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WO2010096722A1 - 3-oxo-2, 3-dihydro- [1,2, 4] triazolo [4, 3-a]pyridines as soluble epoxide hydrolase (seh) inhibitors - Google Patents

3-oxo-2, 3-dihydro- [1,2, 4] triazolo [4, 3-a]pyridines as soluble epoxide hydrolase (seh) inhibitors Download PDF

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WO2010096722A1
WO2010096722A1 PCT/US2010/024829 US2010024829W WO2010096722A1 WO 2010096722 A1 WO2010096722 A1 WO 2010096722A1 US 2010024829 W US2010024829 W US 2010024829W WO 2010096722 A1 WO2010096722 A1 WO 2010096722A1
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Prior art keywords
trifluoromethoxy
pyridine
oxo
triazolo
dihydro
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French (fr)
Inventor
Jun Feng
Walter Keung
Wolfgang Reinhard Ludwig Notz
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Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C07D233/34—Ethylene-urea

Definitions

  • the present invention relates to medicinal chemistry and pharmaceutical science.
  • compounds that inhibit soluble epoxide hydrolase (sEH) are provided herein.
  • Soluble epoxide hydrolase acts upon lipid epoxides, including those of arachidonic acid known as epoxyeicosatrienoic acids (EETs). These lipid epoxides are known effectors of blood pressure and modulators of vascular permeability. The vasodilatory properties of lipid epoxides are associated with an increased open-state probability of calcium-activated potassium channels leading to hyperpolarization of the vascular smooth muscle. Hydrolysis of lipid epoxides by sEH diminishes this activity.
  • EETs epoxyeicosatrienoic acids
  • sEH is a modulator of a large number of pathological conditions including hypertension, diabetes, metabolic syndrome, atherosclerosis, coronary artery disease, angina, ischemia, ischemic stroke, Raynaud's disease, inflammatory processes, genitourinary disorders, conditions of the eye, and renal disease.
  • inhibitors of sEH would have a therapeutic effect in such disorders.
  • Ri is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 4-14 aryl, optionally substituted C3-8 cycloalkyl, optionally substituted
  • Ci- 1 0 heteroaryl, and optionally substituted C3-6 heterocycloalkyl
  • Ar is selected from the group consisting Of C 5-14 aryl and C 1-10 heteroaryl;
  • R 2 is selected from the group consisting of optionally substituted Ci_ 6 alkyl, Ci_s sulfonyl, optionally substituted C 2 - 4 alkenyl, optionally substituted C 1-4 alkoxy, optionally substituted
  • Wi is selected from the group consisting of N and CR 3 ;
  • W 2 is selected from the group consisting of N and CR 3 ;
  • W 3 is selected from the group consisting of N and CR 3 ; provided that no more than one of Wi, W 2 , and W 3 is N; each R 3 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2 - 4 alkenyl, cyano, C 3 _8 cycloalkyl, halo, and hydroxy; and the pharmaceutically acceptable salts thereof.
  • compositions comprising: a compound of formula I and a pharmaceutically acceptable excipient.
  • the compounds of the invention are inhibitors of sEH they are useful for the treatment of conditions associated with sEH, including hypertension.
  • the invention provides methods of treating conditions associated with sEH, comprising: administering to a patient in need thereof an effective amount of a compound of formula I.
  • the present invention provides for the use of compounds of formula I for the manufacture of a medicament, including specifically for the treatment of particular conditions associated with sEH.
  • the present invention also provides an article of manufacture: comprising at least one compound of formula I and a label. Also provided are kits comprising at least one compound of the invention, a label, and apparatus for administration of the inhibitor. [0009] The present invention also provides processes from making sEH inhibitors and intermediates thereof.
  • C 2 - 4 alkenyl refers to a straight or branched alkenyl chain having from two to four carbon atoms and one or more carbon-carbon double bonds, and includes ethylene, propylene, iso-propylene, butylene, iso-butylene, sec-butylene, and the like.
  • optionally substituted C 2 - 4 alkenyl refers to a C 2 - 4 alkenyl optionally having from 1 to 3 substituents independently selected from the group consisting of C 1-4 alkoxy, C 1 -9 amide, C 1-5 oxycarbonyl, cyano, C3-8 cycloalkyl, halo, hydroxy, optionally substituted C 1-10 heteroaryl, and optionally substituted phenyl.
  • Ci_ 4 alkyl refers to a straight or branched alkyl chain having from one to four carbon atoms.
  • Ci_ 4 alkyl refers to a Ci_ 4 alkyl optionally having from 1 to 5 substituents independently selected from the group consisting of amino, C 2 - 4 alkenyl, C 1-4 alkoxy, C 1 -9 amide, C 1-8 alkylamino, C 1-5 oxycarbonyl, cyano, C3-8 cycloalkyl, C 3 _ 8 cycloalkoxy, halo, hydroxy, nitro, oxo, optionally substituted C 3 _ 6 hetero cycloalkyl, optionally substituted C 1-10 heteroaryl, and optionally substituted phenyl.
  • C 1-6 alkyl refers to a straight or branched alkyl chain having from one to six carbon atoms.
  • optionally substituted C 1-6 alkyl refers to a C 1-6 alkyl optionally having from 1 to 7 substituents independently selected from the group consisting of amino, C 1-8 alkylamino, C 2 - 4 alkenyl, C 1-4 alkoxy, C 1 -9 amide, C 1-5 oxycarbonyl, cyano, C3-8 cycloalkyl, halo, hydroxy, optionally substituted C 1-10 heteroaryl, optionally substituted C3-6 heterocycloalkyl, optionally substituted C 1-10 heteroaryl, and optionally substituted phenyl.
  • C 1-8 sulfonyl refers to a sulfonyl linked to a C 1-6 alkyl group, C3-8 cycloalkyl, or an optionally substituted phenyl.
  • C 1-4 alkoxy refers to a C 1-4 alkyl attached through an oxygen atom.
  • Ci_ 4 alkoxy refers to a Ci_ 4 alkoxy optionally having from 1 to 6 substituents independently selected from the group consisting of C 2 - 4 alkenyl, C 1-4 alkoxy, C 1 -9 amide, C 1-5 oxycarbonyl, cyano, C3-8 cycloalkyl, halo, hydroxy, optionally substituted C 1-10 heteroaryl, and optionally substituted phenyl. It is understood that where the optional substituent is Ci_ 4 alkoxy, cyano, halo, or hydroxy then the substituent is not alpha to the alkoxy attachment point.
  • C 2 -6 alkynyl refers to a straight or branched alkynyl chain having from two to six carbon atoms and one or more carbon-carbon triple bonds.
  • optionally substituted C 2 -6 alkynyl refers to a C 2 -6 alkynyl optionally having from 1 to 3 substituents independently selected from the group consisting of C 1-4 alkoxy, C 1 -9 amide, C 1-5 oxycarbonyl, cyano, C3-8 cycloalkyl, halo, hydroxy, optionally substituted C 1-10 heteroaryl, and optionally substituted phenyl.
  • Ci_ 9 amide refers to a primary amide or one having one or two Ci_ 4 alkyls, for example, -CONH 2 , -CONHCH 3 , and -CON(CH 3 ) 2 .
  • Ci_8 alkylamino refers to an amino having one or two Ci_ 4 alkyl.
  • C 4-14 aryl refers to a monocyclic and polycyclic unsaturated, conjugated hydrocarbon having aromatic character and having four to fourteen carbon atoms, and includes phenyl, biphenyl, indenyl, cyclopentyldienyl, fluorenyl, and naphthyl.
  • C 4-14 aryl refers to a C 4-14 aryl optionally having 1 to
  • substituents independently selected from the group consisting of amino, C 1 -9 amide, C 1-8 alkylamino, optionally substituted C 1-4 alkyl, optionally substituted C 1-4 alkoxy, cyano, halogen, hydroxyl, nitro, and C 1-8 sulfonyl.
  • C 4-14 aryloxy refers to a C 4-14 aryl attached through an oxygen atom.
  • optionally substituted C 4-14 aryloxy refers to a C 4-14 aryloxy optionally having 1 to 5 substituents independently selected from the group consisting of amino, C 1-8 alkylamino, C 1-4 alkyl, C 1-4 alkoxy, cyano, halogen, hydroxyl, nitro, C 1-8 sulfonyl, and trifluoromethyl.
  • optionally substituted benzyl refers to a benzyl group optionally having 1 to 3 groups independently selected from the group consisting of halo, C 1-4 alkyl, C 1-4 alkoxy, cyano, and nitro.
  • C 1-5 oxycarbonyl refers to a oxycarbonyl group (-CO 2 H) and C 1-4 alkyl ester thereof.
  • C 3 _s cycloalkyl refers to an alkyl ring having from three to eight carbon atoms, and includes cyclopropyl, 2-methyl cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • optionally substituted C3-8 cycloalkyl refers to a C3-8 cycloalkyl optionally having from 1 to 6 substituents independently selected from the group consisting of optionally substituted C 1-4 alkyl, C 2 - 4 alkenyl, C 1-4 alkoxy, C 1 -9 amide, C 1-8 alkylamino, C 1-5 oxycarbonyl, cyano, C3-8 cycloalkyl, C3-8 cycloalkoxy, halo, hydroxy, nitro, oxo, optionally substituted C 1-10 heteroaryl, and optionally substituted phenyl.
  • C 3 _ 8 cycloalkoxy refers to a C 3 _ 8 cycloalkyl attached through an oxygen atom.
  • halogen and “halo” refers to a chloro, fluoro, bromo or iodo atom.
  • C3_6 heterocycloalkyl refers to a 4 to 10 membered monocyclic saturated ring having one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the term includes azetidine, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, tetrahydrofuran, and the like.
  • optionally substituted C3-6 heterocycloalkyl refers to a heteroC3_6 cycloalkyl optionally substituted on the ring carbons with 1 to 4 substituents independently selected from the group consisting of optionally substituted C 1-4 alkyl, C 2 - 4 alkenyl, C 1-4 alkoxy, C 1 -9 amide, C 1-8 alkylamino, C 1-5 oxycarbonyl, cyano, C3-8 cycloalkyl, C3-8 cycloalkoxy, halo, hydroxy, nitro, oxo, and optionally substituted phenyl; and optionally substituted on any ring nitrogen with a substituent selected from the group consisting of optionally substituted C 1-4 alkyl, C 2 - 4 alkenyl, C3-8 cycloalkyl, optionally substituted C 1-10 heteroaryl, and optionally substituted phenyl.
  • C 1-10 heteroaryl refers to a five to twelve membered monocyclic and polycyclic having unsaturated, conjugated ring(s) having aromatic character and having one to ten carbon atoms and one or more, typically one to four, heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the term includes azepine, diazepine, furan, thiophene, imidazole, isothiazole, isoxazole, oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, thiazole, thiadiazole, triazole, tetrazole, benzazepine, benzodiazepine, benzofuran, benzo thiophene, benzimidazole, imidazopyridine, pyrazolopyridine, quinazoline, thienopyridine, indolizine, imidazopyridine, quinoline, isoquinoline, indole, isoindole, benzoxazole, benzopyrazole, benzothiazole, and the like.
  • optionally substituted C 1-10 heteroaryl refers to a C 1-10 heteroaryl optionally having 1 to 5 substituents on carbon independently selected from the group consisting of amino, C 1 ⁇ amide, C 1-8 alkylamino, optionally substituted C 1-4 alkyl, optionally substituted C 1-4 alkoxy, cyano, halogen, hydroxyl, nitro, and C 1-8 sulfonyl and optionally having substituents on each nitrogen independently selected from the group consisting of optionally substituted Q_ 4 alkyl, Ci_s sulfonyl, and optionally substituted phenyl.
  • oxo refers to an oxygen atom having a double bond to the carbon to which it is attached to form the carbonyl of a ketone or aldehyde. It is understood that as the term is used herein oxo refers to doubly bonded oxygen attached to the group which has the oxo substituent, as opposed to the oxo group being pendant as a formyl group.
  • an acetyl radical is contemplated as an oxo substituted alkyl group and a pryidone radical is contemplated as oxo substituted C 1-10 heteroaryl.
  • C 1-10 heteroaryloxy refers to a C 1-10 heteroaryl attached through an oxygen.
  • optionally substituted C 1-10 heteroaryloxy refers to a C 1-10 heteroaryl optionally having 1 to 5 substituents on carbon independently selected from the group consisting Of C 1-4 alkyl, C 1-4 alkoxy, cyano, halogen, hydroxyl, nitro, oxo, C 1-8 sulfonyl, and trifiuoromethyl and optionally having substituents on each nitrogen independently selected from the group consisting of optionally substituted C 1-4 alkyl, C 1 -S sulfonyl, and optionally substituted phenyl.
  • optionally substituted phenyl refers to a phenyl group optionally having 1 to 5 substituents independently selected from the group consisting of amino, C2-4 alkenyl, C 1-4 alkyl, C 1-4 alkoxy, C 1 ⁇ amide, C 1-8 alkylamino, C 1-5 oxycarbonyl, cyano, halogen, hydrogen, hydroxyl, nitro, C 1-8 sulfonyl, and trifluoromethyl.
  • pharmaceutically acceptable salt refers to salts of pharmaceutically acceptable organic acids and bases or inorganic acids and bases. Such salts are well known in the art and includes those described in Journal of Pharmaceutical Science, 66, 2-19 (1977). Examples are the hydrochloride and mesylate salts.
  • salt refers to organic acids and bases or inorganic acids and bases and included pharmaceutically accpeptable salts and extends to acids and bases that are not generally used in pharmaceuticals, for example the oxalic acid salts.
  • salt refers to organic acids and bases or inorganic acids and bases and included pharmaceutically accpeptable salts and extends to acids and bases that are not generally used in pharmaceuticals, for example the oxalic acid salts.
  • the skilled artisan will appreciate that certain of the compounds of the present invention exist as isomers. All mixtures of stereoisomers, in any ratio, and specific geometric isomers, enantiomers, and diastereomers of the compounds of the invention are contemplated to be within the scope of the present invention.
  • the compounds of the invention include a compound of formula I wherein Ar is C 4-14 aryl.
  • Another embodiment relates to any of the embodiments above or below wherein n is 1.
  • Another embodiment relates to any of the embodiments above or below wherein m is 1 or 2 and at least one of R 2 is selected from the group consisting of hydrogen, cyano, optionally substituted C 1-6 alkyl, optionally substituted C 1-4 alkoxy, optionally substituted C3-6 heterocycloalkyl and optionally substituted C 4-14 aryl.
  • Another embodiment relates to any of the embodiments above or below wherein Ri is selected from the group consisting of hydrogen and optionally substituted C 1-6 alkyl.
  • Another embodiment relates to any of the embodiments above or below wherein Ri is hydrogen.
  • Ri is optionally substituted C 1-4 alkyl having from 1 to 4 substituents independently selected from the group consisting of cyano, halo, hydroxy, optionally substituted C3-6 heterocycloalkyl, optionally substituted C 1-10 heteroaryl, and optionally substituted phenyl.
  • Another embodiment relates to any of the embodiments above or below wherein Ri optionally substituted C 1-4 alkyl having an optionally substituted C 1-10 heteroaryl and the C 1-10 heteroaryl is selected from the group consisting of furan, thiophene, imidazole, pyrazine, pyridazine, pyridine, pyrimidine, thiazole, and quinoline.
  • Another embodiment relates to any of the embodiments above or below wherein Ri is optionally substituted Ci_ 4 alkyl having a cyano.
  • Another embodiment relates to any of the embodiments above or below wherein Ri is optionally substituted Ci_4 alkyl having a hydroxy.
  • Another embodiment relates to any of the embodiments above or below wherein Ri is optionally substituted Ci_ 4 alkyl having from 1 to 4 halo.
  • Another embodiment relates to any of the embodiments above or below wherein m is
  • R 2 is optionally substituted C 1-4 alkoxy.
  • Another embodiment relates to any of the embodiments above or below wherein m is
  • R 2 is C 1-4 alkoxy.
  • Another embodiment relates to any of the embodiments above or below wherein m is
  • R 2 is cyano
  • Another embodiment relates to any of the embodiments above wherein m is 1 or 2 and at least one of R 2 is halo.
  • the compounds of the invention can be prepared by a variety of procedures, some of which are described below. All substituents, unless otherwise indicated, are as previously defined.
  • the products of each step can be recovered by conventional methods including extraction, evaporation, precipitation, chromatography, filtration, trituration, crystallization, and the like.
  • the procedures may require protection of certain groups, for example hydroxy, amino, or carboxy groups to avoid unwanted reactions.
  • the selection, use, and removal of protecting groups is well known and appreciated as standard practice, for examples see T. W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry” John Wiley and Sons, 1991.
  • step 1 depicts the reaction of an appropriate compound of formula (a) with an appropriate compound of formula H 2 N-(CH 2 ) n -Ar-(Pv 2 ) m to give a compound of formula (b).
  • An appropriate compound of formula (a) is one in which W 1 , W 2 , and W 3 are as desired in the final compound of formula I or give rise to W 1 , W 2 , and W 3 are as desired in the final compound of formula I and
  • X 1 is a hydroxyl or a leaving group, such as chloro, bromo, or imidazolyl, an activating moiety, a mixed anhydride of another carboxylic acid, such as formic acid, acetic acid, or a substituted or unsubstituted benzoic acid, or X 1 represents the other part of a symmetrical anhydride formed from two compounds of formula (a) in which Xi is hydroxyl.
  • standard amide forming conditions can be used, such as those using coupling agents, including those used in peptide couplings, such as 2-(lH-7-azabenzotriazol-l-yl)- 1,1,3,3- tetramethyl uronium hexafluorophosphate methanaminium (HATU), dicyclohexylcarbodiimide (DCC), and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
  • an additive such as 4-(dimethylamino)pyridine, 1- hydroxybenzotriazole, and the like may be used to facilitate the reaction.
  • reaction is generally carried out using a base, such as N-methylmorpholine or triethylamine, in a wide variety of suitable solvents such as dichloromethane, dimethylformamide (DMF), N- methylpyrrolidone (NMP), dimethylacetamide (DMAc), tetrahydrofuran (THF), and the like.
  • a base such as N-methylmorpholine or triethylamine
  • suitable solvents such as dichloromethane, dimethylformamide (DMF), N- methylpyrrolidone (NMP), dimethylacetamide (DMAc), tetrahydrofuran (THF), and the like.
  • DMF dimethylformamide
  • NMP N- methylpyrrolidone
  • DMAc dimethylacetamide
  • THF tetrahydrofuran
  • a compound of formula (b) is reacted with hydrazine in a solvent using a suitable base.
  • the reaction can be carried out using an excess of hydrazine.
  • the reaction is carried out in a suitable solvent, such as a lower alcohol, water, and mixtures thereof.
  • the reaction is carried out at temperatures of about 60 0 C to 150 0 C.
  • the reaction mixture may be sealed as a matter of convenience.
  • Ri is as described above and R is selected from the group consisting of C1-4 alkyl, 2,2,2-trichloroethyl, and optionally substituted benzyl followed by cyclization to directly give a compound of formula I.
  • a compound of formula (b) is reacted with a compound of formula (g) in solvent.
  • Typical solvents include water and lower alcohols and mixtures thereof.
  • the reaction is carried out using a suitable base. It will be appreciated the reaction can be carried out without a base, but if a base is not used in the first step, a base will be introduced to facilitate the cyclization to give a compound of formula (e).
  • the cyclization reaction is carried out in a suitable solvent, such as a water and mixtures of water and lower alcohol and mixtures of water and acetic acid. The reaction is carried out at temperatures of about 60 0 C to 150 0 C.
  • Scheme A depicts a ring forming reaction of an appropriate compound of formula (c) with suitable carbonyl reagent to give a compound of formula I in which Ri is hydrogen.
  • suitable carbonyl reagents include carbonyl dichloride, carbonyl dibromide, carbonyl diimidazole, and the like.
  • a compound of formula (c) is reacted with, generally, 1 equivalent of a suitable carbonyl reagent in a suitable solvent such as DMSO and may be carried out using a suitable base, such as triethylamine, diisopropylethylamine, and the like.
  • a suitable base such as triethylamine, diisopropylethylamine, and the like.
  • the reaction typically is carried out at temperatures of from -20 0 C to ambient temperature and require about 1 hour to 2 days.
  • Scheme A depicts the reaction of a compound of formula I in which Ri is hydrogen with a suitable RiX 2 to give a compound of formula I.
  • Suitable compounds of formula RiX 2 are ones in which Ri is as desired in the final compound of formula I or gives rise to Ri as desired.
  • X 2 is a suitable leaving group, the nature of which may vary with the Ri group to be introduced but generally will be a halogen or sulfonate ester.
  • a suitable X 2 may be a halide, such as chloro, bromo, or iodo or a sulfonate ester, such as tosylate, besylate, nosylate, trifluoromethanesulfonate, and the like.
  • a suitable X 2 may be a halide, such as fluoro, chloro, or bromo.
  • a compound of formula I in which Ri is hydrogen is reacted with a molar excess of a compound of formula RiX 2 in a suitable solvent such as DMSO, DMF, THF and the like and may be carried out using a suitable base, such as cesium carbonate, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, and the like.
  • a suitable solvent such as DMSO, DMF, THF and the like
  • a suitable base such as cesium carbonate, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, and the like.
  • the reaction is generally carried out using from 0.9 to 2 equivalents of a compound of formula RiX 2 .
  • the reaction typically is carried out at temperatures of from 0 0 C to 8O 0 C and require about 1 hour to 3 days.
  • a compound of formula (e) can be prepared by a process characterized by the reaction of a compound of formula (g) with a compound of formula (d) Such a reaction is followed by cychzation to give a compound of formula (e)
  • a compound of formula (e) can undergo an optional reaction as described in Scheme A, step 4 using a suitable RiX 2 , followed by deprotection, if required, to give a compound of formula (e) in which Ri is not hydrogen
  • a compound of formula (e) in which Ri is as desired in the final compound of formula I can, either as the carboxylic acid or after activation to -C(O)Xi, undergo an amide forming reaction as described in Scheme A, step 1, with an appropriate compound of formula (f), H 2 N- (CH 2 ) n -Ar-(R 2 ) m , to give a compound of formula I
  • a compound of formula (e) in which Ri is hydrogen can, either as the carboxylic acid or after activation to -C(O)Xi, undergo an amide forming reaction as described in Scheme A, step 1, with an appropriate compound of formula H 2 N-(CH 2 )I 1 -Ar-(R 2 )In to give a compound of formula I in which Ri is hydrogen.
  • step 4 to give a compound of formula I in which Ri is other than hydrogen.
  • compounds of formula (f) can be prepared by a variety of methods as described herein or by methods analogous to those described herein and in the art. Specifically, a compound of formula (f) in which n is 1 can be prepared by reduction of a nitrile or an amide or by halogenations of a methyl (in a toluene derivative) followed by displacement by ammonia or a protected amine, for example NH 2 NBoC or phthalimide.
  • R 2 groups are commercially available or can be installed by various methodologies, for example, hydrolysis, oxidation, reduction, alkylation, amidations, sulfonations, alkynations, alkyenations, arylations such as Suzuki coupling, and the like.
  • Compounds of formula (f) that are included in the present invention are 4-(aminomethyl)-3-(trifluoromethoxy)benzonitrile, (4-nitro-2-(trifluoromethoxy)phenyl)methanamine, (4-iodo-2-
  • Example 1 3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3-dihydro-[l,2,4]triazolo[4,3- a]pyridine-6-carboxamide
  • Example 2 2-(cyanomethyl)-3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 3 2-(3-oxo-6-(2-(trifluoromethoxy)benzylcarbamoyl)-[l,2,4]triazolo[4,3- a]pyridin-2(3H)-yl)acetic acid
  • Example 4 2-(2-amino-2-oxoethyl)-3-oxo-N-(2-(trifiuoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 7 N-(2,3-dimethoxybenzyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3- a]pyridine-6-carboxamide
  • Example 11 3-oxo-2-(pyridin-2-ylmethyl)-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 12 2-(2-(diethylamino)ethyl)-3-oxo-N-(2-(trifiuoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 13 2-(2-(dimethylamino)ethyl)-3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 14 2-(2-morpholinoethyl)-3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 15 2-(2-(lH-imidazol-l-yl)ethyl)-3-oxo-N-(2-(trifluoromethoxy)benzyl)- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • the title compound was synthesized from 3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using l-(2-bromoethyl)-lH-imidazole. Purified by Mass-triggered HPLC (Gradient: 20-40% ACN containing 0.035% TFA in water containing 0.05% TFA) to give the TFA salt.
  • Example 17 (S)-3-oxo-2-((5-oxopyrrolidin-2-yl)methyl)-N-(2- (trifluoromethoxy)benzyl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 18 2-ethyl-3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 20 2-(2-hydroxyethyl)-3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 21 2-(2,3-dihydroxypropyl)-3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • the title compound was synthesized fromN-(2,3-dimethoxybenzyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 2-bromoacetonitrile. Purified by Mass-triggered HPLC (Gradient: 30-60% ACN containing 0.035% TFA in water containing 0.05% TFA).
  • Example 24 3-oxo-2-(2,2,2-trifluoroethyl)-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 25 2-((l-methyl-lH-imidazol-2-yl)methyl)-3-oxo-N-(2- (trifluoromethoxy)benzyl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • the title compound was synthesized from 3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 2-(bromo methyl)- 1 -methyl- lH-imidazole. Purified by Mass-triggered HPLC (Gradient: 20-30% ACN containing 0.035% TFA in water containing 0.05% TFA) to give the TFA salt.
  • Example 26 3-oxo-2-(pyridin-4-ylmethyl)-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 27 3-oxo-2-(pyridin-3-ylmethyl)-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • the title compound was synthesized from 3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 3-(bromomethyl)pyridine. Purified by Mass-triggered HPLC (Gradient: 20-30% ACN containing 0.035% TFA in water containing 0.05% TFA) to give the TFA salt.
  • Example 28 3-oxo-2-(tetrahydro-2H-pyran-4-yl)-N-(2-(trifluoromethoxy)benzyl)- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 30 N-(4-methoxy-2-(trifluoromethoxy)benzyl)-3-oxo-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • the title compound was synthesized by a method similar to Example 1 by using (4- methoxy-2-(trifluoromethoxy)phenyl)methanamine as amine. Purified by Mass-triggered HPLC (Gradient: 30-40% ACN containing 0.035% TFA in water containing 0.05% TFA).
  • Example 32 N-(4-methoxy-2-(trifiuoromethoxy)benzyl)-3-oxo-2-(tetrahydro-2H- pyran-4-yl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • the title compound was synthesized from N-(4-methoxy-2-(trifluoromethoxy)benzyl)- 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 4-iodotetrahydro-2H-pyran. Purified by Mass-triggered HPLC (Gradient: 20-60% ACN containing 0.035% TFA in water containing 0.05% TFA) to give the title compound.
  • the title compound was synthesized fromN-(4-methoxy-2-(trifluoromethoxy)benzyl)- 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 2-bromoethanol. Purified by Mass-triggered HPLC (Gradient: 20-50% ACN containing 0.035% TFA in water containing 0.05% TFA) to give the title compound.
  • Example 34 (R)-N-(4-methoxy-2-(trifluoromethoxy)benzyl)-3-oxo-2-((5- oxopyrrolidin-2-yl)methyl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 36 2-(l-cyanoethyl)-N-(4-methoxy-2-(trifluoromethoxy)benzyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • the title compound was synthesized from N-(4-methoxy-2-(trifluoromethoxy)benzyl)- 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 2-bromopropanenitrile. Purified by Mass-triggered HPLC (Gradient: 40- 60% ACN containing 0.035% TFA in water containing 0.05% TFA) to give the title compound.
  • Example 37 2-(2,3-dihydroxypropyl)-N-(4-methoxy-2-(trifluoromethoxy)benzyl)-3- oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 38 2-(l -amino- 1 -oxopropan-2-yl)-N-(4-methoxy-2- (trifluoromethoxy)benzyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 40 N-(4-bromo-2-(trifluoromethoxy)benzyl)-3-oxo-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 41 N-(4-(cyclopropylsulfonyl)-2-(trifluoromethoxy)benzyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 43 N-(4-(6-aminopyridin-3-yl)-2-(trifluoromethoxy)benzyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 45 N-(4-(3-hydroxyprop-l-ynyl)-2-(trifluoromethoxy)benzyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 47 N-(4-bromo-2-(trifluoromethoxy)benzyl)-2-(2-hydroxyethyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • a title compound was synthesized from N-(4-bromo-2-(trifluoromethoxy)benzyl)-3- oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 2-bromoethanol. Purified by Mass-triggered HPLC (Gradient: 30-50% ACN containing 0.035% TFA in water containing 0.05% TFA).
  • Example 48 2-(2-hydroxyethyl)-N-(4-(methylsulfonyl)-2-(trifluoromethoxy)benzyl)- 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 49 N-(4-(cyclopropylsulfonyl)-2-(trifluoromethoxy)benzyl)-2-(2- hydroxyethyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 50 N-(4-bromo-2-(trifluoromethoxy)benzyl)-2-(2-cyanoethyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 51 2-(2-cyanoethyl)-N-(4-(cyclopropylsulfonyl)-2- (trifluoromethoxy)benzyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 52 N-(4-(2-aminopyrimidin-5-yl)-2-(trifluoromethoxy)benzyl)-2-(2- cyanoethyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 55 N-(4-cyano-2-(trifluoromethoxy)benzyl)-2-(2-hydroxyethyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • N-(4-bromo-2-(trifluorometho xy )benzyl)-3-oxo-2,3-dihy dro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide 550 mg, 1.28 mmol
  • Cs 2 CO 3 623 mg, 1.92 mmol
  • 1,1- difluoro-2-iodoethane 370 mg, 1.92 mmol
  • Example 58 N-(4-(cyclopropylsulfonyl)-2-(trifluoromethoxy)benzyl)-2-(2,2- difluoroethyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 59 N-(4-bromo-2-(trifluoromethoxy)benzyl)-3-oxo-2-(tetrahydro-2H-pyran- 4-yl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 60 N-(4-cyano-2-(trifluoromethoxy)benzyl)-3-oxo-2-(tetrahydro-2H-pyran- 4-yl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 61 N-(4-bromo-2-(trifluoromethoxy)benzyl)-2-(2-morpholinoethyl)-3-oxo-
  • Example 62 N-(4-methoxy-2-(trifiuoromethoxy)benzyl)-2-(2-morpholinoethyl)-3- oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 64 N-(4-(cyclopropylsulfonyl)-2-(trifluoromethoxy)benzyl)-2-(2- morpholinoethyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 66 N-(4-cyano-2-(trifluoromethoxy)benzyl)-2-(2-cyanoethyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • the organic layer was dried with MgSO4 and evaporates to a volume of about 2OmL to give a solid.
  • the solid was collected by filtration and washed with EtOAc/Hexane (1 :1) and further purified by dissolving in 10OmL EtOAc (refluxing) and titration with hexane to about 1 to 1 ratio of EtOAc to Hexane at room temperature. The solid was collected by filtration to give 1.5 g (62.5%) of the title compound.
  • Example 67 (4-methoxy-2-(trifluoromethoxy)phenyl)methanamine [0216] To a mixture of 4-methoxy-2-(trifluoromethoxy)benzaldehyde (10Og, 450 mmol) in 1000 mL of EtOH was added hydroxylamine hydrochloride (38 g, 550 mmol) and potassium acetate (49 g, 500 mmol). The mixture was stirred at 50 0 C for 5 h. The solvent was then removed on rotoray evaporator to give a white solid which was collected by filtration and washed with 2 potions of water. The solid product was dried overnight in vacuum to give 81 grams of the crude 4-methoxy-2-(trifluoromethoxy)benzaldehyde oxime (yield: 75%) that was used in next step without purification.
  • Example 68 N-(4-methoxy-2-(trifluoromethoxy)benzyl)-3-oxo-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 69 2-(2 -hydroxy ethyl)-N-(4-methoxy-2-(trifluoro methoxy)benzyl)-3-oxo- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 70 4-(aminomethyl)-3-(trifluoromethoxy)benzonitrile
  • a mixture of (4-bromo-2-(trifluoromethoxy)phenyl)methanamine HCl salt (2 g, 6.53 mmol), di-tert-butyl dicarbonate (2.85 g, 13.05 mmol) and NaHCO 3 (5.48 g, 65.3 mmol) in dioxane was stirred overnight, then the solvent was removed in vacuum to give a residue.
  • Example 72 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carbonyl chloride [0235] To a solution of 6-chloronicotinic acid (20 g, 127 mmol) in 200 mL of EtOH was added hydrazine hydrate (14.8 mL, 317 mmol). The mixture was refluxed overnight, then cooled to room temperature to give a solid, which was collected by filtration, washed with petroleum ether/EA (2: 1) to give 18 g of 6-hydrazinylnicotinic acid as a yellow solid (Yield: 91%).
  • Example 74 N-((2-(4-fluorophenyl)pyridin-3-yl)methyl)-3-oxo-2-(pyridin-2- ylmethyl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 75 2-(2-cyanoethyl)-N-((2-(4-fluorophenyl)pyridin-3-yl)methyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • the title compound was synthesized from N-((2-(4-fluorophenyl)pyridin-3-yl)methyl)-3-oxo- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 74 by using 3-bromopropanenitrile. Purified by prep HPLC (Column: XB-Cl 8(5uM) 21.2 mm x 150mm) eluting with a gradient 10-60% ACN containing 0.0355 TFA in water containing 0.1% TFA) to give the title compound.
  • Example 76 2-(2,2-difluoroethyl)-N-((2-(4-fluorophenyl)pyridin-3-yl)methyl)-3-oxo- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • the title compound was synthesized from N-((2-(4-fluorophenyl)pyridin-3- yl)methyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 74 by using 2-bromoethanol. Purified by TLC eluted with Pentane/EtOAc (2/1) to give 25 mg of the title compound.
  • reaction mixture was refluxed overnight before slowly adding consecutively 15 mL of H 2 O, 5.7 mL of 15% aq. NaOH solution and 5 mL of H 2 O for quench.
  • the resulting mixture was filtered, and filtrate was dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give the crude title compound as a brown oil which was used without the further purification.
  • Example 80 N-((2-(4-fluorophenyl)pyridin-2-yl)methyl)-3-oxo-2-(pyridin-2- ylmethyl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 81 2-(2,2-difluoroethyl)-N-((2-(4-fluorophenyl)pyridin-2-yl)methyl)-3-oxo- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 82 N-((2-(4-fluorophenyl)pyridin-2-yl)methyl)-2-(2 -hydroxy ethyl)-3-oxo-
  • Example 83 4-(aminomethyl)-3-(trifluoromethoxy)benzonitrile
  • a solution of 4-bromo-l-iodo-2-(trifluoromethoxy)benzene (4.95 g, 13.49 mmol) in THF (80 mL) was cooled in a dry ice/acetone bath under an atmosphere of nitrogen.
  • n-BuLi (16.86 mL, 27.0 mmol) dropwise over 13 min while maintaining an internal temperature ranging from -112° C to -65.5 0 C.
  • the reaction was stirred at -77°C for 60 min.
  • Example 84 2-(2-hydroxyethyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6- carboxylic acid
  • reaction mixture was then heated back to about 94 0 C and stirred at this temperature for about 48 hours.
  • the mixture was then cooled to about 46 0 C and cone HCl (400 mL) was added over 1-2 minutes to give a pH ⁇ 0.
  • the reaction mixture was cooled to room temperature, the solid filtered, the filter cake was rinsed with water (3x250 mL), dried first by suction, then in vacuo at 100 0 C, to afford 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6- carboxylic acid (449.86 g, 2498 mmol, 85 % yield).
  • Example 85 N-(4-cyano-2-(trifluoromethoxy)benzyl)-2-(2-cyanoethyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • Example 86 N-(4-cyano-2-(trifluoromethoxy)benzyl)-3-oxo-2-(pyridin-2-ylmethyl)- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
  • isopropanol 1000 mL was added and atmospheric distillation was continued. After about 720 mL of distillate had been collected, more isopropanol (1000 mL) was added. As the distillation progressed, the internal temperature increased to about 84 0 C. After a total of about 1680 mL of distillate had been collected, the heating was removed and isopropanol (500 mL) was added. The mixture was cooled back to room temperature and acidified with cone HCl (45 mL).
  • Example 87 N-(4-cyano-2-(trifluoromethoxy)benzyl)-3-oxo-2-(pyridin-2-ylmethyl)- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide sulfate [0281] A suspension of N-(4-cyano-2-(trifluoromethoxy)benzyl)-3-oxo-2-(pyridin-2- ylmethyl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide (702 mg, 1.498 mmol) in acetonitrile (60 mL) was heated close to reflux until a clear solution was obtained; then the solution was stirred while cooling.
  • Example 88 N-(4-cyano-2-(trifluoromethoxy)benzyl)-3-oxo-2-(pyridin-2-ylmethyl)- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide hydrochloride [0283] N-(4-Cyano-2-(trifluoromethoxy)benzyl)-3-oxo-2-(pyridin-2-ylmethyl)-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide (3.4 g, 7.26 mmol) was suspended in acetonitrile (250 mL) and heated to reflux, upon which dissolution occurred.
  • Reaction was diluted with 15mL water to give a solid.
  • the solid product was filtered and dried by suction.
  • Solid product was added into 1OmL 30% isopropanol in water, broke up with a spatula, sonicated, and then heated to 65 0 C.
  • An additional 3mL isopropanol was added and again the solid was broken up with a spatula, the mixture was sonicated, then heated to 65 0 C to give a suspension which was allowed to cool to room temperature.
  • the solid was collected by filtration, washed with 1OmL 30% isopropanol in water and dried by suction to give 77.6 mg of the title compound.
  • the compounds of the invention can be administered alone or in the form of a pharmaceutical composition.
  • the compounds of the invention are usually administered in the form of pharmaceutical compositions, that is, in admixture with pharmaceutically acceptable excipients the proportion and nature of which are determined by the properties of the selected compound of the invention, the chosen route of administration, and standard pharmaceutical practice.
  • the present invention provides pharmaceutical compositions comprising: a compound of invention and a pharmaceutically acceptable excipient.
  • a compound of the invention can be administered in any form and route which makes the compound bioavailable.
  • the compounds of the invention can be administered by a variety of routes, including oral and parenteral routes, more particularly by inhalation, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, vaginally, occularly, topically, sublingually, and buccally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, intraadiposally, intrathecally and via local delivery for example by catheter or stent.
  • routes including oral and parenteral routes, more particularly by inhalation, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, vaginally, occularly, topically, sublingually, and buccally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally,
  • compositions of the invention may be administered to the patient, for example, in the form of tablets, capsules, cachets, papers, lozenges, wafers, elixirs, ointments, transdermal patches, aerosols, inhalants, suppositories, solutions, and suspensions.
  • the pharmaceutical compositions of the present invention are prepared in a manner well known in the pharmaceutical art and include at least one of the compounds of the invention as the active ingredient.
  • the amount of a compound of the present invention may be varied depending upon its particular form and may conveniently be between 1 % to about 70% of the weight of the unit dosage form.
  • pharmaceutically acceptable excipient refers to those typically used in preparing pharmaceutical compositions and should be pharmaceutically pure and non-toxic in the amounts used. They generally are a solid, semisolid, or liquid material which can serve as a vehicle or medium for the active ingredient.
  • compositions include diluents, vehicles, carriers, ointment bases, binders, disintegrates, lubricants, glidants, sweetening agents, flavoring agents, gel bases, sustained release matrices, stabilizing agents, preservatives, solvents, suspending agents, buffers, emulsifiers, dyes, propellants, coating agents, and others.
  • the present pharmaceutical compositions are preferably formulated in a unit dosage form, each dosage typically containing from about 0.5 mg to about 200 mg of the compounds of the invention.
  • unit dosage form refers to a physically discrete unit suitable as a single dosage, each unit containing a predetermined quantity of active ingredient, in association with a suitable pharmaceutical excipient, by which one or more is used throughout the dosing regime to produce the desired therapeutic effect.
  • the composition is a pharmaceutical composition adapted for oral administration, such as a liquid formulation, for example, a solution or suspension, adapted for oral administration or a tablet or a capsule.
  • the pharmaceutical composition is a liquid formulation adapted for parenteral administration.
  • the invention provides methods of treating conditions associated with sEH, comprising: administering to a patient in need thereof an effective amount of a compound of the invention.
  • the invention provides a method of inhibiting a sEH: comprising, contacting the enzyme with a compound of the invention.
  • the invention provides a method of inhibiting a sEH: comprising, administering a compound of the invention to a patient in order to inhibit the enzyme in vivo.
  • the invention provides a method of inhibiting a sEH: comprising, administering a first compound to a subject that is converted in vivo to a compound of the invention.
  • compounds of the invention including the compound of formula I, are provided for use as a medicament.
  • the invention also provides the use of compounds of the invention for the manufacture of a medicament to treat the conditions associated with sEH described herein.
  • the compounds of the present invention are stable and are relatively safe in their end use.
  • the compounds of the present invention are useful as sEH inhibitors for a variety of subjects (e.g., humans, non-human mammals and non-mammals).
  • conditions As used herein terms "condition,” “disorder,” and “disease” relate to any unhealthy or abnormal state.
  • condition associated with sEH includes disorders and diseases in which the inhibition of sEH provides a therapeutic benefit, such hypertension, metabolic syndrome, obesity, elevated triglycerides, elevated cholesterol, glucose intolerance, atherosclerosis, coronary artery disease, cardiac fibrosis, angina, ischemia, stroke, renal disease, inflammation, including arthritis, renal inflammation, hepatic inflammation, vascular inflammation, and respiratory inflammation, adult respiratory distress syndrome and chronic obstructive pulmonary disease, emphysema, chronic bronchitis, interstitial lung disease, and idiopathic pulmonary fibrosis, systematic inflammatory response syndrome, pain, itching, irritation of the skin, dermatoses, sunburn, mild burns, prurtius, genitourinary disorders, overactive bladder, outlet obstructions, outlet insufficiency, benign prostatic hyperplasia, interstitial cystitis, erectile dysfunction, incontinence, and the like.
  • renal disease includes treatment of kidney disease, albuminuria, diabetic neuropathy, chronic kidney disease, fibrosis of the kidney, amyloidosis, acquired cystic kidney disease, nephritic syndrome, and proteinuria.
  • treatment of inflammatory conditions includes the treatment of arthritis and that arthritis is presently categorized into several more specific disorders, such as osteoarthritis and rheumatic arthritis, and others all of which are contemplated by the invention.
  • Another example is systematic inflammatory response syndrome which is used to describe inflammation events associated with lupus, sepsis, pancreatitis, multiple trauma, lacerations, brain injury or surgery, hemorrhagic shock and immune-mediated organ injuries and others all of which are contemplated by the invention.
  • itching which includes itching of the skin due to insect bites, allergic reaction, and contact dermatitis, pruritus, eczema, hives, chicken pox, impetigo, and others, all of which are contemplated by the invention.
  • treat include improvement of the conditions described herein. Also, it is also recognized that one skilled in the art may affect the conditions by treating a patient presently afflicted with the disorders or by prophylactically treating a patient believed to be susceptible to such conditions with an effective amount of a compound of invention. Thus, the terms “treat,” “treatment,” and “treating” include all processes providing slowing, interrupting, arresting, controlling, or stopping of the state or progression of the conditions described herein, but does not necessarily indicate a total elimination of all symptoms or a cure of the condition, and is intended to include prophylactic and therapeutic treatment of such disorders.
  • the terms "patient” and “subject” includes humans and non-human animals, for example, mammals, such as mice, rats, guinea pigs, dogs, cats, rabbits, cows, horses, sheep, goats, and pigs. The term also includes birds, fish, reptiles, amphibians, and the like. It is understood that a more particular patient is a human. Also, more particular patients and subjects are non-human mammals, such as mice, rats, and dogs. [0301] As used herein, the term “effective amount” refers to the amount of compound of the invention which treats, upon single or multiple dose administration, a patient suffering from the mentioned condition.
  • an effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances.
  • the dose a number of factors are considered by the attending diagnostician, including, but not limited to: the species of patient; its size, age, and general health; the specific condition, disorder, or disease involved; the degree of or involvement or the severity of the condition, disorder, or disease, the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
  • An effective amount of the present use invention, including a compound of the invention is expected to vary from about 0.1 milligram per kilogram of body weight per day (mg/kg/day) to about 20 mg/kg/day. Specific amounts can be determined by the skilled person.
  • the present invention provides a method for treating metabolic syndrome, comprising: administering to a patient in need thereof an effective amount of a compound of invention.
  • the present invention provides a method for treating hypertension comprising: administering to a patient in need thereof an effective amount of a compound of the invention.
  • a variety therapeutic agents may have a therapeutic additive or synergistic effect when used in combination with sEH inhibitors according to the present invention.
  • Such combination therapy can include administration concurrently or sequentially with therapy and/or an agent for the treatment of any of the conditions associated with sEH.
  • the present compounds may be combined calcium channel blockers, lipid lowering agents, cholesterol lowering agents, such as statins, fibrates, beta-blockers, ACE inhibitors, platelet aggregation inhibitors, diuretics, glucose lowering agents, insulin, and the like.
  • the invention also provides an article of manufacture: comprising at least one compound of the invention and a label.
  • the label may include information about the manufacturer, doses, conditions to be treated, and the use of the compound or pharmaceutical composition.
  • the invention provides a kit: comprising, at least one compound of the invention, a label, and apparatus for administration.
  • the apparatus may include mixing vials, liquids for forming solutions or suspensions, tubing, syringes, and the like.
  • DNA encoding the full-length sequence of the human enzyme was amplified by PCR and cloned into the pI-SUMOstar (LifeSensors), which incorporates a 6 x His_ SUMO tag at N-terminus.
  • DNA encoding the full-length sequence of the rat enzyme was amplified by PCR and cloned into the pFastBacHTb vector (Invitrogen), which incorporates a 6 x His tag at N-terminus
  • Recombinant protein was isolated from cellular extracts by passage over ProBond Nickel resin (Invitrogen).
  • the N-terminal 6 x His SUMO (human sEH) or 6 x His (rat sEH) tag was removed from partially purified sEH protein by incubating with SunoStar Proteinase 1 (LifeSensor) or rTEV enzyme respectively.
  • Partially purified and tag removed sEHs were purified by high pressure liquid chromatography over a BioSep S3000 gel filtration column for human sEH or by Nickel reverse purification and dialyzation for rat sEH. The purity of sEH proteins was determined on denaturing SDS-PAGE gel.
  • the proteins were either stored at -78 oC or - 20 oC in a buffer containing 25mM TRIS-HCl pH 7.6, 125mM NaCl and 50% glycerol for human sEH or in a buffer containing 5OmM TRIS 7.9, 20OmM NaCl, 50% glycerol for rat sEH .
  • the sEH inhibitory properties of test compounds were determined using a black 384- well-plate format under the following reaction conditions: 20 mM Tris pH 7.0, 0.1 mM EDTA, 0.1 mg/ml BSA, 5 ⁇ M PHOME (substrate from Cayman Chemical), 2 nM sEH enzyme, 1% DMSO (from test compound). Reaction product was determined quantitatively by fluorescence intensity using a Fluorescence plate reader (Molecular Devices Gemini) with an excitation wavelength at 330 nm and emission at 465 nm.
  • the assay reaction was initiated as follows: 2 ⁇ l of 5 times intermediate diluted inhibitor was added to each well of the plate, followed by the addition of 4 ⁇ l of 2.5 x sEH enzyme solution and incubated for 10 minutes at room temperature. After incubation, 4 ul of 2.5X substrate solution was added to initiate the reaction. Fluorescence intensities of the resulting reaction mixtures were measured after 20 minute (human sEH) or 10 minute (rat sEH) incubation at room temperature. A dose-response curve was constructed by diluting the test compound 2-fold in 11 subsequent dilutions and determining the percent inhibition of catalytic activity relative to control for each dilution of a single test compound.
  • a dose-response curve is first constructed by plotting on the Y-axis the percent relative to a control compound exhibiting complete inhibition of enzymatic activity versus the concentration of inhibitor on the X-axis.
  • the IC50 value is extrapolated from the dose-response curve at the concentration of test compound which exhibits 50% inhibition relative to control on the Y-axis.
  • the values expressed in Table 1 are pIC 50 (negative log (base 10) of the IC50 in moles per liter). All of the exemplified compounds inhibited human sEH in the assay of Example A with a pIC 50 of greater than about 5.8.
  • Illustrative pIC 5 o values are given in Table 1.
  • Example B Determination of sEH inhibition in cellular assay [0314] The cellular sEH activity can be assayed by its hydration of 14,15-EET and producing 14,15-DHET which is secreted out of the cell into the culture medium (Eagle's MEM (ATCC), 10% Fetal Bovine Serum (Hyclone), 1 x NEAA (Invitrogen), 1 x L- Glutamine (Invitrogen)).
  • Eagle's MEM ATCC
  • 10% Fetal Bovine Serum Hyclone
  • 1 NEAA Invitrogen
  • 1 x L- Glutamine Invitrogen
  • HepG2 hepatocellular carcinoma cells (30,000 cells/well) or ACHN renal cell adenocarcinoma (ATCC) (35,000 cells/well) are seeded in 96-well tissue culture cell bind plates. Cultures are incubated overnight at 370C in a 5% CO2 incubator until cells are attached and spread. 14,15-EET (Biomol International) is added to final concentration of 6 uM and inhibitor is added to the desired final concentration in total volume of 200ul per well. Prior to addition to cells compounds are serially diluted (1 :3) from column 1 to 11 and column 12 contained DMSO vehicle. Compounds are diluted into cell growth medium then compound solution is added to cells.
  • DMSO concentration 0.5%). Cultures are incubated for 2 hours at 370C in a 5% CO2 incubator.
  • the resulting 14,15-DHET amount in the cell culture medium can be directly detected using a 14,15-DHET ELISA kit (Detroit R&D, Inc.), and measuring the OD450 nm with a Spectamax microplate reader (Molecular Devices, San Diego, CA).
  • EC50 values are calculated using non-linear curve-fitting of the secreted 14,15-DHET as a function of compound concentration.
  • Test compounds at 3 mg/kg sEH inhibitor in 0.5 % methyl cellulose or the vehicle control is orally administrated to SHR rats (6 rats/group, 13 weeks old males, Charles River Laboratories) daily for two days.
  • Plasma is collected (200 ⁇ l_ in heparinized tubes at 4 h post dose on day 1 and 4, 8 and 24 h post dose on day 2.
  • the samples are frozen at -80 OC until analysis.
  • the lipids are extracted from the plasma sample with acetonitrile which contains
  • 14,15-DHET-dl 1 [80OuL of IOng/mL] as an internal standard, and the extract is blown dry and reconstituted into 100 ul 60/40 water/acetonitrile.
  • 14,15-DHET calibration was obtained by spike in known amount of 14,15-DHET (0.5, 1, 2.5, 20, 25, 100, 200, 500, 1000, 2000ng/mL) into blank plasma and extract the lipids with 80OuL acetonitrile containing IOng/mL 14,15-DHET-dl 1 as internal standard, and the extract was blown dry and reconstituted into lOOuL 60/40 water/acetonitrile.
  • the 14,15-DHET levels are determined by LC/MRM.
  • mice Male Sprague Dawley (SD) rats (7 - 8 weeks old from Harlan) are surgically implanted under isoflurane anesthesia with an osmotic mini-pump (Alzet 2ML2) which administer 1.0 mg/kg/day Angiotensin II subcutaneously for 14 days.
  • the rats are accessible to food and water ad libitum.
  • the rats are randomized on day 13 (6 rats/group) by systolic blood pressure.
  • the rats are orally dosed with 3 or 10 mg/kg of test compound formulated in 0.5% methylcellulose on day 14 and blood pressure is measured at 4 hr post dosing through non-invasive tail-cuff system under light anesthesia.

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Abstract

Claimed are intermediates in the synthesis of N-Arylmethyl-3-Oxo-2,3-dihydro- [1,2,4]triazolo[4,3-a]pyridine-6-carboxamides as well as a process (A) to arrive at 3-Oxo-2, 3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid. The triazolo[4,3-a]pyridine-6-carboxamides of formula (I) are used as soluble epoxide hydrolase inhibitors (sEH) having therapeutic effect in pathologic conditions such as hypertension, stroke, inflammatory processes, diabetes and a variety of cardiovascular diseases.

Description

3-0X0-2, 3-DIHYDRO- [1 ,2, 4] TRIAZOLO [4, 3-A]PYRIDINES AS
SOLUBLE EPOXIDE HYDROLASE
(SEH) INHIBITORS
FIELD OF THE INVENTION
[0001] The present invention relates to medicinal chemistry and pharmaceutical science. Provided herein are compounds that inhibit soluble epoxide hydrolase (sEH).
BACKGROUND OF THE INVENTION
[0002] Soluble epoxide hydrolase (sEH) acts upon lipid epoxides, including those of arachidonic acid known as epoxyeicosatrienoic acids (EETs). These lipid epoxides are known effectors of blood pressure and modulators of vascular permeability. The vasodilatory properties of lipid epoxides are associated with an increased open-state probability of calcium-activated potassium channels leading to hyperpolarization of the vascular smooth muscle. Hydrolysis of lipid epoxides by sEH diminishes this activity. [0003] sEH is a modulator of a large number of pathological conditions including hypertension, diabetes, metabolic syndrome, atherosclerosis, coronary artery disease, angina, ischemia, ischemic stroke, Raynaud's disease, inflammatory processes, genitourinary disorders, conditions of the eye, and renal disease. Hence, inhibitors of sEH would have a therapeutic effect in such disorders.
[0004] Certain inhibitors of sEH are disclosed in WO 2008/116145, WO 2007/098352, WO 2007/043653, WO 2007/106525, WO 2006/121719, US5955496, and US 6,150,415. Certain inhibitors of stearoyl CoA-desaturase are disclosed in WO 2009/137201.
SUMMARY OF THE INVENTION
[0005] The present invention provides compounds of formula I:
Figure imgf000002_0001
wherein
Ri is selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, optionally substituted C4-14 aryl, optionally substituted C3-8 cycloalkyl, optionally substituted
Ci-10 heteroaryl, and optionally substituted C3-6 heterocycloalkyl;
Ar is selected from the group consisting Of C5-14 aryl and C1-10 heteroaryl;
R2 is selected from the group consisting of optionally substituted Ci_6 alkyl, Ci_s sulfonyl, optionally substituted C2-4 alkenyl, optionally substituted C1-4 alkoxy, optionally substituted
C2-6 alkynyl, amino, C1-8 alkylamino, C1-9 amide, optionally substituted C4-14 aryl, optionally substituted C4-14 aryloxy, C1-5 oxycarbonyl, cyano, optionally substituted C3-8 cycloalkyl, C3-8 cycloalkoxy, halo, optionally substituted C3-6 heterocycloalkyl, optionally substituted C1-10 heteroaryl, optionally substituted C1-10 hetero aryloxy, hydroxy, and nitro; n is 0, 1, 2, or 3; m is 0, 1 , 2, 3 or 4;
Wi is selected from the group consisting of N and CR3;
W2 is selected from the group consisting of N and CR3;
W3 is selected from the group consisting of N and CR3; provided that no more than one of Wi, W2, and W3 is N; each R3 is independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-4 alkenyl, cyano, C3_8 cycloalkyl, halo, and hydroxy; and the pharmaceutically acceptable salts thereof.
[0006] The present invention also provides pharmaceutical compositions, comprising: a compound of formula I and a pharmaceutically acceptable excipient.
[0007] The compounds of the invention are inhibitors of sEH they are useful for the treatment of conditions associated with sEH, including hypertension. Thus, the invention provides methods of treating conditions associated with sEH, comprising: administering to a patient in need thereof an effective amount of a compound of formula I. Further, the present invention provides for the use of compounds of formula I for the manufacture of a medicament, including specifically for the treatment of particular conditions associated with sEH.
-?- [0008] The present invention also provides an article of manufacture: comprising at least one compound of formula I and a label. Also provided are kits comprising at least one compound of the invention, a label, and apparatus for administration of the inhibitor. [0009] The present invention also provides processes from making sEH inhibitors and intermediates thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0010] The term "C2-4 alkenyl" refers to a straight or branched alkenyl chain having from two to four carbon atoms and one or more carbon-carbon double bonds, and includes ethylene, propylene, iso-propylene, butylene, iso-butylene, sec-butylene, and the like. [0011] The term "optionally substituted C2-4 alkenyl" refers to a C2-4 alkenyl optionally having from 1 to 3 substituents independently selected from the group consisting of C1-4 alkoxy, C1-9 amide, C1-5 oxycarbonyl, cyano, C3-8 cycloalkyl, halo, hydroxy, optionally substituted C1-10 heteroaryl, and optionally substituted phenyl.
[0012] The term "Ci_4 alkyl" refers to a straight or branched alkyl chain having from one to four carbon atoms.
[0013] The term "optionally substituted Ci_4 alkyl" refers to a Ci_4 alkyl optionally having from 1 to 5 substituents independently selected from the group consisting of amino, C2-4 alkenyl, C1-4 alkoxy, C1-9 amide, C1-8 alkylamino, C1-5 oxycarbonyl, cyano, C3-8 cycloalkyl, C3_8 cycloalkoxy, halo, hydroxy, nitro, oxo, optionally substituted C3_6 hetero cycloalkyl, optionally substituted C1-10 heteroaryl, and optionally substituted phenyl. [0014] The term "C1-6 alkyl" refers to a straight or branched alkyl chain having from one to six carbon atoms.
[0015] The term "optionally substituted C1-6 alkyl" refers to a C1-6 alkyl optionally having from 1 to 7 substituents independently selected from the group consisting of amino, C1-8 alkylamino, C2-4 alkenyl, C1-4 alkoxy, C1-9 amide, C1-5 oxycarbonyl, cyano, C3-8 cycloalkyl, halo, hydroxy, optionally substituted C1-10 heteroaryl, optionally substituted C3-6 heterocycloalkyl, optionally substituted C1-10 heteroaryl, and optionally substituted phenyl. [0016] The term "C1-8 sulfonyl" refers to a sulfonyl linked to a C1-6 alkyl group, C3-8 cycloalkyl, or an optionally substituted phenyl. [0017] The term "C1-4 alkoxy" refers to a C1-4 alkyl attached through an oxygen atom.
[0018] The term "optionally substituted Ci_4 alkoxy" refers to a Ci_4 alkoxy optionally having from 1 to 6 substituents independently selected from the group consisting of C2-4 alkenyl, C1-4 alkoxy, C1-9 amide, C1-5 oxycarbonyl, cyano, C3-8 cycloalkyl, halo, hydroxy, optionally substituted C1-10 heteroaryl, and optionally substituted phenyl. It is understood that where the optional substituent is Ci_4 alkoxy, cyano, halo, or hydroxy then the substituent is not alpha to the alkoxy attachment point.
[0019] The term "C2-6 alkynyl" refers to a straight or branched alkynyl chain having from two to six carbon atoms and one or more carbon-carbon triple bonds.
[0020] The term "optionally substituted C2-6 alkynyl" refers to a C2-6 alkynyl optionally having from 1 to 3 substituents independently selected from the group consisting of C1-4 alkoxy, C1-9 amide, C1-5 oxycarbonyl, cyano, C3-8 cycloalkyl, halo, hydroxy, optionally substituted C1-10 heteroaryl, and optionally substituted phenyl.
[0021] The term "Ci_9 amide" refers to a primary amide or one having one or two Ci_4 alkyls, for example, -CONH2, -CONHCH3, and -CON(CH3)2.
[0022] The term "Ci_8 alkylamino" refers to an amino having one or two Ci_4 alkyl.
[0023] The term "C4-14 aryl" refers to a monocyclic and polycyclic unsaturated, conjugated hydrocarbon having aromatic character and having four to fourteen carbon atoms, and includes phenyl, biphenyl, indenyl, cyclopentyldienyl, fluorenyl, and naphthyl.
[0024] The term "optionally substituted C4-14 aryl" refers to a C4-14 aryl optionally having 1 to
5 substituents independently selected from the group consisting of amino, C1-9 amide, C1-8 alkylamino, optionally substituted C1-4 alkyl, optionally substituted C1-4 alkoxy, cyano, halogen, hydroxyl, nitro, and C1-8 sulfonyl.
[0025] The term "C4-14 aryloxy" refers to a C4-14 aryl attached through an oxygen atom.
[0026] The term "optionally substituted C4-14 aryloxy" refers to a C4-14 aryloxy optionally having 1 to 5 substituents independently selected from the group consisting of amino, C1-8 alkylamino, C1-4 alkyl, C1-4 alkoxy, cyano, halogen, hydroxyl, nitro, C1-8 sulfonyl, and trifluoromethyl. [0027] The term "optionally substituted benzyl" refers to a benzyl group optionally having 1 to 3 groups independently selected from the group consisting of halo, C1-4 alkyl, C1-4 alkoxy, cyano, and nitro.
[0028] The term "C1-5 oxycarbonyl" refers to a oxycarbonyl group (-CO2H) and C1-4 alkyl ester thereof.
[0029] The term "C3_s cycloalkyl" refers to an alkyl ring having from three to eight carbon atoms, and includes cyclopropyl, 2-methyl cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
[0030] The term "optionally substituted C3-8 cycloalkyl" refers to a C3-8 cycloalkyl optionally having from 1 to 6 substituents independently selected from the group consisting of optionally substituted C1-4 alkyl, C2-4 alkenyl, C1-4 alkoxy, C1-9 amide, C1-8 alkylamino, C1-5 oxycarbonyl, cyano, C3-8 cycloalkyl, C3-8 cycloalkoxy, halo, hydroxy, nitro, oxo, optionally substituted C1-10 heteroaryl, and optionally substituted phenyl.
[0031] The term "C3_8 cycloalkoxy" refers to a C3_8 cycloalkyl attached through an oxygen atom.
[0032] The terms "halogen" and "halo" refers to a chloro, fluoro, bromo or iodo atom. [0033] The term "C3_6 heterocycloalkyl" refers to a 4 to 10 membered monocyclic saturated ring having one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. For example, but not limiting, the term includes azetidine, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, tetrahydrofuran, and the like. [0034] The term "optionally substituted C3-6 heterocycloalkyl" refers to a heteroC3_6 cycloalkyl optionally substituted on the ring carbons with 1 to 4 substituents independently selected from the group consisting of optionally substituted C1-4 alkyl, C2-4 alkenyl, C1-4 alkoxy, C1-9 amide, C1-8 alkylamino, C1-5 oxycarbonyl, cyano, C3-8 cycloalkyl, C3-8 cycloalkoxy, halo, hydroxy, nitro, oxo, and optionally substituted phenyl; and optionally substituted on any ring nitrogen with a substituent selected from the group consisting of optionally substituted C1-4 alkyl, C2-4 alkenyl, C3-8 cycloalkyl, optionally substituted C1-10 heteroaryl, and optionally substituted phenyl.
[0035] The term "C1-10 heteroaryl" refers to a five to twelve membered monocyclic and polycyclic having unsaturated, conjugated ring(s) having aromatic character and having one to ten carbon atoms and one or more, typically one to four, heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. For example, but not limiting, the term includes azepine, diazepine, furan, thiophene, imidazole, isothiazole, isoxazole, oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, thiazole, thiadiazole, triazole, tetrazole, benzazepine, benzodiazepine, benzofuran, benzo thiophene, benzimidazole, imidazopyridine, pyrazolopyridine, quinazoline, thienopyridine, indolizine, imidazopyridine, quinoline, isoquinoline, indole, isoindole, benzoxazole, benzopyrazole, benzothiazole, and the like.
[0036] The term "optionally substituted C1-10 heteroaryl" refers to a C1-10 heteroaryl optionally having 1 to 5 substituents on carbon independently selected from the group consisting of amino, C1^ amide, C1-8 alkylamino, optionally substituted C1-4 alkyl, optionally substituted C1-4 alkoxy, cyano, halogen, hydroxyl, nitro, and C1-8 sulfonyl and optionally having substituents on each nitrogen independently selected from the group consisting of optionally substituted Q_4 alkyl, Ci_s sulfonyl, and optionally substituted phenyl. [0037] The term "oxo" refers to an oxygen atom having a double bond to the carbon to which it is attached to form the carbonyl of a ketone or aldehyde. It is understood that as the term is used herein oxo refers to doubly bonded oxygen attached to the group which has the oxo substituent, as opposed to the oxo group being pendant as a formyl group. For example, an acetyl radical is contemplated as an oxo substituted alkyl group and a pryidone radical is contemplated as oxo substituted C1-10 heteroaryl.
[0038] The term "C1-10 heteroaryloxy" refers to a C1-10 heteroaryl attached through an oxygen. [0039] The term "optionally substituted C1-10 heteroaryloxy" refers to a C1-10 heteroaryl optionally having 1 to 5 substituents on carbon independently selected from the group consisting Of C1-4 alkyl, C1-4 alkoxy, cyano, halogen, hydroxyl, nitro, oxo, C1-8 sulfonyl, and trifiuoromethyl and optionally having substituents on each nitrogen independently selected from the group consisting of optionally substituted C1-4 alkyl, C1-S sulfonyl, and optionally substituted phenyl.
[0040] The term "optionally substituted phenyl" refers to a phenyl group optionally having 1 to 5 substituents independently selected from the group consisting of amino, C2-4 alkenyl, C1-4 alkyl, C1-4 alkoxy, C1^ amide, C1-8 alkylamino, C1-5 oxycarbonyl, cyano, halogen, hydrogen, hydroxyl, nitro, C1-8 sulfonyl, and trifluoromethyl.
[0041] The term "pharmaceutically acceptable salt" refers to salts of pharmaceutically acceptable organic acids and bases or inorganic acids and bases. Such salts are well known in the art and includes those described in Journal of Pharmaceutical Science, 66, 2-19 (1977). Examples are the hydrochloride and mesylate salts.
[0042] The term "salt" refers to organic acids and bases or inorganic acids and bases and included pharmaceutically accpeptable salts and extends to acids and bases that are not generally used in pharmaceuticals, for example the oxalic acid salts. [0043] The skilled artisan will appreciate that certain of the compounds of the present invention exist as isomers. All mixtures of stereoisomers, in any ratio, and specific geometric isomers, enantiomers, and diastereomers of the compounds of the invention are contemplated to be within the scope of the present invention.
[0044] The skilled artisan will appreciate that certain of the compounds of the present invention exist as tautomers. All tautomeric forms the compounds of the invention are contemplated to be within the scope of the present invention.
[0045] The term "compounds of the invention" include the embodiment of formula I and the other embodiments and examples described herein.
[0046] It is understood that the phrase "provided that no more than one of Wi, W2, and W3 is N" does not imply that any of Wi, W2, and W3 must be N, but allows for compounds in which each of Wi, W2, and W3 is CR3.
[0047] In one embodiment the compounds of the invention include a compound of formula I wherein Ar is C4-14 aryl.
[0048] Another embodiment relates to any of the embodiments above wherein Ar is phenyl. [0049] Another embodiment relates to any of the embodiments above or below wherein each of Wi, W2, and W3 is CR3 and each R3 is hydrogen.
[0050] Another embodiment relates to any of the embodiments above or below wherein n is 1.
[0051] Another embodiment relates to any of the embodiments above or below wherein m is 1 or 2 and at least one of R2 is selected from the group consisting of hydrogen, cyano, optionally substituted C1-6 alkyl, optionally substituted C1-4 alkoxy, optionally substituted C3-6 heterocycloalkyl and optionally substituted C4-14 aryl.
[0052] Another embodiment relates to any of the embodiments above or below wherein Ri is selected from the group consisting of hydrogen and optionally substituted C1-6 alkyl.
[0053] Another embodiment relates to any of the embodiments above or below wherein Ri is hydrogen.
[0054] Another embodiment relates to any of the embodiments above or below wherein Ri is optionally substituted C1-4 alkyl having from 1 to 4 substituents independently selected from the group consisting of cyano, halo, hydroxy, optionally substituted C3-6 heterocycloalkyl, optionally substituted C1-10 heteroaryl, and optionally substituted phenyl.
[0055] Another embodiment relates to any of the embodiments above or below wherein Ri optionally substituted C1-4 alkyl having an optionally substituted C1-10 heteroaryl and the C1-10 heteroaryl is selected from the group consisting of furan, thiophene, imidazole, pyrazine, pyridazine, pyridine, pyrimidine, thiazole, and quinoline.
[0056] Another embodiment relates to any of the embodiments above or below wherein Ri is optionally substituted Ci_4 alkyl having a cyano.
[0057] Another embodiment relates to any of the embodiments above or below wherein Ri is optionally substituted Ci_4 alkyl having a hydroxy.
[0058] Another embodiment relates to any of the embodiments above or below wherein Ri is optionally substituted Ci_4 alkyl having from 1 to 4 halo.
[0059] Another embodiment relates to any of the embodiments above or below wherein m is
1 or 2 and at least one of R2 is optionally substituted C1-4 alkoxy.
[0060] Another embodiment relates to any of the embodiments above or below wherein m is
1 or 2 and at least one of R2 is C1-4 alkoxy.
[0061] Another embodiment relates to any of the embodiments above or below wherein m is
1 or 2 and at least one of R2 is cyano.
[0062] Another embodiment relates to any of the embodiments above wherein m is 1 or 2 and at least one of R2 is halo.
[0063] The compounds of the invention can be prepared by a variety of procedures, some of which are described below. All substituents, unless otherwise indicated, are as previously defined. The products of each step can be recovered by conventional methods including extraction, evaporation, precipitation, chromatography, filtration, trituration, crystallization, and the like. The procedures may require protection of certain groups, for example hydroxy, amino, or carboxy groups to avoid unwanted reactions. The selection, use, and removal of protecting groups is well known and appreciated as standard practice, for examples see T. W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991.
Scheme A
Figure imgf000010_0001
[0064] Scheme A, step 1, depicts the reaction of an appropriate compound of formula (a) with an appropriate compound of formula H2N-(CH2)n-Ar-(Pv2)m to give a compound of formula (b). An appropriate compound of formula (a) is one in which W1, W2, and W3 are as desired in the final compound of formula I or give rise to W1, W2, and W3 are as desired in the final compound of formula I and X1 is a hydroxyl or a leaving group, such as chloro, bromo, or imidazolyl, an activating moiety, a mixed anhydride of another carboxylic acid, such as formic acid, acetic acid, or a substituted or unsubstituted benzoic acid, or X1 represents the other part of a symmetrical anhydride formed from two compounds of formula (a) in which Xi is hydroxyl. The preparation of compounds of formula (a) is readily appreciated in the art. Appropriate compounds of formula H2N-(CH2)n-Ar-(R.2)m are readily available and are ones having n, Ar, and m are as desired in the final compound of formula I, and each R2 is as desired in the final compound of formula I or gives rise to an R2 as desired. [0065] Such amide forming reactions are well understood and appreciated in the art. For example, standard amide forming conditions can be used, such as those using coupling agents, including those used in peptide couplings, such as 2-(lH-7-azabenzotriazol-l-yl)- 1,1,3,3- tetramethyl uronium hexafluorophosphate methanaminium (HATU), dicyclohexylcarbodiimide (DCC), and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. If necessary or desired, an additive such as 4-(dimethylamino)pyridine, 1- hydroxybenzotriazole, and the like may be used to facilitate the reaction. Such reactions are generally carried out using a base, such as N-methylmorpholine or triethylamine, in a wide variety of suitable solvents such as dichloromethane, dimethylformamide (DMF), N- methylpyrrolidone (NMP), dimethylacetamide (DMAc), tetrahydrofuran (THF), and the like. [0066] Scheme A, step 2, depicts the reaction of an appropriate compound of formula (b) with hdryazine to give a compound of formula (c). Such reactions are well understood and appreciated in the art.
[0067] For example, a compound of formula (b) is reacted with hydrazine in a solvent using a suitable base. The reaction can be carried out using an excess of hydrazine. The reaction is carried out in a suitable solvent, such as a lower alcohol, water, and mixtures thereof. The reaction is carried out at temperatures of about 600C to 1500C. The reaction mixture may be sealed as a matter of convenience.
[0068] Alternately, a compound of formula (b) can be reacted with a compound of formula (g) below:
Figure imgf000011_0001
wherein Ri is as described above and R is selected from the group consisting of C1-4 alkyl, 2,2,2-trichloroethyl, and optionally substituted benzyl followed by cyclization to directly give a compound of formula I. For example, a compound of formula (b) is reacted with a compound of formula (g) in solvent. Typical solvents include water and lower alcohols and mixtures thereof. Optionally the reaction is carried out using a suitable base. It will be appreciated the reaction can be carried out without a base, but if a base is not used in the first step, a base will be introduced to facilitate the cyclization to give a compound of formula (e). The cyclization reaction is carried out in a suitable solvent, such as a water and mixtures of water and lower alcohol and mixtures of water and acetic acid. The reaction is carried out at temperatures of about 600C to 1500C.
[0069] Scheme A, step 3, depicts a ring forming reaction of an appropriate compound of formula (c) with suitable carbonyl reagent to give a compound of formula I in which Ri is hydrogen. Suitable carbonyl reagents include carbonyl dichloride, carbonyl dibromide, carbonyl diimidazole, and the like.
[0070] For example, a compound of formula (c) is reacted with, generally, 1 equivalent of a suitable carbonyl reagent in a suitable solvent such as DMSO and may be carried out using a suitable base, such as triethylamine, diisopropylethylamine, and the like. The reaction typically is carried out at temperatures of from -200C to ambient temperature and require about 1 hour to 2 days.
[0071] Scheme A, step 4, depicts the reaction of a compound of formula I in which Ri is hydrogen with a suitable RiX2 to give a compound of formula I. Suitable compounds of formula RiX2 are ones in which Ri is as desired in the final compound of formula I or gives rise to Ri as desired. X2 is a suitable leaving group, the nature of which may vary with the Ri group to be introduced but generally will be a halogen or sulfonate ester. For example, where Ri optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C3-6 hetero cycloalkyl a suitable X2 may be a halide, such as chloro, bromo, or iodo or a sulfonate ester, such as tosylate, besylate, nosylate, trifluoromethanesulfonate, and the like. Where Ri is optionally substituted C4-14 aryl or optionally substituted C1-10 heteroaryl a suitable X2 may be a halide, such as fluoro, chloro, or bromo.
[0072] For example, a compound of formula I in which Ri is hydrogen is reacted with a molar excess of a compound of formula RiX2 in a suitable solvent such as DMSO, DMF, THF and the like and may be carried out using a suitable base, such as cesium carbonate, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, and the like. The reaction is generally carried out using from 0.9 to 2 equivalents of a compound of formula RiX2. The reaction typically is carried out at temperatures of from 00C to 8O0C and require about 1 hour to 3 days.
[0073] It is also understood that some compounds of formula I may be elaborated to other compounds of formula I, in an additional step not shown. Such reactions include hydrolysis, oxidation, reduction, alkylation, amidations, sulfonations, alkynations, alkyenations, arylations, and various other displacement reactions, and the like and such reactions may require protection and deprotection
[0074] It is also understood that the product of the present process may be used as a pharmaceutically acceptable salts which would be formed in an optional step, not shown The formation of such salts is well known and readily practiced by the skilled person [0075] The order in which the steps of Scheme A are carried out are not critical For example, a compound of formula (d), below
Figure imgf000013_0001
in which W1, W2, and W3 are as desired in the final compound of formula I or give rise to W1, W2, and W3 are as desired in the final compound of formula I can be reacted with a compound of formula (g) followed by cychzation as described in Scheme A, step 2, to give a compound of formula (e) That is, a compound of formula (e) can be prepared by a process characterized by the reaction of a compound of formula (g) with a compound of formula (d) Such a reaction is followed by cychzation to give a compound of formula (e) A compound of formula (e) can undergo an optional reaction as described in Scheme A, step 4 using a suitable RiX2, followed by deprotection, if required, to give a compound of formula (e) in which Ri is not hydrogen
Figure imgf000013_0002
[0076] A compound of formula (e) in which Ri is as desired in the final compound of formula I can, either as the carboxylic acid or after activation to -C(O)Xi, undergo an amide forming reaction as described in Scheme A, step 1, with an appropriate compound of formula (f), H2N- (CH2)n-Ar-(R2)m, to give a compound of formula I Alternately, a compound of formula (e) in which Ri is hydrogen can, either as the carboxylic acid or after activation to -C(O)Xi, undergo an amide forming reaction as described in Scheme A, step 1, with an appropriate compound of formula H2N-(CH2)I1-Ar-(R2)In to give a compound of formula I in which Ri is hydrogen. As can be readily understood such a compound can undergo Scheme A, step 4 to give a compound of formula I in which Ri is other than hydrogen.
[0077] As is readily appreciated, compounds of formula (f) can be prepared by a variety of methods as described herein or by methods analogous to those described herein and in the art. Specifically, a compound of formula (f) in which n is 1 can be prepared by reduction of a nitrile or an amide or by halogenations of a methyl (in a toluene derivative) followed by displacement by ammonia or a protected amine, for example NH2NBoC or phthalimide. Many R2 groups are commercially available or can be installed by various methodologies, for example, hydrolysis, oxidation, reduction, alkylation, amidations, sulfonations, alkynations, alkyenations, arylations such as Suzuki coupling, and the like. Compounds of formula (f) that are included in the present invention are 4-(aminomethyl)-3-(trifluoromethoxy)benzonitrile, (4-nitro-2-(trifluoromethoxy)phenyl)methanamine, (4-iodo-2-
(trifluoromethoxy)phenyl)methanamine, (4-fluoro-2-(trifluoromethoxy)phenyl)methanamine, (4-chloro-2-(trifluoromethoxy)phenyl)methanamine, (4-(methylsulfonyl)-2- (trifluoromethoxy)phenyl)methanamine, (4-(cyclopropylsulfonyl)-2- (trifluoromethoxy)phenyl)methanamine, 5-(4-(aminomethyl)-3- (trifluoromethoxy)phenyl)pyridin-2-amine, 5-(4-(aminomethyl)-3- (trifluoromethoxy)phenyl)pyrimidin-2-amine, l-(4-(aminomethyl)-3- (trifluoromethoxy)phenyl)-4-hydroxypyrrolidin-2-one, l-(4-(aminomethyl)-3- (trifluoromethoxy)phenyl)imidazolidin-2-one, 3-(4-(aminomethyl)-3-
(trifluoromethoxy)phenyl)oxazolidin-2-one, 4-(aminomethyl)-3-(trifluoromethoxy)aniline, (4- iodo-2-(trifluoromethyl)phenyl)methanamine, (4-(methylsulfonyl)-2- (trifluoromethyl)phenyl)methanamine, (4-(cyclopropylsulfonyl)-2- (trifluoromethyl)phenyl)methanamine, 5-(4-(aminomethyl)-3- (trifluoromethyl)phenyl)pyridin-2-amine, 5-(4-(aminomethyl)-3-
(trifluoromethyl)phenyl)pyrimidin-2-amine, l-(4-(aminomethyl)-3-(trifluoromethyl)phenyl)- 4-hydroxypyrrolidin-2-one, and 1 -(4-(aminomethyl)-3-(trifluoromethyl)phenyl)imidazolidin- 2-one, 3-(4-(aminomethyl)-3-(trifluoromethyl)phenyl)oxazolidin-2-one. [0078] The examples and preparations are illustrative only and are not intended to limit the invention in any way. For example, the above reaction schemes, and variations thereof, can be used to prepare the following:
Figure imgf000015_0001
Figure imgf000016_0001
[0079] The present invention is further illustrated by the following examples and preparations. The terms and abbreviations used in the examples have their usual meaning unless otherwise indicated. Where indicated products of the preparations and examples were purified by Mass-triggered HPLC (Pump: Water 2525; MS: ZQ; Software: MassLynx). Generally, reverse phase chromatography was carried out on column (Gemini 5μ Cl 8 11OA,
AXIA, 30x75 mm, 5 micron) and eluted with gradients of ACN (containing 0.035% TFA) and water (containing 0.05% TFA). After isolation by reverse phase chromatography the product was obtained by drying in a Gene Vac®.
[0080] Example 1: 3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3-dihydro-[l,2,4]triazolo[4,3- a]pyridine-6-carboxamide
Figure imgf000017_0001
[0081] A mixture of 6-chloronicotinoyl chloride (1.0 g, 5.7 mmol) and (2- (trifluoromethoxy)phenyl)methanamine (1.1 g, 5.7 mmol) and 1 mL of triethylamine (Et3N) in dichloromethane (DCM) was stirred at room temperature overnight. The reaction mixture was washed with water, and then dried over MgSO4. Removing solvent via vacuum using a rotary evaporator gave the crude product, 6-chloro-N-(2-
(trifluoromethoxy)benzyl)nicotinamide, which was used without further purification. [M+H] calc'd for CI4HI0CIF3N2O2, 331; found, 331.
[0082] To a suspension of 6-chloro-N-(2-(trifluoromethoxy)benzyl)nicotinamide in EtOH (10 mL) was added anhydrous hydrazine (2 mL). The mixture was heated at 12O0C in a sealed tube overnight. The solvent and excess hydrazine were removed via vacuum using a rotary evaporator to give 6-hydrazinyl-N-(2-(trifluoromethoxy)benzyl)nicotinamide which was obtained and used for next step without further purification. [M+H] calc'd for C21H22N4O, 327; found, 327.
[0083] To a solution of 6-hydrazinyl-N-(2-(trifluoromethoxy)benzyl)nicotinamide (50 mg, 0.15 mmol) in dry DMSO (2 mL) was added carbonyl diimidazole (CDI) (37 mg, 0.23 mmol). The mixture was stirred at room temperature for 2 hours and purified by HPLC (Gradient: 30- 40% ACN containing 0.035% TFA in water containing 0.05% TFA). 1H NMR (400 MHz, MeOD-d4) δ: 9.08 (s, IH), 8.42 (t, J = 4.0, 4.0 Hz, IH), 7.67 (dd, J = 4.0, 12.0 Hz, IH), 7.48 ( dd, J = 4.0, 8.0 Hz, IH), 7.29-7.42 (m, 3H), 7.25 (dd, J = 2.0, 12.0 Hz, IH), 4.64 (d, J = 4.0 Hz, 2H). [M+H] calc'd for Ci5HnF3N4O3, 353; Found, 353. [0084] Example 2: 2-(cyanomethyl)-3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000018_0001
[0085] To a solution of 3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide (112 mg, 0.32 mmol) in 3 mL of dry DMSO was added CS2CO3, followed by 2-bromoacetonitrile (0.352 mmol). The mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered and purified by HPLC (Gradient: 30-60% ACN containing 0.035% TFA in water containing 0.05% TFA). 1H NMR (400 MHz, MeOD-d4) δ: 9.08 (s, IH), 8.42 (t, J = 4.0, 4.0 Hz, IH), 7.67 (dd, J = 4.0, 12.0 Hz, IH), 7.48 ( dd, J = 4.0, 8.0 Hz, IH), 7.29-7.42 (m, 3H), 7.25 (dd, J = 2.0, 12.0 Hz, IH), 5.10 (s, 2H), 4.64 (d, J = 4.0 Hz, 2H). [M+H] calc'd for Ci7Hi2F3N5O3, 392; Found, 392. [0086] Example 3: 2-(3-oxo-6-(2-(trifluoromethoxy)benzylcarbamoyl)-[l,2,4]triazolo[4,3- a]pyridin-2(3H)-yl)acetic acid
Figure imgf000018_0002
[0087] A mixture of 2-(cyanomethyl)-3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide (50 mg, 0.128 mmol) and 4 mL of AcOH/concentrated HCL (1 :1) was heated to 8O0C for 1 hour. The reaction mixture was evaporated in vacuum and purified by HPLC (Gradient: 20-60% ACN containing 0.035% TFA in water containing 0.05% TFA). 1H NMR (400 MHz, MeOD-d4) δ: 8.42 (s, IH), 7.63 (dd, J = 2.0, 12.0 Hz, IH), 7.48 ( dd, J = 4.0, 8.0 Hz, IH), 7.29-7.41 (m, 3H), 7.21 (dd, J = 2.0, 12.0 Hz, IH), 4.77 (s, 2H), 4.64 (s, 2H). [M+H] calc'd for Ci7Hi3F3N4O5, 411; Found, 411. [0088] Example 4: 2-(2-amino-2-oxoethyl)-3-oxo-N-(2-(trifiuoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000019_0001
[0089] The title compound was synthesized from 3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 2-bromoacetamide. Purified by Mass-triggered HPLC (Gradient: 20-60% ACN containing 0.035% TFA in water containing 0.05% TFA). 1H NMR (400 MHz, MeOD-d4) δ: 8.44 (s, IH), 7.64 (dd, J = 2.0, 12.0 Hz, IH), 7.48 ( dd, J = 4.0, 8.0 Hz, IH), 7.29-7.41 (m, 3H), 7.22 (d, J = 8.0 Hz, IH), 4.67 (s, 2H), 4.64 (d, J = 4.0 Hz, 2H). [M+H] calc'd for C17H14F3N5O4, 410; Found, 410.
[0090] Example 5: 3-oxo-2-(pyrimidin-2-yl)-N-(2-(trifluoromethoxy)benzyl)-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000019_0002
[0091] The title compound was synthesized from 3-oxo-N-(2-(trifluoromethoxy)benzyl)- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 2-chloropyrimidine as an alkylating reagent, temperature at 8O0C overnight. Purified by Mass-triggered HPLC (Gradient: 30-60% ACN containing 0.035% TFA in water containing 0.05% TFA). 1H NMR (400 MHz, MeOD-d4) δ: 8.85 (d, J = 4.0 Hz, 2H), 8.42 (s, IH), 7.62 (dd, J = 4.0, 12.0 Hz, IH), 7.48 ( dd, J = 4.0, 8.0 Hz, IH), 7.29-7.45 (m, 4H), 7.23 (dd, J = 2.0, 12.0 Hz, IH), 4.64 (d, J = 4.0 Hz, 2H). [M+H] calc'd for Ci9Hi3F3N6O3, 431; Found, 431.
[0092] Example 6: 2-(2-methoxyethyl)-3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000020_0001
[0093] The title compound was synthesized from 3-oxo-N-(2-(trifluoromethoxy)benzyl)- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using l-bromo-2-methoxyethane. Purified by Mass-triggered HPLC (Gradient: 35-40% ACN containing 0.035% TFA in water containing 0.05% TFA). 1H NMR (400 MHz, MeOD-d4) δ: 8.42 (s, IH), 7.62 (dd, J = 4.0, 12.0 Hz, IH), 7.48 ( dd, J = 4.0, 8.0 Hz, IH), 7.29-7.42 (m, 3H), 7.23 (dd, J = 2.0, 12.0 Hz, IH), 4.64 (d, J = 4.0 Hz, 2H), 4.16 (t, J = 4.0, 8.0 Hz, 2H), 3.78 (t, J = 4.0, 8.0 Hz, 2H), 3.33 (s, 3H). [M+H] calc'd for Ci8Hi7F3N4O4, 411; Found, 411.
[0094] Example 7: N-(2,3-dimethoxybenzyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3- a]pyridine-6-carboxamide
Figure imgf000020_0002
[0095] The title compound was synthesized according to the method described in connection with Example 1 by using (2,3-dimethoxyphenyl)methanamine as amine. Purified by Mass-triggered HPLC (Gradient: 20-40% ACN containing 0.035% TFA in water containing 0.05% TFA). 1H NMR (400 MHz, DMSO-d6) δ: 12.6 (s, IH), 9.03 (t, J = 4.0, 8.0 Hz, IH), 8.53 (s, IH), 7.58 (dd, J = 4.0, 12.0 Hz, IH), 7.26 ( dd, J = 2.0, 8.0 Hz, IH), 6.94- 7.06 (m, 2H), 6.86 (dd, J = 4.0, 8.0 Hz, IH), 4.45 (d, J = 4.0 Hz, 2H), 3.81 (s, 3H), 3.76 (s, 3H). [M+H] calc'd for Ci6Hi6N4O4, 329; Found, 329.
Example 8: 2-methyl-3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3-dihydro-[l ,2,4]triazolo[4,3- a]pyridine-6-carboxamide
Figure imgf000020_0003
[0096] The title compound was synthesized from 3-oxo-N-(2-(trifluoromethoxy)benzyl)- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using iodomethane. Purified by Mass-triggered HPLC (Gradient: 20-90% ACN containing 0.035% TFA in water containing 0.05% TFA). 1H NMR (400 MHz, DMSO-d6) δ: 8.41 (s, IH), 7.61 (dd, J = 4.0, 12.0 Hz, IH), 7.48 ( dd, J = 2.0, 8.0 Hz, IH), 7.30-7.42 (m, 3H), 7.22 (dd, J = 4.0, 12.0 Hz, IH), 4.64 (d, J = 4.0 Hz, 2H), 3.64 (s, 3H). [M+H] calc'd for Ci6Hi3F3N4O3, 366; Found, 366.
[0097] Example 9: 2-(2-fluoroethyl)-3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000021_0001
[0098] The title compound was synthesized 3-oxo-N-(2-(trifiuoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using l-bromo-2-fluoroethane. Purified by Mass-triggered HPLC (Gradient: 30-60% ACN containing 0.035% TFA in water containing 0.05% TFA). 1H NMR (400 MHz, MeOD-d4) δ: 8.09 (t, J = 4.0, 4.0 Hz, IH), 8.43 (s, IH), 7.64 (d, J = 4.0, 12.0 Hz, IH), 7.48 ( dd, J = 4.0, 8.0 Hz, IH), 7.30-7.42 (m, 3H), 7.24 (dd, J = 2.0, 12.0 Hz, IH), 4.84 (t, J = 4.0, 4.0 Hz. IH), 4.72 (t, J = 4.0, 8.0 Hz, IH), 4.64 (d, J = 4.0 Hz, 2H), 4.32 (t, J = 4.0, 8.0 Hz, IH), 4.25 (t, J = 4.0, 8.0 Hz, IH). [M+H] calc'd for Ci7Hi4F4N4O3, 399; Found, 399. [0099] Example 10: 2-(2,2-difluoroethyl)-3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000021_0002
[0100] The title compound was synthesized from 3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 2-bromo-l,l-difluoroethane. Purified by Mass-triggered HPLC (Gradient: 30-70% ACN containing 0.035% TFA in water containing 0.05% TFA). 1H NMR (400 MHz,
DMSO-d6) δ: 8.19 (t, J = 4.0, 4.0 Hz, IH), 8.60 (s, IH), 7.65 (d, J = 4.0, 12.0 Hz, IH), 7.48 ( dd, J = 4.0, 8.0 Hz, IH), 7.35-7.46 (m, 3H), 7.33 (dd, J = 2.0, 8.0 Hz, IH), 6.23-6.53 (m, IH),
4.53 (d, J = 8.0 Hz, 2H), 4.34-4.44 (m, 2H). [M+H] calc'd for Ci7Hi3F5N4O3, 417; Found,
417.
[0101] Example 11 : 3-oxo-2-(pyridin-2-ylmethyl)-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000022_0001
[0102] The title compound was synthesized from 3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 2-(bromomethyl)pyridine. Purified by Mass-triggered HPLC (Gradient: 20-30% ACN containing 0.035% TFA in water containing 0.05% TFA) to give the TFA salt. 1H NMR (400 MHz, MeOD-d4) δ: 8.68 (d, J = 4.0 Hz, IH), 8.46 (s, IH), 8.23-8.29 (m, IH), 7.71-7.79 (m, 2H), 7.66 (dd, J = 4.0, 12.0 Hz, IH), 7.48 (dd, J = 4.0, 8.0 Hz, IH), 7.29-7.42 (m, 3H), 7.22 (dd, J = 2.0, 8.0 Hz, IH), 5.48 (s, 2H), 4.65 (s, 2H). [M+H] calc'd for C2IHi6F3N5O3, 444; Found, 444.
[0103] Example 12: 2-(2-(diethylamino)ethyl)-3-oxo-N-(2-(trifiuoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000022_0002
[0104] The title compound was synthesized from 3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 2-bromo-N,N-diethylethanamine. Purified by Mass-triggered HPLC (Gradient: 20-40% ACN containing 0.035% TFA in water containing 0.05% TFA) to give the TFA salt. 1H NMR (400 MHz, MeOD-d4) δ: 8.46 (s, IH), 7.68 (dd, J = 4.0, 12.0 Hz, IH), 7.48 (d, J = 8.0 Hz, IH), 7.30-7.43 (m, 3H), 7.27 (dd, J = 4.0, 12.0 Hz, IH), 4.65 (s, 2H), 4.42 (t, J = 4.0, 8.0
Hz, 2H), 3.67 (t, J = 4.0, 8.0 Hz, 2H), 3.33-3.40 (m, 4H), 1.33 (t, J = 4.0, 8.0 Hz, 6H). [M+H] calc'd for C2IH24F3N5O3, 452; Found, 452.
[0105] Example 13: 2-(2-(dimethylamino)ethyl)-3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000023_0001
[0106] The title compound was synthesized from 3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamid by a method similar to Example 2 by using 2-bromo-N,N-dimethylethanamine. Purified by Mass-triggered HPLC (Gradient: 20- 40% ACN containing 0.035% TFA in water containing 0.05% TFA) to give the TFA salt. 1H NMR (400 MHz, MeOD-d4) δ: 8.46 (s, IH), 7.68 (dd, J = 4.0, 12.0 Hz, IH), 7.48 (d, J = 8.0 Hz, IH), 7.30-7.42 (m, 3H), 7.27 (dd, J = 4.0, 12.0 Hz, IH), 4.65 (s, 2H), 4.42 (t, J = 4.0, 8.0 Hz, 2H), 3.65 (t, J = 4.0, 8.0 Hz, 2H). [M+H] calc'd for Ci9H20F3N5O3, 424; Found, 424. [0107] Example 14: 2-(2-morpholinoethyl)-3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000023_0002
[0108] The title compound was synthesized from 3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 4-(2-chloroethyl)morpholine. Purified by Mass-triggered HPLC (Gradient: 20-30% ACN containing 0.035% TFA in water containing 0.05% TFA) to give the TFA salt. 1H NMR (400 MHz, MeOD-d4) δ: 8.45 (s, IH), 7.68 (dd, J = 4.0, 12.0 Hz, IH), 7.48 (d, J = 8.0 Hz, IH), 7.30-7.42 (m, 3H), 7.26 (dd, J = 4.0, 12.0 Hz, IH), 4.65 (s, 2H), 4.46 (t, J = 4.0, 8.0 Hz, 2H), 3.68 (t, J = 4.0, 8.0 Hz, 2H), 3.1-4.2 (broad band, 8H). [M+H] calc'd for C2IH22F3N5O4, 466; Found, 466. [0109] Example 15: 2-(2-(lH-imidazol-l-yl)ethyl)-3-oxo-N-(2-(trifluoromethoxy)benzyl)- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000024_0001
[0110] The title compound was synthesized from 3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using l-(2-bromoethyl)-lH-imidazole. Purified by Mass-triggered HPLC (Gradient: 20-40% ACN containing 0.035% TFA in water containing 0.05% TFA) to give the TFA salt. IH NMR (400 MHz, MeOD-d4) δ: 8.91 (s, IH), 8.36 (s, IH), 7.64 (dd, J = 4.0, 12.0 Hz, IH), 7.60 (t, J = 4.0, 4.0 Hz, IH), 7.53 (t, J = 4.0, 4.0 Hz, IH), 7.46 (dd, J = 4.0, 8.0 Hz, IH), 7.30- 7.42 (m, 3H), 7.22 (dd, J = 2.0, 8.0 Hz, IH), 4.72 (dd, J = 4.0, 8.0 Hz, 2H), 4.64 (s, 2H), 4.48 (dd, J = 4.0, 8.0 Hz, 2H). [M+H] calc'd for C20H17F3N6O3, 447; Found, 447. [0111] Example 16: (R)-3-oxo-2-((5-oxopyrrolidin-2-yl)methyl)-N-(2- (trifluoromethoxy)benzyl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000024_0002
[0112] The title compound was synthesized from 3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using l(R)-5-(bromomethyl)pyrrolidin-2-one. Purified by Mass-triggered HPLC (Gradient: 30-40% ACN containing 0.035% TFA in water containing 0.05% TFA). 1H NMR (400 MHz, MeOD-d4) δ: 8.43 (s, IH), 7.63 (dd, J = 4.0, 12.0 Hz, IH), 7.48 (d, J = 8.0 Hz, IH), 7.29-7.42 (m, 3H), 7.24 (dd, J = 2.0, 8.0 Hz, IH), 4.65 (s, 2H), 4.14-4.21 (m, IH), 4.06 (d, J = 8.0 Hz, 2H), 2.24-2.39 (m, 3H), 1.96-2.08 (m, IH). [M+H] calc'd for C20Hi8F3N5O4, 450; Found, 450.
[0113] Example 17: (S)-3-oxo-2-((5-oxopyrrolidin-2-yl)methyl)-N-(2- (trifluoromethoxy)benzyl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000025_0001
[0114] The title compound was synthesized from 3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using l(S)-5-(bromomethyl)pyrrolidin-2-one. Purified by Mass-triggered HPLC (Gradient: 30-40% ACN containing 0.035% TFA in water containing 0.05% TFA). 1H NMR (400 MHz, MeOD-d4) δ: 8.43 (s, IH), 7.63 (dd, J = 4.0, 8.0 Hz, IH), 7.48 (d, J = 8.0 Hz, IH), 7.29-7.42 (m, 3H), 7.24 (dd, J = 2.0, 12.0 Hz, IH), 4.64 (s, 2H), 4.13-4.22 (m, IH), 4.05 (d, J = 4.0 Hz, 2H), 2.26-2.38 (m, 3H), 1.97-2.07 (m, IH). [M+H] calc'd for C20Hi8F3N5O4, 450; Found, 450.
[0115] Example 18: 2-ethyl-3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
[0116] The title compound was synthesized from 3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using iodoethane. Purified by Mass-triggered HPLC (Gradient: 30-60% ACN containing 0.035% TFA in water containing 0.05% TFA). 1H NMR (400 MHz, DMSO-d6) δ: 8.42 (s, IH), 7.62 (dd, J = 4.0, 12.0 Hz, IH), 7.48 (dd, J = 4.0, 8.0 Hz, IH), 7.30-7.42 (m, 3H), 7.23 (dd, J = 4.0, 12.0 Hz, IH), 4.65 (d, J = 4.0Hz, 2H), 4.03 (q, J = 8.0, 16.0 Hz, 2H), 1.40 (t, J = 8.0, 8.0 Hz, 3H). [M+H] calc'd for Ci7Hi5F3N4O3, 381; Found, 381.
[0117] Example 19: 2-(l-cyanoethyl)-3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000026_0001
[0118] The title compound was synthesized from 3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 2-bromopropanenitrile. Purified by Mass-triggered HPLC (Gradient: 40-45% ACN containing 0.035% TFA in water containing 0.05% TFA). 1H NMR (400 MHz, DMSO-d6) δ: 9.20 (t, J = 4.0, 8.0 Hz, IH), 8.60 (s, IH), 7.68 (dd, J = 4.0, 12.0 Hz, IH), 7.35-7.51 (m, 5H), 5.80 (q, J = 8.0, 16.0 Hz, IH), 4.53 (d, J = 4.0 Hz, 2H), 1.73 (d, J = 4.0 Hz, 3H). [M+H] calc'd for Ci8Hi4F3N5O3, 406; Found, 406.
[0119] Example 20: 2-(2-hydroxyethyl)-3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000026_0002
[0120] The title compound was synthesized from 3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 2-bromoethanol. Purified by Mass-triggered HPLC (Gradient: 20-50% ACN containing 0.035% TFA in water containing 0.05% TFA). 1H NMR (400 MHz, DMSO-d6) δ: 9.18 (t, J = 4.0, 8.0 Hz, IH), 8.58 (s, IH), 7.60 (dd, J = 4.0, 12.0 Hz, IH), 7.35-7.51 (m, 4H), 7.24 (dd, J = 12.0 Hz, IH), 4.55 (d, J = 8.0 Hz, 2H), 3.95 (t, J = 4.0, 8.0 Hz, 2H), 3.73 (t, J = 4.0, 4.0 Hz, 2H). [M+H] calc'd for Ci7Hi5F3N4O4, 397; Found, 397.
[0121] Example 21 : 2-(2,3-dihydroxypropyl)-3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000027_0001
[0122] The title compound was synthesized from 3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 3-bromopropane-l,2-diol. Purified by Mass-triggered HPLC (Gradient: 20-50% ACN containing 0.035% TFA in water containing 0.05% TFA). 1H NMR (400 MHz, MeOH-d4) δ: 8.43 (s, IH), 7.66 (dd, J = 4.0, 12.0 Hz, IH), 7.48 (d, J = 8.0 Hz, IH), 7.29-7.42 (m, 3H), 7.24 (dd, J = 4.0, 12.0 Hz, IH), 4.65 (s, 2H), 4.01-4.12 (m, 3H), 3.60 (d, J = 4.0 Hz, 2H). [M+H] calc'd for Ci8Hi7F3N4O5, 427; Found, 427.
[0123] Example 22: 2-(cyanomethyl)-N-(2,3-dimethoxybenzyl)-3-oxo-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000027_0002
[0124] The title compound was synthesized fromN-(2,3-dimethoxybenzyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 2-bromoacetonitrile. Purified by Mass-triggered HPLC (Gradient: 30-60% ACN containing 0.035% TFA in water containing 0.05% TFA). 1H NMR (400 MHz, MeOH-d4) δ: 9.06 (t, J = 4,.O, 8.0 Hz, NH, IH), 8.59 (s, IH), 7.69 (dd, J = 4.0, 12.0 Hz, IH), 7.34 (d, J = 12 Hz, IH), 6.96-7.06 (m, 2H), 6.86 (dd, J = 2.0, 8.0 Hz, IH), 5.27 (s, 2H), 4.46 (d, J = 8.0 Hz, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 3.77 (t, J = 4.0, 8.0 Hz, 2H). [M+H] calc'd for Ci9Hi9N5O4, 382; Found, 382.
[0125] Example 23: N-(2,3-dimethoxybenzyl)-2-(2-methoxyethyl)-3-oxo-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000028_0001
[0126] The title compound was synthesized fromN-(2,3-dimethoxybenzyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 1-bromo -2 -methoxy ethane. Purified by Mass-triggered HPLC (Gradient: 20-60% ACN containing 0.035% TFA in water containing 0.05% TFA). 1H NMR (400 MHz, MeOH-d4) δ: 8.39 (s, IH), 7.61 (dd, J = 4.0, 12.0 Hz, IH), 7.21 (dd, J = 4.0, 12 Hz, IH), 6.88-7.06 (m, 3H), 4.57 (s, 2H), 4.15 (t, J = 4.0, 8.0 Hz, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.77 (t, J = 4.0, 8.0 Hz, 2H), 3.32 (s, 3H). [M+H] calc'd for Ci9H22N4O5, 387; Found, 387. [0127] Example 24: 3-oxo-2-(2,2,2-trifluoroethyl)-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000028_0002
[0128] The title compound was synthesized from 3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using l,l,l-trifluoro-2-iodoethane. Purified by Mass-triggered HPLC (Gradient: 30-60% ACN containing 0.035% TFA in water containing 0.05% TFA). 1H NMR (400 MHz, MeOH-d4) δ: 8.44 (s, IH), 7.66 (d, J = 12.0 Hz, IH), 7.49 (d, J = 8.0 Hz, IH), 7.30-7.43 (m, 3H), 7.24 (dd, J = 12.0 Hz, IH), 4.68-4.78 (m, 2H), 4.65 (s, 2H). [M+H] calc'd for Ci7Hi2F6N4O3, 435; Found, 435.
[0129] Example 25: 2-((l-methyl-lH-imidazol-2-yl)methyl)-3-oxo-N-(2- (trifluoromethoxy)benzyl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000029_0001
[0130] The title compound was synthesized from 3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 2-(bromo methyl)- 1 -methyl- lH-imidazole. Purified by Mass-triggered HPLC (Gradient: 20-30% ACN containing 0.035% TFA in water containing 0.05% TFA) to give the TFA salt. 1H NMR (400 MHz, MeOH-d4) δ: 8.45 (s, IH), 7.77 (dd, J = 4.0, 12.0 Hz, IH), 7.60 (d, J = 4.0 Hz, IH), 7.55 (d, J = 4.0 Hz, IH), 7.47 (dd, J = 4.0, 8.0 Hz, IH), 7.30-7.42 (m, 3H), 7.22 (dd, J = 4.0, 12.0 Hz, IH), 5.58 (s, 2H), 4.64 (s, 2H), 4.01 (s, 3H). [M+H] calc'd for C20Hi7F3N6O3, 447; Found, 447.
[0131] Example 26: 3-oxo-2-(pyridin-4-ylmethyl)-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000029_0002
[0132] The title compound was synthesized from 3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 4-(bromomethyl)pyridine. Purified by Mass-triggered HPLC (Gradient: 20-30% ACN containing 0.035% TFA in water containing 0.05% TFA) to give the TFA salt. 1H NMR (400 MHz, MeOH-d4) δ: 8.80 (d, J = 8.0 Hz, IH), 8.49 (s, IH), 7.96 (d, J = 4.0 Hz, IH), 7.68 (dd, J = 4.0, 12.0 Hz, IH), 7.48 (d, J = 8.0, IH), 7.30-7.42 (m, 3H), 7.25 (dd, J = 4.0, 12.0 Hz, IH), 5.52 (s, 2H), 4.65 (s, 2H). [M+H] calc'd for C2IHi6F3N5O3, 444; Found, 444. [0133] Example 27: 3-oxo-2-(pyridin-3-ylmethyl)-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000030_0001
[0134] The title compound was synthesized from 3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 3-(bromomethyl)pyridine. Purified by Mass-triggered HPLC (Gradient: 20-30% ACN containing 0.035% TFA in water containing 0.05% TFA) to give the TFA salt. 1H NMR (400 MHz, MeOH-d4) δ: 8.92 (s, IH), 8.80 (d, J = 4.0 Hz, IH), 8.58 (d, J = 8.0 Hz, IH), 8.46 (s, IH), 8.02 (dd, J = 8.0, 8.0 Hz, IH), 7.65 (d, J = 12.0, IH), 7.48 (d, J = 4.0 Hz, IH), 7.29- 7.42 (m, 3H), 7.22 (d, J = 8.0 Hz, IH), 5.43 (s, 2H), 4.64 (s, 2H). [M+H] calc'd for C2IHi6F3N5O3, 444; Found, 444.
[0135] Example 28: 3-oxo-2-(tetrahydro-2H-pyran-4-yl)-N-(2-(trifluoromethoxy)benzyl)- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000030_0002
[0136] The title compound was synthesized from 3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 4-iodotetrahydro-2H-pyran. Purified by Mass-triggered HPLC (Gradient: 30-60% ACN containing 0.035% TFA in water containing 0.05% TFA). 1H NMR (400 MHz, MeOH-d4) δ: 8.43 (s, IH), 7.61 (dd, J = 4.0, 12.0 Hz, IH), 7.48 (d, J = 8.0 Hz, IH), 7.30-7.40 (m, 3H), 7.24 (dd, J = 4.0, 12.0 Hz, IH), 4.64 (s, 2H), 4.47-4.57 (m, IH), 4.04-4.11 (m, 2H), 3.54-4.62 (m, 2H), 2.10-2.22 (m, 2H), 1.84-1.91 (m, 2H). [M+H] calc'd for C20Hi9F3N4O4, 437; Found, 437.
[0137] Example 29: 3-oxo-2-(piperidin-4-yl)-N-(2-(trifluoromethoxy)benzyl)-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000031_0001
[0138] The title compound was synthesized from 3-oxo-N-(2-(trifluoromethoxy)benzyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using tert-butyl 4-iodopiperidine- 1 -carboxylate as an alkylating reagent, followed by deprotection (4N HCl). Purified by Mass-triggered HPLC (Gradient: 20-30% ACN containing 0.035% TFA in water containing 0.05% TFA) to give the TFA salt. 1H NMR (400 MHz, MeOH-d4) δ: 8.44 (t, J = 4.0, 4.0 Hz, IH), 7.64 (dd, J = 4.0, 12.0 Hz, IH), 7.48 (d, J = 8.0 Hz, IH), 7.29-7.43 (m, 3H), 7.24 (dd, J = 4.0, 12.0 Hz, IH), 4.60-4.68 (m, 3H), 3.54-3.62 (m, 2H), 3.20-3.28 (m, 2H), 2.27-.239 (m, 2H), 2.16-2.25 (m, 2H). [M+H] calc'd for C20H20F3N5O3, 436; Found, 436.
[0139] Example 30: N-(4-methoxy-2-(trifluoromethoxy)benzyl)-3-oxo-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000031_0002
[0140] The title compound was synthesized by a method similar to Example 1 by using (4- methoxy-2-(trifluoromethoxy)phenyl)methanamine as amine. Purified by Mass-triggered HPLC (Gradient: 30-40% ACN containing 0.035% TFA in water containing 0.05% TFA). 1H NMR (400 MHz, MeOH-d4) δ: 8.40 (t, J = 4.0, 4.0 Hz, IH), 7.59 (dd, J = 4.0, 8.0 Hz, IH), 7.40 (d, J = 8.0 Hz, IH), 7.21 (d, J = 12.0 Hz, IH), 6.92 (dd, J = 4.0, 12.0 Hz, IH), 6.85 (t, J = 4.0, 4.0 Hz, IH), 3.16 (s, 3H), 2.42 (m, IH), 2.17 (m, IH), 1.37 (m, IH), 1.02 (d, J = 8.0 Hz, 3H), 0.95 (d, J = 8.0 Hz, 3H). [M+H] calc'd for Ci6Hi3F3N4O4, 383; Found, 383. [0141] Example 31 : 2-(2,2-difluoroethyl)-N-(4-methoxy-2-(trifluoromethoxy)benzyl)-3-oxo- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000032_0001
[0142] To a solution of N-(4-methoxy-2-(trifluoromethoxy)benzyl)-3-oxo-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide (100 mg, 0.26 mmol) in 2 mL of dry DMSO was added CS2CO3, followed by addition of 2-bromo-l,l-difiuoroethane (74 mg, 0.39 mmol). The mixture was stirred at room temperature for 4 hour, filtered, and purified by Mass- triggered HPLC (Gradient: 30-60% ACN containing 0.035% TFA in water containing 0.05% TFA to give the title compound. 1B NMR (400 MHz, MeOH-d4) δ: 8.44 (s, IH), 7.64 (d, J = 12.0 Hz, IH), 7.41 (d, J = 8.0 Hz, IH), 7.23 (d, J = 12.0 Hz, IH), 6.94 (d, J = 8.0 Hz, IH), 6.86 (s, IH), 6.09-6.41 (m, IH), 4.54 (s, 2H), 4.31-4.42 (m, 2H), 3.81 (s, 3H). [M+H] calc'd for Ci8Hi5F5N4O4, 447; Found, 447.
[0143] Example 32: N-(4-methoxy-2-(trifiuoromethoxy)benzyl)-3-oxo-2-(tetrahydro-2H- pyran-4-yl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000032_0002
[0144] The title compound was synthesized from N-(4-methoxy-2-(trifluoromethoxy)benzyl)- 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 4-iodotetrahydro-2H-pyran. Purified by Mass-triggered HPLC (Gradient: 20-60% ACN containing 0.035% TFA in water containing 0.05% TFA) to give the title compound. 1H NMR (400 MHz, MeOH-d4) δ: 8.45 (s, IH), 7.60 (d, J = 12.0 Hz, IH), 7.41 (d, J = 8.0 Hz, IH), 7.24 (d, J = 12.0 Hz, 2H), 6.94 (dd, J = 4.0, 8.0 Hz, IH), 6.86 (s, IH), 4.45-4.56 (m, 3H), 4.01-4.09 (m, 2H), 3.81 (s, 3H), 3.51-3.60 (m, 2H), 2.06-2.19 (m, 2H), 1.81-1.90 (m, 2H). [M+H] calc'd for C2iH2iF3N4O5, 467; Found, 467. [0145] Example 33: 2-(2-hydroxyethyl)-N-(4-methoxy-2-(trifluoromethoxy)benzyl)-3-oxo- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000033_0001
[0146] The title compound was synthesized fromN-(4-methoxy-2-(trifluoromethoxy)benzyl)- 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 2-bromoethanol. Purified by Mass-triggered HPLC (Gradient: 20-50% ACN containing 0.035% TFA in water containing 0.05% TFA) to give the title compound. 1H NMR (400 MHz, MeOH-d4) δ: 8.39 (s, IH), 7.60 (d, J = 12.0 Hz, IH), 7.40 (d, J = 12.0 Hz, IH), 7.21 (d J = 8.0 Hz, IH), 6.90 (dd, J = 4.0, 8.0 Hz, IH), 6.85 (br s, IH), 4.55 (s, 2H), 4.08 (t, J = 8.0, 8.0 Hz, 2H), 3.91 (t, J = 4.0, 8.0 Hz, IH), 3.80 (s, 3H). [M+H] calc'd for Ci8Hi7F3N4O5, 427; Found, 427.
[0147] Example 34: (R)-N-(4-methoxy-2-(trifluoromethoxy)benzyl)-3-oxo-2-((5- oxopyrrolidin-2-yl)methyl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000033_0002
[0148] The title compound was synthesized from N-(4-methoxy-2-(trifluoromethoxy)benzyl)- 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using l(R)-5-(bromomethyl)pyrrolidin-2-one. Purified by Mass-triggered HPLC (Gradient: 20-50% ACN containing 0.035% TFA in water containing 0.05% TFA to give the title compound. 1H NMR (400 MHz, MeOD-d4) δ: 8.39 (s, IH), 7.61 (d, J = 8.0 Hz, IH), 7.40 (d, J = 12 Hz, IH), 7.21 (d, J = 12 Hz, IH), 6.91 (dd, J = 4.0, 8.0 Hz, IH), 6.85 (br s, IH), 4.55 (s, 2H), 4.11-4.21 (m, IH), 4.05 (d, J = 8.0 Hz, 2H), 3.80 (s, 3H), 2.26-2.39 (m, 3H), 1.96-2.06 (m, IH). [M+H] calc'd for C2IH20F3N5O5, 480; Found, 480. [0149] Example 35: N-(4-methoxy-2-(trifluoromethoxy)benzyl)-3-oxo-2-(pyridin-2- ylmethyl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000034_0001
[0150] To a solution of N-(4-methoxy-2-(trifluoromethoxy)benzyl)-3-oxo-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide (37 mg, 0.097 mmol) in 2 mL of dry DMSO was added CS2CO3 (95 mg, 0.292mmol), followed by addition of 2-
(bromomethyl)pyridine.HBr (25 mg, 0.098 mmol). The mixture was stirred room temperature for 1 hour, filtered, and purified by Mass-triggered HPLC (Gradient: 15-60% ACN containing 0.035% TFA in water containing 0.05% TFA) to give the TFA salt. 1H NMR (400 MHz, MeOD-d4) δ: 8.65 (d, J = 4.0 Hz, IH), 8.44 (s, IH), 8.16-8.21 (m, IH), 7.61-7.71 (m, 3H), 7.40 (d, J = 8.0Hz, IH), 7.20 (d, J = 8.0Hz, IH), 6.91 (dd, J = 44.0, 8.0 Hz, IH), 6.85 (br s, IH), 5.45 (s, 2H), 4.56 (s, 2H), 3.80 (s, 3H), [M+H] calc'd for C22Hi9F3N5O4, 474; Found, 474.
[0151] Example 36: 2-(l-cyanoethyl)-N-(4-methoxy-2-(trifluoromethoxy)benzyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000034_0002
[0152] The title compound was synthesized from N-(4-methoxy-2-(trifluoromethoxy)benzyl)- 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 2-bromopropanenitrile. Purified by Mass-triggered HPLC (Gradient: 40- 60% ACN containing 0.035% TFA in water containing 0.05% TFA) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 9.11 (s, IH), 8.58 (s, IH), 7.67 (d, J = 8.0 Hz, IH), 7.41 (d, J = 8.0 Hz, IH), 7.37 (d, J = 12.0 Hz, IH), 7.00 (d, J = 12.0 Hz, IH), 6.90 (br s, IH), 5.80 (dd, J = 4.0, 12.0 Hz, IH), 4.45 (d, J = 8.0 Hz, 2H), 3.79 (s, 3H), 1.72 (d, J = 4.0 Hz, 3H), [M+H] calc'd for Ci9Hi6F3N5O4, 436; Found, 436. [0153] Example 37: 2-(2,3-dihydroxypropyl)-N-(4-methoxy-2-(trifluoromethoxy)benzyl)-3- oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000035_0001
[0154] The title compound was synthesized from N-(4-methoxy-2-(trifluoromethoxy)benzyl)- 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 3-bromopropane-l,2-diol. Purified by Mass-triggered HPLC (Gradient: 20-50% ACN containing 0.035% TFA in water containing 0.05% TFA to give the title. 1H NMR (400 MHz, DMSO-d6) δ: 8.40 (s, IH), 7.60 (d, J = 8.0 Hz, IH), 7.40 (d, J = 12 Hz, IH), 7.21 (d, J = 8.0 Hz, IH), 6.91 (dd, J = 4.0, 8.0 Hz, IH), 6.84 (br s, IH), 4.55 (s, 2H), 4.05- 4.15 (m, 3H), 3.80 (s, 3H), 3.60 (d, J = 4.0 Hz, 2H). [M+H] calc'd for Ci9Hi9F3N4O6, 457; Found, 457.
[0155] Example 38: 2-(l -amino- 1 -oxopropan-2-yl)-N-(4-methoxy-2- (trifluoromethoxy)benzyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000035_0002
[0156] The title compound was synthesized from N-(4-methoxy-2-(trifluoromethoxy)benzyl)- 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 2-bromopropanamide. Purified by Mass-triggered HPLC (Gradient: 30- 50% ACN containing 0.035% TFA in water containing 0.05% TFA) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 9.10 (t, J = 4.0, 4.0 Hz, IH), 8.57 (s, IH), 7.60 (dd, J = 4.0, 12 Hz, IH), 7.41 (d, J = 8.0 Hz, IH), 7.31 (d, J = 8.0 Hz, IH), 7.00 (dd, J = 4.0, 8.0 Hz, IH), 6.90 (br s, IH), 4.85 (q, J = 8.0, 16.0 Hz, IH), 4.45 (d, J = 4.0Hz, 2H), 3.78 (s, 3H), 1.78 (d, J = 8.0 Hz, 3H). [M+H] calc'd for Ci9Hi8F3N5O5, 454; Found, 454. [0157] Example 39: 2-(2-amino-2-oxoethyl)-N-(4-methoxy-2-(trifluoromethoxy)benzyl)-3- oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000036_0001
[0158] The title compound was synthesized from N-(4-methoxy-2-(trifluoromethoxy)benzyl)- 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 2-bromoacetamide. Purified by Mass-triggered HPLC (Gradient: 20-40% ACN containing 0.035% TFA in water containing 0.05% TFA) 15 mg (isolated yield: 36%) to give the title compound.. 1H NMR (400 MHz, DMSO-d6) δ: 9.10 (t, J = 8.0, 4.0 Hz, IH), 8.57 (s, IH), 7.61 (dd, J = 4.0, 12.0 Hz, IH), 7.41 (d, J = 8.0 Hz, IH), 7.28 (d, J = 12.0 Hz, IH), 7.00 (dd, J = 4.0, 8.0 Hz, IH), 6.90 (br s, IH), 4.50 (s, 2H), 4.45 (d, J = 4.0Hz, 2H), 3.78 (s, 3H) . [M+H] calc'd for Ci8Hi6F3N5O5, 440; Found, 440. [0159] Example 40: N-(4-bromo-2-(trifluoromethoxy)benzyl)-3-oxo-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000036_0002
[0160] The title compound was synthesized by a method similar to Example 1 using (4- bromo-2-(trifluoromethoxy)phenyl)methanamine as amine. Purified by Mass-triggered HPLC (Gradient: 40-60% ACN containing 0.035% TFA in water containing 0.05% TFA). 1H NMR (400 MHz, DMSO-d6) δ: 12.64 (s, IH), 9.18 (t, J = 4.0, 4.0 Hz, NH, IH), 8.53 (s, IH), 7.61- 7.65 (m, 2H), 7.55 (dd, J = 4.0, 12.0 Hz, IH), 7.45 (d, J = 12.0 Hz, IH), 7.27 (dd, J = 4.0, 12.0 Hz, IH), 4.47 (d, J = 4.0 Hz, 2H). [M+H] calc'd for Ci8Hi5F3N4O5S, 431, 433; Found, 431, 433.
[0161] Example 41 : N-(4-(cyclopropylsulfonyl)-2-(trifluoromethoxy)benzyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000037_0001
[0162] A mixture of N-(4-bromo-2-(trifluoromethoxy)benzyl)-3-oxo-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide (54 mg, 0.13 mmol), sodium cyclopropylsulfϊnate (24 mg, 0.19 mmol), CuI (14 mg, 0.07 mmol) andNl,N2- dimethylethane-l,2-diamine (11.5 mg, 0.13 mmol) in 2 mL of 2 mL of DMF was heated in microwave reactor at 15O0C for 1 hour. The solid was filtered off and the crude product was purified by Mass-triggered HPLC (Gradient: 20-40% ACN containing 0.035% TFA in water containing 0.05% TFA) 14 mg (isolated yield: 24%) to give the title compound. 1H NMR (400 MHz, MeOD-d4) δ: 9.21 (t, J = 8.0, 4.0 Hz, NH, IH), 8.47 (s, IH), 7.90 (dd, J = 2.0, 8.0 Hz, IH), 7.81 (t, J = 2.0, 2.0 Hz, IH), 7.75 (d, J = 8.0 Hz, IH), 7.62 (dd, J = 4.0, 8.0 Hz, IH), 7.24 (dd, J = 1.0, 8.0 Hz, IH), 4.72 (d, J = 4.0 Hz, 2H), 2.68-2.77 (m, IH), 1.21-1.27 (m, 2H), 1.05-1.12 (m, 2H). [M+H] calc'd for Ci8Hi5F3N4O5S, 457; Found, 457. [0163] Example 42: N-(4-(methylsulfonyl)-2-(trifluoromethoxy)benzyl)-3-oxo-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000037_0002
[0164] A mixture of N-(4-bromo-2-(trifluoromethoxy)benzyl)-3-oxo-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide (55 mg, 0.13 mmol), sodium methylsulfinate (20 mg, 0.2 mmol), CuI (25 mg, 0.13 mmol) andNl,N2-dimethylethane-l,2-diamine (11.5 mg, 0.13 mmol) in 2 mL of 2 mL of DMF was heated in microwave reactor at 15O0C for 1 hour. The solid was filtered off and the crude product was purified by Mass-triggered HPLC (Gradient: 20-40% ACN containing 0.035% TFA in water containing 0.05% TFA) 25 mg (isolated yield: 45%) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 12.66 (s,
NH, IH), 9.31 (t, J = 4.0, 4.0 Hz, NH, IH), 8.55 (s, IH), 7.96 (dd, J = 4.0, 8.0 Hz, IH), 7.86 (m, IH), 7.76 (d, J = 12.0 Hz, IH), 7.56 (dd, J = 4.0, 12.0 Hz, IH), 7.28 (dd, J = 1.0, 8.0 Hz,
IH), 4.59 (d, J = 8.0 Hz, 2H), 3.31 (s, 3H). [M+H] calc'd for Ci6Hi3F3N4O5S, 431; Found,
431.
[0165] Example 43: N-(4-(6-aminopyridin-3-yl)-2-(trifluoromethoxy)benzyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000038_0001
[0166] A mixture of N-(4-bromo-2-(trifluoromethoxy)benzyl)-3-oxo-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide (36 mg, 0.083 mmol), 5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyridin-2-amine (22 mg, 0.1 mmol) and PdCi2(dppf)2 (5 mg) in 2 mL of 1 ,4-dioxane/2M K2CO3 was heated in microwave reactor at HO0C for 15 min. The solid was filtered off and the crude product was purified by Mass-triggered HPLC (Gradient: 20- 40% ACN containing 0.035% TFA in water containing 0.05% TFA) 4 mg (isolated yield: 11%) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 8.44 (t, J = 4.0, 4.0 Hz, , IH), 8.23 (dd, J = 4.0, 8.0 HZ, IH), 8.15 (s, IH), 7.78 (dd, J = 2.0, 8.0 Hz, IH), 7.57-7.64 (m, 4H), 7.24 (dd, J = 4.0, 12.0 Hz, IH), 7.10 (d, J = 8.0 Hz, IH), 4.68 (s, 2H). [M+H] calc'd for C20Hi5F3N6O3, 445; Found, 445.
[0167] Example 44: N-(4-(2-aminopyrimidin-5-yl)-2-(trifluoromethoxy)benzyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000038_0002
[0168] A mixture of N-(4-bromo-2-(trifluoromethoxy)benzyl)-3-oxo-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide (36 mg, 0.083 mmol), 2-aminopyrimidin-5- ylboronic acid (12 mg, 0.083 mmol) and PdCl2(dppf)2 (5 mg) in 2 mL of 1 ,4-dioxane/2M K2CO3 was heated in microwave reactor at 1100C for 15 min. The solid was filtered off and the crude product was purified by Mass-triggered HPLC (Gradient: 20-50% ACN containing 0.035% TFA in water containing 0.05% TFA) 11.2 mg (isolated yield: 30%) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 12.66 (s, IH), 9.20 (t, J = 8.0, 4.0 Hz, NH, IH), 8.63 (s, 2H), 8.54 (s, IH), 7.49-7.70 (m, 4H), 7.28 (d, J = 12.0 Hz, IH), 4.53 (d, J = 4.0 Hz, 2H). [M+H] calc'd for Ci9Hi4F3N7O3, 446; Found, 446.
[0169] Example 45: N-(4-(3-hydroxyprop-l-ynyl)-2-(trifluoromethoxy)benzyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000039_0001
[0170] A mixture of N-(4-bromo-2-(trifluoromethoxy)benzyl)-3-oxo-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide (50 mg, 0.12 mmol), CuI (4 mg, 0.02 mmol) and tetrakis(triphenylphosphine) palladium (0) (5 mg) in 2 mL of DMF was heated in microwave reactor at 16O0C for 40 min. The solid was filtered off and the crude product was purified by Mass-triggered HPLC (Gradient: 20-40% ACN containing 0.035% TFA in water containing 0.05% TFA) 12 mg (isolated yield: 26%) to give the title compound. 1H NMR (400 MHz, MeOD-d4) δ: 8.43 (s, IH), 7.60 (dd, J = 4.0, 8.0 Hz, IH), 7.45 (d, J = 8.0 Hz, IH), 7.39 (dd, J = 2.0, 8.0 Hz, IH), 7.35 (t, J = 4.0, 4.0 Hz, IH), 7.22 (dd, J = 2.0, 8.0 Hz, IH), 4.62 (d, J = 4.0 Hz, 2H), 4.39 (s, 2H). [M+H] calc'd for Ci8Hi3F3N4O4, 407; Found, 407. [0171] Example 46: N-(4-cyano-2-(trifluoromethoxy)benzyl)-3-oxo-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000039_0002
[0172] A mixture of N-(4-bromo-2-(trifluoromethoxy)benzyl)-3-oxo-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide (50 mg, 0.12 mmol), Zn(CN)2 (14 mg, 0.12 mmol) and tetrakis(triphenylphosphine) palladium (0) (5 mg) in 2 mL of DMF was heated in microwave reactor at 16O0C for 40 min. The solid was filtered off and the crude product was purified by Mass-triggered HPLC (Gradient: 20-50% ACN containing 0.035% TFA in water containing 0.05% TFA) 12 mg (isolated yield: 26%) to give the title compound. 1H NMR (400 MHz, MeOD-d4) δ: 12.65 (s,lH), 9.27 (t, J = 4.0, 8.0 Hz, IH), 8.54 (s, IH), 8.01 (s, IH), 7.89 (dd, J = 4.0, 8.0 Hz, IH), 7.67 (d, J = 8.0 Hz, IH), 7.55 (dd, J = 4.0, 8.0 Hz, IH), 7.28 (dd, J = 2.0, 8.0 Hz, IH), 4.56 (d, J = 4.0 Hz, 2H). [M+H] calc'd for Ci6Hi0F3N5O3, 378; Found, 378.
[0173] Example 47: N-(4-bromo-2-(trifluoromethoxy)benzyl)-2-(2-hydroxyethyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000040_0001
[0174] A title compound was synthesized from N-(4-bromo-2-(trifluoromethoxy)benzyl)-3- oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 2-bromoethanol. Purified by Mass-triggered HPLC (Gradient: 30-50% ACN containing 0.035% TFA in water containing 0.05% TFA). 1H NMR (400 MHz, DMSO- d6) δ: 9.19 (t, J = 8.0, 4.0 Hz, NH, IH), 8.57 (s, IH), 7.61-7.66 (m, 2H), 7.59 (dd, J = 4.0, 12.0 Hz, IH), 7.45 (d, J = 8.0 Hz, IH), 7.31 (dd, J = 2.0, 12.0 Hz, IH), 4.47 (d, J = 4.0 Hz, 2H), 3.94 (t, J = 6.0, 6.0 Hz, 2H), 3.69-3.76 (m, 2H). [M+H] calc'd for CnHi4BrF3N4O4, 475, 477; Found, 475, 477.
[0175] Example 48: 2-(2-hydroxyethyl)-N-(4-(methylsulfonyl)-2-(trifluoromethoxy)benzyl)- 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000041_0001
[0176] A mixture of N-(4-bromo-2-(trifluoromethoxy)benzyl)-2-(2-hydroxyethyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide (43 mg, 0.09 mmol), sodium methylsulfϊnate (15 mg, 0.14 mmol), CuI (10 mg, 0.05 mmol) andNl,N2-dimethylethane- 1,2-diamine (9.2 mg, 0.10 mmol) in 2 mL of 2 mL of DMF was heated in microwave reactor at 15O0C for 1 hour. The solid was filtered off and the crude product was purified by Mass- triggered HPLC (Gradient: 20-30% ACN containing 0.035% TFA in water containing 0.05% TFA) 20 mg (isolated yield: 47%) to give the title compound. 1H NMR (400 MHz, MeOD- d4) δ: 9.19 (t, J = 4.0, 8.0 Hz, NH, IH), 8.45 (s, IH), 7.94 (dd, J = 2.0, 8.0 Hz, IH), 7.87 (s, IH), 7.76 (d, J = 8.0 Hz, IH), 7.62 (dd, J = 2.0, 8.0 Hz, IH), 7.24 (d, J = 8.0 Hz, IH), 4.71 (s, 2H), 4.09 (t, J = 4.0, 8.0 Hz, 2H), 3.93 (t, J = 4.0, 8.0 Hz, 2H), 3.16 (s, 3H). [M+H] calc'd for Ci8Hi7F3N4O6S, 475; Found, 475.
[0177] Example 49: N-(4-(cyclopropylsulfonyl)-2-(trifluoromethoxy)benzyl)-2-(2- hydroxyethyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000041_0002
[0178] A mixture of N-(4-bromo-2-(trifluoromethoxy)benzyl)-2-(2-hydroxyethyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide (60 mg, 0.126 mmol), sodium cyclopropylsulfϊnate (24 mg, 0.19 mmol), CuI (14 mg, 0.07 mmol) andNl,N2- dimethylethane-l,2-diamine (9.2 mg, 0.10 mmol) in 2 mL of 2 mL of DMF was heated in microwave reactor at 15O0C for 1 hour. The solid was filtered off and the crude product was purified by Mass-triggered HPLC (Gradient: 25-35% ACN containing 0.035% TFA in water containing 0.05% TFA) 8 mg (isolated yield: 13%) to give the title compound. 1H NMR (400
MHz, MeOD-d4) δ: 9.21 (t, J = 4.0, 8.0 Hz, NH, IH), 8.46 (s, IH), 7.90 (d, J = 8.0 Hz, IH), 7.81 (s, IH), 7.75 (d, J = 8.0 Hz, IH), 7.63 (dd, J = 2.0, 8.0 Hz, IH), 7.25 (dd, J = 1.0, 8.0 Hz,
IH), 4.71 (s, 2H), 4.09 (t, J = 4.0, 8.0 Hz, 2H), 3.92 (t, J = 4.0, 8.0 Hz, 2H), 2.68-2.77 (m,
IH), 1.21-1.27 (m, 2H), 1.05- 1.12 (m, 2H). [M+H] calc'd for C20Hi9F3N4O6S, 501; Found,
501.
[0179] Example 50: N-(4-bromo-2-(trifluoromethoxy)benzyl)-2-(2-cyanoethyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000042_0001
[0180] The title compound was synthesized fromN-(4-bromo-2-(trifluoromethoxy)benzyl)-3- oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 3-bromopropanenitrile. Purified by Mass-triggered HPLC (Gradient: 30- 60% ACN containing 0.035% TFA in water containing 0.05% TFA) 150 mg (isolated yield: 44%) to give the title compound. [M+H] calc'd for Ci8Hi3F3N5O3, 484, 486; Found, 484, 486. [0181] Example 51: 2-(2-cyanoethyl)-N-(4-(cyclopropylsulfonyl)-2- (trifluoromethoxy)benzyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000042_0002
[0182] A mixture of N-(4-bromo-2-(trifluoromethoxy)benzyl)-2-(2-cyanoethyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide (62 mg, 0.13 mmol), sodium cyclopropylsulfinate (26 mg, 0.2 mmol), CuI (15 mg, 0.08 mmol) and Nl,N2-dimethylethane- 1,2-diamine (0.13 mmol) in 2 mL of 2 mL of DMSO was heated in microwave reactor at 15O0C for 1 hour. The solid was filtered off and the crude product was purified by Mass- triggered HPLC (Gradient: 30-60% ACN containing 0.035% TFA in water containing 0.05% TFA) 6 mg (isolated yield: 9%) to give the title compound. 1H NMR (400 MHz, MeOD-d4) δ: 8.47 (s, IH), 7.90 (dd, J = 2.0, 8.0 Hz, IH), 7.81 (t, J = 2.0, 2.0 Hz, IH), 7.75 (d, J = 8.0 Hz, IH), 7.65 (dd, J = 2.0, 8.0 Hz, IH), 7.25 (dd, J = 1.0, 8.0 Hz, IH), 4.71 (s, 2H), 4.28 (t, J =
8.0, 8.0 Hz, 2H), 3.03 (t, J = 8.0, 8.0 Hz, 2H), 2.69-2.77 (m, IH), 1.21-1.27 (m, 2H), 1.05-
1.12 (m, 2H). [M+H] calc'd for C2IHi8F3N5O5S, 510; Found, 510.
[0183] Example 52: N-(4-(2-aminopyrimidin-5-yl)-2-(trifluoromethoxy)benzyl)-2-(2- cyanoethyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000043_0001
[0184] A mixture of N-(4-bromo-2-(trifluoromethoxy)benzyl)-2-(2-cyanoethyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide (25 mg, 0.052 mmol), 2- aminopyrimidin-5-ylboronic acid (9 mg, 0.062 mmol) and PdCl2(dppf)2 (5 mg) in 2 mL of 1 ,4-dioxane/2M K2CO3 was heated in microwave reactor at 11O0C for 15 min. The solid was filtered off and the crude product was purified by Mass-triggered HPLC (Gradient: 20-40% ACN containing 0.035% TFA in water containing 0.05% TFA) 10 mg (isolated yield: 39%) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 8.60 (s, 2H), 8.44 (s, IH), 7.47- 7.60 (m, 4H), 7.19 (d, J = 8.0 Hz, IH), 4.55 (s, 2H), 4.17 (t, J = 8.0, 8.0 Hz, 2H), 2.94 (t, J = 8.0, 8.0 Hz, 2H). [M+H] calc'd for C22HnF3N8O3, 499; Found, 499. [0185] Example 53: N-(4-cyano-2-(trifluoromethoxy)benzyl)-2-(2-cyanoethyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000043_0002
[0186] A mixture of N-(4-bromo-2-(trifluoromethoxy)benzyl)-2-(2-cyanoethyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide (25 mg, 0.052 mmol), Zn(CN)2 (6 mg, 0.052 mmol) and tetrakis(triphenylphosphine) palladium (0) (5 mg) in 2 mL of DMF was heated in microwave reactor at 16O0C for 40 min. The solid was filtered off and the crude product was purified by Mass-triggered HPLC (Gradient: 30-40% ACN containing 0.035% TFA in water containing 0.05% TFA) 12 mg (isolated yield: 54%) to give the title compound. 1B NMR (400 MHz, DMSO-d6) δ: 9.30 (t, J = 4.0, 8.0 Hz, IH), 8.61 (s, IH), 8.01 (t, J = 2.0, 2.0 Hz, IH), 7.90 (dd, J = 2.0, 8.0 Hz, IH), 7.68 (d, J = 8.0 Hz, IH), 7.62 (dd, J = 4.0, 8.0 Hz, IH), 7.35 (dd, J = 2.0, 8.0 Hz, IH), 4.58 (d, J = 4.0 Hz, 2H), 2H), 4.20 (t, J = 8.0, 8.0 Hz, 2H), 3.04 (t, J = 8.0, 8.0 Hz, 2H). [M+H] calc'd for Ci9Hi3F3N6O3, 431; Found, 431. [0187] Example 54: N-(4-cyano-2-(trifluoromethoxy)benzyl)-3-oxo-2-(pyridin-2-ylmethyl)- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000044_0001
[0188] To a solution of N-(4-cyano-2-(trifluoromethoxy)benzyl)-3-oxo-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide (18 mg, 0.48 mmol) in 2 mL of dry DMSO was added Cs2CO3, followed by addition of 2-(bromomethyl)pyridine (13 mg, 0.53 mmol). The mixture was stirred at room temperature for 1 hour, filtered, and purified by Mass-triggered HPLC (Gradient: 20-40% ACN containing 0.035% TFA in water containing 0.05% TFA) 12 mg (isolated yield: 27%) to give the title compound as its TFA salt. 1H NMR (400 MHz, MeOD-d4) δ: 8.61 (d, J = 4.0 Hz, IH), 8.50 (s, IH), 8.07-8.13 (m, IH), 7.56-7.78 (m, 6H), 7.23 (d, J = 8.0Hz, IH), 5.42 (s, 2H), 4.69 (s, 2H), 3.80 (s, 3H), [M+H] calc'd for C22Hi5F3N6O3, 469; Found, 469.
[0189] Example 55: N-(4-cyano-2-(trifluoromethoxy)benzyl)-2-(2-hydroxyethyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000044_0002
[0190] A mixture of N-(4-bromo-2-(trifluoromethoxy)benzyl)-2-(2-hydroxyethyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide (100 mg, 0.21 mmol), Zn(CN)2 (24.7 mg, 0.21 mmol) and tetrakis(triphenylphosphine) palladium (0) (48.6 mg, 0.041 mmol) in 3 mL of DMF was heated in microwave reactor at 16O0C for 40 min. A solid was filtered off and further purified by Mass-triggered HPLC (Gradient: 20-40% ACN containing 0.035% TFA in water containing 0.05% TFA) to give 34.1 mg (isolated yield: 38.5%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 9.29 (t, J = 4.0, 8.0 Hz, IH), 8.59 (s, IH), 8.01 (t, J = 2.0, 2.0 Hz, IH), 7.90 (dd, J = 2.0, 8.0 Hz, IH), 7.67 (d, J = 8.0 Hz, IH), 7.59 (dd, J = 4.0, 8.0 Hz, IH), 7.31 (dd, J = 2.0, 8.0 Hz, IH), 4.58 (d, J = 4.0 Hz, 2H), 3.95 (t, J = 4.0, 8.0 Hz, 2H), 3.73 (t, J = 4.0, 8.0 Hz, 2H). [M+H] calc'd for Ci8Hi4F3N5O4, 422; Found, 422. [0191] Example 56: N-(4-bromo-2-(trifluoromethoxy)benzyl)-2-(2,2-difluoroethyl)-3-oxo- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000045_0001
[0192] To a solution of N-(4-bromo-2-(trifluoromethoxy)benzyl)-3-oxo-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide (41.7 mg, 0.097 mmol) in 2 mL of dry DMSO was added Cs2CO3 (2 eq.) and stirred for 5 min, followed by addition of l,l-difluoro-2- iodoethane (20 mg, 0.1 mmol). The mixture was stirred at room temperature overnight, filtered, and the filtrate was purified by HPLC (Gradient: 40-60% ACN containing 0.035% TFA in water containing 0.05% TFA) to give 30 mg of the title compound.
Alternately, N-(4-bromo-2-(trifluorometho xy )benzyl)-3-oxo-2,3-dihy dro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide (550 mg, 1.28 mmol) in 30 mL of dry DMSO was added Cs2CO3 (623 mg, 1.92 mmol) and stirred for 5 min, followed by addition of 1,1- difluoro-2-iodoethane (370 mg, 1.92 mmol). The mixture was stirred at room temperature overnight then heated at 500C for 3hr. The reaction was then diluted with water, and extracted with EtOAc, the organic layer separated and evaporated under vacuum to give a residue which was suspended in MeOH, filtered, and washed with MeOH to give 444 mg of the title compound. [M+H] calc'd for CnHi2BrF5N4O3, 495, 497; Found, 495, 497. [0193] Example 57: N-(4-cyano-2-(trifluoromethoxy)benzyl)-2-(2,2-difluoroethyl)-3-oxo- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000046_0001
[0194] A mixture of N-(4-bromo-2-(trifluoromethoxy)benzyl)-2-(2,2-difluoroethyl)-3-oxo- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide (50 mg, 0.101 mmol), Zn(CN)2 (12 mg, 0.101 mmol) and tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol) in 3 mL of DMF was heated in microwave reactor at 16O0C for 40 min. The solid was filtered off and the crude product was purified by Mass-triggered HPLC (Gradient: 30-50% ACN containing 0.035% TFA in water containing 0.05% TFA) to givel8.8 mg (isolated yield: 42.2%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 9.30 (t, J = 4.0, 8.0 Hz, IH), 8.61 (s, IH), 8.01 (s, IH), 7.90 (dd, J = 2.0, 8.0 Hz, IH), 7.68 (d, J = 8.0 Hz, IH), 7.63 (dd, J = 4.0, 8.0 Hz, IH), 7.34 (dd, J = 1.0, 8.0 Hz, IH), 6.19-6.55 (m, IH), 4.58 (d, J = 4.0 Hz, 2H), 4.33-4.45 (m, 2H). [M+H] calc'd for Ci8Hi2F5N5O3, 442; Found, 442.
[0195] Example 58: N-(4-(cyclopropylsulfonyl)-2-(trifluoromethoxy)benzyl)-2-(2,2- difluoroethyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000046_0002
[0196] The title compound was synthesized from N-(4-bromo-2-(trifluoromethoxy)benzyl)-2- (2,2-difluoroethyl)-3-oxo-2,3-dihydro-[l ,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 41. Purified by Mass-triggered HPLC (Gradient: 35-45% ACN containing 0.035% TFA in water containing 0.05% TFA). 1H NMR (400 MHz, DMSO-d6) δ: 9.32 (t, J = 4.0, 8.0 Hz, IH), 8.62 (s, IH), 7.94 (dd, J = 2.0, 8.0 Hz, IH), 7.82 (t, J = 2.0 Hz, IH), 7.77 (d, J = 8.0 Hz, IH), 7.63 (dd, J = 2.0, 8.0 Hz, IH), 7.34 (dd, J = 2.0, 8.0 Hz, IH), 6.23-654 (m, IH), 4.60 (d, J = 4.0 Hz, 2H), 4.34-4.45 (m, 2H), 2.95-3.04 (m, IH), 1.04-1.18 (m, 4H). [M+H] calc'd for C20Hi7F5N4O5S, 442; Found, 442.
[0197] Example 59: N-(4-bromo-2-(trifluoromethoxy)benzyl)-3-oxo-2-(tetrahydro-2H-pyran- 4-yl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000047_0001
[0198] The title compound was synthesized fromN-(4-bromo-2-(trifluoromethoxy)benzyl)-3- oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to
Example 2 by using 4-iodotetrahydro-2H-pyran as an alkylating reagent. [M+H] calc'd for C20H18BrF3N4O4, 442; Found, 442.
[0199] Example 60: N-(4-cyano-2-(trifluoromethoxy)benzyl)-3-oxo-2-(tetrahydro-2H-pyran- 4-yl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000047_0002
[0200] The title compound was synthesized fromN-(4-bromo-2-(trifluoromethoxy)benzyl)-3- oxo-2-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 46. Purified by Mass-triggered HPLC (Gradient: 50-60% ACN containing 0.035% TFA in water containing 0.05% TFA). 1H NMR (400 MHz, DMSO- d6) δ: 9.28 (t, J = 4.0, 8.0 Hz, IH), 8.61 (s, IH), 8.02 (t, J = 1.0, 1.0 Hz, IH), 7.90 (dd, J = 2.0, 8.0 Hz, IH), 7.67 (d, J = 8.0 Hz, IH), 7.59 (dd, J = 2.0, 8.0 Hz, IH), 7.34 (dd, J= 1.0, 8.0 Hz, IH), 4.58 (d, J = 4.0 Hz, 2H), 4.10-4.51 (m, IH), 3.93-4.00 (m, 2H), 3.45-3.54 (m, 2H), 1.91- 2.04 (m, 2H), 1.76-1.85 (m, 2H). M+H] calc'd for C2IHi8F3N4O4, 462; Found, 462. [0201] Example 60: N-(4-(cyclopropylsulfonyl)-2-(trifluoromethoxy)benzyl)-3-oxo-2- (tetrahydro-2H-pyran-4-yl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000047_0003
[0202] The title compound was synthesized fromN-(4-bromo-2-(trifluoromethoxy)benzyl)-3- oxo-2-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 41. Purified by Mass-triggered HPLC (Gradient: 35-45% ACN containing 0.035% TFA in water containing 0.05% TFA). 1H NMR (400 MHz, MeOD- d4) δ: 8.46 (s, IH), 7.90 (dd, J = 2.0, 8.0 Hz, IH), 7.81 (t, J = 2.0 Hz, IH), 7.75 (d, J = 8.0 Hz,
IH), 7.62 (dd, J = 2.0, 8.0 Hz, IH), 7.25 (dd, J = 1.0, 8.0 Hz, IH), 4.71 (d, J = 4.0 Hz, 2H),
4.43-4.57 (m, IH), 4.04-4.11 (m, 2H), 3.54-3.63 (m, 2H), 2.69-2.77 (m, IH), 2.10-2.23 (m,
2H), 1.84-1.91 (m, 2H), 1.21-1.27 (m, 2H), 1.05-1.12 (m, 2H). M+H] calc'd for
C23H23F3N4O6S, 541; Found, 541.
[0203] Example 61: N-(4-bromo-2-(trifluoromethoxy)benzyl)-2-(2-morpholinoethyl)-3-oxo-
2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000048_0001
[0204] The title compound was synthesized from 3-oxo-N-(4-bromo-2- (trifluoromethoxy)benzyl)-2,3-dihydro-[l ,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 using 4-(2-chloroethyl)morpholine as an alkylating reagent. Purified by Mass-triggered HPLC (Gradient: 35-45% ACN containing 0.035% TFA in water containing 0.05% TFA) to give the TFA salt. 1H NMR (400 MHz, MeOD-d4) δ: 8.44 (s, IH), 7.66 (dd, J = 2.0, 8.0 Hz, IH), 7.49-7.55 (m, 2H), 7.41 (d, J = 8.0 Hz, IH), 7.23 (d, J = 8.0 Hz, IH), 4.60 (s, 2H), 4.46 (t, J = 4.0, 8.0, Hz, 2H), 3.69 (t, J = 4.0, 8.0 Hz, 2H), 3.07-4.19 (broad band, 8H). [M+H] calc'd for C2IH2IBrF3N5O4, 544, 546; Found, 544, 546. [0205] Example 62: N-(4-methoxy-2-(trifiuoromethoxy)benzyl)-2-(2-morpholinoethyl)-3- oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000048_0002
[0206] The title compound was synthesized from N-(4-methoxy-2-(trifluoromethoxy)benzyl)- 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 2 by using 4-(2-chloroethyl)morpholine as an alkylating reagent. Purified by Mass- triggered HPLC (Gradient: 30-40% ACN containing 0.035% TFA in water containing 0.05% TFA) to give the TFA salt. 1H NMR (400 MHz, MeOD-d4) δ: 8.42 (s, IH), 7.66 (dd, J = 2.0, 8.0 Hz, IH), 7.41 (d, J = 8.0 Hz, IH), 7.25 (dd, J = 1.0, 8.0 Hz, IH), 6.92 (dd, J = 4.0, 8.0 Hz, IH), 6.84-6.87 (m, IH), 4.56 (s, 2H), 4.46 (t, J = 4.0, 8.0 Hz, 2H), 3.81 (s, 3H), 3.68 (t, J = 4.0, 8.0 Hz, 2H), 2.0-2.7 (broad band, 8H). [M+H] calc'd for C22H24F3N5O5, 496; Found, 496. [0207] Example 63: N-(4-cyano-2-(trifluoromethoxy)benzyl)-2-(2-morphorinoethyl)-3-oxo- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000049_0001
[0208] The title compound was synthesized from N-(4-bromo-2-(trifluoromethoxy)benzyl)-2- (2-morpholinoethyl)-3-oxo-2,3-dihydro-[ 1 ,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 46. Purified by Mass-triggered HPLC (Gradient: 30-40% ACN containing 0.035% TFA in water containing 0.05% TFA) to give the TFA salt. 1H NMR (400 MHz, DMSO-d6) δ: 8.47 (s, IH), 7.76 (t, J = 2.0, 2.0 Hz, IH), 7.73 (dd, J = 2.0, 8.0 Hz, IH), 7.64-7.69 (m, 2H), 7.27 (dd, J = 2.0, 8.0Hz, IH), 4.69 (d, J = 4.0 Hz, 2H), 4.47 (t, J = 4.0, 8.0 Hz, 2H), 3.69 (t, J = 4.0, 8.0 Hz, 2H), 3.10-4.21 (broad band, 8H). [M+H] calc'd for C22H2IF3N6O4, 491; Found, 491.
[0209] Example 64: N-(4-(cyclopropylsulfonyl)-2-(trifluoromethoxy)benzyl)-2-(2- morpholinoethyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000049_0002
[0210] The title compound was synthesized fromN-(4-bromo-2-(trifluoromethoxy)benzyl)-3- oxo-2-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 41. Purified by Mass-triggered HPLC (Gradient: 35-35% ACN containing 0.035% TFA in water containing 0.05% TFA) to give the TFA salt. 1H NMR (400 MHz, DMSO-d6) δ: 8.47 (s, IH), 7.99 (dd, J = 2.0, 8.0 Hz, IH), 7.81 (t, J = 2.0, 2.0 Hz, IH), 7.74 (d, J = 8.0 Hz, IH), 7.68 (dd, J = 2.0, 8.0Hz, IH), 7.27 (dd, J = 1.0, 1.0 Hz, IH), 4.2 (d, J = 4.0 Hz, 2H), 4.47 (t, J = 4.0, 8.0 Hz, 2H), 3.35-4.21 (broad band, 8H), 3.68 (t, J = 4.0, 8.0 Hz, 2H), 2.69-2.79 (m, IH), 1.22-1.27 (m, 2H), 1.05-1.12 (m, 2H). M+H] calc'd for C24H26F3N5O6S, 570; Found, 570. [0211] Example 65: N-(4-bromo-2-(trifluoromethoxy)benzyl)-2-(2-cyanoethyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000050_0001
[0212] To a solution of N-(4-bromo-2-(trifluoromethoxy)benzyl)-3-oxo-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide (5 g, 11.6 mmol) in DMSO (30 mL) was add CS2CO3 (5.12 g, 15.71mmol) at room temperature. The mixture was stirred 5 min then 3- chloropropanenitrile (1.2 ml, 15.3 mmol) was added. The mixture was stirred at room temperature overnight, partitioned with EtOAc and water to give a solid, which was collected by filtration, and washed with EtOAc to give the title compound. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and dried with MgSO4, filtered, and evaporated in vacuo to give an additional amount of the title compound. The combined yield was 3.6g (65%). [M+H] calc'd for Ci8Hi3F3N5O3, 484, 486; Found, 484, 486.
[0213] Example 66: N-(4-cyano-2-(trifluoromethoxy)benzyl)-2-(2-cyanoethyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000050_0002
[0214] To a solution of N-(4-bromo-2-(trifluoromethoxy)benzyl)-2-(2-cyanoethyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide (2.7 g, 5.58 mmol) in DMF (30 ml) was added Zn(CN)2 (0.655 g, 5.58 mmol) and tetrakis(triphenylphosphine) palladium (0) (645 mg, 0.56 mmol). The mixture was purged with N2 for 1 min. The vial was closed and heated 8O0C overnight. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried with MgSO4 and evaporates to a volume of about 2OmL to give a solid. The solid was collected by filtration and washed with EtOAc/Hexane (1 :1) and further purified by dissolving in 10OmL EtOAc (refluxing) and titration with hexane to about 1 to 1 ratio of EtOAc to Hexane at room temperature. The solid was collected by filtration to give 1.5 g (62.5%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 9.30 (t, J = 4.0, 8.0 Hz, IH), 8.61 (s, IH), 8.01 (t, J = 2.0, 2.0 Hz, IH), 7.90 (dd, J = 2.0, 8.0 Hz, IH), 7.68 (d, J = 8.0 Hz, IH), 7.62 (dd, J = 4.0, 8.0 Hz, IH), 7.35 (dd, J = 2.0, 8.0 Hz, IH), 4.58 (d, J = 4.0 Hz, 2H), 2H), 4.20 (t, J = 8.0, 8.0 Hz, 2H), 3.04 (t, J = 8.0, 8.0 Hz, 2H). [M+H] calc'd for Ci9Hi3F3N6O3, 431; Found, 431.
[0215] Example 67: (4-methoxy-2-(trifluoromethoxy)phenyl)methanamine [0216] To a mixture of 4-methoxy-2-(trifluoromethoxy)benzaldehyde (10Og, 450 mmol) in 1000 mL of EtOH was added hydroxylamine hydrochloride (38 g, 550 mmol) and potassium acetate (49 g, 500 mmol). The mixture was stirred at 500C for 5 h. The solvent was then removed on rotoray evaporator to give a white solid which was collected by filtration and washed with 2 potions of water. The solid product was dried overnight in vacuum to give 81 grams of the crude 4-methoxy-2-(trifluoromethoxy)benzaldehyde oxime (yield: 75%) that was used in next step without purification.
[0217] To a solution of 80 g of 4-methoxy-2-(trifluoromethoxy)benzaldehyde oxime in 1000 mL of MeOH was added 70 g of Zn dust and 126 g of ammonium formate. The mixture was stirred at room temperature for 5 h, then the mixture was filtered and the filtrate was evaporated under reduced pressure to give a residue. The residue was combined with 1 L of water and the pH was adjusted to 3-3.5. The aqueous phase was washed with 300 mL OfEt2O. Then the aqueous phase was made basic (pH 11-12) and was extracted with two portions 300 mL OfEt2O. After drying over K2CO3/Na2SO4, the solvent was evaporated on rotoray evaporator to give 36 g (yield: 48%) of the title compound which was used without purification. 1H NMR (400 MHz, MeOH-d4) δ: 7.52 (d, J = 8.59 Hz, IH), 7.03 (dd, J = 8.59, 2.53 Hz, IH), 6.95 (s, IH), 4.13 (s, 2H), 3.85 (s, 3H). [M+H] calc'd for C9Hi0F3NO2, 222; Found, 222.
[0218] Example 68: N-(4-methoxy-2-(trifluoromethoxy)benzyl)-3-oxo-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000051_0001
[0219] To a mixture of (4-methoxy-2-(trifluoromethoxy)phenyl)methanamine (35 g, 158 mmol) in 500 mL of DCM and 30 mL of pyridine was added dropwise 6-chloronicotinoyl chloride (36 g, 221 mmol) in 200 mL of DCM at 00C. After 4 h stirring at room temperature, 500 mL of water was added. The DCM phase was separated and washed with 5% water HCl and then twice with 150 mL of 10% K2C O3 aqueous solution. After evaporation of the solvent under reduced pressure and further drying under vacuum, 44.9 g (yield: 78%) of the crude 6-chloro-N-(4-methoxy-2-(trifluoromethoxy)benzyl)nicotinamide, which was used in the next step without further purification.
[0220] To a suspension of 6-chloro-N-(4-methoxy-2-(trifluoromethoxy)benzyl)nicotinamide (44.7 g, 124 mmol) in 400 mL of EtOH was added anhydrous hydrazine (25 g, 780mmol). The mixture was heated at 1100C in a IL medium pressure round bottomed flask for 8 hours, then the solvent and excess of hydrazine was removed by vacuum and the residue was diluted with 500 mL of water, to give a solid, which was collected by filtration, washed with water, and dried in vacuum to give 30.5 g (yield: 70%) of crude 6-hydrazinyl-N-(4-methoxy-2- (trifluoromethoxy)benzyl)nicotinamide which was obtained that was used in the next step without further purification.
[0221] To a solution of 6-hydrazinyl-N-(4-methoxy-2-(trifluoromethoxy)benzyl)nicotinamide (30 g, 84 mmol) in 200 mL of dry DMSO was added CDI (18.5 g, 114 mmol). The mixture was stirred at room temperature for 4 hours. LCMS showed that the reaction was complete. The mixture was diluted with 1000 mL of water and extracted with 3x400 mL portions of DCM. The organic layers were dried with K2CO3/Na2SO4 overnight and the solvent was evaporated on rotoray evaporator to give 28.5 g of a solid, which was collected by filtration and further purified by washing on the filter with 3x100 mL portions water and one 100 ml of Et2O to givel9 grams of the title compound. 1H NMR. 1H NMR (400 MHz, MeOH-d4) δ: 8.40 (t, J = 4.0, 4.0 Hz, IH), 7.59 (dd, J = 4.0, 8.0 Hz, IH), 7.40 (d, J = 8.0 Hz, IH), 7.21 (d, J = 12.0 Hz, IH), 6.92 (dd, J = 4.0, 12.0 Hz, IH), 6.85 (t, J = 4.0, 4.0 Hz, IH), 3.16 (s, 3H), 2.42 (m, IH), 2.17 (m, IH), 1.37 (m, IH), 1.02 (d, J = 8.0 Hz, 3H), 0.95 (d, J = 8.0 Hz, 3H). [M+H] calc'd for Ci6Hi3F3N4O4, 383; Found, 383.
[0222] Example 69: 2-(2 -hydroxy ethyl)-N-(4-methoxy-2-(trifluoro methoxy)benzyl)-3-oxo- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000053_0001
[0223] To a solution of N-(4-methoxy-2-(trifluoromethoxy)benzyl)-3-oxo-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide (9 g, 23 mmol) in 100 mL of dry DMF was added K3PO4 (8.5 g, 40 mmol). The mixture was stirred for 20 minutes at room temperature and then 2-bromoethanol (3.7 g, 30 mmol) was added. The mixture was stirred at room temperature overnight, then the reaction mixture was filtered and the filtration was evaporated on a rotoray evaporator to give a residue. The residue was dissolved in 100 mL of DCM and washed twice with water; the organic layer was dried over Na2SO4, filtered, and evaporated in vacuum to give a residue. The solid residue was purified on silica gel to give 7.8 g (yield: 76%) of the title compound. 1B NMR (400 MHz, MeOH-d4) δ: 8.39 (s, IH), 7.60 (d, J = 12.0 Hz, IH), 7.40 (d, J = 12.0 Hz, IH), 7.21 (d J = 8.0 Hz, IH), 6.90 (dd, J = 4.0, 8.0 Hz, IH), 6.85 (br s, IH), 4.55 (s, 2H), 4.08 (t, J = 8.0, 8.0 Hz, 2H), 3.91 (t, J = 4.0, 8.0 Hz, IH), 3.80 (s, 3H). [M+H] calc'd for Ci8Hi7F3N4O5, 427; Found, 427. [0224] Example 70: 4-(aminomethyl)-3-(trifluoromethoxy)benzonitrile [0225] A mixture of (4-bromo-2-(trifluoromethoxy)phenyl)methanamine HCl salt (2 g, 6.53 mmol), di-tert-butyl dicarbonate (2.85 g, 13.05 mmol) and NaHCO3 (5.48 g, 65.3 mmol) in dioxane was stirred overnight, then the solvent was removed in vacuum to give a residue. The residue was purified by column chromatography (5 -10% EtOAc in Hexane) to give 2.84 g of crude tert-butyl 4-bromo-2-(trifluoromethoxy)benzylcarbamate. 1H NMR (400 MHz, DMSO- d6) δ: 7.63 (dd, J = 1.77, 8.34 Hz, IH), 7.58 (t, J = 4.0 Hz, IH), 7.47 (t, J = 5.94 Hz, IH), 7.33 (d, J = 8.33 Hz, IH), 4.15 (d, J = 6.06 Hz, 2H), 1.46 (s , 9H).
[0226] A mixture of tert-butyl 4-bromo-2-(trifluoromethoxy)benzylcarbamate (146 mg, 0.394 mmol), Zn(CN)2 (46.3 mg, 0,394 mmol) and tetrakis(triphenylphosphine) palladium (0) (68.4mg, 0.059 mmol) in 2 mL of DMF was degassed for 5 minutes and the heated to 900C overnight, then the reaction mixture was filtered and purified by preparatory LCMS to give tert-butyl 4-cyano-2-(trifluoromethoxy)benzylcarbamate that was used in the next step without further purification. [0227] A solution of tert-butyl 4-cyano-2-(trifluoromethoxy)benzylcarbamate (125 mg,
0.394mmol) in 4 mL of DCM/TFA (9: 1) was stirred at room temperature for 1.5 hours. The solvent was removed and residue was purified by preparatory LCMS to give 63 mg (yield:
48.4%) of the title compound as its TFA salt. 1B NMR (400 MHz, DMSO-d6) δ: 7.78 -7.88
(m, 2H), 7.73-7.78 (m, IH), 4.28 (br. s, 2H).
[0228] Example 71 : (2-(4-fluorophenyl)pyridin-3-yl)methanamine
[0229] A mixture of 2-bromonicotinic acid (10 g, 50 mmol), p-fluorophenylboric acid (9 g,
60 mmol) and the solution OfNa2CO3 (42 g, 400 mmol) in 10OmL H2O was dissolved in 250 mL of DMF and added Pd(PPh3^ (5 g, 4.3 mmol) under N2 atmosphere were combined and heated at 900C for 2.5 hours. LC-MS indicated that the reaction was over. Concentrated and purified by column on silica gel (eluent: DCM/MeOH, 2:1) to give 9 g of 2-(4- fluorophenyl)nicotinic acid as a white solid.
[0230] To a suspension of 2-(4-fluorophenyl)nicotinic acid (5 g, 23 mmol) in 100 mL of THF and cooled in an ice bath was added BH3 in THF (105 mL, 105 mmol). When the addition is complete, the mixture was stirred overnight at room temperature before adding 40 mL of
MeOH. The reaction mixture was filtered, the filtrate concentrated in vacuum, and purified by column on silica gel (eluent: EA:MeOH=20: l) to give 4 g of (2-(4-fluorophenyl)pyridin-3- yl)methanol as a white solid.
[0231] To a solution of (2-(4-fluorophenyl)pyridin-3-yl)methanol (4 g, 20 mmol) in 60 mL of dry DCM was added SOCl2 (3.5 g, 30 mmol) and 0.5 mL of DMF at 00C. The reaction mixture was stirred for 3 hours at room temperature and then was combined with 100 mL of 1
N aq. Na2CO3 solution. The organic layer was separate and the aqueous layer was extracted three times with EtOAc. The combined organic phases were washed by water and brine, dried over Na2Sθ4, filtered, and concentrated to give 3.8 g of 3-(chloromethyl)-2-(4- fluorophenyl)pyridine.
[0232] To a solution of 3-(chloromethyl)-2-(4-fluorophenyl)pyridine (3.5 g, 16 mmol) in 60 mL of DMF was added NaN3 (1.2 g, 19.2 mmol). Then the reaction mixture was stirred at
700C for 6 hours and thenlOO mL of IN aq. Na2S2O3 solution was added. The reaction mixture was extract three times with EtOAc and the combined organic phases were washed by IN aq. Na2S2O3 solution, water, and brine, dried over Na2SC^, filtered, and concentrated to give 3.1 g of 3-(azidomethyl)-2-(4-fluorophenyl)pyridine.
[0233] To a solution of 3-(azidomethyl)-2-(4-fluorophenyl)pyridine (3.1 g, 13.6 mmol) in 30 mL of MeOH was added Pd/C (0.3 g). Then the reaction mixture was stirred under H2 atmosphere at 20 psi (138 kPa) at room temperature for 3 hours, then the reaction was filtered and concentrated to give 2.7 g of the title compound. 1HNMR (CD3OD, 400 MHz) δ: 3.90 (s, 2H), 7.27 (m, 2H), 7.50 (dd, J = 5.2 Hz, 8 Hz , IH), 7.48-7.50 (m, 2H), 7.52-7.57 (m, 2H), 8.09 (dd, J =0.8 Hz, 8 Hz, IH), 8.53 (dd, J = 1.2 Hz, 4.8 Hz , IH).
[0234] Example 72: 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carbonyl chloride [0235] To a solution of 6-chloronicotinic acid (20 g, 127 mmol) in 200 mL of EtOH was added hydrazine hydrate (14.8 mL, 317 mmol). The mixture was refluxed overnight, then cooled to room temperature to give a solid, which was collected by filtration, washed with petroleum ether/EA (2: 1) to give 18 g of 6-hydrazinylnicotinic acid as a yellow solid (Yield: 91%). 1HNMR (DMSO, 400MHz) δ: 8.52 (s, IH), 7.88 (dd, J = 2.0 Hz, 8.8 Hz, IH), 6.63 (d, J = 8.8Hz, IH).
[0236] To a suspension of 6-hydrazinylnicotinic acid (18 g, 117 mmol) in 100 mL of dry THF was added dry pyridine (23 g, 293 mmol), then the mixture was stirred at room temperature for 15 min, then bis(trichloromethyl)carbonate (80 g, 270 mmol) was added slowly. The reaction mixture was stirred overnight at room temperature, then MeOH was added and continued stirring for 15 hours to give a solid. The solid was collected by filtration and washed with petroleum ether/EA (1: 1) to give 20 g of dimethyl 3-oxo-[l,2,4]triazolo[4,3- a]pyridine-2,6(3H)-dicarboxylate. 1HNMR (CDCl3, 400MHz) δ: 3.95 (s, 3H), 4.13 (s, IH), 7.13 (dd, J = 1.6 Hz, 10 Hz, IH), 7.71 (dd, J = 1.6 Hz, 10 Hz, IH), 8.55 (t, J = 2 Hz, IH). [0237] To a solution of dimethyl 3-oxo-[l,2,4]triazolo[4,3-a]pyridine-2,6(3H)-dicarboxylate (10 g, 40 mmol ) in 60 mL of THF and 10 mL of H2O was added LiOH-H2O (4.8 g, 114 mmol), and then the reaction mixture was stirred at room temperature for 6 hours and then was concentrated in vacuo to remove THF, and then 1 mL of aq. HCl solution was added to adjust pH=2 to give a solid which was collected to give 1 Ig of compound 3-oxo-2,3-dihydro- [1 ,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid which was used without the further purification. 1HNMR (DMSO, 400MHz) δ: 7.23 (d, J = IO Hz, IH), 7.48 (dd, J = 1.6 Hz, 10
Hz, IH), 8.25 (s, IH), 9.13 (s, IH), 12.89 (s, IH).
[0238] To a solution of 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (3 g, 16.8 mmol) in 60 mL of dry DCM was added oxalyl chloride (8.8 g, 74 mmol) and 1 mL of
DMF. The reaction mixture was stirred for 6 hrs at room temperature and concentrated to give
[0239] 3 g of the title compound as a gray solid which was used without the further purification.
[0240] Example 73: N-((2-(4-fluorophenyl)pyridin-3-yl)methyl)-3-oxo-2,3-dihydro-
[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000056_0001
[0241] To a solution of (2-(4-fluorophenyl)pyridin-3-yl) methanamine (1.1 g, 6 mmol) in 20 mL of dry DCM was added 5 mL of pyridrine under N2 atmosphere was added 3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carbonyl chloride (2 g, 10 mmol). The reaction mixture was stirred overnight at room temperature and then concentrated in vacuo and purified by column on silica gel (eluent: DCM:MeOH=10:l) to give 0.5 g of the title compound. 1HNMR (CD3OD, 400 MHz) δ: 4.59 (s, IH), 7.25 (m, 3H), 7.48 (q, J = 3.2 Hz, IH), 7.54 (dd, J = 4.8 Hz, 8 Hz, IH), 7.58-7.62 (m, 2H), 7.98 (dd, J = 2 Hz, 8 Hz, IH), 8.37 (t, J = 2 Hz, IH), 8.53 (dd, J = 2 Hz, 8 Hz, IH). [M+H] calc'd for Ci9Hi4FN5O2, 364; Found, 364.
[0242] Example 74: N-((2-(4-fluorophenyl)pyridin-3-yl)methyl)-3-oxo-2-(pyridin-2- ylmethyl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000056_0002
[0243] To a solution of N-((2-(4-fluorophenyi)pyridin-3-yl)methyl)-3-oxo-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide (100 mg, 0.27 mmol) in 2 mL of DMSO was added K2CO3 (41 mg, 0.3 mmol). The reaction mixture was stirred at room temperature for 1 hr. Then 2-(bromomethyl)-pyridine hydrobromide (90 mg, 0.33 mmol) was added. The solution was stirred at 700C for 5 hours, and was filtered, concentrated in vacuo, and purified by column on silica gel (eluent: DCM:MeOH=20:l) to give 20 mg of the title compound. 1HNMR (CD3OD, 400MHz) δ: 4.60 (s, 2H), 5.329 (s, IH), 7.20-7.29 (m, 3H), 7.38 (dd, J = 4.8 Hz, 8.8 Hz, 2H), 7.47 (dd, J = 5.2 Hz, 8 Hz, IH), 7.57-7.61 (m, 3H), 7.83-7.87 (m, IH), 7.97 (d, J = 8 Hz, IH), 8.41(s, IH), 8.50-8.54 (m, 2H). [M+H] calc'd for C25Hi9FN6O2, 455; Found, 455.
[0244] Example 75: 2-(2-cyanoethyl)-N-((2-(4-fluorophenyl)pyridin-3-yl)methyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000057_0001
The title compound was synthesized from N-((2-(4-fluorophenyl)pyridin-3-yl)methyl)-3-oxo- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 74 by using 3-bromopropanenitrile. Purified by prep HPLC (Column: XB-Cl 8(5uM) 21.2 mm x 150mm) eluting with a gradient 10-60% ACN containing 0.0355 TFA in water containing 0.1% TFA) to give the title compound. 1HNMR (CD3OD, 400MHz) δ: 3.05 (t, J = 6.4 Hz, 2H), 4.30 (t, J = 6.4 Hz, 2H), 4.59 (s, IH), 7.24-7.29 (m, 3H), 7.47 (q, J = 3.2 Hz, IH), 7.57- 7.61 (m, 3H), 7.97 (d, J = 8 Hz, IH), 8.37 (s, IH), 8.53 (dd, J = 1.2 Hz, 4.8 Hz, IH). [M+H] calc'd for C22H17FN6O2, 417; Found, 417.
[0245] Example 76: 2-(2,2-difluoroethyl)-N-((2-(4-fluorophenyl)pyridin-3-yl)methyl)-3-oxo- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000058_0001
[0246] The title compound was synthesized from N-((2-(4-fluorophenyl)pyridin-3- yl)methyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 74 by using 1 ,l-difluoro-2-iodoethane. Purified by TLC eluted with
Pentane/EtOAc (3/1) to give 25 mg of the title compound. 1HNMR (CD3OD, 400MHz) δ:
4.40m, 2H), 4.592 (s, IH), 6.11-6.41 (m, IH), 7.23-7.29 (m, 3H), 7.47 (dd, J = 5.2 Hz, 8 Hz,
IH), 7.58-7.61 (m, 3H), 7.97 (d, J = 7.2 Hz, IH), 8.37(s, IH), 8.53(t ,J = 1.2Hz, 2H). [M+H] calc'd for C2IHi6F3N5O2, 428; Found, 428.
[0247] Example 77: N-((2-(4-fluorophenyl)pyridin-3-yl)methyl)-2-(2-hydroxyethyl)-3-oxo-
2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000058_0002
[0248] The title compound was synthesized from N-((2-(4-fluorophenyl)pyridin-3- yl)methyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 74 by using 2-bromoethanol. Purified by TLC eluted with Pentane/EtOAc (2/1) to give 25 mg of the title compound. 1HNMR (CD3OD, 400MHz) δ: 3.94 (d, J = 2.8 Hz, 2H), 4.09 (d, J = 5.2 Hz, 2H), 4.58 (s,lH), 7.20-7.28 (m, 3H), 7.47-7.50 (m, IH), 7.53-7.61 (m ,3H), 8.0 (d, J = 8 Hz, IH), 8.34 (s, IH), 8.53 (d, J = 3.6 Hz, 2H). [M+H] calc'd for C2IHi8FN5O3, 408; Found, 408.
[0249] Example 78: (3-(4-fluorophenyl)pyridin-2-yl)methanamine
[0250] To a solution of compound 3-bromopyridine (90 g, 0.573 mol) in 1 L of dry DCM was added m-CPBA (197 g, 1.146 mol) in a small portions with stirring over a period of 45 min at room temperature. Then the mixture was refluxed for 2 hours, cooled to room temperature, and 2 N aq. NaOH solution was added to the reaction mixture. The aqueous layer was extracted with DCM five times. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 60 g of the crude 3- bromopyridine 1 -oxide which was used without the further purification. [0251] To the solution of 3-bromopyridine 1 -oxide (60 g, 0.347 mol) and NEt3 (70.2 g, 0.694 mol) in 500 mL of ACN was added TMSCN (100.3 g, 0.104 mol) under N2 atmosphere. Then the solution was refluxed overnight, cooled, concentrated in vacuo, and purified by column chromatography on silica gel (eluent: EA:petroleum ether 1:4) to give 55 g of 3- bromopicolinonitrile.
[0252] A mixture of compound 3-bromopicolinonitrile (43 g, 0.236 mol), 4- fluorophenylboronic acid (33 g, 0.236 mol) and the solution OfNa2CO3 (50 g, 0.472 mol) in 235 mL OfH2O was dissolved in 500 mL of DMF and added Pd(PPh3)4 (10 g, 8.67 mmol) under N2 atmosphere. Then the solution was stirred overnight at 900C, then cooled, concentrated in vacuo, and purified by column chromatography on silica gel (eluent: EA/petroleum ether 1 :10) to give 38 g of compound 3-(4-fiuorophenyl)picolinonitrile. [0253] To a solution of 3-(4-fluorophenyl)picolinonitrile (15 g, 75.8 mmol) in 120 mL of dry THF was added LAH (5.76 g, 152 mmol) in a small portions with stirring over a period of 10 min at 00C. Then the reaction mixture was refluxed overnight before slowly adding consecutively 15 mL of H2O, 5.7 mL of 15% aq. NaOH solution and 5 mL of H2O for quench. The resulting mixture was filtered, and filtrate was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude title compound as a brown oil which was used without the further purification.
[0254] Example 79: N-((3-(4-fluorophenyl)pyridin-2-yl)methyl)-3-oxo-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000059_0001
[0255] The title compound was synthesized from 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3- a]pyridine-6-carbonyl chloride by a method similar to Example 73 using (3-(4- fiuorophenyl)pyridin-2-yl)methanamine. 1HNMR (CDCl3, 400MHz) δ: 4.51 (d, J = 5.2 Hz ,2H), 7.22 (d, J = 10 Hz, IH), 7.32 (t, J = 8.8 Hz, 2H), 7.40-7.42 (m, IH), 7.49-7.55 (m, 3H),
7.68 (dd , J = 1.6 Hz, 7.2 Hz, IH) , 8.45 ( s, IH ) ,8.59 (dd, J = 1.6 Hz, 4.8 Hz, IH), 9.03 (t,
J = 5.2 Hz, IH). [M+H] calc'd for Ci9Hi4FN5O2, 364; Found, 364.
[0256] Example 80: N-((2-(4-fluorophenyl)pyridin-2-yl)methyl)-3-oxo-2-(pyridin-2- ylmethyl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000060_0001
[0257] The title compound was synthesized fromN-((3-(4-fluorophenyl)pyridin-2- yl)methyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 74 by using 2-(bromomethyl)-pyridine hydrobromide as an alkylating reagent. 1HNMR (CD3OD, 400MHz) δ: 4.67 (s, 2H), 5.33 (s, 2H), 7.19-7.26 (m, 3H), 7.38 (t, J = 8 Hz, 2H), 7.43-7.50 (m, 3H), 7.58 (dd, J = 1.2 Hz, 10Hz, IH), 7.72-7.74 (m, IH), 7.83- 7.87 (m, IH), 8.42 (s, IH), 8.51 (d, J = 4.8 Hz, IH), 8.58 (d, J = 4 Hz, IH). [M+H] calc'd for C25Hi9FN6O2, 455; Found, 455.
[0258] Example 81 : 2-(2,2-difluoroethyl)-N-((2-(4-fluorophenyl)pyridin-2-yl)methyl)-3-oxo- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000060_0002
[0259] The title compound was synthesized fromN-((3-(4-fluorophenyl)pyridin-2- yl)methyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 74 by using l,l-difluoro-2-iodoethane as an alkylating reagent. HNMR
(CD3OD, 400MHz) δ: 4.35-4.43 (m, 2H), 4.66 (d, J = 8.0 Hz ,1H), 6.11-6.41 (m, IH), 7.24 (t,
J = 8.0 Hz, 3H), 7.43-7.50 (m, 3H), 7.59 (dd, J = 1.2 Hz, 9.6Hz, IH), 7.30(dd, J = 1.2 Hz, 8.0
Hz , IH), 8.38(s, IH), 8.53(dd , J = 1.6Hz, 4.8Hz, 2H). [M+H] calc'd for C2IHi6F3N5O2, 428;
Found, 428.
[0260] Example 82: N-((2-(4-fluorophenyl)pyridin-2-yl)methyl)-2-(2 -hydroxy ethyl)-3-oxo-
2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
[0261] The title compound was synthesized fromN-((3-(4-fluorophenyl)pyridin-2- yl)methyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide by a method similar to Example 74 by using by using 2-bromoethanol as an alkylating reagent. HNMR
(CD3OD, 400MHz) δ: 3.92 (t, J = 5.6 Hz, 2H), 4.09 (t, J = 5.6 Hz, 2H), 4.63 ( s , IH ) ,7.19-
7.24 (m, 3H), 7.42-7.47 (m, 3H), 7.54 (dd , J = 1.6 Hz , 10.0 Hz ,1H), 7.70 (dd, J = 1.6 Hz, 7.6 Hz , IH), 8.36 (t, J = 1.2 Hz , IH), 8.54-8.56 (m, IH). [M+H] calc'd for C2iHi8FN5O3, 408; Found, 408.
[0262] Example 83: 4-(aminomethyl)-3-(trifluoromethoxy)benzonitrile [0263] A solution of 4-bromo-l-iodo-2-(trifluoromethoxy)benzene (4.95 g, 13.49 mmol) in THF (80 mL) was cooled in a dry ice/acetone bath under an atmosphere of nitrogen. To the reaction mixture was added n-BuLi (16.86 mL, 27.0 mmol) dropwise over 13 min while maintaining an internal temperature ranging from -112° C to -65.50C. The reaction was stirred at -77°C for 60 min. Then, DMF (2.2 mL, 28.3 mmol, 2.1 equiv) was added to the reaction mixture dropwise at -76.5 0C. The reaction was stirred at this temperature for 2 hours followed by the addition of a 0.25 M aqueous citric acid solution (55 mL). The bath was removed and the reaction was allowed to reach room temperature. The two phases were separated and the aqueous layer was extracted with MTBE (3x100 mL). The combined organic layers were washed with water (50 mL) and the solvent removed in vacuo to give crude 4-bromo-2-(trifluoromethoxy)benzaldehyde, 3.32g (91%). 1H NMR (d6-DMSO, 400 MHz): 10.18 (s, IH, CHO), 7.89-7.86 (m, 3H, aromatic). 13C NMR (d6-DMSO, 100 MHz): 187.6, 148.93, 131.70, 131.46, 128.85, 127.57, 125.35, 119.73 (q, J = 1032Hz). [0264] 4-Bromo-2-(trifluoromethoxy)benzaldehyde (3.32 g, 12.34 mmol) was dissolved in MeOH (35 mL). The reaction mixture was cooled to about -6 0C and then sodium borohydride (0.47 Ig; 12.34 mmol) was added. After stirring for 60 min, additional sodium borohydride (24 mg, 0.617 mmol) was added. After an additional hour of stirring, the reaction mixture was quenched by addition of acetone (5 mL), followed by slow addition of IN HCl (5 mL). Most of the solvent was removed in vacuo at 35 0C. Water (10 mL) was added to the crude reaction mixture, which was then extracted with MTBE (2x50 mL). The combined organic layers were then washed with half-saturated brine solution (50 mL) and the organic solvent was evaporated in vacuo to give a residue which was purified by flash column chromatography (Hex:EtOAc=4:l) to give (4-bromo-2-(trifluoromethoxy)phenyl)methanol. 1H NMR (de-DMSO, 400 MHz): 7.66-7.64 (m, IH, aromatic), 7.57-7.54 (m, 2H, aromatic), 5.47 (t, J = 4Hz, IH, CH2OH), 4.52 (d, J = 8Hz, 2H, CH2OH).
[0265] (4-Bromo-2-(trifluoromethoxy)phenyl)methanol (0.2 g, 0.738 mmol), zinc cyanide (0.087 g, 0.738 mmol), and tetrakis(triphenylphosphine) palladium (0) (0.085 g, 0.074 mmol) were combined. The vessel was flushed with nitrogen and then dry DMF (1.5 mL) was added. The vessel was again flushed with nitrogen for 1 min, sealed tightly, and the reaction was heated at 80 0C for 17 hours. After quenching by addition of water (1.5 mL), the crude reaction mixture was extracted with MTBE (2x1.5 mL). The organic layers were combined, the solvent was removed in vacuo, and the product was purified by flash chromatography to give 117 mg of 4-(hydroxymethyl)-3-(trifluoromethoxy)benzonitrile. 1H NMR (dβ-DMSO, 400 MHz): 7.94-7.91 (m, 2H, aromatic), 7.81-7.79 (m, IH, aromatic), 5.64 (t, J = 4Hz, IH, CH2OH), 4.63 (d , J = 8Hz, 2H, CH2OH). 13C NMR (d6-DMSO, 100 MHz): 145.03, 141.26, 131.66, 129.50, 124.14, 119.91 (q, J = 1024Hz), 117.49, 110.98, 57.06. [M+H] calc'd for C9H6F3NO2, 218.05; Found, 218.04.
[0266] 4-(Hydroxymethyl)-3-(trifluoromethoxy)benzonitrile (3.48 g, 16.03 mmol) was placed in a vessel and kept under a nitrogen atmosphere. Dichloromethane (32 mL) was added followed by triethylamine (2.70 mL, 19.23 mmol). After stirring for 5 minutes, methanesulfonyl chloride (1.370 mL, 17.63 mmol) was added dropwise. The internal temperature rose from 23 0C to 40 0C during the addition. After 30 min, water (20 mL) was added, the phases were separated and the aqueous layer was washed with MTBE (20 mL). The combined organic phases were concentrated to dryness to give 4-cyano-2- (trifluoromethoxy)benzyl methanesulfonate which was used without further purification. [0267] To 4-cyano-2-(trifluoromethoxy)benzyl methanesulfonate was added DMF (32.0 mL) and, under a nitrogen atmosphere, potassium phthalimide (4.46g, 24.34 mmol) was added to the reaction at 0 0C. The reaction was stirred at this temperature for 60 min, then warmed to room temperature and stirred for 12 hours at room temperature. Water (25 mL) was added to the reaction mixture to give a solid which was collected by filtration, washed thoroughly with water and, dried under vacuum at room temperature to give 4.22g of 4-((l,3-dioxoisoindolin- 2-yl)methyl)-3-(trifluoromethoxy)benzonitrile. 1H NMR (d6-DMSO, 400 MHz): 8.03-8.02 (m, IH, aromatic), 7.94-7.85 (m, 5H, aromatic), 7.71-7.69 (d, J = 8Hz, IH, aromatic), 4.89 (s, 2H). 13C NMR (de-DMSO, 100 MHz): 167.42, 145.91, 134.83, 134.61, 131.74, 131.55, 131.15, 124.60, 123.28, 119.91 (q, J = 1028 Hz), 117.21, 112.11, 36.15. [0268] To a suspension of 4-((l ,3-dioxoisoindolin-2-yl)methyl)-3- (trifluoromethoxy)benzonitrile (1 g, 2.89 mmol) in MeOH (13 mL) was added hydrazine hydrate (0.420 mL, 8.66 mmol; 64 % solution) at room temperature. Then, the mixture was heated to 600C over aboutl5 min. After 2 hours, the reaction was cooled to room temperature, filtered, and the filtrate was concentrated to obtain a white solid, which was slurried in cold isopropanol and then filtered again. Concentration of the filtrate gave the title compound as a solid. 1H NMR (in DMSO, 400 MHz): 7.93-7.84 (m, 3H, aromatic), 3.83 (s, 2H5 CH2NH2), 2.40-2.1 (br s, 2H, CH2NH2). 13C NMR (in DMSO, 100 MHz): 145.59, 143.01, 131.52, 130.37, 124.13, 119.96 (q, J = 1024Hz), 117.57, 110.41. [M+H] calc'd for C9H7F3N2O, 217.10; Found, 217.05.
[0269] Example 84: 2-(2-hydroxyethyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6- carboxylic acid
[0270] To a 5000 mL 3-neckflask was added 6-chloronicotinic acid (462 g, 2932 mmol) followed by methyl carbazate (295 g, 3177 mmol). Then, water (2000 mL) was added at room temperature, followed by isopropanol (150 mL). The resulting suspension was then heated to about 95 0C for about 17 hours using a heating mantle while stirring gently. The reaction was cooled to room temperature to give a solid. 50% Aqueous NaOH (307 mL, 5865 mmol) was added over 30 min. The pH was adjusted to pH=8.4 by addition of cone HCl (about 39 mL). The reaction mixture was then heated back to about 94 0C and stirred at this temperature for about 48 hours. The mixture was then cooled to about 46 0C and cone HCl (400 mL) was added over 1-2 minutes to give a pH~0. The reaction mixture was cooled to room temperature, the solid filtered, the filter cake was rinsed with water (3x250 mL), dried first by suction, then in vacuo at 100 0C, to afford 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6- carboxylic acid (449.86 g, 2498 mmol, 85 % yield). 1H NMR (400 MHz; d6-DMSO): 13.28 (bs, 1 H), 12.65 (bs, 1 H), 8.26 (dd, 1 H, J-1.7 Hz, J- 1 Hz, 1 H), 7.46 (dd, J-1.6 Hz, J-9.9 Hz, 1 H), 7.24 (dd, J-I Hz, J=9.9 Hz); 13C NMR (IOO MHz; d6-DMSO): 114.99, 115.49, 128.26, 128.55, 141.94, 149.64, 165.07; [M+H]+ m/z (pos mode); Found, 180.05. [0271] To a 250 mL 3-neck flask with overhead stirrer was added 3-oxo-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (20.07 g, 112 mmol) followed by acetonitrile (100 mL). Then, diisopropylethylamine (39.5 mL, 226 mmol) was added followed by 2- bromoethanol (16.31 mL, 224 mmol). The reaction mixture was to heated to 65° C. After about 19 hours, more diisopropylethylamine (9.78 mL, 56.0 mmol) was added, followed by more 2-bromoethanol (3.96 mL, 56.0 mmol), and the mixture was stirred at 65° C for an additional 20 hours. The reaction mixture was concentrated by atmospheric distillation. Then, isopropanol (100 mL) was added and the mixture was again concentrated by atmospheric distillation. This process was repeated 3 more times. Then, the mixture was stirred while cooling to room temperature and then further cooled to give a suspension. After about 16 hours, water (40 mL) was added to this suspension and a solution was obtained. Solid NaOH (14.09 g, 353 mmol) was added and the mixture heated to 40-450C for about 5.5 hours, then stirred at room temperature overnight. The reaction mixture was concentrated by vacuum distillation at about 145mbar to an internal temperature of about 45-500C. Once the distillation subsided, more water (40 mL) was added, the internal temperature was increased to about 50-550C, and the distillation continued at about 145mbar. When reaching an internal temperature of 55°C, solids began to precipitate. The distillation was stopped and water (25 mL) was added, resulting in a clear solution (pH=8-9). The mixture was cooled to 0 0C, then, cone HCl (about 30 mL) was added while maintaining an internal temperature of 0-50C. After completion of the addition of HCl, a suspension was obtained which was granulated at about 00C for about 60 minutes, then filtered and rinsed with isopropanol (20 mL). The solid was dried in vacuo at 700C to afford the title compound (21.33 g, 95 mmol, 85 % yield) as a light yellow solid. 1H NMR (400 MHz; d6-DMSO): 13.33 (bs, 1 H), 8.28 (dd, 1 H, J-1.7 Hz, J-1.2 Hz, 1 H), 7.51 (dd, J-1.7 Hz, J-9.8 Hz, 1 H), 7.29 (dd, J-1.2 Hz, J-9.7 Hz); 4.71 (bs, 1 H), 3.95 (t, J-5.7, 2 H), 3.74 (t, J-5.7, 2 H); 13C NMR (100 MHz; d6-DMSO): 48.12, 58.42, 114.97, 115.20, 128.12, 128.70, 140.44, 148.27, 165.01; [M+H]+ m/z (pos mode); Found 224.05.
[0272] Example 85: N-(4-cyano-2-(trifluoromethoxy)benzyl)-2-(2-cyanoethyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000065_0001
[0273] To a 3L 3-neck flask, equipped with an overhead stirrer, was added 3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (101.5 g, 567 mmol) followed by isopropanol (600 mL). To the suspension was added solid NaHCO3 (238 g, 2833 mmol) at room temperature. Next, water (600 mL) was added in three portions while stirring vigorously. The mixture was stirred at room temperature overnight. Then, 3- chloropropanenitrile (133 mL, 1700 mmol) was added, and the thick yellow suspension was heated at 65°C for about 4 hours, then water (250 mL) was added and the the reaction was heated at 65°C for about 20 hours. The resulting clear brown solution (pH=8.9) was cooled to about 23°C and carefully acidified with cone HCl (about 160 mL) until pH=0.35. The mixture was cooled to 2-3 0C, granulated at that temperature for about 5 hours, and then filtered, dried in vacuo at 60-610C to constant weight to afford 2-(2-cyanoethyl)-3-oxo-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (92.22 g, 396 mmol, 69.8 % yield) as a yellow solid. 1H NMR (400 MHz; d6-DMSO): 13.38 (bs, 1 H), 8.29 (dd, J-1.2 Hz, J-1.4 Hz, 1 H), 7.55 (dd, J-1.7 Hz, J-9.8 Hz, 1 H), 7.32 (dd, J=LO Hz, J=9.9 Hz, 1 H), 4.20 (t, J-6.5 Hz, 2 H), 3.04 (t, J~6.5 Hz); 13C NMR (IOO MHz; d6-DMSO): 16.91, 41.13, 114.96, 115.54, 118.32, 128.19, 129.37, 140.98, 147.86, 164.89 ; [M+H]+ m/z (pos mofde); Found, 233.00. [0274] Into a 2L 3-neck flask were added (in the following order) 4-(aminomethyl)-3- (trifluoromethoxy)benzonitrile hydrochloride (54.9 g, 217 mmol), 2-(2-cyanoethyl)-3-oxo- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (50 g, 215 mmol), NMP (50 mL), N-ethyl-N-isopropylpropan-2-amine (75 ml, 431 mmol), lH-benzo[d][l,2,3]triazol-l-ol (HOBt) (32.0 g, 237 mmol), andNl-((ethylimino)methylene)-N3,N3-dimethylpropane-l,3- diamine hydrochloride (EDCI) (45.4 g, 237 mmol). The reaction mixture was stirred at room temperature for 46 hours, then, a mixture of water/isopropanol (85: 15, 1000 mL) was added. The resulting suspension was granulated at room temperature, filtered, and dried by suction to afford the title compound (81.5 g, 189 mmol, 88 % yield).
[0275] Example 86: N-(4-cyano-2-(trifluoromethoxy)benzyl)-3-oxo-2-(pyridin-2-ylmethyl)- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000066_0001
[0276] Using a 3-neck 1000 mL flask with overhead stirring, sulfuric acid (59.5 mL, 1116 mmol) was added to a suspension of 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6- carboxylic acid (100 g, 558 mmol) in EtOH (400 mL, 6851 mmol). The yellow suspension was heated at reflux for about 24 hours. The suspension was then cooled to approximately 300C, the precipitate was filtered, and rinsed with cold EtOH (150 mL,:30 0C) to afford ethyl 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxylate (79.24 g, 382 mmol, 68.5 % yield) as a solid. 1H NMR (400 MHz; d6-DMSO): 12.71 (bs, 1 H), 8.30 (m, 1 H), 7.48 (dd, J=I.8 Hz, J=9.8 Hz, 1 H), 7.29 (dd, J=LO Hz, J=9.9 Hz), 4.32 (quart, J=7.0 Hz, 2 H), 1.33 (t, J=7.1 Hz, 3 H); 13C NMR (IOO MHz; d6-DMSO): 14.03, 61.15, 114.16, 115.77, 128.06, 128.58, 141.84, 149.62, 163.63; [M+H]+ m/z (pos mode); Found, 208.10. [0277] In a 3-neck 3000 mL flask, DMSO (865 mL) was added to a mixture of ethyl 3-oxo- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxylate (86.37 g, 417 mmol) and potassium carbonate (particle size about 325 mesh) (127 g, 917 mmol) at room temperature. An orange suspension was obtained, which was stirred with an overhead stirrer. Next, 2- (chloromethyl)pyridine hydrochloride (77 g, 459 mmol) was added and the suspension was heated to about 100 0C. After about 3 hours, the mixture was cooled to 10-15 0C and an ice- cold solution of cone HCl (18 mL) in water (350 mL) was added within 60-70 min. Then the mixture was granulated for about 19 hours while warming to room temperature. The mixture was cooled to 0-5 0C, then filtered, the filter cake rinsed with cold water (3x170 mL) and then dried in vacuo at about 70 0C until constant weight to afford ethyl 3-oxo-2-(pyridin-2- ylmethyl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxylate (122.49 g, 411 mmol, 99 % yield). 1H NMR (400 MHz; d6-DMSO): 8.51 (m, 1 H), 8.36 (m, 1 H), 7.78 (dt, J=I.8 Hz, 7.6 Hz), 7.53 (dd, J=I.6 Hz, J=9.8 Hz), 7.27-7.33 (m, 3 H), 5.23 (s, 2 H), 4.33 ( quart, J=7.1 Hz, 2 H), 1.34 (t, J=7.3 Hz, 3 H); 13C NMR (IOO MHz; d6-DMSO): 14.01, 50.49, 61.22, 114.57, 115.23, 121.89, 122.83, 128.56, 128.62, 136.96, 140.74, 148.34, 149.19, 155.34, 163.52; [M+H]+ m/z (pos mode); Found, 299.10.
[0278] To a suspension of ethyl 3-oxo-2-(pyridin-2-ylmethyl)-2,3-dihydro-[l,2,4]triazolo[4,3- a]pyridine-6-carboxylate (122.45 g, 410 mmol) in MeOH (1050 mL) was added a solution of sodium hydroxide (19.70 g, 493 mmol) in water (100 mL). The flask with the NaOH-solution was rinsed with water (5 mL) and the rinse added to the reaction mixture. The mixture was stirred at room temperature for about 16 hours. The resulting suspension was concentrated by atmospheric distillation at 66-67 0C. After the removal of about 600 mL of MeOH, isopropanol (1000 mL) was added and atmospheric distillation was continued. After about 720 mL of distillate had been collected, more isopropanol (1000 mL) was added. As the distillation progressed, the internal temperature increased to about 84 0C. After a total of about 1680 mL of distillate had been collected, the heating was removed and isopropanol (500 mL) was added. The mixture was cooled back to room temperature and acidified with cone HCl (45 mL). After granulation overnight, the suspension was filtered and the filter cake was rinsed with isopropanol/water (9: 1 ; 500 mL), and dried at 100 0C in vacuo to afford 3-oxo-2- (pyridin-2-ylmethyl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (123.13 g, 456 mmol, 111 % yield). 1H NMR (400 MHz; d6-DMS0): 13.45 (bs, 1 H), 8.51 (m, 1 H), 8.32 (m, 1 H), 7.78 (dt, J=I.7 Hz, 7.6 Hz), 7.53 (dd, J=I .8 Hz, J=9.9 Hz), 7.30-7.33 (m, 2 H), 7.27 (dd, J=LO Hz, J=9.8 Hz, 1 H), 5.22 (s, 2 H); 13C NMR (100 MHz; d6-DMS0): 50.41, 115.00, 115.39, 121.91, 122.85, 128.34, 129.11, 137.01, 140.84, 148.34, 149.19, 155.38, 164.96; [M+H]+ m/z (pos mode); Found, 271.00.
[0279] Into a 20 mL vial were charged the following substrates and reagents (in the following order): 4-(aminomethyl)-3-(trifluoromethoxy)benzonitrile hydrochloride (1 g, 3.96 mmol), 3- oxo-2-(pyridin-2-ylmethyl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (1.284 g, 4.75 mmol), NMP (8 mL), and diisopropylethylamine (1.383 mL, 7.92 mmol). The mixture was briefly warmed until almost all solids dissolved resulting in a slightly turbid mixture upon stirring. After cooling back to room temperature, lH-benzo[d][l,2,3]triazol-l-ol (HOBt) (0.588 g, 4.35 mmol) was added, followed by Nl-((ethylimino)methylene)-N3,N3- dimethylpropane- 1,3 -diamine hydrochloride (EDCI) (0.911 g, 4.75 mmol) and the mixture was stirred at room temperature for 18.5 hours, then water (8 mL) was added. The resulting suspension was stirred for 95 min, and then filtered. The filter cake was rinsed with water (45 mL), then dried in vacuo at 100 0C to afford the title compound. (1.423 g, 3.04 mmol, 77 % yield).
[0280] Example 87: N-(4-cyano-2-(trifluoromethoxy)benzyl)-3-oxo-2-(pyridin-2-ylmethyl)- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide sulfate [0281] A suspension of N-(4-cyano-2-(trifluoromethoxy)benzyl)-3-oxo-2-(pyridin-2- ylmethyl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide (702 mg, 1.498 mmol) in acetonitrile (60 mL) was heated close to reflux until a clear solution was obtained; then the solution was stirred while cooling. At about 510C sulfuric acid (0.087 mL, 1.573 mmol) was added dropwise via syringe to the solution, upon which formation of a white precipitate occurred; the contents of the syringe were rinsed into the flask with additional acetonitrile (2 mL) and the mixture was stirred gently overnight while cooling back to room temperature. Filtration of the solids and rinsing with acetonitrile (10 mL) followed by drying at 70 0C in vacuo afforded N-(4-cyano-2-(trifluoromethoxy)benzyl)-3-oxo-2-(pyridin-2-ylmethyl)-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide sulfate (680 mg; 1.200 mmol; 80 % yield). 1H NMR (400 MHz; d6-DMSO): 9.6-8.8 (very broad s, 2 H), 9.32 (t, J=5.5 Hz, 1 H), 8.72 (m. 1 H), 8.64 (m, 1 H), 8.18 (dt, J=I.5 Hz, J=7.8 Hz, 1 H), 8.00 (m, 1 H), 7.90 (dd, J=I.5 Hz, J=8.1 Hz, 1 H), 7.62-7.69 (m, 4 H), 7.31 (dd, J=Ll Hz, J=9.9 Hz, 1 H), 5.41 (s, 2 H), 4.59 (d, J=5.6 Hz, 2 H); 13C NMR (100 MHz; d6-DMSO): 37.55, 48.40, 111.47, 114.85, 117.37, 117.81, 118.69, 121.26, 124.03, 124.51, 124.62, 125.71, 129.33, 130.65, 131.71, 137.75, 141.25, 141.66, 145.93, 148.65, 153.01, 163.40; [M+H]+ m/z (pos mode); Found, 469.1.
[0282] Example 88: N-(4-cyano-2-(trifluoromethoxy)benzyl)-3-oxo-2-(pyridin-2-ylmethyl)- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide hydrochloride [0283] N-(4-Cyano-2-(trifluoromethoxy)benzyl)-3-oxo-2-(pyridin-2-ylmethyl)-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide (3.4 g, 7.26 mmol) was suspended in acetonitrile (250 mL) and heated to reflux, upon which dissolution occurred. Then, HCl (4N in dioxane) (3.63 mL, 14.52 mmol) was added at 64-65 °C resulting briefly in a clear solution. Upon further stirring and cooling to room temperature, a precipitate formed, which was granulated for about 3 hours. Filtration, rinsing with acetonitrile (50 mL), and drying under high vacuum afforded N-(4-cyano-2-(trifluoromethoxy)benzyl)-3-oxo-2-(pyridin-2-ylmethyl)- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide hydrochloride (3.166 g, 6.27 mmol, 86 % yield). 1H NMR (400 MHz; d6-DMSO): 9.44 (t, J=5.6 Hz, 1 H), 9-7.5 (very broad s, 1 H), 8.72 (m. 1 H), 8.66 (m, 1 H), 8.20 (dt, J=I .5 Hz, J=7.9 Hz, 1 H), 8.02 (m, 1 H), 7.91 (dd, J=I.6 Hz, J=8.1 Hz, 1 H), 7.65-7.70 (m, 4 H), 7.31 (dd, J=LO Hz, J=9.8 Hz, 1 H), 5.45 (s, 2 H), 4.58 (d, J=5.6 Hz, 2 H); 13C NMR (100 MHz; d6-DMSO): 37.48, 48.14, 111.43, 114.82, 117.39, 117.76, 118.69, 121.25, 124.08, 124.59, 125.79, 129.33, 130.60, 131.72, 137.82, 141.27, 141.83, 145.53, 145.91, 148.66, 152.92, 163.39; [M+H]+ m/z (pos mode); Found, 469.1.
[0284] Example 89: 2-(2-cyanoethyl)-N-(4-methoxy-2-(trifluoromethyl)benzyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000069_0001
[0285] To a 100 mL round-bottomed flask equipped for stirring under nitrogen was added 3- oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (0.50 g, 2.79 mmol). Water (Ratio: 1.000, Volume: 7 ml), 2-propanol (7 ml), 3-chloropropanenitrile (0.219 ml, 2.79 mmol), and sodium bicarbonate (1.172 g, 13.96 mmol) were added and the reaction mixture was allowed to stir at 65 0C for 72h. Most of the solvent was removed via rotovap at 4O0C to give a residue which was treated with IN HCl till pH<l is achieved which gave a solid. Solid product was filtered. Washed with water and dried by suction on filter to give 381 mg of 2- (2-cyanoethyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid. 1H NMR (OMSO-d6, 400 MHz) δ: 13.43 (br. s, IH), 8.29 (dd, J = 1.6, 1.1 Hz, IH), 7.55 (dd, J = 9.7, 1.6 Hz, IH), 7.33 (dd, J = 9.9, 1.3 Hz, IH), 4.19 (t, J = 6.3 HZ, 2H), 3.03 (J = 6.4 Hz, 2H). [M+H] calc'd for Ci0H8N4O3, 233; Found, 233.
[0286] To a 8 mL vial fitted with a teflon cap was added 2-(2-cyanoethyl)-3-oxo-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (100 mg, 0.431 mmol) and IH- benzo[d][l,2,3]triazol-l-ol (61.1 mg, 0.452 mmol) and DMF (2 mL), Nl- ((ethylimino)methylene)-N3,N3-dimethylpropane-l,3-diamine hydrochloride (87 mg, 0.452 mmol) and (4-methoxy-2-(trifluoromethyl)phenyl)methanamine (89 mg, 0.435 mmol) and the reaction mixture was allowed to stir at 250C for 16h. Reaction was then diluted with 15mL water to give a solid. The solid product was filtered and dried by suction, added into 1 OmL 30% isopropanol in water, broke up with a spatula, sonicated, and then heated to 650C to give a solution which was allowed to cool to room temperature to give a solid upon standing. The solid was collected by filtration, washed with 1OmL 30% isopropanol in water and dried by suction to give 132.7 mg of the title compound. 1H NMR (DMSO-d6, 400 MHz) δ: 9.16 (t, J = 5.6 Hz, IH), 8.61 (t, J = 1.4 Hz, IH), 7.64 (dd, J = 9.9, 1.5 Hz, IH), 7.50 (d, J = 8.6 Hz, IH), 7.34 (dd, J = 9.9, 0.8 Hz, IH), 7.20-7.26 (m, 2H), 4.56 (d, J = 5.3 Hz, 2H), 4.20 (t, J = 6.3 Hz, 2H), 3.82 (s, 3H), 3.03 (t, J = 6.3 Hz, 2H). [M+H] calc'd for Ci9Hi6F3N5O3, 420; Found, 420. [0287] Example 90: N-(4-chloro-2-(trifiuoromethyl)benzyl)-2-(2-cyanoethyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide
Figure imgf000071_0001
[0288] To a 8 mL vial fitted with a teflon cap was added 2-(2-cyanoethyl)-3-oxo-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (100 mg, 0.431 mmol) and IH- benzo[d][l,2,3]triazol-l-ol (61.1 mg, 0.452 mmol), DMF (Volume: 2.0 ml), Nl- ((ethylimino)methylene)-N3,N3-dimethylpropane-l,3-diamine hydrochloride (87 mg, 0.452 mmol) and (4-chloro-2-(trifluoromethyl)phenyl)methanamine (91 mg, 0.435 mmol) and the reaction mixture was allowed to stir at 250C for 16h. Reaction was diluted with 15mL water to give a solid. The solid product was filtered and dried by suction. Solid product was added into 1OmL 30% isopropanol in water, broke up with a spatula, sonicated, and then heated to 650C. An additional 3mL isopropanol was added and again the solid was broken up with a spatula, the mixture was sonicated, then heated to 650C to give a suspension which was allowed to cool to room temperature. The solid was collected by filtration, washed with 1OmL 30% isopropanol in water and dried by suction to give 77.6 mg of the title compound. 1H NMR (DMSO-^, 400 MHz) δ: 9.28 (t, J = 5.7 Hz, IH), 8.61-8.65 (m, IH), 7.81 (d, J = 2.3 Hz, IH), 7.76 (dd, J = 8.5, 2.1 Hz, IH), 7.57-7.66 (m, 2H), 7.35 (dd, J = 9.7, 1.1 Hz, IH), 4.60 (d, J = 5.3 Hz, 2H), 4.20 (t, J = 6.3 Hz, 2H), 3.04 (t, J = 6.3 Hz, 2H). [M+H] calc'd for Ci8Hi3ClF3N5O2, 424; Found, 424.
[0289] The compounds of the invention can be administered alone or in the form of a pharmaceutical composition. In practice, the compounds of the invention are usually administered in the form of pharmaceutical compositions, that is, in admixture with pharmaceutically acceptable excipients the proportion and nature of which are determined by the properties of the selected compound of the invention, the chosen route of administration, and standard pharmaceutical practice.
[0290] In another embodiment, the present invention provides pharmaceutical compositions comprising: a compound of invention and a pharmaceutically acceptable excipient. [0291] In effecting treatment of a patient in need of such treatment, a compound of the invention can be administered in any form and route which makes the compound bioavailable. The compounds of the invention can be administered by a variety of routes, including oral and parenteral routes, more particularly by inhalation, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, vaginally, occularly, topically, sublingually, and buccally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, intraadiposally, intrathecally and via local delivery for example by catheter or stent. [0292] One skilled in the art can readily select the proper form and route of administration depending upon the particular characteristics of the compound selected, the disorder or condition to be treated, the stage of the disorder or condition, and other relevant circumstances. The pharmaceutical compositions of the invention may be administered to the patient, for example, in the form of tablets, capsules, cachets, papers, lozenges, wafers, elixirs, ointments, transdermal patches, aerosols, inhalants, suppositories, solutions, and suspensions. [0293] The pharmaceutical compositions of the present invention are prepared in a manner well known in the pharmaceutical art and include at least one of the compounds of the invention as the active ingredient. The amount of a compound of the present invention may be varied depending upon its particular form and may conveniently be between 1 % to about 70% of the weight of the unit dosage form. The term "pharmaceutically acceptable excipient" refers to those typically used in preparing pharmaceutical compositions and should be pharmaceutically pure and non-toxic in the amounts used. They generally are a solid, semisolid, or liquid material which can serve as a vehicle or medium for the active ingredient. Some examples of pharmaceutically acceptable excipients are found in Remington's Pharmaceutical Sciences and the Handbook of Pharmaceutical Excipients and include diluents, vehicles, carriers, ointment bases, binders, disintegrates, lubricants, glidants, sweetening agents, flavoring agents, gel bases, sustained release matrices, stabilizing agents, preservatives, solvents, suspending agents, buffers, emulsifiers, dyes, propellants, coating agents, and others.
[0294] The present pharmaceutical compositions are preferably formulated in a unit dosage form, each dosage typically containing from about 0.5 mg to about 200 mg of the compounds of the invention. The term "unit dosage form" refers to a physically discrete unit suitable as a single dosage, each unit containing a predetermined quantity of active ingredient, in association with a suitable pharmaceutical excipient, by which one or more is used throughout the dosing regime to produce the desired therapeutic effect.
[0295] In one particular variation, the composition is a pharmaceutical composition adapted for oral administration, such as a liquid formulation, for example, a solution or suspension, adapted for oral administration or a tablet or a capsule. In still another particular variation, the pharmaceutical composition is a liquid formulation adapted for parenteral administration. [0296] In another embodiment, the invention provides methods of treating conditions associated with sEH, comprising: administering to a patient in need thereof an effective amount of a compound of the invention. In another embodiment, the invention provides a method of inhibiting a sEH: comprising, contacting the enzyme with a compound of the invention. In another embodiment, the invention provides a method of inhibiting a sEH: comprising, administering a compound of the invention to a patient in order to inhibit the enzyme in vivo. In a further embodiment, the invention provides a method of inhibiting a sEH: comprising, administering a first compound to a subject that is converted in vivo to a compound of the invention.
[0297] In another embodiment, compounds of the invention, including the compound of formula I, are provided for use as a medicament. The invention also provides the use of compounds of the invention for the manufacture of a medicament to treat the conditions associated with sEH described herein. The compounds of the present invention are stable and are relatively safe in their end use. The compounds of the present invention are useful as sEH inhibitors for a variety of subjects (e.g., humans, non-human mammals and non-mammals). [0298] As used herein terms "condition," "disorder," and "disease" relate to any unhealthy or abnormal state. The term "conditions associated with sEH" includes disorders and diseases in which the inhibition of sEH provides a therapeutic benefit, such hypertension, metabolic syndrome, obesity, elevated triglycerides, elevated cholesterol, glucose intolerance, atherosclerosis, coronary artery disease, cardiac fibrosis, angina, ischemia, stroke, renal disease, inflammation, including arthritis, renal inflammation, hepatic inflammation, vascular inflammation, and respiratory inflammation, adult respiratory distress syndrome and chronic obstructive pulmonary disease, emphysema, chronic bronchitis, interstitial lung disease, and idiopathic pulmonary fibrosis, systematic inflammatory response syndrome, pain, itching, irritation of the skin, dermatoses, sunburn, mild burns, prurtius, genitourinary disorders, overactive bladder, outlet obstructions, outlet insufficiency, benign prostatic hyperplasia, interstitial cystitis, erectile dysfunction, incontinence, and the like. Where general terms are used herein to describe conditions associated with sEH it is understood that the more specifically described conditions mentioned in the various diagnostic manuals and other materials are included within the scope of this invention. For example, it is understood that the treatment of renal disease includes treatment of kidney disease, albuminuria, diabetic neuropathy, chronic kidney disease, fibrosis of the kidney, amyloidosis, acquired cystic kidney disease, nephritic syndrome, and proteinuria. For example, it is understood that the treatment of inflammatory conditions includes the treatment of arthritis and that arthritis is presently categorized into several more specific disorders, such as osteoarthritis and rheumatic arthritis, and others all of which are contemplated by the invention. Another example is systematic inflammatory response syndrome which is used to describe inflammation events associated with lupus, sepsis, pancreatitis, multiple trauma, lacerations, brain injury or surgery, hemorrhagic shock and immune-mediated organ injuries and others all of which are contemplated by the invention. Yet another example is itching, which includes itching of the skin due to insect bites, allergic reaction, and contact dermatitis, pruritus, eczema, hives, chicken pox, impetigo, and others, all of which are contemplated by the invention.
[0299] The terms "treat," "treatment," and "treating" include improvement of the conditions described herein. Also, it is also recognized that one skilled in the art may affect the conditions by treating a patient presently afflicted with the disorders or by prophylactically treating a patient believed to be susceptible to such conditions with an effective amount of a compound of invention. Thus, the terms "treat," "treatment," and "treating" include all processes providing slowing, interrupting, arresting, controlling, or stopping of the state or progression of the conditions described herein, but does not necessarily indicate a total elimination of all symptoms or a cure of the condition, and is intended to include prophylactic and therapeutic treatment of such disorders.
[0300] As used herein the terms "patient" and "subject" includes humans and non-human animals, for example, mammals, such as mice, rats, guinea pigs, dogs, cats, rabbits, cows, horses, sheep, goats, and pigs. The term also includes birds, fish, reptiles, amphibians, and the like. It is understood that a more particular patient is a human. Also, more particular patients and subjects are non-human mammals, such as mice, rats, and dogs. [0301] As used herein, the term "effective amount" refers to the amount of compound of the invention which treats, upon single or multiple dose administration, a patient suffering from the mentioned condition. An effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount, the dose, a number of factors are considered by the attending diagnostician, including, but not limited to: the species of patient; its size, age, and general health; the specific condition, disorder, or disease involved; the degree of or involvement or the severity of the condition, disorder, or disease, the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances. An effective amount of the present use invention, including a compound of the invention, is expected to vary from about 0.1 milligram per kilogram of body weight per day (mg/kg/day) to about 20 mg/kg/day. Specific amounts can be determined by the skilled person.
[0302] In a particular embodiment the present invention provides a method for treating metabolic syndrome, comprising: administering to a patient in need thereof an effective amount of a compound of invention. In a more particular embodiment the present invention provides a method for treating hypertension comprising: administering to a patient in need thereof an effective amount of a compound of the invention.
[0303] A variety therapeutic agents may have a therapeutic additive or synergistic effect when used in combination with sEH inhibitors according to the present invention. Such combination therapy can include administration concurrently or sequentially with therapy and/or an agent for the treatment of any of the conditions associated with sEH. [0304] In particular, the present compounds may be combined calcium channel blockers, lipid lowering agents, cholesterol lowering agents, such as statins, fibrates, beta-blockers, ACE inhibitors, platelet aggregation inhibitors, diuretics, glucose lowering agents, insulin, and the like.
[0305] The invention also provides an article of manufacture: comprising at least one compound of the invention and a label. The label may include information about the manufacturer, doses, conditions to be treated, and the use of the compound or pharmaceutical composition.
[0306] In another embodiment the invention provides a kit: comprising, at least one compound of the invention, a label, and apparatus for administration. The apparatus may include mixing vials, liquids for forming solutions or suspensions, tubing, syringes, and the like.
[0307] The activity of compounds as sEH inhibitors may be determined by a variety of methods, including in vitro and in vivo methods. [0308] Example A Inhibition of human and rat sEH
[0309] For human sEH, DNA encoding the full-length sequence of the human enzyme was amplified by PCR and cloned into the pI-SUMOstar (LifeSensors), which incorporates a 6 x His_ SUMO tag at N-terminus. For rat sEH, DNA encoding the full-length sequence of the rat enzyme was amplified by PCR and cloned into the pFastBacHTb vector (Invitrogen), which incorporates a 6 x His tag at N-terminus
[0310] Recombinant protein was isolated from cellular extracts by passage over ProBond Nickel resin (Invitrogen). The N-terminal 6 x His SUMO (human sEH) or 6 x His (rat sEH) tag was removed from partially purified sEH protein by incubating with SunoStar Proteinase 1 (LifeSensor) or rTEV enzyme respectively. Partially purified and tag removed sEHs were purified by high pressure liquid chromatography over a BioSep S3000 gel filtration column for human sEH or by Nickel reverse purification and dialyzation for rat sEH. The purity of sEH proteins was determined on denaturing SDS-PAGE gel. The proteins were either stored at -78 oC or - 20 oC in a buffer containing 25mM TRIS-HCl pH 7.6, 125mM NaCl and 50% glycerol for human sEH or in a buffer containing 5OmM TRIS 7.9, 20OmM NaCl, 50% glycerol for rat sEH .
[0311] The sEH inhibitory properties of test compounds were determined using a black 384- well-plate format under the following reaction conditions: 20 mM Tris pH 7.0, 0.1 mM EDTA, 0.1 mg/ml BSA, 5 μM PHOME (substrate from Cayman Chemical), 2 nM sEH enzyme, 1% DMSO (from test compound). Reaction product was determined quantitatively by fluorescence intensity using a Fluorescence plate reader (Molecular Devices Gemini) with an excitation wavelength at 330 nm and emission at 465 nm.
[0312] The assay reaction was initiated as follows: 2 μl of 5 times intermediate diluted inhibitor was added to each well of the plate, followed by the addition of 4 μl of 2.5 x sEH enzyme solution and incubated for 10 minutes at room temperature. After incubation, 4 ul of 2.5X substrate solution was added to initiate the reaction. Fluorescence intensities of the resulting reaction mixtures were measured after 20 minute (human sEH) or 10 minute (rat sEH) incubation at room temperature. A dose-response curve was constructed by diluting the test compound 2-fold in 11 subsequent dilutions and determining the percent inhibition of catalytic activity relative to control for each dilution of a single test compound. In order to determine the IC50 value of a test compound, a dose-response curve is first constructed by plotting on the Y-axis the percent relative to a control compound exhibiting complete inhibition of enzymatic activity versus the concentration of inhibitor on the X-axis. The IC50 value is extrapolated from the dose-response curve at the concentration of test compound which exhibits 50% inhibition relative to control on the Y-axis. The values expressed in Table 1 are pIC50 (negative log (base 10) of the IC50 in moles per liter). All of the exemplified compounds inhibited human sEH in the assay of Example A with a pIC50 of greater than about 5.8. Illustrative pIC5o values are given in Table 1.
TABLE 1
Figure imgf000077_0001
Figure imgf000078_0001
[0313] Example B Determination of sEH inhibition in cellular assay: [0314] The cellular sEH activity can be assayed by its hydration of 14,15-EET and producing 14,15-DHET which is secreted out of the cell into the culture medium (Eagle's MEM (ATCC), 10% Fetal Bovine Serum (Hyclone), 1 x NEAA (Invitrogen), 1 x L- Glutamine (Invitrogen)).
[0315] HepG2 hepatocellular carcinoma cells (ATCC) (30,000 cells/well) or ACHN renal cell adenocarcinoma (ATCC) (35,000 cells/well) are seeded in 96-well tissue culture cell bind plates. Cultures are incubated overnight at 370C in a 5% CO2 incubator until cells are attached and spread. 14,15-EET (Biomol International) is added to final concentration of 6 uM and inhibitor is added to the desired final concentration in total volume of 200ul per well. Prior to addition to cells compounds are serially diluted (1 :3) from column 1 to 11 and column 12 contained DMSO vehicle. Compounds are diluted into cell growth medium then compound solution is added to cells. Equal amounts of DMSO are added to each well (final DMSO concentration is 0.5%). Cultures are incubated for 2 hours at 370C in a 5% CO2 incubator. The resulting 14,15-DHET amount in the cell culture medium can be directly detected using a 14,15-DHET ELISA kit (Detroit R&D, Inc.), and measuring the OD450 nm with a Spectamax microplate reader (Molecular Devices, San Diego, CA). After background correction and normalization against DMSO-treated cells, EC50 values are calculated using non-linear curve-fitting of the secreted 14,15-DHET as a function of compound concentration.
[0316] Example C Reduction of plasma 14,15-DHET in vivo
[0317] Test compounds at 3 mg/kg sEH inhibitor in 0.5 % methyl cellulose or the vehicle control is orally administrated to SHR rats (6 rats/group, 13 weeks old males, Charles River Laboratories) daily for two days. Plasma is collected (200 μl_ in heparinized tubes at 4 h post dose on day 1 and 4, 8 and 24 h post dose on day 2. The samples are frozen at -80 OC until analysis. The lipids are extracted from the plasma sample with acetonitrile which contains
14,15-DHET-dl 1 [80OuL of IOng/mL] as an internal standard, and the extract is blown dry and reconstituted into 100 ul 60/40 water/acetonitrile. 14,15-DHET calibration was obtained by spike in known amount of 14,15-DHET (0.5, 1, 2.5, 20, 25, 100, 200, 500, 1000, 2000ng/mL) into blank plasma and extract the lipids with 80OuL acetonitrile containing IOng/mL 14,15-DHET-dl 1 as internal standard, and the extract was blown dry and reconstituted into lOOuL 60/40 water/acetonitrile. The 14,15-DHET levels are determined by LC/MRM. The 14,15-DHET was monitored using 337.4/207.1 (Q1/Q3) MRM transition, and 14,15-DHET-dl 1 was monitored using 348.4/207.1 (Q1/Q3) MRM transition. The concentration of 14,15-DHET in plasma sample (in ng/mL) was determined from the calibration curve by integrating and correcting the MRM data using the internal standard. The final results are reported as % reduction of 14,15-DHET relative to vehicle control rats. [0318] Example D Blood pressure lowering effect in vivo
[0319] Male Sprague Dawley (SD) rats (7 - 8 weeks old from Harlan) are surgically implanted under isoflurane anesthesia with an osmotic mini-pump (Alzet 2ML2) which administer 1.0 mg/kg/day Angiotensin II subcutaneously for 14 days. The rats are accessible to food and water ad libitum. The rats are randomized on day 13 (6 rats/group) by systolic blood pressure. The rats are orally dosed with 3 or 10 mg/kg of test compound formulated in 0.5% methylcellulose on day 14 and blood pressure is measured at 4 hr post dosing through non-invasive tail-cuff system under light anesthesia.

Claims

What is claimed is:
1. A compound selected from the group consisting of 6-chloro-N-(4-methoxy-2- (trifluoromethoxy)benzyl)nicotinamide, 6-hydrazinyl-N-(4-methoxy-2- (trifluoromethoxy)benzyl)nicotinamide, (2-(4-fluorophenyl)pyridin-3-yl)methanamine, 2-(4- fluorophenyl)nicotinic acid, (2-(4-fluorophenyl)pyridin-3-yl)methanol, 3-(chloromethyl)-2-(4- fluorophenyl)pyridine, 3-(azidomethyl)-2-(4-fluorophenyl)pyridine, 3-oxo-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carbonyl chloride, dimethyl 3-oxo-[l,2,4]triazolo[4,3- a]pyridine-2,6(3H)-dicarboxylate, 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6- carboxylic acid, (3-(4-fluorophenyl)pyridin-2-yl)methanamine, 4-(aminomethyl)-3- (trifluoromethoxy)benzonitrile, (4-nitro-2-(trifluoromethoxy)phenyl)methanamine, (4-fluoro- 2-(trifiuoromethoxy)phenyl)methanamine, (4-chloro-2- (trifluoromethoxy)phenyl)methanamine, (4-(methylsulfonyl)-2- (trifluoromethoxy)phenyl)methanamine, (4-(cyclopropylsulfonyl)-2- (trifluoromethoxy)phenyl)methanamine, 5-(4-(aminomethyl)-3- (trifluoromethoxy)phenyl)pyridin-2-amine, 5-(4-(aminomethyl)-3- (trifluoromethoxy)phenyl)pyrimidin-2-amine, l-(4-(aminomethyl)-3- (trifluoromethoxy)phenyl)-4-hydroxypyrrolidin-2-one, l-(4-(aminomethyl)-3- (trifluoromethoxy)phenyl)imidazolidin-2-one, 3-(4-(aminomethyl)-3-
(trifluoromethoxy)phenyl)oxazolidin-2-one, 4-(aminomethyl)-3-(trifluoromethoxy)aniline, (4- (methylsulfonyl)-2-(trifiuoromethyl)phenyl)methanamine, (4-(cyclopropylsulfonyl)-2- (trifluoromethyl)phenyl)methanamine, 5-(4-(aminomethyl)-3- (trifluoromethyl)phenyl)pyridin-2-amine, 5-(4-(aminomethyl)-3-
(trifluoromethyl)phenyl)pyrimidin-2-amine, l-(4-(aminomethyl)-3-(trifluoromethyl)phenyl)- 4-hydroxypyrrolidin-2-one, and 1 -(4-(aminomethyl)-3-(trifluoromethyl)phenyl)imidazolidin- 2-one, 3-(4-(aminomethyl)-3-(trifluoromethyl)phenyl)oxazolidin-2-one; 2-(2 -hydro xyethyl)- 3-oxo-2,3-dihydro-[l ,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid; 2-(2-cyanoethyl)-3-oxo- 2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid; and 3-oxo-2-(pyridin-2- ylmethyl)-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid; or a salt thereof.
2. A process for making a compound of the formula
Figure imgf000081_0001
wherein
Ri is selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, optionally substituted C4-14 aryl, optionally substituted C3-8 cycloalkyl, optionally substituted
Ci-io heteroaryl, and optionally substituted C3-6 heterocycloalkyl;
Wi is selected from the group consisting of N and CR3;
W2 is selected from the group consisting of N and CR3;
W3 is selected from the group consisting of N and CR3; provided that no more than one of Wi, W2, and W3 is N; and each R3 is independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-4 alkenyl, cyano, C3-8 cycloalkyl, halo, and hydroxy; comprising the steps of reacting a compound of the formula
Figure imgf000081_0002
wherein X is a halogen and a compound of the formula
Figure imgf000081_0003
wherein Ri is as described above and R is selected from the group consisting of C1-4 alkyl, 2,2,2 -trichloroethyl, and optionally substituted benzyl; to give a compound of the formula
Figure imgf000081_0004
and cyclization.
3. A process according to claim 2 wherein Ri is hydrogen.
4. A process according to any one of claims 2 or 3 where R is methyl.
5. A process according to any one of claims 2 to 4 wherein W1, W2, and W3 is each CR3 and each R3 is hydrogen.
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