino[2,3-^[l,3]oxazin-4-one
Figure imgf000080_0002
Following the procedure for Step B in Example 1, using 3-aminopyrazine-2-carboxylic acid (139 mg, 1.0 mmol), 1-naphthalenecarbonyl chloride (191 mg, 1.0 mmol), DIPEA (284 mg, 2.2 mmol), and HATU (419 mg, 1.1 mmol) provided the title compound as a DMF (6 mL) solution which was used directly in Step A. MS (ESI) (M+H)+ 275.82.
Example 44 N-(Cyclohexylmethyl)-3-(l-naphthoylamino)pyrazine-2-carboxamide
Figure imgf000081_0001
Following the procedure for Step A in Example 1, using 2-(l-naphthyl)-4H-pyrazino[2,3- fi?][l,3]oxazin-4-one (69 mg, 0.25 mmol), and cyclohexylmethylamine (113 mg, 1.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (6 mg, 5 %). 1H NMR (400 MHz, CD3OD) δ 0.96 (m, 2H), 1.22 (m, 3H), 1.72 (m, 6H), 3.19 (m, 2H), 7.55 (m, 3H), 7.95 (m, 2H), 8.06 (m, IH), 8.48 (m, 3H); MS (ESI) (M+H)+ 389.0.
Example 45 iV-(Cyclobutylmethyl)-3-(l-naphthoylamino)pyrazine-2-carboxamide
Figure imgf000081_0002
Following the procedure for Step A in Example 1, using 2-(l-naphthyl)-4H-pyrazino[2,3- d][l,3]oxazin-4-one (69 mg, 0.25 mmol), and cyclobutylmethylamine (85 mg, 1.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (8 mg, 7 %). 1H NMR (400 MHz, CD3OD) δ 1.75 (m, 2H), 1.86 (m, 2H), 2.03 (m, 2H), 2.59 (m, IH), 3.36 (m, 2H), 7.57 (m, 3H), 7.95 (m, 2H), 8.06 (m, IH), 8.48 (m, 3H); MS (ESI) (M+H)+ 361.0.
Example 46 N-(Cyclopentylmethyl)-3-(l-naphthoylamino)pyrazine-2-carboxamide
Figure imgf000082_0001
Following the procedure for Step A in Example 1, using 2-(l-naphthyl)-4H-pyrazino[2,3- d][l,3]oxazin-4-one (69 mg, 0.25 mmol), and cyclopentylmethylamme (99 mg, .1.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (9.5 mg, 8 %). 1H NMR (400 MHz, CD3OD) δ 1.27 (m, 3H), 1.63 (m, 5H), 2.19 (m, IH), 3.29 (m, 2H), 7.58 (m, 3H), 7.95 (m, 2H), 8.06 (m, IH), 8.48 (m, 3H); MS (ESI) (M+H)+ 375.0.
Example 47 7V-(2-Cyclohexylethyl)-3-(l-naphthoylamino)pyrazine-2-carboxamide
Figure imgf000082_0002
Following the procedure for Step A in Example 1, using 2-(l-naphthyl)-4H-pyrazino[2,3- ci][l,3]oxazin-4-one (83 mg, 0.3 mmol), and (2-cyclohexylethyl)amine hydrochloride (164 mg, 1.0 mmol) provided the title compound as its TFA salt after purification by reversed- phase ΗPLC (48 mg, 31 %). 1H NMR (400 MHz, CDC13) δ 0.94 (m, 2H), 1.20 (m, 4H), 1.51 (m, 2H), 1.71 (m, 5H), 3.44 (m, 2H), 7.56 (m, 3H), 7.89 (d, J=8.0 Hz, IH), 7.98 (m, 2H), 8.15 (m, IH), 8.28 (s, IH), 8.62 (d, J=8.0 Hz, IH), 8.70 (s, IH), 12.77 (s, IH); MS (ESI) (M+H)+ 403.0.
Example 48 3-[(4-Methyl-l-naphthoyl)amino]-N-pentylpyrazine-2-carboxamide
Figure imgf000083_0001
Step A: 3-[(4-Methyl-l-naphthoyl)amino]-N-pentylpyrazine-2-carboxamide
Figure imgf000083_0002
A solution of methyl 3-[(4-methyl-l-naphthoyl)amino]pyrazine-2-carboxylate (257 mg, 0.8 mmol) and pentan-1 -amine (174 mg, 2.0 mmol) in 15 mL MeCN was heated at 100 °C for 2 hr. After removal of solvents, the residue was purified by reversed-phase HPLC to give the title compound as its TFA salt (225 mg, 57 %). 1H NMR (400 MHz, CD3OD) δ 0.86 (t, J =7.6 Hz, 3 H), 1.29 (m, 4H), 1.55 (m, 2H), 2.71 (s, 3H), 3.30 (t, J=7.6 Hz, 2H), 7.40 (d, J=8.0 Hz, IH), 7.56 (m, 2H), 7.83 (d, J=8.0 Hz, IH), 8.08 (m, IH), 8.35 (s,lH), 8.52 (m,2H). MS (ESI) (M+H)+ 377.0. Step B: Methyl 3-[(4-methyl-l-naphthoyl)amino]pyrazine-2-carboxylate
Figure imgf000083_0003
At 90 °C a solution of 4-methyl-l-naphthalenecarbonyl chloride (12 mmol) in CH2C1CH2C1 (20 mL) was slowly added into a solution of methyl 3-aminopyrazine-2- carboxylate (1.53 g, 10.0 mmol) and DMAP (100 mg) in CH2C1CH2C1(100 mL) and pyridine (10 mL) during a period of six hours. The resulting reaction mixture was stiπed at the same temperature overnight, and was then condensed, and extracted by EtOAc, washed by brine, dried over MgSO4. Removal of solvents provided a crude product, which was purified by flash silica gel column using heptane/EtOAc (10:0 to 0:10) to give the title product as a solid (1.5 g, 47 %): XH NMR (400 MHz, CDC13) δ IH NMR (400 MHz, CD3OD) 2.77 (s, 3H), 3.94 (s, 3H), 7.46 (d, J=8.0 Hz, IH), 7.60 (m, 2H), 7.79 (d, J=8.0 Hz, IH), 8.14 (d, J=8.0 Hz, IH), 8.42 (m,lH), 8.50 (m, IH), 8.64 (m,lH).
Example 49 Ar-(3-Methylbutyl)-3-[(4-methyl-l-naphthoyl)amino]pyrazine-2-carboxamide
Figure imgf000084_0001
Following the procedure for Step A in Example 48, using methyl 3-[(4-methyl-l- naphthoyl)amino]pyrazine-2-carboxylate (129 mg, 0.4 mmol) and 3-methylbutan-l -amine (87 mg, 1.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase HPLC (85 mg, 43 %). 1H NMR (400 MHz, CD3OD) δ 0.87 (d, J =7.6 Hz, 6 H), 1.42 (m, 2H), 1.56 (m, IH), 2.68 (s, 3H), 3.31 (dd, J=7.6, 4.0 Hz, 2H), 7.38 (d, J=8.0 Hz, IH), 7.54 (m, 2H), 7.81 (d, J=8.0 Hz, IH), 8.05 (m, IH), 8.32 (s,lH), 8.52 (m, 2H); MS (ESI) (M+H)+ 377.0.
Example 50 /y-(Cyclobutylmethyl)-3-[(4-methyl-l-naphthoyl)amino]pyrazine-2-carboxamide
Figure imgf000084_0002
Following the procedure for Step A in Example 48, using methyl 3-[(4-methyl-l- naphthoyl)amino]pyrazine-2-carboxylate (1.6 g, 5.0 mmol) and (cyclobutylmethylamine (0.84 g, 10.0 mmol) provided the title compound after purification by silica gel column (720 mg, 39 %). 1H NMR (400 MHz, CD3OD) δ 1.75 (m, 2 H), 1.86 (m, 2 H), 2.04 (m, 2H), 2.59 (m, IH), 2.75 (s, 3H), 3.37 (d, J=7.6 Hz, 2H), 7.44 (d, J=8.0 Hz, IH), 7.59 (m, 2H), 7.85 (d, J=8.0 Hz, IH), 8.12 (dd, J=8.0 Hz, IH), 8.38 (d, J=2.4 Hz,lH), 8.54 (m, IH), 8.55 (m,lH); MS (ESI) (M+H)+ 375.0.
Example 51
3-[(4-Methyl-l-naphthoyl)amino]-iV-(tetrahydro-2H-pyran-4-ylmethyl)pyrazine-2- carboxamide
Figure imgf000085_0001
Following the procedure for Step A in Example 48, using methyl 3-[(4-methyl-l- naphthoyl)amino]pyrazine-2-carboxylate (64 mg, 0.2 mmol) and (tetrahydro-2H-pyran-4- ylmethyl)amine (34 mg, 0.4 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (28 mg, 27 %). 1H NMR (400 MHz, CD3OD) δ 1.30 (m, 2 H), 1.63 (m, 2 H), 1.86 (m, 1 H), 2.75 (s, 3H), 3.24 (m, 2 H), 3.34 (m, 2H), 3.89 (m, 2 H), 7.44 (d, J=8.0 Hz, IH), 7.59 (m, 2H), 7.85 (d, J=8.0 Hz, IH), 8.12 (dd, J=8.0 Hz, IH), 8.38 (d, J=2.4 Hz,lH), 8.54 (m, IH), 8.55 (m,lH); MS (ESI) (M+H)+ 405.0.
Example 52 iY-(Cyclobutylmethyl)-3-[(4-ethyl-l-naphthoyl)amino]pyrazine-2-carboxamide
Figure imgf000085_0002
Step A: N-(Cyclobutylmethyl)-3-[(4-ethyl-l-naphthoyl)amino]pyrazine-2- carboxamide
Figure imgf000086_0001
Following the procedure for Step A in Example 48, using methyl 3-[(4-ethyl-l- naphthoyl)amino]pyrazine-2-carboxylate (0.3 mmol) and (cyclobutylmethyl)amine (85 mg, 1.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase HPLC (52 mg, 35 %). 1H NMR (400 MHz, CD3OD) δ 1.38 (t, J=7.6 Hz, 3H), 1.75 (m, 2 H), 1.85 (m, 2 H), 2.02 (m, 2H), 2.58 (m, IH), 3.16 (d, J=7.6 Hz, 2H), 3.36 (q, J=7.2 Hz, 2H), 7.45 (d, J=8.0 Hz, IH), 7.57 (m, 2H), 7.87 (d, J=8.0 Hz, IH), 8.16 (dd, J=8.0 Hz, IH), 8.37 (d, J=2.4 Hz,lH), 8.52 (m, IH), 8.54 (d, J=2.4 Hz,lH); MS (ESI) (M+H)+ 389.0. Step B: Methyl 3-[(4-ethyl-l-naphthoyl)amino]pyrazine-2-carboxylate
Figure imgf000086_0002
Following the procedure for Step B in Example 48, using 4-ethyl-l-naphthalenecarbonyl chloride (0.45 mmol) and methyl 3-aminopyrazine-2-carboxylate (46 mg, 0.3 mmol) provided a crude methyl 3-[(4-ethyl-l-naphthoyl)amino]pyrazine-2-carboxylate, which was used directly in the Step A.
Example 53 iV-(Cyclohexylmethyl)-3-[(4-ethyl-l-naphthoyl)ammo]pyrazine-2-carboxamide
Figure imgf000087_0001
Following the procedure for Step A in Example 48, using methyl 3-[(4-ethyl-l- naphthoyl)amino]pyrazine-2-carboxylate (101 mg, 0.3 mmol) and
(cyclohexylmethyl)amine (113 mg, 1.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase HPLC (94 mg, 59 %). 1H NMR (400 MHz, CD3OD) δ 0.96 (m, 2H), 1.21 (m, 4H),1.39 (t, J=7.6 Hz, 3H), 1.60 (m, 1 H), 1.71 (m, 4 H), 3.17 (d, J=7.6 Hz, 2H), 3.18 (q, J=7.6 Hz, 2H), 7.47 (d, J=8.6 Hz, IH), 7.57 (m, 2H), 7.88 (d, J=7.6 Hz, IH), 8.19 (dd, J=8.0, 1.6 Hz, IH), 8.42 (m, IH), 8.52 (m, IH), 8.59 (m, IH); MS (ESI) (M+H)+ 417.0.
Example 54
3-[(4-EthyI-l-naphthoyl)amino]-iV-(tetrahydro-2i9,-pyran-4-ylmethyl)pyrazine-2- carboxamide
Figure imgf000087_0002
Following the procedure for Step A in Example 48, using methyl 3-[(4-ethyl-l- naphthoyl)amino]pyrazine-2-carboxylate (101 mg, 0.3 mmol) and (tetrahydro-2H-pyran-4- ylmethyl)amine (51 mg, 0.6 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (32 mg, 20 %). 1H NMR (400 MHz, CD3OD) δ 1.30 (m, 2 H), 1.39 (t, J=7.6 Hz, 3H), 1.63 (m, 2 H), 1.86 (m, 1 H), 3.18 (q, J=7.6 Hz, 2H), 3.24 (m, 2 H), 3.34 (m, 2H), 3.89 (m, 2 H), 7.47 (d, J=8.6 Hz, IH), 7.59 (m, 2H), 7.88 (d, J=7.6 Hz, IH), 8.19 (dd, J=8.0, 1.6 Hz, IH), 8.42 (m, IH), 8.52 (m, IH), 8.59 (m, IH); MS (ESI) (M+H)+ 419.0.
Example 55 N-(Cyclobutylmethyl)- 3-{[4-(lH-l,2,3-triazol-l-ylmethyl)-l- naphthoyl]amino}pyrazine-2-carboxamide
Figure imgf000088_0001
Step A: N-(Cyclobutylmethyl)- 3-{[4-(l#-l,2,3-triazol-l-ylmethyl)-l- naphthoyl]amino}pyrazine-2-carboxamide
Figure imgf000088_0002
Following the procedure for Step A in Example 48, using methyl 3-{[4-(lH-l,2,3-triazol- l-ylmethyl)-l-naphthoyl]amino}pyrazine-2-carboxylate (34 mg, 0.09 mmol) and (cyclobutylmethylamine (85 mg, 1.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (17 mg, 35 %). 1H NMR (400 MHz, CD3OD) δ 1.76 (m, 2 H), 1.90 (m, 2 H), 2.05 (m, 2 H), 2.61 (m, 1 H), 3.38 (m, 2H), 6.22 (s, 2H), 7.47 (d, J=8.0 Hz, IH), 7.64 (m, 2H), 7.76 (s, IH), 7.94 (d, J=8.0 Hz, IH), 7.99 (s, IH), 8.24 (d, J=8.0 Hz, IH), 8.43 (m, IH), 8.51 (m, IH), 8.56 (m, IH); MS (ESI) (M+H)+ 442.4. Step B: Methyl 3-{[4-(lJΪ-l,2,3-triazol-l-ylmethyl)-l-naphthoyl]amino}pyrazine-2- carboxylate
Figure imgf000089_0001
To a stirring solution of methyl 3-[(4-methyl-l-naphthoyl)amino]pyrazine-2-carboxylate (210 mg, 0.65 mmol) and NBS (462 mg, 2.6 mmol) in 20 mL of C1CH2CH2C1 at r.t was added l, -azobis(cyclohexanecarbonitrile (5 mg). The solution was heated at 110 °C for 2 hr, and was then cooled to r.t. After removal of solvents (<20 °C), the residue was dissolved in 10 mL DMF, and followed by addition of 1,2,3-triazole (690 mg, 10 mmol). The resulting solution was then stirred for 4 hr at r.t. After removal of solvents, the residue was purified by MPLC (EtOAc) to give methyl 3-{[4-(lH-l,2,3-triazol-l-ylmethyl)-l- naphthoyl]amino}ρyrazine-2-carboxylate (102 mg, 40 %). MS (ESI) (M)+ 388.91.
Example 56 iV-(Cyclohexylmethyl)- 3-{[4-(lJΗ-l,2,3-triazol-l-ylmethyl)-l- naphthoyl]amino}pyrazine-2-carboxamide
Figure imgf000089_0002
Following the procedure for Step A in Example 48, using methyl 3-{[4-(lH-l,2,3-triazol- l-ylmethyl)-l-naphthoyl]amino}pyrazine-2-carboxylate (34 mg, 0.09 mmol) and (cyclohexylmethyl)amine (113 mg, 1.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (16 mg, 33 %). 1H MR (400 MHz, CD3OD) δ 0.98 (m, 2 H), 1.21 (m, 3H), 1.73 (m, 6 H), 3.19 (m, 2 H), 6.22 (s, 2H), 7.48 (d, J=8.0 Hz, IH), 7.65 (m, 2H), 7.77 (s, IH), 7.95 (d, J=8.0 Hz, IH), 7.99 (s, IH), 8.24 (d, J=8.0 Hz, IH), 8.43 (m, IH), 8.54 (m, IH), 8.58 (m, IH); MS (ESI) (M+H)+ 470.0. Example 57
N-(Tetrahydro-2JH-pyran-4-ylmethyl)-3-{[4-(lJE?-l,2,3-triazol-l-ylmethyl)-l- naphthoyl]amino}pyrazine-2-carboxamide
Figure imgf000090_0001
Following the procedure for Step B in Example 55, using 3-[(4-methyl-l- naphthoyl)amino]-N-(tetrahydro-2H-pyran-4-ylmethyl)pyrazine-2-carboxamide (50 mg, 0.12 mmol) and 1,2,3-triazole (69 mg, 1.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (14 mg, 20 %). 1H ΝMR (400 MHz, CD3OD) δ 1.30 (m, 2 H), 1.63 (m, 2 H), 1.89 (m, 1 H), 3.24 (m, 2 H), 3.36 (m, 2H), 3.88 (m, 2 H), 6.21 (s, 2H), 7.45 (d, J=7.6 Hz, IH), 7.64 (m, 2H), 7.76 (s, IH), 7.93 (d, J=7.6 Hz, IH), 7.98 (s, IH), 8.24 (d, J=8.0 Hz, IH), 8.42 (m, IH), 8.52 (m, IH), 8.59 (m, IH); MS (ESI) (M+H)+ 472.0.
Example 58 N-(3-Methylbutyl)-3-{[4-(lHr-l,253-triazol-l-ylmethyl)-l-naphthoyl]amino}pyrazine-2- carboxamide
Figure imgf000090_0002
Following the procedure for Step B in Example 55, using N-(3-methylbutyl)-3-[(4-methyl- l-naphthoyl)amino]pyrazine-2-carboxamide (40 mg TFA salt, 0.08 mmol) and 1,2,3- triazole (69 mg, 1.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase HPLC (13 mg, 30 %). 1H ΝMR (400 MHz, CD3OD) δ 0.87 (d, J =7.6 Hz, 6 H), 1.42 (m, 2H), 1.56 (m, IH), 3.31 (m, 2H), 6.22 (s, 2H), 7.47 (d, J=8.0 Hz, IH), 7.64 (m, 2H), 7.76 (s, IH), 7.94 (d, J=8.0 Hz, IH), 7.99 (s, IH), 8.24 (d, J=8.0 Hz, IH), 8.43 (m, IH), 8.51 (m, IH), 8.56 (m, IH); MS (ESI) (M+H)+ 444.0.
Example 59
3-{[4-(Methoxymethyl)-l-naphthoyl]amino}-N-(tetrahydro-2fl-pyran-4- ylmethyl)pyrazine-2-carboxamide
Figure imgf000091_0001
To a stirring solution of 3-[(4-methyl-l-naphthoyl)amino]-N-(tetrahydro-2H-pyran-4- ylmethyl)pyrazine-2-carboxamide (50 mg, 0.12 mmol) and BS (266 mg, 1.5 mmol) in 20 mL of C1CΗ2CΗ C1 at r.t was added l,r-azobis(cyclohexanecarbonitrile (5 mg). The solution was heated at 110 °C for 3 hr, and was then cooled to r.t. After removal of solvents (<20 °C), the residue was dissolved in 10 mL MeOH, and followed by addition of ΝaOMe solution (2 mL, 10 % in MeOH). The resulting solution was then stiπed for 4 hr at r.t. After standard workup, the residue was purified by reversed-phase HPLC to give the title compound as its TFA salt (6 mg, 9 %). 1H ΝMR (400 MHz, CD3OD) δ 1.30 (m, 2 H), 1.634 (m, 2 H), 1.87 (m, 1 H), 3.26 (m, 2 H), 3.36 (m, 2H), 3.49 (s, 3H), 3.91 (m, 2 H), 4.98 (s, 2H), 7.61 (m, 2H), 7.66 (d, J=7.6 Hz, IH), 7.92 (d, J=7.6 Hz, IH), 8.19 (d, J=8.0 Hz, IH), 8.40 (m, IH), 8.51 (m, IH), 8.59 & 9.24 (m, IH); MS (ESI) (M+H)+ 435.0.
Example 60 iV-(Cyclobutylmethyl)-3-{[4-(methoxymethyl)-l-naphthoyl]amino}pyrazine-2- carboxamide
Figure imgf000092_0001
Following the procedure in Example 59, using N-(cyclobutylmethyl)-3-[(4-methyl-l- naphthoyl)amino]pyrazine-2-carboxamide (50 mg, 0.13 mmol) provided the title compound as its TFA salt after purification by reversed-phase HPLC (20 mg, 29 %). 1H ΝMR (400 MHz, CD3OD) δ 1.76 (m, 2 H), 1.90 (m, 2 H), 2.05 (m, 2 H), 2.61 (m, 1 H), 3.38 (m, 2H), 3.49 (s, 3H), 3.91 (m, 2 H), 4.99 (s, 2H), 7.62 (m, 2H), 7.66 (d, J=7.6 Hz, IH), 7.93 (d, J=7.6 Hz, IH), 8.20 (d, J=8.0 Hz, IH), 8.40 (m, IH), 8.50 (m, IH), 8.59 (m, IH); MS (ESI) (M+H)+ 405.0.
Example 61 N-(Cyclohexylmethyl)-3-[(4-methoxy-l-naphthoyl)amino]pyrazine-2-carboxamide
Figure imgf000092_0002
Step A: N-(Cyclohexylmethyl)-3-[(4-methoxy-l-naphthoyl)amino]pyrazine-2- carboxamide
Figure imgf000093_0001
Following the procedure for Step A in Example 48, using methyl 3-[(4-methoxy-l- naphthoyl)amino]pyrazine-2-carboxylate (169 mg, 0.5 mmol) and
(cyclohexylmethyl)amine (113 mg, 1.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase HPLC (122 mg, 46 %). 1H NMR (400 MHz, CD3OD) δ 0.87 (m, 2 H), 1.10 (m, 3H), 1.64 (m, 6 H), 3.09 (d, J=7.6 Hz, 2 H), 3.94 (s, 3H), 6.85 (d, J=8.0 Hz, 1 H), 7.43 (m, IH), 7.51 (m, IH), 7.91 (d, J=8.0 Hz, 1 H), 8.20 (d, J=8.0 Hz, 1 H), 8.25 (s, IH), 8.45 (s, IH), 9.58 (d, J=8.0 Hz, IH); MS (ESI) (M+H)+ 419.0.
Step B: Methyl 3-[(4-Methoxy-l-naphthoyl)amino]pyrazine-2-carboxylate
Figure imgf000093_0002
Following the procedure for Step B in Example 48, using 4-mefhoxy-l- naphthalenecarbonyl chloride (3.0 mmol and methyl 3-aminopyrazine-2-carboxylate (459 mg, 3.0 mmol) provided the title compound after purification (584 mg, 58 %).
Example 62 3-{[5-Bromo-4-(lr7-l,2,3-triazol-l-ylmethyl)-l-naphthoyl]amino}-iV- (cyclohexylmethyl)pyrazine-2-carboxamide
Figure imgf000094_0001
To a stirring solution of N-(cyclohexylmethyl)-3-[(4-methyl-l-naphthoyl)amino]pyrazine- 2-carboxamide (100 mg, 0.25 mmol) andΝBS (231 mg, 1.3 mmol) in 20 mL of CICH2CH2CI at r.t was added l, -azobis(cyclohexanecarbonitrile (5 mg). The solution was heated at 110 °C for 24 hr, and was then cooled to r.t. After removal of solvents (<20 °C), the residue was dissolved in 10 mL MeCΝ, and followed by addition of 1,2,3-triazole (345 mg, 5 mmol). The resulting solution was then stiπed for 4 hr at r.t. After condensation, the residue was purified to provide the title compound as its TFA salt by reversed-phase HPLC (35 mg, 21 %). 1H ΝMR (400 MHz, CD3OD) δ 0.88 (m, 2 H), 1.12 (m, 3H), 1.64 (m, 6 H), 3.09 (m, 2 H), 4.79 (s, 2H), 7.38 (d, J=8.0 Hz, 1 H), 7.55 (m, IH), 7.66 (s, IH), 7.84 (d, J=8.0 Hz, 1 H), 7.88 (s, IH), 8.14 (d, J=8.0 Hz, 1 H), 8.42 (d, J=8.0 Hz, 1 H), 8.60 (s, IH), 8.93 (m, IH); MS (ESI) (M+H)+ 547.7.
Example 63
3-[(4-Methoxy-l-naphthoyl)amino]-N-(tetrahydrofuran-2-ylmethyl)pyridine-2- carboxamide
Figure imgf000094_0002
Following the procedure for Step A in Example 1, using 2-(4-methoxy-l-naphthyl)-4H- pyrido[3,2-ci][l,3]oxazin-4-one (12 mg, 0.04 mmol), and (tetrahydrofuran-2- ylmethyl)amine (20 mg, 0.2 mmol) provided the title compound (4.5 mg, 28 %). MS (ESI) (M+Η)+ = 406.2.
Example 64
N-(l,4-Dioxan-2-ylmethyl)-3-[(4-methoxy-l-naphthoyl)amino]pyridine-2- carboxamide
Figure imgf000095_0001
Following the procedure for Step A in Example 1, using 2-(4-methoxy-l-naphthyl)-4H- pyrido[3,2-d][l,3]oxazin-4-one (12 mg, 0.04 mmol), and (l,4-dioxan-2-ylmethyl) amine (23 mg, 0.2 mmol) provided the title compound (4.5 mg, 28 %). MS (ESI) (M+Η)+ = 422.2.
Example 65
3-[(4-Methoxy-l-naphthoyl)amino]-iV-(tetrahydro-2i?-pyran-4-yl)pyridiιτιe-2- carboxamide
Figure imgf000095_0002
Following the procedure for Step A in Example 1, using 2-(4-methoxy-l-naphthyl)-4H- pyrido[3,2-d][l,3]oxazin-4-one (100 mg, 0.33 mmol), and tetrahydro-2H-pyran-4-amine (101 mg, 1.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase HPLC (34 mg, 20 %). 1H NMR (400 MHz, CD3OD) δ 1.71 (m, 2 H), 1.85 (m, 2 H), 3.27 (m, 2 H), 3.49 (m, 2 H), 3.93 (m, 2 H), 4.05 (m, IH), 4.08 (s, 3H), 7.02 (d, J=8.4 Hz, 1 H), 7.59 (m, 3H), 7.92 (d, J=8.0 Hz, 1 H), 8.34 (m, 2 H), 8.53 (d, J=8.0 Hz, 1 H), 9.26 (d, J=8.0 Hz, IH); MS (ESI) (M+H)+ = 406.0.
Example 66
3-[(4-Methoxy-l-naphthoyl)amino]-N-[2-(tetrahydro-2JfiT-pyran-4-yl)ethyl]pyridine-2- carboxamide
Figure imgf000096_0001
Following the procedure for Step A in Example 1, using 2-(4-methoxy-l-naphthyl)-4H- pyrido[3,2-G7][l,3]oxazin-4-one (100 mg, 0.33 mmol), and [2-(tetrahydro-2H-pyran-4- yl)ethyl]amine (129 mg, 1.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (34 mg, 19 %). 1HNMR (400 MHz, CDC13) δ 1.35 (m, 2 H), 1.63 (m, 5 H), 3.38 (m, 2 H), 3.46 (m, 2 H), 3.95 (m, 2 H), 4.06 (s, 3H), 6.88 (d, J=8.0 Hz, 1 H), 7.52 (m, 2H), 7.60 (m, IH), 7.93 (d, J=8.0 Hz, 1 H), 8.26 (d, J=4.4 Hz, IH), 8.35 (d, J=8.0 Hz, 1 H), 8.42 (brs, IH), 8.64 (d, J=8.0 Hz, 1 H), 9.39 (dd, J=8.4, 1.2 Hz, IH), 12.75 (brs, IH); MS (ESI) (M+H)+ = 434.0.
Example 67
3-[(4-Methoxy-l-naphthoyl)amino]-iV-[(2R)-piperidin-2-ylmethyl]pyridine-2- carboxamide
Figure imgf000097_0001
Following the procedure for Step A in Example 1, using 2-(4-methoxy-l-naphthyl)-4H- pyrido[3,2-d][l,3]oxazin-4-one (100 mg, 0.33 mmol), and [(2R)-piperidin-2- ylmethyl] amine (114 mg, 1.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (58 mg, 33 %). 1H NMR (400 MHz, CD3OD) δ 1.54 (m, 3 H), 1.83 (m, 3 H), 2.85 (m, IH), 3.27 (m, 2 H), 3.59 (m, 2 H), 4.07 (s, 3H), 6.96 (d, J=8.0 Hz, 1 H), 7.62 (m, 3H), 7.91 (d, J=8.0 Hz, 1 H), 8.31 (d, J=4.4 Hz, IH), 8.38 (d, J=8.0 Hz, 1 H), 8.48 (d, J=8.0 Hz, 1 H), 9.24 (d, J=8.0 Hz, IH); MS (ESI) (M+H)+ = 419.0.
Example 68
3-[(4-Methoxy-l-naphthoyl)amino]-iV-(morpholin-3-ylmethyl)pyridine-2- carboxamide
Figure imgf000097_0002
Step A: 3-[(4-Methoxy-l-naphthoyl)amino]-iV-(morpholin-3-ylmethyl)pyridine-2- carboxamide
Figure imgf000098_0001
The crude tert-butyl 3-{[({3-[(4-methoxy-l-naphthoyl)amino]pyridin-2- yl}carbonyl)amino]methyl} morpholine-4-carboxylate from Step B was treated with 4 N HCl in dioxane for 1 hr at r.t. After evaporation, the residue was purified by reversed-phase HPLC to provide the title compound as its TFA salt (56 mg, 32 % for two steps). 1H NMR (400 MHz, CD3OD) δ 3.02 (m, IH), 3.21 (m, 2H), 3.47 (m, 2H), 3.59 (m, 2H), 3.82 (m, IH), 3.90 (m, IH), 4.07 (s, 3H), 6.97 (d, J=8.0 Hz, 1 H), 7.56 (m, 3H), 7.91 (d, J=8.0 Hz, 1 H), 8.3 l(d, J=4.4 Hz, IH), 8.38 (d, J=8.0 Hz, 1 H), 8.48 (d, J=8.0 Hz, 1 H), 9.25 (d, J=8.0 Hz, IH); MS (ESI) (M+H)+ = 421.0.
Step B: tart-Butyl 3-{[({3-[(4-methoxy-l-naphthoyl)amino]pyridin~2- yl} carbonyl)amino] methyl} morpholine-4-carboxylate
Figure imgf000098_0002
Following the procedure for Step A in Example 1, using 2-(4-methoxy~l-naphthyl)-4H- pyrido[3,2- ][l,3]oxazin-4-one (100 mg, 0.33 mmol), and tert-butyl 3- (aminomethyl)morpholiιιe-4-carboxylate (216 mg, 1.0 mmol) provided crude tert-butyl 3- {[({3-[(4-methoxy-l-naphthoyl)amino]pyridin-2-yl}carbonyl)amino]methyl} morpholine- 4-carboxylate, which was used directly in Step A.
Example 69 N-[(l-Hydroxycyclohexyl)methyl]-3-[(4-methoxy-l-naphthoyl)amino]pyridine-2- carboxamide
Figure imgf000099_0001
Following the procedure for Step A in Example 1, using 2-(4-methoxy-l-naphthyl)-4H- pyrido[3,2-d][l,3]oxazin-4-one (100 mg, 0.33 mmol), l-(aminomethyl)cyclohexanol hydrochloride (165 mg, 1.0 mmol), and DIPEA (1 mL) provided. the title compound as its TFA salt after purification by reversed-phase ΗPLC (58 mg, 32 %). 1H NMR (400 MHz, CDC13) δ 1.28 (m, 2 H), 1.58 (m, 8 H), 2.07 (brs, 1 H), 3.45 (d, J=6.4 Hz, 2 H), 4.06 (s, 3H), 6.87 (d, J=8.0 Hz, 1 H), 7.53 (m, 2H), 7.59 (m, IH), 7.92 (d, J=8.0 Hz, 1 H), 8.27(m, 1 H), 8.32 (d, J=8.0 Hz, IH), 8.64 (d, J=8.0 Hz, 1 H), 8.79 (s, IH), 9.39 (d, J=8.0 Hz, IH), 12.69 (s, IH); MS (ESI) (M+H)+ = 434.0.
Example 70 N-(Cyclohexylmethyl)-3-[(4-ethoxy-l-naphthoyl)amino]pyridine-2-carboxamide
Figure imgf000099_0002
Step A: N-(Cyclohexylmethyl)-3-[(4-ethoxy-l-naphthoyl)amino]pyridine-2- carboxamide
Figure imgf000100_0001
Following the procedure for Step A in Example 48, using methyl 3-[(4-ethoxy-l- naphthoyl)amino]pyridine-2-carboxylate (100 mg, 0.29 mmol) and (cyclohexylmethylamine (113 mg, 1.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase HPLC (36 mg, 23 %). X NMR (400 MHz, CDC13) δ 1.0 (m, 2H), 1.23 (m, 3 H), 1.59 (m, 5H), 1.76 (m, 4H), 3.25 (m, 2 H), 4.26 (m, 2H), 6.85 (d, J=8.0 Hz, 1 H), 7.52 (m, 3H), 7.92 (d, J=8.0 Hz, 1 H), 8.25 (s, 1 H), 8.37 (d, J=8.0 Hz, IH), 8.59 (s, IH), 8.60 (d, J=8.0 Hz, 1 H), 9.38 (d, J=8.0, Hz, IH), 12.8 (s, IH); MS (ESI) (M+H)+ 432.0.
Step B: Methyl 3-[(4-ethoxy-l-naphthoyl)amino]pyridine-2-carboxylate
Figure imgf000100_0002
4-Ethoxy-l-naphthoic acid (7.0 mmol) in 50 mL CH2C12 was treated with oxalyl chloride (10 mL, 2.0 M in CH2C12, 20 mmol) at r.t for 1 hr, and then heated to 50 °C for lhr. The reaction mixture was then condensed to afford 4-ethoxy-l-naphthalenecarbonyl chloride, which was added into a solution of 3-amino-2-pyridinecarboxylic acid (7.0 mmol) and DIPEA (14 mmol) in DMF (40 mL) at 0 °C. After stirred for 1 hr at r.t, and for 1 hr at 50 °C, K CO3 (1.86 g, 14 mmol) was added into the reaction mixture, and followed by addition of Mel (3.1 mL, 50 mmol) in portion at r.t. After stiπed overnight, the reaction mixture was condensed, and extracted by EtOAc, washed by brine, dried over MgSO . Removal of solvents provided a crude methyl 3-[(4-ethoxy-l-naphthoyl)amino]pyridine-2- carboxylate as a solid (2.25 g, 92 %), which was used directly in Step A. Example 71 3-[(4-Ethoxy-l-naphthoyl)amino]-iV-pentylpyridine-2-carboxamide
Figure imgf000101_0001
Following the procedure for Step A in Example 48, using methyl 3-[(4-ethoxy-l- naphthoyl)amino]pyridine-2-carboxylate (100 mg, 0.29 mmol) and pentan-1 -amine (130 mg, 1.5 mmol) provided the title compound as its TFA salt after purification by reversed- phase HPLC (16 mg, 11 %). 1H NMR (400 MHz, CDC13) δ 0.91 (t, J=7.6 Hz, 3H), 1.37 (m, 4 H), 1.59 (m, 5H), 3.41 (m, 2 H), 4.27 (m, 2H), 6.85 (d, J=8.0 Hz, 1 H), 7.52 (m, 3H), 7.92 (d, J=8.0 Hz, 1 H), 8.25 (s, 1 H), 8.37 (d, J=8.0 Hz, IH), 8.48 (s, IH), 8.63 (d, J=8.0 Hz, 1 H), 9.38 (d, J=8.0, Hz, IH), 12.8 (s, IH); MS (ESI) (M+H)+ 406.0.
Example 72
3-[(4-Ethoxy-l-naphthoyl)amino]-iV-(tetrahydro-2jQr-pyran-4-ylmethyl)pyridine-2- carboxamide
Figure imgf000101_0002
Following the procedure for Step A in Example 48, using methyl 3-[(4-ethoxy-l- naphthoyl)amino]pyridine-2-carboxylate (100 mg, 0.29 mmol) and (tetrahydro-2H-pyran- 4-ylmethyl)amine (172 mg, 1.5 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (18 mg, 12 %). 1H NMR (400 MHz, CDC13) δ 1.41 (m, 2 H), 1.59 (m, 3H), 1.68 (m, 2H), 1.82 (m, 1 H), 3.34 (m, 2 H), 3.44 (m, 2 H), 4.05 (m, 2 H), 4.28 (m, 2H), 6.85 (d, J=8.0 Hz, 1 H), 7.55 (m, 3H), 7.90 (d, J=8.0 Hz, 1 H), 8.27 (d, J=4.0 Hz, 1 H), 8.37 (d, J=8.0 Hz, IH), 8.57 (d, J=8.0 Hz, 1 H), 8.62 (s, IH), 9.38 (d, J=8.0, Hz, IH), 12.7 (s, IH); MS (ESI) (M+H)+ 434.0.
Example 73 iV-(Cyclopentylmethyl)-3-[(4-ethoxy-l-naphthoyl)amino]pyridine-2-carboxamide
Figure imgf000102_0001
Following the procedure for Step A in Example 48, using methyl 3-[(4-ethoxy-l- naphthoyl)amino]pyridine-2-carboxylate (100 mg, 0.29 mmol) and (cyclopentylmethyl)amine (149 mg, 1.5 mmol) provided the title compound as its TFA salt after purification by reversed-phase HPLC (36 mg, 24 %). 1H NMR (400 MHz, CDC13) δ 1.25 (m, 2 H), 1.59 (m, 7H), 1.82 (m, 2H), 2.18 (m, 1 H), 3.35 (m, 2 H), 4.27 (m, 2H), 6.85 (d, J=8.0 Hz, 1 H), 7.52 (m, 3H), 7.92 (d, J=8.0 Hz, 1 H), 8.35 (s, 1 H), 8.37 (d, J=8.0 Hz, IH), 8.56 (s, IH), 8.61 (d, J=8.0 Hz, 1 H), 9.38 (d, J=8.0, Hz, IH), 12.8 (s, IH); MS (ESI) (M+H)+ 418.0.
Example 74
3-[(4-Ethoxy-l-naphthoyl)amino]-iV-[2-(tetrahydro-2JH-pyran-4-yl)ethyl]pyridine-2- carboxamide
Figure imgf000102_0002
Following the procedure for Step A in Example 48, using methyl 3-[(4-ethoxy-l- naphthoyl)amino]pyridine-2-carboxylate (100 mg, 0.29 mmol) and 2-(tetrahydro-2H- pyran-4-yl)ethanamine (194 mg, 1.5 mmol) provided the title compound as its TFA salt after purification by reversed-phase HPLC (84 mg, 52 %). X NMR (400 MHz, CDC13) δ 1.35 (m, 2 H), 1.59 (m, 7H), 2.28 (m, 1 H), 3.38 (m, 2 H), 3.47 (m, 2 H), 3.95 (m, 2 H), 4.27 (m, 2H), 6.85 (d, J=8.0 Hz, 1 H), 7.52 (m, 3H), 7.90 (d, J=8.0 Hz, 1 H), 8.25 (d, J=4.0 Hz, 1 H), 8.35 (d, J=8.0 Hz, IH), 8.48 (s, IH), 8.64 (d, J=8.0 Hz, 1 H), 9.38 (d, J=8.0, Hz, IH), 12.7 (s, IH); MS (ESI) (M+H)+ 448.0
Example 75 iV-(Cyclobutylmethyl)-3-[(4-ethoxy-l-naphthoyl)amino]pyridine-2-carboxamide
Figure imgf000103_0001
Following the procedure for Step A in Example 48, using methyl 3-[(4-ethoxy-l- naphthoyl)amino]pyridine-2-carboxylate (100 mg, 0.29 mmol) and (cyclobutylmethylamine (128 mg, 1.5 mmol) provided the title compound as its TFA salt after purification by reversed-phase HPLC (14 mg, 10 %). X NMR (400 MHz, CDC13) δ 1.60 (m, 3H), 1.69-1.78 (m, 2 H), 1.81-1.91 (m, 2 H), 1.99-2.07 (m, 2 H), 2.51-2.62 (m, 1 H), 3.34 (m, 2 H), 4.27 (m, 2H), 6.85 (d, J=8.0 Hz, 1 H), 7.52 (m, 3H), 7.92 (d, J=8.0 Hz, 1 H), 8.35 (s, 1 H), 8.37 (d, J=8.0 Hz, IH), 8.56 (s, IH), 8.61 (d, J=8.0 Hz, 1 H), 9.38 (d, J=8.0, Hz, IH), 12.8 (s, IH); MS (ESI) (M+H)+ 404.0.
Example 76 /y-Cyclobutyl-3-[(5-methyl-l-naphthoyl)amino]pyridine-2-carboxamide
Figure imgf000103_0002
Following the procedure for Step A in Example 1, using 2-(4-methyl-l-naphthyl)-4H- pyrido[3,2-d][l,3]oxazin-4-one (193 mg, 0.67 mmol), and cyclobutylamine (200 mg, 2.81 mmol) provided the title compound after purification by MPLC on silica gel using hexane/EtOAc (4:1) (200 mg, 83 %). X NMR (400 MHz, CD3OD) δ 1.71 - 1.85 (m, 2 H), 2.05 - 2.20 (m, 2 H), 2.22 - 2.41 (m, 2 H), 2.76 (s, 3 H), 4.34 - 4.51 (m, 1 H), 7.45 (dd, J=7.32, 0.88 Hz, 1 H), 7.52 - 7.66 (m, 3 H), 7.78 (d, J=7.23 Hz, 1 H), 8.08 - 8.20 (m, 1 H), 8.37 (dd, J=4.49, 1.56 Hz, 1 H), 8.42 - 8.48 (m, 1 H), 9.28 (dd, J=8.49, 1.46 Hz, 1 H). MS (ESI) (M+H)+ 360.0. Anal. Calcd for C22H2iN3O2 (359.43): C, 73.52; H, 5.89; N, 11.69. Found: C, 73.44; H 5.08; N, 11.48.
Example 77 3-(l-Naphthoylamino)-iV-[(2R)-piperidin-2-ylmethyl]pyridine-2-carboxamide
Figure imgf000104_0001
Step A. 3-(l-Naphthoylamino)-iV-[(2R)-piperidin-2-ylmethyl]pyridine-2-carboxamide
Figure imgf000104_0002
Following the procedure for Step A in Example 1, using 2-(4-methyl-l-Naphthalenyl)-H- pyrido[3,2-c0[l,3]oxazin-4-one (260.0 mg, 0.9 mmol) and [(2i?)-piperidin-2- ylmethyl] amine (for preparation, see following Steps B, C and D) (260.0 mg, 2.28 mmol) in DMF (8.0 mL) provided the title compound after purification by MPLC on silica gel using CΗ2Cl2/MeOΗ (20:1). (162 mg, 45%) as a white solid. [α]D: +17.4 ° (c 0.265, EtOH). IH NMR (400 MHz, CD3OD) δ 1.54 (m, 3 H), 1.87 (m, 3 H), 2.75 (s, 3 H), 2.85 (m, 1 H), 3.24 (m, 2 H), 3.53 (dd, J=14.65, 3.71 Hz, 1 H), 3.61 (dd, J= 14.6, 7.6 Hz, 1 H), 7.42 (d, J=7.23 Hz, 1 H),7.61 (m, 3 H), 7.79 (d, J=7.23 Hz, 1 H), 8.14 (m, 1 H), 8.40 (dd, J=4.49, 1.56 Hz, 1 H), 8.44 (dd, J=7.32, 1.46 Hz, 1 H), 9.27 (dd, J=8.59, 1.37 Hz, 1 H). MS (ESI) (M+H)+ = 403.0. Anal. Calcd for C24H26N4O2 + 1.40 TFA +2.10 H2O: C, 53.65; H, 5.31; N, 9.34. Found: C, 53.61; H, 5.32; N, 9.49. Step B. tart-Butyl (2R)-2-(aminocarbonyl)piperidine-l-carboxylate
Figure imgf000105_0001
HATU (5.60 g, 14.7 mmol) was added to a mixture of the (2R)-l-(tert- butoxycarbonyl)ρiperidine-2-carboxylic acid (2.29 g, 10 mmol), ammonium chloride (3.21 g, 60 mmol) and DIPEA (3.88 g, 30 mmol) in DMF (70 mL) at 0 °C. The mixture was stirred for 18 h at room temperature, diluted with H2O (100 mL) and extracted with EtOAc (3x100 mL). The combined organic phases were washed with 10% Na2CO3 solution (2x30 mL), brine (2x30 mL) and dried with Na2SO . After filtration and concentration, the title compound was purified by MPLC on silica gel using hexane/EtOAc(l:l) (2.28 g, 100 %) as a white solid. X NMR(400 MHz, CDC13) δ 1.46 (s, 9 H), 1.63 (m, 2 H), 2.22 (m, 1 H), 2.91 (m, 1 H), 3.06 (m, 3 H), 4.01 (m, 1 H), 4.71 (m, 1 H), 6.46 (s broad, 2 H). MS (ESI) (M+H)+ = 228.92 Step C. (2R)-Piperidine-2-carboxamide
Figure imgf000105_0002
tert-Butyl (2R)-2-(aminocarbonyl)piperidine-l-carboxylate (2.28 g, 10 mmol) was treated with 4 NHC1 in dioxane (60 mL, 240 mmol) for 4 h at room temperature. After evaporation of the solvent, the title compound was washed with ether and dried in vacuo (HCl salt, 1.65 g, 100 %). IH ΝMR (400 MHz, DMSO-D6) δ 1.36 - 1.81 (m, 5 H), 2.11 (m, 1 H), 2.77 - 2.97 (m, 1 H), 3.16 (m, 1 H), 3.67 (m, 1 H), 7.54 (s, 1 H), 7.94 (s, 1 H), 8.61 (s, 1 H), 9.22 (s, 1 H).
Step D. [(2R)-Piperidin-2-ylmethyl] amine
Figure imgf000106_0001
(2i?)-piperidine-2-carboxamide (HCl salt, 1.65 g, 10 mmol) was treated with LAH (2.2 g, 58 mmol) in THF (150 mL) for 18 h at room temperature and 3 h at reflux. The mixture was cooled down, quenched with MeOH (10 mL) and H2O (10 mL). Na2SO4 (100 g) was added. The resulting mixture was stirred for 2h at room temperature. After filtration and evaporation of the solvent (1.14 g, 100 %) of the title compound was obtained as a crude product, which was directly used for next step.
Example 78 3-(l-Naphthoylamino)-iV-[(2S)-piperidin-2-ylmethyl]pyridine-2-carboxamide
Figure imgf000106_0002
Step A. 3-(l-Naphthoylamino)-N-[(2S)-piperidin-2-ylmethyl]pyridine-2-carboxamide
Figure imgf000106_0003
Following the procedure for Step A in Example 1, using 2-(4-methyl-l-Naphthalenyl)-H- pyrido[3,2-d][l,3]oxazin-4-one (110 mg, 0.38 mmol) and [(2S)-piperidin-2- ylmethyl] amine (110 mg, 0.96 mmol) (for preparation, see following Steps B, C and D) in DMF (8.0 mL) provided the title compound after purification by MPLC on silica gel using CH2Cl2/MeOH (20:1) (61.8 mg, 40 %) as a white solid. [α]D -14.2 ° (c 0.265, EtOH). IH NMR (400 MHz, CD3OD) δ 1.54 (m, 3 H), 1.87 (m, 3 H) 2.74 (s, 3 H), 2.84 (m, 1 H), 3.22 (m, 2 H), 3.52 (dd, J=14.65, 3.71 Hz, 1 H), 3.60 (m, 1 H), 7.40 (d, J=7.23 Hz, 1 H), 7.59 (m, 3 H), 7.78 (d, J=7.22 Hz, 1 H), 8.12 (d, J=8.01 Hz, 1 H), 8.38 (d, J=3.51 Hz, 1 H), 8.43 (m, 1 H), 9.25 (d, J=8.01 Hz, 1 H). MS (ESI) (M+H)+ = 403.3. Anal. Calcd for C24H26N4O2 + 1.20 TFA +0.10 H2O: C, 58.60; H, 5.10; N, 10.35. Found: C, 58.52; H, 5.17; N, 10.36. Step B. tart-Butyl (2S)-2-(aminocarbonyl)piperidine-l-carboxylate
Figure imgf000107_0001
Following the procedure for Step B in example 77, using HATU (5.56 g, 14.6 mmol, (2S)- l-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (2.29 g, 10 mmol), ammonium chloride (3.20 g, 60 mmol) and DIPEA (3.88 g, 30 mmol) in DMF (70 mL) provided the title compound after purification by MPLC on silica gel using hexane/EtOAc(l:l) (2.28 g, 100 %) as a white solid. IH NMR (400 MHz, CDC13) δ 1.47 (s, 9 H), 1.52 (m, 3 H), 1.64 (m, 3 H), 2.89 (s broad, 2 H), 4.04 (s broad, 1 H), 6.06 (s broad, 1 H), 6.21 (s broad, 1 H). MS (ESI) (M+H)+ = 228.92 Step C. (2S)-Piperidine-2-carboxamide
Figure imgf000107_0002
Following the procedure for Step C in example 77, using tert-Butyl (2S)-2- (aminocarbonyl)piperidine-l-carboxylate (2.28 g, 10 mmol) and 4 NHC1 in dioxane (60 mL, 240 mmol) provided the title compound (HCl salt, 1.65 g, 100 %). 1H MR (400 MHz, DMSO-D6) δ 1.33 - 1.80 (m, 5 H), 2.08 (m, 1 H), 2.85 (m, 1 H), 3.15 (m, 1 H), 3.51 - 3.75 (m, 1 H), 7.53 (s, 1 H), 7.88 (s, 1 H), 8.58 (s, 1 H), 9.07 (s, 1 H). Step D. [(2S)-Piperidin-2-ylmethyl]amine
Figure imgf000108_0001
Following the procedure for Step D in example 77, using (2i?)-piperidine-2-carboxamide (HCl salt, 1.65 g 10 mmol) and LAH (2.6 g, 68 mmol) in THF (150 mL) provided the title compound ( 1.14g, 100 %) as a crude product, which was directly used for next step.
Example 79 3-(l-Naphthoylamino)-iV-(pyridin-2-ylmethyl)pyridine-2-carboxamide
Figure imgf000108_0002
Following the procedure for Step A in Example 1, using 2-(l-Naphthalenyl)-H-pyrido[3,2- ][l,3]oxazin-4-one (54.9 mg, 0.2 mmol) and (pyridin-2-ylmethyl)amine (74.2 mg, 0.68 mmol) in DMF (2.0 mL) provided the title compound as a white solid. Yield: 56.3 mg (74%). 1Η NMR (400 MHz, CD3OD) δ 4.91 (s, 2 H), 7.55 (m, 3 H), 7.68 (dd, J=8.69, 4.59 Hz, 1 H), 7.84 (dd, J=7.22, 1.17 Hz, 1 H), 7.94 (m, 2 H), 8.05 (dd, J=8.20, 3.71 Hz, 2 H), 8.39 (dd, J=6.25, 3.71 Hz, 1 H), 8.44 (dd, J=4.59, 1.46 Hz, 1 H), 8.55 (t, J=8.01 Hz, 1 H), 8.69 (d, J=6.05 Hz, 1 H), 9.30 (m, 1 H). MS (ESI) (M+H)+ = 383.0. Anal. Calcd for C23H18N4O2 + 2.10 HCl +1.30 H2O: C, 57.27; H, 4.74; N, 11.61. Found: C, 57.35; H, 4.71; N, 11.65.
Example 80 3-(4-Methyll-naphthoylamino)-iV-(pyridin-2-ylmethyl)pyridine-2-carboxamide
Figure imgf000109_0001
Following the procedure for Step A in Example 1, using 2-(4-Methyl-l-naphthalenyl)-H- pyrido[3,2-rf][l,3]oxazin-4-one (86.5 mg, 0.3 mmol)and (pyridin-2-ylmethyl)amine (105.0 mg, 0.97 mmol) in DMF (3.0 mL) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC using 10-85% MeCN/Η2O (54.9 mg, 36 %). IH NMR (400 MHz, CD3OD) δ 2.74 (s, 3 H), 4.71 (s, 2 H), 7.41 (m, 2 H), 7.57 (m, 3 H), 7.64 (dd, J=8.59, 4.49 Hz, 1 H), 7.77 (d, J=7.22 Hz, 1 H), 7.92 (m, 1 H), 8.12 (m, 1 H), 8.40 (dd, J=4.49, 1.37 Hz, 1 H), 8.46 (m, 1 H), 8.51 (s, 1 H), 9.30 (dd, J=8.59, 1.37 Hz, 1 H). MS (ESI) (M+H)+ = 397.0. Anal. Calcd for C2 H2oN4O2 + 0.2 TFA +0.20 H2O: C, 69.31 ; H, 4.91; N, 13.25. Found: C, 69.27; H, 4.96; N, 13.22.
Example 81 3-[(4-Amino-l-naphthoyl)amino]-iV-(cyclohexylmethyl)pyridine-2-carboxamide
Figure imgf000109_0002
Step A. 3-[(4-Amino-l-naphthoyl)amino]-iV-(cyclohexylmethyl)pyridine-2- carboxamide
Figure imgf000110_0001
tert-Butyl (4-{[(2-{[(cyclohexylmethyl)amino]carbonyl}pyridin-3-yl)amino]carbonyl}-l- naphthyl)carbamate (14.2 mg, 0.028 mmol) in CH2CI2 (1.5 mL) was treated with trifluoroacetic acid (1.5 mL). The reaction mixture was stirred for 3 h at room temperature. After concentration and lyophihzation, the title compound was obtained as TFA salt (14.0 mg, 97 %). IH NMR (400 MHz, CD3OD) δ 0.86 - 1.00 (m, 2 H), 1.07 - 1.29 (m, 4 H), 1.48 - 1.58 (m, 1 H), 1.68 (m, 4 H), 3.14 (d, J=6.83 Hz, 2 H), 6.79 (d, J=8.01 Hz, 1 H), 7.36 - 7.54 (m, 3 H), 7.74 (d, J=8.01 Hz, 1 H), 8.00 (dd, J=8.40, 0.78 Hz, 1 H), 8.25 (dd, J=4.49, 1.17 Hz, 1 H), 8.54 (d, J=8.20 Hz, 1 H,) 9.18 (dd, J=8.59, 1.37 Hz, 1 H). MS (ESI) (M+H)+ = 403.3. Anal. Calcd for C2 H26N4O2 +0.30 TFA+0.50 EtOAc+0.50 H2O (495.77): C, 65.66 , H, 6.36; N, 11.30. Found: C, 65.54 ; H, 6.42; N, 11.34. Step B. tart-Butyl [4-(4-oxo-4J?-pyrido[3,2-</][l,3]oxazin-2-yl)-l-naphthyl]carbamate
Figure imgf000110_0002
Oxalyl chloride (0.28 mL, 2.0M, 0.56 mmol) in CH2C12 was added to a solution of A-[(tert- butoxycarbonyl)amino]-l-naphthoic acid (72.7 mg, 0.25 mmol) in CH2C12 (5 mL). Stirring for 4.5 h at room temperature and evaporation of the solvent, the residue was dissolved in CH2C1 (5 mL). 3-Amino-2-pyridinecarboxylic acid (34.5 mg , 0.25 mmol) and DIPEA (105 uL, 77.8 mg, 0.60 mmol) were added at 0 °C. Stirring for 2 h at room temperature and evaporation of the solvent, DMF (5 mL), DIPEA (105 uL, 77.8 mg, 0.60 mmol) and then HATU (104.6 mg, 0.28 mmol) were added. The resulting mixture was stirred overnight at room temperature. The title compound was formed and directly used for next step. Step C. tart-Butyl (4-{[(2-{[(cyclohexyImethyl)amino]carbonyl}pyridin-3- yl)amino]carbonyl}-l-naphthyl)carbamate
Figure imgf000111_0001
A solution of tert-Butyl [4-(4-oxo-4H-pyrido[3,2-<i][l,3]oxazin-2-yl)-l- naphthyl] carbamate (0.25 mmol) in DMF (5 mL) (for preparation see following Step B) was treated with cyclohexane methylamine (160 uL, 139 mg, 0.1.2 mmol) at 0 °C. The mixture was stirred for 18 h at room temperature. After evaporation of the solvent, the title compound was purified by MPLC on silica gel using hexane/EtOAc (4:1) (29.4 mg, 23%). 1Η NMR (400 MHz, CD3OD) δ 0.91 - 1.04 (m, 2 H), 1.12 - 1.30 (m, 4 H,) 1.56 (s, 9 H), 1.59 - 1.80 (m, 5 H), 3.19 (d, J=7.03 Hz, 2 H,) 7.53 - 7.65 (m, 3 H), 7.81 - 7.86 (m, 1 H), 7.88 - 7.94 (m, 1 H), 8.14 (dd, J=6.74, 3.22 Hz, 1 H), 8.36 (dd, J=4.39, 1.27 Hz, 1 H), 8.46 - 8.55 (m, 1 H), 9.28 (dd, J=8.49, 1.27 Hz, 1 H). MS (ESI) (M+H)+ = 503.3. Anal. Calcd for C29H34N4O4+ 0.5 HCl+0.3 H2O (526.25): C, 66.19, H, 6.72, N, 10.65; Found: C, 66.14 ; H, 6.73; N, 10.24..
Example 82 N-(Cyclohexylmethyl)-3-[(4-methyl-l-naphthalenylcarbonyl)amino]-2- pyridinecarboxamide
Figure imgf000112_0001
Step A. N-(Cyclohexylmethyl)-3-[(4-methyl-l-naphthalenylcarbonyl)amino]-2- pyridinecarboxamide
Figure imgf000112_0002
4-Methyl-l-naphthalenecarbonyl chloride (80 mg, 0.39 mmol) was added to a solution of 3-amino-N-(cyclohexylmethyl)pyridine-2-carboxamide (61 mg, 0.26 mmol) (for preparation see following step B) and DMAP (64 mg, 0.52 mmol) in CH2C12 (10 mL) at 0 °C. The mixture was stirred overnight at room temperature, quenched with saturated ΝaHCO3 solution (5 mL), and extracted with EtOAc (3x50 mL). The combined organic phases were washed with brine (2x10 mL) and dried with Na2SO . After filtration and concentration, the title compound was purified by MPLC on silica gel using hexane/EtOAc (4:1) (96 mg, 92 %). X NMR (400 MHz, CD3OD) δ 0.88 - 1.05 (m, 2 H), 1.09 - 1.34 (m, 3 H), 1.52 - 1.68 (m, 2 H), 1.68 - 1.81 (m, 4 H), 2.76 (s, 3 H), 3.18 (d, J=6.83 Hz, 2 H), 7.39 - 7.50 (m, 1 H), 7.54 - 7.65 (m, 3 H), 7.80 (d, J=7.23 Hz, 1 H), 8.06 - 8.18 (m, 1 H), 8.36 (dd, J=4.49, 1.56 Hz, 1 H) ,8.43 - 8.50 (m, 1 H), 9.29 (dd, J=8.59, 1.56 Hz, 1 H). MS (ESI) (M+H)+ 402.0. Anal. Calcd for C25H27N3O2 + 0.10 H2O (403.31): C, 74.45; H, 6.80; N, 10.42. Found: C, 74.42; H 6.89; N, 10.13. Step B.3-Amino-iV-(cyclohexylmethyl)pyridine-2-carboxamide
Figure imgf000113_0001
3-Aminopyridine-2-carboxylic acid (138 mg, 1.0 mmol) was added to a solution of cyclohexane methylamine (226 mg, 2. 0 mmol) and DIPEA (259 mg, 0.35 mmol) in DMF (5 mL). After stiπing for 30 min, HATU (456 mg, 1.2 mmol) was added at 0 °C. The resulting mixture was stirred overnight at room temperature, quenched with water (50 ml), and extracted with EtOAc (3x40 mL). The combined organic phases were washed with water (2x5 mL), brine (5 mL), and dried with Na2SO4. After filtration and concentration, the title compound was purified by MPLC on silica gel using hexane/EtOAc (1:1) (124 mg, 53 %). MR (400 MHz, CDC13) δ 0.93 - 1.07 (m, 2 H), 1.13 - 1.32 (m, 3 H), 1.51 - 1.70 (m, 2 H), 1.70 - 1.86 (m, 4 H), 3.26 (t, J=6.64 Hz, 2 H), 6.00 (s, 2 H), 7.00 (dd, J=8.40, 1.37 Hz, 1 H), 7.15 (dd, J-8.40, 4.30 Hz, 1 H), 7.85 (dd, J=4.30, 1.37 Hz, 1 H), 8.22 (s, 1 H). (MS (ESI) (M+H)+ 233.89.
Example 83 iV-(Cyclohexylmethyl)-3-[(2,2-dimethylbutanoyl)amino]pyridine-2-carboxamide
Figure imgf000113_0002
Following the procedure for Step A in Example 82, using 2,2-Dimethylbutanoyl chloride (30.0 mg, 0.223 mmol), 3-amino-N-(cyclohexylmethyl)pyridine-2-carboxamide (24.3 mg, 0.104 mmol) and DMAP (30.0 mg, 0.246 mmol) in CH2C12 (5 mL) provided the title compound after purification by MPLC on silica gel using hexane/EtOAc (9:1) (31.2 mg, 91 %). X ΝMR (400 MHz, CD3OD) δ 0.88 (t, J=7.52 Hz, 3 H), 0.94 - 1.08 (m, 2 H), 1.16 - 1.25 (m, 2 H), 1.28 (s, 6 H,) 1.28 - 1.35 (m, 2 H), 1.56 - 1.64 (m, 1 H), 1.68 (q, j=7.42 Hz, 2 H), 1.72 - 1.82 (m, 4 H), 3.24 (d, J=6.83 Hz, 2 H), 7.48 (dd, J=8.59, 4.49 Hz, 1 H), 8.27 (dd, J=4.49, 1.37 Hz, 1 H), 9.04 (dd, J=8.59, 1.37 Hz, 1 H). MS(ESI) (M+H)+ 332.0. Anal. Calcd for C19H29Ν3O2 + 0.1 H2O (333.26): C, 68.48; H, 8.81; N, 12.61. Found: C, 68.61; H 8.92; N, 12.28.. Example 84
3-[(4-Amino-l-naphthoyl)amino]-iV-(tetrahydro-2JEιr-pyran-4-ylmethyl)pyridine-2- carboxamide
Figure imgf000114_0001
Step A. 3-[(4-Amino-l-naphthoyl)amino]-iV-(tetrahydro-2Jϊ-pyran-4- ylmethyl)pyridine-2-carboxamide
Figure imgf000114_0002
tert-Butyl (4- {[(2- {[(tetrahydro-2H-pyran-4-ylmethyl)amino]carbonyl}pyridin-3- yl)amino]carbonyl}-l-naphthyl)carbamate (377.0 mg, 0.747 mmol) in CΗ2C12 (5 mL) was treated with 4NHCl/dioxane (5 mL). The reaction mixture was stiπed for 4 h at room temperature. After concentration and dried in vacuo, the title compound was obtained as a white solid (374.7 mg, 100 %). IH ΝMR (400 MHz, CD3OD) δ 1.20 - 1.38 (m, 2 H), 1.64 (m, 2 H), 1.77 - 1.95 (m, 1 H), 3.25 (d, J=7.03 Hz, 2 H), 3.31 - 3.41 (m, 2 H), 3.83 - 3.98 (m, 2 H), 7.55 - 7.64 (m, 1 H), 7.66 - 7.75 (m, 3 H), 7.93 (d, J=7.81 Hz, 1 H), 8.01 - 8.12 (m, 1 H), 8.37 (d, J=2.73 Hz, 1 H), 8.53 - 8.65 (m, 1 H), 9.27 (d, J=8.59 Hz, 1 H). MS (ESI) (M+H)+ = 405.0. Anal. Calcd for C23H24Ν4O3+l .70 HCl (466.46): C, 59.22; H, 5.55; N, 12.01. Found: C, 59.28; H 5.45; N, 11.87. Step B. tart-Butyl (4-{[(2-{[(tetrahydro-2JΪ-pyran-4- ylmethyl)amino]carbonyl}pyridin-3-yl)amino]carbonyl}-l-naphthyl)carbamate
Figure imgf000115_0001
Oxalyl chloride (3.8 lnL, 2.0M, 7.6 mmol) in CH2C12 was added to a solution of A-[{tert- butoxycarbonyl)amino]-l-naphthoic acid (985.8 mg, 3.42 mmol) and DMAP (459.6 mg, 3.76 mmol) in CH2C12 (70 mL) at 0 °C. Stirring for 2 h at room temperature and evaporation of the solvent and excess oxalyl chloride, the residue was dissolved in CH C12 (70 mL). A solution of 3-amino-N-(tetrahydro-2H-pyran-4-ylmethyl)pyridine-2- carboxamide (807.2 mg, 3.42 mmol) and DMAP(459.6 mg, 3.76 mmol) in (10 mL) was added. The resulting mixture was stiπed overnight at room temperature, washed with saturated ΝaΗCO3 solution (2x1 OmL) and dried overNa2SO4. The title compound was purified by MPLC on silica gel using hexane/EtOAc (1:1) (377.0 mg, 22 %) as a white solid. X NMR (400 MHz, CD3OD) δ 1.22 - 1.39 (m, 2 H), 1.56 (s, 9 H), 1.59 - 1.69 (m, 2 H), 1.79 - 1.95 (m, 1 H), 3.25 (d, J=7.03 Hz, 2 H), 3.32 - 3.44 (m, 2 H), 3.90 (dd, J=11.42, 3.03 Hz, 2 H,) 7.53 - 7.66 (m, 3 H), 7.79 - 7.87 (m, 1 H), 7.88 - 7.96 (m, 1 H), 8.14 (dd, J=6.54, 3.42 Hz, 1 H), 8.36 (dd, J=4.49, 1.37 Hz, 1 H), 8.50 (dd, J=6.54, 3.03 Hz, 1 H), 9.27 (dd, J=8.59, 1.56 Hz, 1 H). MS (ESI) (M+H)+ 505.0. Anal. Calcd for C28H32N4O5+0.50 MeOH (520.01): C, 65.75; H, 6.58; N, 10.76. Found: C, 65.76; H 6.51; N, 10.65..
Example 85 3-{[4-(Acetylamino)-l-naphthoyl]amino}-Λ'-(tetrahydro-2jgr-pyran-4- ylmethyl)pyridine-2-carboxamide
Figure imgf000116_0001
Acetyl chloride (7.7 mg, 0.099 mmol) was added to a solution of 3 -[(4- Amino- 1- naphthoyl)amino]-N-(tetrahydro-2H-pyran-4-ylmethyl)pyridine-2-carboxamide hydrochloride (33.4 mg, 0.076 mmol) and DMAP (23.2 mg, 0.19mmol) in CΗ2C12 (5 mL). The reaction mixture was stirred overnight at room temperature, diluted with CH2C12 (100 mL), washed with saturated ΝaHCO3 solution (2x10 mL) and dried over Na2SO4. After filtration and concentration, the title compound was purified by MPLC on silica gel using hexane/EtOAc (1:1) (27.3 mg, 81 %). IH NMR (400 MHz, CD3OD) δ 1.22 - 1.39 (m, 2 H), 1.63 (m, 2 H), 1.78 - 1.93 (m, 1 H), 2.30 (s, 3 H), 3.24 (d, J=6.83 Hz, 2 H), 3.31 - 3.41 (m, 2 H), 3.90 (m, 2 H), 7.56 - 7.65 (m, 3 H), 7.83 (d, J=8.01 Hz, 1 H), 7.90 - 7.94 (m, 1 H), 8.08 - 8.21 (m, 1 H), 8.37 (dd, J=4.49, 1.37 Hz, 1 H), 8.45 - 8.56 (m, 1 H), 9.28 (dd, J=8.59, 1.56 Hz, 1 H). MS (ESI) (M+H)+ 447.0. Anal. Calcd for C25H26N4O4+0.20 HCl +0.40 EtOAc(499.25): C, 64.96; H, 6.06, N, 11.22. Found: C, 65.05; H, 6.03; N, 11.16.
Example 86
3-[( -{[(Methylamino)carbonyl]amino}-l-naphthoyl)amino]- V-(tetrahydro-2Ja,- pyran-4-ylmethyl)pyridine-2-carboxamide
Figure imgf000117_0001
DIPEA(12.6 mg, 17μL, 0.0976 mmol) was added to a suspension of 3-[(4-amino-l-naphthoyl)amino]-N-(tetrahydro-2H-pyran-4-ylmethyl)pyridine-2- carboxamide hydrochloride (36.0 mg, 0.0816 mmol) in 1,2-dichloroethane (3 mL). Stirring for 10 min, a clear solution was formed. Methylisocyanate (20 μL) was added. The reaction mixture was heated for 3 days at 60 °C, diluted with CΗ2C12 (100 mL), washed with brine (2x10 mL) and dried over Νa2SO4. After filtration and concentration, the title compound was purified by MPLC on silica gel using hexane/EtOAc (1:1) (23.4 mg, 62 %). IH NMR (400 MHz, CD3OD) δ 1.22 - 1.38 (m, 2 H), 1.64 (m, 2 H), 1.78 - 1.95 (m, 1 H), 2.84 (s, 3 H), 3.25 (d, J=6.83 Hz, 2 H,) 3.32 - 3.42 (m, 2 H), 3.91 (m, 2 H), 7.55 - 7.64 (m, 3 H), 7.86 - 7.92 (m, 1 H), 7.95 - 8.01 (m, 1 H), 8.12 (dd, J=6.74, 3.03 Hz, 1 H), 8.35 (dd, J=4.49, 1.56 Hz, 1 H), 8.49 - 8.57 (m, 1 H), 9.27 (dd, J=8.49, 1.46 Hz, 1 H). MS (ESI) (M+H)+ 462.0. Anal. Calcd for C25H27N5O4+ 0.6 MeOH: C, 63.96; H, 6.16; N, 14.57; Found: C, 64.17; H, 6.17; N, 14.30.
Example 87 Methyl (4-{ [(2-{ [(tetrahydro-2Jϊ-pyran-4-ylmethyl)amino] carbonyl}pyridin-3- yl)amino]carbonyl}-l-naphthyl)carbamate
Figure imgf000118_0001
A solution of 3-[(4-amino-l -naphthoyl)amino]-N-(tetrahydro-2H-pyran-4- ylmethyl)pyridine-2-carboxamide (45.9 mg, 0.114 mmol), DMAP(56.0 mg, 0.458 mmol) and methyl chloroformate (122 mg, 100 μL, 1.29 mmol) in MeCΝ(5 mL) was heated at 100 °C in a Personal Chemistry SmithSynthesizer microwave instrument for 1 h. After concentration, the title compound was purified by MPLC on silica gel using hexane EtOAc (1:1) (18.3 mg, 38 %). 1Η NMR (400 MHz, CD3OD) δ 1.20 - 1.44 (m, 2 H), 1.64 (m, 2 H), 1.76 - 2.03 (m, 1 H), 3.26 (m, 2 H) 3.32 - 3.46 (m, 2 H), 3.83 (s, 3 H), 3.91 (m, 2 H), 7.45 - 7.72 (m, 3 H), 7.83 - 7.99 (m, 2 H), 8.08 - 8.22 (m, 1 H), 8.38 (dd, J=4.49, 1.37 Hz, 1 H), 8.47 - 8.60 (m, 1 H), 9.29 (dd, J=8.59, 1.56 Hz, 1 H). MS (ESI) (M+H)+ 463.0. Anal. Calcd for C25H26N4O5+ 0.1 HCl +0.9 MeCN+0.3 H2O(508.51): C, 63.30, H, 5.83, N, 13.50 Found: C, 63.20 ; H, 5.83; N, 13.45.
Example 88 N-(Cyclohexyloxy)-3-[(4-methyl-l-naphthoyl)amino]pyridine-2-carboxamide
Figure imgf000118_0002
Step A. iV-(Cyclohexyloxy)-3-[(4-methyl-l-naphthoyl)amino]pyridine-2-carboxamide
Figure imgf000119_0001
4-Methyl-l-naphthoyl chloride (126.6 mg, 0.62 mmol) was added to a solution of 3-amino- N-(cyclohexyloxy)pyridine-2-carboxamide (97.0 mg, 0.41 mmol) (for preparation see following step B) and DMAP (100.2 mg, 82 mmol) in CH2C12 (10 mL) at 0 °C. The mixture was stiπed overnight at room temperature, quenched with saturated ΝaHCθ3 solution (5 mL), and extracted with EtOAc (3x50 mL). The combined organic phases were washed with brine (10 mL) and dried over Na2SO4. After evaporation of the solvent, the title compound was purified by MPLC on silica gel using hexane EtOAc (1:1) (30.5 mg, 18 %). IH NMR (400 MHz, CD3OD) δ 1.14 - 1.36 (m, 3 H), 1.38 - 1.59 (m, 3 H), 1.72 - 1.82 (m, 2 H), 1.93 - 2.04 (m, 2 H), 2.76 (s, 3 H), 3.82 - 3.97 (m, 1 H), 7.45 (d, J=7.23 Hz, 1 H), 7.53 - 7.67 (m, 3 H), 7.80 (d, J=7.23 Hz, 1 H), 8.07 - 8.17 (m, 1 H), 8.35 (dd, J=4.49, 1.37 Hz, 1 H), 8.43 - 8.48 (m, 1 H), 9.26 (dd, J=8.59, 1.37 Hz, 1 H). MS (ESI) (M+H)+ = 404.0. Anal. Calcd for C24H25N3O3 + 0.20 TFA+0.3 H2O(431.69): C, 67.89; H, 6.02; N, 9.73. Found: C, 67.98; H 6.04; N, 9.54. Step B. 3-Amino-N-(cyclohexyloxy)pyridine-2-carboxamide
Figure imgf000119_0002
HATU ( g, 6.10 mmol) was added to a solution of O C-cycrlohexylhyodroxylamine (prepared as ref. A. Miyake et alJ. Antibiot. 53 (10), 1071-1085, 2000) (0.86 g, 7.50 mmol), DIPEA (1.29 g, 10.0 mmol) and 3-aminopyridine-2-carboxylic acid (0.69 g, 5.00 mmol) in DMF (20 mL) at 0 °C. The mixture was stiπed overnight at room temperature, diluted with EtOAc (200 mL), washed with H2O (2x10 mL), brine (10 mL) and dried over Na2SO4. After evaporation of the solvent, the title compound was purified by MPLC on silica gel using hexane/EtOAc (1 : 1) (1.35 g, 100 %) as a white solid. IH NMR (400 MHz, CDC13) δ 1.30 (m, 2 H), 1.52 (m, 4 H), 1.80 (m, 2 H), 2.06 (m, 2 H), 3.96 (m, 1 H), 5.93 (s, 2 H), 7.00 (dd, J=8.40, 1.37 Hz, 1 H), 7.17 (dd, J=8.40, 4.30 Hz, 1 H), 7.82 (dd, J=4.30, 1.37 Hz, I H), 10.12 (s, 1 H).
Example 89 3-[(4-Methyl-l-naphthoyl)amino]-N-[(l-methylpiperidin-2-yl)methyl]pyridine-2- carboxamide
Figure imgf000120_0001
To a solution of 3-[(4-methyl-l-naphthoyl)amino]-N-(piperidin-2-ylmethyl)pyridine-2- carboxamide (TFA salt, 161 mg) and formaldehyde (37 % in H20, 100 mg) in CH2CI2 (15 mL) at r.t, was added ΝaBH(OAc)3 (300 mg) in one portion. The reaction mixture was stiπed at r.t for 3 hours, and then concentrated. The residue was dissolved in EtOAc, washed with aqueous NH4C1, dried (Na2SO4), filtered and concentrated. Purification by reversed-phase HPLC provided the title compound as its TFA salt (34 mg, 20 %). X NMR (400 MHz, CD3OD) δ 1.60 (m, 3H), 1.84 (m, 2H), 2.06 (m, IH), 2.77 (s, 3H), 2.86 (m, IH), 3.01 (s, 3H), 3.02 (m, IH), 3.25 (m, IH), 3.42 (m, IH), 3.58 (m, IH), 3.98 (m, IH), 7.43 (d, J=7.6 Hz, 1 H), 7.61 (m, 3 H), 7.80 (d, J=7.6 Hz, 1 H), 8.15 (d, J=8.0 Hz, 1 H), 8.41 (dd, J=4.4, 1.2 Hz, 1 H), 8.46 (dd, J=8.0, 0.8 Hz, 1 H), 9.28 (dd, J=8.8, 0.8 Hz, 1 H); MS (ESI) (M+H)+ 417.3.
Example 90 3-[(4-EthyI-l-naphthoyl)amino]-iV-(tetrahydro-2JΪ-pyran-4-ylmethyl)pyridine-2- carboxamide
Figure imgf000121_0001
Following the procedure for Step A in Example 1, using 2-(4-ethyl-l-naphthyl)-4H- pyrido[3,2-d][l,3]oxazin-4-one (76 mg, 0.25 mmol), and tetrahydro-2H-pyran-4- methanamine (115 mg, 1.0 mmol) provided the title compound after purification by silica gel column (18 mg, 17 %). X NMR (400 MHz, CD3OD) δ 1.30 (m, 2 H), 1.39 (t, J=7.6 Hz, 3H), 1.62 (m, 2 H), 1.87 (m, 1 H), 3.18 (q, J=7.6 Hz, 2H), 3.23 (m, 2 H), 3.34 (m, 2 H), 3.88 (m, 2 H), 7.46 (d, J=7.6 Hz, 1 H), 7.60 (m, 3 H), 7.81 (d, J=7.6 Hz, 1 H), 8.18 (d, J=8.0 Hz, 1 H), 8.35 (d, J=4.4 Hz, 1 H), 8.46 (d, J=8.0 Hz, 1 H), 9.27 (d, J=8.0 Hz, 1 H); MS (ESI) (M+H)+ = 418.0.
Example 91 3-[(4-Ethyl-l-naphthoyl)amino]-iV-(piperidin-2-ylmethyl)pyridine-2-carboxamide
Figure imgf000121_0002
Following the procedure for Step A in Example 1, using 2-(4-ethyl-l-naphthyl)-4H- pyrido[3,2-cT][l,3]oxazin-4-one (76 mg, 0.25 mmol) and (piperidin-2-yl-methyl)amine (114 mg, 1.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (16 mg, 12 %). X NMR (400 MHz, CD3OD) δ 1.38 (t, J=7.6 Hz, 3H), 1.55 (m, 3H), 1.85 (m, 3H), 2.84 (m, IH), 3.18 (q, J=7.6 Hz, 2H), 3.29 (m, 2H), 3.56 (m, 2H), 7.43 (d, J=7.6 Hz, 1 H), 7.62 (m, 3 H), 7.81 (d, J=7.6 Hz, 1 H), 8.18 (d, J=8.0 Hz, 1 H), 8.39 (d, J=4.4 Hz, 1 H), 8.44 (d, J=8.0 Hz, 1 H), 9.26 (d, J=8.0 Hz, 1 H); MS (ESI) (M+H)+ 417.0.
Example 92
3-[(4-Isopropyl-l-naphthoyl)amino]-iV-(tetrahydro-2J3-pyran-4-ylmethyl)pyridine-2- carboxamide
Following the procedure for Step A in Example 1, using 2-(4-isopropyl-l-naphthyl)-4H- pyrido[3,2-c ][l,3]oxazin-4-one (79 mg, 0.25 mmol), and tetrahydro-2H-pyran-4- methanamine (115 mg, 1.0 mmol) provided the title compound (32 mg, 30 %). X NMR (400 MHz, CD3OD) δ 1.30 (m, 2 H), 1.33 (d, J=6.8 Hz, 6H), 1.67 (m, 2 H), 1.87 (m, 1 H), 3.06 (m, IH), 3.30 (m, 2 H), 3.38 (m, 2 H), 3.92 (m, 2 H), 7.49 (m, 2 H), 7.70 (brs, 1 H), 7.91 (m, 2 H), 7.98 (dd, J=8.0, 4.0 Hz, 1 H), 8.28 (d, J=4.0 Hz, 1 H), 8.45 (brs, 1 H), 9.18 (d, J=8.0 Hz, 1 H); MS (ESI) (M+H)+ = 432.2.
Example 93 N-(2-Hydroxyethyl)-3-(l-naphthoylamino)pyridine-2-carboxamide
Figure imgf000122_0002
Following the procedure for Step A in Example 1, using 2-(l-naphthalenyl)-4H- pyrido[3,2-d][l,3]oxazin-4-one (100 mg, 0.36 mmol), and 2-aminoethanol (122 mg, 2.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase HPLC (75 mg, 46 %). MS (ESI) (M+H)+ 336.0.
Example 94 3-[(4-Isopropyl-l-naphthoyl)amino]-N-(piperidin-2-ylmethyl)pyridine-2-carboxamide
Figure imgf000123_0001
Following the procedure for Step A in Example 1, using 2-(4-isopropyl-l-naphthyl)-4H- pyrido[3,2- ][l,3]oxazin-4-one (79 mg, 0.25 mmol), and (piperidin-2-yl-methyl)amine (114 mg, 1.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (25 mg, 18 %). X NMR (400 MHz, CD3OD) δ 1.35 (d, J=6.8 Hz, 6H),1.60 (m, 3H), 1.90 (m, 3H), 2.87 (m, IH), 3.11 (m, IH), 3.33 (m, 2H), 3.66 (m, 2H), 7.54 (dd, J=8.0, 4.0 Hz, 1 H), 7.60 (m, IH), 7.76 (brs, 1 H), 7.94 (m, 2 H), 8.02 (dd, J=8.0, 4.0 Hz, 1 H), 8.36 (d, J=4.0 Hz, 1 H), 8.51 (brs, 1 H), 9.24 (d, J=8.0 Hz, 1 H); MS (ESI) (M+H)+ 431.3.
Example 95
3-{[4-(Methoxymethyl)-l-naphthoyl]amino}-iV-(piperidin-2-ylmethyl)pyridine-2- carboxamide
Figure imgf000123_0002
Step A.3-{[4-(Methoxymethyl)-l-naphthoyl]amino}-N-(piperidin-2- ylmethyl)pyridine-2-carboxamide
Figure imgf000124_0001
The crude tert-butyl 2-({[(3-{[4-(methoxymethyl)-l-naphthoyl]amino}pyridin-2- yl)carbonyl]amino}methyl)piperidine-l-carboxylate (crude, 0.3 mmol) from Step D was treated with TFA in CH2C12 (1 : 1) for 2 hrs at r.t. Removal of solvents gave a residue which was purified by reversed-phase HPLC to provide the title compound as its TFA salt (38 mg, 23%). XNMR (400 MHz, CD3OD) δ 1.55 (m, 3H), 1.88 (m, 3H), 2.85 (m, IH), 3.23 (m, 2H), 3.49 (s, 3H), 3.55 (m, 2H), 4.97 (s, 2H), 7.61 (m, 3 H), 7.66 (dd, J=8.0, 4.0Hz, IH), 7.86 (d, J=8.0 Hz, 1 H), 8.18 (d, J=8.0 Hz, 1 H), 8.41 (d, J=4.0 Hz, 1 H), 8.44 (d, J=8.0 Hz, 1 H), 9.28 (dd, J=8.0 Hz, 1 H); MS (ESI) (M+H)+ 433.0. Step B. tart-Butyl 2-({[(3-ammopyridin-2-yl)carbonyl]amino}methyl)piperidine-l- carboxylate
Figure imgf000124_0002
To a solution of 3-aminopyridine-2-carboxylic acid (552 mg, 4.0 mmol), tert-butyl 2- (aminomethyl)piperidine-l-carboxylate (1.28 g, 6.0 mmol,) and DIPEA (6.0 mmol) in DMF (25 mL)/THF (10 mL), was added HATU (2.3 g, 6.0 mmol) in one portion. The solution was stiπed for 1 hr at r.t and for 1 hr at 50 °C, and then concentrated. The residue was dissolved in EtOAc, washed with brine, dried (Na2SO4), filtered and concentrated. Purification by MPLC afforded the title compound (1.05 g, 79 %). Step C. tart-Butyl 2-({[(3-{[4-(bromomethyl)-l-naphthoyl]amino}pyridin-2- yl)carbonyl]amino}methyl)piperidine-l-carboxylate
Figure imgf000125_0001
To a suspension of 4-(bromomethyl)-l-naphthoic acid (100 mg, 0.38 mmol) in CH2θ2 (5 mL) at room temperature, was added oxalyl chloride (0.5 mL, 1.0 mmol) drop wise. The solution was stirred at room temperature for 10 minutes, and then heated at 50°C for 30 minutes. After removal of solvents, the residue was added to a solution of tert-Butyl 2- ({[(3-aminopyridin-2-yl)carbonyl]amino}methyl)piperidine-l-carboxylate (100 mg, 0.3 mmol) and DIPEA (1.0 mmol) in CH2O2 (10 mL) at 0°C. The reaction mixture was stirred at r.t for 2 hr, and was then concentrated. The residue was used directly in Step D. Step D. tart-Butyl 2-({[(3-{[4-(methoxymethyl)-l-naphthoyI]amino}pyridin-2- yl)carbonyl] amino}methyl)piperidine-l-carboxylate
Figure imgf000125_0002
To a solution of tert-butyl 2-({[(3-{[4-(bromomethyl)-l-naphthoyl]amino}pyridin-2- yl)carbonyl]amino}methyl)piperidine-l-carboxylate (crude, 0.3 mmol) in MeOH (10 mL) was added NaOMe (30 % in MeOH, 1.0 mL) at 0°C. The solution was stirred at room temperature for 1 hr, and was then concentrated. The residue was dissolved in EtOAc, washed with brine, and dried (Na2SO4). Removal of solvents afforded the crude title compound, which was used directly in Step A.
Example 96 3-{[4-(Ethoxymethyl)-l-naphthoyl]amino}-iV-(piperidin-2-ylmethyl)pyridine-2- carboxamide
Figure imgf000126_0001
Step A.3-{[4-(Ethoxymethyl)-l-naphthoyl]amino}-iV-(piperidin-2-ylmethyl)pyridine- 2-carboxamide
Figure imgf000126_0002
The crude tert-butyl 2-({[(3-{[4-(ethoxymethyl)-l-naphthoyl]amino}pyridin-2- yl)carbonyl]amino}methyl)piperidine-l-carboxylate from Step B was treated with TFA in
CH2C12 (1:1) for 2 hrs at r.t. Removal of solvents gave a residue which was purified by reversed-phase HPLC to provide the title compound as its TFA salt (55 mg, 57 %). MS
(ESI) (M+H)+ 447.0.
Step B. tart-Butyl 2-({[(3-{[4-(ethoxymethyl)-l-naphthoyl]amino}pyridin-2- yl)carbonyl]amino}methyl)piperidine-l-carboxylate
Figure imgf000126_0003
To a solution of tert-butyl 2-({[(3-{[4-(bromomethyl)-l-naphthoyl]amino}pyridin-2- yl)carbonyl]amino}methyl)piperidine-l-carboxylate (100 mg) in EtOH (5 mL) was added NaOEt (100 mg) at 0°C. The solution was stiπed at room temperature for 1 hr, and was then concentrated. The residue was dissolved in EtOAc, washed with brine, and dried (Na2SO4). Removal of solvents afforded the crude title compound, which was used directly in Step A.
Examples 97 iV-(piperidin-2-ylmethyl)-3-{[4-(lJΪ-l,2,4-triazol-l-ylmethyl)-l-naphthoyl]amino} pyridine-2-carboxamide
Figure imgf000127_0001
Step A. N-(piperidin-2-ylmethyl)-3-{[4-(lfl-l,2,4-triazol-l-ylmethyl)-l- naphthoyl] amino}pyridine-2-carboxamide
Figure imgf000127_0002
The crude products from Step B were treated with TFA in CH2Ci2 (1:1) for 2 hrs at r.t. Removal of solvents gave a residue, which was purified by reversed-phase HPLC to provide N-(piperidin-2-ylmethyl)-3 - { [4-( IH- 1 ,2,4-triazol- 1 -ylmethyl)- 1 - naphthoyl]amino}pyridine-2-carboxamide as its TFA salt (25 mg, 21 %). X ΝMR (400 MHz, CD3OD) δ 1.54 (m, 3H), 1.88 (m, 3H), 2.84 (m, IH), 3.22 (m, 2H), 3.56 (m, 2H), 6.02 (s, 2H), 7.34 (d, J=8.0 Hz, 1 H), 7.66 (m, 3 H), 7.87 (d, J=8.0 Hz, 1 H), 8.05 (s, IH), 8.25 (d, J=8.0 Hz, 1 H), 8.41 (dd, J=4.0 Hz, 1 H), 8.48 (d, J=8.0 Hz, 1 H), 8.63 (s, IH),
9.28 (d, J=8.0 Hz, 1 H); MS (ESI) (M+H)+ 470.0.
Step B. tart-Butyl 2-({[(3-{[4-(lJΪ-l,2,4-triazol-l-ylmethyl)-l- naphthoyl]amino}pyridin-2-yl)carbonyl]amino}methyl)piperidine-l-carboxylate
Figure imgf000128_0001
To a solution of tert-butyl 2-({[(3-{[4-(bromomethyl)-l-naphthoyl]amino}pyridin-2- yl)carbonyl]amino}methyl)piperidine-l-carboxylate (100 mg) in DMF (5 mL) was added 1,2,4-triazole (300 mg, 4.3 mmol) at r.t. The solution was stirred at 90°C for 2 hr, and was then concentrated. The residue was dissolved in EtOAc, washed with brine, and dried (Na2SO ). Removal of solvents afforded crude products, which were used directly in Step A.
Examples 98 & 99
N-(Piperidin-2-ylmethyl)-3-{[4-(lfl-l,2,3-triazol-l-ylmethyl)-l-naphthoyl]amino} pyridine-2-carboxamide
N-(Piperidin-2-ylmethyl)-3-{[4-(2fir-l,2.3-triazol-2-ylmethyl)-l-naphthoyl]amino} pyridine-2-carboxamide
Figure imgf000128_0002
Step A. iV-(Piperidin-2-ylmethyl)-3-{[4-(lJHr-l,2,3-triazol-l-ylmethyl)-l- naphthoyl]amino}pyridine-2-carboxamide AndN-(Piperidin-2-ylmethyl)-3-{[4-(2Jr7-l,2,3-triazol-2-ylmethyl)-l- naphthoyl]amino}pyridine-2-carboxamide
Figure imgf000129_0001
The crude products from Step B were treated with TFA in CH2O2 (1:1) for 2 hrs at r.t. Removal of solvents gave a residue, which was purified by reversed-phase HPLC to provide N-(piperidin-2-ylmethyl)-3- { [4-(lH- 1 ,2,3-triazol- 1 -ylmethyl)- 1 - naphthoyl]amino}pyridine-2-carboxamide as its TFA salt (58 mg, 32 %). X ΝMR (400 MHz, CD3OD) δ 1.54 (m, 3H), 1.88 (m, 3H), 2.84 (m, IH), 3.22 (m, 2H), 3.56 (m, 2H), 6.21 (s, 2H), 7.35 (d, J=8.0 Hz, 1 H), 7.64 (m, 3 H), 7.77 (s, IH), 7.87 (d, J=8.0 Hz, 1 H), 8.02 (s, IH), 8.26 (d, J=8.0 Hz, 1 H), 8.41 (d, J=4.0 Hz, 1 H), 8.47 (d, J=8.0 Hz, 1 H), 9.27 (d, J=8.0 Hz, 1 H); MS (ESI) (M+H)+ 470.0.
AndN-(piperidin-2-ylmethyl)-3-{[4-(2H-l,2,3-triazol-2-ylmethyl)-l- naphthoyl]amino}ρyridine-2-carboxamide as its TFA salt (12 mg, 7 %). X ΝMR (400 MHz, CD3OD) δ 1.54 (m, 3H), 1.88 (m, 3H), 2.84 (m, IH), 3.24 (m, 2H), 3.56 (m, 2H), 6.18 (s, 2H), 7.32 (d, J=8.0 Hz, 1 H), 7.63 (m, 3 H), 7.73 (s, 2H), 7.85 (d, J=8.0 Hz, 1 H), 8.30 (d, J=8.0 Hz, 1 H), 8.41 (dd, J=4.4, 1.2 Hz, 1 H), 8.45 (d, J=8.0 Hz, 1 H), 9.27 (d, J=8.0 Hz, 1 H); MS (ESI) (M+H)+ 470.0. Step B. tart-Butyl 2-({[(3-{[4-(127-l,2,3-triazol-l-ylmethyl)-l- naphthoyl]amino}pyridin-2-yl)carbonyl]amino}methyl)piperidine-l-carboxylate and tart-Butyl 2-({ [(3-{ [4-(2 -l,2,3-triazol-2-ylmethyl)-l-naphthoyl] amino}pyridin-2- yl)carbonyl]amino}methyl)piperidine-l-carboxylate
Figure imgf000130_0001
To a solution of tert-butyl 2-({[(3-{[4-(bromomethyl)-l-naphthoyl]amino}pyridin-2- yl)carbonyl]amino}methyl)piperidine-l-carboxylate (150 mg) in DMF (5 mL) was added 1,2,4-triazole (500 mg, 7.2 mmol) at r.t. The solution was stiπed at 90°C for 2 hr, and was then concentrated. The residue was dissolved in EtOAc, washed with brine, and dried (Na2SO4). Removal of solvents afforded crude products, which were used directly in Step A.
Example 100
3-[(4-Methyl-l-naphthoyl)amino]-iV-[2-(tetrahydro-2J3-pyran-4-yl)ethyl]pyridine-2- carboxamide
Figure imgf000130_0002
Following the procedure for Step A in Example 1, using 2-(4-methyl-l-naphthyl)-4H- pyrido[3,2-rf][l,3]oxazin-4-one (960 mg, 3.3 mmol), and [2-(tetrahydro-2H-pyran-4- yl)ethyl] amine (1.29 g, 10.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (584 mg, 33 %). X NMR (400 MHz, CDC13) δ 1.35 (m, 2 H), 1.63 (m, 5 H), 2.75 (s 3 H), 3.40 (m, 4 H), 3.97 (m, 2 H), 7.40 (d, J=8.0 Hz, 1 H), 7.53 (dd, J = 8.0, 4.0 Hz, IH), 7.58 (m, IH), 7.81 (d, J=8.0 Hz, 1 H), 8.06 (m, IH), 8.27 (d, J=4.0 Hz, IH), 8.44 (m, 1 H), 8.58 (m, IH), 9.40 (dd, J=8.0, 1.2 Hz, IH), 12.78 (brs, IH); MS (ESI) (M+H)+ = 418.0.
Example 101 3-{[4-(Methoxymethyl)-l-naphthoyl]amino}-iV-[2-(tetrahydro-2H-pyran-4- yl)ethyl]pyridine-2-carboxamide
Figure imgf000131_0001
Step A. 3-{[4-(Methoxymethyl)-l-naphthoyl]amino}-iV-[2-(tetrahydro-2H-pyran-4- yl)ethyl]pyridine-2-carboxamide
Figure imgf000131_0002
To a solution of 3-{[4-(bromomethyl)-l-naphthoyl]amino}-N-[2-(tetrahydro-2H-pyran-4- yl)ethyl]pyridine-2-carboxamide from Step B in MeOΗ (10 mL) was added ΝaOMe (30 % in MeOΗ, 1.0 mL) at 0°C. The solution was stirred at room temperature for 1 hr, and was then concentrated. The residue was dissolved in EtOAc, washed with brine, and dried (Νa2SO4). Removal of solvents afforded a residue, which was purified by reversed-phase ΗPLC to provide the title compound as its TFA salt (9 mg, 7 %). X NMR (400 MHz, CDC13) δ 1.34 (m, 2 H), 1.60 (m, 5 H), 3.43 (m, 4 H), 3.48 (s 3 H), 3.95 (m, 2 H), 4.96 (s, 2H), 7.54 (dd, J = 8.0, 4.0 Hz, IH), 7.59 (m, 3H), 7.87 (d, J=4.0 Hz, 1 H), 8.14 (m, IH), 8.28 (d, J=4.0 Hz, IH), 8.43 (m, 1 H), 8.56 (m, IH), 9.41 (dd, J=8.0, 1.2 Hz, IH), 12.82 (brs, IH); MS (ESI) (M+H)+ = 448.0.
Step B.3-{ [4-(Bromomethyl)-l-naphthoyl] amino}-N-[2-(tetrahydro-21?-pyran-4- yl)ethyl] pyridine-2-carboxamide
Figure imgf000132_0001
To a solution of 3-[(4-methyl-l-naphthoyl)amino]-N-[2-(tetrahydro-2H-pyran-4- yl)ethyl]pyridine-2-carboxamide (100 mg, 0.24 mmol) andΝBS (150 mg, 0.8 mmol) in 5 l,2-C2Η4Cl2 (20 mL) at room temperature, was added 1,1 '-azobis(cyclohexanecarbonitrile) (5 mg) in one portion. The solution was heated at 80°C for 2.5 hours, cooled to room temperature, concentrated and the residue was used directly in Step A.
Example 102 l o 3-[(4-Methyl-l-naphthoyl)amino] -iV-(morpholm-3-ylmethyl)pyridine-2-carboxamide
Figure imgf000132_0002
Step A: 3-[(4-MethyI-l-naphthoyI)amino]-N-(morpholin-3-ylmethyl)pyridine-2- carboxamide
Figure imgf000132_0003
The crude tez-t-butyl 3-{[({3-[(4-methyl-l-naphthoyl)amino]pyridin-2- yl}carbonyl)amino]methyl} morpholine-4-carboxylate from Step B was treated with TFA in CH2CI2 (1:1) for 1 hr at r.t. After evaporation, the residue was purified by reversed- phase HPLC to provide the title compound as its TFA salt (29 mg, 16 % for two steps). X NMR (400 MHz, CD3OD) δ 2.68 (s, 3H), 3.02 (m, IH), 3.21 (m, 2H), 3.47 (m, 2H), 3.59 (m, 2H), 3.82 (m, IH), 3.92 (m, IH), 7.34 (d, J=8.0 Hz, IH), 7.54 (m, 3H), 7.71 (d, J=8.0 Hz, 1 H), 8.06 (d, J=8.0 Hz, 1 H), 8.32 (m, 1 H), 8.39 (d, J=8.0 Hz, 1 H), 9.20 (d, J=8.0 Hz, IH); MS (ESI) (M+H)+ = 405.2.
Step B: tart-Butyl 3-{[({3-[(4-methyl-l-naphthoyl)amino]pyridin-2- yl}carbonyl)amino]methyl}morpholine-4-carboxylate
Figure imgf000133_0001
Following the procedure for Step A in Example 1, using 2-(4-methyl-l-naphthyl)-4H- pyrido[3,2-flT][l,3]oxazin-4-one (100 mg, 0.35 mmol), and tert-butyl 3- (aminomethyl)morpholine-4-carboxylate (216 mg, 1.0 mmol) provided crude tert-butyl 3- {[({3-[(4-methyl-l-naphthoyl)amino]pyridin-2-yl}carbonyl)amino]methyl} morpholine-4- carboxylate, which was used directly in Step A.
Example 103 N-cyclopentyl-3-[(l-naphthalenylcarbonyl)amino]-2-pyridinecarboxamide
Figure imgf000133_0002
A solution of 2-(l-naphthyl)-4H-pyrido[3,2-rf][l,3]oxazin-4-one (100 mg, 0.365 mmol) in DMF (1 mL) was treated with cyclopentylamine (0.22 mL, 2.16 mmol) at room temperature. The mixture was stirred for 3 h at room temperature. After evaporation of the solvent, the residue was purified by reversed-phase HPLC (40-95% CH3CN in H2O) to provide the title compound as its TFA salt (22.1 mg, 13%). X NMR (400 MHz, CDC13) δ 1.52-1.66 (m, 4 H), 1.70-1.80 (m, 2 H), 1.94-2.02 (m, 2 H), 4.18-4.25 (m, 1 H), 7.54-7.62 (m, 4 H), 7.89-7.91 (m, 1 H), 7.93-7.97 (m, 1 H), 8.05-8.07 ( , 1 H), 8.34 (dd, J=4.49, 1.37 Hz, 1 H), 8.42-8.45 (m, 1 H), 9.28 (dd, J=8.59, 1.37 Hz, 1 H); MS (ESI) (M+H)+ 360.0; Anal. (C, H, N) calcd for C22H2iN3O2+0.40CH3OH: C 72.28, H 6.12, N 11.29; found C 72.23, H 6.03, N 11.13.
Example 104
N-butyI-3-[[[4-(lJrT-l,2,3-triazoI-l-yImethyl)-l-naphthalenyl]carbonyl]ammo]-2- pyridinecarboxamide
Figure imgf000134_0001
Step A. N-butyl-3-[[[4-(lj9r-l,2,3-triazol-l-ylmethyl)-l-naphthalenyl]carbonyl]amino]- 2-pyridinecarboxamide
Figure imgf000134_0002
To a solution of methyl 3-{[4-(lH-l,2,3-triazol-l-ylmethyl)-l-naphthoyl]amino}pyridine- 2-carboxylate (100 mg, 0.26 mmol) in DMF (1.7 mL) was added butylamine (0.15 mL, 1.51 mmol) at room temperature. The solution was heated at 80°C for 2 hours and cooled to room temperature. Evaporation of the solvent and purification by reversed-phase ΗPLC (40-95% CH3CN in H2O) afforded the title compound as its TFA salt (16.5 mg, 3%). X NMR (400 MHz, CDC13) δ 0.95 (t, J=7.32 Hz, 3 H), 1.36-1.46 (m, 2 H), 1.57-1.64 (m, 2 H), 3.39 (q, J=7.03 Hz, 2 H), 6.07 (s, 2 H), 7.45 (d, J=7.22 Hz, 1 H), 7.53 (dd, J=8.59, 4.49 Hz, 1 H), 7.57-7.63 (m, 2 H), 7.74 (br.s, 1 H), 7.88 (d, J=7.22 Hz, 1 H), 8.00-8.02 (m, 1 H), 8.30 (dd, J=4.49, 1.46 Hz, 1 H), 8.45-8.51 (m, 1 H), 8.54-8.57 (m, 1 H), 9.39 (dd, J=8.59, 1.46 Hz, 1 H), 12.95 (s, 1 H); MS (ESI) (M+H)+ 429.0; Anal. (C, H, N) calcd for C24H24N6O2: C 67.27, H 5.65, N 19.61; found C 68.29, H 5.74, N 19.50.
Step B. Methyl 3-{[4-(bromomethyl)-l-naphthoyl] amino}pyridine-2-carboxylate
Figure imgf000135_0001
To a solution of methyl 3-[(4-methyl-l-naphthoyl)amino]pyridine-2-carboxylate (700mg, 2.2 mmol) and NBS (979 mg, 5.5 mmol) in DCE (44 mL) at room temperature, was added l,r-azobis(cyclohexanecarbonitrile) (30 mg, 0.12 mmol), in one portion. The solution was heated at 110°C for 2 hours, and then cooled to room temperature. The solution was concentrated, and the residue was used directly in Step C. MS (ESI) (M+H)+ 400.92. Step C. Methyl 3-{[4-(lJET-l,253-triazol-l-ylmethyl)-l-naphthoyl]amino}pyridine-2- carboxylate
Figure imgf000135_0002
To a solution of methyl 3-{[4-(bromomethyl)-l-naphthoyl]amino}pyridine-2-carboxylate (410 mg, 1.05 mmol) in DMF (20 mL) at room temperature, was added 1,2,3-triazole (1.8 mL, 31.2 mmol), in one portion. The solution was heated at 100°C for 1 hour, and then cooled to room temperature. The solution was concentrated, and the residue was used directly in Step A. MS (ESI) (M+H)+ 387.95.
Example 105 iV-(cyclopropylmethyl)-3-[[[4-(lHr-l,2,3-triazol-l-yImethyl)-l-naphthalenyl] carbonyl]amino]-2-pyridinecarboxamide
Figure imgf000136_0001
Following the procedure for Step A in Example 104, using methyl 3-{[4-(lH-l,2,3-triazol- l-ylmethyl)-l-naphthoyl] amino }pyridine-2-carboxy late (200 mg, 0.52 mmol) and cyclopropanemethylamine (0.27 mL, 3.12 mmol) provided the title compound as its TFA salt (42.2 mg, 15 %) following purification by reversed-phase ΗPLC (40-95% CΗ3CN in H2O). X NMR (400 MHz, CDC13) δ 0.26-0.30 (m, 2 H), 0.55-0.60 (m, 2 H), 1.01-1.11 (m, 1 H), 3.26 (dd, J=7.03, 5.86 Hz, 2 H), 6.08 (s, 2 H), 7.43 (s, 1 H), 7.47 (d, J=7.42 Hz, 1 H),
7.55 (dd, J=8.59, 4.49 Hz, 1 H), 7.57-7.64 (m, 2 H), 7.75 (s, 1 H), 7.88 (d, J=7.42 Hz, 1 H), 7.98-7.80 (m, 1 H), 8.33 (dd, J=4.49, 1.56 Hz, 1 H), 8.55-8.57 (m, 2 H), 9.39 (dd, J=8.59,
1.56 Hz, 1 H), 12.94 (s, 1 H); MS (ESI) (M+H)+ 427.0; Anal. (C, H, N) calcd for C24H22N6O2+0.10CF3COOH+0.10CH3OH: C 66.17, H 5.14, N 19.05; found C 66.26, H 5.24, N 19.10.
Example 106 N-(cyclopentylmethyl)-3-[[[4-(lfl-l,2,3-triazol-l-ylmethyl)-l-naphthalenyl] carbonyl]amino]-2-pyridinecarboxamide
Figure imgf000137_0001
Following the procedure for Step A in Example 104, using methyl 3-{[4-(lH-l,2,3-triazol- l-ylmethyl)-l-naphthoyl] amino }pyridine-2-carboxy late (200 mg, 0.52 mmol) and cyclopentanemethylamine (0.92 mL, 3.12 mmol, 3.4 M in MeOΗ) provided the title compound as its TFA salt (16.3 mg, 6%) following purification by reversed-phase ΗPLC (50-95% CΗ3CN in H2O). X NMR (400 MHz, CDC13) δ 1.22-1.30 (m, 2 H), 1.53-1.67 (m, 4 H), 1.76-1.85 (m, 2 H), 2.12-2.21 (m, 1 H), 3.32-3.35 (m, 2 H), 3.49 (s, 1 H), 6.07 (s, 2 H), 7.40 (s, 1 H), 7.45 (d, J=7.42 Hz, 1 H), 7.54 (dd, J=8.59, 4.49 Hz, 1 H), 7.57-7.63 (m, 2 H), 7.70 (s, 1 H), 7.88 (d, J=7.42 Hz, 1 H), 8.00-8.02 (m, 1 H), 8.30 (dd, J=4.49, 1.37 Hz, 1 H), 8.51-8.57 (m, 1 H), 9.39 (dd, J=8.59, 1.37 Hz, 1 H), 12.95 (s, 1 H); MS (ESI) (M+H)+ 455.0; Anal. (C, H, N) calcd for C26H26N6O2+0.10CF3COOH+0.40CH3OH: C 66.73, H 5.83, N 17.55; found C 66.85, H 5.70, N 17.43.
Example 107
iV-hexyl-3-[[[4-(lJ3-l,2,3-triazol-l-ylmethyl)-l-naphthalenyl]carbonyl]amino]-2- pyridinecarboxamide
Figure imgf000138_0001
Following the procedure for Step A in Example 104, using methyl 3-{[4-(lH-l,2,3-triazol- l-ylmethyl)-l-naphthoyl] amino }pyridine-2-carboxy late (100 mg, 0.26 mmol) in DMF (1 mL) and hexylamine (0.2 mL, 1.51 mmol) provided the title compound as its TFA salt (27.6 mg, 18%) following purification by reversed-phase ΗPLC (40-95% CΗ3CN in H2O). X NMR (400 MHz, CDC13) δ 0.86-0.90 (m, 3 H), 1.28-1.41 (m, 6 H), 1.58-1.65 (m, 2 H), 3.36-3.41 (m, 2 H), 6.07 (s, 2 H), 7.40 (s, 1 H), 7.44 (d, J=7.42 Hz, 1 H), 7.53 (dd, J=8.59, 4.49 Hz, 1 H), 7.56-7.63 (m, 2 H), 7.70 (s, 1 H), 7.88 (d, J=7.42 Hz, 1 H), 8.00-8.02 (m, 1 H), 8.30 (dd, J=4.49, 1.46 Hz, 1 H), 8.47-8.50 (m, 1 H), 8.55-8.57 (m, 1 H), 9.39 (dd, J=8.59, 1.46 Hz, 1 H), 12.95 (s, 1 H); MS (ESI) (M+H)+ 457.0; Anal. (C, H, N) calcd for C26H28N6O2+1.80H2O: C 63.87, H 6.51, N 17.19; found C 63.36, H 5.77, N 18.92.
Example 108
N-[3-(dimethylamino)propyl]-3-[[[4-(liϊ-l,2,3-triazol-l-ylmethyl)-l-naphthalenyl] carbonyl]amino]-2-pyridinecarboxamide
Figure imgf000138_0002
Following the procedure for Step A in Example 104, using methyl 3-{[4-(lH-l,2,3-triazol- l-ylmethyl)-l-naphthoyl] amino }pyridine-2-carboxy late (100 mg, 0.26 mmol) in DMF (1 mL) andNN-dimethyl-l,3-propanediamine (0.2 mL, 1.51 mmol) provided the title compound as its TFA salt (83.7 mg, 56%) following purification by reversed-phase ΗPLC (20-50% CΗ3CΝ in H2O). X NMR (400 MHz, CDC13) δ 2.06-2.10 (m, 2 H), 2.80 (s, 6 H), 3.07-3.11 (m, 2 H), 3.46-3.51 (q, 2 H), 6.07 (s, 2 H), 7.39 (d, J=7.22 Hz, 1 H), 7.49 (s, 1 H), 7.54 (dd, J=8.59, 4.49 Hz, 1 H), 7.57-7.64 (m, 2 H), 7.72 (s, 1 H), 7.84 (d, J=7.22 Hz, 1 H), 8.01-8.03 (m, 1 H), 8.30 (dd, J=4.49, 1.37 Hz, 1 H), 8.54-8.57 (m, 1 H), 8.75-8.78 (m, 1 H), 9.36 (dd, J=8.59, 1.37 Hz, 1 H), 12.68 (s, 1 H); MS (ESI) (M+H)+ 458.0; Anal. (C, H, N) calcd for C25H27N7O2+1.60CF3COOH+0.70H2O: C 51.90, H 4.62, N 15.10; found C 51.89, H 4.63, N 15.02.
Example 109
N-[2-(4-morpholinyl)ethyl]-3-[[[4-(liϊ-l,2,3-triazol-l-ylmethyl)-l-naphthalenyl] carbonyl]amino]-2-pyridinecarboxamide
Figure imgf000139_0001
Following the procedure for Step A in Example 104, using methyl 3-{[4-(lH-l,2,3-triazol- l-ylmethyl)-l-naphthoyl]amino}pyridine-2-carboxylate (100 mg, 0.26 mmol) in DMF (1 mL) and 4(2-aminoethyl)morpholine (0.2 mL, 1.51 mmol) provided the title compound as its TFA salt (66.4 mg, 42%) following purification by reversed-phase ΗPLC (10-95% CΗ3CN in H2O). X NMR (400 MHz, CDC13) δ 2.68-3.00 (m, 2 H), 3.33-3.36 (m, 2 H), 3.66-3.70 (m, 2 H), 3.78-4.03 (m, 6 H), 6.07 (s, 2 H), 7.38 (d, J=7.42 Hz, 1 H), 7.52 (dd, J=8.59, 4.49 Hz, 1 H), 7.58-7.65 (m, 2 H), 7.80 (m, 1 H), 7.84 (d, J=7.42 Hz, 1 H), 7.96- 7.80 (m, 1 H), 8.13-8.14 (m, 1 H), 8.27 (dd, J=4.49, 1.37 Hz, 1 H), 8.51-8.55 (m, 1 H), 9.02-9.05 (m, 1 H), 9.32 (dd, J=8.59, 1.37 Hz, 1 H), 12.50 (s, 1 H); MS (ESI) (M+H) 486.0.
Examples 110 & 111 iV-(Cyclohexylmethyl)-3-{[4-(lH-l,2,3-triazol-l-ylmethyl)-l-naphthoyl]amino} pyridine-2-carboxamide and 7V-(cyclohexylmethyl)-3-{[4-(2H-l,2,3-triazol-2- ylmethyl)-l-naphthoyl]amino}pyridine-2-carboxamide
Figure imgf000140_0001
Step A. N-(Cyclohexylmethyl)-3-{[4-(lH-l,2,3-triazol-l-ylmethyl)-l- naphthoyl] amino} pyridine-2-carboxamide and N-(cyclohexylmethyl)-3-{[4~(2H-l,2,3- triazol-2-ylmethyl)-l-naphthoyl]amino}pyridine-2-carboxamide
Figure imgf000140_0002
Following the procedure for Step A in Example 104, using the crude products from Step C (116 mg, 0.3 mmol) and (cyclohexylmethylamine (170 mg, 1.5 mmol) provided N- (cyclohexylmethyl)-3 - { [4-( IH- 1 ,2,3 -triazol- 1 -ylmethyl)- 1 -naphthoyl] amino} pyridine-2- carboxamide as its TFA salt after purification by reversed-phase ΗPLC (59 mg, 34 %). X ΝMR (400 MHz, CDC13) δ 0.90 (m, 2 H), 1.16 (m, 3H), 1.66 (m, 6 H), 3.12 (d, J=6.8 Hz, 2 H), 6.15 (s, 2 H), 7.41 (d, J=8.0 Hz, 1 H), 7.56 (dd, J=8.6, 4.5 Hz, IH), 7.59 (m, 2H), 7.75 (brs, 1 H), 7.84 (d, J=8.0 Hz, 1 H), 7.95 (brs, 1 H), 8.17 (m, 1 H), 8.32 (dd, J= .5, 1.3 Hz, 1 H), 8.46 (m, 1 H), 9.23 (dd, J=8.6, 1.3 Hz, IH); MS (ESI) (M+H)+ 469.0; And N-(cyclohexylmethyl)-3 - { [4-(2H-l ,2,3-triazol-2-ylmethyl)- 1 - naphthoyl]amino}pyridine-2-carboxamide as its TFA salt (59 mg, 34 %). ΝMR (400 MHz, CDC13) δ 0.93 (m, 2H), 1.17 (m, 3H), 1.68 (m, 6H), 3.12 (d, J=6.8 Hz, 2H), 6.14 (s, 2H), 7.33 (d, J=8.0 Hz, 1 H), 7.56 (m, 3 H), 7.71 (s, 2H), 7.83 (d, J=8.0 Hz, 1 H), 8.24 (m, 1 H), 8.32 (m, 1 H), 8.46 (m, 1 H), 9.23 (d, J=8.0 Hz, 1 H); MS (ESI) (M+H)+ 469.2. Step B. Methyl 3-{[4-(bromomethyl)-l-naphthoyl] amino}pyridine-2-carboxylate
To a solution of methyl 3-[(4-methyl-l-naphthoyl)amino]pyridine-2-carboxylate (96 mg, 0.3 mmol) and NBS (107 mg, 0.6 mmol) in DCE (20 mL) at room temperature, was added 1,1 '-azobis(cyclohexanecarbonitrile) (5 mg), in one portion. The solution was heated at 110°C for 2 hours, and then cooled to room temperature. The solution was concentrated, and the residue was used directly in Step C. MS (ESI) (M+H)+ 400.92. Step C. Methyl 3-{[4-(LH-l,2,3-triazol-l-ylmethyl)-l-naphthoyl]amino}pyridine-2- carboxylate and methyl 3-{[4-(2H-l,2,3-triazol-2-ylmethyl)-l-naphthoyl]amino} pyridine-2-carboxylate
Figure imgf000141_0002
To a solution of crude methyl 3-{[4-(bromomethyl)-l-naphthoyl]amino}pyridine-2- carboxylate from Step C (0.3 mmol) in DMF (5 mL) at room temperature, was added 1,2,3-triazole (138 mg, 2.0 mmol), in one portion. The solution was heated at 100°C for 1 hour, and then cooled to room temperature. The solution was concentrated, and the residue was used directly in Step A.
Example 112 N-Pentyl-3-{[4-(lH-l,2,3-triazol-l-ylmethyl)-l-naphthoyl]amino}pyridine-2- carboxamide
Figure imgf000142_0001
Following the procedure for Step A in Example 104, using methyl 3-{[4-(lH-l,2,3-triazol- l-ylmethyl)-l-naphthoyl]amino}pyridine-2-carboxylate (116 mg, 0.3 mmol) andpentan- 1-amine (130 mg, 1.5 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (55 mg, 33 %). X NMR (400 MHz, CDC13) δ AZM1229-49; MS (ESI) (M+H)+ 443.0.
Example 113 N-[2-(Tetrahydro-2Jr7-pyran-4-yl)ethyl]-3-{[4-(lH-l,2,3-triazol-l-ylmethyl)-l- naphthoyl]amino}pyridine-2-carboxamide
Figure imgf000142_0002
Following the procedure for Step A in Example 104, using methyl 3-{[4-(lH-l,2,3-triazol- 1 -ylmethyl)- 1 -naphthoyl] amino }pyridine-2-carboxy late (116 mg, 0.3 mmol) and 2- (tetrahydro-2H-pyran-4-yl)ethanamine (194 mg, 1.5 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (118 mg, 66 %). X NMR (400 MHz, CD3OD) δ 1.21 (m, 2 H), 1.49 (m, 3H), 1.60 (m, 2 H), 3.30 (m, 4 H), 3.84 (m, 2 H), 6.15 (s, 2 H), 7.39 (d, J=8.0 Hz, 1 H), 7.55 (dd, J=8.6, 4.5 Hz, IH), 7.59 (m, 2H), 7.74 (brs, 1 X, 7.84 (d, J=8.0 Hz, 1 H), 7.95 (brs, 1 H), 8.18 (m, 1 H), 8.31 (dd, J=4.5, 1.3 Hz, 1 H), 8.46 (m, 1 H), 9.22 (dd, J=8.6, 1.3 Hz, IH); MS (ESI) (M+H)+ 448.0.
Example 114 iV-[2-(lH-Pyrrol-l-yl)ethyl]-3-{[4-(lJH-l,2,3-triazol-l-ylmethyl)-l-naphthoyl]amino} pyridine-2-carboxamide
Figure imgf000143_0001
Following the procedure for Step A in Example 104, using methyl 3-{[4-(lH-l,2,3-triazol- l-ylmethyl)-l-naphthoyl]amino}pyridine-2-carboxylate (116 mg, 0.3 mmol) and [2-(lH- pyrrol-l-yl)ethyl]amine (165 mg, 1.5 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (39 mg, 22 %). X NMR (400 MHz, CD3OD) δ 3.58 (d, J=6.4 Hz, 2 H), 4.02 (d, J=6.4 Hz, 2 H), 5.98 (brs, 2H), 6.15 (s, 2 H), 6.63 (brs, 2H), 7.38 (d, J=8.0 Hz, 1 H), 7.53 (dd, J=8.6, 4.5 Hz, IH), 7.59 (m, 2H), 7.74 (brs, 1 H), 7.82 (d, J=8.0 Hz, 1 H), 7.95 (brs, 1 H), 8.17 (m, 1 H), 8.28 (dd, J=4.5, 1.3 Hz, 1 H), 8.46 (m, 1 H), 9.20 (dd, J=8.6, 1.3 Hz, IH); MS (ESI) (M+H)+ 466.0.
Example 115
N-[3-(lJr7-Imidazol-l-yl)propyl]-3-{[4-(lH-l,2,3-triazol-l-ylmethyl)-l- naphthoyl]amino}pyridine-2-carboxamide
Figure imgf000143_0002
Following the procedure for Step A in Example 104, using methyl 3-{[4-(lH-l,2,3-triazol- 1 -ylmethyl)- 1 -naphthoyl] amino }pyridine-2-carboxylate (116 mg, 0.3 mmol) and [3-(lH- imidazol-l-yl)propyl] amine (188 mg, 1.5 mmol) provided the title compound as its TFA salt after purification by reversed-phase HPLC (92 mg, 52 %). X NMR (400 MHz, CD3OD) δ 2.15 (m, 2 H), 3.39 (m, 2 H), 4.26 (m, 2H), 6.17 (s, 2 H), 7.37 (d, J=8.0 Hz, 1 H), 7.46 (m, IH), 7.59 (m, 4H), 7.75 (brs, 1 H), 7.84 (d, J=8.0 Hz, 1 H), 8.0 (brs, 1 H), 8.19 (m, 1 H), 8.36 (dd, J=4.5, 1.3 Hz, 1 H), 8.46 (m, 1 H), 8.90 (s, IH), 9.22 (dd, J=8.6, 1.3 Hz, IH); MS (ESI) (M+H)+ 481.0.
Example 116
N-[3-(lH-Pyrazol-l-yl)propyl]-3-{[4-(lH-l,2,3-triazol-l-ylmethyl)-l-naphthoyl] amino}pyridine-2-carboxamide
Figure imgf000144_0001
Following the procedure for Step A in Example 104, using methyl 3-{[4-(lH-l,2,3-triazol- l-ylmethyl)-l-naphthoyl]amino}pyridine-2-carboxylate (116 mg, 0.3 mmol) and [3-(lH- pyrazol-l-yl)propyl] amine (188 mg, 1.5 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (62 mg, 35 %). X NMR (400 MHz, CD3OD) δ 2.01 (m, 2 H), 3.23 (m, 2 H), 4.13 (m, 2H), 6.04 (s, 2 H), 6.18 (s, IH), 7.23 (d, J=8.0 Hz, 1 H), 7.43 (m, IH), 7.47 (m, 3H), 7.58 (brs, 1 H), 7.69 (m, IH), 7.74 (d, J=8.0 Hz, 1 H), 7.88 (brs, 1 H), 8.06 (m, 1 H), 8.21 (d, J=4.5 Hz, 1 H), 8.41 (m, 1 H), 9.11 (d, J=8.0 Hz, IH); MS (ESI) (M+H)+ 481.0.
Example 117
N-[2-(lH-Imidazol-l-yl)ethyl]-3-{[4-(lH-l,2,3-triazol-l-ylmethyl)-l-naphthoyl] amino}pyridine-2-carboxamide
Figure imgf000144_0002
Following the procedure for Step A in Example 104, using methyl 3-{[4-(lH-l,2,3-triazol- l-ylmethyl)-l-naphthoyl]amino}pyridine-2-carboxylate (116 mg, 0.3 mmol) and [2-(lH- imidazol-l-yl)ethyl] amine (167 mg, 1.5 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (48 mg, 28 %). X NMR (400 MHz, CD3OD) δ 3.77 (m, 2 H), 4.40 (m, 2H), 6.14 (s, 2 H), 7.33 (d, J=8.0 Hz, 1 H), 7.44 (s, IH), 7.57 (m, 4H), 7.74 (brs, 1 H), 7.77 (d, J=8.0 Hz, 1 H), 7.98 (brs, 1 H), 8.17 (d, J=8.0 Hz, 1 H), 8.30 (m, 1 H), 8.43 (d, J=8.0 Hz, 1 H), 8.90 (s, IH), 9.17 (dd, J=8.0 Hz, IH); MS (ESI) (M+H)+ 467.0.
Example 118
N-[2-(lH-l,2,4-Triazol-l-yl)ethyl]-3-{[4-(lH-l,2,3-triazol-l-ylmethyl)-l-naphthoyl] amino} pyridine-2-carboxamide
Figure imgf000145_0001
Following the procedure for Step A in Example 104, using methyl 3-{[4-(lH-l,2,3-triazol- l-ylmethyl)-l-naphthoyl]amino}pyridine-2-carboxylate (116 mg, 0.3 mmol) and 2-(lH- l,2,4-triazol-l-yl)ethanamine (168 mg, 1.5 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (46 mg, 26 %). X NMR (400 MHz, CD3OD) δ 3.78 (m, 2 H), 4.46 (m, 2H), 6.19 (s, 2 H), 7.42 (d, J=8.0 Hz, 1 H), 7.59 (m, 3H), 7.75 (brs, 1 H), 7.83 (d, J=8.0 Hz, 1 H), 7.98 (brs, 1 H), 8.17 (s, 1 H), 8.21 (m, 1 H), 8.32 (m, IH), 8.45 (d, J=8.0 Hz, 1 H), 8.77 (s, IH), 9.23 (d, J=8.0 Hz, IH); MS (ESI) (M+H)+ 468.0.
Example 119 7V-(2-MethoxyethyI)-3-{[4-(lH-l,2,3-triazol-l-ylmethyl)-l-naphthoyl]amino} pyridine- 2-carboxamide
Figure imgf000146_0001
Following the procedure for Step A in Example 104, using methyl 3-{[4-(lH-l,2,3-triazol- 1 -ylmethyl)- 1 -naphthoyl] amino }pyridine-2-carboxy late (58 mg, 0.15 mmol) and (2- methoxyethyl)amine (75 mg, 1.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (42 mg, 51 %). X NMR (400 MHz, CD3OD) δ 3.35 (s, 3 H), 3.52 (m, 4H), 6.21 (s, 2 H), 7.46 (d, J=8.0 Hz, 1 H), 7.63 (m, 3H), 7.75 (brs, 1 H), 7.89 (d, J=8.0 Hz, 1 H), 7.97 (brs, 1 H), 8.23 (m, 1 H), 8.37 (dd, J=8.0, 1.3Hz, 1 H), 8.48 (m, IH), 9.28 (dd, J=8.0, 1.4 Hz, IH); MS (ESI) (M+H)+ 431.0.
Example 120
7V-(2-Ethoxyethyl)-3-{[4-(lH-l,2,3-triazol-l-ylmethyl)-l-naphthoyl]amino}pyridine-2- carboxamide
Figure imgf000146_0002
Following the procedure for Step A in Example 104, using methyl 3-{[4-(lH-l,2,3-triazol- 1 -ylmethyl)- 1 -naphthoyl] amino }pyridine-2-carboxy late (58 mg, 0.15 mmol) and (2- ethoxyethyl)amine (89 mg, 1.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (22 mg, 26 %). X NMR (400 MHz, CD3OD) δ 1.16 (t, J=6.8 Hz, 3H), 3.51 (m, 4H), 3.56 (m, 2H), 6.19 (s, 2 H), 7.44 (d, J=8.0 Hz, 1 H), 7.61 (m, 3H), 7.75 (brs, 1 H), 7.87 (d, J=8.0 Hz, 1 H), 7.96 (brs, 1 H), 8.21 (m, 1 H), 8.35 (dd, J=8.0, 1.3Hz, 1 H), 8.48 (m, IH), 9.27 (dd, J=8.0, 1.4 Hz, IH); MS (ESI) (M+H)+ 445.0. Example 121 iV-(2-Propoxyethyl)-3-{[4-(lH-l,2,3-triazol-l-ylmethyl)-l-naphthoyl]amino} pyridine-
2-carboxamide
Figure imgf000147_0001
Following the procedure for Step A in Example 104, using methyl 3-{[4-(lH-l,2,3-triazol- 1 -ylmethyl)- l-naphthoyl]amino}pyridine-2-carboxylate (58 mg, 0.15 mmol) and (2- propoxyethyl)amine (103 mg, 1.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (43 mg, 51 %). X NMR (400 MHz, CD3OD) δ 0.86 (t, J=7.4 Hz, 3H), 1.53 (m, 2H), 3.39 (m, 2H), 3.49 (m, 2H), 3.53 (m, 2H), 6.15 (s, 2 H), 7.39 (d, J=8.0 Hz, 1 H), 7.58 (m, 3H), 7.75 (brs, 1 H), 7.84 (d, J=8.0 Hz, 1 H), 7.97 (brs, 1 H), 8.17 (m, 1 H), 8.31 (m, 1 H), 8.46 (m, IH), 9.22 (d, J=8.0 Hz, IH); MS (ESI) (M+H)+ 459.0.
Example 122 N-(3-Methoxypropyl)-3-{[4-(lH-l,2,3-triazol-l-ylmethyl)-l-naphthoyl]amino} pyridine-2-carboxamide
Figure imgf000147_0002
Following the procedure for Step A in Example 104, using methyl 3-{[4-(lH-l,2,3-triazol- l-ylmethyl)-l-naphthoyl]amino}pyridine-2-carboxylate (58 mg, 0.15 mmol) and (3- methoxypropyl)amine (89 mg, 1.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (39 mg, 46 %). X NMR (400 MHz, CD3OD) δ 1.81 (m, 2H), 3.29 (s, 3H), 3.42 (m, 2H), 3.44 (m, 2H), 6.16 (s, 2 H), 7.41 (d, J=8.0 Hz, 1 H), 7.58 (m, 3H), 7.73 (brs, 1 H), 7.85 (d, J=8.0 Hz, 1 H), 7.94 (brs, 1 H), 8.19 (m, 1 H), 8.33 (dd, J=4.5, 1.4Hz, 1 H), 8.46 (m, IH), 9.23 (dd, J=8.0, 1.4 Hz, IH); MS (ESI) (M+H)4 445.0.
Example 123 iV-(3-Ethoxypropyl)-3-{[4-(lHr-l,2,3-triazol-l-ylmethyl)-l-naphthoyl]ammo} pyridine- 2-carboxamide
Figure imgf000148_0001
Following the procedure for Step A in Example 104, using methyl 3-{[4-(lH-l,2,3-triazol- l-ylmethyl)-l-naphthoyl]amino}pyridine-2-carboxylate (58 mg, 0.15 mmol) and (3- ethoxypropyl)amine (103 mg, 1.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (38 mg, 44 %). X NMR (400 MHz, CD3OD) δ 1.18 (t, J=7.0 Hz, IH), 1.83 (m, 2H), 3.50 (m, 4H), 3.52 (m, 2H), 6.21 (s, 2 H), 7.47 (d, J=8.0 Hz, 1 H), 7.63 (m, 3H), 7.76 (brs, 1 H), 7.88 (d, J=8.0 Hz, 1 H), 7.98 (brs, 1 H), 8.22 (m, 1 H), 8.36 (dd, J=4.5, 1.4Hz, 1 H), 8.48 (m, IH), 9.27 (dd, J=8.0, 1.4 Hz, IH); MS (ESI) (M+H)+ 459.0.
Example 124
/V-AUyl-3-{[4-(lH-l,2,3-triazol-l-ylmethyl)-l-naphthoyl]amino}pyridine-2- carboxamide
Figure imgf000148_0002
Following the procedure for Step A in Example 104, using methyl 3-{[4-(lH-l,2,3-triazol- l-ylmethyl)-l-naphthoyl]amino}pyridine-2-carboxylate (58 mg, 0.15 mmol) and allylamine (57 mg, 1.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase HPLC (42 mg, 53 %). X NMR (400 MHz, CD3OD) δ 3.92 (d, J=5.5 Hz, 2H), 5.08 (m, IH), 5.19 (m, IH), 5.85 (m, IH), 6.13 (s, 2 H), 7.37 (d, J=8.0 Hz, 1 H), 7.56 (m, 3H), 7.72 (brs, 1 H), 7.82 (d, J=8.0 Hz, 1 H), 7.92 (brs, 1 H), 8.16 (m, 1 H), 8.31 (dd, J=4.5, 1.4Hz, 1 H), 8.46 (m, IH), 9.22 (dd, J=8.0, 1.4 Hz, IH); MS (ESI) (M+H)+ 413.0.
Example 125 iV-Propyl-3-{[4-(lH-l,2,3-triazol-l-ylmethyl)-l-naphthoyl]amino}pyridine-2- carboxamide
Figure imgf000149_0001
Following the procedure for Step A in Example 104, using methyl 3-{[4-(lH-l,2,3-triazol- 1 -ylmethyl)- l-naphthoyl]amino}pyridine-2-carboxylate (58 mg, 0.15 mmol) and propylamine (59 mg, 1.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (32 mg, 40 %). X NMR (400 MHz, CD3OD) δ 0.89 (t, J=7.4 Hz, 3H), 1.56 (m, 2H), 3.24 (m, 2H), 6.13 (s, 2 H), 7.37 (d, J=8.0 Hz, 1 H), 7.56 (m, 3H), 7.72 (brs, 1 H), 7.83 (d, J=8.0 Hz, 1 H), 7.93 (brs, 1 H), 8.16 (m, 1 H), 8.31 (dd, 3=4.5, 1.4Hz, 1 H), 8.46 (m, IH), 9.21 (dd, J=8.0, 1.4 Hz, IH); MS (ESI) (M+H)+ 415.0.
Example 128 N-[(tetrahydro-2fi-pyran-4-yl)methyl]-3-[[[4-(lH-l,2,3-triazol-l-ylmethyl)-l- naphthalenyl] carbonyl] amino]- 2-pyridinecarboxamide
Figure imgf000150_0001
Step A.7V-[(tetrahydro-2H-pyran-4-yl)methyl]-3-[[[4-(lH-l,2,3-triazol-l-ylmethyl)-l- naphthalenyl] carbonyl] amino] - 2-pyridinecarboxamide
Figure imgf000150_0002
To a solution of 3- {[4-(lH-l, 2,3 -triazol- 1 -ylmethyl)- 1 -naphthoyl] amino }pyridine-2- carboxylic acid (20 mg, 0.054 mmol, see Step D for its preparation) and DIPEA (60 μL, 0.324 mmol) at room temperature in DMF (1 mL), was added ΗATU (14 mg, 0.12 mmol) in one portion. The solution was heated at 50°C for 1 hour, cooled to room temperature and 4-tetrahydropyranmethylamine was added. The solution was heated at 50°C for 30 minutes. After evaporation of the solvent, the residue was purified by reversed-phase ΗPLC (15-95% CΗ3CN in H2O) to provide the title compound as its TFA salt (8.18 mg, 32%). X NMR (400 MHz, CDC13) δ 1.37-1.51 (m, 2 H), 1.66-1.70 (m, J=12.69 Hz, 2 H), 1.81-1.92 (m, 1 H), 3.31 (t, J=6.64 Hz, 2 H), 3.36-3.42 (m, 2 H), 3.98-4.02 (m, 2 H), 6.09 (s, 2 H), 7.44-7.46 (m, 1 H), 7.48 (d, J=7.22 Hz, 1 H), 7.56 (dd, J=8.59, 4.49 Hz, 1 H), 7.61-7.65 (m, 2 H), 7.79 (s, 1 H), 7.88 (d, J=7.23 Hz, 1 H), 7.98-7.80 (m, 1 H), 8.31 (dd, J=4.49, 1.37 Hz, 1 H), 8.54-8.56 (m, 1 H), 8.60-8.64 (m, 1 H), 9.40 (dd, J=8.59, 1.56 Hz, 1 H), 12.86 (s, 1 H); MS (ESI) (M+H)+ 471.0; Anal. (C, H, N) calcd for C26H26N6O3+0.20CF3COOH+0.20CH3OH: C 60.93, H 6.26, N 14.91; found C 61.17, H
5.69, N 14.25.
Step B. 4-(bromomethyl)-l-naphthoyl chloride
Figure imgf000151_0001
To a suspension of 4-(bromomethyl)-l-naphthoic acid (112 mg, 0.42 mmol) in CH2CI2 (5 mL) at room temperature, was added oxalyl chloride (0.63 mL, 1.26 mmol) drop wise. The solution was stirred at room temperature for 10 minutes, and then heated at 50°C for 30 minutes. The solution was concentrated, and the residue was used directly in Step C. Step C. 3-{ [4-(bromomethyl)-l -naphthoyl] amino} pyridine-2-carboxylic acid
Figure imgf000151_0002
To a suspension of 3-aminopyridine-2-carboxylic acid (48.4 mg, 0.35 mmol) and DIPEA
(0.12 mL, 0.7 mmol) in DMF (4.5 mL) at 0°C, was added 4-(bromomethyl)-l -naphthoyl chloride (119 mg, 0.42 mmol, see Step D for its preparation). The solution was stiπed at room temperature overnight. The solution was concentrated, and the residue was used directly in Step D. MS (ESI) (M+H)+ 385.79.
Step D. 3-{[4-(li?-l,2,3-triazoI-l-ylmethyl)-l-naphthoyl]amino}pyridine-2-carboxylic acid
Figure imgf000152_0001
To a solution of 3-{[4-(bromomethyl)-l-naphthoyl]amino}pyridine-2-carboxylic acid (134.8 mg, 0.35 mmol, see Step C for its preparation) in DMF (1 mL) at room temperature, was added 1,2,3-triazole (200 mg, excess), in one portion. The solution was heated at 90°C for 1 hour, concentrated and the residue was used directly in Step A. MS (ESI) (M+H)+ 373.94.
Examples 129 & 130
N-[(tetrahydro-2JH-pyran-4-yl)methyl]-3-[[[4-(4Hr-l,2,4-triazol-4-ylmethyl)-l- naphthalenyl] carbonyl] amino] -2-pyridinecarboxamide andN-[(tetrahydro-2H-pyran-4-yl)methyl]-3-[[[4-(lJH-l,2,4-triazol-l-ylmethyl)-l- naphthalenyl] carbonyl] amino]-2-pyridinecarboxamide
Figure imgf000152_0002
Step A. iV-[(tetrahydro-2JH-pyran-4-yl)methyl]-3-[[[4-(4fl-l,2,4-triazol-4-ylmethyl)-l- naphthalenyl] carbonyl] amino]-2-pyridinecarboxamide and N-[(tetrahydro-2H-pyran-4-yl)methyl]-3-[[[4-(lir-l,2,4-triazol-l-ylmethyl)-l- naphthalenyl] carbonyl] amino]-2-pyridinecarboxamide
Figure imgf000153_0001
To a solution of 1,2,4-triazole (116.1 mg, 1.68 mmol) at room temperature in DMF (1 mL) was added 3-{[4-(bromomethyl)-l-naphthoyl]amino}-N-(tetrahydro-2H-pyran-4- ylmethyl)pyridine-2-carboxamide (100 mg, 0.21 mmol, see Step B for its preparation). The solution was heated at 90°C for 30 minutes and cooled to room temperature. After evaporation of the solvent, the residue was purified by reversed-phase ΗPLC (20-50% CΗ3CΝ in H2O) to provide isomer 1 as its TFA salt (14.27 mg, 29%). X NMR (400 MHz, CDC13) δ 1.33-1.44 (m, 2 H), 1.66-1.69 (m, 2 H), 1.80-1.92 (m, 1 H), 3.31 (t, J=6.64 Hz, 2 H), 3.35-3.41 (m, 2 H), 3.99 (dd, J=l 1.33, 3.52 Hz, 2 H), 5.77 (s, 2 H), 7.40 (d, J=7.23 Hz, 1 H), 7.56 (dd, J=8.59, 4.49 Hz, 1 H), 7.68 (m, 2 H), 7.86 (m, 2 H), 8.31 (dd, J=4.49, 1.17 Hz, 1 H), 8.51 (br. s., 1 H), 8.61 (m, 2 H), 9.39 (dd, J=8.59, 1.17 Hz, 1 H), 12.93 (s, 1 H); MS (ESI) (M+H)+ 471.0; Anal. (C, H, N) calcd for C26H26N6O3+1.50CF3COOH+0.20H2O: C 53.99, H 4.36, N 13.03; found C 53.94, H 4.33, N 12.99, and isomer 2 as its TFA salt (13.16 mg, 27%). X NMR (400 MHz, CDC13) δ 1.33-1.44 (m, 2 H), 1.63-1.69 (m, 2 H), 1.80-1.92 (m, 1 H), 3.31 (t, J=6.54 Hz, 2 H), 3.35- 3.41 (m, 2 H), 3.97-4.01 (m, 2 H), 5.89 (s, 2 H), 7.46 (d, J=7.23 Hz, 1 H), 7.55 (dd, J=8.59, 4.49 Hz, 1 H), 7.61-7.66 (m, 2 H), 7.89 (d, J=7.23 Hz, 1 H), 7.96-7.99 (m, 1 H), 8.14 (s, 1 H), 8.19 (s, 1 H), 8.30 (dd, J=4.49, 1.17 Hz, 1 H), 8.58 (m, 2 H), 9.40 (dd, J=8.59, 1.17 Hz, 1 H), 12.88 (s, 1 H); MS (ESI) (M+H)+ 471.0; Anal. (C, H, N) calcd for C26H26N6O3+0.20CH3CN+1.60CF3COOH+0.10H2O: C 53.63, H 4.32, N 13.10; found C 53.56, H 4.28, N 13.14.
Step B. 3-{ [4-(bromomethyl)-l-naphthoyl] amino}-iV-(tetrahydro-2iϊ-pyran-4- ylmethyl)pyridine-2-carboxamide
Figure imgf000154_0001
To a solution of 3-[(4-methyl-l-naphthoyl)amino]-N-(tetrahydro-2H-pyran-4- ylmethyl)pyridine-2-carboxamide (400 mg, 0.99 mmol) andΝBS (356 mg, 2 mmol) in 1,2-C2Η2C12 (20 mL) at room temperature, was added l,r-azobis(cyclohexanecarbonitrile) (15 mg, 0.06 mmol), in one portion. The solution was heated at 80°C for 2.5 hours, then cooled to room temperature, concentrated and the residue was used directly in Step A. MS (ESI) (M+H)+ 483.87.
Example 131
3-[ [ [4-(l-pyrrolidinylmethyl)-l-naphthalenyl] carbonyl] amino] -N-[(tetrahydro-2H- pyran-4-yl)methyl]-2-pyridinecarboxamide
Figure imgf000154_0002
Following the procedure for Step A in Example 129/130, using 3-{[4-(bromomethyl)-l- naphthoyl] amino } -N-(tetrahydro-2H-pyran-4-ylmethyl)pyridine-2-carboxamide (100 mg, 0.21 mmol), and pyπolidine (0.14 mL, 2.16 mmol) provided the title compound as its TFA salt (13.9 mg, 14%) following purification by reversed-phase ΗPLC (15-95% CΗ3CΝ in H2O). X NMR (400 MHz, CDC13) δ 1.33-1.44 (m, 2 H), 1.68 (d, J=12.89 Hz, 2 H), 1.83- 1.91 (m, 1 H), 2.04-2.18 (m, 4 H), 2.88-3.00 (m, 2 H), 3.31 (t, J=6.64 Hz, 2 H), 3.35-3.41 (m, 2 X, 3.72-3.86 (m, 2 H), 3.99 (dd, J=11.23, 3.42 Hz, 2 H), 4.83 (s, 2 H), 7.56 (dd, J=8.59, 4.49 Hz, 1 H), 7.64-7.72 (m, 2 H), 7.76 (d, J=7.23 Hz, 1 H), 7.90 (d, J=7.42 Hz, 1 H), 8.17 (d, J=8.01 Hz, 1 H), 8.31 (dd, J=4.49, 1.17 Hz, 1 H), 8.55-8.62 (m, 2 H), 9.39 (dd, J=8.59, 1.17 Hz, 1 H), 12.90 (s, 1 H); MS (ESI) (M+H)+ 473.2. Anal. (C, H, N) calcd for C28H32N4O3+1.70CF3COOH: C 56.59, H 5.10, N 8.41; found C 56.67, H 5.14, N 8.43.
Example 132
3-[[[4-(lH-pyrazol-l-ylmethyl)-l-naphthalenyl]carbonyl]amino]-iV-[(tetrahydro-2H- pyran-4-yl)methyl]- 2-pyridinecarboxamide
Figure imgf000155_0001
Following the procedure for Step A in Example 129/130, using 3-{[4-(bromomethyl)-l- naphthoyl] amino } -N-(tetrahydro-2H-pyran-4-ylmethyl)pyridine-2-carboxamide (100 mg, 0.21 mmol), and pyrazole (114.4 mg, 1.68 mmol) provided the title compound as its TFA salt (25.9 mg, 26%) following purification by reversed-phase ΗPLC (30-60% CΗ3CΝ in H2O). X NMR (400 MHz, CDC13) δ 1.32-1.43 (m, 2 H), 1.65-1.69 (m, 2 H), 1.81-1.90 (m, 1 H), 3.30 (t, J=6.64 Hz, 2 H), 3.35-3.40 (m, 2 H), 3.98 (dd, J=l 1.33, 3.52 Hz, 2 H), 5.85 (s, 2 H), 6.29-6.30 (m, 1 H), 7.24 (d, J=7.42 Hz, 1 H), 7.34 (d, J=2.15 Hz, 1 H), 7.54 (dd, J=8.49, 4.49 Hz, 1 H), 7.58-7.62 (m, 2 H), 7.85 (d, J=7.42 Hz, 1 H), 8.02-8.05 (m, 1 H), 8.28 (dd, J=4.49, 1.27 Hz, 1 H), 8.56-8.59 (m, 2 H), 9.40 (dd, J=8.49, 1.27 Hz, 1 H), 12.82 (s, 1 H); MS (ESI) (M+H)+ 470.0.
Example 133 iV-[(tetrahydro-2H-pyran-4-yl)methyl]-3-[[[4-(2H-tetrazol-2-ylmethyl)-l- naphthalenyl]carbonyl]amino]-2-pyridinecarboxamide
Figure imgf000156_0001
Following the procedure for Step A in Example 129/130, using 3-{[4-(bromomethyl)-l- naphthoyl]amino}-N-(tetrahydro-2H-pyran-4-ylmethyl)pyridine-2-carboxamide (100 mg, 0.21 mmol), and tetrazole (117.7 mg, 1.68 mmol) provided the title compound as its TFA salt (17.4 mg, 3%) following purification by reversed-phase ΗPLC (40-95% CΗ3CΝ in H2O). MR (400 MHz, CDC13) δ 1.38 (m, 1 H) 1.67 (m, J=12.89 Hz, 3 H) 1.86 (m, 1 H) 3.31 (t, J=6.64 Hz, 2 H) 3.37 (m, 2 H) 3.98 (dd, J=l 1.42, 3.42 Hz, 1 H) 6.10 (s, 2 H) 7.52 (d, J=7.42 Hz, 1 H) 7.56 (dd, J=8.59, 4.49 Hz, 1 H) 7.64 (m, 2 H) 7.90 (d, J=7.23 Hz, 1 H) 7.93 (m, 1 H) 8.31 (dd, J=4.49, 1.37 Hz, 1 H) 8.42 (s, 1 H) 8.59 (m, 2 H) 9.39 (dd, J=8.59, 1.17 Hz, 1 H) 12.91 (s, 1 H); MS (ESI) (M+H)+ 472.0; Anal. (C, H, N) calcd for C25H25N7O3+0.30CH3CN+0.10CF3COOH: C 62.18, H 5.38, N 19.91; found C 62.20, H 5.29, N 19.74.
Example 134
N-(Tetrahydro-2H-pyran-4-yl)-3-[[[4-(lH-l,2,3-triazol-l-ylmethyl)-l- naphthalenyl]carbonyl]amino]-2-pyridinecarboxamide
Figure imgf000157_0001
Step A. iV-(Tetrahydro-2Jr7-pyran-4-yl)-3-[[[4-(lJr7-l,2,3-triazol-l-ylmethyl)-l- naphthalenyl] carbonyl] amino]-2-pyridinecarboxamide
Figure imgf000157_0002
To a solution of 3-{[4-(bromometlιyl)-l-naphthoyl]amino}-N-(tetrahydro-2H-pyran-4- yl)pyridine-2-carboxamide (100 mg, 0.214 mmol, see Step B for its preparation) at room temperature in DMF (1.07 mL) was added 1,2,3-triazole (0.1 mL, 1.712 mmol). The solution was heated at 90°C for 30 minutes and cooled to room temperature. After evaporation of the solvent, the residue was purified by reversed-phase ΗPLC (30-90% CΗ3CΝ in H2O) to provide the title compound as its TFA salt (18.6 mg, 19%). X NMR (400 MHz, CDC13) δ 1.63-1.73 (m, 2 H), 1.82-1.83 (m, 2 H), 3.44-3.50 (m, 2 H), 3.92-3.95 (m, 2 H), 3.98-4.04 (m, 1 H), 6.20 (s, 2 H), 7.45 (d, J=7.42 Hz, 1 H), 7.60-7.66 (m, 3 H), 7.73-7.79 (br.s, 1 H), 7.88 (br.s, 1 H), 7.94-8.03 (m, 1 H), 8.22-8.24 (m, 1 H), 8.37-8.38 (m, 1 H), 8.47-8.49 (m, 1 H), 9.26-9.28(m, 1 H); MS (ESI) (M+H)+ 457.0; Anal. (C, H, N) calcd for C25H24N6O3+0.20CF3COOH: C 63.65, H 5.09, N 17.53; found C 63.60, H 5.11, N 17.37. Step B.3-{ [4-(bromomethyl)-l-naphthoyl] amino}-Λ'-(tetrahydro-2Jf/-pyran-4- yl)pyridine-2-carboxamide
Figure imgf000158_0001
To a solution of 3-[(4-methyl-l-naphthoyl)amino]-N-(tetrahydro-2H-pyran-4-yl)pyridine- 2-carboxamide (410 mg, 1.05 mmol) andΝBS (374 mg, 2.1 mmol) in 1,2-C2Η2C12 (21 mL) at room temperature, was added l, -azobis(cyclohexanecarbonitrile) (15 mg, 0.06 mmol), in one portion. The solution was heated at 90°C for 2 hours, and then cooled to room temperature. The solution was concentrated, and the residue was used directly in Step A. MS (ESI) (M+H)+ 469.88.
Example 135
3-[[[4-(lH-imidazol-l-ylmethyl)-l-naphthalenyl]carbonyl]amino]-Ar-(tetrahydro-2J3- pyran-4-yl)-2-pyridinecarboxamide
Figure imgf000158_0002
Following the procedure for Step A in Example 134, using 3-{[4-(bromomethyl)-l- naphthoyl]amino}-N-(tetrahydro-2H-pyran-4-ylmethyl)pyridine-2-carboxamide (100 mg, 0.21 mmol), and imidazole (116 mg, 1.71 mmol) provided the title compound as its TFA salt (30.8 mg, 25%) following purification by reversed-phase ΗPLC (10-90% CΗ3CΝ in H2O). NMR (400 MHz, CDC13) δ 1.64-1.74 (m, 2 H), 1.82-1.85 (m, 2 H), 3.43-3.49 (m, 2 H), 3.93-3.96 (m, 2 H), 3.96-4.04 (m, 1 H), 6.04 (s, 2 H), 7.58-7.63 (m, 3 H), 7.66-7.72 (m, 3 H), 7.93 (d, J=7.42 Hz, 1 H), 8.13-8.15 (m, 1 H), 8.39 (d, J=3.51 Hz, 1 H), 8.49-8.53 (m, 1 H), 9.05 (s, 1 H), 9.28 (dd, J=8.59, 0.98 Hz, 1 H); MS (ESI) (M+H)+ 456.0; Anal. (C, H, N) calcd for C 6H25N5O3+l .40CF3COOH+0.20H2O: C 55.91, H 4.37, N 11.32; found C 55.89, H 4.24, N 11.25.
Example 136
3-[[[4-(lH-pyrazol-l-ylmethyl)-l-naphthalenyl]carbonyl]amino]-N-(tetrahydro-2H- pyran-4-yl)-2-pyridinecarboxamide
Figure imgf000159_0001
Following the procedure for Step A in Example 134, using 3-{[4-(bromomethyl)-l- naphthoyl]amino} -N-(tetrahydro-2H-pyran-4-ylmethyl)pyridine-2-carboxamide (100 mg, 0.21 mmol), and pyrazole (116 mg, 1.71 mmol) provided the title compound as its TFA salt (20.5 mg, 21%) following purification by reversed-phase ΗPLC (30-90% CΗ3CΝ in H2O). X NMR (400 MHz, CDC13) δ 1.60-1.70 (m, 2 H), 1.93-1.96 (m, 2 H), 3.48-3.54 (m, 2 H), 3.99-4.02 (m, 2 H), 4.04-4.12 (m, 1 H), 5.89 (s, 2 H), 6.32-6.33 (m, 1 H), 7.28-7.32 (m, 2 H), 7.55 (dd, J=8.59, 4.49 Hz, 1 H), 7.58-7.63 (m, 2 H), 7.69-7.69 (m, 1 H), 7.85 (d, J=7.23 Hz, 1 H), 7.98-8.01 (m, 1 H), 8.30 (dd, J=4.49, 1.17 Hz, 1 H), 8.41-8.43 (m, 1 H), 8.55-8.58 (m, 1 H), 9.40 (dd, J=8.59, 1.17 Hz, 1 H), 12.81 (br.s, 1 H); MS (ESI) (M+H)+ 456.0; Anal. (C, H, N) calcd for C26H25N5O3+0.50CF3COOH+0.50CH3CN+0.10CH3OH: C 62.94, H 5.15, N 14.37; found C 62.89, H 4.89, N 14.45.
Example 137 3-[[[4-(methoxymethyl)-l-naphthalenyl]carbonyl]amino]-iV-[(tetrahydro-2H-pyran-4- yl)methyl]-2-pyridinecarboxamide
Figure imgf000160_0001
Following the procedure for Step A in Example 134, using 3-{[4-(bromomethyl)-l- naphthoyl]amino}-N-(tetrahydro-2H-pyran-4-ylmethyl)pyridine-2-carboxamide (100 mg, 0.21 mmol), methanol (3 mL, 0.07 mmol) andΝaOMe (1 mL, excess, 25-30%. solution in MeOΗ) provided the title compound as its TFA salt (16 mg, 14%) following purification by reversed-phase ΗPLC (30-90% CΗ3CΝ in H2O). X NMR (400 MHz, CDC13) δ 1.50 (t, J=7.52 Hz, 3 H), 1.61-1.71 (m, 2 H), 1.92-1.95 (m, 2 H), 3.16 (q, J=7.42 Hz, 2 H), 3.47- 3.53 (m, 2 H), 3.98-4.01 (m, 2 H), 4.03-4.12 (m, 1 H), 5.70 (s, 2 H), 6.88 (d, J=1.17 Hz, 1 H), 7.05 (d, J=7.23 Hz, 1 H), 7.43 (d, J=1.17 Hz, 1 H), 7.57 (dd, J=8.59, 4.49 Hz, 1 H), 7.69-7.71 (m, 2 H), 7.79-7.81 (m,l H), 7.85-7.87 (m,l H), 8.33 (dd, J=4.49, 1.27 Hz, 1 H), 8.44-8.46 (m, 1 H), 8.61-8.63 (m, 1 H), 9.38 (dd, J=8.59, 1.27 Hz, 1 H), 12.90 (s, 1 H); MS (ESI) (M+H)+ 484.0; Anal. (C, H, N) calcd for C28H29N5O3+1.60CF3COOH+0.10H2O: C 56.12, H 4.65, N 10.49; found C 56.10, H 4.70, N 10.45.
Example 138
3-[[[4-(methoxymethyl)-l-naphthalenyl]carbonyl]amino]-iV-[(tetrahydro-2H-pyran-4- yl)methyl]-2-pyridinecarboxamide
Figure imgf000161_0001
Following the procedure for Step A in Example 134, using 3-{[4-(bromomethyl)-l- naphthoyl] amino } -N-(tetrahydro-2H-pyran-4-ylmethyl)pyridine-2-carboxamide (100 mg, 0.21 mmol), methanol (3 mL, 0.07 mmol) andΝaOMe (1 mL, excess, 25-30% solution in MeOΗ) provided the title compound as its TFA salt (32.2 mg, 28%) following purification by reversed-phase ΗPLC (30-90% CΗ3CΝ in H2O). X NMR (400 MHz, CDC13) δ 1.37 (m, 2 H) 1.66 (m, J=12.89, 1.76 Hz, 2 H) 1.84 (m, 1 H) 3.35 (m, 4 H) 3.48 (s, 3 H) 3.98 (m, 2 H) 4.95 (s, 2 H) 7.53 (dd, J=8.59, 4.49 Hz, 1 H) 7.59 (m, 3 H) 7.87 (d, J=7.22 Hz, 1 H) 8.14 (m, 1 H) 8.27 (dd, J=4.49, 1.37 Hz, 1 H) 8.56 (m, 2 H) 9.41 (dd, J=8.59, 1.37 Hz, 1 H) 12.79 (s, 1 H); MS (ESI) (M+H)+ 434.0; Anal. (C, H, N) calcd for C25H27N3O4+0.20CH3CN: C 69.07, H 6.30, N 10.15; found C 69.16, H 6.39, N 10.25.
Example 139
3-[(4-benzyl-l-naphthoyl)amino]-iV-(tetrahydro-2Hr-pyran-4-ylmethyl)pyridine-2- carboxamide
Figure imgf000161_0002
To a solution of 3-{[4-(bromomethyl)-l-naphthoyl]amino}-N-(terrahydro-2H-pyran-4- ylmethyl)pyridine-2-carboxamide (150 mg, 0.31 mmol) and phenyl boronic acid (61 mg, 0.5 mmol) in TΗF (4 mL) was added 2M Νa2CO3 aq (0.39 mL, 0.78 mmol) at room temperature. The solution was degassed by bubbling N through it for 20 minutes and tetrakis(triphenylphosphine)palladium (35.8 mg, 0.031 mmol) was added in one portion at room temperature. The suspension was heated at reflux for 4 hours and cooled to room temperature. After evaporation of the solvent, the residue was purified by MPLC (0-100% EtOAc in Hexanes) followed by reversed-phase HPLC (30-95% CH3CN in H2O) to provide the title compound as its TFA salt (27.6 mg, 15%). X NMR (400 MHz, CDC13) δ 1.33-1.43 (m, 2 H), 1.65-1.69 (m, 2 H), 1.81-1.92 (m, 1 H), 3.31 (t, J=6.64 Hz, 2 H), 3.34- 3.41 (m, 2 H), 3.96-3.40 (m, 2 H), 4.49 (s, 2 H), 7.20-7.24 (m, 3 H), 7.28-7.35 (m, 3 H), 7.49-7.57 (m, 3 H), 7.84 (d, J=7.42 Hz, 1 H), 8.06-8.08 (m, 1 H), 8.27 (dd, J=4.49, 1.37 Hz, 1 H), 8.57-8.59 (m, 2 H), 9.42 (dd, J=8.59, 1.37 Hz, 1 H), 12.77 (br.s, 1 H); MS (ESI) (M+H)+ 480.0; Anal. (C, H, N) calcd for C30H29N3O3+0.10CH3OH+0.20H2O: C 74.33, H 6.18, N 8.64; found C 74.43, H 6.03, N 8.63.
Example 140
3-[[[4-(3-furanylmethyl)-l-naphthalenyl]carbonyl]amino]-iV-[(tetrahydro-2i -pyran-
4-yl)methyl]-2-pyridinecarboxamide
Figure imgf000162_0001
To a solution of 3-{[4-(bromomethyl)-l-naphthoyl]amino}-N-(tetrahydro-2H-pyran-4- ylmethyl)pyridine-2-carboxamide (100 mg, 0.21 mmol), and 3-furanboronic acid (37.6 mL, 0.34 mmol) in DME (2.8 mL) was added 2M Νa2CO3 aq (0.27 mL, 0.53 mmol) at room temperature. The solution was degassed by bubbling N2 through it for 20 minutes and tetrakis(triphenylphosphine)palladium (24.3 mg, 0.021 mmol) was added in one portion at room temperature. The suspension was heated at reflux for 3.5 hours and cooled to room temperature. After evaporation of the solvent, the residue was redissolved in CH2CI2. Extraction with CH2C12 (2x), washing with brine (lx), drying (Na2SO4), filtration and concentration of the solvent provided the title compound as its TFA salt (25.7 mg, 21%) following purification by reversed-phase HPLC (40-90% CH3CN in H2O). X NMR (400 MHz, CDC13) δ 1.38 (m, 2 H), 1.67 (m, 2 H), 1.86 (m, 1 H) 3.31 (m, 2 H), 3.37 (m, 2 H), 3.98 (m, 2 H), 4.27 (s, 2 H), 6.29 (s, 1 H), 7.18 (s, 1 H), 7.41 (m, 2 H), 7.55 (m, 3 H), 7.84 (d, J=7.22 Hz, 1 H), 8.11 (m, 1 H), 8.27 (dd, J=4.59, 1.27 Hz, 1 H), 8.58 (m, 2 H), 9.41 (dd, J=8.59, 1.27 Hz, 1 H), 12.77 (br.s, 1 H); MS (ESI) (M+H)+ 470.0.
Example 141
3-[[[4-(2-furanylmethyl)-l-naphthalenyl]carbonyl]amino]-iV-[(tetrahydro-2H-pyran-
4-yl)methyl]-2-pyridinecarboxamide
Figure imgf000163_0001
Following the procedure in Example 140, using 3-{[4-(bromomethyl)-l- naphthoyl]amino} -N-(tetrahydro-2H-pyran-4-ylmethyl)pyridine-2-carboxamide (100 mg, 0.21 mmol), 2-furanylboronic acid (37.6 mg, 0.34 mmol), toluene (2.8 mL) and ethanol (0.56 mL) instead of DME, 2M a2CO3 aq (0.27 mL, 0.53 mmol) and tetrakis(triphenylphosphine)palladium (24.3 mg, 0.021 mmol) provided the title compound as its TFA salt (33.1 mg, 27%) following purification by reversed-phase ΗPLC (40-90% CΗ3CN in H2O). X NMR (400 MHz, CDC13) δ 1.67 (m, 4 H), 1.85 (m, 1 H), 3.31 (m, 2 H), 3.38 (m, 2 H), 3.98 (m, 2 H), 4.47 (s, 2 H), 5.98 (m, 1 H), 6.30 (m, 1 H), 7.36 (m, 1 H), 7.40 (d, J=7.23 Hz, 1 H),7.53 (dd, J=8.69, 4.59 Hz, 1 H), 7.57 (m, 2 H), 7.84 (d, J=7.23 Hz, 1 H), 8.11 (m, 1 H), 8.27 (dd, J=4.39, 1.46 Hz, 1 H), 9.41 (dd, J=8.69, 1.27 Hz, 1 H), 12.77 (s, 1 H); MS (ESI) (M+H)+ 470.0; Anal. (C, H, N) calcd for C28H27N3O4+0.20CH3CN+0.20CF3COOH: C 61.11, H 5.60, N 8.95; found C 69.20, H 5.68, N 9.00.
Example 142 iy-[(tetrahydro-2H-pyran-4-yl)methyl]-3-[[[4-(2-thienylmethyl)-l-naphthalenyl] carbonyl]amino]-2-pyridinecarboxamide
Figure imgf000164_0001
Following the procedure in Example 140, using 3-{[4-(bromomethyl)-l- naphthoyl]amino}-N-(tetrahydro-2H-pyran-4-ylmethyl)pyridine-2-carboxamide (100 mg, 0.21 mmol), 2-thioρheneboronic acid (43.5 mg, 0.34 mmol), 2M Νa2CO3 aq (0.27 mL, 0.53 mmol) and tetrakis(triphenylphosphine)palladium (24.3 mg, 0.021 mmol) provided the title compound as its TFA salt (13.9 mg, 11%) following purification by reversed- phase ΗPLC (30-90% CΗ3CN in H2O). X NMR (400 MHz, CDC13) δ 1.38 (m, 2 H), 1.64 (m, 2 H), 1.86 (m, 1 H), 3.31 (m, 2 H), 3.37 (m, 2 H), 3.98 (m, 2 H), 4.65 (s, 2 H), 6.78 (dd, J=3.51, 1.17 Hz, 1 H), 6.92 (dd, J=5.08, 3.51 Hz, 1 H), 7.16 (dd, J=5.08, 1.17 Hz, 1 H), 7.45 (d, J=7.42 Hz, 1 H), 7.53 (dd, J=8.59, 4.49 Hz, 1 H), 7.57 (m, 2 H), 7.85 (d, J=7.42 Hz, 1 H), 8.12 (m, 1 H), 8.27 (dd, J=4.49, 1.37 Hz, 1 H), 8.58 (m, 2 H), 9.41 (dd, J=8.59, 1.37 Hz, 1 H), 12.78 (s, 1 H); MS (ESI) (M+H)+ 486.0; Anal. (C, H, N) calcd for C28H27N3O3S+0.10CF3COOH+0.30H2O: C 67.42, H 5.56, N 8.36; found C 67.40, H 5.39, N 8.42.
Example 143 N-[(tetrahydro-2H-pyran-4-yl)methyl]-3-[[[4-(3-thienylmethyl)-l- naphthalenyl] carbonyl] amino] -2-pyridinecarboxamide
Figure imgf000165_0001
Following the procedure in Example 140, using 3-{[4-(bromomethyl)-l- naphthoyl] amino} -N-(tetrahydro-2H-pyran-4-ylmethyl)pyridine-2-carboxamide (100 mg, 0.21 mmol), 3-thiopheneboronic acid (43.5 mg, 0.34 mmol), 2M Νa2CO3 aq (0.27 mL, 0.53 mmol) and tetrakis(triphenylphosphine)palladium (24.3 mg, 0.021 mmol) provided the title compound as its TFA salt (22.7 mg, 18%) following purification by reversed- phase ΗPLC (50-90% CΗ3CN in H2O). X NMR (400 MHz, CDC13) δ 1.34-1.43 (m, 2 H), 1.65-1.69 (m, J=13.47, 2.54 Hz, 2 H), 1.80-1.92 (m, 1 H), 3.30-3.33 (m, 2 H), 3.35-3.41 (m, 2 H), 3.95-4.01 (m, 2 H), 4.48 (s, 2 H), 6.90-6.91 (m, 1 H), 6.97 (dd, J=4.98, 1.27 Hz, 1 H), 7.28 (dd, J=4.98, 2.93 Hz, 1 H), 7.38 (d, J=7.23 Hz, 1 H), 7.51-7.58 (m, 3 H), 7.84 (d, J=7.42 Hz, 1 H), 8.07-8.09 (m, 1 H), 8.27 (dd, J=4.49, 1.37 Hz, 1 H), 8.57-8.59 (m, 2 H), 9.42 (dd, J=8.59, 1.37 Hz, 1 H), 12.77 (s, 1 H); MS (ESI) (M+H)+ 486.0; Anal. (C, H, N) calcd for C28H27N3O3S+0.20CF3COOH+0.10CH3CN+0.10CH3OH: C 66.84, H 5.45, N 8.42; found C 66.90, H 5.26, N 8.41.
Example 144 N-(2-methylcyclohexyl)-3-[(l-naphthalenylcarbonyl)amino]-2-pyridinecarboxamide
Figure imgf000165_0002
Following the procedure for Step A in Example 1, using 2-(l-naphthalenyl)-4H- pyrido[3,2- ][l,3]oxazin-4-one (100 mg, 0.36 mmol), and 2-methylcyclohexylamine (0.30 mL, 2.16 mmol) provided the title compound as its TFA salt (19.8 mg, 11 %) following purification by reversed-phase ΗPLC (45-95% CΗ3CN in H2O). X NMR (400 MHz, CDC13) δ 0.90 (d, J=6.44 Hz, 3 H), 1.05-1.14 (m, 1 H), 1.27-1.41 (m, 3 H), 1.48-1.57 (m, 1 H), 1.66-1.90 (m, 4 H), 3.44-3.50 (m, 1 H), 7.55-7.63 (m, 4 H), 7.90-7.92 (m, 1 H), 7.95- 7.98 (m, 1 H), 8.06-8.08 (m, 1 H), 8.38 (dd, J=4.49, 1.37 Hz, 1 H), 8.43-8.45 (m, 1 H), 9.31 (dd, J=8.59, 1.37 Hz, 1 H); MS (ESI) (M+H)+ 388.0; Anal. (C, H, N) calcd for C24H25N3O2+0.20CH3OH: C 73.79, H 6.60, N 10.67; found C 73.86, H 6.53, N 10.61.
Example 145
3-[(l-naphthalenylcarbonyl)amino]-iV-[2-(l-pyrrolidinyl)ethyl]-2- pyridinecarboxamide
Figure imgf000166_0001
Following the procedure for Step A in Example 1, using 2-(l-naphthalenyl)-4H- pyrido[3,2-J][l,3]oxazin-4-one (100 mg, 0.36 mmol), and l-(2-aminoethyl)pyπolidine (0.30 mL, 2.16 mmol) provided the title compound as its TFA salt (26.3 mg, 15 %) following purification by reversed-phase ΗPLC (20-50% CΗ3CN in H2O). X NMR (400 MHz, CDC13) δ 1.82-1.94 (m, 2 H), 2.01-2.12 (m, 2 H), 3.01-3.11 (m, 2 H), 3.39 (t, J=5.86 Hz, 2 H), 3.67-3.74 (m, 4 H), 7.54-7.60 (m, 3 H), 7.63 (dd, J=8.59, 4.49 Hz, 1 H), 7.88- 7.90 (m, 1 H), 7.93-7.98 (m, 1 H), 8.06-8.08 (m, 1 H), 8.39 (dd, J=4.49, 1.37 Hz, 1 H), 8.40-8.43 (m, 1 H), 9.24 (dd, J=8.59, 1.37 Hz, 1 H); MS (ESI) (M+H)+ 389.0; Anal. (C, H, N) calcd for C23H24N4O2+1.50CF3COOH+0.20H2O: C 55.46, H 4.64, N 9.95; found C 55.43, H 4.62, N 9.91.
Example 146 Λr-(cyclobutylmethyl)-3-[[2-(4-morpholinyl)benzoyl]amino]-2-pyridinecarboxamide
Figure imgf000167_0001
To a solution of 3-amino-N-(cyclobutylmethyl)pyridine-2-carboxamide (100 mg, 0.49 mmol), DIPEA (0.17 mL, 0.97 mmol) and 2-morpholino benzoic acid (203 mg, 0.97 mmol) at room temperature in DMF (1.6 mL), was added HATU (369 mg, 0.97 mmol) in one portion at room temperature. The solution was heated at 100°C over night. After evaporation of the solvent, the residue was purified by reversed-phase HPLC (30-95% CH3CΝ in H2O) to provide the title compound as its TFA salt (50.8 mg, 20%). X NMR (400 MHz, DMSO-D6) δ 1.66-1.83 (m, 4 H), 1.91-1.99 (m, 2 H), 2.58-2.52 (m, 1 H), 2.95- 2.97 (m, 4 H), 3.29-3.32 (m, 2 H), 3.61-3.63 (m, 4 H), 7.13-7.19 (m, 2 H), 7.48-7.53 (m, 1 H), 7.62-7.66 (m, 2 H), 8.35 (dd, J=4.49, 1.56 Hz, 1 H), 9.09-9.12 (m, 1 H), 9.19-9.21 (m, 1 H), 13.02 (s, 1 H); MS (ESI) (M+H)+ 395.2; Anal. (C, H, N) calcd for C22H26N4O3+0.10H2O: C 66.68, H 6.66, N 14.14; found C 66.60, H 6.74, N 14.10.
Example 147 iV-(Tetrahydro-2H-pyran-4-ylmethyl)-3-({4-[(3JΪ-[l,2,3]triazolo[4,5-6]pyridin-3- yloxy)methyl]-l-naphthoyl}amino)pyridine-2-carboxamide
Figure imgf000167_0002
Following the procedure for Step A in Example 129/130, using 3-{[4-(bromomethyl)-l- naphthoyl] amino }-N-(tetrahydro-2H-pyran-4-ylmethyl)ρyridine-2-carboxamide ( 47 mg, 0.1 mmol), and 3H-[l,2,3]triazolo[4,5-b]pyridin-3-ol (136 mg, 1.0 mmol) provided the title compound (25 mg, 38 %). X ΝMR (400 MHz, CDC13) δ 1.40 (m, 2 H), 1.67 (m, 2 H), 1.87 (m, 1 H), 3.31 (m, 2 H), 3.40 (m, 2 H), 3.99 (m, 2 H), 6.13 (s, 2 H), 7.45 (dd, J=8.0, 4.0 Hz, 1 H), 7.56 (dd, J=8.0, 4.0 Hz, 1 H), 7.67 (t, J=8.0 Hz, 1 H), 7.70 (d, J=8.0 Hz, 1 H), 7.77 (t, J=8.0 Hz, 1 H), 7.81 (d, J=8.0 Hz, 1 H), 8.31 (d, J=4.0 Hz, 1 H), 8.42 (d, J=8.0 Hz, 1 H), 8.54 (d, J=8.0 Hz, 1 H), 8.60 (m, 1 H), 8.63 (d, J=8.0 Hz, 1 H), 8.76 (d, J=4.0 Hz, 1 H), 9.40 (d, J=8.0 Hz, 1 H), 12.84 (s, 1 H); MS (ESI) (M+H)+ = 438.0.
Example 148 3-(l-Νaphthoylamino)-N-(pyrrolidin-2-ylmethyl)pyridine-2-carboxamide
Figure imgf000168_0001
Step A. 3-(l-Naphthoylammo)-iV-(pyrrolidin-2-ylmethyl)pyridine-2-carboxamide
Figure imgf000168_0002
The crude tert-butyl 2-[({[3-(l-naphthoylamino)pyridin-2- yl]carbonyl}amino)methyl]pyrrolidine-l-carboxylate from Step B was treated with 4 N HCl in dioxane for 2 hrs at r.t. Removal of solvents gave a residue which was purified by reversed-phase HPLC to provide the title compound as its TFA salt (54 mg, 31 %). X NMR (400 MHz, CD3OD) δ 1.80 (m, IH), 2.03 (m, 2H), 2.21 (m, IH), 3.20 (m, IH), 3.28 (m, IH), 3.68 (m, 3H), 7.60 (m, 3 H), 7.68 (m IH), 7.91 (d, J=8.0 Hz, 1 H), 7.98 (d, J=8.0 Hz, 1 H), 8.09 (d, J=8.0 Hz, 1 H), 8.42 (m, 2 H), 9.31 (d, J=8.0 Hz, 1 H); MS (ESI)
(M+H)+ 375.2.
Step B. tart-Butyl 2-[({[3-(l-naphthoylamino)pyridin-2- yl]carbonyl}amino)methyl]pyrrolidine-l-carboxylate
Figure imgf000169_0001
Following the procedure for Step A in Example 1, using 2-(l-naphthalenyl)-4H- pyrido[3,2-< |[l,3]oxazin-4-one (100 mg, 0.36 mmol), and tert-butyl 2- (aminomethyl)pyrrolidine-l-carboxylate ( 300 mg, 1.5 mmol) provided a crude product, which was used in Step A directly.
Example 149 iV-[(l-Methylpyrrolidin-2-yl)methyl]-3-(l-naphthoylamino)pyridine-2-carboxamide
Figure imgf000169_0002
Following the procedure in Example 89, using 3-(l-naphthoylamino)-N-(pyrrolidin-2- ylmethyl)pyridine-2-carboxamide (TFA salt, 30 mg) and formaldehyde (37 % in Η20, 100 mg) provided the title compound as its TFA salt after purification by reversed-phase HPLC. MR (400 MHz, CD3OD) δ 1.96 (m, 2H), 2.08 (m, IH), 2.28 (m, IH), 2.97 (s, 3H), 3.12 (m, IH), 3.67 (m, 3H), 3.88 (m, IH), 7.59 (m, 3 H), 7.61 (m IH), 7.91 (d, J=8.0 Hz, 1 H), 7.98 (d, J=8.0 Hz, 1 H), 8.09 (d, J=8.0 Hz, 1 H), 8.42 (m, 2 H), 9.28 (d, J=8.0 Hz, 1 H); MS (ESI) (M+H)+ 389.2. Example 150 N-[(l-Methylpiperidin-2-yl)methyl]-3-(l-naphthoylamino)pyridine-2-carboxamide
Figure imgf000170_0001
Following the procedure in Example 89, using 3-(l-naphthoylamino)-N-(piperidin-2- ylmethyl)pyridine-2-carboxamide (TFA salt, 100 mg) and formaldehyde (37 % in H2O, 100 mg) provided the title compound as its TFA salt after purification by reversed-phase HPLC (52 mg, 51 %). X ΝMR (400 MHz, CD3OD) δ 1.67 (m, 3H), 1.86 (m, 2H), 2.05 (m, IH), 3.02 (s, 3H), 3.03 (m, IH), 3.25 (m, IH), 3.44 (m, IH), 3.60 (m, IH), 3.96 (m, IH), 7.58 (m, 3 H), 7.61 (m IH), 7.91 (d, J=7.2 Hz, 1 H), 7.98 (d, J=8.0 Hz, 1 H), 8.09 (d, J=8.0 Hz, 1 H), 8.42 (m, 2 H), 9.29 (d, J=8.0 Hz, 1 H); MS (ESI) (M+H)+ 403.3.
Example 151 N-[(l-Acetylpiperidin-2-yl)methyl]-3-(l-naphthoylamino)pyridine-2-carboxamide
Figure imgf000170_0002
To a solution of 3-(l-naphthoylamino)-N-(piperidin-2-ylmethyl)pyridine-2-carboxamide (100 mg, 0.26 mmol) and DIPEA (129 mg, 1.0 mmol) in CH2C12 (10 mL) was added acetyl chloride (78 mg, 1.0 mmol) at r.t. After 1 hr, the reaction mixture was condensed. The residue was purified by reversed-phase HPLC to provide the title compound as its TFA salt. X ΝMR (400 MHz, CD3OD) δ 1.34 (m, IH), 1.65 (m, 5H), 2.02 & 1.98 (s, 3H), 2.85 (m, IH), 3.37 (m, 2H), 3.55-3.95 (m, IH), 4.10-4.50 (m, IH), 7.57 (m, 4 H), 7.90 (d, J=8.0 Hz, 1 H), 7.97 (m, IH), 8.05 (d, J=8.0 Hz, 1 H), 8.36 (m, 1 H), 8.42 (d, J=8.0 Hz, 1 H), 9.29 (d, J=8.0 Hz, 1 H); MS (ESI) (M+H)+ 431.0.
Example 152 Methyl 2-[({[3-(l-naphthoylamino)pyridin-2-yl]carbonyl}amino)methyl]piperidine-l- carboxylate
Figure imgf000171_0001
Following the procedure in Example 151, using 3-(l-naphthoylamino)-N-(piperidin-2- ylmethyl)pyridine-2-carboxamide (100 mg, 0.26 mmol) and methyl chloroformate (94 mg, 1.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase HPLC. X MR (400 MHz, CD3OD) δ 1.34 (m, IH), 1.58 (m, 5H), 2.99 (m, IH), 3,28 (m, IH), 3.45 (s, 3H), 3.79 (m, IH), 3.89 (m, IH), 4.47 (m, IH), 7.56 (m, 4 H), 7.91 (m, 2 H), 8.04 (d, J=8.0 Hz, 1 H), 8.31 (brs, 1 H), 8.43 (d, J=8.0 Hz, 1 H), 9.25 (d, J=8.0 Hz, 1 H); MS (ESI) (M+H)+ 447.0.
Example 153 iV-(Cyclopentylmethyl)-4-(l-naphthoylamino)nicotinamide
Figure imgf000171_0002
Following the procedure for Step A in Example 1, using 2-(l-naphthyl)-4H-pyrido[4,3- ][l,3]oxazin-4-one (55 mg, 0.2 mmol) and (cyclopentylmethyl)amine (99 mg, 1.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (36 mg, 37 %). X NMR (400 MHz, CD3OD) δ 1.29 (m, 2H), 1.58 (m, 2H), 1.65 (m, 2H), 1.80 (m, 2H), 2.21 (m, IH), 3.32(m, 2H), 7.65 (m, 3H), 8.01 (m, 2H), ), 8.17 (d, J= 8.0 Hz, IH), 8.54 (m, IH), ), 8.77 (m, IH), 9.07 (s, IH), 9.28 (d, J = 8.0 Hz, IH); MS (ESI) (M+H)+ 374.2.
Example 154 N-Cyclopentyl-4-(l-naphthoylamino)nicotinamide
Figure imgf000172_0001
Following the procedure for Step A in Example 1, using 2-(l-naphthyl)-4H-pyrido[4,3- <J][l,3]oxazin-4-one (55 mg, 0.2 mmol) and cyclopentylamine (85 mg, 1.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (62 mg, 66 %). X NMR (400 MHz, CD3OD) δ 1.63 (m, 4H), 1.78 (m, 2H), 2.03 (m, 2H), 4.31 (m, IH), 7.63 (m, 3H), 8.01 (m, 2H), ), 8.16 (d, J= 8.0 Hz, IH), 8.54 (m, IH), ), 8.76 (m, IH), 9.09 (s, IH), 9.25 (d, J = 8.0 Hz, IH); MS (ESI) (M+H)+ 360.3.
Example 155 iV-(Cyclopropylmethyl)-4-(l-naphthoylamino)nicotinamide
Figure imgf000172_0002
Following the procedure for Step A in Example 1, using 2-(l-naphthyl)-4H-pyrido[4,3- -i][l,3]oxazm-4-one (55 mg, 0.2 mmol) and cyclopropylmethylamine (71 mg, 1.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (9 mg, 10 %). X NMR (400 MHz, CD3OD) δ 1 0.02 (m, 2H), 0.28 (m, 2H), 0.85 (m, IH), 2.98 (d, J=7.2 Hz, IH), 7.36 (m, 3H), 7.74 (m, 2H), ), 7.89 (d, J= 8.0 Hz, IH), 8.27 (m, IH), ), 8.49 (m, IH), 8.83 (s, IH), 8.98 (m, IH); MS (ESI) (M+H)+ 346.3.
Example 156 iV-Isobutyl-4-(l-naphthoylamino)nicotinamide
Figure imgf000173_0001
Following the procedure for Step A in Example 1, using 2-(l-naphthyl)-4H-pyrido[4,3- ][l,3]oxazin-4-one (55 mg, 0.2 mmol) and isobutylamine (73 mg, 1.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (9 mg, 10 %). X NMR (400 MHz, CD3OD) δ 0.97 (d, J=6.6 Hz, 6H), 1.93 (m, IH), 3.22 (d, J=7:0 Hz, IH), 7.63 (m, 3H), 8.01 (m, 2H), ), 8.17 (d, J= 8.0 Hz, IH), 8.54 (m, IH), ), 8.78 (m, IH), 9.10 (s, IH), 9.32 (d, J = 8.0 Hz, IH); MS (ESI) (M+H)+ 348.3.
Example 157 iV-(Cyclobutylmethyl)-4-[(4-methyl-l-naphthoyl)amino]nicotinamide
Figure imgf000173_0002
Step A. N-(Cyclobutylmethyl)-4-[(4-methyl-l-naphthoyl)amino]nicotinamide
Figure imgf000174_0001
Following the procedure for Step A in Example 1, using 2-(4-methyl-l-naphthyl)-4H- pyrido[4,3-( ][l,3]oxazm-4-one (58 mg, 0.2 mmol) and (cyclobutylmethylamine (85 mg, 1.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (28 mg, 29 %). MR (400 MHz, CD3OD) δ 1.79 (m, 2H), 1.89 (m, 2H), 2.09 (m, 2H), 2.62 (m, IH), 2.77 (s, 3H), 3.41 (d, J=7.4 Hz, 2H), 7.48 (d, J=7.4 Hz, IH), 7.64 (m, 2H), 7.89(d, J=7.4 Hz, IH)), 8.14 (d, J= 8.0 Hz, IH), 8.57 (m, IH), ), 8.71 (m, IH), 9.04 (s, IH), 9.23 (m, IH); MS (ESI) (M+H)+ 374.2. Step B. 2-(4-Methyl-l-naphthyl)-4JH-pyrido[4,3-<fl[l,3]oxazin-4-one
Figure imgf000174_0002
Following the procedure for Step B in Example 1, using 4-aminonicotinic acid (55 mg, 0.4 mmol), 4-methyl-l-naphthalenecarbonyl chloride (102 mg, 0.5 mmol), DIPEA (284 mg, 2.2 mmol), and then HATU (419 mg, 1.1 mmol) provided the title compound as a DMF (6 mL) solution which was used directly in Step A. MS (ESI) (M+H)+ 288.8.
Example 158 N-(CyclopentyImethyl)-4-[(4-methyl-l-naphthoyl)amino]nicotinamide
Figure imgf000175_0001
Following the procedure for Step A in Example 1, using 2-(4-methyl-l-naphthyl)-4H- pyrido[4,3- ][l,3]oxazin-4-one (58 mg, 0.2 mmol) and (cyclopentylmethyl)amine (99 mg, 1.0 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (18 mg, 18 %). X NMR (400 MHz, CD3OD) δ 1.29 (m, 2H), 1.58 (m, 2H), 1.65 (m, 2H), 1.80 (m, 2H), 2.22 (m, IH), 2.78 (s, 3H), 3.32 (m, 2H), 7.50 (d, J=7.4 Hz, IH), 7.64 (m, 2H), 7.91 (d, J=7.4 Hz, IH), ), 8.16 (d, J= 8.0 Hz, IH), 8.59 (m, IH), ), 8.75 (m, IH), 9.06 (s, IH), 9.26 (m, IH); MS (ESI) (M+H)+ 388.3.
Example 159
3-{[4-(Hydroxymethyl)-l-naphthoyl]amino}-iV-(tetrahydro-2Hr-pyran-4- ylmethyl)py ridine-2-carb oxamide
Figure imgf000175_0002
Step A.3-{[4-(Hydroxymethyl)-l-naphthoyl]amino}-iV-(tetrahydro-2JrJ-pyran-4- ylmethyl)p yridine-2-carb oxamide
Figure imgf000176_0001
Oxalyl chloride (0.011 mL, 0.115 mmol) was added to a mixture of 4-{[(2-{[(Tetrahydro- 2H-pyran-4-ylmethyl)amino]carbonyl}pyridin-3-yl)amino]carbonyl}-l-naphthoic acid (50 mg, 0.11 mmol) and DCE (20 mL) at 0°C. The reaction mixture was allowed to warm to ambient temperature and oxalyl chloride (0.005 mL, 0.057 mmol) was added. The reaction mixture was heated to 70°C, stirred for 1 hr and cooled to 0°C. NaBELt (22 mg, 0.57 mmol) and iodine (one crystal) were added. The reaction mixture was stirred for 1 hr. at 0°C and quenched with MeOΗ (5 mL). The solvent was concentrated and the product was purified by preparative reverse-phase ΗPLC to provide the TFA salt of the title compound as white powder (41 mg, 67 %); X NMR (400 MHz, CHLOROFORM-D) δ 1.31 - 1.45 (m, 2 H), 1.67 (dt, J=13.03, 1.78 Hz, 2 H), 1.78 - 1.96 (m, 3 H), 3.31 (t, J=6.64 Hz, 2 H), 3.37 (td, J=11.77, 2.05 Hz, 2 H), 3.98 (dd, J=11.52, 3.71 Hz, 2 H), 5.20 (d, J=0.59 Hz, 2 H), 7.54 (dd, J=8.59, 4.49 Hz, 1 H), 7.57 - 7.62 (m, 2 H), 7.64 (d, J=7.42 Hz, 1 H), 7.87 (d, J=7.23 Hz, 1 H), 8.09 - 8.16 (m, 1 H), 8.28 (dd, J=4.49, 1.37 Hz, 1 H), 8.52 - 8.61 (m, 1 H), 9.40 (dd, J=8.59, 1.37 Hz, 1 H), 12.80 (s, 1 H); MS (ESI) (M+H)+ 420.0: Anal. Calcd. for
C24H25N3O4 + 0.10 TFA + 0.20 H2O: C, 67.15; H, 5.94; N, 9.71. Found: C, 67.09; H, 5.78; N, 9.58.
Step B. S-Amino-iV-^etrahydro^H-pyran^-ylmethy^pyridine^-carboxamide
Figure imgf000176_0002
HATU (2.63 g, 6.93 mmol) and 4-aminomethyltetrahydropyran (0.80 g, 6.94 mmol) were added to a solution of 3-amino-2-pyridine carboxylic acid (0.91 g, 6.60 mmol) and DIPEA (1.26 mL, 7.26 mmol) in DMF (120 mL) at 0°C. The reaction mixture was allowed to warm to ambient temperature and heated to 50°C for 3 hrs. The solvent was concentrated and the residue was recovered in EtOAc (300 mL). The solution was washed with water, saturated NaHCO3 solution, brine and dried over anhydrous Na2SO4. The solvent was concentrated and the product was purified on silica gel by flash chromatography using Et3N 0.1%, MeOH 3% and Acetone 5% in DCM to provide the title compound as white solid (1.40 g, 90 %).
Step C. Naphthalene- 1,4-dicarbonyl dichloride
Figure imgf000177_0001
Naphtalene 1,4-dicarboxylic acid (0.25 g, 1.15 mmol) was added to SOCl2 (10 mL). The reaction mixture was heated to reflux and stirred for 3 hrs. The resulting solution was cooled to ambient temperature and the solvent was concentrated. The residue was dried under vacuum. The crude product was used for the next step without further purification. Step D. 4-{[(2-{[(Tetrahydro-2H-pyran-4-ylmethyl)amino]carbonyl}pyridin-3- yl)amino] carbonyl}-l-naphthoic acid
Figure imgf000177_0002
A solution of 3-Amino-N-(tetrahydro-2H-pyran-4-ylmethyl)pyridine-2-carboxamide (67 mg, 0.28 mmol) and DIPEA (1 mL, 5.74 mmol) in DCE (2 mL) was added to a solution of naphthalene- 1,4-dicarbonyl dichloride (example 1, step C) in DCE (20 mL). The reaction mixture was stiπed for 3 hrs. at ambient temperature and quenched with water (20 mL). The organic layer was separated and dried over anhydrous Νa2SO4. The solvent was concentrated and the product was purified by preparative reverse-phase ΗPLC to provide the TFA salt of the title compound as white powder (20 mg, 16 %). X NMR (400 MHz, DMSO-D6) δ 1.49 (dd, J=12.89, 2.15 Hz, 2 H), 2.07 (d, J=3.91 Hz, 2 H), 3.12 (m, 2 H), 3.19 (m, 2 H), 3.32 (s, 2 H), 3.78 (dd, J=10.74, 3.32 Hz, 2 H), 3.89 (s, 1 H), 7.67 (t, J=7.71 Hz, 1 H), 7.73 (dd, J=8.59, 4.69 Hz, 2 H), 7.92 (d, J=7.42 Hz, 1 H), 8.19 (d, J=7.62 Hz, 1 H), 8.35 (d, J=8.20 Hz, 1 H), 8.42 (dd, J=4.49, 1.37 Hz, 1 H), 8.85 (d, J=8.40 Hz, 1 H), 9.20 (dd, J=8.49, 1.27 Hz, 1 H), 12.96 (s, 1 H); MS (ESI) (M+H)+ 434.0; Anal. Calcd. for C24H23N3O5 + 0.20 TFA + 0.10 H2O: C, 63.98; H, 5.15; N, 9.17. Found: C, 64.09; H, 5.15; N, 9.02.
Example 160
3-{[4-(Piperidin-l-ylmethyl)-l-naphthoyl]amino}-N-(tetrahydro-2H-pyran-4- ylmethyl)py ridine-2-carb oxamide
Figure imgf000178_0001
Methane sulfonyl chloride (0.011 mL, 0.14 mmol) was added to a solution of 3-{[4- (Hydroxymethyl)- 1 -naphthoyl]amino} -N-(tetrahydro-2H-pyran-4-ylmethyl)pyridine-2- carboxamide (50 mg, 0.11 mmol) and Et3Ν (0.032 mL, 0.17 mmol) in DCM (20 mL) at 0°C. The reaction mixture was allowed to warm to ambient temperature and stirred for 4 hrs. The solvent was concentrated and the product was recovered in DMF (10 mL). Morpholine (0.10 mL, 1.19 mmol) and KI (69 mg, 0.41 mmol) were added to the resulting solution. The reaction mixture was heated to 80°C for 2 hrs. The solvent was concentrated and the product was purified by preparative reverse-phase ΗPLC to provide the TFA salt of the title compound as white powder (49 mg, 68 %); X NMR (400 MHz, CHLOROFORM-D) δ 1.30 - 1.47 (m, 2 H), 1.67 (dd, J=13.86, 2.73 Hz, 2 H), 1.79 - 1.96 (m, 1 H), 3.31 (t, J=6.64 Hz, 2 H), 3.38 (td, J=11.81, 2.15 Hz, 2 H), 3.91 - 4.05 ( , 8 H), 4.74 - 4.81 (m, 2 H), 7.56 (dd, J=8.59, 4.49 Hz, 1 H), 7.61 - 7.75 (m, 2 H), 7.82 (d, J=7.42 Hz, 1 H), 7.91 (d, J=7.22 Hz, 1 H), 8.17 (d, J=7.81 Hz, 1 H), 8.31 (dd, J=4.49, 1.37 Hz, 1 H), 8.54 - 8.58 (m, 1 H), 8.60 (t, J=6.44 Hz, 1 H), 9.39 (dd, J=8.59, 1.37 Hz, 1 H), 12.91 (s, 1 H); MS (ESI) (M+H)+ 489.2; Anal. Calcd. for C28H32N4O4 + 1.10 TFA + 1.60 H2O + 0.50 MeCN: C, 57.56; H, 5.58; N, 8.89. Found: C, 57.62; H, 5.55; N, 8.86.
Example 161 3-[(4-{[(2-Hydroxyethyl)amino]methyl}-l-naphthoyl)amino]-iV-(tetrahydro-2Jr7- pyran-4-ylmethyl)pyridine-2-carboxamide
Figure imgf000179_0001
Following the procedure in Example 160, using ethanolamine (0.072 mL, 1.19 mmol) provided the title compound as its TFA salt after purification by reversed-phase HPLC (44 mg, 64 %). X NMR (400 MHz, CHLOROFORM-D) δ 1.30 - 1.47 (m, 2 H), 1.67 (dd, J=12.99, 1.86 Hz, 2 H), 1.78 - 1.96 (m, 1 H), 2.20 - 2.34 (m, 1 H), 2.65 - 2.83 (m, 1 H), 3.31 (t, J=6.64 Hz, 2 H), 3.38 (td, J=11.77, 2.05 Hz, 2 H), 3.91 (q, J=9.24 Hz, 2 H), 3.99 (dd, J=l 1.23, 3.22 Hz, 2 H), 4.27 - 4.40 (m, 2 H), 4.71 - 4.79 (m, 2 H), 7.56 (dd, J=8.59, 4.49 Hz, 1 H), 7.61 - 7.76 (m, 3 H), 7.91 (d, J=7.22 Hz, 1 H), 8.08 (d, J=7.81 Hz, 1 H), 8.31 (dd, J=4.49, 1.56 Hz, 1 H), 8.56 (dd, J=8.20, 1.37 Hz, 1 H), 8.61 (t, J=6.15 Hz, 1 H), 9.39 (dd, J=8.59, 1.37 Hz, 1 H), 12.90 (s, 1 H); MS (ESI) (M+H)+ 463.0; Anal. Calcd. for C26H30N4O4 + 1.80 TFA + 1.60 H2O + 0.50 MeCN: C, 51.25; H, 5.13; N, 8.79. Found: C, 51.30; H, 5.09; N, 8.81.
Example 162
3-({4-[(Dimethylamino)methyl]-l-naphthoyl}amino)-N-(tetrahydro-2H-pyran-4- ylmethyl)pyridine-2-carboxamide
Figure imgf000179_0002
Following the procedure in Example 160, using dimethylamine hydrochloride (89 mg, 1.07 mmol) provided the title compound as its TFA salt after purification by reversed-phase HPLC (30 mg, 44 %). X NMR (400 MHz, CHLOROFORM-D) δ 1.30 - 1.47 (m, 2 H), 1.62 - 1.73 (m, 2 H), 1.78 - 1.96 (m, 1 H), 2.87 (s, 6 H), 3.31 (t, J=6.64 Hz, 2 H), 3.38 (td, J=11.81, 1.95 Hz, 2 H), 3.99 (dd, J=11.13, 3.71 Hz, 2 H), 4.73 - 4.82 (m, 2 H), 7.56 (dd, J=8.59, 4.49 Hz, 1 H), 7.63 - 7.74 (m, 2 H), 7.78 (d, J=7.42 Hz, 1 H), 7.92 (d, J=7.42 Hz, 1 H), 8.16 (d, J=7.81 Hz, 1 H), 8.31 (dd, J=4.49, 1.37 Hz, 1 H), 8.57 (d, J=8.20 Hz, 1 H), 8.60 (t, J=6.54 Hz, 1 H), 9.39 (dd, J=8.59, 1.37 Hz, 1 H), 12.91 (s, 1 H); MS (ESI) (M+H)+ 447.0; Anal. Calcd. for C26H3oN4O3 + 1.60 TFA + 0.90 H2O: C, 54.36; H, 5.22; N, 8.68. Found: C, 54.37; H, 5.24; N, 8.48.
Example 163
3-{[4-(lJr -Imidazol-l-ylmethyl)-l-naphthoyl]amino}-iV-(tetrahydro-2H-pyran-4- ylmethyl)pyridine-2-carboxamide
Figure imgf000180_0001
Following the procedure in Example 160, using imidazole (81 mg, 1.19 mmol, after imidazole addition, the reaction mixture was heated to 80°C and stiπed overnight) provided the title compound as its TFA salt after purification by reversed-phase HPLC (20 mg, 28 %). X NMR (400 MHz, CHLOROFORM-D) δ 1.29 - 1.48 (m, 2 H), 1.67 (d, J=12.89 Hz, 2 H), 1.79 - 1.93 (m, 1 H), 3.31 (t, J=6.64 Hz, 2 H), 3.37 (td, J=11.77, 1.86 Hz, 2 H), 3.98 (dd, J=11.13, 4.10 Hz, 2 H), 5.81 (s, 2 H), 7.06 (s, 1 H), 7.38 (s, 1 H), 7.47 (d, J=7.42 Hz, 1 H), 7.56 (dd, J=8.59, 4.49 Hz, 1 H), 7.62 - 7.71 (m, 2 H), 7.82 - 7.88 (m, 1 H), 7.90 (d, J=7.23 Hz, 1 H), 8.31 (dd, J=4.59, 1.46 Hz, 1 H), 8.54 - 8.66 (m, 2 H), 8.85 (s, 1 H), 9.39 (dd, J=8.59, 1.37 Hz, 1 H), 12.92 (s, 1 H); MS (ESI) (M+H)+ 470.0.
Example 164 3-{[4-(Azetidin-l-ylmethyl)-l-naphthoyl]amino}-iV-(tetrahydro-2Hr-pyran-4- ylmethyl)pyridine-2-carboxamide
Figure imgf000181_0001
Following the procedure in Example 160, using azetidine (68 mg, 1.19 mmol, after azetidine addition, the reaction mixture was heated to 80°C and stiπed overnight) provided the title compound as its TFA salt after purification by reversed-phase HPLC (42 mg, 61 %). X NMR (400 MHz, CHLOROFORM-D) δ 1.30 - 1.47 (m, 2 H), 1.67 (dd, J=12.99, 1.86 Hz, 2 H), 1.78 - 1.96 (m, 1 H), 2.20 - 2.34 (m, 1 H), 2.65 - 2.83 (m, 1 H), 3.31 (t, J=6.64 Hz, 2 H), 3.38 (td, J=11.77, 2.05 Hz, 2 H), 3.91 (q, J=9.24 Hz, 2 H), 3.99 (dd, J=11.23, 3.22 Hz, 2 H), 4.27 - 4.40 (m, 2 H), 4.71 - 4.79 (m, 2 H), 7.56 (dd, J=8.59, 4.49 Hz, 1 H), 7.61 - 7.76 (m, 3 H), 7.91 (d, J=7.22 Hz, 1 H), 8.08 (d, J=7.81 Hz, 1 H), 8.31 (dd, J=4.49, 1.56 Hz, 1 H), 8.56 (dd, J=8.20, 1.37 Hz, 1 H), 8.61 (t, J=6.15 Hz, 1 H), 9.39 (dd, J=8.59, 1.37 Hz, 1 H), 12.90 (s, 1 H); MS (ESI) (M+H)+ 459.2; Anal. Calcd. for C27H30N4O3 + 1.60 TFA + 0.80 H2O: C, 55.34; H, 5.11; N, 8.55. Found: C, 55.29; H, 5.14; N, 8.50.
Example 165
Methyl 4-{[(2-{[(tetrahydro-2H-pyran-4-ylmethyI)amino]carbonyl}pyridin-3- yl)amino] carbonyl}-! -naphthoate
Figure imgf000181_0002
Oxalyl chloride (0.011 mL, 0.115 mmol) was added to a mixture of 4-{[(2-{[(Tetrahydro- 2H-pyran-4-ylmethyl)amino]carbonyl}pyridin-3-yl)amino]carbonyl}-l-naphthoic acid (50 mg, 0.11 mmol) and DCE (20 mL) at 0°C. The reaction mixture was allowed to warm to ambient temperature and oxalyl chloride (0.005 mL, 0.057 mmol) was added. The reaction mixture was heated to 70°C, stiπed for 1 hr., cooled to 0°C and quenched with MeOΗ (5 mL). The solvent was concentrated and the product was purified by preparative reverse- phase ΗPLC to provide the TFA salt of the title compound as white powder (20 mg, 30 %). MR (400 MHz, CHLOROFORM-D) δ 1.30 - 1.46 (m, 2 H), 1.66 (dd, J=12.89, 1.76 Hz, 2 H), 1.77 - 1.92 (m, 1 H), 3.29 (t, J=6.64 Hz, 2 H), 3.37 (td, J=11.81, 1.95 Hz, 2 H), 3.97 (dd, J=11.13, 3.51 Hz, 2 H), 4.03 (s, 3 H), 7.54 (dd, J=8.59, 4.49 Hz, 1 H), 7.58 - 7.70 (m, 2 H), 7.87 (d, J=7.42 Hz, 1 H), 8.20 (d, J=7.42 Hz, 1 H), 8.29 (dd, J=4.49, 1.37 Hz, 1 H), 8.49 (d, J=8.01 Hz, 1 H), 8.57 (t, J=6.05 Hz, 1 H), 8.90 (d, J=8.20 Hz, 1 H), 9.40 (dd, J=8.59, 1.37 Hz, 1 H), 12.88 (s, 1 H); MS (ESI) (M+H)+ 448.0; Anal. Calcd. for C25H25 3O5 + 0.30 H2O: C, 66.30; H, 5.70; N, 9.28. Found: C, 66.38; H, 5.67; N, 8.97.
Example 166
NA Dimethyl-N,-(2-{[(tetrahydro-2fl-pyran-4-ylmethyl)amino]carbonyl}pyridin-3- yl)naphthalene-l,4-dicarboxamide
Figure imgf000182_0001
Following the procedure for Example 165, using dimethylamine hydrochloride (75 mg, 0.91 mmol) provided the title compound as its TFA salt after purification by reversed- phase HPLC (30 mg, 43 %); XNMR (400 MHz, CHLOROFORM-D) δ 1.32 - 1.47 (m, 2 H), 1.62 - 1.73 (m, 2 H), 1.80 - 1.95 (m, 1 H), 2.74 (s, 3 H), 2.85 (s, 2 H), 3.27 - 3.34 (m, 4 H), 3.39 (td, J=l 1.81, 1.95 Hz, 2 H), 4.00 (dd, J=l 1.23, 3.42 Hz, 2 H), 7.51 (d, J=7.23 Hz, 1 H), 7.55 (dd, J=8.59, 4.49 Hz, 1 H), 7.57 - 7.65 (m, 2 H), 7.78 - 7.85 (m, 1 H), 7.92 (d, J=7.22 Hz, 1 H), 8.29 (dd, J=4.59, 1.46 Hz, 1 H), 8.52 - 8.63 (m, 1 H), 9.40 (dd, J=8.59, 1.37 Hz, 1 H), 12.86 (s, 1 H); MS (ESI) (M+H)+ 461.0; Anal. Calcd. for C26H28N4O4 + 0.50 TFA: C, 62.66; H, 5.55; N, 10.83. Found: C, 62.80; H, 5.59; N, 10.64.
Example 167
2-HydroxyethyI 4-{[(2-{[(tetrahydro-2i?-pyran-4-ylmethyl)ammo]carbonyl}pyridin-3- yl)amino]carbonyl}-l-naphfhoate
Figure imgf000183_0001
Following the procedure for Example 165, using ethylene glycol (171 mg, 2.76 mmol) provided the title compound as its TFA salt after purification by reversed-phase HPLC (20 mg, 12 %); X NMR (400 MHz, CHLOROFORM-D) δ 1.30 - 1.46 (m, 2 H), 1.66 (dd, J=12.89, 1.95 Hz, 2 H), 1.75 - 1.94 (m, 1 H), 3.15 (s, 1 H), 3.37 (td, J=11.81, 1.95 Hz, 2 H), 3.93 - 4.07 (m, 4 H), 4.51 - 4.61 (m, 2 H), 7.54 (dd, J=8.59, 4.49 Hz, 1 H), 7.58 - 7.72 (m, 2 H), 7.87 (d, J=7.42 Hz, 1 H), 8.23 (d, J=7.62 Hz, 1 H), 8.29 (dd, J=4.49, 1.56 Hz, 1 H), 8.50 (dd, J=8.20, 0.98 Hz, 1 H), 8.58 (t, J=6.15 Hz, 1 H), 8.88 (d, J=7.62 Hz, 1 H), 9.39 (dd, J=8.59, 1.37 Hz, 1 H), 12.89 (s, 1 H); MS (ESI) (M+H)+ 478.0; Anal. Calcd. for C26H27N3O6 + 0.30 TFA + 0.20 H2O: C, 62.00; H, 5.42; N, 8.15. Found: C, 61.93; H, 5.27; N, 8.15.
Example 168 3-[(l-Benzofuran-2-ylcarbonyl)amino]-iV-(tetrahydro-2JSr-pyran-4-ylmethyl)pyridine- 2-carboxamide
Figure imgf000183_0002
Following the procedure for Step A in Example 30, using 2-benzofurancarboxylic acid (172 mg, 1.06 mmol) and 3-Amino-N-(tetrahydro-2H-pyran-4-ylmethyl)pyridine-2- carboxamide (250 mg, 1.06 mmol) provided the title compound as its TFA salt after purification by reversed-phase ΗPLC (100 mg, 19 %); X ΝMR (400 MHz, DMSO-D6) δ 1.23 (m, 2 H), 1.59 (dd, J=12.89, 1.76 Hz, 2 H), 3.26 (m, 4 H), 3.84 (dd, J=11.52, 2.54 Hz, 2 H), 7.38 (m, 1 H), 7.53 (td, J=7.81, 1.37 Hz, 1 H), 7.68 (dd, J=8.59, 4.49 Hz, 1 H), 7.74 (d, J=0.98 Hz, 1 H), 7.80 (dd, J=34.47, 8.49 Hz, 2 H), 8.40 (dd, J=4.39, 1.47 Hz, 1 H), 9.11 (dd, J=8.59, 1.56 Hz, 1 H), 9.31 (t, J=6.25 Hz, 1 H), 13.39 (s, 1 H); MS (ESI) (M+H)+ 380.2; Anal. Calcd. for C21H2ιΝ3O4 + 0.20 H2O: C, 65.85; H, 5.63; N, 10.97. Found: C, 65.79; H, 5.57; N, 11.09.
Example 169 N-(Cyclohexylmethyl)-3-[(4-iodo-l-naphthoyl)amino]pyridine-2-carboxamide
Figure imgf000184_0001
Step A. N-(Cyclohexylmethyl)-3-[(4-iodo-l-naphthoyl)amino]pyridine-2-carboxamide
Figure imgf000184_0002
Oxalyl chloride (0.26 mL, 3.0 mmol) was added to a solution of 4-Iodo-l-naphthoic acid (580 mg, 1.85 mmol) in DCE (100 mL) at 0°C. DMF (1 drop) was added and the reaction mixture was stirred for 1 hr. at 0°C. A solution of 3-Amino-N-(cyclohexylmethyl)pyridine- 2-carboxamide (465 mg, 1.9 mmol) and DIPEA (0.65 mL, 3.7 mmol) in DCE (20 mL) was added. The reaction mixture was heated to 70°C and stirred overnight. The solvent was concentrated and the product was purified on silica gel by flash chromatography to provide the title compound as white solid (810 mg, 84 %); X NMR (400 MHz, CHLOROFORM- D) δ 1.00 (m, 2 H), 1.20 (m, 3 H), 1.56 (m, 2 H), 1.74 (m, 3 H), 3.23 (t, J=6.64 Hz, 2 H), 7.52 (dd, J=8.59, 4.49 Hz, 1 H), 7.57 (d, J=7.62 Hz, 1 H), 7.61 (m, 2 H), 8.18 (m, 2 H), 8.29 (dd, J=4.49, 1.56 Hz, 1 H), 8.46 (m, 1 H), 9.37 (dd, J=8.59, 1.37 Hz, 1 H), 12.94 (s, 1 H); MS (ESI) (M+H)+ 514.0. Step B. 4-Iodo-l-naphthonitrile
Figure imgf000185_0001
A solution of NaNO2 (0.83 g, 12.1 mmol) in water (10 mL) was added over 30 min. to a mixture of 4-amino-l-naphtonitrile (1.94 g, 11.5 mmol), concentrated HCl (12 mL) and glacial acetic acid (25 mL) at 0°C. The reaction mixture was stiπed for 1.5 hr. and cold water (25 mL) was added. A solution of KI (2.29 g, 13.8 mmol) and iodine (1.75 g, 6.9 mmol) in water (15 mL) was added. The reaction mixture was stirred for 2 hrs. at 0°C and allowed to warm to ambient temperature. The product was extracted with EtOAc, washed with water and brine, and dried over anhydrous Na2SO . The solvent was concentrated and the product was purified on silica gel by flash chromatography to provide the title compound as white solid (2,21 g, 67 %). Step C. 4-Iodo-l-naphthoic acid
Figure imgf000185_0002
4-iodo-l-naphthonitrile (2.21 g, 7.92 mmol), concentrated HCl (20 mL) and glacial acetic acid (10 mL) were mixed together and heated to 130°C overnight in a closed reaction vessel. The reaction mixture was cooled to ambient temperature and filtered. The residue was recovered in EtAOc and dried over anhydrous Na2SO4. The solvent was concentrated to provide the title compound as white solid (1.59 g, 67 %)
Example 170 iV-(CyclohexylmethyI)-3-[(4-piperidin-l-yl-l-naphthoyl)amino]pyridine-2- carboxamide
Figure imgf000186_0001
An oven dried reaction flask was loaded with Pd2(dba)3 (3.5 mg, 0.0038 mmol), N- (Cyclohexylmethyl)-3-[(4-iodo-l-naphthoyl)amino]pyridine-2-carboxamide (100 mg, 0.19 mmol), 2-dicyclohexylphosphino-2'-(Ν,Ν-dimethylamino)biphenyl (3.1 mg, 0.0078 mmol), 1.0 M solution LiHMDS in THF (0.62 mL, 0.62 mmol), piperidine (0.023 mL, 0.23 mmol) and anhydrous THF (1.5 mL) under nitrogen atmosphere. The reaction mixture was heated to 65°C and stiπed overnight. The reaction was cooled to ambient temperature and filtered. The solvent was concentrated and the product was purified on silica gel by MPLC to provide the title compound as white solid (36 mg, 39 %); X NMR (400 MHz, CHLOROFORM-D) δ 0.87 - 1.08 (m, 2 H), 1.09 - 1.34 (m, 3 H), 1.52 - 1.63 (m, 2 H), 1.63 - 1.82 (m, 7 H), 1.82 - 1.92 (m, 3 H), 2.98 - 3.17 (m, J=5.47, 3.32 Hz, 2 H), 3.20 - 3.30 ( , 2 H), 7.07 (d, J=7.81 Hz, 1 H), 7.44 - 7.61 (m, 3 H), 7.84 - 7.95 (m, 1 H), 8.18 - 8.30 ( , 2 H), 8.49 - 8.57 (m, J=6.64 Hz, 1 H), 8.58 - 8.63 (m, 1 H), 9.36 - 9.43 (m, 1 H), 12.77 (s, 1 H); MS (ESI) (M+H)+ 471.3; Anal. Calcd. for C26H3oN4O2 + 0.10 H2O: C, 73.73; H, 7.30; N, 11.86. Found: C, 73.66; H, 7.24; N, 11.87.
Example 171 3-[(4-Azetidin-l-yl-l-naphthoyl)amino]-iV-(cyclohexylmethyl)pyridine-2-carboxamide
Figure imgf000186_0002
Following the procedure for example 170 (heating at 65 °C for 3 days and re-crystallizing in MeOH after flash chromatography) using azetidine (18 mg, 0.35 mmol) provided the title compound as a white solid (75 mg, 58 %); X NMR (400 MHz, CHLOROFORM-D) δ 0.92 - 1.05 (m, 2 H), 1.10 - 1.31 (m, 2 H), 1.52 - 1.62 (m, 2 H), 1.62 - 1.70 (m, 1 H), 1.70 - 1.84 (m, 4 H), 2.40 - 2.50 (m, 2 H), 3.26 (t, J=6.64 Hz, 2 H), 4.24 - 4.31 (m, 4 H), 6.49 (d, J=8.01 Hz, 1 H), 7.37 - 7.44 (m, 1 H), 7.48 (dd, J=8.59, 4.49 Hz, 1 H), 7.50 - 7.55 (m, 1 H), 7.88 (d, J=8.20 Hz, 1 H), 7.99 (d, J=8.59 Hz, 1 H), 8.23 (dd, J=4.49, 1.56 Hz, 1 H), 8.52 (t, J=6.05 Hz, 1 H), 8.72 (dd, J=8.59, 0.78 Hz, 1 Η , 9.37 (dd, J=8.59, 1.56 Hz, 1 H), 12.72 (s, 1 H); MS (ESI) (M+H)+ 443.1; Anal. Calcd. for C27H30N4O2: C, 73.28; H, 6.83; N, 12.66. Found: C, 73.25; H, 6.88; N, 12.69.
Example 172
N-(Cyclohexylmethyl)-3-({4-[ethyl(methyl)amino]-l-naphthoyl}amino)pyridine-2- carboxamide
Figure imgf000187_0001
Following the procedure for example 170, using ethylmethylamine (0.05 mL, 0.58 mmol) and purifying by reverse-phase preparative HPLC provided the TFA salt of the title compound as a white solid (68 mg, 31 %); X NMR (400 MHz, CHLOROFORM-D) δ 0.91 - 1.06 (m, 2 H), 1.12 - 1.32 (m, 4 H), 1.52 - 1.63 (m, 1 H), 1.63 - 1.84 (m, 4 H), 2.18 (s, 3 H), 3.09 (s, 3 H), 3.21 - 3.28 (m, 2 H), 3.44 (q, J=6.90 Hz, 2 H), 7.30 (d, J=7.81 Hz, 1 H), 7.52 (dd, J=8.59, 4.49 Hz, 1 H), 7.57 - 7.64 (m, 2 H), 7.90 (d, J=7.81 Hz, 1 H), 8.28 (dd, J=4.49, 1.37 Hz, 1 H), 8.30 - 8.38 (m, 1 H), 8.56 (t, J=6.35 Hz, 1 H), 8.58 - 8.64 (m, 1 H), 9.39 (dd, J=8.59, 1.37 Hz, 1 H), 12.87 (s, 1 H); MS (ESI) (M+H)+ 445.0; Anal. Calcd. for C 7H32N4O2 + 0.70 TFA + 0.10 H2O + 0.10 MeCN: C, 64.78; H, 6.31; N, 10.83. Found: C, 64.81; H, 6.07; N, 10.90. Example 173 iV-(Cyclohexylmethyl)-3-[(4-pyrrolidin-l-yl-l-naphthoyl)amino]pyridine-2- carboxamide
Figure imgf000188_0001
Following the procedure for example 170, using pyπolidine (0.02 mL, 0.23 mmol) provided the title compound as a white solid (25 mg, 28 %); X NMR (400 MHz, CHLOROFORM-D) δ 0.88 - 1.07 (m, 2 H), 1.09 - 1.33 (m, 3 H), 1.54 - 1.62 (m, 3 H), 1.67 (d, J=11.72 Hz, 1 H), 1.70 - 1.83 (m, 2 H), 1.98 - 2.08 (m, 4 H), 3.26 (t, J=6.64 Hz, 2 H), 3.45 - 3.55 (m, 4 H), 6.89 (d, J=8.20 Hz, 1 H), 7.39 - 7.46 (m, 1 H), 7.46 - 7.55 (m, 2 H), 7.87 (d, J=8.01 Hz, 1 H), 8.19 - 8.25 (m, 2 H), 8.53 (t, J=5.86 Hz, 1 H), 8.68 (dd, J=8.59, 0.78 Hz, 1 H), 9.38 (dd, J=8.59, 1.37 Hz, 1 H), 12.73 (s, 1 H); MS (ESI) (M+H)+ 457.2; Anal. Calcd. for C28H32N4O2 + 0.20 H2O: C, 73.08; H, 7.10; N, 12.17. Found: C, 73.08; H, 7.18; N, 11.90.
Example 174
N-(Cyclohexylmethyl)-3-{[4-(4-isopropylpiperazin-l-yl)-l-naphthoyl]amino}pyridine-
2-carboxamide
Figure imgf000188_0002
Following the procedure for example 170, using N-isopropylpiperazine (30 mg, 0.23 mmol) and purifying by reverse-phase preparative HPLC provided the TFA salt of the title compound as a white solid (33 mg, 27 %); X NMR (400 MHz, CHLOROFORM-D) δ 0.91 - 1.07 (m, 1 H), 1.12 - 1.33 (m, 2 H), 1.48 (d, J=6.64 Hz, 5 H), 1.52 - 1.62 (m, 1 H), 1.66 (d, J=13.67 Hz, 1 H), 1.70 - 1.83 (m, 3 H), 1.88 (s, 6 H), 3.25 (t, J=6.54 Hz, 3 H), 3.52 (d, J=6.83 Hz, 3 H), 3.68 (d, J=9.76 Hz, 2 H), 7.21 (d, J=7.62 Hz, 1 H), 7.48 - 7.62 (m, 2 H), 7.89 (d, J=7.62 Hz, 1 H), 8.06 - 8.12 (m, 1 H), 8.28 (dd, J=4.49, 1.56 Hz, 1 H), 8.54 (t, J=6.15 Hz, 1 H), 8.57 - 8.62 (m, 1 H), 9.37 (dd, J=8.59, 1.37 Hz, 1 H), 12.89 (s, 1 H); MS (ESI) (M+H)+ 514.2; Anal. Calcd. for C3iH39N5O2 + 1.50 TFA + 0.20 H2O: C, 59.33; H, 5.99; N, 10.17. Found: C, 59.40; H, 5.97; N, 9.94.
Example 175 iV-(Cyclohexylmethyl)-3-({4-[3-(diethylamino)pyrroIidin-l-yI]-l- naphthoyl}amino)pyridine-2-carboxamide
Figure imgf000189_0001
Following the procedure for example 170 using NN-diethylpyrrolidin-3 -amine (33 mg, 0.23 mmol) and purifying by reverse-phase preparative HPLC provided the TFA salt of the title compound as a white solid (37 mg, 29 %); X ΝMR (400 MHz, CHLOROFORM-D) δ 0.91 - 1.07 (m, 2 H), 1.12 - 1.32 (m, 3 H), 1.42 (q, J=6.90 Hz, 6 H), 1.52 - 1.63 (m, 1 H), 1.67 (d, J=l 1.13 Hz, 1 H), 1.70 - 1.85 (m, 4 H), 2.40 - 2.66 (m, 4 H), 3.11 - 3.22 (m, 1 H), 3.25 (t, J=6.64 Hz, 2 H), 3.33 - 3.46 (m, 2 H), 3.47 - 3.62 (m, 2 H), 3.84 (dd, J=10.25, 6.35 Hz, 1 H), 3.97 - 4.09 (m, 1 H), 7.07 (d, J=8.01 Hz, 1 H), 7.47 - 7.60 (m, 3 H), 7.86 (d, J=7.81 Hz, 1 H), 8.10 (d, J=7.81 Hz, 1 H), 8.26 (dd, J=4.49, 1.37 Hz, 1 H), 8.54 (t, J=6.54 Hz, 1 H), 8.61 (dd, J=8.30, 1.27 Hz, 1 H), 9.37 (dd, J=8.59, 1.37 Hz, 1 H), 12.84 (s, 1 H); MS (ESI) (M+H)+ 528.3; Anal. Calcd. for C32H4iΝ5θ2 + 1.50 TFA: C, 60.16; H, 6.13; N, 10.02. Found: C, 60.14; H, 6.07; N, 9.85.
Example 176 i\^-(2-{[(Cyclohexylmethyl)amino]carbonyl}pyridm-3-yl)-iy^V-dimethylnaphthalene- 1,4-dicarboxamide
Figure imgf000190_0001
Step A. iV-(2-{[(Cyclohexylmethyl)amino] carbonyl} pyridin-3-yl)-/V,/V- dimethylnaphthalene-1 ,4-dicarb oxamide
Figure imgf000190_0002
Following the procedure for Step A in Example 30 (coπect??), using 4-{[(2- {[(Cyclohexylmethyl)amino]carbonyl}pyridin-3-yl)amino]carbonyl}-l-naphthoic acid (100 mg, 0.23 mmol), dimethylamine hydrochloride (187 mg, 2.31 mmol) and Et3N (0.48 mL, 3.47 mmol) and purifying by reverse-phase preparative HPLC provided the TFA salt of the title compound as white powder (30 mg, 43 %); X NMR (400 MHz, CHLOROFORM-D) δ 0.91 - 1.06 (m, 2 H), 1.09 - 1.33 (m, 3 H), 1.51 - 1.62 (m, 1 H), 1.63 - 1.84 (m, 5 H), 2.84 (s, 3 H), 3.24 (t, J=6.54 Hz, 2 H), 3.27 - 3.30 (m, 3 H), 7.47 - 7.55 (m, 2 H), 7.55 - 7.65 (m, 2 H), 7.78 - 7.86 (m, 1 H), 7.92 (d, J=7.23 Hz, 1 H), 8.29 (dd, J=4.49, 1.56 Hz, 1 H), 8.49 - 8.60 (m, 2 H), 9.39 (dd, J=8.49, 1.46 Hz, 1 H), 12.94 (s, 1 H); MS (ESI) (M+H)+ 459.0; Anal. Calcd. for C27H30N4O3 + 0.40 TFA + 0.10 H2O: C, 65.99; H, 6.10; N, 11.07. Found: C, 65.90; H, 6.00; N, 11.04. Step B. 4-{ [(2-{ [(Cyclohexylmethyl)amino] carbonyl} pyridin-3-yl)amino] carbonyl}-l- naphthoic acid
Figure imgf000191_0001
A solution of 3-Amino-N-(cyclohexylmethyl)pyridine-2-carboxamide (500 mg, 2.14 mmol, see step B. of example 82 for its preparation) and DIPEA (0.37 mL, 2.14 mmol) in THF (2 mL) was added to a solution of naphthalene- 1,4-dicarbonyl dichloride (1.6 g, 6.4 mmol, see step C. of example 159 for its preparation) in THF (300 mL) at 0°C. The reaction mixture was allowed to warm to ambient temperature and ΝaOH 0.1 M (10 drops) and MeCΝ (50 mL) were added. The reaction mixture was stirred for 2 hrs. and the solvent volume was reduced. The resulting precipitate was filtered, washed with small portions of cold THF and air dried to provide the pure title compound as a white solid (600 mg, 64 %).
Example 177 iV-(Cyclohexylmethyl)-3-{[4-(methoxymethyl)-l-naphthoyl]amino}pyridine-2- carboxamide
Figure imgf000191_0002
Step A. iV-(Cyclohexylmethyl)-3-{[4-(methoxymethyl)-l-naphthoyl]amino}pyridine-2- carboxamide
Figure imgf000192_0001
Following the procedure for Example 160, usingN-(cyclohexylmethyl)-3-{[4- (hydroxymethyl)-l -naphthoyl] amino }pyridine-2-carboxamide (103 mg, 0.24 mmol) and ΝaOMe 25% in MeOH (10 mL) and purifying by reverse-phase preparative HPLC provided the TFA salt of title compound as white powder (30 mg, 22 %); X ΝMR (400 MHz, CHLOROFORM-D) δ 0.91 - 1.05 ( , 2 H), 1.10 - 1.32 (m, 3 H), 1.52 - 1.62 (m, 1 H), 1.61 - 1.70 (m, 1 H), 1.70 - 1.83 (m, 4 H), 3.24 (t, J=6.54 Hz, 2 H), 3.44 - 3.50 (m, 3 H), 4.95 (s, 2 H), 7.52 (dd, J=8.59, 4.49 Hz, 1 H), 7.55 - 7.63 (m, 3 H), 7.87 (d, J=7.42 Hz, 1 H), 8.10 - 8.17 (m, 1 H), 8.28 (d, J=3.91 Hz, 1 H), 8.47 - 8.59 (m, 2 H), 9.40 (d, J=8.40 Hz, 1 H), 12.87 (s, 1 H); MS (ESI) (M+H)+ 432.0.
Step B. N-(Cyclohexylmethyl)-3-{ [4-(hydroxymethyl)-l-naphthoyl] amino}pyridine-2- carboxamide
Figure imgf000192_0002
Following the procedure for Step A in Example 159, using 4-{[(2- {[(Cyclohexylmethyl)amino]carbonyl}pyridin-3-yl)amino]carbonyl}-l-naphthoic acid (600 mg, 1.39 mmol, see step B. of example 27 (not correct! !) for its preparation) and purifying on silica gel by flash chromatography provided the title compound as a white solid (307 mg, 52%).
Example 178 iV-(Cyclohexylmethyl)-3-({4-[(dimethylamino)methyl]-l-naphthoyl}amino)pyridine-2- carboxamide
Figure imgf000193_0001
Following the procedure for example 160, using N-(cyclohexylmethyl)-3-{[4- (hydroxymethyl)-l-naphthoyl]amino}pyridine-2-carboxamide (103 mg, 0.24 mmol) provided the TFA salt of the title compound as a white solid (20 mg, 14 %); X ΝMR (400 MHz, CHLOROFORM-D) δ 0.90 - 1.07 (m, 2 H), 1.11 - 1.30 (m, 2 H), 1.66 - 1.82 (m, 4 H), 2.84 (s, 6 H), 3.23 (t, J=6.64 Hz, 2 H), 4.76 (s, 2 H), 7.54 (dd, J=8.49, 4.59 Hz, 1 H), 7.61 - 7.74 (m, 2 H), 7.84 (dd, J=59.56, 7.42 Hz, 2 H), 8.17 (d, J=7.42 Hz, 1 H), 8.31 (dd, J=4.49, 1.37 Hz, 1 H), 8.56 (dd, J=8.20, 0.98 Hz, 2 H), 9.38 (dd, J=8.59, 1.37 Hz, 1 H), 12.99 (s, 1 H); MS (ESI) (M+H)+ 445.2; Anal. Calcd. for C27H32Ν4O2 + 1.40 TFA: C, 59.24; H, 5.57; N, 9.27. Found: C, 59.64; H, 4.51; N, 9.29.
Example 179 iV-(Cyclobutylmethyl)-3-{[4-(lJΪ-pyrrol-l-ylmethyl)-l-naphthoyl]amino}pyridine-2- carboxamide
Figure imgf000193_0002
Step A. N-(Cyclobutylmethyl)-3-{[4-(lH-pyrrol-l-ylmethyl)-l- naphthoyl]amino}pyridine-2-carboxamide
Figure imgf000194_0001
(4-{[(2-{[(Cyclobutylmethyl)amino]carbonyl}pyridin-3-yl)amino]carbonyl}-l- naphthyl)methyl methanesulfonate (85 mg, 0.18 mmol) from step D, pyπole (624 mg, 9.30 mmol), Kl (33 mg, 0.20 mmol) and DMF (2 mL) were mixed together and heated to 80°C for 1 hrs. The solvent was concentrated and the residue was recovered in EtOAc. The solution was washed with saturated NaHCO3 solution, water, brine and dried over anhydrous Na2SO4. The solvent was concentrated and the product was purified by preparative reverse-phase HPLC to provide the TFA salt of the title compound as a white powder (29 mg, 28 %); X NMR (400 MHz, CHLOROFORM-D) δ 1.67 - 1.84 (m, 3 H), 1.85 - 1.97 (m, 2 H), 2.04 - 2.17 (m, 2 H), 2.52 - 2.64 (m, 1 H), 3.42 (dd, J=7.13, 6.15 Hz, 2 H), 4.45 - 4.50 (m, 2 H), 6.06 - 6.11 (m, 1 H), 6.18 (q, J=2.73 Hz, 1 H), 6.62 - 6.68 (m, 1 H), 7.38 (d, J=7.42 Hz, 1 H), 7.48 - 7.61 (m, 3 H), 7.84 (d, J=7.23 Hz, 1 H), 8.09 - 8.15 (m, 1 H), 8.28 (dd, J=4.49, 1.56 Hz, 1 H), 8.45 (t, J=5.76 Hz, 1 H), 8.54 - 8.59 (m, 1 H), 9.40 (dd, J=8.59, 1.56 Hz, 1 H), 12.86 (s, 1 H); MS (ESI) (M+H)+ 439.0; Anal. Calcd. for C27H26N4O2 + 5.10 TFA + 7.00 MeCN + 5.10 H2O: C, 43.95; H, 4.49; N, 11.01. Found: C, 44.13; H, 4.14; N, 10.93.
Step B. 4-{ [(2-{ [(Cyclobutylmethyl)amino] carbonyl} pyridin-3-yl)amino] carbonyl}-l- naphthoic acid
Figure imgf000194_0002
A solution of 3-Amino-N-(cyclobutylmethyl)pyridine-2-carboxamide (3.0 g, 14.6 mmol) and Et3Ν (2.6 mL, 14.6 mmol) in MeCN (50 mL) was added to a solution of naphthalene- 1,4-dicarbonyl dichloride (4.7 g, 18.5 mmol, see step C. of example 159 for its preparation) in MeCN (700 mL) at 0°C. The reaction mixture was stirred for 2 hrs. and NaOH 0.1 M solution (0.44 mL) was added. The reaction mixture was stirred for 1 extra hrs. and NaOH 0.1 M solution (excess) was added. The solvent was concentrated and water was added to the residue. The precipitate was filtered and the filtrate was acidified with concentrated HCl. The resulting precipitate was filtered. The precipitates were recovered in DCM, combined and dried over anhydrous Na2SO4. The solvent was concentrated to provide the pure title compound as beige solid (5.43 g, 92 %).
Step C. N-(Cyclobutylmethyl)-3-{ [4-(hydroxymethyl)-l -naphthoyl] amino} pyridine-2- carboxamide
Figure imgf000195_0001
Following the procedure for Step A in Example 159, using 4-{[(2- {[(Cyclobutylmethyl)amino]carbonyl}pyridin-3-yl)amino]carbonyl}-l-naphthoic acid (1.33 g, 3.30 mmol) from step B and performing a work-up in EtOAc provided the pure title compound as pale yellow oil (1.01 g, 78 %).
Step D. (4-{[(2-{[(Cyclobutylmethyl)amino]carbonyl}pyridin-3-yl)amino]carbonyl}-l- naphthyl)methyl methanesulfonate
Figure imgf000195_0002
Methane sulfonyl chloride (0.24 mL, 3.11 mmol) was added to a solution of N- (Cyclobutylmemyl)-3-{[4-(hydroxymethyl)-l-naphfhoyl]amino}pyridine-2-carboxamide (1.01 g, 2.59 mmol) from step C and Et3Ν (0.45 mL, 3.23 mmol) in DCM (150 mL) at 0°C. The reaction mixture was allowed to warm to ambient temperature and stirred for 3 hrs. The reaction mixture was washed with NaHCO3 saturated solution, water, brine and dried over anhydrous Na2SO4. The solvent was concentrated and the product was purified on silica gel by flash chromatography to provide the title compound as colorless oil (342 mg, 28 %).
Example 180 iV-(Cyclobutylmethyl)-3-{[4-(lH-l,2,3-triazol-l-ylmethyl)-l- naphthoyl]amino}pyridine-2-carboxamide
Figure imgf000196_0001
Following the procedure for example 179, using 1,2,3-triazole (0.64 g, 9.30 mmol) provided the TFA salt of the title compound as white powder (63 mg, 64 %); 1H NMR (400 MHz, CHLOROFORM-D) δ 1.68 - 1.81 (m, 2 H), 1.85 - 1.98 (m, 2 H), 2.05 - 2.16 (m, 2 H), 2.52 - 2.65 (m, 1 H), 3.42 (dd, J=7.13, 6.15 Hz, 2 H), 6.08 (s, 2 H), 7.43 (s, 1 H), 7.48 (d, J=7.23 Hz, 1 H), 7.54 (dd, J=8.59, 4.49 Hz, 1 H), 7.57 - 7.66 (m, 2 H), 7.76 (s, 1 H), 7.88 (d, J=7.42 Hz, 1 H), 7.95 - 8.02 (m, 1 H), 8.30 (dd, J=4.49, 1.37 Hz, 1 H), 8.48 (t, J=5.76 Hz, 1 H), 8.52 - 8.59 (m, 1 H), 9.39 (dd, J=8.59, 1.56 Hz, 1 H), 12.95 (s, 1 H); MS (ESI) (M+H)+ 441.0; Anal. Calcd. for C25H24N6O2 + 0.30 TFA: C, 64.77 ; H, 5.16 ; N, 17.70. Found: C, 64.75; H, 5.04; N, 17.30.
Example 181 iV-(Cyclobutylmethyl)-3-{[4-(lJrT-pyrazol-l-ylmethyl)-l-naphthoyl]amino}pyridine-2- carboxamide
Figure imgf000197_0001
Following the procedure for example 179, using pyrazole (0.72 g, 10.5 mmol) provided the TFA salt of the title compound as white powder (33 mg, 32 %); X NMR (400 MHz, CHLOROFORM-D) δ 1.67 - 1.81 (m, 2 H), 1.84 - 1.98 (m, 2 H), 2.04 - 2.16 (m, 2 H), 2.52 - 2.64 (m, 1 H), 3.42 (dd, J=7.22, 6.25 Hz, 2 H), 5.85 (s, 2 H), 6.30 (s, 1 H), 7.22 - 7.28 (m, 1 H), 7.33 (s, 1 H), 7.52 (dd, J=8.59, 4.49 Hz, 1 H), 7.56 - 7.61 (m, 2 H), 7.61 - 7.65 (m, 1 H), 7.85 (d, J=7.42 Hz, 1 H), 7.98 - 8.06 (m, 1 H), 8.28 (dd, J=4.49, 1.56 Hz, 1 H), 8.44 (t, J=5.76 Hz, 1 H), 8.53 - 8.61 (m, 1 H), 9.39 (dd, J=8.59, 1.37 Hz, 1 H), 12.90 (s, 1 H); MS : (ESI) (M+H)+ 440.0; Anal. Calcd. for C26H25N5O2 + 0.70 TFA + 0.10 H2O + 0.80 MeCN: C, 62.88 ; H, 5.15 ; N, 14.66 . Found: C, 62.89; H, 4.86 ; N, 14.66 .
Example 182
N-(Cyclobutylmethyl)-3-[(4-{[ethyl(methyl)amino]methyl}-l- naphthoyl)amino]pyridine-2-carboxamide
Figure imgf000197_0002
Following the procedure for example 179, using ethylmethylamine (0.55 g, 9.30 mmol) provided the TFA salt of the title compound as white powder (95 mg, 96 %); X NMR (400 MHz, CHLOROFORM-D) δ 1.43 (t, J=7.23 Hz, 3 H), 1.67 - 1.82 (m, 2 H), 1.84 - 1.99 (m, 2 H), 2.05 - 2.16 (m, 2 H), 2.52 - 2.65 (m, 1 H), 2.75 (s, 3 H), 2.96 - 3.10 (m, 1 H), 3.42 (dd, J=7.03, 6.25 Hz, 3 H), 4.65 - 4.92 (m, 2 H), 7.54 (dd, J=8.59, 4.49 Hz, 1 H), 7.61 - 7.74 (m, 2 H), 7.85 (dd, J=49.79, 7.42 Hz, 2 H), 8.16 (d, J=8.20 Hz, 1 H), 8.31 (dd, J=4.49, 1.56 Hz, 1 H), 8.47 (t, J=5.76 Hz, 1 H), 8.55 (dd, J=8.40, 1.17 Hz, 1 H), 9.38 (dd, J=8.59, 1.37 Hz, 1 H), 12.98 (s, 1 H); MS (ESI) (M+H)+ 431.3; Anal. Calcd. for C26H3oN4O2 + 1.90 TFA + 1.00 H2O + 0.60 MeCN: C, 53.97; H, 5.22; N, 9.34. Found: C, 53.93; H, 5.19; N, 9.40.
Example 183
A^(Cyclobutylmethyl)-3-{[4-(lH-imidazol-l-ylmethyl)-l-naphthoyl]amino}pyridine-2- carboxamide
Figure imgf000198_0001
Following the procedure for example 179, using imidazole (0.33 g, 4.84 mmol) provided the TFA salt of the title compound as white powder (50 mg, 18 %); X NMR (400 MHz, CHLOROFORM-D) δ 1.68 - 1.81 (m, 2 H), 1.83 - 1.99 (m, 2 H), 2.04 - 2.16 (m, 2 H), 2.52 - 2.64 (m, 1 H), 3.37 - 3.45 (m, 2 H), 5.83 (s, 2 H), 7.04 (s, 1 H), 7.36 (s, 1 H), 7.46 (d, J=7.42 Hz, 1 H), 7.54 (dd, J=8.59, 4.49 Hz, 1 H), 7.60 - 7.69 (m, 2 H), 7.82 - 7.92 (m, 2 H), 8.31 (dd, J=4.49, 1.37 Hz, 1 H), 8.47 (t, J=5.96 Hz, 1 H), 8.55 - 8.62 (m, 1 H), 8.98 (s, 1 H), 9.38 (dd, J=8.59, 1.37 Hz, 1 H), 13.00 (s, 1 H), MS (ESI) (M+H)+ 440.0; Anal. Calcd. for C26H25N5O2 + 1.20 TFA + 0.10 H2O: C, 59.00; H, 4.60; N, 12.11. Found: C, 59.05; H, 4.72; N, 12.04.
Example 184 /Y-(CycIobutylmethyl)-3-({4-[(dimethylamino)methyl]-l-naphthoyl}amino)pyridine-2- carboxamide
Figure imgf000199_0001
Following the procedure for example 179, using dimethylamine hydrochloride (0.20 g, 2.45 mmol) provided the TFA salt of the title compound as white powder (30 mg, 44 %); X NMR (400 MHz, CHLOROFORM-D) δ 1.69 - 1.80 (m, 2 H), 1.85 - 1.98 (m, 2 H), 2.05 - 2.16 (m, 2 H), 2.53 - 2.64 (m, 1 H), 2.84 (s, 6 H), 3.38 - 3.45 (m, 2 H), 4.73 - 4.79 (m, 2 H), 7.55 (dd, J=8.49, 4.59 Hz, 1 H), 7.63 - 7.74 (m, 2 H), 7.85 (dd, J=60.44, 7.32 Hz, 2 H), 8.17 (d, J=7.81 Hz, 1 H), 8.31 (dd, J=4.49, 1.37 Hz, 1 H), 8.46 (t, J=5.66 Hz, 1 H), 8.56 (dd, J=8.40, 1.17 Hz, 1 H), 9.38 (dd, J=8.59, 1.56 Hz, 1 H), 12.99 (s, 1 H), MS (ESI) (M+H)+ 417.3; Anal. Calcd. for C25H 8N O2 + 1.30 TFA + 0.70 H2O: C, 57.42; H, 5.36; N, 9.70. Found: C, 57.50; H, 5.31; N, 9.65.
Example 185
N-(CycIobutylmethyl)-3-{[4-(methoxymethyl)-l-naphthoyl]amino}pyridine-2- carboxamide
Figure imgf000199_0002
Following the procedure for example 179, using NaOMe 20% in MeOH (15 mL) provided the TFA salt of the title compound as white powder (30 mg, 44 %); X NMR (400 MHz, CHLOROFORM-D) δ 1.68 - 1.81 (m, 2 H), 1.83 - 1.99 (m, 2 H), 2.03 - 2.16 (m, 2 H), 2.52 - 2.64 (m, 1 H), 3.42 (t, J=6.05 Hz, 2 H), 3.47 (s, 3 H), 4.92 - 4.99 (m, 2 H), 7.52 (dd, J=3.12, 1.37 Hz, 1 H), 7.59 (dd, J=6.64, 2.73 Hz, 3 H), 7.87 (d, J=7.23 Hz, 1 H), 8.14 (dd, J=6.64, 2.93 Hz, 1 H), 8.28 (s, 1 H), 8.43 (s, 1 H), 8.56 (dd, J=6.64, 2.93 Hz, 1 H), 9.40 (d, J=8.20 Hz, 1 H), 12.87 (s, 1 H); MS (ESI) (M+H)+ 404.0; Anal. Calcd. for C24H25N3O3 + 0.10 H2O: C, 71.13; H, 6.27; N, 10.37. Found: C, 71.07; H, 6.53; N, 9.91.
Example 186 iV-(CyclobutyImethyl)-3-{[4-(ethoxymethyl)-l-naphthoyl]amino}pyridine-2- carboxamide
Figure imgf000200_0001
NaH 60% suspension in oil (0.20 g, 5.00 mmol) was slowly added to EtOH (20 mL) at 0°C. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 hr. The solution was cooled to 0°C and a solution of (4-{[(2-
{[(Cyclobutylmethyl)amino]carbonyl}ρyridin-3-yl)amino]carbonyl}-l-naphthyl)methyl methanesulfonate (60 mg, 0.12 mmol) in EtOH (2mL) was added. The reaction mixture was allowed to warm to ambient temperature, heated to 70°C and stiπed for 3 hrs. The solvent was concentrated and the product was purified by preparative reverse-phase HPLC to provide the TFA salt of the title compound as white solid (40 mg, 58 %); X NMR (400 MHz, CHLOROFORM-D) δ 1.29 (t, J=6.93 Hz, 3 H), 1.67 - 1.82 (m, 2 H), 1.84 - 1.97 (m, 2 H), 2.03 - 2.16 (m, 2 H), 2.53 - 2.64 (m, 1 H), 3.37 - 3.48 (m, J=3.51 Hz, 2 H), 3.64 (q, J=7.03 Hz, 2 H), 5.00 (s, 2 H), 7.48 - 7.55 (m, 1 H), 7.55 - 7.64 (m, 3 H), 7.87 (d, J=6.83 Hz, 1 H), 8.15 (dd, J=6.44, 3.12 Hz, 1 H), 8.27 (s, 1 H), 8.45 (s, 1 H), 8.56 (dd, J=6.35, 2.83 Hz, 1 H), 9.42 (d, J=6.64 Hz, 1 H), 12.87 (s, 1 H); MS (ESI) (M+H)+ 418.0; Anal. Calcd. for C25H27N3O3: C, 71.92; H, 6.52; N, 10.06. Found: C, 71.94; H, 6.18; N, 9.64.
Example 187 iV-(2-{[(Cyclobutylmethyl)amino]carbonyl}pyridin-3-yl)-iVyV-dimethylnaphthalene- 1,4-dicarboxamide
Figure imgf000201_0001
Following the procedure for Step A in Example 30 (coπect??), using 4-{[(2- { [(Cy clobutylmethyl)amino] carbonyl} pyridin-3 -yl)amino] carbonyl} - 1 -naphthoic acid (50 mg, 0.12 mmol), dimethylamine hydrochloride (100 mg, 1.23 mmol) and Et3N (0.20 mL, 1.23 mmol) and purifying by preparative reversed-phase HPLC provided the TFA salt of the title compound as a white powder (25 mg, 37 %); X NMR (400 MHz, CHLOROFORM-D) δ 1.69 - 1.81 (m, 2 H), 1.84 - 1.97 (m, 2 H), 2.05 - 2.21 (m, 2 H), 2.54 - 2.64 (m, 1 H), 2.84 (s, 3 H), 3.29 (s, 3 H), 3.40 - 3.45 (m, 2 H), 7.50 (d, J=7.22 Hz, 1 H), 7.53 (dd, J=8.59, 4.49 Hz, 1 H), 7.56 - 7.64 (m, 2 H), 7.80 - 7.85 (m, 1 H), 7.92 (d, J=7.42 Hz, 1 H), 8.29 (dd, J=4.49, 1.17 Hz, 1 H), 8.45 (t, J=5.57 Hz, 1 H), 8.57 (dd, J=7.81, 1.56 Hz, 1 H), 9.40 (dd, J=8.49, 1.46 Hz, 1 H), 12.94 (s, 1 H); MS (ESI) (M+H)+ 431.0; Anal. Calcd. for C25H26N4O3 + 0.30 H2O: C, 68.88; H, 6.15; N, 12.85. Found: C, 68.89; H, 5.99; N, 12.75.
Example 188 iV-(Cyclohexylmethyl)-3-{[4-(dimethylamino)-l-naphthoyl]amino}pyrazine-2- carboxamide
Figure imgf000201_0002
Step A. iV-(CycIoheχyImethyI)-3-{[4-(dimethylamino)-l-naphthoyl]amino}pyrazme-2- carboxamide
Figure imgf000202_0001
Methyl 3-{[4-(dimethylamino)-l-naphthoyl]amino}pyrazine-2-carboxylate (100 mg, 0.28 mmol) and cyclohexylmethylamine (0.18 mL, 1.42 mmol) in EtOH (25 mL) were heated to 90°C for 2 days. The solvent was concentrated and the product was purified by reverse- phase HPLC to provide the TFA salt of the title compound as a yellow solid (105 mg, 67 %); X NMR (400 MHz, CHLOROFORM-D) δ 0.83 - 0.89 (m, J=7.03 Hz, 1 H), 0.92 - 1.06 (m, 2 H), 1.12 - 1.32 (m, 3 H), 1.52 - 1.64 (m, 1 H), 1.64 - 1.82 (m, 4 H), 3.07 (s, 6 H), 3.27 (t, J=6.64 Hz, 2 H), 7.21 (d, J=8.01 Hz, 1 H), 7.54 - 7.62 (m, 2 H), 7.94 (d, J=7.81 Hz, 1 H), 8.22 - 8.32 (m, 3 H), 8.68 - 8.75 (m, 2 H), 12.71 (s, 1 H); MS (ESI) (M+H)+ 432.0; Anal. Calcd. for C25H29N5O2 + 0.60 TFA + 0.10 H2O: C, 62.72; H, 5.99; N, 13.96. Found: C, 62.91; H, 6.06; N, 13.06.
Step B. Methyl 3-{[4-(dimethylamino)-l-naphthoyl]amino}pyrazine-2-carboxylate
Figure imgf000202_0002
Oxalyl chloride (1.70 mL, 19.5 mmol) was added to a solution of 4-(dimethylamino)-l- naphthoic acid (2.63 g, 12.2 mmol) in DCE (125 mL) at 0°C. The reaction mixture was allowed to warm to ambient temperature, heated to 85°C and stiπed for 10 min. The reaction mixture was evaporated to dryness and the red residue was suspended in DCE (30 mL). The resulting suspension was added drop wise via a pump syringe over 7 hrs. to a solution of methyl 3-aminopyrazine-2-carboxylate (1.25 g, 8.16 mmol) and pyridine (4.75 mL, 58.7 mmol) in DCE (125 mL) at 80°C. The reaction mixture was stirred for 10 hrs at 80°C, cooled to ambient temperature and washed with 0.1M HCl solution. The solvent was concentrated and the product was purified on silica gel by MPLC to provide the title compound as white solid (1.24 g, 43 %)
Example 189 iV-(Cyclohexylmethyl)-3-{[5-(dimethyIamino)-l-naphthoyl]amino}pyridine-2- carboxamide
Figure imgf000203_0001
Step A. N-(Cyclohexylmethyl)-3-{[5-(dimethylamino)-l-naphthoyl]amino}pyridine-2- carboxamide
Figure imgf000203_0002
Following the procedure for Step B in Example 188, using 3-Amino-N- (cyclohexylmethyl)pyridine-2-carboxamide (279 mg, 1.19 mmol) and 5-(Dimethylamino)- 1 -naphthoic acid (387 mg, 1.79 mmol) and purifying the product by preparative reverse- phase HPLC provide the TFA salt of the title compound as yellow solid (30 mg, 4 %); 1H ΝMR (400 MHz, CHLOROFORM-D) δ 0.82 - 0.89 (m, 1 H), 0.92 - 1.05 (m, 2 H), 1.12 - 1.31 (m, 3 H), 1.52 - 1.62 ( , 1 H), 1.63 - 1.83 (m, 4 H), 3.21 - 3.25 (m, 2 H), 3.25 - 3.30 (m, 6 H), 7.47 - 7.51 (m, 1 H), 7.53 (dd, J=8.59, 4.49 Hz, 1 H), 7.55 - 7.61 (m, 1 H), 7.73 (dd, J=8.59, 7.23 Hz, 1 H), 7.98 (d, J=7.03 Hz, 1 H), 8.30 (dd, J=4.49, 1.37 Hz, 1 H), 8.45 8.58 (m, 3 H), 9.37 (dd, J=8.59, 1.37 Hz, 1 H), 12.96 (s, 1 H); MS (ESI) (M+H)+ 431.0; Anal. Calcd. for C26H30N4O2 + 0.30 TFA: C, 68.74; H, 6.57; N, 12.05. Found: C, 69.20; H, 6.01; N, 10.06. Step B-C-D-E. 5-(Dimethylamino)-l-naphthoic acid
Figure imgf000204_0001
X = COOH, Y = N02
A 3 M solution of diazomethane in Et2O (25 mL) was added to a solution of 5 -nitro- 1- naphthoic acid (2.40 g, 11.0 mmol) in THF (150 mL) at 0°C. The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The solvent was concentrated and the product recovered in EtOAc (150 mL). The resulting solution was shaken overnight with 10% Pd/C in a Parr apparatus under 50 PSI hydrogen. The mixture was filtered on a celite pad and the solvent was concentrated. The residue, K2CO3 (7.64 g, 55.2 mmol) and Mel (4.69 g, 33.1 mmol) in THF were heated to 72°C for 3 days. The solvent was concentrated. The product was recovered in EtOAc, washed with saturated NaHCO3 solution, water, brine and dried over anhydrous Na2SO . The solvent was concentrated and the product was purified on silica gel by MPLC using EtOAc in heptane 10 to 20% to provide colorless oil. The oil was mixed with 2 M NaOH (100 mL). The mixture was heated to 95°C and stirred overnight. The reaction mixture was cooled to 0°C and acidified with concentrated HCl (18 mL). The product was extracted with Et2θ, EtOAc and DCM. The organic phases were combined and dried with anhydrous a2SO . The solvent was concentrated to provide the pure title compound as yellow solid. Yield: 1.36 g (56%).
Example 190 3-{[4-(Dimethylamino)-l-naphthoyI]amino}-iV-(piperidm-2-ylmethyl)pyridme-2- carboxamide
Figure imgf000205_0001
Step A. 3-{[4-(Dimethylamino)-l-naphthoyl]amino}-Λ-(piperidin-2- ylmethyl)pyridine-2-carboxamide
Figure imgf000205_0002
The TFA salt of tert-Butyl 2-({[(3-{[4-(dimethylamino)-l-naphthoyl]amino}pyridin-2- yl)carbonyl]amino}methyl)piperidine-l-carboxylate (56 mg, 0.086 mmol) was added to TFA (5 mL) at 0°C. The reaction mixture was allowed to warm to ambient temperature and stiπed for 3 hrs. The solvent was concentrated and the product was purified by preparative reverse-phase HPLC to provide the TFA salt of the title compound as a white solid (30 mg, 64 %); XNMR (400 MHz, CHLOROFORM-D) δ 1.40 (t, J=13.08 Hz, 1 H), 1.48 - 1.74 (m, 3 H), 1.74 - 1.89 (m, 2 H), 2.65 - 2.80 (m, 1 H), 3.16 (s, 6 H), 3.28 (d, J=12.89 Hz, 1 H), 3.42 - 3.63 (m, 2 H), 7.36 (d, J=7.81 Hz, 1 H), 7.47 (dd, J=8.59, 4.49 Hz, 1 H), 7.57 - 7.67 (m, 2 H), 7.85 (d, J=7.81 Hz, 1 H), 8.21 (d, J=3.71 Hz, 1 H), 8.25 - 8.32 (m, 1 H), 8.53 - 8.61 (m, 1 H), 8.93 (t, J=6.15 Hz, 1 H), 9.27 (dd, J=8.59, 0.98 Hz, 2 H), 12.46 (s, 1 H); MS (ESI) (M+H)+ 432.2; Anal. Calcd. for C25H29 5O2 + 2.50 TFA + 0.20 H2O: C, 50.03; H, 4.46; N, 9.72. Found: C, 50.00; H, 4.47; N, 9.78.
Step B. tart-Butyl 2-({[(3-aminopyridin-2-yl)carbonyl]amino}methyl)piperidine-l- carboxylate
Figure imgf000206_0001
Following the procedure for Step B in Example 30, using tert-butyl 2- (aminomethyl)piperidine-l-carboxylate (0.49 g, 2.30 mmol) and purifying on silica gel by flash chromatography provided the title compound as colorless oil (477 mg, 92 %). Step C. tart-Butyl 2-({[(3-{[4-(dimethylammo)-l-naphthoyl]amino}pyridin-2- yl)carbonyl]amino}methyl)piperidine-l-carboxylate
Figure imgf000206_0002
Oxalyl chloride (0.10 mL, 1.24 mmol) was added to a solution of 4-(dimethylamino)-l- naphthoic acid (0.17 g, 0.82 mmol) in DCM (40 mL) at 0°C. The reaction mixture was allowed to warm to ambient temperature and stiπed for 1 hr. The solvent was concenfrated. The product was purified by preparative reverse-phase HPLC to provide the TFA salt of the title compound as a white solid (56 mg, 10 %).
Example 191 3-{[4-(dimethylamino)-l-naphthoyl]amino}-N-pentylpyridine-2-carboxamide
Figure imgf000206_0003
Following the procedure for Step A in Example 1, using 2-[4-(dimethylamino)-l- naphthyl]-4H-pyrido[3,2-c/][l,3]oxazin-4-one (0.47 mmol) and amylamine (0.27 mL, 2.36 mmol) provided the title compound (26 mg, 14 %). X NMR (400 MHz, CDC13) δ ppm 0.89 (t, J= 6.93Hz, 3H), 1.26-1.41 (m, 4H), 1.53-1.68 (m, 2H), 2.95 (s, 6H), 3.38 (q, J= 6.96Hz, 2H), 7.08 (d, J= 7.42Hz, IH), 7.43-7.59 (m, 3H), 7.87 (d, J= 7.81Hz, IH), 8.18- 8.32 (m, 2H), 8.45 (t, J= 4.78Hz, IH), 8.57-8.65 (m, IH), 9.38 (dd, J= 8.59, 1.17Hz, IH), 12.78 (s, IH); Found: C, 69.01; H, 6.87; N, 13.05. C24H2sN4θ2 x 0.3HC1 x 0.1H2O has C, 69.09; H, 6.88; N, 13.43%; MS (ESI) (M+H)+ 405.0
Example 192 3-{[4-(dimethylamino)-l-naphthoyl]amino}-iV-hexylpyridine-2-carboxamide
Figure imgf000207_0001
Following the procedure for Step A in Example 1, using 2-[4-(dimethylamino)-l- naphthyl]-4H-pyrido[3,2-<i][l,3]oxazin-4-one (0.57 mmol) and hexylamine (0.38 mL, 2.85 mmol) provided the title compound. X NMR (400 MHz, CD3OD) δ ppm 0.81 (t, J= 7.42Hz, 6H), 1.21-1.33 (m, 4H), 1.38-1.50 (m, IH), 2.85 (s, 6H), 3.17-3.24 (m, 2H), 7.05 (d, J= 7.81Hz, IH), 7.40-7.52 (m, 3H), 7.76 (d, J= 7.81Hz, IH), 8.14-8.20 (m, IH), 8.24 (dd, J= 4.49, 1.37Hz, IH), 8.37-8.45 (m, IH), 8.89 (t, J= 5.27Hz, IH), 9.17 (dd, J= 8.59, 1.37Hz, IH), 12.77 (s, IH); MS (ESI) (M+H)+ 419.0
Example 193 3-{[4-(dimethylamino)-l-naphthoyl]amino}-iV-[3-(dimethylamino)propyl]pyridine-2- carboxamide
Figure imgf000208_0001
Following the procedure for Step A in Example 1, using 2-[4-(dimethylamino)-l- naphthyl]-4H-pyrido[3,2-d][l,3]oxazin-4-one (0.57 mmol) and N,N-dimethylρropane-l,3- diamine (0.36 mL; 2.85 mmol) provided the title compound. MS (ESI) (M+Η)+ 419.0
Example 194 3-{[4-(dimethylamino)-l-naphthoyl]amino}-N-propylpyridine-2-carboxamide
Figure imgf000208_0002
Following the procedure for Step A in Example 1, using 2-[4-(dimethylamino)~l- naphthyl]-4H-ρyrido[3,2--fj[l,3]oxazin-4-one (0.57 mmol) and propylamine (0.93 mL; 11.40 mmol) provided the title compound. X ΝMR (400 MHz, CD3OD) δ ppm 0.85 (t, J= 7.42Hz, 3H), 1.52 (sext, 2H), 2.92 (s, 6H), 3.17-3.25 (m, 2H), 7.16 (d, J= 8.01Hz, IH), 7.45-7.53 (m, 3H), 7.79 (d, J= 8.01Hz, IH), 8.14-8.20 (m, IH), 8.25 (dd, J= 4.49, 1.56Hz, IH), 8.39-8.45 (m, IH), 9.17 (dd, J= 8.59, 1.56Hz, IH); MS (ESI) (M+H)+ 377.0
Example 195 3-{[4-(dimethyIamino)-l-naphthoyl]amino}-iV-(2-ethylbuιyl)pyridine-2-carboxamide
Figure imgf000209_0001
Following the procedure for Step A in Example 1, using 2-[4-(dimethylamino)-l- naphthyl]-4H-pyrido[3,2-<i][l,3]oxazin-4~one (0.57 mmol) and (2-ethylbutyl)amine (0.37 mL; 2.85 mmol) provided the title compound. X NMR (400 MHz, CDC13) δ ppm 0.72- 1.00 (m, 3 H), 1.14-1.49 ( , 6H), 1.49-1.73 (m, 2H), 2.96 (s, 6H), 3.39 (q, J= 6.51Hz, 2H), 6.97-7.21 (m, IH), 7.38-7.68 (m, 3H), 7.87 (d, J= 6.44Hz, IH), 8.14-8.37 (m, 2H), 8.46 (s, IH), 8.61 (d, J= 7.62Hz, IH), 9.38 (d, J= 8.01Hz, IH), 12.79 (s, IH); Found: C, 68.43; H, 6.93; N, 12.18. C25H3oN4O2 x 0.6HC1 has C, 68.18; H, 7.00; N, 12.72%; MS (ESI) (M+H)+ 419.0
Example 196 iV-(cyclohexylmethyl)-3-{[(5-phenyl-l,3-oxazol-4-yl)carbonyl]amino}pyridine-2- carboxamide
Figure imgf000209_0002
To a stock solution of 3-amino-N-(cyclohexylmethyl)pyridine-2-carboxamide in dimethylformamide (1.02 mmol) was added more dimethylformamide (3 mL), diisopropylethyl amine (0.81 mL; 4.65 mmol) followed by 5-phenyl-l,3-oxazole-4- carbonyl chloride (193 mg; 0.93 mmol). The reaction mixture was stiπed over weekend, then was heated to 100°C and stiπed for 3 days. The reaction mixture was concentrated under reduced pressure. The residue was taken in ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give the crude material. The crude material was suspended in acetonitrile and filtered to give the title compound. X NMR (400 MHz, CDC13) δ ppm 0.93-1.10 (m, 2H), 1.09-1.36 (m, 3H), 1.46-1.91 (m, 6H), 3.35 (t, J= 6.54Hz, 2H), 7.38- 7.55 (m, 4H), 8.01 (s, IH), 8.18-8.30 (m, 3H), 8.53 (t, J= 5.37Hz, IH), 9.30 (dd, J= 8.59, 1.37Hz, IH), 13.50 (s, IH); MS (ESI) (M+H)+ 405.0
Example 197 iV-butyl-3-{[4-(dimethylamino)-l-naphthoyl]amino}pyridine-2-carboxamide
Figure imgf000210_0001
Following the procedure for Step A in Example 1, using 2-[4-(dimethylamino)-l- naphthyl]-4H-pyrido[3,2-^[l,3]oxazin-4-one (0.47 mmol) and N-butylamine (0.23 mL; 2.33 mmol) provided the title compound (16%). X ΝMR (400 MHz, CDC13) δ ppm 0.93 (t, J = 7.32Hz, 3H), 1.40 (sext, J= 7.61Hz, 2H), 1.59 (quint, J= 7.37Hz, 2H), 3.02 (s, 6H), 3.39 (q, J= 7.03Hz, 2H), 7.10-7.24 (br. s, IH), 7.49 (dd, J= 8.59, 4.49Hz, IH), 7.56 (dd, J = 6.44, 3.12Hz, 2H), 7.87 (d, J= 7.81Hz, IH), 8.24 (dd, J= 4.49, 1.56Hz, IH), 8.31-8.43 (br. s, IH), 8.46 (t, J= 5.37Hz, IH), 8.56-8.65 (m, IH), 9.37 (dd, J= 8.59, 1.37Hz, IH), 12.82 (s, IH); MS (ESI) (M+H)+ 391.0
Example 198 3-{[(5-phenyl-l,3-oxazol-4-yl)carbonyl]amino}-N-(tetrahydro-2H-pyran-4- ylmethyl)pyridine-2-carboxamide
Figure imgf000211_0001
To a room temperature solution of 3-amino-N-(tetrahydro-2H-pyran-4-ylmethyl)pyridine- 2-carboxamide (200 mg; 0.85 mmol) in dimethylformamide (2.6 mL) was added diisopropylethyl amine (0.67 mL; 3.86 mmol) followed by 5-phenyl-l,3-oxazole-4- carbonyl chloride (160 mg; 0.77 mmol). The reaction mixture was stirred over weekend, then was heated to 100°C and stirred for 3 days. The reaction mixture was concentrated under reduced pressure. The residue was taken in ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give the crude material. The crude material was suspended in acetonitrile and filtered to give the title compound (24%). X ΝMR (400 MHz, CDC13) δ ppm 1.41 (dq, J= 12.10, 4.49Hz, 2H), 1.70 (d, J= 12.89, 2H), 1.85-1.99 (m, IH), 3.34- 3.46 (m, 4H), 3.99 (dd, J= 11.42, 4.20Hz, 2H), 7.41-7.53 (m, 4H), 8.02 (s, IH), 8.20-8.27 (m, 3H), 8.57 (t, J= 5.96Hz, IH), 9.31 (dd, J= 8.69, 1.27Hz, IH), 13.42 (s, IH); MS (ESI) (M+H)+ 407.0
Example 199
3-{[4-(dimethylamino)-l-naphthoyl]amino}-N-[3-(lH-imidazol-l-yl)propyl]pyridine- 2-carboxamide
Figure imgf000212_0001
Following the procedure for Step A in Example 1, using 2-[4-(dimethylamino)-l- naphthyl]-4H-pyrido[3,2-< |[l,3]oxazin-4-one (0.58 mmol) and l-(3- aminoρropyl)imidazole (0.35 mL; 2.91 mmol) provided the title compound (15%). X NMR (400 MHz, CD3OD) δ ppm 2.10 (quint., J= 6.83Hz, 2H), 3.34 (t, J= 6.44Hz, 2H), 3.44 (s, 6H), 4.21 (t, J= 7.13Hz, 2H), 7.43 (t, J= 1.66Hz, IH), 7.53-7.61 (m, 2H), 7.71 (dt, J= 7.71, 1.17Hz, IH), 7.80 (dt, J= 7.03, 1.36Hz, IH), 7.99 (q, J= 7.88Hz, 2H), 8.28 (d, J = 8.59Hz, IH), 8.33 (dd, J= 4.49, 1.37Hz, IH), 8.49 (d, J= 8.40Hz, IH), 8.86 (t, J= 1.27Hz, IH), 9.18 (dd, J= 8.59, 1.37Hz, IH); Found: C, 50.62; H, 5.16; N, 13.84. C25H26N6O2 x 4.1HC1 x 0.1H2O has C, 50.57; H, 5.14; N, 14.15%; MS (ESI) (M+H)+ 443.0.
Example 200
N-(4,4-difluorocyclohexyl)-3-(l-naphthoylamino)pyridine-2-carboxamide (IUPAC name)
Figure imgf000212_0002
Following the procedure for Step A in Example 1, using 2-(l-naphthalenyl)-4H- ρyrido[3,2-c ][l,3]oxazin-4-one (274 mg, 1.00 mmol), and 4,4-difluorocyclohexanamine (405 mg, 3.00 mmol) provided the title compound (109 mg, 27 %) after purification by flash column chromatography (heptan/EtOAc 2:1). NMR (400 MHz, CDC13) δ 1.64- 1.74 (m, 2H), 1.79-1.85 (m, 2H), 2.00-2.14 (m, 2H), 3.93-4.02 (m, IH), 7.50-7.58 (m, 4H), 7.86-7.90 (m, 2H), 7.97 (d, J=8.3 Hz, IH), 8.26 (dd, J=4.4, 1.2 Hz, IH), 8.40 (d, J=7.9 Hz, IH), 8.51 (d, J=8.3 Hz, IH), 9.39 (d, J=8.7 Hz, IH), 12,70 (br s, IH); MS (ESI) (M+H)+ 410.1
Example 201 iV-(3,5-dijuuorobenzyl)-3-(l-naphthoylamino)pyridine-2-carboxamide (IUPAC name)
Figure imgf000213_0001
Following the procedure for Step A in Example 1, using 2-(l-naphthalenyl)-4H- pyrido[3,2-cf][l,3]oxazin-4-one (137 mg, 0.50 mmol), and 3,5-difluorobenzylamine (215 mg, 1.50 mmol) provided the title compound (16 mg, 8 %) after purification by flash column chromatography (heptan/EtOAc 5:2). NMR (400 MHz, CDC13) δ 4.56 (d, J=8.5 Hz, 2H), 6.66-6.72 (m, IH), 6.80-6.85 (m, 2H), 7.50-7.58 (m, 4H), 7.86-7.90 (m, 2H), 7.97 (d, J=8.1 Hz, IH), 8.27 (d, J=4.4 Hz, IH), 8.52 (d, J=8.5 Hz, IH), 8.83 (br s, IH), 9.42 (d, J=8.5 Hz, IH), 12,62 (br s, IH); MS (ESI) (M-H)- 416.0
Example 202 iV-(4-morpholin-4-ylbenzyl)-3-(l-naphthoylamino)pyridine-2-carboxamide (IUPAC name)
Figure imgf000214_0001
Following the procedure for Step A in Example 1, using 2-(l-naphthalenyl)-4H- pyrido[3,2-d][l,3]oxazin-4-one (137 mg, 0.50 mmol), and l-(4-morpholin-4- ylphenyl)methanamine (288 mg, 1.50 mmol) provided the title compound (44 mg, 19 %) after purification by flash column chromatography (heptan/EtOAc 1 : 1 and CΗ2Cl2:Et2O 20:1). X NMR (400 MHz, CDC13) δ 3.10-3.13 (m, 4H), 3.81-3.84 (m, 4), 4.49 (d, J=5.8 Hz, 2H), 6.84-6.88 (m, 2H), 7.21-7.24 (m, 2H), 7.48-7.58 (m, 4H), 7.87-7.92 (m, 2H), 7.97 (d, J=8.2 Hz, IH), 8.27 (dd, J=4.4, 1.2 Hz, IH), 8.53 (d, J=8.3 Hz, IH), 8.65 (br s, IH), 9.39 (dd, J=8.5, 1.0 Hz, IH), 12,80 (br s, IH); MS (ESI) (M+H)+ 467.2
Example 203
6-Methoxy-3-[(4-[l,2,3]triazol-l-ylmethyl-naphthalene-l-carbonyl)-amino]-pyridine- 2-carboxylic acid cyclohexylmethyl-amide (IUPAC name)
Figure imgf000214_0002
Step A. 3-Amino-6-methoxy-pyridine-2-carboxylic acid
Figure imgf000215_0001
3-Acetylamino-6-methoxy-pyridine-2-carboxylic acid [Besly; Goldberg; JCSOA9; J. Chem. Soc; 2448, 2455] { .96 g, 37.88 mmol) was boiled for 80 min with 2.5 N NaOH(aq> sat) (80 ml). The solution was adjusted to pH 4 with 4 N HCl(aq) at 0 °C. The formed precipitate was collected, washed with cold water and air dried to give 5.65 g (89%) of 3- Amino-6-methoxy-pyridine-2-carboxylic acid. MS (ESI) (M+H)+ 169.14. Step B. 6-Methoxy-3-[(4-methyl-naphthalene-l-carbonyl)-amino]-pyridine-2-carboxylic acid methyl ester
Figure imgf000215_0002
To a solution of 3-Amino-6-methoxy-pyridine-2-carboxylic acid (1.78 g, 10.6 mmol) from step A in anhydrous DMF (30 ml) was addedDLPEA (11.07 ml, 63.6 mmol) and4-methyl- 1-naphthalenecarbonyl chloride (2.65 g, 12.95 mmol) under nitrogen. After stirred for 1 h at r.t., and for 1 h at 50 °C, K2CO3 (2.2 g, 15.9 mmol) was added into the reaction mixture followed by addition of Mel (3.3 ml, 53 mmol) in portions at r.t.. After stirred overnight, the reaction mixture was condensed, and the residue was suspended in water, and the crystals filtered, washed with water, ethanol and air dried. The crude product (2.7 g) was suspended in ethyl acetate/methanol, and the crystals filtered, washed with methanol, ether and air dried to give 2 g (54%) of 6-Methoxy-3-[(4-methyl-naphthalene-l-carbonyl)- amino]-pyridine-2 -carboxylic acid methyl ester. MS (ESI) (M+H)+ 351.10.
Step C. 6-Methoxy-3-[(4-[l,2,3]triazol-l-ylmethyl-naphthalene-l-carbonyl)-amino]- pyridine-2-carboxylic acid methyl ester
Figure imgf000216_0001
To a mixture of 6-Methoxy-3-[(4-methyl-naphthalene-l-carbonyl)-amino]-pyridine-2- carboxylic acid methyl ester (1.8 g, 5.14 mmol) from step B in CC14 (100 ml) was added NBS (0.96 g, 5.39 mmol) and benzoyl peroxide (0.125 g, 0.51 mmol). The reaction mixture was refluxed for 1.5 h under nitrogen. DMF (2.5 ml) and 1,2,3-triazole (2.98 ml, 51.4 mmol) was added, and the reaction mixture was refluxed overnight. After removal of solvents, the residue was suspended in cold water. The formed precipitate was collected, washed with water, air dried and purified by column chromatography on silica gel using first CH2C12 and then CH2Cl2/MeOH (100:1) as eluent to give 1.55 g (72%) of 6-Methoxy- 3-[(4-[l ,2,3]triazol-l -ylmethyl-naphthalene-l-carbonyl)-amino]-pyridine-2-carboxylic acid methyl ester. MS (ESI) (M+H)+ 418.13.
Step D. 6-Methoxy-3-[(4-[l,2,3]friazol-l-ylmethyl-naphthalene-l-carbonyl)-amino]- pyridine-2-carboxylic acid cyclohexylmethyl-amide
Figure imgf000216_0002
A solution of 6-Methoxy-3 - [(4- [ 1 ,2,3 ]triazol- 1 -ylmethyl-naphthalene- 1 -carbonyl)-amino] - pyridine-2-carboxylic acid methyl ester (0.5 g, 1.2 mmol) from step C and cyclohexanemethylamine (0.41 g, 3.6 mmol) in DMF (3 ml) was heated at 80 °C for 40 min. The solution was evaporated under reduced pressure, and the residue was dissolved in dichloromethane. After addition of water (50 ml) and 2 N HCl(aq) (13 ml), the organic phase was separated, washed with NaHCO3(aq, sat), brine, dried and evaporated under reduced pressure. The residue was purified by preparative HPLC using acetonitrile and ammonium acetate buffer (30:70 to 95:5) as eluent to give 517 mg (86%) of 6-Methoxy-3- [(4-[l,2,3]triazol-l-ylmethyl-naphthalene-l-carbonyl)-amino]-pyridine-2-carboxylic acid cyclohexylmethyl-amide.
X-NMR (600 MHz, CDC13): 0.93-1.02 (m, 2H), 1.09-1.27 (m, 3H), 1.50-1.58 (m, IH), 1.62-1.78 (m, 5H), 3.22 (t, J=6.66 Hz, 2H), 3.94 (s, 3H), 6.04 (s, 2H), 7.01 (d, J=9.1 Hz, IH), 7.36 (s, IH), 7.41 (d, J=7.18 Hz, IH), 7.53-7.60 (m, 2H), 7.66 (s, IH), 7.83 (d, J=7.17 Hz, IH), 7.98 (d, J=7.82 Hz, IH), 8.23 (t, J=6.5 Hz, IH), 8.53 (d, J=8.52 Hz, IH), 9.31 (d, J=9.1 Hz, IH), 12.62 (s, IH). MS (ESI) (M+H)+ 499.12.
Example 204
6-Hydroxy-3-[(4-[l,2,3]triazoI-l-ylmethyI-naphthalene-l-carbonyl)-amino]-pyridme- 2-carboxylic acid cyclohexylmethyl-amide (IU AC name)
Figure imgf000217_0001
A mixture of 6-Methoxy-3-[(4-[l,2,3]triazol-l-ylmethyl-naphthalene-l-carbonyl)-amino]- pyridine-2-carboxylic acid cyclohexylmethyl-amide (0.29 g, 0.58 mmol) and pyridine hydrochloride (7.3 g, 63.17 mmol) was heated at 150 °C for 25 min. Water was added at r.t. The formed precipitate was collected, washed with water, dried and purified by preparative HPLC using acetonitrile and ammonium acetate buffer (25:75 to 95:5) to give the title compound (193 mg, 69%).
X-NMR (500 MHz, CD3OD): 0.92-1.02 (m, 2H), 1.12-1.30 (m, 3H), 1.50-1.60 (m, IH), 1.62-1.78 (m, 5H), 3.15 (d, J=7.04 Hz, 2H), 6.19 (s, 2H), 6.96 (d, J=8.91 Hz, IH), 7.47 (d, J=7.04 Hz, IH), 7.60-7.66 (m, 2H), 7.73 (d, J=0.94 Hz, IH), 7.84 (d, J=7.04 Hz, IH), 7.94 (d, J=0.94 Hz, IH), 8.19-8.24 (m, IH), 8.43-8.48 (m, IH), 9.12 (d, J=8.92 Hz, IH). MS (ESI) (M+H)+ 485.15.
Example 205 6-Methoxy-3-[(4-[l,2,3]triazol-l-yImethyl-naphthalene-l-carbonyl)-amino]-pyridine- 2-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide (IUPAC name)
Figure imgf000218_0001
A solution of 6-Methoxy-3-[(4-[l,2,3]triazol-l-ylmethyl-naphthalene-l-carbonyl)-amino]- pyridine-2-carboxylic acid methyl ester (0.5 g, 1.2 mmol) and 4-tetrahydropyranmethyl amine (0.395 g, 3.42 mmol) in DMF (3 ml) was heated at 80 °C for 3 h. The solution was evaporated under reduced pressure. The residue was purified by preparative HPLC using acetonitrile and ammonium acetate buffer (20:80 to 90:10) to give the title compound (473 mg, 79%).
1NMR (300 MHz, CDC13): 1.30-1.41 (m, 2H), 1.60-1.70 (m, 2H), 1.80-1.94 (m, IH), 3.26- 3.43 (m, 4H), 3.96 (s, 3H), 3.96-4.02 (m, 2H), 6.06 (s, 2H), 7.04 (d, J=9.23 Hz, IH), 7.39 (d, J=0.84 Hz, IH), 7.43 (d, J=7.22 Hz, IH), 7.54-7.64 (m, 2H), 7.69 (d, J=0.84 Hz, IH), 7.85 (d, J=7.21 Hz, IH), 7.96-8.04 (m, IH), 8.27 (t, J=6.21 Hz, IH), 8.51-8.59 (m, IH), 9.33 (d, J=9.07 Hz, IH), 12.55 (s, IH). MS (ESI) (M+H)+ 501.12.
Example 206 6-Hydroxy-3-[(4-[l,2,3]triazoI-l-ylmethyl-naphthalene-l-carbonyl)-amino]-pyridine- 2-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide (IUPAC name)
Figure imgf000219_0001
The compound was prepared according to the procedure for 6-Hydroxy-3-[(4- [1 ,2,3]triazol- 1-ylmethyl-naphthalene- l-carbonyl)-amino]-pyridine-2-carboxylic acid cyclohexylmethyl-amide in 80% isolated yield.
X-NMR (300 MHz, CD3OD): 1.22-1.40 (m, 2H), 1.57-1.69 (m, 2H), 1.74-1.92 (m, IH), 3-20-3.42 (m, 4H), 3.85-3.96 (m, 2H), 6.20 (s, 2H), 6.96 (d, J=9.07 Hz, IH), 7.46 (d, J=7.39 Hz, IH), 7.58-7.69 (m, 2H), 7.74 (s, IH), 7.85 (d, J=7.22 Hz, IH), 7.95 (s, IH), 8.18-8.27 (m, IH), 8.41-8.50 (m, IH), 9.12 (d, J=9.07 Hz, IH). MS (ESI) (M+H)+ 487.12.
Example 207
6-Propoxy-3-[(4-[l,2,3]triazol-l-ylmethyl-naphthalene-l-carbonyl)-amino]-pyridine- 2-carboxyϊic acid cyclohexylmethyl-amide (IUPAC name)
Figure imgf000219_0002
A mixture of 6-Hydroxy-3-[(4-[l,2,3]triazol-l-ylmethyl-naphthalene-l-carbonyl)-amino]- pyridine-2-carboxylic acid cyclohexylmethyl-amide (7 mg, 0.014 mmol), silver carbonate (50 mg, 0.18 mmol) and 4 drops of 1-iodopropane in acetonitrile (1.5 ml) was refluxed for 1 h. Dichloromethane and water were added at r.t. The organic layer was separated, washed with NaHCO3(aq, sat), water, brine, dried and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using CH2Cl2/MeOH (100:2.5) as eluent to give the title compound (4.5 mg, 59%).
X-NMR (500 MHz, CDC13): 0.93-1.04 (m, 2H), 1.07 (t, J=7.51 Hz, 3H), 1.11-1.32 (m, 3H), 1.52-1.62 (m, IH), 1.64-1.80 (m, 6H), 1.81-1.90 (m, 2H), 3.24 (t, J=6.58 Hz, 2H), 4.24 (t, J=6.57 Hz, 2H), 6.06 (s, 2H), 7.02 (d, J=8.92 Hz, IH), 7.38 (d, J=0.94 Hz, IH), 7.44 (d, J=7.51 Hz, IH), 7.55-7.62 (m, 2H), 7.69 (d, J=0.94 Hz, IH), 7.85 (d, J=7.04 Hz, IH), 8.0 (dd, J=7.98, 1.41 Hz, IH), 8.23 (t, J=6.11 Hz, IH), 8.55 (dd, J=7.51, 1.87 Hz, IH), 8.32 (d, J=9.39 Hz, IH), 12.63 (s, IH). MS (ESI) (M+H)+ 527.31.

Claims

What is claimed is:
1. A compound of formula I or a pharmaceutically acceptable salt thereof, diastereomers, enantiomers, or mixtures thereof:
Figure imgf000221_0001
I wherein: one of A1, A2, A3 or A4 is N and the remaining are each and independently CR1; and R1 is independently selected from hydrogen, halogen, cyano, amino, acetylamino, hydroxyl, alkoxy, alkyl, halogenated alkoxy, alkylene, halogenated alkyl, halogenated alkenyl and NR5R6; R2 is selected from
Figure imgf000222_0001
wherein said group used in defining R2 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, halogenated alkoxy, cyano, nitro, alkoxy, hydroxy, hydroxy-alkyl, amino, alkyl-aryl, alkoxy, alkoxy-alkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, amino-alkyl, alkyl-amino-carbonyl, heteroaryl-carbonyl, heterocyclyl-carbonyl, arylcarbonyl, heterocyclyl, cycloalkyl, heteroaryl, heteroarylalkyl, aryl, aryl-alkyl and-NR5R6; R3 is selected from hydrogen and alkyl; R4 is selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl used in defining R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, alkylcarbonyl, cyano, nitro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxycarbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, aryl-alkyl and -NR5R6; and n is selected from 0, 1, 2, 3, 4 and 5; or R3 and R4 together with the nitrogen atom to which they are attached may form a group selected from heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms; wherein said heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms used in defining R3 and R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, cyano, nitro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxy-carbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, aryl-Cι-6alkyl and -NR5R6, wherein each of R5 and R6 is independently selected from hydrogen, C1-6alkyl, C2- 6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyC1-6 alkyl, alkoxy, C3.6cycloalkyl, C3-6cycloalkyl-C1-6alkyl, C1-6alkylcarbonyl, C3-6heterocyclyl and
C3-6heterocyclyl-Cι.6alkyl; wherein said C1-6alkyl, C2-6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyC1-6 alkyl, alkoxy, C3-6cycloalkyl, C3.
6cycloalkyl-C1-6alkyl, d.6alkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-C1-6alkyl used in defining R5 and R6 are optionally substituted by one or more groups selected from halogen, cyano, nitro, Cj-6 alkoxy, C1-6 alkyl and hydroxy; with a proviso that when n=0 then R4 is not thiazolyl or 5-chloropyridinyl; with a further proviso that when R2 is phenyl then n=0 and R4 is not unsubstituted methyl, C3 alkyl or unsubstituted C4 alkyl; and with a further proviso that said compound of formula I is not any one of
3-(benzoylamino)-N-benzylpyridine-2-carboxamide;
3-(benzoylamino)-N-pyridin-3-ylpyridine-2-carboxamide;
3-(benzoylamino)-N-phenylpyridine-2-carboxamide;
3-(benzoylamino)-N-(3-nitrophenyl)pyridine-2-carboxamide; 3-(benzoylamino)-N-(4-methoxyphenyl)pyridine-2-carboxamide;
3-(benzoylamino)-N-[4-(dimethylamino)phenyl]pyridine-2-carboxamide;
N-(2-hydroxyethyl)-4-(2-naphthoylamino)nicotinamide;
4-(benzoylamino)-N-(2-hydroxyethyl)nicotinamide;
3-(benzoylamino)-2,6-dimethyl-N-phenylisonicotinamide; 3-(benzoylamino)-2,6-dimethyl-N-(3-nitrophenyl)isonicotinamide;
2-(benzoylamino)-N-[cyano(2-thienyl)metlιyl]nicotinamide; and
2-(benzoylamino)-N-[cyano(phenyl)methyl]nicotinamide.
2. A compound according to claim 1 wherein R1 is independently selected from hydrogen, halogen, hydroxyl, alkoxy, alkyl, halogenated alkoxy, and halogenated alkyl; and R2 is selected from
Figure imgf000224_0001
Figure imgf000224_0002
Figure imgf000224_0003
and 0/
wherein said group used in defining R2 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, halogenated alkoxy, cyano, nifro, alkylalkoxy, hydroxy-alkyl, alkoxy, alkoxyalkyl, alkylamino, amino-alkyl, alkyl-amino- carbonyl, heterocyclyl, heteroaryl, heteroarylalkyl, aryl-alkyl and-NR R ; R3 is selected from hydrogen and alkyl; R4 is selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl used in defining R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, alkyl-carbonyl, cyano, nitro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxy-carbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, and -NR5R6; and n is selected from 0, 1, 2, 3, 4 and 5; or R3 and R4 together with the nitrogen atom to which they are attached may form a group selected from heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms; wherein said heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms used in defining R3 and R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, cyano, nitro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxy-carbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, aryl-C1-6alkyl and -NR5R6, wherein each of R5 and R6is independently selected from hydrogen, C1-6alkyl, C2- 6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl,
Figure imgf000225_0001
alkyl, alkoxy, C3.6cycloalkyl, C3-6cycloalkyl-Cι-6alkyl, C1-6alkylcarbonyl, C -6heterocyclyl and C3-6heterocyclyl-C1-6alkyl; wherein said C1-6alkyl, C2-6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, Cι-6 alkoxycarbonyl, hydroxyC1-6 alkyl, alkoxy, C3-6cycloalkyl, C3- 6cycloalkyl-C1-6alkyl, C1-6alkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-C1-6alkyl used in defining R5 and R6 are optionally substituted by one or more groups selected from halogen, cyano, nitro, C1-6 alkoxy, C1-6 alkyl and hydroxy.
3. A compound according to claim 1 or 2 wherein R1 is independently selected from hydrogen, fluoro, chloro, hydroxyl, alkoxy, alkyl, halogenated alkoxy, and halogenated alkyl; and R2 is selected from
Figure imgf000225_0002
wherein said group used in defining R2 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, halogenated alkoxy, alkyl-alkoxy, hydroxy-alkyl, alkoxy, alkoxyalkyl, alkylamino, amino-alkyl, alkyl-amino-carbonyl, heterocyclyl, heteroaryl, heteroarylalkyl and-NR5R6; R3 is selected from hydrogen and alkyl; R4 is selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl used in defining R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, alkyl-carbonyl, cyano, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxy- carbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, and -NR5R6; and n is selected from 0, 1, 2, 3, 4 and 5; or R3 and R4 together with the nitrogen atom to which they are attached may form a group selected from heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms; wherein said heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms used in defining R3 and R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, cyano, nitro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxy-carbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, aryl-C1-6alkyl and -NR5R6, wherein each of R5 and R6 is independently selected from hydrogen, C^aUcyl, C2. 6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyC1-6 alkyl, alkoxy, C3-6cycloalkyl, C3-6cycloalkyl-Cι.6alkyl, C1-6alkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-C1-6alkyl; wherein said C1-6alkyl, C2-6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyC1-6 alkyl, alkoxy, C3-6cycloalkyl, C3- gcycloalkyl-Ci.δalkyl, Ci-βalkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-C1-6alkyl used in defining R5 and R6 are optionally substituted by one or more groups selected from halogen, C1-6 alkoxy, C1-6 alkyl and hydroxy.
4. A compound of formula IB or a pharmaceutically acceptable salt thereof, diastereomers, enantiomers, or mixtures thereof:
Figure imgf000226_0001
IB wherein: A is each and independently CR1; and R1 is independently selected from hydrogen, halogen, cyano, amino, acetylamino, hydroxyl, alkoxy, alkyl, halogenated alkoxy, alkylene, halogenated alkyl, halogenated alkenyl and NR5R6; R2 is selected from
Figure imgf000227_0001
wherein said group used in defining R2 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, halogenated alkoxy, cyano, nitro, alkoxy, hydroxy, hydroxy-alkyl, amino, alkyl-aryl, alkoxy, alkoxy-alkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, amino-alkyl, alkyl-amino-carbonyl, heteroaryl-carbonyl, heterocyclyl-carbonyl, arylcarbonyl, heterocyclyl, cycloalkyl, heteroaryl, heteroarylalkyl-, aryl, aryl-alkyl and-NR5R6; R3 is selected from hydrogen and alkyl; R4 is selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl used in defining R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, alkylcarbonyl, cyano, nitro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxy- carbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, aryl-alkyl and -NR5R6; and n is selected from 0, 1, 2, 3, 4 and 5; or R3 and R4 together with the nitrogen atom to which they are attached may form a group selected from heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms; wherein said heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms used in defining R3 and R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, cyano, nitro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxy-carbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, aryl-Cι,6alkyl and -NR5R6, wherein each of R5 and R6 is independently selected from hydrogen, C1-6alkyl, C2- 6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyC1-6 alkyl, alkoxy, C3-6cycloalkyl, C3-6cycloalkyl-Cι.6alkyL C1-6alkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-Cι-6alkyl; wherein said C1-6alkyl, C2-6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1- alkoxycarbonyl, hydroxyC1-t5 alkyl, alkoxy, C3-6cycloalkyl, C3- 6cycloalkyl-C1-6alkyl, Cι.6alkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl~C1-6alkyl used in defining R5 and R6 are optionally substituted by one or more groups selected from halogen, cyano, nifro, C1-6 alkoxy, C1-6 alkyl and hydroxy; with a proviso that said compound of formula IB is not any one of 3-[(4-tert- butylbenzoyl)amino]-N-(5-chloro-pyridin-2-yl)pyrazine-2-carboxamide; N-[2-(lH- imidazol-2-yl)ethyl]-3-[[4-(l,l-dimethylethyl)benzoyl]amino]-2-pyrazinecarboxamide and 3-(benzoylamino)-N-(methoxycarbonylmethyl)pyrazine-2-carboxamide.
5. A compound according to claim 4 wherein A is each and individually CR1; R1 is independently selected from hydrogen, halogen, hydroxyl, alkoxy, alkyl, halogenated alkoxy, and halogenated alkyl; R2 is selected from
Figure imgf000229_0001
wherein said group used in defining R2 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, halogenated alkoxy, cyano, nitro, alkylalkoxy, hydroxy-alkyl, alkoxy, alkoxyalkyl, alkylamino, amino-alkyl, alkyl-amino- carbonyl, heterocyclyl, heteroaryl, heteroarylalkyl, aryl-alkyl and -NR5R6; R3 is selected from hydrogen and alkyl; R4 is selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl used in defining R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, alkyl-carbonyl, cyano, nitro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxy-carbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, and -NR5R6; and n is selected from 0, 1, 2, 3, 4 and 5; or R3 and R4 together with the nitrogen atom to wliich they are attached may form a group selected from heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms; wherein said heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms used in defining R3 and R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, cyano, nifro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxy-carbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, aryl-Cι.6alkyl and -NR5R6, wherein each of R5 and R6 is independently selected from hydrogen, C1-6alkyl, C2- 6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyC1-6 alkyl, alkoxy, C3-6cycloalkyl, C3- cycloalkyl-C1-6alkyl, C1-6alkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-C1-6alkyl; wherein said C1-6alkyl, C2-6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyC1-6 alkyl, alkoxy, C3-6cycloalkyl, C3- 6cycloalkyl-C1-6alkyl, C1-6alkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-C1-6alkyl used in defining R5 and R6 are optionally substituted by one or more groups selected from halogen, cyano, nitro, Cι-6 alkoxy, C1-6 alkyl and hydroxy.
6. A compound according to claim 4 or 5, wherein A is each and individually CR1; R is independently selected from hydrogen, fluoro, chloro, hydroxyl, alkoxy, alkyl, halogenated alkoxy, and halogenated alkyl; R2 is selected from
Figure imgf000230_0001
wherein said group used in defining R is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, halogenated alkoxy, alkyl-alkoxy, hydroxy-alkyl, alkoxy, alkoxyalkyl, alkylamino, amino-alkyl, alkyl-amino-carbonyl, heterocyclyl, heteroaryl, heteroarylalkyl and-NR5R6; R3 is selected from hydrogen and alkyl; R4 is selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl used in defining R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, alkyl-carbonyl, cyano, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxycarbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, and -NR5R6; and n is selected from 0, 1, 2, 3, 4 and 5; or R3 and R4 together with the nitrogen atom to which they are attached may form a group selected from heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms; wherein said heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms used in defining R3 and R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, cyano, nitro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxy-carbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, aryl-C1-6alkyl and -NR5R6, wherein each of R5 and R6 is independently selected from hydrogen, C1-6alkyl, C2„ 6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyC1-6 alkyl, alkoxy, C3-6cycloalkyl, C3-6cycloalkyl-C1-6alkyl, Cι.6alkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-Cι-6alkyl; wherein said C1-6alkyl, C2-6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyC1-6 alkyl, alkoxy, C3-6cycloalkyl, C3. 6cycloalkyl-C1.6alkyl, Cι-6alkylcarbonyl, C3-6heterocyclyl and C3- heterocyclyl-C1-6alkyl used in defining R5 and R6 are optionally substituted by one or more groups selected from halogen, C1-6 alkoxy, C1-6 alkyl and hydroxy.
7. A compound of formula IA or a pharmaceutically acceptable salt thereof, diastereomers, enantiomers, or mixtures thereof:
Figure imgf000231_0001
wherein: one of A1, A2 or A3 is N and the remaining are each and independently CR1; and R1 is independently selected from hydrogen, halogen, cyano, amino, acetylamino, hydroxyl, alkoxy, alkyl, halogenated alkoxy, alkylene, halogenated alkyl, halogenated alkenyl and NR5R6; R is selected from
Figure imgf000232_0001
wherein said group used in defining R2 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, halogenated alkoxy, cyano, nitro, alkoxy, hydroxy, hydroxy-alkyl, amino, alkyl-aryl, alkoxy, alkoxy-alkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, amino-alkyl, alkyl-amino-carbonyl, heteroaryl-carbonyl, heterocyclyl-carbonyl, arylcarbonyl, heterocyclyl, cycloalkyl, heteroaryl, heteroarylalkyl-, aryl, aryl-alkyl and-NR5R6; R3 is selected from hydrogen and alkyl; R4 is selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl used in defining R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, alkylcarbonyl, cyano, nifro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxycarbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, aryl-alkyl and -NR5R6; and n is selected from 0, 1, 2, 3, 4 and 5; or R3 and R4 together with the nitrogen atom to which they are attached may form a group selected from heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms; wherein said heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms used in defining R3 and R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, cyano, nitro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxy-carbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, aryl-C1-6alkyl and -NR5R6, wherein each of R5 and R6 is independently selected from hydrogen, C1-6alkyl, C2- 6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyC1-6 alkyl, alkoxy, C3-6cycloalkyl, C3-6cycloalkyl-C1-6alkyl, C1-6alkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-C1-6alkyl; wherein said C1-6alkyl, C2-6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyC1-6 alkyl, alkoxy, C3-6cycloalkyl, C3- 6cycloalkyl-C1-6alkyl, C1-6alkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-C1-6alkyl used in defining R5 and R6 are optionally substituted by one or more groups selected from halogen, cyano, nifro, C1-6 alkoxy, C1-6 alkyl and hydroxy; with a proviso that when n=0 then R4 is not thiazolyl or 5-chloropyridinyl; with a further proviso that when R2 is phenyl then n=0 and R4 is not unsubstituted methyl, C3 alkyl or unsubstituted C4 alkyl; and with a further proviso that said compound of formula IA is not any one of
3-(benzoylamino)-N-benzylpyridine-2-carboxamide; 3-(benzoylamino)-N-pyridin-3-ylpyridine-2-carboxamide; 3-(benzoylamino)-N-phenylpyridine-2-carboxamide; 3-(benzoylamino)-N-(3-nitrophenyl)pyridine-2-carboxamide; 3-(benzoylamino)-N-(4-methoxyphenyl)pyridine-2-carboxamide;
3-(benzoylamino)-N-[4-(dimethylamino)phenyl]pyridine-2-carboxamide; N-(2-hydroxyethyl)-4-(2-naphthoylamino)nicotinamide; 4-(benzoylamino)-N-(2-hydroxyethyl)nicotinamide; 3-(benzoylamino)-2,6-dimethyl-N-phenylisonicotinamide; and 3-(benzoylamino)-2,6-dimethyl-N-(3-nitrophenyl)isonicotinamide.
8. A compound according to claim 7 wherein R1 is independently selected from hydrogen, halogen, hydroxyl, alkoxy, alkyl, halogenated alkoxy, and halogenated alkyl; and R is selected from
Figure imgf000234_0001
wherein said group used in defining R2 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, halogenated alkoxy, cyano, nifro, alkylalkoxy, hydroxy- alkyl, alkoxy, alkoxyalkyl, alkylamino, amino-alkyl, alkyl-amino- carbonyl, heterocyclyl, heteroaryl, -heteroarylalkyl-, aryl-alkyl and-NR5R6; R3 is selected from hydrogen and alkyl; R4 is selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl used in defining R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, alkyl-carbonyl, cyano, nitro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxy-carbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, and -NR5R6; and n is selected from 0, 1, 2, 3, 4 and 5; or R3 and R4 together with the nitrogen atom to which they are attached may form a group selected from heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms; wherein said heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms used in defining R3 and R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, cyano, nitro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxy-carbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, aryl-C1-6alkyl and -NR5R6, wherein each of R5 and R6is independently selected from hydrogen, C1-6alkyl, C2- 6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyC1-6 alkyl, alkoxy, C3-6cycloalkyl, C3-6cycloalkyl-C1-6alkyl, C1-6alkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-C1-6alkyl; wherein said Cι-6alkyl, C2-6alkenyl, alkoxyC1-6 alkyl, C1- alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyC1-6 alkyl, alkoxy, C3-6cycloalkyl, C3- 6cycloalkyl-C1-6alkyl, C1-6alkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-C1-6alkyl used in defining R5 and R6 are optionally substituted by one or more groups selected from halogen, cyano, nitro, C1-6 alkoxy, C1-6 alkyl and hydroxy.
9. A compound according to claim 7 or 8 wherein R1 is independently selected from hydrogen, fluoro, chloro, hydroxyl, alkoxy, alkyl, halogenated alkoxy, and halogenated alkyl; and R2 is selected from
Figure imgf000235_0001
wherein said group used in defining R2 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, halogenated alkoxy, alkyl-alkoxy, hydroxy- alkyl, alkoxy, alkoxyalkyl, alkylamino, amino-alkyl, alkyl-amino-carbonyl, heterocyclyl, heteroaryl, -heteroarylalkyl- and-NR5R6; R3 is selected from hydrogen and alkyl; R4 is selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl used in defining R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, alkyl-carbonyl, cyano, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxycarbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, and -NR5R6; and n is selected from 0, 1, 2, 3, 4 and 5; or R3 and R4 together with the nitrogen atom to which they are attached may form a group selected from heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms; wherein said heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms used in defining R3 and R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, cyano, nitro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxy-carbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, aryl-C1-6alkyl and -NR5R6, wherein each of R5 and R6 is independently selected from hydrogen, C1-6alkyl, C2-
6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyC1-6 alkyl, alkoxy, C3-6cycloalkyl, C3-6cycloalkyl-C1-6alkyl, C1-6alkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-Cι-6alkyl; wherein said C1-6alkyl, C2-6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyC1- alkyl, alkoxy, C3-6cycloalkyl, C3- 6cycloalkyl-Cι-6alkyl, C1-6alkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-Cι.6alkyl used in defining R5 and R6 are optionally substituted by one or more groups selected from halogen, C1-6 alkoxy, C1-6 alkyl and hydroxy.
10. A compound selected from: N-(Cyclobutylmethyl)-3-[(l-naphthalenylcarbonyl)amino]-2-pyridinecarboxamide;
N- [2-(4-Morpholinyl)ethyl] -3 - [( 1 -naphthalenylcarbonyl)amino] -2-pyridinecarboxamide;
N-4-morpholinyl-3-[(l-naphthalenylcarbonyl)amino]-2-pyridinecarboxamide;
3-[(l-Naphthalenylcarbonyl)amino]-N-[(tetrahydro-2H-pyran-4-yl)methyl]-2- pyridinecarboxamide; N-Cyclohexyl-3-[(l-naphthalenylcarbonyl)amino]-2-pyridinecarboxamide;
N-(3-Methylcyclohexyl)-3-[(l-naphthalenylcarbonyl)amino]-2-pyridinecarboxamide;
N-Cyclobutyl-3-[(l-naphthalenylcarbonyl)amino]-2-pyridinecarboxamide;
N-(Cyclohexylmethyl)-3-[(l-naphthalenylcarbonyl)amino]-2-pyridinecarboxamide;
3-[(l-Naphthalenylcarbonyl)amino]-N-(tetrahydro-2H-pyran-4-yl)-2-pyridinecarboxamide; 3-[(l-Naphthalenylcarbonyl)amino]-N-[2-(l-piperidinyl)ethyl]-2-pyridinecarboxamide;
N-(2-Hydroxypropyl)-3-[(l-naphthalenylcarbonyl)amino]-2-pyridinecarboxamide;
N-(2-Hydroxybutyl)-3-[(l-naphthalenylcarbonyl)amino]-2-pyridinecarboxamide; N-(Cyclopentylmethyl)-3 - [( 1 -naphthalenylcarbonyl)amino] -2-pyridinecarboxamide;
3-[(l-Naphthalenylcarbonyl)amino]-N-(2-piperidinylmethyl)-2-pyridinecarboxamide;
N-(2,2-Dimethylpropyl)-3-(l-naphthoylamino)pyridine-2-carboxamide;
N-(2-Methoxy- 1 -methylethyl)-3 -( 1 -naphthoylamino)pyridine-2-carboxamide ; N- [( 1 -Hydroxy cy clohexyl)methyl] -3 -( 1 -naphthoylamino)pyridine-2-carboxamide;
N-(Cyclobutylmethyl)-3 - [[(4-methyl- 1 -naphthalenyl)carbonyl] amino]-2- pyridinecarboxamide;
3 - [[(4-Methyl- 1 -naphthalenyl)carbonyl] amino] -N- [(tefrahy dro-2H-pyran-4-yl)methyl] -2- pyridinecarboxamide; 3-[(4-Methyl-l-naphfhoyl)amino]-N-(piperidin-2-yhnethyl)pyridine-2-carboxamide;
N-(Cyclobutylmethyl)-3 - [[(4-methoxy- 1 -naphthalenyl)carbonyl] amino] -2- pyridinecarboxamide;
3-[(4-Methoxy-l-naphthoyl)amino]-N-(tefrahydro-2H-pyran-4-ylmethyl)pyridine-2- carboxamide; N-(Cy clohexylmethyl)-3 - [ [ [4-(dimethylamino)- 1 -naphthalenyl] carbonyl] amino] -2- pyridinecarboxamide;
3-[[[4-(Dimethylamino)-l-naphthalenyl]carbonyl]amino]-N-[(tetrahydro-2H-pyran-4- yl)methyl]-2-pyridinecarboxamide;
N-(Cyclobutylmethyl)-3-[[[4-(dimethylamino)-l-naphthalenyl]carbonyl]amino]-2- pyridinecarboxamide;
N-(Cyclobutyloxy)-3 - [( 1 -naphthalenylcarbonyl)amino] -2-pyridinecarboxamide;
N-(Cyclopentyloxy)-3-[(l-naphthalenylcarbonyl)amino]-2-pyridinecarboxamide;
N-(Cyclohexyloxy)-3-[(l-naphthalenylcarbonyl)amino]-2-pyridinecarboxamide;
N-(Cyclohexyloxy)-3 - [(4-methoxy- 1 -naphthalenylcarbonyl)amino] -2- pyridinecarboxamide;
N-(Cyclobutylmethyl)-3-[(2-methoxybenzoyl)amino]-2-pyridinecarboxamide;
N- [2- [[(Cyclobutylmethyl)amino] carbonyl] -3 -pyridinyl] -4-quinolinecarboxamide;
N-[2-[[(Cyclobutylmethyl)amino]carbonyl]-3-pyridinyl]-5-isoquinolinecarboxamide;
N-(Cyclobutylmethyl)-3-[[(2,3-dihydro-l,4-benzodioxin-5-yl)carbonyl]amino]-2- pyridinecarboxamide;
N-(Cyclobutylmethyl)-3-[[(2,3-dihydro-7-benzofuranyl)carbonyl]amino]-2- pyridinecarboxamide; N-(Cyclobutylmethyl)-3-[(3-methoxy-2-methylbenzoyl)amino]-2-pyridinecarboxamide;
N-(2-{[(Tetrahydro-2H-pyran-4-ylmethyl)amino]carbonyl}pyridin-3-yl)quinoline-4- carboxamide;
N-(2-{[(Tetrahydro-2H-pyran-4-ylmethyl)amino]carbonyl}pyridin-3-yl)isoquinoline-5- carboxamide;
N-(2-{[(Tetrahydro-2H-pyran-4-ylmethyl)amino]carbonyl}pyridin-3-yl)quinoline-5- carboxamide;
N-(Cyclohexylmethyl)-4-(l-naphthoylamino)nicotinamide;
N-(Cyclobutylmethyl)-4-(l-naphthoylamino)nicotinamide; N-(Cyclohexylmethyl)-3-(l -naphthoylamino)isonicotinamide;
N-Cyclobutyl-3-(l-naphthoylamino)isonicotinamide;
3-(l-Naphthoylamino)-N-(tetrahydro-2H-pyran-4-ylmethyl)pyrazine-2-carboxamide;
N-(Cyclohexylmethyl)-3-(l-naphthoylamino)pyrazine-2-carboxamide;
N-(Cyclobutylmethyl)-3-(l-naphthoylamino)pyrazine-2-carboxamide; N-(Cyclopentylmethyl)-3-(l -naphthoylamino)pyrazine-2-carboxamide;
N-(2-Cyclohexylethyl)-3-(l-naphthoylamino)pyrazine-2-carboxamide;
3-[(4-Methyl-l-naphthoyl)amino]-N-pentylpyrazine-2-carboxamide;
N-(3-Methylbutyl)-3-[(4-methyl-l-naphthoyl)amino]pyrazine-2-carboxamide;
N-(Cyclobutylmethyl)-3-[(4-methyl-l-naphthoyl)amino]pyrazine-2-carboxamide; 3-[(4-Methyl-l-naphthoyl)amino]-N-(tetrahydro-2H-pyran-4-ylmethyl)pyrazine-2- carboxamide;
N-(Cyclobutylmethyl)-3 -[(4-ethyl- 1 -naphthoyl)amino]pyrazine-2-carboxamide;
N-(Cyclohexylmethyl)-3-[(4-ethyl-l-naphthoyl)amino]pyrazine-2-carboxamide;
3-[(4-Ethyl-l-naphthoyl)amino]-N-(tetrahydro-2H-pyran-4-ylmethyl)pyrazine-2- carboxamide;
N-(Cyclobutylmethyl)- 3 - { [4-( 1 H- 1,2,3 -triazol- 1 -ylmethyl)- 1 -naphthoyl] amino } pyrazine-
2-carboxamide;
N-(Cyclohexylmethyl)- 3 - { [4-( 1 H- 1,2,3 -triazol- 1 -ylmethyl)- 1 -naphthoyl] amino } pyrazine-
2-carboxamide; N-(Tefrahydro-2H-pyran-4-ylmethyl)-3-{[4-(lH-l,2,3-triazol-l-ylmethyl)-l- naphthoyl]amino}pyrazine-2-carboxamide; N-(3-Methylbutyl)-3-{[4-(lH-l,2,3-triazol-l-ylmethyl)-l-naphthoyl]amino}pyrazine-2- carboxamide;
3-{[4-(Methoxymethyl)-l-naphthoyl]amino}-N-(tefrahydro-2H-pyran-4- ylmethyl)pyrazine-2-carboxamide; N-(Cyclobutylmethyl)-3-{[4-(methoxymethyl)-l-naphthoyl]amino}pyrazine-2- carboxamide;
N-(Cyclohexylmethyl)-3-[(4-methoxy-l-naphthoyl)amino]pyrazine-2-carboxamide;
3 - { [5 -Bromo-4-( IH- 1,2,3 -triazol- 1 -ylmethyl)- 1 -naphthoyl] amino } -N-
(cyclohexyhnethyl)pyrazine-2-carboxamide; 3 - [(4-Methoxy- 1 -naphthoyl)amino] -N-(tefrahydrofuran-2-ylmethyl)pyridine-2- carboxamide;
N-(l,4-Dioxan-2-ylmethyl)-3-[(4-methoxy-l-naphthoyl)amino]pyridine-2-carboxamide;
3-[(4-Methoxy-l-naphthoyl)amino]-N-(tefrahydro-2H-pyran-4-yl)pyridine-2-carboxamide;
3 - [(4-Methoxy- 1 -naphthoyl)amino]-N- [2-(tetrahydro-2H-pyran-4-yl)ethyl]pyridine-2- carboxamide;
3-[(4-Methoxy-l-naphthoyl)amino]-N-[(2R)-piperidin-2-ylmethyl]ρyridine-2- carboxamide;
3 - [(4-Methoxy- 1 -naphthoyl)amino] -N-(morpholin-3 -ylmethyl)pyridine-2-carboxamide;
N- [( 1 -Hy droxycy clohexyl)methyl] -3 -[(4-methoxy- 1 -naphthoyl)amino]pyridine-2- carboxamide;
N-(Cyclohexylmethyl)-3-[(4-ethoxy-l-naphthoyl)amino]pyridine-2-carboxamide;
3-[(4-Ethoxy-l-naphthoyl)amino]-N-pentylpyridine-2-carboxamide;
3-[(4-Ethoxy-l-naphthoyl)amino]-N-(tetrahydro-2H-pyran-4-ylmethyl)pyridine-2- carboxamide; N-(Cyclopentylmethyl)-3-[(4-ethoxy-l-naphthoyl)amino]pyridine-2-carboxamide;
3-[(4-Ethoxy-l-naphthoyl)amino]-N-[2-(tetrahydro-2H-pyran-4-yl)ethyl]pyridine-2- carboxamide;
N-(Cyclobutylmethyl)-3-[(4-ethoxy-l-naphthoyl)amino]pyridine-2-carboxamide;
N-Cyclobutyl-3-[(5-methyl-l-naphthoyl)amino]pyridine-2-carboxamide; 3-(l-Naphthoylamino)-N-[(2R)-piperidin-2-ylmethyl]pyridine-2-carboxamide;
3-(l-Naphthoylamino)-N-[(2S)-piperidin-2-ylmethyl]pyridine-2-carboxamide;
3-(l-Naphthoylamino)-N-( yridin-2-ylmethyl)pyridine-2-carboxamide; 3-(4-Methyll-naphthoylamino)-N-(pyridin-2-ylmethyl)pyridine-2-carboxamide;
3-[(4-Amino-l-naphthoyl)amino]-N-(cyclohexylmethyl)pyridine-2-carboxamide;
N-(Cyclohexylmethyl)-3-[(4-methyl-l-naphthalenylcarbonyl)amino]-2- pyridinecarboxamide; N-(Cyclohexylmethyl)-3-[(2,2-dimethylbutanoyl)amino]pyridine-2-carboxamide;
3 -[(4-Amino- 1 -naphthoyl)amino] -N-(tefrahydro-2H-pyran-4-ylmethyl)pyridine-2- carboxamide;
3-{[4-(Acetylamino)-l-naphthoyl]amino}-N-(tetrahydro-2H-pyran-4-ylmethyl)pyridine-2- carboxamide; 3 -[(4- { [(Methylamino)carbonyl] amino} - 1 -naphthoyl)amino]-N-(tefrahydro-2H-pyran-4- ylmethyl)pyridine-2-carboxamide;
Methyl (4-{[(2-{[(tetrahydro-2H-pyran-4-ylmethyl)amino]carbonyl}pyridin-3- yl)amino]carbonyl}-l-naphthyl)carbamate;
N-(Cyclohexyloxy)-3-[(4-methyl-l-naphthoyl)amino]pyridine-2-carboxamide; 3 -[(4-Methyl- 1 -naphthoyl)amino] -N- [(1 -methy lpiperidin-2-yl)methyl]ρyridine-2- carboxamide;
3 -[(4-Ethyl- 1 -naphthoyl)amino]-N-(tefrahydro-2H-pyran-4-ylmethyl)pyridine-2- carboxamide;
3-[(4-Ethyl-l-naphthoyl)amino]-N-(piperidin-2-ylmethyl)pyridine-2-carboxamide; 3 - [(4-Isopropyl- 1 -naphthoyl)amino] -N-(tetrahydro-2H-pyran-4-ylmethyl)pyridine-2- carboxamide;
N-(2-Hydroxyethyl)-3-(l-naphthoylamino)pyridine-2-carboxamide;
3-[(4-Isopropyl-l-naphthoyl)amino]-N-(piperidin-2-ylmethyl)pyridine-2-carboxamide;
3-{[4-(Methoxymethyl)-l-naphthoyl]amino}-N-(piperidin-2-ylmethyl)pyridine-2- carboxamide;
3- { [4-(Ethoxymethyl)- 1 -naphthoyl]amino} -N-(piperidin-2-ylmethyl)pyridine-2- carboxamide;
N-(ρiperidin-2-ylmethyl)-3-{[4-(lH-l,2,4-triazol-l-ylmethyl)-l- naphthoyl]amino}pyridine-2-carboxamide; N-(Piperidin-2-ylmethyl)-3 - { [4-( 1 H- 1 ,2,3 -triazol- 1 -ylmethyl)- 1 -naphthoyl] amino } pyridine-2-carboxamide; N-(Piperidin-2-ylmethyl)-3-{[4-(2H-l,2,3-triazol-2-ylmethyl)-l-naρhthoyl]amino} pyridine-2-carboxamide;
3-[(4-Methyl-l-naphthoyl)amino]-N-[2-(tetrahydro-2H-pyran-4-yl)ethyl]pyridine-2- carboxamide; 3-{[4-(Methoxymethyl)-l-naphthoyl]amino}-N-[2-(tetrahydro-2H-pyran-4- yl)ethyl]ρyridine-2-carboxamide;
3 -[(4-Methyl- 1 -naphthoyl)amino]-N-(morpholin-3 -ylmethyl)pyridine-2-carboxamide;
N-cyclopentyl-3-[(l-naphthalenylcarbonyl)amino]-2 -pyridinecarboxamide;
N-butyl-3-[[[4-(lH-l,2,3-triazol-l-ylmethyl)-l-naphthalenyl]carbonyl]amino]-2- pyridinecarboxamide;
N-(cyclopropylmefhyl)-3-[[[4-(lH- 1 ,2,3-triazol- 1 -ylmethyl)- 1 - naphthalenyl]carbonyl]amino]-2-pyridinecarboxamide;
N-(cyclopentylmethyl)-3-[[[4-(lH- 1 ,2,3-triazol- 1 -ylmethyl)- 1 - naphthalenyl] carbonyl] amino] -2-pyridinecarboxamide; N-hexyl-3-[[[4-(lH- 1 ,2,3-triazol- 1 -ylmethyl)- 1 -naphthalenyl]carbonyl]amino]-2- pyridinecarboxamide;
N-[3-(dimethylamino)propyl]-3-[[[4-(lH-l,2,3-triazol-l-ylmethyl)-l- naphthalenyl] carbonyl] amino] -2-pyridinecarboxamide;
N-[2-(4-morpholinyl)ethyl]-3-[[[4-(lH-l,2,3-triazol-l-ylmethyl)-l- naphthalenyl] carbonyl] amino] -2-pyridinecarboxamide;
N-(Cyclohexylmethyl)-3- { [4-( 1 H- 1 ,2,3-triazol- 1 -ylmethyl)- 1 -naphthoyl]amino } pyridine-
2-carboxamide;
N-(cyclohexy lmethyl)-3 - { [4-(2H- 1,2,3 -triazol-2-y hnethy 1)- 1 -naphthoyl] amino } pyridine-2- carboxamide; N-Pentyl-3-{[4-(lH-l,2,3-triazol-l-ylmethyl)-l-naphthoyl]amino}pyridine-2- carboxamide;
N-[2-(Tetrahydro-2H-pyran-4-yl)ethyl]-3-{[4-(lH-l,2,3-friazol-l-ylmethyl)-l- naphthoyl]amino}ρyridine-2-carboxamide;
N-[2-(lH-Pyrrol-l-yl)ethyl]-3-{[4-(lH-l,2,3-triazol-l-ylmethyl)-l- naphthoyl]amino}ρyridine-2-carboxamide;
Ν-[3-(lΗ-Imidazol-l-yl)propyl]-3-{[4-(lΗ-l,2,3-triazol-l-ylmethyl)-l- naphthoyl]amino}pyridine-2-carboxamide; N-[3-(lH-Pyrazol-l-yl)propyl]-3-{[4-(lH-l,2,3-triazol-l-ylmethyl)-l- naphthoyl]amino}pyridine-2-carboxamide;
N-[2-(lH-Imidazol-l-yl)ethyl]-3-{[4-(lH-l,2,3-triazol-l-ylmethyl)-l- naphthoyl]amino}pyridine-2-carboxamide; N-[2-(lH-l,2,4-Triazol-l-yl)ethyl]-3-{[4-(lH-l,2,3-triazol-l-ylmethyl)-l- naphthoyl] amino } pyridine-2-carboxamide;
N-(2-Methoxyethyl)-3-{[4-(lH-l,2,3-triazol-l-ylmethyl)-l-naphthoyl]amino}pyridine-2- carboxamide;
N-(2-Ethoxyethyl)-3-{[4-(lH-l,2,3-friazol-l-ylmethyl)-l-naphthoyl]amino}pyridine-2- carboxamide;
N-(2-Propoxy ethyl)-3 - { [4-( IH- 1 ,2,3-triazol- 1 -ylmethyl)- 1 -naphthoyl] amino } pyridine-2- carboxamide;
Ν-(3-Methoxypropyl)-3-{[4-(lΗ-l,2,3-triazol-l-ylmethyl)-l-naphthoyl]amino}pyridine-2- carboxamide; Ν-(3 -Ethoxypropyl)-3 - { [4-( 1 H- 1 ,2,3-triazol- 1 -ylmethyl)- 1 -naphthoyl] amino} pyridine-2- carboxamide;
N- Ally 1-3 - { [4-( 1 H- 1 ,2,3-triazol- 1 -ylmethyl)- 1 -naphthoyl] amino } pyridine-2-carboxamide ;
N-Propyl-3 - { [4-( 1 H- 1 ,2,3-triazol- 1 -ylmethyl)- 1 -naphthoyl] amino }pyridine-2- carboxamide; N-[(tetrahydro-2H-pyran-4-yl)methyl]-3-[[[4-(lH-l,2,3-friazol-l-ylmethyl)-l- naphthalenyl] carbonyl] amino] - 2-pyridinecarboxamide;
N-[(tetrahydro-2H-ρyran-4-yl)methyl]-3-[[[4-(4H-l,2,4-triazol-4-ylmethyl)-l- naphthalenyl]carbonyl]amino]-2-pyridinecarboxamide;
N-[(tetrahydro-2H-pyran-4-yl)methyl]-3-[[[4-(lH-l,2,4-triazol-l-ylmethyl)-l- naphthalenyl] carbonyl] amino] -2-pyridinecarboxamide;
3-[[[4-(l-pyπolidinylmethyl)-l-naphthalenyl]carbonyl]amino]-N-[(tefrahydro-2H-pyran-4- yl)methyl]-2-pyridinecarboxamide;
3-[[[4-(l H-pyrazol- 1 -ylmethyl)- 1 -naphthalenyl] carbonyl] amino] -N- [(tefrahy dro-2H-pyran-
4-yl)methyl]- 2-pyridinecarboxamide; N-[(tefrahydro-2H-ρyran-4-yl)methyl]-3-[[[4-(2H-tefrazol-2-ylmethyl)-l- naphthalenyl]carbonyl]amino]-2-pyridinecarboxamide; N-(Tefrahydro-2H-pyran-4-yl)-3-[[[4-(lH- 1 ,2,3-triazol- l-ylmethyl)-l - naphthalenyl]carbonyl]amino]-2-pyridinecarboxamide; 3-[[[4-(lH-imidazol-l-ylmethyl)-l-naphthalenyl]carbonyl]amino]-N-(tetrahydro-2H- pyran-4-yl)-2-pyridinecarboxamide; 5 3-[[[4-(lH-pyrazol- 1 -ylmethyl)- 1 -naphthalenyl]carbonyl]amino]-N-(tetrahydro-2H-pyran- 4-yl)-2-pyridinecarboxamide; 3-[[[4-(methoxymethyl)-l-naphthalenyl]carbonyl]amino]-N-[(tetrahydro-2H-pyran-4- yl)methyl]-2-pyridinecarboxamide; 3-[[[4-(methoxymethyl)-l-naphthalenyl]carbonyl]amino]-N-[(tetrahydro-2H-pyran-4- l o yl)methyl] -2-pyridinecarboxamide; 3-[(4-benzyl-l-naphthoyl)amino]-N-(tefrahydro-2H-pyran-4-ylmethyl)pyridine-2- carboxamide; 3-[[[4-(3-furanylmethyl)-l-naphthalenyl]carbonyl]amino]-N-[(tetrahydro-2H-pyran-4- yl)methyl]-2-pyridinecarboxamide; is 3-[[[4-(2-furanylmethyl)-l-naphthalenyl]carbonyl]amino]-N-[(tetrahydro-2H-pyran-4- yl)methyl] -2-pyridinecarboxamide; N-[(tetrahydro-2H-pyran-4-yl)methyl]-3-[[[4-(2-thienylmethyl)-l-naphthalenyl] carbonyl]amino]-2-pyridinecarboxamide; N- [(tefrahy dro-2H-pyran-4-yl)methy 1] -3 - [[ [4-(3 -thienylmethyl)- 1 - 20 naphthalenyl] carbonyl] amino] -2-pyridinecarboxamide; N-(2-methylcyclohexyl)-3-[(l-naphthalenylcarbonyl)amino]-2-pyridinecarboxamide; 3 -[( 1 -naphthalenylcarbonyl)amino] -N-[2-( 1 -pyrrolidinyl)ethyl]-2-pyridinecarboxamide; N-(cyclobutylmethyl)-3-[[2-(4-morpholinyl)benzoyl]amino]-2-pyridinecarboxamide; N-(Tetrahydro-2H-pyran-4-ylmethyl)-3-({4-[(3H-[l,2,3]triazolo[4,5-b]pyridin-3- 25 yloxy)methyl]- 1 -naphthoyl} amino)pyridine-2-carboxamide; 3-(l-Naphthoylamino)-N-(pyπolidin-2-ylmethyl)pyridine-2-carboxamide; N-[(l-Methylpyrrolidin-2-yl)methyl]-3-(l-naphthoylamino)pyridine-2-carboxamide; N-[(l-Methylpiperidin-2-yl)methyl]-3-(l-naphthoylamino)pyridine-2-carboxamide; N-[(l-Acetylpiperidin-2-yl)methyl]-3-(l-naphthoylamino)pyridine-2-carboxamide; 0 Methyl 2-[({[3-(l-naphthoylamino)pyridin-2-yl]carbonyl}amino)methyl]piperidine-l- carboxylate; N-(Cyclopentylmethyl)-4-( 1 -naphthoylamino)nicotinamide; N-Cyclopentyl-4-(l-naphthoylamino)nicotinamide;
N-(Cyclopropylmethyl)-4-(l-naphthoylamino)nicotinamide;
N-Isobutyl-4-(l-naphthoylamino)nicotinamide;
N-(Cyclobutylmethyl)-4-[(4-methyl-l-naphthoyl)amino]nicotinamide; N-(Cyclopentylmethyl)-4-[(4-methyl- 1 -naphthoyl)amino]nicotinamide;
3 - { [4-(Hy droxymethyl)- 1 -naphthoyl] amino } -N-(tetrahy dro-2H-pyran-4- ylmethyl)pyridine-2-carboxamide;
3-{[4-(Piperidin-l-ylmethyl)-l-naphthoyl]amino}-N-(tefrahydro-2H-pyran-4- ylmethyl)pyridine-2-carboxamide; 3-[(4-{[(2-Hydroxyethyl)amino]methyl}-l-naphthoyl)amino]-N-(tetrahydro-2H-pyran-4- ylmethyl)pyridine-2-carboxamide;
3 -( {4-[(Dimethylamino)methyl]- 1 -naphthoyl} amino)-N-(tetrahydro-2H-pyran-4- ylmethyl)pyridine-2-carboxamide;
3 - { [4-( 1 H-Imidazol- 1 -ylmethyl)- 1 -naphthoyl] amino } -N-(tefrahy dro-2H-pyran-4- ylmethyl)pyridine-2-carboxamide;
3- { [4-(Azetidin- 1 -ylmethyl)- 1 -naphthoyl] amino } -N-(tetrahydro-2H-pyran-4- ylmethyl)pyridine-2-carboxamide;
Methyl 4-{[(2-{[(tefrahydro-2H-pyran-4-ylmethyl)amino]carbonyl}pyridin-3- yl)amino]carbonyl} -1 -naphthoate; N,N-Dimethyl-N'-(2-{[(tefrahydro-2H-pyran-4-ylmethyl)amino]carbonyl}pyridin-3- yl)naρhthalene- 1 ,4-dicarboxamide;
2-Hydroxyethyl 4-{[(2-{[(tetrahydro-2H-pyran-4-ylmethyl)amino]carbonyl}pyridin-3- yl)amino]carbonyl}-l-naphthoate;
3-[(l-Benzofuran-2-ylcarbonyl)ammo]-N-(tefrahydro-2H-pyran-4-ylmetlιyl)pyridine-2- carboxamide;
N-(Cyclohexylmethyl)-3-[(4-iodo-l-naphthoyl)amino]pyridine-2-carboxamide;
N-(Cyclohexylmethyl)-3 - [(4-piperidin- 1 -yl- 1 -naphthoy l)amino]pyridine-2-carboxamide;
3-[(4-Azetidin-l-yl-l-naphthoyl)amino]-N-(cyclohexylmethyl)pyridine-2-carboxamide;
N-(Cyclohexylmethyl)-3 -( {4-[ethyl(methyl)amino]- 1 -naphthoyl} amino)pyridine-2- carboxamide;
N-(Cyclohexylmethyl)-3-[(4-pyπolidin- 1 -yl- 1 -naphthoyl)amino]ρyridine-2-carboxamide; N-(Cyclohexylmethyl)-3-{[4-(4-isopropylpiperazin-l-yl)-l-naphthoyl]amino}pyridine-2- carboxamide;
N-(Cyclohexylmethyl)-3-({4-[3-(diethylamino)pyrrolidin-l-yl]-l- naphthoyl}amino)pyridine-2-carboxamide; N'-(2-{[(Cyclohexylmethyl)amino]carbonyl}pyridin-3-yl)-N,N-dimethylnaphthalene-l,4- dicarboxamide;
N-(Cyclohexylmethyl)-3-{[4-(methoxymethyl)-l-naphthoyl]amino}pyridine-2- carboxamide;
N-(Cyclohexyhnethyl)-3 -( {4-[(dimethylamino)methyl]- 1 -naphthoyl} amino)pyridine-2- carboxamide;
N-(Cyclobutylmethyl)-3 - { [4-( 1 H-pyπol- 1 -ylmethyl)- 1 -naphthoyl] amino } pyridine-2- carboxamide;
N-(Cyclobutylmethyl)-3 - { [4-( IH- 1 ,2,3-triazol- 1 -ylmethyl)- 1 -naphthoyl] amino } pyridine-2- carboxamide; N-(Cyclobutylmethyl)-3 - { [4-( 1 H-pyrazol- 1 -ylmethyl)- 1 -naphthoyl] amino } pyridine-2- carboxamide;
N-(Cyclobutylmethyl)-3 -[(4- { [ethyl(methyl)amino]methyl} - 1 -naphthoyl)amino]pyridine-
2-carboxamide;
N-(Cyclobutylmethyl)-3 - { [4-( 1 H-imidazol- 1 -ylmethyl)- 1 -naphthoyl] amino } pyridine-2- carboxamide;
N-(Cyclobutylmethyl)-3-({4-[(dimethylamino)methyl]-l-naphthoyl}amino)pyridine-2- carboxamide;
N-(Cyclobuty hnethy l)-3 - { [4-(methoxymethyl)- 1 -naphthoyl] amino } pyridine-2- carboxamide; N-(Cyclobutylmethyl)-3-{[4-(ethoxymethyl)-l-naphthoyl]amino}pyridine-2-carboxamide;
N'-(2-{[(Cyclobutylmemyl)amino]carbonyl}pyridin-3-yl)-N,N-dimethylnaphthalene-l,4- dicarboxamide;
N-(Cyclohexylmethyl)-3-{[4-(dimethylamino)-l-naphthoyl]amino}pyrazine-2- carboxamide; N-(Cyclohexylmethyl)-3 - { [5 -(dimethylamino)- 1 -naphthoyl] amino } pyridine-2- carboxamide; 3 - { [4-(Dimethylamino)- 1 -naphthoyl] amino } -N-(piperidin-2-ylmethyl)pyridine-2- carboxamide;
3-{[4-(dimethylamino)-l-naphthoyl]amino}-N-pentylpyridine-2-carboxamide;
3-{[4-(dimethylamino)-l-naphthoyl]amino}-N-hexylpyridine-2-carboxamide; 3-{[4-(dimethylamino)-l-naphthoyl]amino}-N-[3-(dimethylamino)propyl]pyridine-2- carboxamide;
3 - { [4-(dimethylamino)- 1 -naphthoyl] amino } -N-propylpyridine-2-carboxamide;
3- { [4-(dimethylamino)- 1 -naphthoyl] amino} -N-(2-ethylbutyl)pyridine-2-carboxamide;
N-(cyclohexylmethy l)-3 - { [(5 -phenyl- 1 ,3 -oxazol-4-yl)carbonyl] amino } pyridine-2- carboxamide;
N-butyl-3-{[4-(dimethylamino)-l-naphthoyl]amino}pyridine-2-carboxamide;
3-{[(5-phenyl-l,3-oxazol-4-yl)carbonyl]amino}-N-(tetrahydro-2H-pyran-4- ylmethyl)pyridine-2-carboxamide;
3 - { [4-(dimethylamino)- 1 -naphthoyl] amino } -N-[3 -( 1 H-imidazol- 1 -yl)propyl]pyridine-2- carboxamide;
N-(4,4-difluorocyclohexyl)-3-(l-naphthoylamino)pyridine-2-carboxamide;
N-(3,5-difluorobenzyl)-3-(l-naphthoylamino)pyridine-2-carboxamide;
N-(4-morpholin-4-ylbenzyl)-3-(l-naphthoylamino)pyridine-2-carboxamide;
6-Methoxy-3-[(4-[l,2,3]triazol-l-ylmethyl-naphthalene-l-carbonyl)-amino]-pyridine-2- carboxylic acid cyclohexylmethyl-amide;
6-Hydroxy-3-[(4-[l,2,3]triazol-l-ylmethyl-naphthalene-l-carbonyl)-amino]-pyridine-2- carboxylic acid cyclohexylmethyl-amide;
6-Methoxy-3-[(4-[l,2,3]triazol-l-ylmethyl-naphthalene-l-carbonyl)-amino]-pyridine-2- carboxylic acid (tefrahydro-pyran-4-ylmethyl)-amide; 6-Hydroxy-3-[(4-[l,2,3]triazol-l-ylmethyl-naphthalene-l-carbonyl)-amino]-pyridine-2- carboxylic acid (tetrahydro-pyran-4-ylmefhyl)-amide;
6-Propoxy-3-[(4-[l,2,3]triazol-l-ylmethyl-naphthalene-l-carbonyl)-amino]-pyridine-2- carboxylic acid cyclohexylmethyl-amide; and pharmaceutically acceptable salts thereof.
11. A compound according to any one of claims 1 - 10 for use as a medicament.
12. The use of a compound according to any one of claims 1-10 in the manufacture of a medicament for the therapy of pain.
13. The use of a compound according to any one of claims 1 - 10 in the manufacture of a medicament for the therapy of functional gastrointestinal disorders.
14. The use of a compound according to any one of claims 1-10 in the manufacture of a medicament for the treatment of iπitable bowel syndrome.
15. The use of a compound according to any one of claims 1 - 10 in the manufacture of a medicament for the treatment of anxiety, cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, and cardiavascular disorders.
16. The use of a compound according to any one of claims 1-10 in the manufacture of a medicament for the treatment of gastroesophageal reflux disorder.
17. A pharmaceutical composition comprising a compound according to any one of claims 1-10 and a pharmaceutically acceptable carrier.
18. A method for the therapy of functional gastrointestinal disorders in a warm-blooded animal, comprising the step of administering to said animal in need of such therapy a therapeutically effective amount of a compound according to any one of claims 1-10.
19. A method for the therapy of irritable bowel syndrome in a warm-blooded animal, comprising the step of administering to said animal in need of such therapy a therapeutically effective amount of a compound according to any one of claims 1-10.
20. A method for the therapy of gastroesophageal reflux disorder in a warm-blooded animal, comprising the step of administering to said animal in need of such therapy a therapeutically effective amount of a compound according to any one of claims 1-10.
21. A method for preparing a compound of formula I,
Figure imgf000248_0001
I comprising the step of reacting a compound of formula II,
Figure imgf000248_0002
π with a compound of RJ(CH2)nRXH, in the presence of a base, such as an DIPEA, a solvent such as DMF, wherein one of A1, A2, A3 or A4 is N and the remaining are each and independently CR1; and R1 is independently selected from hydrogen, halogen, cyano, amino, acetylamino, hydroxyl, alkoxy, alkyl, halogenated alkoxy, alkylene, halogenated alkyl, halogenated alkenyl and NR5R6; R2 is selected from
Figure imgf000249_0001
wherein said group used in defining R2 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, halogenated alkoxy, cyano, nitro, alkoxy, hydroxy, hydroxy-alkyl, amino, alkyl-aryl, alkoxy, alkoxy-alkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, amino-alkyl, alkyl-amino-carbonyl, heteroaryl-carbonyl, heterocyclyl-carbonyl, arylcarbonyl, heterocyclyl, cycloalkyl, heteroaryl, heteroarylalkyl-, aryl, aryl-alkyl and-NR5R6; R3 is selected from hydrogen and alkyl; R4 is selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl used in defining R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, alkylcarbonyl, cyano, nitro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxycarbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, aryl-alkyl and -NR5R6; and n is selected from 0, 1, 2, 3, 4 and 5; or R3 and R together with the nitrogen atom to which they are attached may form a group selected from heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms; wherein said heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms used in defining R3 and R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, cyano, nitro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxy-carbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, aryl-C1-6alkyl and -NR5R6, wherein each of R5 and R6 is independently selected from hydrogen, C1-6alkyl, C2- 6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyC1-6 alkyl, alkoxy, C3-6cycloalkyl, C3-6cycloalkyl-C1-6alkyl, C1-6alkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-C1-6alkyl; wherein said C1-6alkyl, C2-6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyC1-6 alkyl, alkoxy, C3-6cycloalkyl, C - 6cycloalkyl-C1-6alkyl, C1-6alkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-C1-6alkyl used in defining R5 and R6 are optionally substituted by one or more groups selected from halogen, cyano, nitro, C1-6 alkoxy, C1-6 alkyl and hydroxy; with a proviso that when n=0 then R4 is not thiazolyl or 5-chloropyridinyl; with a further proviso that when R2 is phenyl then n=0 and R4 is not unsubstituted methyl, C3 alkyl or unsubstituted C4 alkyl; and with a further proviso that said compound of formula I is not any one of
3-(benzoylamino)-N-benzylpyridine-2-carboxamide; 3 -(benzoylamino)-N-pyridin-3 -ylpyridine-2-carboxamide ; 3-(benzoylamino)-N-phenylpyridine-2-carboxamide; 3-(benzoylamino)-N-(3-nitrophenyl)pyridine-2-carboxamide; 3-(benzoylamino)-N-(4-methoxyphenyl)pyridine-2-carboxamide;
3-(benzoylamino)-N-[4-(dimethylamino)phenyl]pyridine-2-carboxamide; N-(2-hydroxyethyl)-4-(2-naphthoylamino)nicotinamide; 4-(benzoylamino)-N-(2-hydroxyethyl)nicotinamide; 3-(benzoylamino)-2,6-dimethyl-N-phenylisonicotinamide; 3-(benzoylamino)-2,6-dimethyl-N-(3-nitrophenyl)isonicotinamide; 2-(benzoylamino)-N-[cyano(2-thienyl)methyl]nicotinamide; and 2-(benzoylamino)-N-[cyano(phenyl)methyl]nicotinamide.
22. A method for preparing a compound of formula IB,
Figure imgf000251_0001
IB comprising the step of reacting a compound of foπnula IIB,
Figure imgf000251_0002
IIB with a compound of R3(CH2)nR4NH, in the presence of a base, such as an DIPEA, a solvent such as DMF, wherein: A is each and independently CR1; and R1 is independently selected from hydrogen, halogen, cyano, amino, acetylamino, hydroxyl, alkoxy, alkyl, halogenated alkoxy, alkylene, halogenated alkyl, halogenated alkenyl and NR5R6; R2 is selected from
Figure imgf000252_0001
wherein said group used in defining R2 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, halogenated alkoxy, cyano, nifro, alkoxy, hydroxy, hydroxy-alkyl, amino, alkyl-aryl, alkoxy, alkoxy-alkyl, alkylcarbonyl, alkoxycarbonyl, alkylamino, amino-alkyl, alkyl-amino-carbonyl, heteroaryl-carbonyl, heterocyclyl-carbonyl, arylcarbonyl, heterocyclyl, cycloalkyl, heteroaryl, heteroarylalkyl-, aryl, aryl-alkyl and-NR5R6; R3 is selected from hydrogen and alkyl; R4 is selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, heteroaryl and heterocyclyl used in defining R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, alkylcarbonyl, cyano, nifro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxycarbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, aryl-alkyl and -NR5R6; and n is selected from 0, 1, 2, 3, 4 and 5; or R3 and R together with the nitrogen atom to which they are attached may form a group selected from heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms; wherein said heterocyclyl which is optionally fused with a five or six membered ring containing one or more heteroatoms used in defining R3 and R4 is optionally substituted by one or more groups selected from halogen, halogenated alkyl, alkyl, cyano, nifro, amino, amino-alkyl, alkoxy, halogenated alkoxy, hydroxy, alkoxy-alkyl, alkoxy-aryl, alkoxy-carbonyl, heterocyclic moiety, aryl, aryl-alkyl, heterocyclic-alkyl, hydroxy-alkyl, heteroaryl, alkyl-heteroaryl, aryl-C1-6alkyl and -NR5R6, wherein each of R5 and R6 is independently selected from hydrogen, C1-6alkyl, C2. 6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, hydroxyC1-6 alkyl, alkoxy, C3-6cycloalkyl, C3-6cycloalkyl-Cι-6alkyl, C1-6alkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-C1-6alkyl; wherein said C1-6alkyl, C2-6alkenyl, alkoxyC1-6 alkyl, C1-6 alkylcarbonyl, Cι-6 alkoxycarbonyl, hydroxyCi-e alkyl, alkoxy, C3-6cycloalkyl, C3- 6cycloalkyl-C1-6alkyl, Ci.ealkylcarbonyl, C3-6heterocyclyl and C3-6heterocyclyl-C1-6alkyl used in defining R5 and R6 are optionally substituted by one or more groups selected from halogen, cyano, nifro, C1-6 alkoxy, C1-6 alkyl and hydroxy; with a proviso that said compound of formula IB is not any one of 3-[(4-tert- butylbenzoyl)amino]-N-(5-chloro-pyridin-2-yl)pyrazine-2-carboxamide; N-[2-(lH- imidazol-2-yl)ethyl]-3-[[4-(l,l-dimethylethyl)benzoyl]amino]-2-pyrazinecarboxamide and 3-(benzoylamino)-N-(methoxycarbonylmethyl)pyrazine-2-carboxamide.
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Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007061360A2 (en) * 2005-11-24 2007-05-31 Astrazeneca Ab Novel 3-bicyclocarbonylaminopyridine-2-carboxamides or 3-bicyclocarbonylaminopyrazine-2-carboxamides
WO2009009550A1 (en) * 2007-07-09 2009-01-15 Abbott Laboratories Novel compounds as cannabinoid receptor ligands
EP2070924A1 (en) 2007-12-10 2009-06-17 Bayer Schering Pharma Aktiengesellschaft New 2 hetarylthiazol-4-carboxylic acid derivatives, their manufacture and use as medicine
EP2070916A1 (en) 2007-12-10 2009-06-17 Bayer Schering Pharma Aktiengesellschaft 2-Arylthiazol-4-carboxylic acid derivatives, their manufacture and use as medicine
EP2070925A1 (en) 2007-12-10 2009-06-17 Bayer Schering Pharma Aktiengesellschaft New 2-substituted tiazol-4-carboxylic acid derivatives, their manufacture and use as medicine
US7700599B2 (en) 2006-06-28 2010-04-20 Glaxo Group Limited Gpr38 Receptor Agonists
US8012981B2 (en) 2006-06-15 2011-09-06 Glaxo Group Limited Benzylpiperazine derivatives as motilin receptor agonists
US8536175B2 (en) 2008-05-23 2013-09-17 Novartis Ag Quinoxaline carboxamide derivatives as protein tyrosine kinase inhibitors
US8735434B2 (en) 2007-05-18 2014-05-27 Abbvie Inc. Compounds as cannabinoid receptor ligands
US8779144B2 (en) 2006-03-16 2014-07-15 Evotec (Us) Inc. Bicycloheteroaryl compounds as P2X7 modulators and uses thereof
US8835475B2 (en) 2007-04-17 2014-09-16 Abbvie Inc. Compounds as cannabinoid receptor ligands
US8841334B2 (en) 2006-05-31 2014-09-23 Abbvie Inc. Compounds as cannabinoid receptor ligands and uses thereof
US8846730B2 (en) 2008-09-08 2014-09-30 Abbvie Inc. Compounds as cannabinoid receptor ligands
US8859596B2 (en) 2008-09-16 2014-10-14 Abbvie Inc. Compounds as cannabinoid receptor ligands
US8865753B2 (en) 2007-03-28 2014-10-21 Abbvie Inc. Compounds as cannabinoid receptor ligands
US8895592B2 (en) 2008-12-16 2014-11-25 Abbvie Inc. Compounds as cannabinoid receptor ligands
US9006275B2 (en) 2006-05-31 2015-04-14 Abbvie Inc. Compounds as cannabinoid receptor ligands and uses thereof
US9161538B2 (en) 2012-07-19 2015-10-20 Nippon Soda Co., Ltd. Pyridine compound and agricultural fungicide
US9193713B2 (en) 2007-10-12 2015-11-24 Abbvie Inc. Compounds as cannabinoid receptor ligands
EP2876107A4 (en) * 2012-07-19 2016-04-06 Hanmi Pharm Ind Co Ltd Isoquinoline-5-carboxamide derivative having inhibitory activity for protein kinase
WO2018199175A1 (en) 2017-04-27 2018-11-01 石原産業株式会社 N-(4-pyridyl) nicotinamide compound or salt thereof
WO2021220178A1 (en) 2020-04-29 2021-11-04 Cominnex Zrt. Iap antagonists and their therapeutic applications

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2006274212B2 (en) 2005-07-26 2011-06-09 Glaxo Group Limited Benzylpiperazine derivates and their medical use
GB0524814D0 (en) 2005-12-05 2006-01-11 Glaxo Group Ltd Compounds
KR20120087936A (en) * 2009-10-06 2012-08-07 선에시스 파마슈티컬스 인코포레이티드 Heterocyclic compounds useful as pdk1 inhibitors
EA201690846A1 (en) * 2013-11-06 2016-08-31 Бристол-Маерс Сквибб Компани SUBSTITUTED PYRIDINE DERIVATIVES, SUITABLE AS GSK-3 INHIBITORS
SG11201603209XA (en) 2013-11-06 2016-05-30 Bristol Myers Squibb Co Gsk-3 inhibitors
JP2019131470A (en) * 2016-05-20 2019-08-08 石原産業株式会社 Pest control agent containing n-(4-pyridyl) benzamide compound or salt thereof as active ingredient
CN107880024A (en) * 2017-12-11 2018-04-06 张玉玲 A kind of cannabinoid receptor agonists and its synthetic method for being used to treat inflammation

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0054132A1 (en) * 1980-12-12 1982-06-23 Dr. Karl Thomae GmbH Pyrimidones, their preparation and medicines containing them
WO2002070483A1 (en) * 2001-03-05 2002-09-12 E. I. Du Pont De Nemours And Company Heterocyclic diamide invertebrate pest control agents
WO2004029026A1 (en) * 2002-09-27 2004-04-08 Glaxo Group Limited Pyridine derivatives as cb2 receptor modulators

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3046871A1 (en) * 1980-12-12 1982-07-22 Dr. Karl Thomae Gmbh, 7950 Biberach 2-Amino:alkoxy-phenyl-quinazolin-4-one derivs. - and -pyrido-pyrimidin-4-one derivs. prepd. by reaction of e.g. halo-alkoxy or epoxy-alkoxy cpds. with amine(s)
GB9717576D0 (en) * 1997-08-19 1997-10-22 Xenova Ltd Pharmaceutical compounds

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0054132A1 (en) * 1980-12-12 1982-06-23 Dr. Karl Thomae GmbH Pyrimidones, their preparation and medicines containing them
WO2002070483A1 (en) * 2001-03-05 2002-09-12 E. I. Du Pont De Nemours And Company Heterocyclic diamide invertebrate pest control agents
WO2004029026A1 (en) * 2002-09-27 2004-04-08 Glaxo Group Limited Pyridine derivatives as cb2 receptor modulators

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE CAPLUS [online] ISMAIL A.G. ET AL: "Synthesis of pyrido(4,3-d)pyrimidin-4(3H)-ones from 4-aminonicotinic acid.", XP002991687, Database accession no. (1968:29670) *
JOURNAL OF THE CHEMICAL SOCIETY (SECTION) C: ORGANIC., no. 24, 1967, pages 2613 - 2617 *

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8236953B2 (en) 2004-12-29 2012-08-07 Glaxo Group Limited Process for preparing piper azine derivatives
WO2007061360A3 (en) * 2005-11-24 2007-07-26 Astrazeneca Ab Novel 3-bicyclocarbonylaminopyridine-2-carboxamides or 3-bicyclocarbonylaminopyrazine-2-carboxamides
WO2007061360A2 (en) * 2005-11-24 2007-05-31 Astrazeneca Ab Novel 3-bicyclocarbonylaminopyridine-2-carboxamides or 3-bicyclocarbonylaminopyrazine-2-carboxamides
US8779144B2 (en) 2006-03-16 2014-07-15 Evotec (Us) Inc. Bicycloheteroaryl compounds as P2X7 modulators and uses thereof
US9006275B2 (en) 2006-05-31 2015-04-14 Abbvie Inc. Compounds as cannabinoid receptor ligands and uses thereof
US8841334B2 (en) 2006-05-31 2014-09-23 Abbvie Inc. Compounds as cannabinoid receptor ligands and uses thereof
US8012981B2 (en) 2006-06-15 2011-09-06 Glaxo Group Limited Benzylpiperazine derivatives as motilin receptor agonists
US8853218B2 (en) 2006-06-28 2014-10-07 Glaxo Group Limited Compounds
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US8865753B2 (en) 2007-03-28 2014-10-21 Abbvie Inc. Compounds as cannabinoid receptor ligands
US8835475B2 (en) 2007-04-17 2014-09-16 Abbvie Inc. Compounds as cannabinoid receptor ligands
US8735434B2 (en) 2007-05-18 2014-05-27 Abbvie Inc. Compounds as cannabinoid receptor ligands
WO2009009550A1 (en) * 2007-07-09 2009-01-15 Abbott Laboratories Novel compounds as cannabinoid receptor ligands
JP2010533194A (en) * 2007-07-09 2010-10-21 アボット・ラボラトリーズ Novel compounds as cannabinoid receptor ligands
US8338623B2 (en) 2007-07-09 2012-12-25 Abbvie Inc. Compounds as cannabinoid receptor ligands
US9193713B2 (en) 2007-10-12 2015-11-24 Abbvie Inc. Compounds as cannabinoid receptor ligands
EP2070916A1 (en) 2007-12-10 2009-06-17 Bayer Schering Pharma Aktiengesellschaft 2-Arylthiazol-4-carboxylic acid derivatives, their manufacture and use as medicine
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US8815901B2 (en) 2008-05-23 2014-08-26 Novartis Ag Quinoline carboxamide derivatives as protein tyrosine kinase inhibitors
US8674099B2 (en) 2008-05-23 2014-03-18 Novartis Ag Quinoxaline carboxamide derivatives as protein tyrosine kinase inhibitors
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US8846730B2 (en) 2008-09-08 2014-09-30 Abbvie Inc. Compounds as cannabinoid receptor ligands
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US11912684B2 (en) 2017-04-27 2024-02-27 Ishihara Sangyo Kaisha, Ltd. N-(4-pyridyl)nicotinamide compound or salt thereof
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