WO2010129848A2 - 2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamides - Google Patents

2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamides Download PDF

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WO2010129848A2
WO2010129848A2 PCT/US2010/034000 US2010034000W WO2010129848A2 WO 2010129848 A2 WO2010129848 A2 WO 2010129848A2 US 2010034000 W US2010034000 W US 2010034000W WO 2010129848 A2 WO2010129848 A2 WO 2010129848A2
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benzyl
dioxo
tetrahydropyrimidine
carboxamide
trifluoromethoxy
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PCT/US2010/034000
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French (fr)
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WO2010129848A3 (en
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Jun Feng
Walter Keung
Matthew Lardy
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Takeda Pharmaceutical Company Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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.
  • Ar is selected from the group consisting of C 4 _i 4 aryl and C 1-10 heteroaryl
  • Ri is selected from the group consisting of hydrogen, optionally substituted C3-8 cycloalkyl, optionally substituted C3-6 heterocycloalkyl, and optionally substituted Ci_6 alkyl;
  • R 2 is selected from the group consisting of optionally substituted Ci_ 6 alkyl, Ci.g sulfonyl, optionally substituted C2-4 alkenyl, optionally substituted Ci_4 alkoxy, optionally substituted C2-6 alkynyl, amino, Ci_8 alkylamino, Ci_ 2 o amide, optionally substituted C 4 -I 4 aryl, optionally substituted C 4 _i4 aryloxy, C 1 .
  • compositions which comprise a compound of formula I, tautomer, or pharmaceutically acceptable salt as defined above, and a pharmaceutically acceptable excipient.
  • the compounds of the invention are inhibitors of sEH that are useful for the treatment of conditions associated with sEH, including hypertension.
  • the invention provides methods of treating conditions associated with sEH, which comprise administering to a patient in need of treatment an effective amount of a compound of formula I, tautomer, or pharmaceutically acceptable salt as defined above.
  • the present invention provides for the use of compounds of formula I, tautomer, or pharmaceutically acceptable salt as defined above, 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, which comprises at least one compound of formula I, tautomer, or pharmaceutically acceptable salt as defined above, and a label.
  • kits which comprise at least one compound of the invention, a label, and apparatus for administration of the inhibitor.
  • the present invention also provides processes from making sEH inhibitors and intermediates thereof.
  • Compounds of this invention include all pharmaceutically acceptable complexes, salts, solvates, and hydrates thereof.
  • Compounds of this invention also include all stereoisomers, tautomers, and polymorphic forms thereof, including all crystalline and amorphous forms, whether they are pure, substantially pure, or mixtures.
  • substituted when used in connection with a chemical substituent or moiety (e.g., an alkyl group), means that one or more hydrogen atoms of the substituent or moiety have been replaced with one or more non-hydrogen atoms or groups, provided that valence requirements are met and that a chemically stable compound results from the substitution.
  • a chemical substituent or moiety e.g., an alkyl group
  • C2-4 alkenyl refers to a straight or branched hydrocarbon chain having from two to four carbon atoms and one or more carbon-carbon double bonds, and includes ethenyl, 1-propen-l-yl, l-propen-2-yl, 2-propen-l-yl, 1-buten-l-yl, l-buten-2-yl, 3-buten-l-yl, 3-buten-2-yl, 2-buten-l-yl, 2-buten-2-yl, 2 -methyl- 1-propen-l-yl, 2-methyl- 2-propen-l-yl, 1,3-butadien-l-yl, l,3-butadien-2-yl, 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 Ci_4 alkoxy, Ci_9 amide, Ci_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 hydrocarbon chain having from one to four carbon atoms, and includes methyl, ethyl, n-propyl, /-propyl, n-butyl, s- butyl, /-butyl, and /-butyl.
  • 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, Ci_ 4 alkoxy, Ci_ 4 thioalkoxy, Ci_g amide, Ci_g alkylamino, Ci_ 5 oxycarbonyl, cyano, C3-8 cycloalkyl, C3-8 cycloalkoxy, halo, hydroxy, nitro, oxo, optionally substituted C3-6 heterocycloalkyl, optionally substituted C 1-10 heteroaryl, and optionally substituted phenyl.
  • Ci_ 6 alkyl refers to a straight or branched alkyl chain having from one to six carbon atoms.
  • optionally substituted Ci_6 alkyl refers to a Ci_6 alkyl optionally having from 1 to 7 substituents independently selected from the group consisting of amino, Ci_g alkylamino, C2-4 alkenyl, Ci_4 alkoxy, Ci_4 thioalkoxy, Ci_9 amide, Ci_5 oxycarbonyl, cyano, C 3 _ 8 cycloalkyl, halo, hydroxy, optionally substituted
  • C3_6 heterocycloalkyl optionally substituted C 1-10 heteroaryl, and optionally substituted phenyl.
  • Ci_8 sulfonyl refers to a sulfonyl linked to a Ci_6 alkyl group
  • Ci_4 alkoxy refers to a Ci_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 C2-4 alkenyl, Ci_ 4 alkoxy, Ci_ 9 amide, Ci_ 5 oxycarbonyl, cyano, C 3 _ 8 cycloalkyl, halo, hydroxy, optionally substituted C 1-10 heteroaryl, and optionally substituted phenyl.
  • C2-6 alkynyl refers to a straight or branched hydrocarbon chain having from two to six carbon atoms and one or more carbon-carbon triple bonds.
  • alkynyl groups examples include ethynyl, 1-propyn-l-yl, 2-propyn-l-yl, 1-butyn-l-yl,
  • 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 Ci_4 alkoxy, Ci_9 amide, Ci_5 oxycarbonyl, cyano, C3-8 cycloalkyl, halo, hydroxy, optionally substituted C 1-10 heteroaryl, and optionally substituted phenyl.
  • Ci_9 amide refers to an amide having two groups independently selected from the group consisting of hydrogen and Ci_4 alkyl, for example, -C(O)NH2,
  • Ci_ 2 o amide refers to an amide having two groups independently selected from the group consisting of hydrogen, optionally substituted Ci_6 alkyl, C3-8 cycloalkyl, optionally substituted C 1-10 heteroaryl, optionally substituted C3-6 heterocycloalkyl, optionally substituted C 1-10 heteroaryl, and optionally substituted C 4-14 aryl or an amide formed by an N-linked, optionally substituted nitrogen-containing C 3 _ 6 heterocycloalkyl, for example, (piperidin-l-yl)carbonyl.
  • Ci_ 7 amido refers to a -NHC(O)R group in which R is Ci_ 6 alkyl.
  • Ci_5 carbamoyl refers to an O- or N-linked carbamate having a terminal Ci_ 4 alkyl.
  • Ci_5 ureido refers to a Ci_4 alkyl-urea group.
  • Ci_g alkylamino refers to an amino group substituted with one or two
  • Ci_4 alkyl groups are Ci_4 alkyl groups.
  • C 4 -I 4 aryl refers to a monocyclic or 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 _i 4 aryl refers to a C 4 _i 4 aryl optionally having 1 to 5 substituents independently selected from the group consisting of amino, Ci_g alkylamino, Ci_7 amido, Ci_2o amide, hydroxycarbamimidoyl, Ci_5 carbamoyl, Ci_6 sulfonylamido, C 0 - 6 sulfonylamino, Ci_ 5 ureido, optionally substituted Q_ 4 alkyl, optionally substituted Ci_ 4 alkoxy, cyano, halogen, hydroxyl, nitro, Ci_5 oxycarbonyl, and Ci_8 sulfonyl and optionally having 2 of the optional substituents taken together to form an optionally substituted C 3-6 heterocycloalkyl.
  • C 4 _i 4 aryloxy refers to a C 4 _i 4 aryl attached through an oxygen atom.
  • C 4 _i 4 aryloxy refers to a C 4 _i 4 aryloxy optionally having 1 to 5 substituents independently selected from the group consisting of amino, Ci_g alkylamino, d_ 4 alkyl, Ci_ 4 alkoxy, cyano, halogen, hydroxyl, nitro, Ci_g sulfonyl, and trifluoromethyl.
  • Ci_ 5 oxycarbonyl refers to an oxycarbonyl group (-CO 2 H) and Ci_ 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.
  • 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 Ci_ 4 alkyl, C 2 - 4 alkenyl, Ci_ 4 alkoxy, Ci_9 amide, Ci_7 amido, Ci_ 8 alkylamino, Ci_ 5 oxycarbonyl, cyano, C 3 _ 8 cycloalkyl, C 3 _ 8 cycloalkoxy, halo, hydroxy, nitro, oxo, optionally substituted C 1-10 heteroaryl, and optionally substituted phenyl.
  • C3_8 cycloalkoxy refers to a C3_8 cycloalkyl attached through an oxygen atom.
  • C 3 _ 6 heterocycloalkyl refers to a 4 to 10 membered monocyclic saturated or partially (but not fully) unsaturated ring having one to four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the term includes, but is not limited to azetidine, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, tetrahydrofuran, hexahydropyrimidine, tetrahydropyrimidine, dihydroimidazole, and the like.
  • optionally substituted C3-6 heterocycloalkyl refers to a C3_6 heterocycloalkyl optionally substituted on the ring carbons with 1 to 4 substituents independently selected from the group consisting of optionally substituted Ci_ 4 alkyl, C2-4 alkenyl, Ci_4 alkoxy, Ci_9 amide, Ci_7 amido, Ci_8 alkylamino, Ci_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 Ci_ 4 alkyl, C 2 - 4 alkenyl, C 3 _s cycloalkyl, optionally substituted C3-6 heterocycloalkyl, optionally substituted C 1-10 heteroaryl, and optionally substituted phenyl.
  • optionally substituted nitrogen-containing C 3 _ 6 heterocycloalkyl refers to a 4 to 10 membered monocyclic saturated or partially (but not fully) unsaturated ring having at least one nitrogen and optionally one or more additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the term includes, but is not limited to azetidine, pyrrolidine, piperidine, piperazine, morpholine, and the like.
  • heterocycloalkyl When optionally substituted such a nitrogen-containing C 3 _ 6 heterocycloalkyl may have on the ring carbons 1 to 4 substituents independently selected from the group consisting of optionally substituted Ci_ 4 alkyl, C2-4 alkenyl, Ci_ 4 alkoxy, Ci_9 amide, Ci_g alkylamino, Ci_5 oxycarbonyl, cyano, C3-8 cycloalkyl, C3-8 cycloalkoxy, halo, hydroxy, nitro, oxo, optionally substituted C3-6 heterocycloalkyl, and optionally substituted phenyl; and may be optionally substituted on any additional ring nitrogen with a substituent selected from the group consisting of optionally substituted Ci_ 4 alkyl, C2-4 alkenyl, C3_8 cycloalkyl, optionally substituted C 1-10 heteroaryl, and optionally substituted phenyl.
  • substituents independently selected from the group consisting of optionally substituted Ci
  • C 1-10 heteroaryl refers to five to twelve membered monocyclic or polycyclic unsaturated and 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, but is not limited to azepine, diazepine, furan, thiophene, imidazole, isothiazole, isoxazole, oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, thiazole, thiadiazole, triazole, tetrazole, benzazepine, benzodiazepine, benzofuran, benzothiophene, benzimidazole, imidazopyridine, pyrazolopyridine, pyrrolopyridine, quinazoline, thienopyridine, indolizine, imidazopyridine, quinoline, isoquinoline, indole, isoindole, benzoxazole, benzoxadiazole, 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, Ci_7 amido, Ci_8 alkylamino, Ci_2o amide, hydroxycarbamimidoyl, Ci_5 carbamoyl, Ci_6 sulfonylamido, Co-6 sulfonylamino,Ci_5 ureido, optionally substituted Ci_4 alkyl, optionally substituted Ci_4 alkoxy, cyano, halogen, hydroxyl, oxo, nitro, Ci_5 oxycarbonyl, and Ci_g sulfonyl and optionally having substituents on each nitrogen independently selected from the group consisting of optionally substituted C M alkyl, Ci_g sulfonyl, optionally substituted C3-6 heterocycloalkyl, 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 pyridone 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, Ci_ 4 alkoxy, cyano, halogen, hydroxyl, nitro, oxo, Ci_ 8 sulfonyl, and trifluoromethyl and optionally having substituents on each nitrogen independently selected from the group consisting of optionally substituted C M alkyl, Ci_g sulfonyl, and optionally substituted phenyl.
  • phenyl refers to a phenyl group optionally having 1 to 5 substituents independently selected from the group consisting of amino, C 2 - 4 alkenyl, C 1-4 alkyl, Ci_4 alkoxy, Ci_9 amide, Ci_8 alkylamino, Ci_5 oxycarbonyl, cyano, halogen, hydrogen, hydroxyl, nitro, Ci_ 8 sulfonyl, and trifluoromethyl.
  • Ci_ 6 sulfonylamido refers to a -NHS(O) 2 -R group wherein R is Ci_ 6 alkyl.
  • Co-6 sulfonylamino refers to a -S(O) 2 NH-R group wherein R is selected from the group consisting of hydrogen and is Ci_6 alkyl.
  • Ci_4 thioalkoxy refers to a Ci_4 alkyl attached through a sulfur atom.
  • 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 include those described in Journal of Pharmaceutical Science, 66, 2-19
  • stereoisomer and “stereoisomers” of a compound with given stereochemical configuration refer to the opposite enantiomer of the compound and to any diastereoisomers, including geometrical isomers (ZIE) of the compound.
  • ZIE geometrical isomers
  • a compound has S,R,Z stereochemical configuration, its stereoisomers would include its opposite enantiomer having R,S,Z configuration, and its diastereomers having S,S,Z configuration, R,R,Z configuration, S,R,E configuration, R,S,E configuration, S,S,E configuration, and R,R,E configuration.
  • stereochemical configuration of a compound is not specified, then “stereoisomer” refers to any one of the possible stereochemical configurations of the compound.
  • substantially pure stereoisomer and variants thereof refer to a sample containing a compound having a specific stereochemical configuration and which comprises at least about 95% of the sample.
  • pure stereoisomer and variants thereof refer to a sample containing a compound having a specific stereochemical configuration and which comprises at least about 99.5% of the sample.
  • pure stereoisomer refers to a sample containing a compound having a specific stereochemical configuration and which comprises at least about 99.5% of the sample.
  • One embodiment relates to compounds of formula I wherein Ar is C 4 _i 4 aryl.
  • Another embodiment relates to compounds of formula I wherein Ar is phenyl.
  • Another embodiment relates to compounds of formula I wherein Ar is pyridyl.
  • Another embodiment relates to compounds of formula I and embodiments a, b, c, and d, above, and f, g, h, i, j, k, 1, m, n, o, p, q, r, and s, below, in which n is 1.
  • Another embodiment relates to compounds of formula I and embodiments a, b, c, d, and e, above, and g, h, i, j, k, 1, m, n, o, p, q, r, and s, below, in which m is 1 or 2 and
  • R 2 is selected from the group consisting of optionally substituted Ci_ 6 alkyl, optionally substituted Ci_4 alkoxy, cyano, halo, optionally substituted C3-6 heterocycloalkyl and optionally substituted C 4-14 aryl.
  • Another embodiment relates to compounds of formula I and embodiments a, b, c, d, and e, above, and h, i, j, k, 1 m, n, o, p, q, r, and s, below, in which m is 2 and each R 2 is independently selected from the group consisting of optionally substituted Ci_6 alkyl, optionally substituted Ci_4 alkoxy, cyano, halo, optionally substituted C3-6 heterocycloalkyl and optionally substituted C 4-14 aryl.
  • Another embodiment relates to compounds of formula I and embodiments a, b, c, d, e, f, and g, above, and o, p, q, r, and s, below, in which Ri is optionally substituted Ci_
  • Another embodiment relates to compounds of formula I and embodiments a, b, c, d, e, f, and g, above, and o, p, q, r, and s, below, in which Ri is optionally substituted Ci_
  • alkyl having from 1 to 4 substituents independently selected from the group consisting of optionally substituted C3-8 cycloalkyl, optionally substituted C3-6 heterocycloalkyl, optionally substituted C 1-10 heteroaryl, and optionally substituted phenyl.
  • Another embodiment relates to compounds of formula I and embodiments a, b, c, d, e, f, and g, above, and o, p, q, r, and s, below, in which Ri is optionally substituted Ci_
  • alkyl having from 1 to 4 substituents independently selected from the group consisting of optionally substituted C3_8 cycloalkyl, optionally substituted C3_6 heterocycloalkyl, optionally substituted C 1-10 heteroaryl, and optionally substituted phenyl.
  • Another embodiment relates to compounds of formula I and embodiments a, b, c, d, e, f, and g, above, and o, p, q, r, and s, below, in which Ri is optionally substituted Ci_
  • Another embodiment relates to compounds of formula I and embodiments a, b, c, d, e, f, and g, above, and o, p, q, r, and s, below, in which Ri is optionally substituted Ci_
  • Another embodiment relates to compounds of formula I and embodiments a, b, c, d, e, f, and g, above, and o, p, q, r, and s, below in which Ri is optionally substituted Ci_ 4 alkyl having an optionally substituted C 1-10 heteroaryl.
  • n Another embodiment relates to compounds of formula I and embodiments a, b, c, d, e, f, and g, above, and o, p, q, r, and s, below, in which Ri is optionally substituted C 1- 4 alkyl having an optionally substituted phenyl.
  • Another embodiment relates to compounds of formula I and embodiments a, b, c, d, e, f, h, i, j, k, 1, m, and n, above, in which m is 1 or 2 and one of R 2 is optionally substituted C3_6 heterocycloalkyl.
  • Another embodiment relates to compounds of formula I and embodiments a, b, c, d, e, f, h, i, j, k, 1, m, and n, above, in which m is 1 or 2 and one of R 2 is optionally substituted C 4-14 aryl.
  • Another embodiment relates to compounds of formula I and embodiments a, b, c, d, e, f, h, i, j, k, 1, m, and n, above, in which m is 1 or 2 and one of R 2 is optionally substituted C 4 -I 4 aryl having 1 to 2 substituents independently selected from the group consisting of amino, Ci_8 alkylamino, Ci_7 amido, Ci_ 2 o amide, optionally substituted Ci_ 4 alkyl, optionally substituted Ci_ 4 alkoxy, cyano, halogen, and Ci_g sulfonyl. [0076] r.
  • Another embodiment relates to compounds of formula I and embodiments a, b, c, d, e, f, h, i, j, k, 1, m, and n, above, in which m is 1 or 2 and one of R 2 is optionally substituted Ci_io heteroaryl.
  • Another embodiment relates to compounds of formula I and embodiments a, b, c, d, e, h, i, j, k, 1, m, and n, above, in which m is 1 or 2 and one of R 2 is optionally substituted Ci_io heteroaryl having 1 to 2 substituents independently selected from the group consisting of amino, Ci_8 alkylamino, Ci_7 amido, Ci_ 2 o amide, optionally substituted Q_ 4 alkyl, optionally substituted Ci_ 4 alkoxy, cyano, halogen, and Ci_g sulfonyl.
  • the compounds of the invention can be prepared by a variety of procedures, some of which are described below.
  • Scheme A depicts the reaction of an appropriate compound of formula (a) with an appropriate compound of formula (b) to give a compound of formula I.
  • An appropriate compound of formula (a) is one in which Ri is as desired in the final compound of formula I or gives rise to Ri as desired in the final compound of formula I;
  • Xi 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
  • Xi represents the other part of a symmetrical anhydride formed from two compounds of formula (a) in which Xi is hydroxyl; and
  • G is a hydrogen or a protecting group.
  • amide forming reactions are well understood and appreciated in the art.
  • 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 uranium hexafluorophosphate methanaminium (HATU), dicyclohexylcarbodiimide (DCC), and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
  • coupling agents including those used in peptide couplings, such as 2-(lH-7-azabenzotriazol-l-yl)- 1,1,3,3-tetramethyl uranium hexafluorophosphate methanaminium (HATU), dicyclohexylcarbodiimide (DCC), and l-(3-dimethylaminopropyl)-3-ethylcar
  • 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 JV-methylmorpholine or triethylamine, in a wide variety of suitable solvents such as dichloromethane, dimethylformamide, tetrahydrofuran, and the like.
  • 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
  • the compound of formula (a) or formula I is reacted with a molar excess OfRiX 2 in a suitable solvent such as dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, and the like and the reaction may be carried out using a suitable base, such as cesium carbonate, sodium carbonate, potassium carbonate, triethylamine, diethyl-z-propylamine, lithium hydride, sodium hydride, 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 80 0 C and require about 1 hour to 3 days.
  • a compound of formula (a) having a protecting group G and/or where Xi is a lower alkyl alkoxy, these groups may be removed before the amidation depicted in Scheme A or where a compound of formula I except having a G protecting is alkylated the protecting group G is removed in another step, not shown, to give a compound of formula I.
  • some compounds of formula I may be elaborated to other compounds of formula I, in additional steps not shown.
  • a compound of formula I in which R 2 is halogen, generally bromo can undergo a variety of arylations to give compound in which R 2 is optionally substituted C 4 _i 4 aryl and optionally substituted Ci_io heteroaryl.
  • Compounds of formula I may be elaborated in a variety of ways, in an additional step not shown. Such reactions include hydrolysis, oxidation, reduction, alkylation, amidations, sulfonations, alkynations, alkenations, and the like.
  • 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, buccally, intraperitoneally, intraarterially, transdermally, transbuccally, intraadiposally, intrathecally, and via local delivery, for example, by catheter or stent.
  • 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.
  • 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, semi-solid, 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, emulsif ⁇ ers, 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 regimen 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, or a solid formulation, such as 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 sEH comprising contacting the enzyme with a compound of the invention.
  • the invention provides a method of inhibiting 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 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.
  • condition 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 as hypertension, obesity, elevated triglycerides, elevated cholesterol, glucose intolerance, metabolic syndrome, atherosclerosis, coronary artery disease, 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, pruritus, genitourinary disorders, overactive bladder, outlet obstructions, outlet insufficiency, benign prostatic hyperplasia, interstitial cystitis,
  • 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 and all of which are contemplated by the invention.
  • Another example is systematic inflammatory response syndrome which is used to describe inflammation events associated with 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.
  • treatment 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.
  • treating include improvement of the conditions described herein. 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 the invention.
  • treat include all processes providing slowing, interrupting, arresting, controlling, or stopping of the 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 term "patient” includes humans and non-human animals, for example, mammals, such as mice, rats, guinea pigs, dogs, cats, rabbits, cows, horses, sheep, goats, and pigs.
  • 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 are non-human mammals, such as mice, rats, and dogs.
  • 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.
  • an effective amount of the present use 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.
  • the present invention provides a method for treating hypertension, comprising administering to a patient in need thereof an effective amount of a compound of invention.
  • 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 the invention.
  • 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.
  • the activity of compounds as sEH inhibitors may be determined by a variety of methods, including in vitro and in vivo methods.
  • DNA encoding the full-length sequence of the human enzyme was amplified by PCR and cloned into the pI-SUMOstar vector (LifeSensors), which incorporates a 6 x His-SUMO tag at the 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 the N-terminus.
  • Recombinant protein was isolated from cellular extracts by passage over ProBondTM 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 SUMOstar Protease 1 (LifeSensor) or rTEV enzyme, respectively.
  • SUMOstar Protease 1 LifeSensor
  • rTEV enzyme rTEV enzyme
  • 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°C or -20 0 C 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 (pH 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 ((3-phenyl-oxiranyl)-acetic acid cyano-(6- methoxy-naphthalen-2-yl)-methyl ester, sEH substrate from Cayman Chemical), 1 nM sEH enzyme, 1% DMSO (from test compound).
  • the 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 a solution containing the test compound and having a concentration that is 5 times the desired concentration in the reaction mixture, was added to each well of the plate, followed by the addition of 4 ⁇ L of a 2.5 nM solution of the sEH enzyme. The mixture is incubated for 10 minutes at room temperature. After incubation, 4 ⁇ L of a 12.5 ⁇ M 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 obtained 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 (test compound) 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 inhibition of cellular sEH activity can be assayed by measuring a compound's ability to inhibit sEH-mediated hydration of 14,15-epoxyeicosatrienoic acid (14,15-EET) to give 14,15-dihydroxyeicosatrienoic acid (14,15-DHET), which is secreted out of the cell into culture medium comprised of Eagle's MEM (ATCC), 10% Fetal Bovine Serum (Hyclone), 1 x NEAA (Invitrogen), and 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 cellBINDTM tissue culture plates. The cultures are incubated overnight at 37°C in a 5% CO 2 incubator until cells attach and spread. 14,15-EET (Biomol International) is added to a final concentration of 6 ⁇ M and inhibitor (test compound) is added to the desired final concentration in a total volume of 200 ⁇ L per well. Prior to their addition to the cells, the compounds are serially diluted (1 :3 in cell growth medium) from column 1 to 11 in a separate tissue culture plate; column 12 contains DMSO vehicle.
  • the diluted compounds are added to cells and equal amounts of DMSO are added to each well so that the final DMSO concentration in each well is 0.5%.
  • the cultures are incubated for 2 hours at 37°C in a 5% CO 2 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 OD at 450 nm with a Spectramax 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 (spontaneously hypertensive rats, 6 rats/group, 13-week old males, Charles River Laboratories) daily for two days.
  • Plasma is collected (200 ⁇ L in heparinized tubes at 4 hours post dose on day 1 and at 4, 8 and 24 hours post dose on day 2. The samples are frozen at -80 0 C until analysis.
  • the lipids are extracted from the plasma sample with acetonitrile which contains 14,15-DHET-Jn [800 ⁇ L of 10 ng/mL] as an internal standard, and the extract is blown dry and reconstituted into 100 ⁇ L 60/40 water/acetonitrile.
  • Calibration of 14,15-DHET is obtained by spiking a known amount of 14,15-DHET (0.5, 1, 2.5, 20, 25, 100, 200, 500, 1000, 2000 ng/mL) into blank plasma and extracting the lipids with 800 ⁇ L acetonitrile containing 10 ng/mL 14,15-DHET-Jn as an internal standard.
  • the extract is blown dry and reconstituted into 100 ⁇ L 60/40 water/acetonitrile.
  • the 14,15-DHET levels are determined by LC/MRM- MS.
  • the 14,15-DHET is monitored using 337.4/207.1 (Q1/Q3) MRM transition, and 14,15-DHET-Jn is monitored using 348.4/207.1 (Q1/Q3) MRM transition.
  • the concentration of 14,15-DHET in plasma sample (in ng/mL) is 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.
  • mice Male Sprague Dawley (SD) rats (7-8 weeks old from Harlan) are surgically implanted under isoflurane anesthesia with an osmotic mini-pump (AlzetTM 2ML2) which administers 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 hours post dosing through non-invasive tail-cuff system under light anesthesia.
  • PREPARATION 1 3-(benzyloxymethyl)-2,6-dioxo-N-(2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide [0116] A. 3-(Benzyloxymethyl)-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxylic acid
  • PREPARATION 2 3-(benzyloxymethyl)-l-(2-morpholinoethyl)-2,6-dioxo- l,2,3,6-tetrahydropyrimidine-4-carboxylic acid hydrochloride salt
  • PREPARATION 4 l-(2-(l/f-pyrazol-l-yl)ethyl)-3-(benzyloxymethyl)-2,6- dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxylic acid.
  • PREPARATION 5 3-(benzyloxymethyl)-l-((3-ethyl-l,2,4-oxadiazol-5- yl)methyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxylic acid [0127] To methyl 2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxylate (943 mg, 5.54 mmol) was added DMF (17 mL). The mixture was cooled with an ice bath and lithium hydride (69.6 mg, 8.31 mmol) was then added in portions.
  • PREPARATION 8 (3-(4-fluorophenyl)pyridin-2-yl)methanamine [0139] A. 3-(4-fluorophenyl)picolinonitrile
  • PREPARATION 9 (2-(4-fluorophenyl)pyridin-3-yl)methanamine [0144] A. 2-(4-Fluorophenyl)nicotinaldehyde
  • PREPARATION 10 (4-(4-fluorophenyl)pyridin-3-yl)methanamine [0149]
  • the title compound was prepared in a manner similar to the method described in Preparation 9, using 4-bromonicotinaldehyde in step A to give an intermediate, 4-(4- fluorophenyl)nicotinaldehyde, which was purified by column chromatography (3% methanol in dichloromethane). MS [M+H] found 202.
  • the intermediate was used without further purification to give the title compound, which was purified by mass-triggered HPLC (5% ACN in water containing 0.05% TFA). MS [M+H] found 203.
  • PREPARATION 11 (3 -(4-fluorophenyl)furan-2-yl)methanamine [0151]
  • the title compound was prepared in a manner similar to the method described in Preparation 9, using 3-bromofuran-2-carbaldehyde in step A to give an intermediate, 3-(4- fluorophenyl)furan-2-carbaldehyde, which was purified by column chromatography (2.5% methanol in dichloromethane). MS [M+H] found 191.
  • PREPARATION 12 (3-(4-fluorophenyl)thiophen-2-yl)methanamine [0153]
  • the title compound was prepared in a manner similar to the method described in Preparation 9, using 3-bromothiophene-2-carbaldehyde in step A to give an intermediate, 3-(4-fluorophenyl)thiophen-2-carbaldehyde, which was purified by column chromatography (2.5% methanol in dichloromethane). MS [M+H] found 207.
  • the intermediate was used to prepare the title compound, which was purified by mass- triggered HPLC (gradient: 5 to 25% ACN in water containing 0.05% TFA). MS [M+H] found 208.
  • PREPARATION 13 (4-(4-fluorophenyl)thiophen-3 -yl)methanamine [0155]
  • the title compound was prepared in a manner similar to the method described in Preparation 9, using 4-bromothiophene-3-carbaldehyde in step A to give 4-(4- fluorophenyl)thiophene-3-carbaldehyde, which was purified by column chromatography (2.5% methanol in dichloromethane). MS [M+H] found 207.
  • the intermediate was used to prepare the title compound, which was purified by mass-triggered HPLC (gradient: 5 to 25% ACN in water containing 0.05% TFA). MS [M+H] found 208.
  • EXAMPLE 1 N-(2,4-dichlorobenzyl)-l-methyl-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 7 l-(2,2-difluoroethyl)-2,6-dioxo-N-(2-(trifluoromethoxy)benzyl)-
  • EXAMPLE 8 l-(4-(methylsulfonyl)benzyl)-2,6-dioxo-N-(2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 15 l-(3-cyanobenzyl)-2,6-dioxo-N-(2-(trifiuoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 17 l-(3-hydroxypropyl)-2,6-dioxo-N-(2-(trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 18 2,6-dioxo-l-((tetrahydrofuran-2-yl)methyl)-N-(2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 24 l-(2-morpholinoethyl)-2,6-dioxo-N-(2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 25 l-cyclopentyl-2,6-dioxo-N-(2-(trifluoromethoxy)benzyl)-l,2,3,6- tetrahydropyrimidine-4-carboxamide
  • Example 6 using bromocyclopentane in place of (bromomethyl)cyclopropane, and was purified by mass-triggered HPLC (50% ACN in water containing 0.05% TFA).
  • EXAMPLE 26 l-neopentyl-2,6-dioxo-N-(2-(trifluoromethoxy)benzyl)-l,2,3,6- tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 27 l-((2,4-dioxo-l,2,3,4-tetrahydropyrimidin-5-yl)methyl)-2,6- dioxo- ⁇ /-(2-(trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 29 l-(2-(i/f-pyrazol-l-yl)ethyl)-2,6-dioxo-N-(2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 30 l-((4-isobutylmorpholin-2-yl)methyl)-2,6-dioxo-N-(2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 32 2,6-dioxo-l-(2-(2-oxopyrrolidin-l-yl)ethyl)-N-(2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 33 l-(2-(isopropyl(methyl)amino)-2-oxoethyl)-2,6-dioxo-N-(2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 36 2,6-dioxo-l-(2-(2-oxo-2,3-dihydro-l/f-imidazol-l-yl)ethyl)-N- (2-(trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 37 l-(2-(l/f-l,2,4-triazol-l-yl)ethyl)-2,6-dioxo-N-(2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 40 l-(3-(l/f-pyrazol-l-yl)propyl)-2,6-dioxo-N-(2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 43 l-benzyl-N-(4-methoxy-2-(trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 45 N-(4-bromo-2-(trifiuoromethoxy)benzyl)- 1 -(2-morpholinoethyl)- 2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 46 N-(4-methoxy-2-(trifluoromethoxy)benzyl)- 1 -(2- morpholinoethyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 47 l-(2-(l/f-pyrazol-l-yl)ethyl)-N-(4-bromo-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 48 l-(2-(l/f-pyrazol-l-yl)ethyl)-N-(4-methoxy-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 49 N-(4-bromo-2-(trifluoromethoxy)benzyl)-l-((3-ethyl- 1,2,4- oxadiazol-5-yl)methyl)-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 50 1 -((3-ethyl- l,2,4-oxadiazol-5-yl)methyl)-N-(4-methoxy-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 51 N-(4-(2-aminopyrimidin-5-yl)-2-(trifiuoromethoxy)benzyl)-2,6- dioxo- 1 -(pyridin-2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 52 N-(4-(5-aminopyrazin-2-yl)-2-(trifluoromethoxy)benzyl)-l- benzyl-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 53 l-benzyl-2,6-dioxo-N-((3-(trifiuoromethoxy)biphenyl-4- yl)methyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 54 l-benzyl-2,6-dioxo-N-(4-(pyridin-3-yl)-2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 55 1 -benzyl-iV-((4 ' -(methylsulfonyl)-3 -(trifluoromethoxy)biphenyl- 4-yl)methyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 56 l-benzyl-N-(4-(2-methoxypyrimidin-5-yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 57 1 -benzyl-iV-((4 ' -carbamoyl-3 -(trifluoromethoxy)biphenyl-4- yl)methyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 58 l-benzyl-N-(4-(2,6-dimethoxypyridin-3-yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 59 methyl 4'-((l-benzyl-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4- carboxamido)methyl)-3 ' -(trifluoromethoxy)biphenyl-4-ylcarbamate
  • EXAMPLE 60 l-benzyl-N-(4-(2-fiuoropyridin-4-yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 62 l-benzyl-N-(4-(3,5-dimethyl-l/f-pyrazol-4-yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • Example 63 l-benzyl-N-(4-(6-hydroxypyridin-3-yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • Example 64 l-benzyl-2,6-dioxo- ⁇ /-((3-(trifluoromethoxy)-4'-ureidobiphenyl-4- yl)methyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • Example 65 N-(4-(benzo[c][l,2,5]oxadiazol-5-yl)-2-(trifluoromethoxy)benzyl)- 1 -benzyl-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 66 N-(4-(2-aminopyrimidin-5-yl)-2-(trifiuoromethoxy)benzyl)-l- benzyl-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 67 l-benzyl-2,6-dioxo-N-(4-(2-oxoindolin-5-yl)-2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 68 N-(4-(l/f-pyrrolo[3,2- ⁇ ]pyridin-6-yl)-2- (trifluoromethoxy)benzyl)- 1 -benzyl-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4- carboxamide
  • EXAMPLE 69 l-benzyl-N-(4-(furan-2-yl)-2-(trifluoromethoxy)benzyl)-2,6- dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 70 N-(4-(5-acetylthiophen-2-yl)-2-(trifiuoromethoxy)benzyl)-l- benzyl-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 71 l-benzyl-N-(4-(2,4-dioxo-l,2,3,4-tetrahydropyrimidin-5-yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 72 l-benzyl-N-(4-(furan-3-yl)-2-(trifiuoromethoxy)benzyl)-2,6- dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 73 1 -benzyl-N-((4 ' -(methylsulfonamido)-3- (trifluoromethoxy)biphenyl-4-yl)methyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4- carboxamide
  • EXAMPLE 74 l-benzyl-N-((3'-(methylsulfonamido)-3- (trifluoromethoxy)biphenyl-4-yl)methyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4- carboxamide
  • EXAMPLE 75 l-benzyl-2,6-dioxo-N-(4-(quinolin-3-yl)-2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 76 l-benzyl-2,6-dioxo-N-(4-(pyrimidin-5-yl)-2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 77 N-(4-(l/f-indol-4-yl)-2-(trifluoromethoxy)benzyl)-l-benzyl-2,6- dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 78 l-benzyl-N-(4-(5-methoxypyridin-3-yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 79 l-benzyl-iV-(4-(l -methyl- l/f-pyrazol-4-yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 80 l-benzyl-N-(4-(6-morpholinopyridin-3-yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 82 l-benzyl-2,6-dioxo-N-((3'-sulfamoyl-3- (trifluoromethoxy)biphenyl-4-yl)methyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 83 l-benzyl-N-(4-(2-(dimethylamino)pyrimidin-5-yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 84 N-(4-(l/f-pyrazol-5-yl)-2-(trifluoromethoxy)benzyl)-l-benzyl- 2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • Example 51 using l-benzyl- ⁇ /-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and lH-pyrazol-4-ylboronic acid, and was purified by mass-triggered HPLC (gradient: 5 to 95% ACN in water containing 0.05% TFA). MS
  • EXAMPLE 87 l-benzyl-N-(4-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrimidin-5-yl)-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 88 N-(4-(lH-pyrrolo[2,3- ⁇ ]pyridin-5-yl)-2- (trifluoromethoxy)benzyl)- 1 -benzyl-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4- carboxamide
  • EXAMPLE 89 l-benzyl-N-(4-(l-(2-morpholinoethyl)-l/f-pyrazol-4-yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 90 (£)-l-benzyl- ⁇ H(4'-( ⁇ T-hydroxycarbamimidoyl)-3- (trifluoromethoxy)biphenyl-4-yl)methyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4- carboxamide
  • EXAMPLE 91 1 -benzyl-N-(4-(6-(methylcarbamoyl)pyridin-3 -yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 92 l-benzyl-N-(4-(2-cyanopyrimidin-5-yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 94 methyl 5-(4-((l-benzyl-2,6-dioxo-l ,2,3,6-tetrahydropyrimidine- 4-carboxamido)methyl)-3-(trifluoromethoxy)phenyl)pyridin-2-ylcarbamate
  • EXAMPLE 95 l-benzyl-N-(4-(6-(hydroxymethyl)pyridin-3-yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 96 5-(4-((l-benzyl-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4- carboxamido)methyl)-3 -(trifluoromethoxy)phenyl)picolinic acid
  • EXAMPLE 97 N-(4-(l-(3-methoxypropyl)-lH-pyrazol-4-yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 -(pyridin-2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine- 4-carboxamide
  • EXAMPLE 98 N-(4-(l -(3-hydroxypropyl)- l/f-pyrazol-4-yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 -(pyridin-2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine- 4-carboxamide
  • EXAMPLE 99 l-benzyl-N-(4-(cyclopropylsulfonyl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 100 N-(4-(cyclopropylsulfonyl)-2-(trifluoromethoxy)benzyl)- 1 -(2- morpholinoethyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 101 N-(4-(cyclopropylsulfonyl)-2-(trifluoromethoxy)benzyl)-2,6- dioxo- 1 -(pyridin-2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 102 (5)-N-(4-(4-hydroxy-2-oxopyrrolidin-l-yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 -(pyridin-2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine- 4-carboxamide
  • EXAMPLE 103 (5)-N-(4-(4-Hydroxy-2-oxopyrrolidin- 1 -yl)-2- (trifluoromethoxy)benzyl)- 1 -(2-morpholinoethyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine- 4-carboxamide
  • EXAMPLE 105 N-(4-cyano-2-(trifiuoromethoxy)benzyl)-2,6-dioxo- 1 -(pyridin- 2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 106 N-(4-cyano-2-(trifiuoromethoxy)benzyl)- 1 -(2- morpholinoethyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 108 N-((3-(4-fiuorophenyl)pyridin-2-yl)methyl)-2,6-dioxo- 1 - (pyridin-2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 109 l-benzyl-N-((2-(4-fluorophenyl)pyridin-3-yl)methyl)-2,6- dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 110 N-((2-(4-fiuorophenyl)pyridin-3-yl)methyl)-l-(2- morpholinoethyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 111 N-((2-(4-fluorophenyl)pyridin-3-yl)methyl)-2,6-dioxo- 1 - (pyridin-2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 112 l-benzyl-N-((4-(4-fluorophenyl)pyridin-3-yl)methyl)-2,6- dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 113 1 -benzyl-N-((3-(4-fluorophenyl)furan-2-yl)methyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 114 l-benzyl-N-((3-(4-fluorophenyl)thiophen-2-yl)methyl)-2,6- dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 115 1 -benzyl-N-((4-(4-fluorophenyl)thiophen-3-yl)methyl)-2,6- dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 116 l-benzyl-N-((4'-fiuorobiphenyl-2-yl)methyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 118 N-((4'-fluorobiphenyl-2-yl)methyl)-l-(2-morpholinoethyl)-2,6- dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 119 4-(( l-benzyl-2,6-dioxo- 1,2,3, 6-tetrahydropyrimidine-4- carboxamido)methyl)-3 -(trifluoromethoxy)benzoic acid
  • EXAMPLE 120 l-benzyl-N-(4-(cyclohexylcarbamoyl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 121 l-benzyl-N- ⁇ 4-[(cyclohexylmethyl)carbamoyl]-2- (trifluoromethoxy)benzyl ⁇ -2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 122 (S)- 1 -benzyl-N-(4-(2-carbamoylpyrrolidine- 1 -carbonyl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 123 l-benzyl-N-(4-(3-cyanophenylcarbamoyl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 124 l-benzyl-N-(4-(4-methoxyphenylcarbamoyl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 125 l-benzyl-N-(4-(benzyl(methyl)carbamoyl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 126 l-benzyl-JV-(4-(4-cyanobenzylcarbamoyl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 127 l-benzyl-N-(4-(methyl(l-methylpyrrolidin-3-yl)carbamoyl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 128 (R)- 1 -benzyl-2,6-dioxo-JV-(4-( 1 -phenylethylcarbamoyl)-2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • Example 120 using (7?)-l-phenylethanamine in place of cyclohexanamine, and was purified by mass-triggered HPLC (gradient: 25 to 95% ACN in water containing 0.05%
  • EXAMPLE 129 (5)-N-(4-(3-acetamidopyrrolidine-l-carbonyl)-2-
  • EXAMPLE 130 l-benzyl-N-(4-(2-(cyanomethyl)phenylcarbamoyl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 132 (5)-l-benzyl-N-(4-(3-hydroxypyrrolidine-l-carbonyl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 133 l-benzyl-N-(4-(3-hydroxybenzylcarbamoyl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 134 l-benzyl-N-(4-(5-fiuoropyridin-2-ylcarbamoyl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • EXAMPLE 135 l-benzyl-2,6-dioxo-N-(4-(tetrahydro-2/f-pyran-4-ylcarbamoyl)- 2-(trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • Example 120 using tetrahydro-2H-pyran-4-amine in place of cyclohexanamine, and was purified by mass-triggered HPLC (gradient: 25 to 95% ACN in water containing 0.05%
  • EXAMPLE 136 l-benzyl-N-[4- ⁇ [(5-methylisoxazol-3-yl)methyl]carbamoyl ⁇ -2-
  • Example 120 using (5-methylisoxazol-3-yl)methanamine in place of cyclohexanamine, and was purified by mass-triggered HPLC (gradient: 25 to 95% ACN in water containing
  • EXAMPLE 138 l-benzyl-N-(4-(l,5-dimethyl-l/f-pyrazol-3-ylcarbamoyl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
  • Example 120 using l,5-dimethyl-lH-pyrazol-3-amine in place of cyclohexanamine, and was purified by mass-triggered HPLC (gradient: 25 to 95% ACN in water containing
  • EXAMPLE 139 l-benzyl-N-[4- ⁇ [(l-methylpiperidin-4-yl)methyl]carbamoyl ⁇ -2-
  • Example 120 using (l-methylpiperidin-4-yl)methanamine in place of cyclohexanamine.
  • EXAMPLE 140 l-benzyl-N-[4- ⁇ [(l-methylpyrrolidin-3-yl)methyl]carbamoyl ⁇ -
  • Example 120 using (l-methylpyrrolidin-3-yl)methanamine in place of cyclohexanamine.
  • EXAMPLE 141 l-benzyl-2,6-dioxo-N-[4- ⁇ [(6-oxo-l,6-dihydropyridin-3- yl)methyl]carbamoyl ⁇ -2-(trifluoromethoxy)benzyl]- 1,2,3, 6-tetrahydropyrimidine-4- carboxamide
  • Table 1 lists sEH inhibition data for many of the compounds described in the examples, which were tested in accordance with the assay described on page 17 of the specification using human sEH.
  • the inhibition data in Table 1 are expressed in terms of PIC50, which is the negative of the base-ten logarithm of IC50, where IC50 is the concentration in moles per liter of the test compound at 50% inhibition.
  • the compounds listed by Example number

Abstract

Disclosed are sEH inhibitors of formula (I), wherein the variables are as defined herein, as well as pharmaceutical compositions, kits, and articles of manufacture that contain such compounds. Also disclosed are methods and intermediates for making the compounds and the use of such compounds to treat various disorders, diseases, and conditions associated with sEH.

Description

2,6-DIOXO- 1,2,3, ό-TETRAHYDROPYRIMIDINE^-CARBOXAMIDES
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 2008/138126, WO 2008/116145, WO 2007/098352, WO 2007/043653, WO 2007/044491, WO 2006/121719, and US 6,150,415.
SUMMARY OF THE INVENTION
[0005] The present invention provides compounds of formula I:
Figure imgf000002_0001
or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, wherein: Ar is selected from the group consisting of C4_i4 aryl and C1-10 heteroaryl; Ri is selected from the group consisting of hydrogen, optionally substituted C3-8 cycloalkyl, optionally substituted C3-6 heterocycloalkyl, and optionally substituted Ci_6 alkyl;
R2 is selected from the group consisting of optionally substituted Ci_6 alkyl, Ci.g sulfonyl, optionally substituted C2-4 alkenyl, optionally substituted Ci_4 alkoxy, optionally substituted C2-6 alkynyl, amino, Ci_8 alkylamino, Ci_2o amide, optionally substituted C4-I4 aryl, optionally substituted C4_i4 aryloxy, C 1.5 oxycarbonyl, cyano, optionally substituted C3_g cycloalkyl, C3-8 cycloalkoxy, halo, optionally substituted C3-6 heterocycloalkyl, optionally substituted C1-10 heteroaryl, optionally substituted C1-10 heteroaryloxy, hydroxy, and nitro; n is 0, 1, 2, or 3; and m is 0, 1, 2, 3 or 4.
[0006] The present invention also provides pharmaceutical compositions, which comprise a compound of formula I, tautomer, or pharmaceutically acceptable salt as defined above, and a pharmaceutically acceptable excipient.
[0007] The compounds of the invention are inhibitors of sEH that are useful for the treatment of conditions associated with sEH, including hypertension. Thus, the invention provides methods of treating conditions associated with sEH, which comprise administering to a patient in need of treatment an effective amount of a compound of formula I, tautomer, or pharmaceutically acceptable salt as defined above. Furthermore, the present invention provides for the use of compounds of formula I, tautomer, or pharmaceutically acceptable salt as defined above, 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, which comprises at least one compound of formula I, tautomer, or pharmaceutically acceptable salt as defined above, and a label. Also provided are kits, which comprise 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. [0010] Compounds of this invention include all pharmaceutically acceptable complexes, salts, solvates, and hydrates thereof. Compounds of this invention also include all stereoisomers, tautomers, and polymorphic forms thereof, including all crystalline and amorphous forms, whether they are pure, substantially pure, or mixtures.
DETAILED DESCRIPTION OF THE INVENTION
[0011] The term "substituted" when used in connection with a chemical substituent or moiety (e.g., an alkyl group), means that one or more hydrogen atoms of the substituent or moiety have been replaced with one or more non-hydrogen atoms or groups, provided that valence requirements are met and that a chemically stable compound results from the substitution.
[0012] The term "C2-4 alkenyl" refers to a straight or branched hydrocarbon chain having from two to four carbon atoms and one or more carbon-carbon double bonds, and includes ethenyl, 1-propen-l-yl, l-propen-2-yl, 2-propen-l-yl, 1-buten-l-yl, l-buten-2-yl, 3-buten-l-yl, 3-buten-2-yl, 2-buten-l-yl, 2-buten-2-yl, 2 -methyl- 1-propen-l-yl, 2-methyl- 2-propen-l-yl, 1,3-butadien-l-yl, l,3-butadien-2-yl, and the like.
[0013] 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 Ci_4 alkoxy, Ci_9 amide, Ci_5 oxycarbonyl, cyano, C3-8 cycloalkyl, halo, hydroxy, optionally substituted C1-10 heteroaryl, and optionally substituted phenyl.
[0014] The term "Ci_4 alkyl" refers to a straight or branched hydrocarbon chain having from one to four carbon atoms, and includes methyl, ethyl, n-propyl, /-propyl, n-butyl, s- butyl, /-butyl, and /-butyl.
[0015] 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, Ci_4 alkoxy, Ci_4 thioalkoxy, Ci_g amide, Ci_g alkylamino, Ci_5 oxycarbonyl, cyano, C3-8 cycloalkyl, C3-8 cycloalkoxy, halo, hydroxy, nitro, oxo, optionally substituted C3-6 heterocycloalkyl, optionally substituted C1-10 heteroaryl, and optionally substituted phenyl.
[0016] The term "Ci_6 alkyl" refers to a straight or branched alkyl chain having from one to six carbon atoms. [0017] The term "optionally substituted Ci_6 alkyl" refers to a Ci_6 alkyl optionally having from 1 to 7 substituents independently selected from the group consisting of amino, Ci_g alkylamino, C2-4 alkenyl, Ci_4 alkoxy, Ci_4 thioalkoxy, Ci_9 amide, Ci_5 oxycarbonyl, cyano, C3_8 cycloalkyl, halo, hydroxy, optionally substituted
C3_6 heterocycloalkyl, optionally substituted C1-10 heteroaryl, and optionally substituted phenyl.
[0018] The term "Ci_8 sulfonyl" refers to a sulfonyl linked to a Ci_6 alkyl group,
C3_8 cycloalkyl, or an optionally substituted phenyl.
[0019] The term "Ci_4 alkoxy" refers to a Ci_4 alkyl attached through an oxygen atom.
[0020] 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, Ci_4 alkoxy, Ci_9 amide, Ci_5 oxycarbonyl, cyano, C3_8 cycloalkyl, halo, hydroxy, optionally substituted C1-10 heteroaryl, and optionally substituted phenyl.
[0021] The term "C2-6 alkynyl" refers to a straight or branched hydrocarbon chain having from two to six carbon atoms and one or more carbon-carbon triple bonds.
Examples of alkynyl groups include ethynyl, 1-propyn-l-yl, 2-propyn-l-yl, 1-butyn-l-yl,
3-butyn-l-yl, 3-butyn-2-yl, 2-butyn-l-yl, and the like.
[0022] 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 Ci_4 alkoxy, Ci_9 amide, Ci_5 oxycarbonyl, cyano, C3-8 cycloalkyl, halo, hydroxy, optionally substituted C1-10 heteroaryl, and optionally substituted phenyl.
[0023] The term "Ci_9 amide" refers to an amide having two groups independently selected from the group consisting of hydrogen and Ci_4 alkyl, for example, -C(O)NH2,
-C(O)NHCH3, and -C(O)N(CH3)2.
[0024] The term "Ci_2o amide" refers to an amide having two groups independently selected from the group consisting of hydrogen, optionally substituted Ci_6 alkyl, C3-8 cycloalkyl, optionally substituted C1-10 heteroaryl, optionally substituted C3-6 heterocycloalkyl, optionally substituted C1-10 heteroaryl, and optionally substituted C4-14 aryl or an amide formed by an N-linked, optionally substituted nitrogen-containing C3_6 heterocycloalkyl, for example, (piperidin-l-yl)carbonyl.
[0025] The term "Ci_7 amido" refers to a -NHC(O)R group in which R is Ci_6 alkyl. [0026] The term "Ci_5 carbamoyl" refers to an O- or N-linked carbamate having a terminal Ci_4 alkyl.
[0027] The term "Ci_5 ureido" refers to a Ci_4 alkyl-urea group.
[0028] The term "Ci_g alkylamino" refers to an amino group substituted with one or two
Ci_4 alkyl groups.
[0029] The term "C4-I4 aryl" refers to a monocyclic or polycyclic unsaturated, conjugated hydrocarbon having aromatic character and having four to fourteen carbon atoms, and includes phenyl, biphenyl, indenyl, cyclopentyldienyl, fluorenyl, and naphthyl.
[0030] The term "optionally substituted C4_i4 aryl" refers to a C4_i4 aryl optionally having 1 to 5 substituents independently selected from the group consisting of amino, Ci_g alkylamino, Ci_7 amido, Ci_2o amide, hydroxycarbamimidoyl, Ci_5 carbamoyl, Ci_6 sulfonylamido, C0-6 sulfonylamino, Ci_5 ureido, optionally substituted Q_4 alkyl, optionally substituted Ci_4 alkoxy, cyano, halogen, hydroxyl, nitro, Ci_5 oxycarbonyl, and Ci_8 sulfonyl and optionally having 2 of the optional substituents taken together to form an optionally substituted C3-6 heterocycloalkyl.
[0031] The term "C4_i4 aryloxy" refers to a C4_i4 aryl attached through an oxygen atom.
[0032] The term "optionally substituted C4_i4 aryloxy" refers to a C4_i4 aryloxy optionally having 1 to 5 substituents independently selected from the group consisting of amino, Ci_g alkylamino, d_4 alkyl, Ci_4 alkoxy, cyano, halogen, hydroxyl, nitro, Ci_g sulfonyl, and trifluoromethyl.
[0033] The term "Ci_5 oxycarbonyl" refers to an oxycarbonyl group (-CO2H) and Ci_4 alkyl ester thereof.
[0034] 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.
[0035] 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 Ci_4 alkyl, C2-4 alkenyl, Ci_4 alkoxy, Ci_9 amide, Ci_7 amido, Ci_8 alkylamino, Ci_5 oxycarbonyl, cyano, C3_8 cycloalkyl, C3_8 cycloalkoxy, halo, hydroxy, nitro, oxo, optionally substituted C1-10 heteroaryl, and optionally substituted phenyl. [0036] The term "C3_8 cycloalkoxy" refers to a C3_8 cycloalkyl attached through an oxygen atom.
[0037] The terms "halogen" and "halo" refer to chloro, fluoro, bromo or iodo. [0038] The term "C3_6 heterocycloalkyl" refers to a 4 to 10 membered monocyclic saturated or partially (but not fully) unsaturated ring having one to four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. For example, the term includes, but is not limited to azetidine, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, tetrahydrofuran, hexahydropyrimidine, tetrahydropyrimidine, dihydroimidazole, and the like.
[0039] The term "optionally substituted C3-6 heterocycloalkyl" refers to a C3_6 heterocycloalkyl optionally substituted on the ring carbons with 1 to 4 substituents independently selected from the group consisting of optionally substituted Ci_4 alkyl, C2-4 alkenyl, Ci_4 alkoxy, Ci_9 amide, Ci_7 amido, Ci_8 alkylamino, Ci_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 Ci_4 alkyl, C2-4 alkenyl, C3_s cycloalkyl, optionally substituted C3-6 heterocycloalkyl, optionally substituted C1-10 heteroaryl, and optionally substituted phenyl.
[0040] The term "optionally substituted nitrogen-containing C3_6 heterocycloalkyl" refers to a 4 to 10 membered monocyclic saturated or partially (but not fully) unsaturated ring having at least one nitrogen and optionally one or more additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. For example, the term includes, but is not limited to azetidine, pyrrolidine, piperidine, piperazine, morpholine, and the like. When optionally substituted such a nitrogen-containing C3_6 heterocycloalkyl may have on the ring carbons 1 to 4 substituents independently selected from the group consisting of optionally substituted Ci_4 alkyl, C2-4 alkenyl, Ci_4 alkoxy, Ci_9 amide, Ci_g alkylamino, Ci_5 oxycarbonyl, cyano, C3-8 cycloalkyl, C3-8 cycloalkoxy, halo, hydroxy, nitro, oxo, optionally substituted C3-6 heterocycloalkyl, and optionally substituted phenyl; and may be optionally substituted on any additional ring nitrogen with a substituent selected from the group consisting of optionally substituted Ci_4 alkyl, C2-4 alkenyl, C3_8 cycloalkyl, optionally substituted C1-10 heteroaryl, and optionally substituted phenyl. [0041] The term "C1-10 heteroaryl" refers to five to twelve membered monocyclic or polycyclic unsaturated and 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, the term includes, but is not limited to azepine, diazepine, furan, thiophene, imidazole, isothiazole, isoxazole, oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, thiazole, thiadiazole, triazole, tetrazole, benzazepine, benzodiazepine, benzofuran, benzothiophene, benzimidazole, imidazopyridine, pyrazolopyridine, pyrrolopyridine, quinazoline, thienopyridine, indolizine, imidazopyridine, quinoline, isoquinoline, indole, isoindole, benzoxazole, benzoxadiazole, benzopyrazole, benzothiazole, and the like. [0042] 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, Ci_7 amido, Ci_8 alkylamino, Ci_2o amide, hydroxycarbamimidoyl, Ci_5 carbamoyl, Ci_6 sulfonylamido, Co-6 sulfonylamino,Ci_5 ureido, optionally substituted Ci_4 alkyl, optionally substituted Ci_4 alkoxy, cyano, halogen, hydroxyl, oxo, nitro, Ci_5 oxycarbonyl, and Ci_g sulfonyl and optionally having substituents on each nitrogen independently selected from the group consisting of optionally substituted CM alkyl, Ci_g sulfonyl, optionally substituted C3-6 heterocycloalkyl, and optionally substituted phenyl. [0043] 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 pyridone radical is contemplated as oxo substituted C1-10 heteroaryl. [0044] The term "C1-10 heteroaryloxy" refers to a C1-10 heteroaryl attached through an oxygen.
[0045] 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, Ci_4 alkoxy, cyano, halogen, hydroxyl, nitro, oxo, Ci_8 sulfonyl, and trifluoromethyl and optionally having substituents on each nitrogen independently selected from the group consisting of optionally substituted CM alkyl, Ci_g sulfonyl, and optionally substituted phenyl.
[0046] 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, Ci_4 alkoxy, Ci_9 amide, Ci_8 alkylamino, Ci_5 oxycarbonyl, cyano, halogen, hydrogen, hydroxyl, nitro, Ci_8 sulfonyl, and trifluoromethyl.
[0047] The term "Ci_6 sulfonylamido" refers to a -NHS(O)2-R group wherein R is Ci_6 alkyl.
[0048] The term "Co-6 sulfonylamino" refers to a -S(O)2NH-R group wherein R is selected from the group consisting of hydrogen and is Ci_6 alkyl.
[0049] The term "Ci_4 thioalkoxy" refers to a Ci_4 alkyl attached through a sulfur atom.
[0050] 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 include those described in Journal of Pharmaceutical Science, 66, 2-19
(1977). Examples are the hydrochloride and mesylate salts.
[0051] The terms "stereoisomer" and "stereoisomers" of a compound with given stereochemical configuration refer to the opposite enantiomer of the compound and to any diastereoisomers, including geometrical isomers (ZIE) of the compound. For example, if a compound has S,R,Z stereochemical configuration, its stereoisomers would include its opposite enantiomer having R,S,Z configuration, and its diastereomers having S,S,Z configuration, R,R,Z configuration, S,R,E configuration, R,S,E configuration, S,S,E configuration, and R,R,E configuration. If the stereochemical configuration of a compound is not specified, then "stereoisomer" refers to any one of the possible stereochemical configurations of the compound.
[0052] The term "substantially pure stereoisomer" and variants thereof refer to a sample containing a compound having a specific stereochemical configuration and which comprises at least about 95% of the sample.
[0053] The term "pure stereoisomer" and variants thereof refer to a sample containing a compound having a specific stereochemical configuration and which comprises at least about 99.5% of the sample. [0054] It is understood that, where the terms defined herein mention a number of carbon atoms, that the mentioned number refers to the mentioned group and does not include any carbons that may be present in any optional substituent(s).
[0055] The skilled artisan will appreciate that certain compounds of the present invention exist as stereoisomers. 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.
[0056] The skilled artisan will appreciate that certain compounds of the present invention exist as tautomers. All tautomeric forms of the compounds of the invention are contemplated to be within the scope of the present invention.
[0057] The skilled artisan will appreciate that certain compounds of the present invention may exist as solvates and hydrates, and that all such forms of the compounds of the invention are contemplated to be within the scope of the present invention.
[0058] The term "compounds of the invention" include the embodiment of formula I and the other embodiments and examples described herein.
[0059] a. One embodiment relates to compounds of formula I wherein Ar is C4_i4 aryl.
[0060] b. Another embodiment relates to compounds of formula I wherein Ar is phenyl.
[0061] c. One embodiment relates to compounds of formula I wherein Ar is C1-10 heteroaryl.
[0062] d. Another embodiment relates to compounds of formula I wherein Ar is pyridyl.
[0063] e. Another embodiment relates to compounds of formula I and embodiments a, b, c, and d, above, and f, g, h, i, j, k, 1, m, n, o, p, q, r, and s, below, in which n is 1.
[0064] f. Another embodiment relates to compounds of formula I and embodiments a, b, c, d, and e, above, and g, h, i, j, k, 1, m, n, o, p, q, r, and s, below, in which m is 1 or 2 and
R2 is selected from the group consisting of optionally substituted Ci_6 alkyl, optionally substituted Ci_4 alkoxy, cyano, halo, optionally substituted C3-6 heterocycloalkyl and optionally substituted C4-14 aryl.
[0065] g. Another embodiment relates to compounds of formula I and embodiments a, b, c, d, and e, above, and h, i, j, k, 1 m, n, o, p, q, r, and s, below, in which m is 2 and each R2 is independently selected from the group consisting of optionally substituted Ci_6 alkyl, optionally substituted Ci_4 alkoxy, cyano, halo, optionally substituted C3-6 heterocycloalkyl and optionally substituted C4-14 aryl.
[0066] h. Another embodiment relates to compounds of formula I and embodiments a, b, c, d, e, f, and g, above, and o, p, q, r, and s, below, in which Ri is optionally substituted Ci_
6 alkyl.
[0067] i. Another embodiment relates to compounds of formula I and embodiments a, b, c, d, e, f, and g, above, and o, p, q, r, and s, below, in which Ri is optionally substituted Ci_
4 alkyl having from 1 to 4 substituents independently selected from the group consisting of optionally substituted C3-8 cycloalkyl, optionally substituted C3-6 heterocycloalkyl, optionally substituted C1-10 heteroaryl, and optionally substituted phenyl.
[0068] j. Another embodiment relates to compounds of formula I and embodiments a, b, c, d, e, f, and g, above, and o, p, q, r, and s, below, in which Ri is optionally substituted Ci_
4 alkyl having from 1 to 4 substituents independently selected from the group consisting of optionally substituted C3_8 cycloalkyl, optionally substituted C3_6 heterocycloalkyl, optionally substituted C1-10 heteroaryl, and optionally substituted phenyl.
[0069] k. Another embodiment relates to compounds of formula I and embodiments a, b, c, d, e, f, and g, above, and o, p, q, r, and s, below, in which Ri is optionally substituted Ci_
4 alkyl having an optionally substituted C3_8 cycloalkyl.
[0070] 1. Another embodiment relates to compounds of formula I and embodiments a, b, c, d, e, f, and g, above, and o, p, q, r, and s, below, in which Ri is optionally substituted Ci_
4 alkyl having an optionally substituted C3_6 heterocycloalkyl.
[0071] m. Another embodiment relates to compounds of formula I and embodiments a, b, c, d, e, f, and g, above, and o, p, q, r, and s, below in which Ri is optionally substituted Ci_4 alkyl having an optionally substituted C1-10 heteroaryl.
[0072] n. Another embodiment relates to compounds of formula I and embodiments a, b, c, d, e, f, and g, above, and o, p, q, r, and s, below, in which Ri is optionally substituted C1- 4 alkyl having an optionally substituted phenyl.
[0073] o. Another embodiment relates to compounds of formula I and embodiments a, b, c, d, e, f, h, i, j, k, 1, m, and n, above, in which m is 1 or 2 and one of R2 is optionally substituted C3_6 heterocycloalkyl. [0074] p. Another embodiment relates to compounds of formula I and embodiments a, b, c, d, e, f, h, i, j, k, 1, m, and n, above, in which m is 1 or 2 and one of R2 is optionally substituted C4-14 aryl.
[0075] q. Another embodiment relates to compounds of formula I and embodiments a, b, c, d, e, f, h, i, j, k, 1, m, and n, above, in which m is 1 or 2 and one of R2 is optionally substituted C4-I4 aryl having 1 to 2 substituents independently selected from the group consisting of amino, Ci_8 alkylamino, Ci_7 amido, Ci_2o amide, optionally substituted Ci_4 alkyl, optionally substituted Ci_4 alkoxy, cyano, halogen, and Ci_g sulfonyl. [0076] r. Another embodiment relates to compounds of formula I and embodiments a, b, c, d, e, f, h, i, j, k, 1, m, and n, above, in which m is 1 or 2 and one of R2 is optionally substituted Ci_io heteroaryl.
[0077] s. Another embodiment relates to compounds of formula I and embodiments a, b, c, d, e, h, i, j, k, 1, m, and n, above, in which m is 1 or 2 and one of R2 is optionally substituted Ci_io heteroaryl having 1 to 2 substituents independently selected from the group consisting of amino, Ci_8 alkylamino, Ci_7 amido, Ci_2o amide, optionally substituted Q_4 alkyl, optionally substituted Ci_4 alkoxy, cyano, halogen, and Ci_g sulfonyl. [0078] 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.
Figure imgf000012_0001
(a) (b) [0079] Scheme A depicts the reaction of an appropriate compound of formula (a) with an appropriate compound of formula (b) to give a compound of formula I. An appropriate compound of formula (a) is one in which Ri is as desired in the final compound of formula I or gives rise to Ri as desired in the final compound of formula I; Xi 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 Xi represents the other part of a symmetrical anhydride formed from two compounds of formula (a) in which Xi is hydroxyl; and G is a hydrogen or a protecting group. The preparation of compounds of formula (a) is readily appreciated in the art. Appropriate compounds of formula (b) are readily available and are ones having n and Ar and 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 in the final product of formula I.
[0080] 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 uranium 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 JV-methylmorpholine or triethylamine, in a wide variety of suitable solvents such as dichloromethane, dimethylformamide, tetrahydrofuran, and the like.
[0081] It is also understood that there are variations of the Scheme A above, particularly for the introduction of Ri and R2 as desired in the final compound of formula I. [0082] For example, a compound of formula (a) in which Ri is hydrogen, Xi is hydroxyl or a lower alkyl alkoxy, and G is a protecting group or a compound of formula I, (except having a G protecting group) in which Ri is hydrogen and can be alkylated with a suitable alkylating agent, 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. For such alkylations, 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, the compound of formula (a) or formula I is reacted with a molar excess OfRiX2 in a suitable solvent such as dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, and the like and the reaction may be carried out using a suitable base, such as cesium carbonate, sodium carbonate, potassium carbonate, triethylamine, diethyl-z-propylamine, lithium hydride, sodium hydride, 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 800C and require about 1 hour to 3 days. Where a compound of formula (a) is used having a protecting group G and/or where Xi is a lower alkyl alkoxy, these groups may be removed before the amidation depicted in Scheme A or where a compound of formula I except having a G protecting is alkylated the protecting group G is removed in another step, not shown, to give a compound of formula I. [0083] In addition, it is also understood that some compounds of formula I may be elaborated to other compounds of formula I, in additional steps not shown. For example, a compound of formula I in which R2 is halogen, generally bromo, can undergo a variety of arylations to give compound in which R2 is optionally substituted C4_i4 aryl and optionally substituted Ci_io heteroaryl. Compounds of formula I may be elaborated in a variety of ways, in an additional step not shown. Such reactions include hydrolysis, oxidation, reduction, alkylation, amidations, sulfonations, alkynations, alkenations, and the like. [0084] 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.
[0085] In another embodiment, the present invention provides pharmaceutical compositions comprising: a compound of invention and a pharmaceutically acceptable excipient.
[0086] 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, buccally, intraperitoneally, intraarterially, transdermally, transbuccally, intraadiposally, intrathecally, and via local delivery, for example, by catheter or stent.
[0087] 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.
[0088] 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, semi-solid, 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, emulsifϊers, dyes, propellants, coating agents, and others.
[0089] 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 regimen to produce the desired therapeutic effect. [0090] 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, or a solid formulation, such as a tablet or a capsule. In still another variation, the pharmaceutical composition is a liquid formulation adapted for parenteral administration.
[0091] 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 sEH comprising contacting the enzyme with a compound of the invention. In another embodiment, the invention provides a method of inhibiting 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 sEH comprising administering a first compound to a subject that is converted in vivo to a compound of the invention.
[0092] 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.
[0093] 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 as hypertension, obesity, elevated triglycerides, elevated cholesterol, glucose intolerance, metabolic syndrome, atherosclerosis, coronary artery disease, 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, pruritus, 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 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 and all of which are contemplated by the invention. Another example is systematic inflammatory response syndrome which is used to describe inflammation events associated with 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. [0094] The terms "treat," "treatment," and "treating" include improvement of the conditions described herein. 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 the invention. Thus, the terms "treat," "treatment," and "treating" include all processes providing slowing, interrupting, arresting, controlling, or stopping of the 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.
[0095] As used herein the term "patient" 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 are non-human mammals, such as mice, rats, and dogs.
[0096] 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, 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.
[0097] In a 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 invention. In another 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 the invention.
[0098] 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.
[0099] 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.
[0100] BIOLOGICAL ACTIVITY
[0101] The activity of compounds as sEH inhibitors may be determined by a variety of methods, including in vitro and in vivo methods.
[0102] A. Inhibition of human and rat sEH
[0103] For human sEH, DNA encoding the full-length sequence of the human enzyme was amplified by PCR and cloned into the pI-SUMOstar vector (LifeSensors), which incorporates a 6 x His-SUMO tag at the 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 the N-terminus. [0104] 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 SUMOstar Protease 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°C or -200C 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 (pH 7.9), 20OmM NaCl, 50% glycerol for rat sEH. [0105] 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 ((3-phenyl-oxiranyl)-acetic acid cyano-(6- methoxy-naphthalen-2-yl)-methyl ester, sEH substrate from Cayman Chemical), 1 nM sEH enzyme, 1% DMSO (from test compound). The 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. [0106] The assay reaction was initiated as follows: 2 μL of a solution containing the test compound and having a concentration that is 5 times the desired concentration in the reaction mixture, was added to each well of the plate, followed by the addition of 4 μL of a 2.5 nM solution of the sEH enzyme. The mixture is incubated for 10 minutes at room temperature. After incubation, 4 μL of a 12.5 μM 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 obtained 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 (test compound) 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. [0107] B. Determination of sEH inhibition in cellular assay [0108] The inhibition of cellular sEH activity can be assayed by measuring a compound's ability to inhibit sEH-mediated hydration of 14,15-epoxyeicosatrienoic acid (14,15-EET) to give 14,15-dihydroxyeicosatrienoic acid (14,15-DHET), which is secreted out of the cell into culture medium comprised of Eagle's MEM (ATCC), 10% Fetal Bovine Serum (Hyclone), 1 x NEAA (Invitrogen), and 1 x L-Glutamine (Invitrogen). [0109] HepG2 hepatocellular carcinoma cells (ATCC) (30,000 cells/well) or ACHN renal cell adenocarcinoma (ATCC) (35,000 cells/well) are seeded in 96-well cellBIND™ tissue culture plates. The cultures are incubated overnight at 37°C in a 5% CO2 incubator until cells attach and spread. 14,15-EET (Biomol International) is added to a final concentration of 6 μM and inhibitor (test compound) is added to the desired final concentration in a total volume of 200 μL per well. Prior to their addition to the cells, the compounds are serially diluted (1 :3 in cell growth medium) from column 1 to 11 in a separate tissue culture plate; column 12 contains DMSO vehicle. The diluted compounds are added to cells and equal amounts of DMSO are added to each well so that the final DMSO concentration in each well is 0.5%. The cultures are incubated for 2 hours at 37°C 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 OD at 450 nm with a Spectramax 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. [0110] C. Reduction of plasma 14,15-DHET in vivo
[0111] Test compounds at 3 mg/kg sEH inhibitor in 0.5 % methyl cellulose or the vehicle control is orally administrated to SHR rats (spontaneously hypertensive rats, 6 rats/group, 13-week old males, Charles River Laboratories) daily for two days. Plasma is collected (200 μL in heparinized tubes at 4 hours post dose on day 1 and at 4, 8 and 24 hours post dose on day 2. The samples are frozen at -800C until analysis. The lipids are extracted from the plasma sample with acetonitrile which contains 14,15-DHET-Jn [800 μL of 10 ng/mL] as an internal standard, and the extract is blown dry and reconstituted into 100 μL 60/40 water/acetonitrile. Calibration of 14,15-DHET is obtained by spiking a known amount of 14,15-DHET (0.5, 1, 2.5, 20, 25, 100, 200, 500, 1000, 2000 ng/mL) into blank plasma and extracting the lipids with 800 μL acetonitrile containing 10 ng/mL 14,15-DHET-Jn as an internal standard. The extract is blown dry and reconstituted into 100 μL 60/40 water/acetonitrile. The 14,15-DHET levels are determined by LC/MRM- MS. The 14,15-DHET is monitored using 337.4/207.1 (Q1/Q3) MRM transition, and 14,15-DHET-Jn is monitored using 348.4/207.1 (Q1/Q3) MRM transition. The concentration of 14,15-DHET in plasma sample (in ng/mL) is 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.
[0112] D. Blood pressure lowering effect in vivo
[0113] 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 administers 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 hours post dosing through non-invasive tail-cuff system under light anesthesia.
EXAMPLES
[0114] The present invention is further illustrated by the following examples and preparations. The examples and preparations do not limit the scope of the invention in any way. The terms and abbreviations used in the examples have their usual meaning unless otherwise indicated. For example, DMF is dimethyl formamide, ACN is acetonitrile, TFA is trifluoroacetic acid, etc.
[0115] PREPARATION 1 : 3-(benzyloxymethyl)-2,6-dioxo-N-(2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide [0116] A. 3-(Benzyloxymethyl)-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxylic acid
[0117] Methyl 2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxylate (4.63 g, 27.2 mmol) was suspended in DMF (100 niL) and cooled in an ice bath. LiH (95%, 0.33 g, 40.8 mmol) was added at once and stirred for 20 minutes. Benzyloxymethyl chloride (90%,
5.12 g, 32.6 mmol) was slowly added via syringe at 00C. The mixture was stirred at 00C for 2 hours. Water (100 mL) was added to the reaction and the solvent was evaporated under vacuum at 55°C to give a residue. The residue was partitioned between IN NaOH
(150 mL) and benzene (100 mL). The mixture was transferred to a separatory funnel and the organic phase was separated. The separated aqueous layer was acidified with concentrated HCl to pH=3. The precipitate was isolated by filtration and the filtrate was transferred to a separatory funnel and extracted with n-BuOH (4 x 100 mL). The organic layers were combined and solvent was evaporated under vacuum to give the title compound. MS [M+H] found 277.
[0118] B. 3-(benzyloxymethyl)-2,6-dioxo-N-(2-(trifluoromethoxy)benzyl)-l,2,3,6- tetrahydropyrimidine-4-carboxamide
[0119] 3-(Benzyloxymethyl)-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxylic acid
(1.00 g, 3.62 mmol), HATU (2.06 g, 5.43 mmol) and JV-methylmorpholine (1.10 g, 10.86 mmol) were dissolved in DMF (14 mL). (2-(Trifluoromethoxy)phenyl)methanamine (0.83 g, 4.34 mmol) was added and the mixture was allowed to stir overnight at room temperature. Solvent was evaporated under vacuum to give a residue, which was triturated with 5% methanol in dichloromethane. The resulting solid was isolated by filtration and dried under vacuum to give the title compound. MS [M+H] found 450.
[0120] PREPARATION 2: 3-(benzyloxymethyl)-l-(2-morpholinoethyl)-2,6-dioxo- l,2,3,6-tetrahydropyrimidine-4-carboxylic acid hydrochloride salt
[0121] To methyl 2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxylate (3.0 g, 17.63 mmol) was added DMF (70.5 mL). The mixture was cooled with an ice bath and lithium hydride (0.221 g, 26.5 mmol) was then added in portions. The mixture was stirred for 20 minutes and ((chloromethoxy)methyl)benzene (3.00 mL, 19.40 mmol) in DMF (10 mL) was added slowly via syringe. The mixture was stirred a 00C for 30 minutes. Lithium hydride (0.295 g, 35.3 mmol) was then added in portions and stirred for 10 minutes. Sodium iodide (2.64 g, 17.63 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (3.94 g, 21.16 mmol) was added in portions and stirred at 00C for 30 minutes. The ice bath was removed and then stirred at room temperature for 1 hour. The reaction mixture heated to 400C for 3 days. The mixture was cooled to room temperature. Water (25 mL) and methanol (25 mL) were then added to the mixture and solvents evaporated under vacuum. IN NaOH (100 mL) and methanol (100 mL) were added and the mixture was heated to 600C for 1 hour. Solvents were evaporated under vacuum at 65°C to give a residue, which was partitioned between IN NaOH (100 mL) and diethyl ether (50 mL) and transferred to a separatory funnel. The organic layer was separated and the aqueous layer was washed with ether (2 x 50 mL). The aqueous layer was then acidified to pH=3 with IN HCl. The aqueous layer was washed with diethyl ether (2 x 150 mL). The aqueous phase was extracted with n-BuOH (5 x 100 mL). The organic layers from the n-BuOH extraction were combined and solvent was evaporated under vacuum to give the title compound which can be carried to the next step without further purification. MS [M+H] found 390. [0122] PREPARATION 3: 3-(benzyloxymethyl)-2,6-dioxo-l-(pyridin-2-ylmethyl)- 1 ,2,3,6-tetrahydropyrimidine-4-carboxylic acid.
[0123] Methyl 2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxylate (5 g, 29.4 mmol) and DMF (118 mL) were combined and the resultant mixture was cooled with an ice bath. Lithium hydride (0.369 g, 44.1 mmol) was added in portions. The mixture was stirred for 20 minutes and ((chloromethoxy)methyl)benzene (5.00 mL, 32.3 mmol) was added via syringe. The mixture was stirred a 00C for 30 minutes. Lithium hydride (0.492 g, 58.8 mmol) was then added in portions and stirred for 10 minutes. 2-(Bromomethyl)pyridine hydrobromide (8.92 g, 35.3 mmol) was added in portions and stirred at 00C over 1 hour. The bath was removed and then stirred at room temperature for 2 hours. Water (25 mL) and methanol (25 mL) were added and the solvents were evaporated under vacuum at 65°C to leave a red oily solid, which was partitioned between IN NaOH (100 mL) and diethyl ether (50 mL). The organic layer was separated. The aqueous layer was washed with diethyl ether (2 x 50 mL) and the aqueous layer was acidified to pH=4 with 3N HCl. The aqueous layer was washed with diethyl ether (2 x 50 mL). The aqueous layer was then extracted with n-BuOH (4 x 100 mL). The organic layers from the n-BuOH extraction were combined and the solvent was evaporated under vacuum to give a solid, which was triturated with acetone and cooled in an ice bath. The resulting solid was isolated by filtration and dried under vacuum to give 4.86 g of a first crop of the title compound; a second and third crop were isolated to give a total of 5.53g of the title compound. MS [M+H] found 368.
[0124] PREPARATION 4: l-(2-(l/f-pyrazol-l-yl)ethyl)-3-(benzyloxymethyl)-2,6- dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxylic acid.
[0125] To methyl 2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxylate (900 mg, 5.29 mmol) was added DMF (17 mL). The mixture was cooled with an ice bath and lithium hydride (66.4 mg, 7.94 mmol) was then added in portions. The mixture was stirred for 20 minutes and ((chloromethoxy)methyl)benzene (0.899 mL, 5.82 mmol) in DMF (3 mL) was then added slowly via syringe. The mixture was stirred a 00C for 30 minutes. Lithium hydride (66.4 mg, 7.94 mmol) was then added in portions and stirred for 10 minutes. Sodium iodide (793 mg, 5.29 mmol) and l-(2-chloroethyl)-l/f-pyrazole (829 mg, 6.35 mmol) were added in portions and then stirred at 00C for 30 minutes. The ice bath was removed. The mixture was stirred at room temperature for 4 hours and then heated to 500C with stirring for 3 days. The reaction mixture was cooled to room temperature. Water (25 mL) and methanol (25 mL) were added and the solvents were evaporated under vacuum at 65°C to give a residue, which was partitioned between IN NaOH (75 mL) and diethyl ether (50 mL). The organic layer was separated and the aqueous layer was washed with diethyl ether (2 x 50 mL). The aqueous layer was then acidified to pH=3 with IN HCl and then extracted with n-BuOH (5 x 100 mL). The organic layers from the n-BuOH extraction were combined and the solvent was evaporated under vacuum to give a residue which was purified by HPLC (40% ACN in water containing 0.05% TFA) to give the title compound. MS [M+H] found 371.
[0126] PREPARATION 5: 3-(benzyloxymethyl)-l-((3-ethyl-l,2,4-oxadiazol-5- yl)methyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxylic acid [0127] To methyl 2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxylate (943 mg, 5.54 mmol) was added DMF (17 mL). The mixture was cooled with an ice bath and lithium hydride (69.6 mg, 8.31 mmol) was then added in portions. The mixture was stirred for 20 minutes and ((chloromethoxy)methyl)benzene (0.942 mL, 6.10 mmol) in DMF (3 mL) was then added slowly via syringe. The mixture was stirred a 00C for 30 minutes. Lithium hydride (69.6 mg, 8.31 mmol) was added in portions and stirred for 10 minutes. 5- (Chloromethyl)-3-ethyl-l,2,4-oxadiazole (975 mg, 6.65 mmol) was added in portions and stirred at 00C for 30 minutes. The ice bath was removed and the reaction was stirred at room temperature for 4 hours. Water (20 mL) and methanol (20 mL) were added and the solvents were evaporated under vacuum at 65°C to leave a residue. The residue was partitioned between IN NaOH (50 mL) and diethyl ether (50 mL) and transferred to a separatory funnel. The organic layer was separated. The aqueous was washed with diethyl ether (2 x 100 mL). The aqueous layer was acidified to pH=3 with IN HCl. The aqueous layer was extracted with diethyl ether (2 x 150 mL). The organic layers after acidification were combined and washed with brine (100 mL). The organics were dried over magnesium sulfate, filtered, and the solvent was evaporated under vacuum to give the title compound which can be used without further purification. MS [M+H] found 387. [0128] PREPARATION 6: l-(3-methoxypropyl)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)- lH-pyrazole
[0129] A. 4-bromo-l-(3-methoxypropyl)-lH-pyrazole
[0130] Cesium carbonate (1.11 g, 3.40 mmol) and 4-bromo-lH-pyrazole (250 mg, 1.70 mmol) were suspended in DMF (8.5 mL). l-Bromo-3-methoxypropane (312 mg, 2.041 mmol) was added and the mixture was heated to 500C overnight. The mixture was filtered and the solvent was evaporated from the filtrate under vacuum to give a residue, which was purified by column chromatography (gradient: 0 to 2.5% methanol in dichloromethane) to give the title compound. MS [M+H] found 219. 1H NMR (400 MHz, CHLOROFORM-J) δ ppm 2.04 - 2.13 (m, 2 H), 3.28 - 3.34 (m, 5 H), 4.20 (t, J=6.82 Hz, 2 H), 7.41 (s, 1 H), 7.46 (s, 1 H).
[0131] B. l-(3-methoxypropyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l/f- pyrazole
[0132] PdCl2(dppf) (35.9 mg, 0.049 mmol), sodium acetate (242 mg, 2.94 mmol), 4- bromo-l-(3-methoxypropyl)-l/f-pyrazole (215 mg, 0.981 mmol) and 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(l,3,2-dioxaborolane) (748 mg, 2.94 mmol) were added to an oven- dried Schlenk flask. The solids were subjected to 4 cycles of nitrogen and vacuum. DMF (13.1 mL) was added and the mixture was heated to 800C overnight. The mixture was filtered and the filtrate was purified by mass-triggered HPLC (gradient: 45 to 50% ACN in water containing 0.05% TFA) to give the title compound. MS [M+H] found 267. [0133] PREPARATION 7: 3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l/f- pyrazol- 1 -yl)propan- 1 -ol
[0134] A. 3-(4-Bromo-l/f-pyrazol-l-yl)propan-l-ol
[0135] Cesium carbonate (1.11 g, 3.40 mmol) and 4-bromo-lH-pyrazole (250 mg, 1.70 mmol) were suspended in DMF (8.5 mL). 3-Bromopropan-l-ol (178 μL, 2.041 mmol) was added and the mixture heated to 500C overnight. The mixture was cooled to room temperature, filtered, and the solvent from the filtrate was evaporated under vacuum to give a residue. The residue was purified by column chromatography (gradient: 0 to 2.5% methanol in dichloromethane) to give the title compound. MS [M+H] found 205. 1H NMR (400 MHz, CHLOROFORM-J) δ ppm 2.06 (quin, 2 H), 2.33 (quin, J=6.32 Hz, 1 H), 3.65 (br. s., 1 H), 4.21 - 4.32 (m, 2 H), 4.34 (t, J=6.06 Hz, 1 H), 4.88 (br. s., 1 H), 7.41 - 7.52 (m, 2 H).
[0136] B. 3-(4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)-l/f-pyrazol-l-yl)propan- l-ol
[0137] PdCl2(dppf) (28.7 mg, 0.039 mmol), sodium acetate (193 mg, 2.355 mmol), 3-(4- bromo-l/f-pyrazol-l-yl)propan-l-ol (161 mg, 0.785 mmol) and 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(l,3,2-dioxaborolane) (598 mg, 2.355 mmol) were added to an oven- dried Schlenk flask. The solids were subjected to 4 cycles of nitrogen and vacuum. DMF (10.5mL) was added and the mixture was heated to 800C overnight. The reaction mixture was cooled to room temperature, filtered, and the filtrate was purified by mass-triggered HPLC (gradient: 25 to 30% ACN in water containing 0.05% TFA) to give the title compound. MS [M+H] found 253.
[0138] PREPARATION 8: (3-(4-fluorophenyl)pyridin-2-yl)methanamine [0139] A. 3-(4-fluorophenyl)picolinonitrile
[0140] To 3-bromopicolinonitrile (200 mg, 1.093 mmol) and 4-fluorophenylboronic acid (183 mg, 1.311 mmol) was added dioxane (5.5 mL) and sodium bicarbonate (sat.) (5.5 mL) in a microwave vial. PdCl2(dppf) (40.0 mg, 0.055 mmol) was added. The mixture was sonicated and microwaved as a high absorber at 115°C for 20 minutes. Solvent was evaporated under vacuum to give a residue, which was partitioned between water (50 mL) and ethyl acetate (50 mL) and filtered. The filtrate was transferred to a separatory funnel. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The organic layers were combined and washed with brine (25 mL). The organics were dried over sodium sulfate and filtered. The solvent was evaporated under vacuum to give the title compound which was used in the next step without further purification. MS [M+H] found 199. [0141] B. (3-(4-Fluorophenyl)pyridin-2-yl)methanamine
[0142] 3-(4-fluorophenyl)picolinonitrile (325 mg, 1.640 mmol) and 10% palladium on carbon (Degussa™, 175 mg, 0.164 mmol) was combined with EtOH (40 mL) and hydrogenated in a Parr hydrogenator overnight at 35 psi. The mixture was filtered and the solvent was evaporated from the filtrate under vacuum to give a residue, which was partitioned between IN HCl (50 mL) and ethyl acetate (50 mL). The mixture was transferred to a separatory funnel and the organic layer was separated. The aqueous layer was washed with ethyl acetate (2 x 50 mL). The aqueous layer was made basic with IN NaOH (pH=12). Ethyl acetate (50 mL) was added to the aqueous layer and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (2 x 50 mL). The organic layers were combined and washed with brine (25 mL). The organics were dried over sodium sulfate and filtered. The solvent from the filtrate was evaporated under vacuum to leave a residue, which was purified by mass-triggered HPLC (gradient: 20 to 25% ACN in water containing 0.05% TFA) to give the title compound. MS [M+H] found 203. 1U NMR (400 MHz, CHLOROFORM-J) δ ppm 4.27 (s, 1 H), 7.14 - 7.20 (m, 2 H), 7.24 - 7.29 (m, 2 H), 7.50 (dd, J=7.83, 5.05 Hz, 1 H), 7.79 (dd, J=7.83, 1.77 Hz, 1 H), 8.56 (dd, J=5.05, 1.52 Hz, 1 H), 9.65 - 9.98 (m, 2 H).
[0143] PREPARATION 9: (2-(4-fluorophenyl)pyridin-3-yl)methanamine [0144] A. 2-(4-Fluorophenyl)nicotinaldehyde
[0145] 2-Bromonicotinaldehyde (250 mg, 1.34mmol), 4-fluorophenylboronic acid (226 mg, 1.61 mmol), dioxane (6.7 mL) and sodium bicarbonate (sat.) (6.7 mL) were added to a microwave vial. PdCl2(dppf) (49 mg, 0.067 mmol) was added. The mixture was sonicated and microwaved as a high absorber at 115°C for 20 minutes. Solvent was evaporated under vacuum to give a residue. The residue was partitioned between water (50 mL) and ethyl acetate (50 mL) and filtered. The filtrate was transferred to a separatory funnel. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The organic layers were combined and washed with brine (25 rnL). The organics were dried over sodium sulfate and filtered. The solvent from the filtrate was evaporated under vacuum to give the title compound. The material was carried forward to the next step without further purification. MS [M+H] found 202. [0146] B. (2-(4-Fluorophenyl)pyridin-3-yl)methanamine
[0147] 2-(4-Fluorophenyl)nicotinaldehyde (270 mg, 1.367 mmol) and 7 N ammonia methanol (6.8 mL) was stirred overnight at room temperature. Sodium borohydride (112 mg, 2.95 mmol) was added at once and stirred at room temperature for 5 hours. The solvent was evaporated under vacuum to give a residue, which was partitioned between IN NaOH (25 mL) and ethyl acetate (25 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 25 mL). The organic layers were combined and washed with brine (50 mL). The organics were dried over sodium sulfate and filtered. The solvent from the filtrate was evaporated under vacuum to give a residue, which was purified by mass-triggered HPLC (5% ACN in water containing 0.05% TFA) to give the title compound. MS [M+H] found 203. 1H NMR (400 MHz, DMSO-J6) δ ppm 3.70 (s, 2 H), 7.24 - 7.32 (m, 2 H), 7.38 (dd, J=7.71, 4.67 Hz, 1 H), 7.61 - 7.68 (m, 2 H), 8.00 (dd, J=7.71, 1.64 Hz, 1 H), 8.50 (dd, J=4.67, 1.64 Hz, 1 H). [0148] PREPARATION 10: (4-(4-fluorophenyl)pyridin-3-yl)methanamine [0149] The title compound was prepared in a manner similar to the method described in Preparation 9, using 4-bromonicotinaldehyde in step A to give an intermediate, 4-(4- fluorophenyl)nicotinaldehyde, which was purified by column chromatography (3% methanol in dichloromethane). MS [M+H] found 202. The intermediate was used without further purification to give the title compound, which was purified by mass-triggered HPLC (5% ACN in water containing 0.05% TFA). MS [M+H] found 203. [0150] PREPARATION 11 : (3 -(4-fluorophenyl)furan-2-yl)methanamine [0151] The title compound was prepared in a manner similar to the method described in Preparation 9, using 3-bromofuran-2-carbaldehyde in step A to give an intermediate, 3-(4- fluorophenyl)furan-2-carbaldehyde, which was purified by column chromatography (2.5% methanol in dichloromethane). MS [M+H] found 191. 1H NMR (400 MHz, DMSO-J6) δ ppm 7.08 (d, J=I.77 Hz, 1 H), 7.30 - 7.38 (m, 2 H), 7.77 - 7.84 (m, 2 H), 8.16 (d, J=LOl Hz, 1 H), 9.69 (s, 1 H). The intermediate was used to prepared the title compound, which was purified by mass-triggered HPLC (gradient: 5 to 25% ACN in water containing 0.05% TFA). MS [M+H] found 192.
[0152] PREPARATION 12: (3-(4-fluorophenyl)thiophen-2-yl)methanamine [0153] The title compound was prepared in a manner similar to the method described in Preparation 9, using 3-bromothiophene-2-carbaldehyde in step A to give an intermediate, 3-(4-fluorophenyl)thiophen-2-carbaldehyde, which was purified by column chromatography (2.5% methanol in dichloromethane). MS [M+H] found 207. The intermediate was used to prepare the title compound, which was purified by mass- triggered HPLC (gradient: 5 to 25% ACN in water containing 0.05% TFA). MS [M+H] found 208.
[0154] PREPARATION 13 : (4-(4-fluorophenyl)thiophen-3 -yl)methanamine [0155] The title compound was prepared in a manner similar to the method described in Preparation 9, using 4-bromothiophene-3-carbaldehyde in step A to give 4-(4- fluorophenyl)thiophene-3-carbaldehyde, which was purified by column chromatography (2.5% methanol in dichloromethane). MS [M+H] found 207. The intermediate was used to prepare the title compound, which was purified by mass-triggered HPLC (gradient: 5 to 25% ACN in water containing 0.05% TFA). MS [M+H] found 208. [0156] EXAMPLE 1 : N-(2,4-dichlorobenzyl)-l-methyl-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide
Figure imgf000029_0001
[0157] l-Methyl-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxylic acid (111 mg, 0.65 mmol), 2,4-dichlorophenylmethanamine (114 mg, 0.65 mmol), JV-methylmorpholine (NMM) (71 mg, 0.7 mmol), and EEDQ (193 mg, 0.8 mmol) in DMF (3 mL) were combined. The mixture was heated to 55°C overnight. The mixture was diluted with MeOH. The product was filtered off and rinsed with MeOH to give the title compound. MS [M+H] found 329. 1H NMR (400 MHz, DMSO-J6) δ ppm 3.13 (s, 3 H), 4.46 (d, J = 8.0 Hz, 2 H), 6.25 (s, 1 H), 7.39-7.46 (m, 2H), 7.64 (s, 1 H), 9.40 (t, J= 4.0 Hz, 1 H), 11.11 (s, I H).
[0158] EXAMPLE 2: N-(2-chloro-4-(methylsulfonyl)benzyl)-l-methyl-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000030_0001
[0159] The title compound was prepared in a manner similar to the method described in
Example 1, using 2-chloro-4-methylsulfonylbenzylamine in place of 2,4- dichlorophenylmethanamine. MS [M+H] found 373. 1U NMR (400 MHz, DMSO-J6) δ ppm 3.13 (s, 3 H), 3.27 (s, 3H), 4.46 (d, J= 8.0 Hz, 2 H), 6.25 (s, 1 H), 7.35-7.47 (m, 2H),
7.64 (s, 1 H), 9.40 (t, J = 4.0 Hz, 1 H), 11.11 (s, 1 H).
[0160] EXAMPLE 3: l-methyl-2,6-dioxo-N-(2-(trifluoromethoxy)benzyl)-l,2,3,6- tetrahydropyrimidine-4-carboxamide
Figure imgf000030_0002
[0161] The title compound was prepared in a manner similar to the method described in Example 1, using 2-trifluoromethoxybenzylamine in place of 2,4- dichlorophenylmethanamine. MS [M+H] found 344. 1U NMR (400 MHz, DMSO-J6) δ ppm 3.13 (s, 3 H), 4.47 (d, J= 4.0 Hz, 2 H), 6.24 (s, 1 H), 7.34-7.49 (m, 4H), 9.40 (t, J = 4.0 Hz, I H), 11.10 (s, I H).
[0162] EXAMPLE 4: N-(4-chloro-2-(methylsulfonyl)benzyl)-l-methyl-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000030_0003
[0163] The title compound was prepared in a manner similar to the method described in Example 1, using 2-chloro-4-methylsulfonylbenzylamine in place of 2,4- dichlorophenylmethanamine. MS [M+H] found 373. 1U NMR (400 MHz, DMSO-J6) δ ppm 3.14 (s, 3 H), 3.42 (s, 3H), 4.81 (d, J= 8.0 Hz, 2 H), 6.27 (s, 1 H), 7.62 (d, J= 8.0 Hz, 1 H), 7.82(dd, J= 2.0, 8.0 Hz, 1 H), 7.90 (d, J= 4.0 Hz, 1 H), 9.57 (t, J= 4.0 Hz, 1 H), 11.16 (s, I H).
[0164] EXAMPLE 5 : N-(4-methoxy-2-(trifluoromethoxy)benzyl)- 1 -methyl-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000031_0001
[0165] The title compound was prepared in a manner similar to the method described in Example 1, using (4-methoxy-2-(trifluoromethoxy)phenyl)methanamine in place of 2,4- dichlorophenylmethanamine. MS [M+H] found 374. 1U NMR (400 MHz, DMSO-J6) δ ppm 3.13 (s, 3 H), 3.79 (s, 3 H), 4.40 (d, J= 8.0 Hz, 2 H), 6.21 (s, 1 H), 6.90 (s, IH), 7.00 (d, J= 8.0 Hz, 1 H), 7.39 (d, J= 8.0 Hz, 1 H), 9.31 (t, J= 4.0 Hz, 1 H), 11.03 (s, 1 H). [0166] EXAMPLE 6: l-(cyclopropylmethyl)-2,6-dioxo-N-(2-(trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000031_0002
[0167] A. 3-(Benzyloxymethyl)- 1 -(cyclopropylmethyl)-2,6-dioxo-iV-(2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide [0168] To 3-(benzyloxymethyl)-2,6-dioxo-Λ/-(2-(trifluoromethoxy)benzyl)-l,2,3,6- tetrahydropyrimidine-4-carboxamide (130 mg, 289 μmol) and cesium carbonate (236 mg, 723 μmol) in DMF (0.73 mL) was added (bromomethyl)cyclopropane (59 mg, 434 μmol). The mixture was allowed to stir at room temperature for 4 hours. The mixture was filtered and the filtrate was purified by mass-triggered HPLC (gradient: 60 to 80% ACN in water containing 0.05% TFA) to give the title compound.
[0169] B. l-(Cyclopropylmeώyl)-2,6-dioxo-iV-(2-(trifluoromethoxy)benzyl)-l, 2,3,6- tetrahydropyrimidine-4-carboxamide
[0170] Anisole (3 lmg, 289 μmol) and TFA (10 mL) were added to 3-
(benzyloxymethyl)-l-(cyclopropylmethyl)-2,6-dioxo-N-(2-(trifluoromethoxy)benzyl)- l,2,3,6-tetrahydropyrimidine-4-carboxamide. The mixture was heated to reflux for 1 hour.
The reaction was cooled to room temperature and the solvent was evaporated under vacuum to give the title compound, which was purified by mass-triggered HPLC
(gradient: 40 to 60% ACN in water containing 0.05% TFA). MS [M+H] found 384.
[0171] EXAMPLE 7: l-(2,2-difluoroethyl)-2,6-dioxo-N-(2-(trifluoromethoxy)benzyl)-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000032_0001
[0172] The title compound was prepared in a manner similar to the method described in Example 6, using l,l-difluoro-2-iodoethane in place of (bromomethyl)cyclopropane, and was purified by mass-triggered HPLC (gradient: 40 to 75% ACN in water containing 0.05% TFA). MS [M+H] found 394.
[0173] EXAMPLE 8: l-(4-(methylsulfonyl)benzyl)-2,6-dioxo-N-(2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000032_0002
[0174] The title compound was prepared in a manner similar to the method described in Example 6, using l-(bromomethyl)-4-(methylsulfonyl)benzene in place of (bromomethyl)cyclopropane, and was purified by mass-triggered HPLC (gradient: 40 to 75% ACN in water containing 0.05% TFA). MS [M+H] found 498. [0175] EXAMPLE 9: l-(2-hydroxyethyl)-2,6-dioxo-N-(2-(trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000033_0001
[0176] The title compound was prepared in a manner similar to the method described in Example 6, using 2-bromoethanol in place of (bromomethyl)cyclopropane, and was purified by mass-triggered HPLC (gradient: 30 to 45% ACN in water containing 0.05% TFA). MS [M+H] found 374.
[0177] EXAMPLE 10: 2,6-dioxo-l-(pyridin-2-ylmethyl)-N-(2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000033_0002
[0178] The title compound was prepared in a manner similar to the method described in Example 6, using 2-(bromomethyl)pyridine hydrobromide in place of (bromomethyl)cyclopropane. Purification by mass-triggered HPLC (gradient: 30 to 55% ACN in water containing 0.05% TFA) gave the title compound as a TFA salt. MS [M+H] found 421.
[0179] EXAMPLE 11 : 1 -(2-amino-2-oxoethyl)-2,6-dioxo-N-(2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000033_0003
[0180] The title compound was prepared in a manner similar to the method described in Example 6, using 2-bromoacetamide in place of (bromomethyl)cyclopropane, and was purified by mass-triggered HPLC (gradient: 35 to 75% ACN in water containing 0.05% TFA). MS [M+H] found 387.
EXAMPLE 12: l-(3-amino-3-oxopropyl)-2,6-dioxo-Λ/-(2-(trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000034_0001
[0181] The title compound was prepared in a manner similar to the method described in Example 6, using 3-bromopropanamide in place of (bromomethyl)cyclopropane, and was purified by mass-triggered HPLC (gradient: 45 to 60% ACN in water containing 0.05% TFA). MS [M+H] found 401.
[0182] EXAMPLE 13 : (R)-2,6-dioxo- 1 -((5-oxopyrrolidin-2-yl)methyl)-N-(2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000034_0002
[0183] The title compound was prepared in a manner similar to the method described in Example 6, using (i?)-5-(bromomethyl)pyrrolidin-2-one in place of (bromomethyl)cyclopropane, and was purified by mass-triggered HPLC (45% ACN in water containing 0.05% TFA). MS [M+H] found 427. [0184] EXAMPLE 14: l-(2,3-dihydroxypropyl)-2,6-dioxo-N-(2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000034_0003
[0185] The title compound was prepared in a manner similar to the method described in Example 6, using 3-bromopropane-l,2-diol in place of (bromomethyl)cyclopropane, and was purified by mass-triggered HPLC (gradient: 25 to 30% ACN in water containing 0.05% TFA). MS [M+H] found 404.
[0186] EXAMPLE 15: l-(3-cyanobenzyl)-2,6-dioxo-N-(2-(trifiuoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000035_0001
[0187] The title compound was prepared in a manner similar to the method described in Example 6, using 3-(bromomethyl)benzonitrile in place of (bromomethyl)cyclopropane, and was purified by mass-triggered HPLC (gradient: 45 to 60% ACN in water containing 0.05% TFA). MS [M+H] found 445.
[0188] EXAMPLE 16: 2,6-dioxo-l-(pyridin-3-ylmethyl)-N-(2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000035_0002
[0189] The title compound was prepared in a manner similar to the method described in Example 6, using 3-(bromomethyl)pyridine hydrobromide in place of (bromomethyl)cyclopropane. Purification by mass-triggered HPLC (gradient: 25 to 30% ACN in water containing 0.05% TFA) gave the title compound as a TFA salt. MS [M+H] found 421.
[0190] EXAMPLE 17: l-(3-hydroxypropyl)-2,6-dioxo-N-(2-(trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000036_0001
[0191] The title compound was prepared in a manner similar to the method described in Example 6, using 3-bromopropan-l-ol in place of (bromomethyl)cyclopropane, and was purified by mass-triggered HPLC (gradient: 45 to 55% ACN in water containing 0.05% TFA). MS [M+H] found 388.
[0192] EXAMPLE 18: 2,6-dioxo-l-((tetrahydrofuran-2-yl)methyl)-N-(2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000036_0002
[0193] The title compound was prepared in a manner similar to the method described in Example 6, using 2-(bromomethyl)tetrahydrofuran in place of
(bromomethyl)cyclopropane, and was purified by mass-triggered HPLC (gradient: 55 to 70% ACN in water containing 0.05% TFA). MS [M+H] found 414. [0194] EXAMPLE 19: l-(4-cyanobenzyl)-2,6-dioxo-N-(2-(trifiuoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000036_0003
[0195] The title compound was prepared in a manner similar to the method described in Example 6, using 4-(bromomethyl)benzonitrile in place of (bromomethyl)cyclopropane, and was purified by mass-triggered HPLC (gradient: 45 to 65% ACN in water containing 0.05% TFA). MS [M+H] found 445. [0196] EXAMPLE 20: l-(3-cyanopropyl)-2,6-dioxo-N-(2-(trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000037_0001
[0197] The title compound was prepared in a manner similar to the method described in Example 6, using 4-bromobutanenitrile in place of (bromomethyl)cyclopropane, and was purified by mass-triggered HPLC (gradient: 40 to 45% ACN in water containing 0.05% TFA). MS [M+H] found 397.
[0198] EXAMPLE 21 : 1 -(2-fiuorobenzyl)-2,6-dioxo-N-(2-(trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000037_0002
[0199] The title compound was prepared in a manner similar to the method described in Example 6, using l-(bromomethyl)-2-fluorobenzene in place of
(bromomethyl)cyclopropane, and was purified by mass-triggered HPLC (gradient: 50 to 55% ACN in water containing 0.05% TFA). MS [M+H] found 438. [0200] EXAMPLE 22: l-(3-hydroxy-2,2-dimethylpropyl)-2,6-dioxo-N-(2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000037_0003
[0201] The title compound was prepared in a manner similar to the method described in Example 6, using 3-bromo-2,2-dimethylpropan-l-ol in place of (bromomethyl)cyclopropane, and was purified by mass-triggered HPLC (gradient: 45 of 55% ACN in water containing 0.05% TFA). MS [M+H] found 416. [0202] EXAMPLE 23: l-(2-(dimethylamino)ethyl)-2,6-dioxo-N-(2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000038_0001
[0203] The title compound was prepared in a manner similar to the method described in Example 6, using 2-chloro-Λf,Λ/-dimethylethanamine hydrochloride in place of (bromomethyl)cyclopropane, and was purified by mass-triggered HPLC (gradient: 20 to 30% ACN in water containing 0.05% TFA). MS [M+H] found 401. 1H NMR (400 MHz, DMSO-Je) δ ppm 2.86 (d, J=4.29 Hz, 6 H), 3.28 - 3.36 (m, 2 H), 4.09 (t, J=5.81 Hz, 2 H), 4.50 (d, J=5.81 Hz, 2 H), 6.30 (d, J=1.52 Hz, 1 H), 7.34 - 7.48 (m, 4 H), 9.31 (br. s., 1 H), 9.47 (t, J=5.68 Hz, 1 H), 11.31 (s, 1 H).
[0204] EXAMPLE 24: l-(2-morpholinoethyl)-2,6-dioxo-N-(2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000038_0002
[0205] The title compound was prepared in a manner similar to the method described in
Example 6, using 4-(2-chloroethyl)morpholine hydrochloride in place of
(bromomethyl)cyclopropane, and was purified by mass-triggered HPLC (gradient: 20 to
30% ACN in water containing 0.05% TFA). MS [M+H] found 443.
[0206] EXAMPLE 25: l-cyclopentyl-2,6-dioxo-N-(2-(trifluoromethoxy)benzyl)-l,2,3,6- tetrahydropyrimidine-4-carboxamide
Figure imgf000039_0001
[0207] The title compound was prepared in a manner similar to the method described in
Example 6, using bromocyclopentane in place of (bromomethyl)cyclopropane, and was purified by mass-triggered HPLC (50% ACN in water containing 0.05% TFA). MS
[M+H] found 398.
[0208] EXAMPLE 26: l-neopentyl-2,6-dioxo-N-(2-(trifluoromethoxy)benzyl)-l,2,3,6- tetrahydropyrimidine-4-carboxamide
Figure imgf000039_0002
[0209] The title compound was prepared in a manner similar to the method described in Example 6, using l-bromo-2,2-dimethylpropane in place of (bromomethyl)cyclopropane, and was purified by mass-triggered HPLC (gradient: 55 to 60% ACN in water containing 0.05% TFA). MS [M+H] found 400.
[0210] EXAMPLE 27: l-((2,4-dioxo-l,2,3,4-tetrahydropyrimidin-5-yl)methyl)-2,6- dioxo-Λ/-(2-(trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000039_0003
[0211] The title compound was prepared in a manner similar to the method described in Example 6, using 5-(chloromethyl)pyrimidine-2,4(lH,3H)-dione in place of (bromomethyl)cyclopropane, and was purified by mass-triggered HPLC (gradient: 35 to 40% ACN in water containing 0.05% TFA). MS [M+H] found 454. [0212] EXAMPLE 28: l-(methoxymethyl)-2,6-dioxo-N-(2-(trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000040_0001
[0213] The title compound was prepared in a manner similar to the method described in Example 6, using chloro(methoxy)methane in place of (bromomethyl)cyclopropane, and was purified by mass-triggered HPLC (gradient: 35 to 40% ACN in water containing 0.05% TFA). MS [M+H] found 374.
[0214] EXAMPLE 29: l-(2-(i/f-pyrazol-l-yl)ethyl)-2,6-dioxo-N-(2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000040_0002
[0215] The title compound was prepared in a manner similar to the method described in Example 6, using l-(2-chloroethyl)-lH-pyrazole in place of (bromomethyl)cyclopropane, and was purified by mass-triggered HPLC (40% ACN in water containing 0.05% TFA). MS [M+H] found 424.
[0216] EXAMPLE 30: l-((4-isobutylmorpholin-2-yl)methyl)-2,6-dioxo-N-(2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000040_0003
[0217] The title compound was prepared in a manner similar to the method described in Example 6, using 2-(chloromethyl)-4-isobutylmorpholine in place of (bromomethyl)cyclopropane. Purification by mass-triggered HPLC (30% ACN in water containing 0.05% TFA) gave the title compound as a TFA salt. MS [M+H] found 485. [0218] EXAMPLE 31 : 1 -(2-(methylthio)ethyl)-2,6-dioxo-iV-(2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000041_0001
[0219] The title compound was prepared in a manner similar to the method described in Example 6, using (2-chloroethyl)(methyl)sulfane in place of (bromomethyl)cyclopropane, and was purified by mass-triggered HPLC (gradient: 45 to 50% ACN in water containing 0.05% TFA). MS [M+H] found 404.
[0220] EXAMPLE 32: 2,6-dioxo-l-(2-(2-oxopyrrolidin-l-yl)ethyl)-N-(2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000041_0002
[0221] The title compound was prepared in a manner similar to the method described in Example 6, using l-(2-chloroethyl)pyrrolidin-2-one in place of
(bromomethyl)cyclopropane, and was purified by mass-triggered HPLC (50% ACN in water containing 0.05% TFA). MS [M+H] found 441.
[0222] EXAMPLE 33: l-(2-(isopropyl(methyl)amino)-2-oxoethyl)-2,6-dioxo-N-(2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000041_0003
[0223] The title compound was prepared in a manner similar to the method described in Example 6, using 2-chloro-ΛMsopropyl-Λ/-methylacetamide in place of (bromomethyl)cyclopropane, and was purified by mass-triggered HPLC (55% ACN in water containing 0.05% TFA). MS [M+H] found 443. [0224] EXAMPLE 34: l-((2-methylthiazol-4-yl)methyl)-2,6-dioxo-N-(2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000042_0001
[0225] The title compound was prepared in a manner similar to the method described in Example 6, using 4-(chloromethyl)-2-methylthiazole in place of
(bromomethyl)cyclopropane, and was purified by mass-triggered HPLC (gradient: 50 to 55% ACN in water containing 0.05% TFA). MS [M+H] found 441. [0226] EXAMPLE 35: l-((3-ethyl-l,2,4-oxadiazol-5-yl)methyl)-2,6-dioxo-N-(2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000042_0002
[0227] The title compound was prepared in a manner similar to the method described in Example 6, using 5-(chloromethyl)-3-ethyl-l,2,4-oxadiazole in place of (bromomethyl)cyclopropane, and was purified by mass-triggered HPLC (gradient: 50 to 55% ACN in water containing 0.05% TFA). MS [M+H] found 440. [0228] EXAMPLE 36: 2,6-dioxo-l-(2-(2-oxo-2,3-dihydro-l/f-imidazol-l-yl)ethyl)-N- (2-(trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000043_0001
[0229] The title compound was prepared in a manner similar to the method described in Example 6, using l-(2-chloroethyl)-lH-imidazol-2(3H)-one in place of (bromomethyl)cyclopropane, and was purified by mass-triggered HPLC (gradient: 40 to 45% ACN in water containing 0.05% TFA). MS [M+H] found 440. [0230] EXAMPLE 37: l-(2-(l/f-l,2,4-triazol-l-yl)ethyl)-2,6-dioxo-N-(2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000043_0002
[0231] The title compound was prepared in a manner similar to the method described in Example 6, using l-(2-chloroethyl)-lH-l,2,4-triazole in place of
(bromomethyl)cyclopropane, and was purified by mass-triggered HPLC (gradient: 45 to 50% ACN in water containing 0.05% TFA). MS [M+H] found 425. [0232] EXAMPLE 38: l-((5-ethyl-l,3,4-oxadiazol-2-yl)methyl)-2,6-dioxo-N-(2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000043_0003
[0233] The title compound was prepared in a manner similar to the method described in Example 6, using 2-(chloromethyl)-5-ethyl-l,3,4-oxadiazole in place of (bromomethyl)cyclopropane, and was purified by mass-triggered HPLC (50% ACN in water containing 0.05% TFA). MS [M+H] found 440. [0234] EXAMPLE 39: l-(2-(diethylamino)ethyl)-2,6-dioxo-N-(2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000044_0001
[0235] The title compound was prepared in a manner similar to the method described in Example 6, using 2-chloro-N,Λ/-diethylethanamine hydrochloride in place of (bromomethyl)cyclopropane. Purification by mass-triggered HPLC (gradient: 30 to 35% ACN in water containing 0.05% TFA) gave the title compound as a TFA salt. MS [M+H] found 429.
[0236] EXAMPLE 40: l-(3-(l/f-pyrazol-l-yl)propyl)-2,6-dioxo-N-(2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000044_0002
[0237] The title compound was prepared in a manner similar to the method described in
Example 6, using l-(3-chloropropyl)-lH-pyrazole hydrochloride in place of
(bromomethyl)cyclopropane, and was purified by mass-triggered HPLC (gradient: 50 to
55% ACN in water containing 0.05% TFA). MS [M+H] found 438.
[0238] EXAMPLE 41 : l-benzyl-2,6-dioxo-N-(2-(trifluoromethoxy)benzyl)-l,2,3,6- tetrahydropyrimidine-4-carboxamide
Figure imgf000044_0003
[0239] l-Benzyl-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxylic acid (100 mg, 0.41 mmol), HATU (232 mg, 0.61 mmol), JV-methylmorpholine (124 mg, 1.22 mmol) and DMF (1.6 niL) were combined. (2-(Trifluoromethoxy)phenyl)methanamine (93 mg, 0.49 mmol) was added and the mixture was stirred overnight at room temperature to give the title compound, which was purified by mass-triggered HPLC (gradient: 45 to 70% ACN in water containing 0.05% TFA). MS [M+H] found 420. 1U NMR (400 MHz, DMSO-J6) δ ppm 4.49 (d, 2 H), 4.95 (s, 2 H), 6.28 (s, 1 H), 7.21 - 7.34 (m, 5 H), 7.34 - 7.50 (m, 4 H), 9.41 (t, J=5.68 Hz, 1 H), 11.24 (br. s., 1 H); mp = 215.8-231.2°C. [0240] EXAMPLE 42: l-benzyl-N-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000045_0001
[0241] To l-benzyl-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxylic acid (445mg, 1.81mmol), HATU (1.03 g, 2.72 mmol), JV-methylmorpholine (551 mg, 5.43 mmol) and DMF (7.2 mL) was added (4-bromo-2-(trifluoromethoxy)phenyl)methanamine (587 mg, 2.17 mmol) and the reaction was stirred overnight at room temperature. The solvent was evaporated under vacuum to give a residue which was purified by column chromatography (2.5% methanol in dichloromethane) to give a solid. The solid was triturated with methanol and cooled in an ice bath. The resulting solid was then collected by filtration and dried under vacuum to give the title compound. MS [M+H] found 498. 1H NMR (400 MHz, DMSO-J6) δ ppm 4.43 (d, 2 H), 4.95 (s, 2 H), 6.26 (s, 1 H), 7.21 - 7.35 (m, 5 H), 7.44 (d, J=8.59 Hz, 1 H), 7.60 - 7.66 (m, 2 H), 9.42 (t, J=5.68 Hz, 1 H), 11.25 (s, 1 H). [0242] EXAMPLE 43: l-benzyl-N-(4-methoxy-2-(trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000045_0002
[0243] The title compound was prepared in a manner similar to the method described in Example 42, using (4-methoxy-2-(trifluoromethoxy)phenyl)methanamine in place of (4- bromo-2-(trifluoromethoxy)phenyl)methanamine, and was purified by mass-triggered HPLC (55% ACN in water containing 0.05% TFA). MS [M+H] found 450. 1U NMR (400 MHz, DMSO-J6) δ ppm 3.77 (br. s., 3 H), 4.40 (d, 2 H), 4.95 (s, 2 H), 6.25 (s, 1 H), 6.90 (s, 1 H), 6.99 (dd, J=8.84, 2.53 Hz, 1 H), 7.21 - 7.34 (m, 5 H), 7.40 (d, J=8.59 Hz, 1 H), 9.32 (t, J=5.68 Hz, 1 H), 11.21 (br. s., 1 H); mp = 201.6-215.90C.
[0244] EXAMPLE 44 : N-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo- 1 -(pyridin- 2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000046_0001
[0245] A. 2,6-Dioxo- 1 -(pyridin-2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxylic acid
[0246] To 3-(benzyloxymethyl)-2,6-dioxo-l-(pyridin-2-ylmethyl)-l,2,3,6- tetrahydropyrimidine-4-carboxylic acid (6.7 g, 18.24 mmol) and anisole (1.986 ml, 18.24 mmol) was added TFA (10 mL). The mixture was heated to reflux (about 95°C) for 1.5 hours. The reaction was cooled to room temperature and the solvent was evaporated under vacuum to give a residue, which was triturated with acetone and sonicated. The mixture was cooled in an ice bath and the resulting solid was isolated by filtration and was dried under vacuum to give the title compound. 1H NMR (400 MHz, OMSO-dβ) δ ppm 5.12 (s,
2 H), 6.20 (d, J=1.77 Hz, 1 H), 7.34 - 7.42 (m, 2 H), 7.88 (td, J=7.71, 1.77 Hz, 1 H), 8.52
(dt, J=4.61, 1.61 Hz, 1 H), 11.40 (d, J=1.52 Hz, 1 H). MS [M+H] found 248.
[0247] B. Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo- 1 -(pyridin-2-ylmethyl)-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
[0248] To 2,6-dioxo- 1 -(pyridin-2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxylic acid (Ig, 4.05 mmol), HATU (2.307 g, 6.07 mmol), (4-bromo-2-
(trifluoromethoxy)phenyl)methanamine hydrochloride (1.488 g, 4.85 mmol) and DMF
(16.2 mL) was added JV-methylmorpholine (1.3 mL, 12.14 mmol). The mixture was stirred overnight at room temperature. The solvent was subsequently evaporated under vacuum to give a residue, which was triturated with methanol and the mixture was cooled in an ice bath. The resulting solid was collected by filtration. The solid was again suspended in methanol and heated to dissolve most of the solid. The mixture was allowed to cool to room temperature and then cooled in an ice bath to give a solid, which was isolated by filtration and dried under vacuum to give the title compound as a TFA salt. MS [M+H] found 499. 1H NMR (400 MHz, DMSO-Je) δ ppm 4.45 (d, 2 H), 5.07 (s, 2 H), 6.27 (s, 1 H), 7.22 - 7.28 (m, 2 H), 7.46 (d, J=8.84 Hz, 1 H), 7.62 - 7.67 (m, 2 H), 7.74 (td, J=7.64, 1.89 Hz, 1 H), 8.40 - 8.46 (m, 1 H), 9.47 (t, J=5.68 Hz, 1 H), 11.23 (s, 1 H); mp = 238.0- 239.5°C.
[0249] EXAMPLE 45 : N-(4-bromo-2-(trifiuoromethoxy)benzyl)- 1 -(2-morpholinoethyl)- 2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000047_0001
[0250] A. l-(2-Morpholinoethyl)-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxylic acid
[0251] To 3-(benzyloxymethyl)-l-(2-morpholinoethyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxylic acid hydrochloride (1.13 g, 2.65 mmol) and anisole
(0.289 mL, 2.65 mmol) was added TFA (20 mL). The mixture was heated to reflux for 1.5 hours. The solvent was evaporated under vacuum to give a residue. The residue was dissolved in water (20 mL) and DMSO (20 mL) and was purified by mass-triggered HPLC
(gradient: 0 to 5% ACN in water containing 0.05% TFA) to give the title compound as a
TFA salt. MS [M+H] found 270.
[0252] B. Λ/-(4-Bromo-2-(trifluoromethoxy)benzyl)- 1 -(2-morpholinoethyl)-2,6-dioxo-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
[0253] To 1 -(2-morpholinoethyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxylic acid (365 mg, 1.356 mmol), HATU (773 mg, 2.033 mmol) and (4-bromo-2-(trifluoro- methoxy)phenyl)methanamine hydrochloride (499 mg, 1.627 mmol) was added DMF (5.4 mL). JV-Methylmorpholine (447 μL, 4.07 mmol) was added and the mixture was stirred overnight at room temperature. The solvent was evaporated under vacuum to give a residue. The residue was purified by mass-triggered HPLC (gradient: 40 to 45% ACN in water containing 0.05% TFA) to give the title compound as a TFA salt. MS [M+H] found 521. 1H NMR (400 MHz, DMSO-J6) δ ppm 3.13 (br. s., 2 H), 3.33 - 3.66 (m, 6 H), 3.95 - 4.16 (m, 4 H), 4.45 (d, J=5.81 Hz, 2 H), 6.29 (s, 1 H), 7.41 (d, J=8.84 Hz, 1 H), 7.62 - 7.68 (m, 2 H), 9.47 (s, 1 H), 11.40 (br. s., 1 H).
[0254] EXAMPLE 46 : N-(4-methoxy-2-(trifluoromethoxy)benzyl)- 1 -(2- morpholinoethyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000048_0001
[0255] The title compound was prepared in a manner similar to the method described in Example 45, using (4-methoxy-2-(trifluoromethoxy)phenyl)methanamine in place of (4- bromo-2-(trifluoromethoxy)phenyl)methanamine hydrochloride. Purification by mass- triggered HPLC (gradient: 30 to 35% ACN in water containing 0.05% TFA) gave the title compound as a TFA salt. MS [M+H] found 473. 1H NMR (400 MHz, DMSO-J6) δ ppm 3.04 - 3.19 (m, 2 H), 3.38 (br. s., 2 H), 3.60 (br. s., 4 H), 3.77 (s, 3 H), 3.94 - 4.15 (m, 4 H), 4.41 (d, J=5.56 Hz, 2 H), 6.28 (s, 1 H), 6.88 - 6.93 (m, 1 H), 7.00 (dd, J=8.59, 2.53 Hz, 1 H), 7.37 (d, J=8.59 Hz, 1 H), 9.39 (t, J=5.68 Hz, 1 H), 11.33 (s, 1 H). [0256] EXAMPLE 47: l-(2-(l/f-pyrazol-l-yl)ethyl)-N-(4-bromo-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000048_0002
[0257] A. l-(2-(l/f-Pyrazol-l-yl)ethyl)-2,6-dioxo- 1,2,3, 6-tetrahydropyrimidine-4- carboxylic acid
[0258] To 1 -(2-(l/f-pyrazol- 1 -yl)ethyl)-3-(benzyloxymethyl)-2,6-dioxo- 1 ,2,3,6- tetrahydropyrimidine-4-carboxylic acid (106 mg, 0.286 mmol) and anisole (0.031 mL, 0.286 mmol) was added TFA (10 mL). The mixture was heated to 95°C for 1 hour and 15 minutes. The reaction was cooled to room temperature, and the solvent was evaporated under vacuum to give a residue. The residue was triturated with diethyl ether to afford a solid, which was isolated by filtration and dried under vacuum to give the title compound. MS [M+H] found 251.
[0259] B. l-(2-(l/f-Pyrazol-l-yl)ethyl)-N-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6- dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
[0260] To l-(2-(l/f-pyrazol-l-yl)ethyl)-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4- carboxylic acid (44 mg, 0.176 mmol), HATU (100 mg, 0.264 mmol), (4-bromo-2- (trifluoromethoxy)phenyl)methanamine hydrochloride (81 mg, 0.264 mmol) was added DMF (879 μL). JV-Methylmorpholine (58.0 μL, 0.528 mmol) was then added and the mixture was stirred overnight at room temperature. The solvent was evaporated under vacuum to give a residue. The residue was purified by mass-triggered HPLC (gradient: 55 to 60% ACN in water containing 0.05% TFA) to give the title compound. MS [M+H] found 502. 1H NMR (400 MHz, DMSO-J6) δ ppm 4.09 - 4.15 (m, 2 H), 4.28 - 4.34 (m, 2 H), 4.43 (d, J=5.56 Hz, 2 H), 6.15 - 6.19 (m, 2 H), 7.37 (d, J=1.77 Hz, 1 H), 7.43 (d, J=8.59 Hz, 1 H), 7.62 - 7.69 (m, 3 H), 9.41 (t, J=5.81 Hz, 1 H), 11.11 (d, J=1.52 Hz, 1 H). [0261] EXAMPLE 48: l-(2-(l/f-pyrazol-l-yl)ethyl)-N-(4-methoxy-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000049_0001
[0262] The title compound was prepared in a manner similar to the method described in Example 47, using (4-methoxy-2-(trifluoromethoxy)phenyl)methanamine in place of (4- bromo-2-(trifluoromethoxy)phenyl)methanamine hydrochloride, and was purified by HPLC (gradient: 45 to 55% ACN in water containing 0.05% TFA). MS [M+H] found 454. 1H NMR (400 MHz, DMSO-J6) δ ppm 3.78 (s, 3 H), 4.09 - 4.15 (m, 2 H), 4.28 - 4.33 (m, 2 H), 4.39 (d, J=5.56 Hz, 2 H), 6.16 (s, 1 H), 6.17 - 6.19 (m, 1 H), 6.88 - 6.92 (m, 1 H), 7.00 (dd, J=8.59, 2.53 Hz, 1 H), 7.35 - 7.41 (m, 2 H), 7.67 (d, J=2.27 Hz, 1 H), 9.32 (t, J=5.68 Hz, 1 H); mp = 233.3-233.4°C. [0263] EXAMPLE 49: N-(4-bromo-2-(trifluoromethoxy)benzyl)-l-((3-ethyl- 1,2,4- oxadiazol-5-yl)methyl)-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000050_0001
[0264] A. l-((3-Ethyl-l,2,4-oxadiazol-5-yl)methyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxylic acid
[0265] To 3-(benzyloxymethyl)- 1 -((3-ethyl- 1 ,2,4-oxadiazol-5-yl)methyl)-2,6-dioxo- l,2,3,6-tetrahydropyrimidine-4-carboxylic acid (1.23 g, 3.18 mmol) and anisole (0.693 niL, 6.37 mmol) was added TFA (10 mL). The mixture was heated to reflux for 1 hour. The reaction was cooled to room temperature, and the solvent was evaporated under vacuum to give a residue. The residue was triturated with dichloromethane and cooled in an ice bath. The resulting solid was isolated by vacuum filtration. A second crop was recovered from the filtrate. The two crops were combined and dried under vacuum to give a total of 321 mg of the title compound. MS [M+H] found 267. [0266] B. N-(4-Bromo-2-(trifluoromethoxy)benzyl)- 1 -((3-ethyl- 1 ,2,4-oxadiazol-5- yl)methyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide [0267] To l-((3-ethyl-l,2,4-oxadiazol-5-yl)methyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxylic acid (306 mg, 1.149 mmol), HATU (656 mg, 1.72 mmol) and (4-bromo-2-(trifluoromethoxy)phenyl)methanamine hydrochloride (528 mg, 1.72 mmol) was added DMF (5.7 mL). JV-Methylmorpholine (379 μL, 3.45 mmol) was added and the mixture was stirred overnight at room temperature. The solvent was evaporated under vacuum and the residue was purified by mass-triggered HPLC (55% ACN in water containing 0.05% TFA) to give the title compound. MS [M+H] found 518. 1H NMR (400 MHz, DMSO-J6) δ ppm 1.18 (t, J=7.58 Hz, 3 H), 2.68 (q, J=7.58 Hz, 2 H), 4.45 (d, J=5.81 Hz, 2 H), 5.21 (s, 2 H), 6.30 (s, 1 H), 7.46 (d, J=8.59 Hz, 1 H), 7.60 - 7.67 (m, 2 H), 9.50 (t, J=5.68 Hz, 1 H), 11.52 (s, 1 H); mp = 191.1-206.80C. [0268] EXAMPLE 50: 1 -((3-ethyl- l,2,4-oxadiazol-5-yl)methyl)-N-(4-methoxy-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000051_0001
[0269] The title compound was prepared in a manner similar to the method described in Example 49, using (4-methoxy-2-(trifluoromethoxy)phenyl)methanamine in place of (4- bromo-2-(trifluoromethoxy)phenyl)methanamine hydrochloride, and was purified by mass-triggered HPLC (55% ACN in water containing 0.05% TFA). MS [M+H] found 470. [0270] EXAMPLE 51 : N-(4-(2-aminopyrimidin-5-yl)-2-(trifiuoromethoxy)benzyl)-2,6- dioxo- 1 -(pyridin-2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000051_0002
Λ/-(4-Bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo- 1 -(pyridin-2-ylmethyl)- 1 ,2,3,6- tetrahydropyrimidine-4-carboxamide (100 mg, 0.200 mmol), 2-aminopyrimidin-5- ylboronic acid (33.4 mg, 0.240 mmol), dioxane (1 mL) and sodium bicarbonate (sat., 1 mL) were added to a microwave vial. PdCl2(dppf) (7.33 mg, 10.02 μmol) was added and the tube was capped. The mixture was sonicated and microwaved as a high absorber at 1100C for 15 minutes. The solvent was evaporated under vacuum to give a residue, which was triturated with methanol (2 mL). The mixture was filtered and the filtrate was purified by mass-triggered HPLC (15% ACN in water containing 0.05% TFA) to give the title compound. MS [M+H] found 514. 1H NMR (400 MHz, DMSO-J6) δ ppm 4.53 (d, J=5.56 Hz, 2 H), 5.10 (s, 2 H), 6.30 (d, J=I.52 Hz, 1 H), 7.08 (d, J=9.60 Hz, 1 H), 7.29 - 7.36 (m, 2 H), 7.59 (d, J=8.08 Hz, 1 H), 7.68 - 7.74 (m, 2 H), 7.82 (td, J=7.71, 1.77 Hz, 1 H), 8.20 - 8.34 (m, 2 H), 8.37 (d, J=IJl Hz, 1 H), 8.48 (d, J=4.29 Hz, 1 H), 9.54 (t, J=5.81 Hz, 1 H), 11.28 (s, 1 H); mp = 207.7-220.10C.
[0271] EXAMPLE 52: N-(4-(5-aminopyrazin-2-yl)-2-(trifluoromethoxy)benzyl)-l- benzyl-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000052_0001
[0272] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrazin-2-amine, and was purified by mass-triggered HPLC (gradient: 45 to 70% ACN in water containing 0.05% TFA). MS [M+H] found 513.
[0273] EXAMPLE 53: l-benzyl-2,6-dioxo-N-((3-(trifiuoromethoxy)biphenyl-4- yl)methyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000052_0002
[0274] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and phenylboronic acid, and was purified by mass- triggered HPLC (gradient: 40 to 75% ACN in water containing 0.05% TFA). MS [M+H] found 496.
[0275] EXAMPLE 54: l-benzyl-2,6-dioxo-N-(4-(pyridin-3-yl)-2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000052_0003
[0276] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and pyridin-3-ylboronic acid. Purification by mass- triggered HPLC (gradient: 20 to 50% ACN in water containing 0.05% TFA) gave the title compound as a TFA salt. MS [M+H] found 497.
[0277] EXAMPLE 55: 1 -benzyl-iV-((4 ' -(methylsulfonyl)-3 -(trifluoromethoxy)biphenyl- 4-yl)methyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000053_0001
[0278] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and 4-(methylsulfonyl)phenylboronic acid, and was purified by mass-triggered HPLC (gradient: 35 to 70% ACN in water containing 0.05% TFA). MS [M+H] found 574.
[0279] EXAMPLE 56: l-benzyl-N-(4-(2-methoxypyrimidin-5-yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000053_0002
[0280] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and 2-methoxypyrimidin-5-ylboronic acid. Purification by mass-triggered HPLC (gradient: 30 to 65% ACN in water containing 0.05% TFA) gave the title compound as a TFA salt. MS [M+H] found 528. [0281 ] EXAMPLE 57: 1 -benzyl-iV-((4 ' -carbamoyl-3 -(trifluoromethoxy)biphenyl-4- yl)methyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000054_0001
[0282] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and 4-carbamoylphenylboronic acid, and was purified by mass-triggered HPLC (gradient: 25 to 65% ACN in water containing 0.05% TFA). MS [M+H] found 539.
[0283] EXAMPLE 58: l-benzyl-N-(4-(2,6-dimethoxypyridin-3-yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000054_0002
[0284] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and 2,6-dimethoxypyridin-3-ylboronic acid. Purification by mass-triggered HPLC (gradient: 40 to 75% ACN in water containing 0.05% TFA) gave the title compound as a TFA salt. MS [M+H] found 557. [0285] EXAMPLE 59: methyl 4'-((l-benzyl-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4- carboxamido)methyl)-3 ' -(trifluoromethoxy)biphenyl-4-ylcarbamate
Figure imgf000054_0003
[0286] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and 4-(methoxycarbonylamino)phenylboronic acid, and was purified by mass-triggered HPLC (gradient: 35 to 70% ACN in water containing 0.05% TFA). MS [M+H] found 569.
[0287] EXAMPLE 60: l-benzyl-N-(4-(2-fiuoropyridin-4-yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000055_0001
[0288] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and 2-fluoropyridin-4-ylboronic acid. Purification by mass-triggered HPLC (gradient: 35 to 70% ACN in water containing 0.05% TFA) gave the title compound as a TFA salt. MS [M+H] found 515.
[0289] EXAMPLE 61 : N-(4-(6-aminopyridin-3-yl)-2-(trifiuoromethoxy)benzyl)- 1 - benzyl-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000055_0002
[0290] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2-amine, and was purified by mass-triggered HPLC (gradient: 15 to 60% ACN in water containing 0.05% TFA). MS [M+H] found 512. [0291] EXAMPLE 62: l-benzyl-N-(4-(3,5-dimethyl-l/f-pyrazol-4-yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000056_0001
[0292] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and 3,5-dimethyl-4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-lH-pyrazole, and was purified by HPLC (gradient: 20 to 50% ACN in water containing 0.05% TFA). MS [M+H] found 514. [0293] Example 63: l-benzyl-N-(4-(6-hydroxypyridin-3-yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000056_0002
[0294] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2-ol, and was purified by mass-triggered HPLC (gradient: 15 to 60% ACN in water containing 0.05% TFA). MS [M+H] found 513.
[0295] Example 64: l-benzyl-2,6-dioxo-Λ/-((3-(trifluoromethoxy)-4'-ureidobiphenyl-4- yl)methyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000056_0003
[0296] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)urea, and was purified by mass-triggered HPLC (gradient: 20 to 60% ACN in water containing 0.05% TFA). MS [M+H] found 554.
[0297] Example 65: N-(4-(benzo[c][l,2,5]oxadiazol-5-yl)-2-(trifluoromethoxy)benzyl)- 1 -benzyl-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000057_0001
[0298] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and benzo[c][l,2,5]oxadiazol-5-ylboronic acid, and was purified by mass-triggered HPLC (gradient: 40 to 75% ACN in water containing 0.05% TFA). MS [M+H] found 538.
[0299] EXAMPLE 66: N-(4-(2-aminopyrimidin-5-yl)-2-(trifiuoromethoxy)benzyl)-l- benzyl-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000057_0002
[0300] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and 2-aminopyrimidin-5-ylboronic acid. Purification by mass-triggered HPLC (gradient: 20 to 50% ACN in water containing 0.05% TFA) gave the title compound as a TFA salt. MS [M+H] found 513. 1H NMR (400 MHz, DMSO-J6) δ ppm 4.49 (d, J=5.81 Hz, 2 H), 4.96 (s, 2 H), 6.28 (s, 1 H), 6.91 (s, 2 H), 7.21 - 7.36 (m, 5 H), 7.51 (d, J=8.08 Hz, 1 H), 7.60 - 7.68 (m, 2 H), 8.61 (s, 2 H), 9.43 (t, J=5.68 Hz, 1 H), 11.25 (s, I H).
[0301] EXAMPLE 67: l-benzyl-2,6-dioxo-N-(4-(2-oxoindolin-5-yl)-2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000058_0001
[0302] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)indolin-2-one, and was purified by mass-triggered HPLC (gradient: 25 to 65% ACN in water containing 0.05% TFA). MS [M+H] found 551. [0303] EXAMPLE 68: N-(4-(l/f-pyrrolo[3,2-δ]pyridin-6-yl)-2- (trifluoromethoxy)benzyl)- 1 -benzyl-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4- carboxamide
Figure imgf000058_0002
[0304] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and 6-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)- lH-pyrrolo[3,2-δ]pyridine. Purification by mass-triggered HPLC (gradient: 15 to 60% ACN in water containing 0.05% TFA) gave the title compound as a TFA salt. MS [M+H] found 536. [0305] EXAMPLE 69: l-benzyl-N-(4-(furan-2-yl)-2-(trifluoromethoxy)benzyl)-2,6- dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000059_0001
[0306] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and furan-2-ylboronic acid, and was purified by mass-triggered HPLC (gradient: 5 to 95% ACN in water containing 0.05% TFA). MS [M+H] found 486.
[0307] EXAMPLE 70: N-(4-(5-acetylthiophen-2-yl)-2-(trifiuoromethoxy)benzyl)-l- benzyl-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000059_0002
[0308] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and 5-acetylthiophen-2-ylboronic acid, and was purified by mass-triggered HPLC (gradient: 5 to 95% ACN in water containing 0.05% TFA). MS [M+H] found 544.
[0309] EXAMPLE 71 : l-benzyl-N-(4-(2,4-dioxo-l,2,3,4-tetrahydropyrimidin-5-yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000059_0003
[0310] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and 2,4-dioxo-l ,2,3,4-tetrahydropyrimidin-5- ylboronic acid, and was purified by mass-triggered HPLC (gradient: 5 to 95% ACN in water containing 0.05% TFA). MS [M+H] found 530.
[0311] EXAMPLE 72: l-benzyl-N-(4-(furan-3-yl)-2-(trifiuoromethoxy)benzyl)-2,6- dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000060_0001
[0312] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and furan-3-ylboronic acid, and was purified by mass-triggered HPLC (gradient: 5 of 95% ACN in water containing 0.05% TFA). MS [M+H] found 486.
[0313] EXAMPLE 73 : 1 -benzyl-N-((4 ' -(methylsulfonamido)-3- (trifluoromethoxy)biphenyl-4-yl)methyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4- carboxamide
Figure imgf000060_0002
[0314] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and 4-(methylsulfonamido)phenylboronic acid, and was purified by mass-triggered HPLC (gradient: 5 to 95% ACN in water containing 0.05% TFA). MS [M+H] found 589. [0315] EXAMPLE 74: l-benzyl-N-((3'-(methylsulfonamido)-3- (trifluoromethoxy)biphenyl-4-yl)methyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4- carboxamide
Figure imgf000061_0001
[0316] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and 2,4-dioxo-l ,2,3,4-tetrahydropyrimidin-5- ylboronic acid, and was purified by mass-triggered HPLC (gradient: 5 to 95% ACN in water containing 0.05% TFA). MS [M+H] found 589. [0317] EXAMPLE 75: l-benzyl-2,6-dioxo-N-(4-(quinolin-3-yl)-2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000061_0002
[0318] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and quinolin-3-ylboronic acid. Purification by mass- triggered HPLC (gradient: 5 to 95% ACN in water containing 0.05% TFA) gave the title compound as a TFA salt. MS [M+H] found 547. [0319] EXAMPLE 76: l-benzyl-2,6-dioxo-N-(4-(pyrimidin-5-yl)-2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000062_0001
[0320] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and pyrimidin-5-ylboronic acid, and was purified by mass-triggered HPLC (gradient: 5 to 95% ACN in water containing 0.05% TFA). MS [M+H] found 498.
[0321] EXAMPLE 77: N-(4-(l/f-indol-4-yl)-2-(trifluoromethoxy)benzyl)-l-benzyl-2,6- dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000062_0002
[0322] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and lH-indol-4-ylboronic acid, and was purified by mass-triggered HPLC (gradient: 5 to 95% ACN in water containing 0.05% TFA). MS [M+H] found 535.
[0323] EXAMPLE 78: l-benzyl-N-(4-(5-methoxypyridin-3-yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000062_0003
[0324] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and 3-methoxy-5-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)pyridine. Purification by mass-triggered HPLC (gradient: 5 to 95% ACN in water containing 0.05% TFA) gave the title compound as a TFA salt. MS [M+H] found 527.
[0325] EXAMPLE 79: l-benzyl-iV-(4-(l -methyl- l/f-pyrazol-4-yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000063_0001
[0326] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and l-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole, and was purified by mass-triggered HPLC (gradient: 5 to 95% ACN in water containing 0.05% TFA). MS [M+H] found 500. [0327] EXAMPLE 80: l-benzyl-N-(4-(6-morpholinopyridin-3-yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000063_0002
[0328] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and 4-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2-yl)morpholine. Purification by mass-triggered HPLC (gradient: 5 to 95% ACN in water containing 0.05% TFA) gave the title compound as a TFA salt. MS [M+H] found 582. [0329] EXAMPLE 81 : l-benzyl-2,6-dioxo-iV-(4-(l -propyl- lH-pyrazol-4-yl)-2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000064_0001
[0330] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and l-propyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole, and was purified by mass-triggered HPLC (gradient: 5 to 95% ACN in water containing 0.05% TFA). MS [M+H] found 528. [0331] EXAMPLE 82: l-benzyl-2,6-dioxo-N-((3'-sulfamoyl-3- (trifluoromethoxy)biphenyl-4-yl)methyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000064_0002
[0332] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and 3-sulfamoylphenylboronic acid, and was purified by mass-triggered HPLC (gradient: 5 to 95% ACN in water containing 0.05% TFA). MS [M+H] found 575.
[0333] EXAMPLE 83: l-benzyl-N-(4-(2-(dimethylamino)pyrimidin-5-yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000065_0001
[0334] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and Λ/,Λ/-dimethyl-5-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)pyrimidin-2-amine. Purification by mass-triggered HPLC (gradient: 5 to 95% ACN in water containing 0.05% TFA) gave the title compound as a TFA salt. MS [M+H] found 541.
[0335] EXAMPLE 84: N-(4-(l/f-pyrazol-5-yl)-2-(trifluoromethoxy)benzyl)-l-benzyl- 2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000065_0002
[0336] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and lH-pyrazol-5-ylboronic acid, and was purified by mass-triggered HPLC (gradient: 5 to 95% ACN in water containing 0.05% TFA). MS [M+H] found 486.
[0337] EXAMPLE 85: N-(4-(l/f-pyrazol-4-yl)-2-(trifluoromethoxy)benzyl)-l-benzyl- 2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000065_0003
[0338] The title compound was prepared in a manner similar to the method described in
Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and lH-pyrazol-4-ylboronic acid, and was purified by mass-triggered HPLC (gradient: 5 to 95% ACN in water containing 0.05% TFA). MS
[M+H] found 486.
[0339] EXAMPLE 86: l-benzyl-2,6-dioxo-N-(2-(trifluoromethoxy)-4-(3-
(trifluoromethyl)-lH-pyrazol-4-yl)benzyl)-l,2,3,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000066_0001
[0340] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and 3-(trifluoromethyl)- lH-pyrazol-4-ylboronic acid, and was purified by mass-triggered HPLC (gradient: 5 to 95% ACN in water containing 0.05% TFA). MS [M+H] found 554.
[0341] EXAMPLE 87: l-benzyl-N-(4-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrimidin-5-yl)-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide
Figure imgf000066_0002
[0342] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and l,3-dimethyl-5-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)pyrimidine-2,4(l/f,3H)-dione, and was purified by mass-triggered HPLC (gradient: 5 to 95% ACN in water containing 0.05% TFA). MS [M+H] found 558. [0343] EXAMPLE 88: N-(4-(lH-pyrrolo[2,3-δ]pyridin-5-yl)-2- (trifluoromethoxy)benzyl)- 1 -benzyl-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4- carboxamide
Figure imgf000067_0001
[0344] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and 5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)- lH-pyrrolo[2,3-δ]pyridine. Purification by mass-triggered HPLC (gradient: 5 to 95% ACN in water containing 0.05% TFA) gave the title compound as a TFA salt. MS [M+H] found 536.
[0345] EXAMPLE 89: l-benzyl-N-(4-(l-(2-morpholinoethyl)-l/f-pyrazol-4-yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000067_0002
[0346] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and 4-(2-(4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan- 2-yl)-lH-pyrazol-l-yl)ethyl)morpholine, and was purified by mass-triggered HPLC (gradient: 5-95% ACN in water containing 0.05% TFA). MS [M+H] found 599. [0347] EXAMPLE 90: (£)-l-benzyl-ΛH(4'-(ΛT-hydroxycarbamimidoyl)-3- (trifluoromethoxy)biphenyl-4-yl)methyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4- carboxamide
Figure imgf000068_0001
[0348] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and (E)-4-(7V -hydroxycarbamimidoyl)phenylboronic acid, and was purified by mass-triggered HPLC (gradient: 5 to 95% ACN in water containing 0.05% TFA). MS [M+H] found 554.
[0349] EXAMPLE 91 : 1 -benzyl-N-(4-(6-(methylcarbamoyl)pyridin-3 -yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000068_0002
[0350] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and Λ/-methyl-5-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)picolinamide. Purification by mass-triggered HPLC (gradient: 5 to 95% ACN in water containing 0.05% TFA) gave the title compound as a TFA salt. MS [M+H] found 554.
[0351] EXAMPLE 92: l-benzyl-N-(4-(2-cyanopyrimidin-5-yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000069_0001
[0352] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrimidine-2-carbonitrile, and was purified by mass-triggered HPLC (gradient: 5 to 95% ACN in water containing 0.05% TFA). MS [M+H] found 523. [0353] EXAMPLE 93 : N-(4-(6-acetamidopyridin-3-yl)-2-(trifluoromethoxy)benzyl)- 1 - benzyl-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000069_0002
[0354] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and iV-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2-yl)acetamide. Purification by mass-triggered HPLC (gradient: 5 to 95% ACN in water containing 0.05% TFA) gave the title compound as a TFA salt. MS [M+H] found, 554.
[0355] EXAMPLE 94: methyl 5-(4-((l-benzyl-2,6-dioxo-l ,2,3,6-tetrahydropyrimidine- 4-carboxamido)methyl)-3-(trifluoromethoxy)phenyl)pyridin-2-ylcarbamate
Figure imgf000069_0003
[0356] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and methyl 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-ylcarbamate. Purification by mass-triggered HPLC (gradient: 5 to 95% ACN in water containing 0.05% TFA) gave the title compound as a TFA salt. MS [M+H] found, 570.
[0357] EXAMPLE 95: l-benzyl-N-(4-(6-(hydroxymethyl)pyridin-3-yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000070_0001
[0358] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and 6-(hydroxymethyl)pyridin-3-ylboronic acid. Purification by mass-triggered HPLC (gradient: 5 to 95% ACN in water containing 0.05% TFA) gave the title compound as a TFA salt. MS [M+H] found 527. [0359] EXAMPLE 96: 5-(4-((l-benzyl-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4- carboxamido)methyl)-3 -(trifluoromethoxy)phenyl)picolinic acid
Figure imgf000070_0002
[0360] The title compound was prepared in a manner similar to the method described in Example 51, using l-benzyl-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide and 5-boronopicolinic acid. Purification by mass- triggered HPLC (gradient: 5 to 95% ACN in water containing 0.05% TFA) gave the title compound as a TFA salt. MS [M+H] found 541. [0361] EXAMPLE 97: N-(4-(l-(3-methoxypropyl)-lH-pyrazol-4-yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 -(pyridin-2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine- 4-carboxamide
Figure imgf000071_0001
[0362] PdCl2(dppf) (3.32 mg, 4.54 μmol), N-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6- dioxo- 1 -(pyridin-2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide (45.3 mg, 0.091 mmol), l-(3-methoxypropyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l/f- pyrazole (29 mg, 0.109 mmol) were suspended in dioxane (454 μL) and sodium bicarbonate (sat., 454 μL) in a microwave tube. The tube was capped and the mixture was heated in the microwave to 115°C for 15 minutes as a high absorber. Solvent was evaporated under vacuum to give a residue. The residue was sonicated with methanol (2 mL) and filtered. The filtrate was purified by mass-triggered HPLC (gradient: 25 to 30% ACN in water containing 0.05% TFA) to give the title compound. MS [M+H] found 559. 1H NMR (400 MHz, DMSO-J6) δ ppm 2.03 (t, J=6.82 Hz, 2 H), 3.23 (s, 3 H), 3.30 (t, 2 H), 4.16 (t, J=7.07 Hz, 2 H), 4.48 (d, J=5.81 Hz, 2 H), 5.12 (s, 2 H), 6.30 (d, J=2.02 Hz, 1 H), 7.35 - 7.42 (m, 2 H), 7.45 (d, J=8.08 Hz, 1 H), 7.54 - 7.56 (m, 1 H), 7.61 (dd, J=8.08, 1.77 Hz, 1 H), 7.89 (d, J=I.77 Hz, 1 H), 7.97 (s, 1 H), 8.31 (s, 1 H), 8.50 - 8.54 (m, 1 H), 9.42 - 9.46 (m, 1 H), 11.29 (d, J=I.77 Hz, 1 H).
[0363] EXAMPLE 98 : N-(4-(l -(3-hydroxypropyl)- l/f-pyrazol-4-yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 -(pyridin-2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine- 4-carboxamide
Figure imgf000071_0002
[0364] A. 3-(4-Bromo-lH-pyrazol-l-yl)propan-l-ol [0365] Cesium carbonate (1.11 g, 3.40 mmol) and 4-bromo-l/f-pyrazole (250 mg, 1.70 mmol) were suspended in DMF (8.5 rnL). 3-Bromopropan-l-ol (178 μL, 2.041 mmol) was added and heated to 500C overnight. The mixture was cooled to room temperature, filtered, and solvent from the filtrate was evaporated under vacuum to give a residue. The residue was purified by column chromatography (gradient: 0 to 2.5% methanol in dichloromethane) to give the title compound. MS [M+H] found 205. 1H NMR (400 MHz, CHLOROFORM- d) δ ppm 2.06 (quin, 2 H), 2.33 (quin, J=6.32 Hz, 1 H), 3.65 (br. s., 1 H), 4.21 - 4.32 (m, 2 H), 4.34 (t, J=6.06 Hz, 1 H), 4.88 (br. s., 1 H), 7.41 - 7.52 (m, 2 H). [0366] B. 3-(4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)-l/f-pyrazol-l-yl)propan- l-ol
[0367] PdCl2(dppf) (28.7 mg, 0.039 mmol), sodium acetate (193 mg, 2.355 mmol), 3-(4- bromo-l/f-pyrazol-l-yl)propan-l-ol (161 mg, 0.785 mmol) and 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(l,3,2-dioxaborolane) (598 mg, 2.355 mmol) were added to an oven- dried Schlenk flask. The solids were subjected to 4 cycles of nitrogen and vacuum. DMF (10.5mL) was added and the mixture was heated to 800C overnight. The reaction mixture was cooled to room temperature, filtered, and the filtrate was purified by mass-triggered HPLC (gradient: 25 to 30% ACN in water containing 0.05% TFA) to give the title compound. MS [M+H] found 253.
[0368] C. N-(4-(l-(3-Hydroxypropyl)-l/f-pyrazol-4-yl)-2-(trifluoromethoxy)benzyl)- 2,6-dioxo- 1 -(pyridin-2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide [0369] PdCl2(dppf) (4.60 mg, 6.28 μmol), N-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6- dioxo-1 -(pyridin-2-ylmethyl)- 1,2, 3, 6-tetrahydropyrimidine-4-carboxamide (62.7 mg, 0.126 mmol), 3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)propan- l-ol (38 mg, 0.151 mmol) were suspended in dioxane (628 μL) and sodium bicarbonate (sat., 628 μL) in a microwave tube. The tube was capped and was heated in the microwave to 115°C for 15 minutes. Solvent was evaporated under vacuum to give a residue, which was sonicated with methanol (2 mL) and filtered. The filtrate was purified by mass- triggered HPLC (gradient: 20 to 25% ACN in water containing 0.05% TFA) to give the title compound. MS [M+H] found 545.
[0370] EXAMPLE 99: l-benzyl-N-(4-(cyclopropylsulfonyl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000073_0001
[0371] l-Benzyl-N-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo- 1,2,3,6- tetrahydropyrimidine-4-carboxamide (32 mg, 64 μmol), sodium cyclopropanesulfϊnate (12 mg, 96 μmol), copper(I) iodide (6 mg, 32 μmol) were added to a microwave tube. DMSO (320 μL) and N,ΛT-dimethylethylenediamine (6 mg, 64 μmol) were added to the mixture, which was degassed by bubbling nitrogen for 5 minutes. The microwave tube was capped and microwaved at 1500C for 1 hour as a high absorber. The mixture was filtered and the filtrate was purified by mass-triggered HPLC (50% ACN in water containing 0.05% TFA) to give the title compound. MS [M+H] found 524.
[0372] EXAMPLE 100 : N-(4-(cyclopropylsulfonyl)-2-(trifluoromethoxy)benzyl)- 1 -(2- morpholinoethyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000073_0002
[0373] The title compound was prepared in a manner similar to the method described in Example 99, using N-(4-bromo-2-(trifluoromethoxy)benzyl)-l-(2-morpholinoethyl)-2,6- dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxamide in place of l-benzyl-iV-(4-bromo-2- (trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxamide. Purification by mass-triggered HPLC (gradient: 20 to 30% ACN in water containing 0.05% TFA) gave the title compound as a TFA salt. MS [M+H] found 547. 1H NMR (400 MHz, DMSO-J6) δ ppm 1.03 - 1.19 (m, 4 H), 2.96 - 3.05 (m, 1 H), 3.05 - 3.16 (m, 2 H), 3.38 (br. s., 2 H), 3.61 (br. s., 3 H), 3.96 (s, 3 H), 4.12 (t, J=5.56 Hz, 2 H), 4.57 (d, J=5.56 Hz, 2 H), 6.33 (d, J=I.26 Hz, 1 H), 7.73 (d, J=8.34 Hz, 1 H), 7.82 (t, J=I.52 Hz, 1 H), 7.95 (dd, J=8.08, 1.77 Hz, 1 H), 9.63 (t, J=5.68 Hz, 1 H), 11.37 (s, 1 H). [0374] EXAMPLE 101 : N-(4-(cyclopropylsulfonyl)-2-(trifluoromethoxy)benzyl)-2,6- dioxo- 1 -(pyridin-2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000074_0001
[0375] A. 3-(Benzyloxymethyl)-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
[0376] To 3-(benzyloxymethyl)-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxylic acid (1.00 g, 3.62 mmol), (4-bromo-2-(trifluoromethoxy)phenyl)methanamine hydrochloride (1.11 g, 3.62 mmol), N-methylmorpholine (73 2mg, 7.24 mmol) and EEDQ (895 mg, 3.62 mmol) was added DMF (9.1 mL). The mixture was heated to 550C overnight. Solvent was evaporated under vacuum to give a residue. The residue was purified by column chromatography (2.5% methanol in dichloromethane) to give the title compound. MS [M+H] found 528.
[0377] B. 3-(Benzyloxymethyl)-N-(4-(cyclopropylsulfonyl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide [0378] The title compound was prepared in a manner similar to the method in Example 99, using 3-(benzyloxymethyl)-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo- l,2,3,6-tetrahydropyrimidine-4-carboxamide in place of l-benzyl-JV-(4-bromo-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide, and was purified by mass-triggered HPLC (gradient: 45 to 50% ACN in water containing 0.05% TFA). MS [M+H] found 554.
[0379] C. 3-(Benzyloxymethyl)-N-(4-(cyclopropylsulfonyl)-2-
(trifluoromethoxy)benzyl)-2,6-dioxo- 1 -(pyridin-2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine- 4-carboxamide
[0380] To 3-(benzyloxymethyl)-JV-(4-(cyclopropylsulfonyl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide (167 mg, 302 μmol), cesium carbonate (344 mg, 1.06 mmol) and 2-(bromomethyl)pyridine hydrobromide (76 mg, 302 μmol) was added DMF (1.5 mL). The mixture was stirred at room temperature for 5 hours. The mixture was filtered and the filtrate was purified by mass-triggered HPLC (gradient: 40 to 45% ACN in water containing 0.05% TFA) to give the title compound. MS [M+H] found 645.
[0381] D. N-(4-(Cyclopropylsulfonyl)-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l- (pyridin-2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide [0382] To 3-(benzyloxymethyl)-JV-(4-(cyclopropylsulfonyl)-2-
(trifluoromethoxy)benzyl)-2,6-dioxo- 1 -(pyridin-2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine- 4-carboxamide (111 mg, 172 μmol) and anisole (19mg, 172 μmol) was added TFA (10 mL). The mixture was heated to reflux for 1 hour and 15 minutes. The mixture was cooled to room temperature. The solvent was evaporated under vacuum to give a residue which was purified by mass-triggered HPLC (gradient: 25 to 30% ACN in water containing 0.05% TFA) to give the title compound as a TFA salt. MS [M+H] found 525. 1H NMR (400 MHz, DMSO-J6) δ ppm 1.04 - 1.13 (m, 2 H), 1.13 - 1.20 (m, 2 H), 2.96 - 3.05 (m, 1 H), 4.58 (d, J=5.56 Hz, 2 H), 5.12 (s, 2 H), 6.32 (d, J=I.77 Hz, 1 H), 7.34 - 7.41 (m, 2 H), 7.78 (d, J=8.08 Hz, 1 H), 7.82 (t, J=1.52 Hz, 1 H), 7.88 (td, J=7.71, 1.77 Hz, 1 H), 7.95 (dd, J=8.08, 1.77 Hz, 1 H), 8.51 (dd, J=5.05, 1.01 Hz, 1 H), 9.60 (t, J=5.68 Hz, 1 H), 11.30 (s, I H).
[0383] EXAMPLE 102: (5)-N-(4-(4-hydroxy-2-oxopyrrolidin-l-yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 -(pyridin-2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine- 4-carboxamide
Figure imgf000075_0001
H
[0384] A. 3-(Benzyloxymethyl)-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo- 1 - (pyridin-2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide [0385] To 3-(benzyloxymethyl)-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo- l,2,3,6-tetrahydropyrimidine-4-carboxamide (433 mg, 0.820 mmol) and cesium carbonate (935 mg, 2.87 mmol) was added DMF (4.1 mL). 2-(Bromomethyl)pyridine hydrobromide
(228 mg, 0.902 mmol) was added and the mixture was heated at 55°C for 80 minutes. The reaction was cooled to room temperature, the solvent was evaporated under vacuum, and the resulting residue was partitioned between water (25 mL) and ethyl acetate (25 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (1 x 25 mL). The organic phases were combined and washed with brine (25 mL), dried over sodium sulfate, and filtered. The solvent was evaporated and the resulting residue was triturated with diethyl ether and filtered to give the title compound. MS [M+H] found 619. 1H NMR (400 MHz, DMSO-J6) δ ppm 4.41 (d, J=5.81 Hz, 2 H) 4.44 - 4.48 (m, 2 H), 5.13 (s, 2 H), 5.48 (s, 2 H), 6.09 (s, 1 H), 7.22 - 7.35 (m, 9 H), 7.40 (d, J=8.34 Hz, 1 H), 7.59 (d, J=I.52 Hz, 1 H), 7.75 (dd, J=7.58, 1.77 Hz, 1 H), 8.40 (d, J=4.04 Hz, 1 H), 9.67 (s, 1 H).
[0386] B. (5)-3-(Benzyloxymethyl)-N-(4-(4-hydroxy-2-oxopyrrolidin-l-yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 -(pyridin-2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine- 4-carboxamide
[0387] To a vessel containing 3-(benzyloxymethyl)-JV-(4-bromo-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 -(pyridin-2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine- 4-carboxamide (100 mg, 0.161 mmol), (5)-4-hydroxypyrrolidin-2-one (32.6 mg, 0.323 mmol), potassium phosphate tribasic (68.5 mg, 0.323 mmol), copper(I) iodide (6.15 mg, 0.032 mmol) and N,Λ^-dimethylethane-l,2-diamine (6.95 μL, 0.065 mmol) was added dioxane (3.2 mL). Nitrogen was blown over the top of the reaction mixture and the vessel was covered with a PTFE cap. The mixture was sonicated and then heated to 1100C for 18 hours. The reaction was cooled to room temperature. The mixture was filtered and the filtrate was purified by mass-triggered HPLC (gradient: 30 to 40% ACN in water containing 0.05% TFA) to give the title compound. MS [M+H] found 640. [0388] C. (5)-N-(4-(4-Hydroxy-2-oxopyrrolidin- 1 -yl)-2-(trifluoromethoxy)benzyl)-2,6- dioxo- 1 -(pyridin-2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide [0389] To (5)-3-(benzyloxymethyl)-N-(4-(4-hydroxy-2-oxopyrrolidin- 1 -yl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 -(pyridin-2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine- 4-carboxamide (67 mg, 0.105 mmol) and anisole (0.011 ml, 0.105 mmol) was added TFA (10 mL). The mixture was heated to reflux for 1.5 hours. The reaction was cooled to room temperature. The solvent was evaporated under vacuum and the resulting residue was purified by mass-triggered HPLC (gradient: 15 to 25% ACN in water containing 0.05% TFA) to give the title compound. MS [M+H] found 520. 1H NMR (400 MHz, DMSO-J6) δ ppm 2.26 - 2.37 (m, 1 H), 2.87 (dd, J=17.18, 6.06 Hz, 1 H), 3.61 (d, J=IOM Hz, 1 H), 4.06 (dd, J=10.48, 5.18 Hz, 1 H), 4.36 - 4.43 (m, 2 H), 4.47 (d, J=5.81 Hz, 2 H), 5.11 (s, 2 H), 6.28 (d, J=I.77 Hz, 1 H), 7.31 - 7.40 (m, 2 H), 7.42 - 7.51 (m, 2 H), 7.86 (td, J=7.77, 1.64 Hz, 1 H), 8.03 (t, J=I.64 Hz, 1 H), 8.50 (dt, J=2.97, 1.42 Hz, 1 H), 9.44 (t, J=5.68 Hz, 1 H), 11.27 (d, J= 1.77 Hz, 1 H); mp = 198.6-214.9°C. [0390] EXAMPLE 103 : (5)-N-(4-(4-Hydroxy-2-oxopyrrolidin- 1 -yl)-2- (trifluoromethoxy)benzyl)- 1 -(2-morpholinoethyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine- 4-carboxamide
Figure imgf000077_0001
[0391] To a vessel containing Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-l-(2- morpholinoethyl)-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxamide (65 mg, 0.125 mmol), (iS)-4-hydroxypyrrolidin-2-one (25.2 mg, 0.249 mmol), potassium phosphate tribasic (52.9 mg, 0.249 mmol) and copper(I) iodide (4.75 mg, 0.025 mmol) was added dioxane (2.5 mL). Nitrogen was blown over the top of the reaction mixture and the vessel was covered with a PTFE cap. The mixture was sonicated and then heated to 1100C for 18 hours. The reaction was cooled to room temperature. The mixture was filtered and the filtrate was purified by mass-triggered HPLC (gradient: 20 to 25% ACN in water containing 0.05% TFA) to give the title compound as a TFA salt. MS [M+H] found 542. [0392] EXAMPLE 104: l-benzyl-N-(4-cyano-2-(trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000077_0002
[0393] l-Benzyl-N-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide (84 mg, 169 μmol), Zn(CN)2 (20 mg, 169 μmol), and Pd(PPh3 )4 (29 mg, 25 μmol) were added to a microwave tube. DMF (0.68 mL) was added and the mixture was degassed by bubbling nitrogen for 5 minutes. The tube was capped and heated overnight at 900C. The reaction mixture was cooled to room temperature, filtered, and the filtrate was purified by mass-triggered HPLC (gradient: 20 to 30% ACN in water containing 0.05% TFA) to give the title compound. MS [M+H] found 445. 1H NMR (400 MHz, DMSO-J6) δ ppm 4.53 (d, J=5.81 Hz, 2 H), 4.96 (s, 2 H), 6.28 (s, 1 H), 7.21 - 7.34 (m, 5 H), 7.67 (d, J=8.08 Hz, 1 H), 7.90 (dd, J=8.08, 1.52 Hz, 1 H), 8.01 (t, J=1.52 Hz, 1 H), 9.51 (t, J=5.81 Hz, I H), 11.27 (s, 1 H); mp = 208.3-218.90C. [0394] EXAMPLE 105 : N-(4-cyano-2-(trifiuoromethoxy)benzyl)-2,6-dioxo- 1 -(pyridin- 2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000078_0001
[0395] The title compound was prepared in a manner similar to the method described in Example 104, using Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l-(pyridin-2- ylmethyl)-l,2,3,6-tetrahydropyrimidine-4-carboxamide in place of 1 -benzyl-JV-(4-bromo- 2-(trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide, and was purified by mass-triggered HPLC (gradient: 20 to 30% ACN in water containing 0.05% TFA). MS [M+H] found 446. 1H NMR (400 MHz, DMSO-J6) δ ppm 4.55 (d, 2 H), 5.10 (s, 2 H), 6.30 (s, 1 H), 7.32 (d, J=7.33 Hz, 2 H), 7.69 (d, J=7.83 Hz, 1 H), 7.81 (t, j=6.95 Hz, 1 H), 7.92 (d, J=7.83 Hz, 1 H), 8.03 (s, 1 H), 8.47 (d, J=4.55 Hz, 1 H), 9.52 - 9.61 (m, 1 H), 11.30 (br. s., 1 H); mp = 270.8-282.30C. [0396] EXAMPLE 106 : N-(4-cyano-2-(trifiuoromethoxy)benzyl)- 1 -(2- morpholinoethyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000079_0001
[0397] The title compound was prepared in a manner similar to the method described in Example 104, using Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-l-(2-morpholinoethyl)-2,6- dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxamide in place of l-benzyl-iV-(4-bromo-2- (trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxamide. Purification by mass-triggered HPLC (gradient: 20 to 25% ACN in water containing 0.05% TFA) gave the title compound as a TFA salt. MS [M+H] found 468. [0398] EXAMPLE 107: l-benzyl-N-((3-(4-fluorophenyl)pyridin-2-yl)methyl)-2,6- dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000079_0002
[0399] The title compound was prepared in a manner similar to the method described in Example 42, using l-benzyl-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxylic acid and (3-(4-fluorophenyl)pyridin-2-yl)methanamine. Purification by mass-triggered HPLC (40% ACN in water containing 0.05% TFA) gave the title compound as a TFA salt. MS [M+H] found 431. 1H NMR (400 MHz, DMSO-J6) δ ppm 4.48 (d, J=5.56 Hz, 2 H), 4.94 (s, 2 H), 6.21 (d, J=LOl Hz, 1 H), 7.21 - 7.37 (m, 7 H), 7.41 (dd, J=7.83, 4.80 Hz, 1 H), 7.48 - 7.54 (m, 2 H), 7.68 (dd, J=7.58, 1.77 Hz, 1 H), 8.58 (dd, J=4.80, 1.77 Hz, 1 H), 9.29 (t, J=5.56 Hz, I H), 11.13 (s, I H).
[0400] EXAMPLE 108 : N-((3-(4-fiuorophenyl)pyridin-2-yl)methyl)-2,6-dioxo- 1 - (pyridin-2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000080_0001
[0401] The title compound was prepared in a manner similar to the method described in Example 107, using 2,6-dioxo-l-(pyridin-2-ylmethyl)-l,2,3,6-tetrahydropyrimidine-4- carboxylic acid and (3-(4-fluorophenyl)pyridin-2-yl)methanamine. Purification by mass- triggered HPLC (gradient: 20 to 25% ACN in water containing 0.05% TFA) gave the title compound as a TFA salt. MS [M+H] found 432. 1H NMR (400 MHz, DMSO-J6) δ ppm 4.53 (d, J=5.31 Hz, 2 H), 5.13 (s, 2 H), 6.24 (d, J=1.77 Hz, 1 H), 7.31 - 7.39 (m, 2 H), 7.46 (br. s., 2 H), 7.50 - 7.58 (m, 3 H), 7.80 - 7.87 (m, 1 H), 7.96 (t, J=7.20 Hz, 1 H), 8.52 - 8.58 (m, 1 H), 8.64 (dd, J=4.93, 1.64 Hz, 1 H), 9.36 (t, J=5.31 Hz, 1 H), 11.20 (s, 1 H). [0402] EXAMPLE 109: l-benzyl-N-((2-(4-fluorophenyl)pyridin-3-yl)methyl)-2,6- dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000080_0002
[0403] The title compound was prepared in a manner similar to the method described in Example 42, using l-benzyl-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxylic acid and (2-(4-fluorophenyl)pyridin-3-yl)methanamine, and was purified by mass-triggered HPLC (40% ACN in water containing 0.05% TFA). MS [M+H] found 431. 1H NMR (400 MHz, DMSO-J6) δ ppm 4.45 (d, J=5.56 Hz, 2 H), 4.92 - 4.97 (m, 2 H), 6.21 (d, J=2.02 Hz, 1 H), 7.21 - 7.39 (m, 7 H), 7.52 (dd, J=7.83, 4.80 Hz, 1 H), 7.61 - 7.69 (m, 2 H), 7.97 (dd, J=7.71, 1.14 Hz, 1 H), 8.61 (dd, J=4.80, 1.52 Hz, 1 H), 9.41 (t, J=5.68 Hz, 1 H), 11.21 (d, J=I.77 Hz, 1 H); mp = 89.6-102.50C.
[0404] EXAMPLE 110: N-((2-(4-fiuorophenyl)pyridin-3-yl)methyl)-l-(2- morpholinoethyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000081_0001
[0405] The title compound was prepared in a manner similar to the method described in Example 109, using l-(2-morpholinoethyl)-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4- carboxylic acid and (2-(4-fluorophenyl)pyridin-3-yl)methanamine. Purification by mass- triggered HPLC (gradient: 5 to 10% ACN in water containing 0.05% TFA) gave the title compound as a TFA salt. MS [M+H] found 454. 1U NMR (400 MHz, DMSO-J6) δ ppm 3.03 - 3.19 (m, 2 H), 3.38 (br. s., 2 H), 3.59 (br. s., 4 H), 4.11 (t, J=5.81 Hz, 4 H), 4.47 (d, J=5.56 Hz, 2 H), 6.24 (d, J=I.77 Hz, 1 H), 7.29 - 7.38 (m, 2 H), 7.50 (dd, J=7.83, 4.80 Hz, 1 H), 7.61 - 7.69 (m, 2 H), 7.90 (dd, J=7.83, 1.52 Hz, 1 H), 8.58 - 8.64 (m, 1 H), 9.48 (t, J=5.68 Hz, 1 H), 11.32 (d, J=I.77 Hz, 1 H).
[0406] EXAMPLE 111 : N-((2-(4-fluorophenyl)pyridin-3-yl)methyl)-2,6-dioxo- 1 - (pyridin-2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000081_0002
[0407] The title compound was prepared in a manner similar to the method described in Example 109, using 2, 6-dioxo-l -(pyridin-2-ylmethyl)- 1,2, 3, 6-tetrahydropyrimidine-4- carboxylic acid and (2-(4-fluorophenyl)pyridin-3-yl)methanamine. Purification by mass- triggered HPLC (gradient: 10 to 15% ACN in water containing 0.05% TFA) gave the title compound as a TFA salt. MS [M+H] found 432. 1H NMR (400 MHz, DMSO-J6) δ ppm 4.47 (d, J=5.56 Hz, 2 H), 5.10 (s, 2 H), 6.23 (d, J=1.77 Hz, 1 H), 7.32 - 7.40 (m, 4 H), 7.55 (dd, J=7.83, 5.05 Hz, 1 H), 7.64 - 7.71 (m, 2 H), 7.86 (td, J=7.71, 1.77 Hz, 1 H), 8.01 (dd, J=7.83, 1.26 Hz, 1 H), 8.47 - 8.51 (m, 1 H), 8.63 (dd, J=4.93, 1.64 Hz, 1 H), 9.46 (t,
J=5.68 Hz, 1 H), 11.23 (d, J=I.77 Hz, 1 H). [0408] EXAMPLE 112: l-benzyl-N-((4-(4-fluorophenyl)pyridin-3-yl)methyl)-2,6- dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000082_0001
[0409] The title compound was prepared in a manner similar to the method described in Example 42, using l-benzyl-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxylic acid and (4-(4-fluorophenyl)pyridin-3-yl)methanamine. Purification by mass-triggered HPLC (gradient: 35 to 40% ACN in water containing 0.05% TFA) gave the title compound as a TFA salt. MS [M+H] found 431. 1H NMR (400 MHz, DMSO-J6) δ ppm 4.46 (d, J=5.31 Hz, 2 H), 4.92 - 4.96 (m, 2 H), 6.15 (d, J=1.77 Hz, 1 H), 7.21 - 7.41 (m, 7 H), 7.51 - 7.60 (m, 3 H), 8.67 (d, J=5.05 Hz, 1 H), 8.75 (s, 1 H), 9.32 (t, J=5.43 Hz, 1 H), 11.20 (d, J=I.77 Hz, I H).
[0410] EXAMPLE 113: 1 -benzyl-N-((3-(4-fluorophenyl)furan-2-yl)methyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000082_0002
[0411] The title compound was prepared in a manner similar to the method described in Example 42, using l-benzyl-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxylic acid and (3-(4-fluorophenyl)furan-2-yl)methanamine, and was purified by mass-triggered HPLC (gradient: 60 to 65% ACN in water containing 0.05% TFA). MS [M+H] found 420. [0412] EXAMPLE 114: l-benzyl-N-((3-(4-fluorophenyl)thiophen-2-yl)methyl)-2,6- dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000083_0001
[0413] The title compound was prepared in a manner similar to the method described in Example 42, using l-benzyl-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxylic acid and (3-(4-fluorophenyl)thiophen-2-yl)methanamine, and was purified by mass-triggered HPLC (65% ACN in water containing 0.05% TFA). MS [M+H] found 436. 1H NMR (400 MHz, DMSO-J6) δ ppm 4.59 (d, 2 H), 4.94 (s, 2 H), 6.21 (d, J=LOl Hz, I H), 7.11 (d, J=5.31 Hz, 1 H), 7.20 - 7.34 (m, 7 H), 7.48 - 7.58 (m, 3 H), 9.49 - 9.57 (m, 1 H), 11.24 (s, 1 H). m.p.=233.0-247.8.
[0414] EXAMPLE 115: 1 -benzyl-N-((4-(4-fluorophenyl)thiophen-3-yl)methyl)-2,6- dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000083_0002
[0415] The title compound was prepared in a manner similar to the method described in Example 42, using l-benzyl-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxylic acid and (4-(4-fluorophenyl)thiophen-3-yl)methanamine, and was purified by mass-triggered HPLC (65% ACN in water containing 0.05% TFA). MS [M+H] found 436. 1U NMR (400 MHz, DMSO-ώ) δ ppm 4.38 (d, 2 H), 4.95 (s, 2 H), 6.17 (s, 1 H), 7.19 - 7.35 (m, 7 H), 7.42 - 7.56 (m, 4 H), 9.30 (s, 1 H), 11.19 (s, 1 H); mp=229.4-237.9°C.
[0416] EXAMPLE 116: l-benzyl-N-((4'-fiuorobiphenyl-2-yl)methyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide
Figure imgf000084_0001
[0417] The title compound was prepared in a manner similar to the method described in Example 42, using benzyl-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxylic acid and (4'-fluorobiphenyl-2-yl)methanamine, and was purified by mass-triggered HPLC (55% ACN in water containing 0.05% TFA). MS [M+H] found 430. 1U NMR (400 MHz, DMSO-J6) δ ppm 4.34 (d, 2 H), 4.94 (s, 2 H), 6.21 (s, 1 H), 7.19 - 7.48 (m, 13 H), 9.27 (t, J=5.56 Hz, 1 H), 11.16 (s, 1 H); mp = 227.0-230.50C.
[0418] EXAMPLE 117: N-((4'-fluorobiphenyl-2-yl)methyl)-2,6-dioxo-l-(pyridin-2- ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000084_0002
[0419] The title compound was prepared in a manner similar to the method described in Example 42, using 2,6-dioxo-l-(pyridin-2-ylmethyl)-l,2,3,6-tetrahydropyrimidine-4- carboxylic acid and (4'-fluorobiphenyl-2-yl)methanamine, and was purified by mass- triggered HPLC (gradient: 30 to 35% ACN in water containing 0.05% TFA) to give a residue. The residue was triturated with diethyl ether and the resultant solid was isolated by filtration and dried under vacuum to give the title compound. MS [M+H] found 431. [0420] EXAMPLE 118: N-((4'-fluorobiphenyl-2-yl)methyl)-l-(2-morpholinoethyl)-2,6- dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000085_0001
[0421] The title compound was prepared in a manner similar to the method described in Example 42, using l-(2-morpholinoethyl)-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4- carboxylic acid and (4'-fluorobiphenyl-2-yl)methanamine, and was purified by mass- triggered HPLC (gradient: 35 to 40% ACN in water containing 0.05% TFA). MS [M+H] found 453; mp = 215.1-241.7°C.
[0422] EXAMPLE 119: 4-(( l-benzyl-2,6-dioxo- 1,2,3, 6-tetrahydropyrimidine-4- carboxamido)methyl)-3 -(trifluoromethoxy)benzoic acid
Figure imgf000085_0002
[0423] To l-benzyl-Λ/-(4-cyano-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide (282 mg, 635 μmol) was added methanol (15 mL) and 10% NaOH (2.4 mL). The mixture was heated to 85°C for 8 hours. The solvent was evaporated under vacuum to give a residue, which was partitioned between IN NaOH (30 mL) and dichloromethane (25 mL). The organic layer was separated and the aqueous layer was washed with dichloromethane (2 x 25 mL) and acidified with concentrated HCl to pH=2. Ethyl acetate (100 mL) was added to the aqueous layer; the resulting organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 75 mL). The organic layers were combined, washed with brine (50 mL), dried over sodium sulfate, and filtered. The solvent from the filtrate was evaporated under vacuum to give the title compound that was used without further purification. MS [M+H] found 464. 1H NMR (400 MHz, DMSO-J6) δ ppm 4.53 (d, J=5.56 Hz, 2 H), 4.96 (s, 2 H), 6.29 (d, J=I.26 Hz, 1 H), 7.22 - 7.34 (m, 5 H), 7.61 (d, J=8.08 Hz, 1 H), 7.80 (t, J=I.64 Hz, 1 H), 7.94 (dd, J=8.08, 1.52 Hz, 1 H), 9.50 (t, J=5.68 Hz, 1 H), 11.26 (s, 1 H). [0424] EXAMPLE 120: l-benzyl-N-(4-(cyclohexylcarbamoyl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000086_0001
[0425] To 4-(( 1 -benzyl-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamido)methyl)- 3-(trifluoromethoxy)benzoic acid (9.3 mg, 0.020 mmol), HATU (11.4 mg, 0.03 mmol) and JV-methylmorpholine (12.1 mg, 0.12 mmol) was added DMF (0.5 mL). Cyclohexanamine (3.0 mg, 0.03 mmol) was added and the mixture was stirred overnight at room temperature. Purification by mass-triggered HPLC (gradient: 25 to 95% ACN in water containing 0.05% TFA) gave the title compound. MS [M+H] found 545. [0426] EXAMPLE 121 : l-benzyl-N-{4-[(cyclohexylmethyl)carbamoyl]-2- (trifluoromethoxy)benzyl} -2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000086_0002
[0427] The title compound was prepared in a manner similar to the method described in Example 120, using cyclohexylmethanamine in place of cyclohexanamine, and was purified by mass-triggered HPLC (gradient: 25 to 95% ACN in water containing 0.05% TFA). MS [M+H] found 559.
[0428] EXAMPLE 122 : (S)- 1 -benzyl-N-(4-(2-carbamoylpyrrolidine- 1 -carbonyl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000087_0001
[0429] The title compound was prepared in a manner similar to the method described in Example 120, using (5)-pyrrolidine-2-carboxamide in place of cyclohexanamine, and was purified by mass-triggered HPLC (gradient: 20 to 50% ACN in water containing 0.05% TFA). MS [M+H] found 560.
[0430] EXAMPLE 123: l-benzyl-N-(4-(3-cyanophenylcarbamoyl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000087_0002
[0431] The title compound was prepared in a manner similar to the method described in Example 120, using 3-aminobenzonitrile in place of cyclohexanamine, and was purified by mass-triggered HPLC (gradient: 25 to 95% ACN in water containing 0.05% TFA). MS [M+H] found 564.
[0432] EXAMPLE 124: l-benzyl-N-(4-(4-methoxyphenylcarbamoyl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000087_0003
[0433] The title compound was prepared in a manner similar to the method described in Example 120, using 4-methoxyaniline in place of cyclohexanamine, and was purified by mass-triggered HPLC (gradient: 25 to 95% ACN in water containing 0.05% TFA). MS [M+H] found 569.
[0434] EXAMPLE 125: l-benzyl-N-(4-(benzyl(methyl)carbamoyl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000088_0001
[0435] The title compound was prepared in a manner similar to the method described in Example 120, using N-methyl-1-phenylmethanamine in place of cyclohexanamine, and was purified by mass-triggered HPLC (gradient: 25 to 95% ACN in water containing 0.05% TFA). MS [M+H] found 567.
[0436] EXAMPLE 126: l-benzyl-JV-(4-(4-cyanobenzylcarbamoyl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000088_0002
[0437] The title compound was prepared in a manner similar to the method described in Example 120, using 4-(aminomethyl)benzonitrile in place of cyclohexanamine, and was purified by mass-triggered HPLC (gradient: 25 to 95% ACN in water containing 0.05% TFA). MS [M+H] found 578.
[0438] EXAMPLE 127: l-benzyl-N-(4-(methyl(l-methylpyrrolidin-3-yl)carbamoyl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000089_0001
[0439] The title compound was prepared in a manner similar to the method described in Example 120, using N, l-dimethylpyrrolidin-3 -amine in place of cyclohexanamine, and was purified by mass-triggered HPLC (gradient: 5 to 60% ACN in water containing 0.05% TFA). MS [M+H] found 560.
[0440] EXAMPLE 128 : (R)- 1 -benzyl-2,6-dioxo-JV-(4-( 1 -phenylethylcarbamoyl)-2- (trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000089_0002
[0441] The title compound was prepared in a manner similar to the method described in
Example 120, using (7?)-l-phenylethanamine in place of cyclohexanamine, and was purified by mass-triggered HPLC (gradient: 25 to 95% ACN in water containing 0.05%
TFA). MS [M+H] found 567.
[0442] EXAMPLE 129: (5)-N-(4-(3-acetamidopyrrolidine-l-carbonyl)-2-
(trifluoromethoxy)benzyl)- 1 -benzyl-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4- carboxamide
Figure imgf000090_0001
[0443] The title compound was prepared in a manner similar to the method described in Example 120, using (5)-JV-(pyrrolidin-3-yl)acetamide in place of cyclohexanamine, and was purified by mass-triggered HPLC (gradient: 20 to 50% ACN in water containing 0.05% TFA). MS [M+H] found 574.
[0444] EXAMPLE 130: l-benzyl-N-(4-(2-(cyanomethyl)phenylcarbamoyl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000090_0002
[0445] The title compound was prepared in a manner similar to the method described in Example 120, using 2-(2-aminophenyl)acetonitrile in place of cyclohexanamine, and was purified by mass-triggered HPLC (gradient: 25 to 95% ACN in water containing 0.05% TFA). MS [M+H] found 578.
[0446] EXAMPLE 131 : (R)- 1 -benzyl-N-(4-(3-hydroxypyrrolidine- 1 -carbonyl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000091_0001
H
[0447] The title compound was prepared in a manner similar to the method described in Example 120, using (i?)-pyrrolidin-3-ol in place of cyclohexanamine, and was purified by mass-triggered HPLC (gradient: 20 to 50% ACN in water containing 0.05% TFA). MS [M+H] found 533.
[0448] EXAMPLE 132: (5)-l-benzyl-N-(4-(3-hydroxypyrrolidine-l-carbonyl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000091_0002
[0449] The title compound was prepared in a manner similar to the method described in Example 120, using (5)-pyrrolidin-3-ol in place of cyclohexanamine, and was purified by mass-triggered HPLC (gradient: 20 to 50% ACN in water containing 0.05% TFA). MS [M+H] found 533.
[0450] EXAMPLE 133: l-benzyl-N-(4-(3-hydroxybenzylcarbamoyl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000091_0003
[0451] The title compound was prepared in a manner similar to the method described in Example 120, using 3-(aminomethyl)phenol in place of cyclohexanamine, and was purified by mass-triggered HPLC (gradient: 25 to 95% ACN in water containing 0.05% TFA). MS [M+H] found 569.
[0452] EXAMPLE 134: l-benzyl-N-(4-(5-fiuoropyridin-2-ylcarbamoyl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000092_0001
[0453] The title compound was prepared in a manner similar to the method described in Example 120, using 5-fluoropyridin-2-amine in place of cyclohexanamine. Purification by mass-triggered HPLC (gradient: 25 to 95% ACN in water containing 0.05% TFA) gave the title compound as a TFA salt. MS [M+H] found 558.
[0454] EXAMPLE 135: l-benzyl-2,6-dioxo-N-(4-(tetrahydro-2/f-pyran-4-ylcarbamoyl)- 2-(trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000092_0002
[0455] The title compound was prepared in a manner similar to the method described in
Example 120, using tetrahydro-2H-pyran-4-amine in place of cyclohexanamine, and was purified by mass-triggered HPLC (gradient: 25 to 95% ACN in water containing 0.05%
TFA). MS [M+H] found 547.
[0456] EXAMPLE 136: l-benzyl-N-[4-{[(5-methylisoxazol-3-yl)methyl]carbamoyl}-2-
(trifluoromethoxy)benzyl]-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000093_0001
[0457] The title compound was prepared in a manner similar to the method described in
Example 120, using (5-methylisoxazol-3-yl)methanamine in place of cyclohexanamine, and was purified by mass-triggered HPLC (gradient: 25 to 95% ACN in water containing
0.05% TFA). MS [M+H] found 558.
[0458] EXAMPLE 137: N-(4-(l-acetylpiperidin-4-ylcarbamoyl)-2-
(trifluoromethoxy)benzyl)- 1 -benzyl-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4- carboxamide
Figure imgf000093_0002
[0459] The title compound was prepared in a manner similar to the method described in Example 120, using l-(4-aminopiperidin-l-yl)ethanone in place of cyclohexanamine, and was purified by mass-triggered HPLC (gradient: 20 to 50% ACN in water containing 0.05% TFA). MS [M+H] found 588.
[0460] EXAMPLE 138: l-benzyl-N-(4-(l,5-dimethyl-l/f-pyrazol-3-ylcarbamoyl)-2- (trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000094_0001
[0461] The title compound was prepared in a manner similar to the method described in
Example 120, using l,5-dimethyl-lH-pyrazol-3-amine in place of cyclohexanamine, and was purified by mass-triggered HPLC (gradient: 25 to 95% ACN in water containing
0.05% TFA). MS [M+H] found 557.
[0462] EXAMPLE 139: l-benzyl-N-[4-{[(l-methylpiperidin-4-yl)methyl]carbamoyl}-2-
(trifluoromethoxy)benzyl]-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000094_0002
[0463] The title compound was prepared in a manner similar to the method described in
Example 120, using (l-methylpiperidin-4-yl)methanamine in place of cyclohexanamine.
Purification by mass-triggered HPLC (gradient: 5 to 60% ACN in water containing 0.05%
TFA) gave the title compound as a TFA salt. MS [M+H] found 574.
[0464] EXAMPLE 140: l-benzyl-N-[4-{[(l-methylpyrrolidin-3-yl)methyl]carbamoyl}-
2-(trifluoromethoxy)benzyl]-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxamide
Figure imgf000095_0001
[0465] The title compound was prepared in a manner similar to the method described in
Example 120, using (l-methylpyrrolidin-3-yl)methanamine in place of cyclohexanamine.
Purification by mass-triggered HPLC (gradient: 5 to 60% ACN in water containing 0.05%
TFA) gave the title compound as a TFA salt. MS [M+H] found 560.
[0466] EXAMPLE 141 : l-benzyl-2,6-dioxo-N-[4-{[(6-oxo-l,6-dihydropyridin-3- yl)methyl]carbamoyl}-2-(trifluoromethoxy)benzyl]- 1,2,3, 6-tetrahydropyrimidine-4- carboxamide
Figure imgf000095_0002
[0467] The title compound was prepared in a manner similar to the method described in Example 120, using 5-(aminomethyl)pyridin-2(lH)-one in place of cyclohexanamine, and was purified by mass-triggered HPLC (gradient: 20 to 50% ACN in water containing 0.05% TFA). MS [M+H] found 570.
[0468] Table 1 lists sEH inhibition data for many of the compounds described in the examples, which were tested in accordance with the assay described on page 17 of the specification using human sEH. The inhibition data in Table 1 are expressed in terms of PIC50, which is the negative of the base-ten logarithm of IC50, where IC50 is the concentration in moles per liter of the test compound at 50% inhibition. As indicated in Table 1, the compounds (listed by Example number) inhibited human sEH with a pICso of less than about 6 (A), between 6 and 7.5 (B), and greater than 7.5 (C). TABLE 1 pICso Ex pICso Ex pICso Ex pICso Ex pICso Ex pICso
A 26 B 51 C 76 C 101 C 126 C
A 27 B 52 C 77 C 102 C 127 B
B 28 B 53 C 78 C 103 C 128 C
A 29 B 54 C 79 C 104 C 129 C
B 30 B 55 C 80 C 105 C 130 C
C 31 C 56 B 81 C 106 B 131 C
B 32 B 57 C 82 C 107 C 132 C
B 33 B 58 C 83 C 108 B 133 C
A 34 B 59 C 84 C 109 C 134 C
B 35 B 60 C 85 C 110 C 135 C
B 36 B 61 C 86 C 111 B 136 C
B 37 B 62 C 87 B 112 B 137 C
B 38 B 63 C 88 C 113 B 138 C
B 39 A 64 C 89 C 114 C 139 C
C 40 B 65 C 90 C 115 C 140 B
B 41 C 66 C 91 C 116 C 141 C
B 42 C 67 C 92 C 117 C
B 43 C 68 C 93 C 118 C
C 44 C 69 C 94 C 119 C
B 45 C 70 C 95 C 120 C
C 46 C 71 C 96 C 121 C
A 47 C 72 C 97 C 122 C
A 48 C 73 C 98 C 123 C
B 49 C 74 C 99 C 124 C
B 50 C 75 C 100 B 125 C

Claims

WHAT IS CLAIMED IS:
1. A compound of formula I
Figure imgf000097_0001
or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, wherein:
Ar is selected from the group consisting of C4-I4 aryl and C1-10 heteroaryl;
Ri is selected from the group consisting of hydrogen, optionally substituted
C3_8 cycloalkyl, optionally substituted C3-6 heterocycloalkyl, and optionally substituted Ci_6 alkyl;
R2 is selected from the group consisting of optionally substituted Ci_6 alkyl, Ci_g sulfonyl, optionally substituted C2_4 alkenyl, optionally substituted Ci_4 alkoxy, optionally substituted C2-6 alkynyl, amino, Ci_g alkylamino, Ci_2o amide, optionally substituted C4_i4 aryl, optionally substituted C4_i4 aryloxy, Ci_5 oxycarbonyl, cyano, optionally substituted C3-S cycloalkyl, C3_8 cycloalkoxy, halo, optionally substituted C3_6 heterocycloalkyl, optionally substituted C1-10 heteroaryl, optionally substituted C1-10 heteroaryloxy, hydroxy, and nitro; n is 0, 1, 2, or 3; and m is O, 1, 2, 3 or 4.
2. A compound, tautomer, or pharmaceutically acceptable salt according to claim 1, wherein Ar is C4_i4 aryl.
3. A compound, tautomer, or pharmaceutically acceptable salt according to claim 2, wherein Ar is phenyl.
4. A compound, tautomer, or pharmaceutically acceptable salt according to any one of claims 1 to 3, wherein n is 1.
5. A compound, tautomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4, wherein m is 1 or 2.
6. A compound, tautomer, or pharmaceutically acceptable salt according to any one of claims 1 to 5, wherein each R2 is independently selected from the group consisting of optionally substituted Ci_6 alkyl, optionally substituted Ci_4 alkoxy, cyano, halo, optionally substituted C3-6 heterocycloalkyl, and optionally substituted C4-I4 aryl.
7. A compound, tautomer, or pharmaceutically acceptable salt according to any one of claims 1 to 6, wherein Ri is optionally substituted Ci_4 alkyl having from 1 to 4 substituents independently selected from the group consisting of optionally substituted C3- 8 cycloalkyl, optionally substituted C3-6 heterocycloalkyl, optionally substituted C1-10 heteroaryl, and optionally substituted phenyl.
8. A compound, tautomer, or pharmaceutically acceptable salt according to any one of claims 1 to 7, wherein Ri is optionally substituted Ci_4 alkyl having an optionally substituted C3_8 cycloalkyl.
9. A compound, tautomer, or pharmaceutically acceptable salt according to any one of claims 1 to 7, wherein Ri is optionally substituted Ci_4 alkyl having an optionally substituted C3-6 heterocycloalkyl.
10. A compound, tautomer, or pharmaceutically acceptable salt according to any one of claims 1 to 7, wherein Ri is optionally substituted Ci_4 alkyl having an optionally substituted C1-10 heteroaryl.
11. A compound, tautomer, or pharmaceutically acceptable salt according to any one of claims 1 to 7, wherein Ri is optionally substituted Ci_4 alkyl having an optionally substituted phenyl.
12. A compound according to claim 1, which is selected from: Λ/-(2,4-dichlorobenzyl)- 1 -methyl-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4- carboxamide; N-(2-chloro-4-(methylsulfonyl)benzyl)-l-methyl-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide; 1 -methyl-2,6-dioxo-Λ/-(2-(trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-
4-carboxamide; Λ/-(4-chloro-2-(methylsulfonyl)benzyl)- 1 -methyl-2,6-dioxo- 1 ,2,3 ,6- tetrahydropyrimidine-4-carboxamide; Λ/-(4-methoxy-2-(trifluoromethoxy)benzyl)- 1 -methyl-2,6-dioxo- 1 ,2,3,6- tetrahydropyrimidine-4-carboxamide; 1 -(cyclopropylmethyl)-2,6-dioxo-Λ/-(2-(trifluoromethoxy)benzyl)- 1 ,2,3,6- tetrahydropyrimidine-4-carboxamide; 1 -(2,2-difluoroethyl)-2,6-dioxo-N-(2-(trifluoromethoxy)benzyl)- 1 ,2,3 ,6- tetrahydropyrimidine-4-carboxamide; 1 -(4-(methylsulfonyl)benzyl)-2,6-dioxo-Λ/-(2-(trifluoromethoxy)benzyl)- 1 ,2,3,6- tetrahydropyrimidine-4-carboxamide; 1 -(2-hydroxyethyl)-2,6-dioxo-Λ/-(2-(trifluoromethoxy)benzyl)- 1 ,2,3,6- tetrahydropyrimidine-4-carboxamide; 2,6-dioxo- 1 -(pyridin-2-ylmethyl)-Λ/-(2-(trifluoromethoxy)benzyl)- 1 ,2,3,6- tetrahydropyrimidine-4-carboxamide; l-(2-amino-2-oxoethyl)-2,6-dioxo-Λ/-(2-(trifluoromethoxy)benzyl)-l,2,3,6- tetrahydropyrimidine-4-carboxamide; l-(3-amino-3-oxopropyl)-2,6-dioxo-Λ/-(2-(trifluoromethoxy)benzyl)-l, 2,3,6- tetrahydropyrimidine-4-carboxamide; (i?)-2,6-dioxo-l-((5-oxopyrrolidin-2-yl)methyl)-Λ/-(2-(trifluoromethoxy)benzyl)-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; l-(2,3-dihydroxypropyl)-2,6-dioxo-Λ/-(2-(trifluoromethoxy)benzyl)-l,2,3,6- tetrahydropyrimidine-4-carboxamide; l-(3-cyanobenzyl)-2,6-dioxo-Λ/-(2-(trifluoromethoxy)benzyl)-l, 2,3,6- tetrahydropyrimidine-4-carboxamide; 2,6-dioxo- 1 -(pyridin-3 -ylmethyl)-Λ/-(2-(trifluoromethoxy)benzyl)- 1 ,2,3,6- tetrahydropyrimidine-4-carboxamide; l-(3-hydroxypropyl)-2,6-dioxo-N-(2-(trifluoromethoxy)benzyl)-l, 2,3,6- tetrahydropyrimidine-4-carboxamide; ,6-dioxo-l-((tetrahydrofuran-2-yl)methyl)-Λ/-(2-(trifluoromethoxy)benzyl)-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; 1 -(4-cyanobenzyl)-2,6-dioxo-Λ/-(2-(trifluoromethoxy)benzyl)- 1 ,2,3,6- tetrahydropyrimidine-4-carboxamide; l-(3-cyanopropyl)-2,6-dioxo-Λ/-(2-(trifluoromethoxy)benzyl)-l,2,3,6- tetrahydropyrimidine-4-carboxamide; 1 -(2-fluorobenzyl)-2,6-dioxo-Λ/-(2-(trifluoromethoxy)benzyl)- 1 ,2,3,6- tetrahydropyrimidine-4-carboxamide; l-(3-hydroxy-2,2-dimethylpropyl)-2,6-dioxo-Λ/-(2-(trifluoromethoxy)benzyl)-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; 1 -(2-(dimethylamino)ethyl)-2,6-dioxo-Λ/-(2-(trifluoromethoxy)benzyl)- 1 ,2,3,6- tetrahydropyrimidine-4-carboxamide; 1 -(2-morpholinoethyl)-2,6-dioxo-Λ/-(2-(trifluoromethoxy)benzyl)- 1 ,2,3,6- tetrahydropyrimidine-4-carboxamide; 1 -cyclopentyl-2,6-dioxo-N-(2-(trifluoromethoxy)benzyl)- 1 ,2,3,6- tetrahydropyrimidine-4-carboxamide; 1 -neopentyl-2,6-dioxo-Λ/-(2-(trifluoromethoxy)benzyl)- 1,2,3,6- tetrahydropyrimidine-4-carboxamide; l-((2,4-dioxo-l,2,3,4-tetrahydropyrimidin-5-yl)methyl)-2,6-dioxo-N-(2-
(trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; 1 -(methoxymethyl)-2,6-dioxo-N-(2-(trifluoromethoxy)benzyl)- 1,2,3,6- tetrahydropyrimidine-4-carboxamide; 1 -(2-( lH-pyrazol- 1 -yl)ethyl)-2,6-dioxo-Λ/-(2-(trifluoromethoxy)benzyl)- 1 ,2,3,6- tetrahydropyrimidine-4-carboxamide; l-((4-isobutylmorpholin-2-yl)methyl)-2,6-dioxo-Λ/-(2-(trifluoromethoxy)benzyl)-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; 1 -(2-(methylthio)ethyl)-2,6-dioxo-N-(2-(trifluoromethoxy)benzyl)- 1 ,2,3,6- tetrahydropyrimidine-4-carboxamide 2,6-dioxo- 1 -(2-(2-oxopyrrolidin- 1 -yl)ethyl)-N-(2-(trifluoromethoxy)benzyl)-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; l-(2-(isopropyl(methyl)amino)-2-oxoethyl)-2,6-dioxo-iV-(2-
(trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; l-((2-methylthiazol-4-yl)methyl)-2,6-dioxo-Λ/-(2-(trifluoromethoxy)benzyl)-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; l-((3-ethyl-l,2,4-oxadiazol-5-yl)methyl)-2,6-dioxo-N-(2-
(trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide 2,6-dioxo- 1 -(2-(2-oxo-2,3-dihydro- lH-imidazol- 1 -yl)ethyl)-N-(2-
(trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; 1 -(2-( IH- 1 ,2,4-triazol- 1 -yl)ethyl)-2,6-dioxo-N-(2-(trifluoromethoxy)benzyl)-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; l-((5-ethyl-l,3,4-oxadiazol-2-yl)methyl)-2,6-dioxo-N-(2-
(trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; 1 -(2-(diethylamino)ethyl)-2,6-dioxo-Λ/-(2-(trifluoromethoxy)benzyl)- 1 ,2,3,6- tetrahydropyrimidine-4-carboxamide; 1 -(3-( lH-pyrazol- 1 -yl)propyl)-2,6-dioxo-Λ/-(2-(trifluoromethoxy)benzyl)- 1 ,2,3,6- tetrahydropyrimidine-4-carboxamide; 1 -benzyl-2,6-dioxo-Λ/-(2-(trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-
4-carboxamide; 1 -benzyl-N-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3,6- tetrahydropyrimidine-4-carboxamide; 1 -benzyl-Λ/-(4-methoxy-2-(trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3,6- tetrahydropyrimidine-4-carboxamide; Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l-(pyridin-2-ylmethyl)-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)- 1 -(2-morpholinoethyl)-2,6-dioxo- 1 ,2,3,6- tetrahydropyrimidine-4-carboxamide; Λ/-(4-methoxy-2-(trifluoromethoxy)benzyl)-l-(2-morpholinoethyl)-2,6-dioxo-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; 1 -(2-( lH-pyrazol- 1 -yl)ethyl)-Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; 1 -(2-( lH-pyrazol- 1 -yl)ethyl)-Λ/-(4-methoxy-2-(trifluoromethoxy)benzyl)-2,6- dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; Λ/-(4-bromo-2-(trifluoromethoxy)benzyl)- 1 -((3-ethyl- 1 ,2,4-oxadiazol-5-yl)methyl)-
2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; l-((3-ethyl-l,2,4-oxadiazol-5-yl)methyl)-N-(4-methoxy-2-
(trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4- carboxamide; Λ/-(4-(2-aminopyrimidin-5-yl)-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l-(pyridin-
2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; Λ/-(4-(5-aminopyrazin-2-yl)-2-(trifluoromethoxy)benzyl)-l-benzyl-2,6-dioxo-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; l-benzyl-2,6-dioxo-Λ/-((3-(trifluoromethoxy)biphenyl-4-yl)methyl)-l,2,3,6- tetrahydropyrimidine-4-carboxamide; l-benzyl-2,6-dioxo-Λ/-(4-(pyridin-3-yl)-2-(trifluoromethoxy)benzyl)-l,2,3,6- tetrahydropyrimidine-4-carboxamide; l-benzyl-Λ/-((4'-(methylsulfonyl)-3-(trifluoromethoxy)biphenyl-4-yl)methyl)-2,6- dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; l-benzyl-Λ/-(4-(2-methoxypyrimidin-5-yl)-2-(trifluoromethoxy)benzyl)-2,6-dioxo-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; l-benzyl-Λ/-((4'-carbamoyl-3-(trifluoromethoxy)biphenyl-4-yl)methyl)-2,6-dioxo-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; l-benzyl-Λ/-(4-(2,6-dimethoxypyridin-3-yl)-2-(trifluoromethoxy)benzyl)-2,6- dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; methyl 4'-((I -benzyl-2,6-dioxo- 1 ,2,3,6-tetrahydropyrimidine-4- carboxamido)methyl)-3'-(trifluoromethoxy)biphenyl-4-ylcarbamate; l-benzyl-Λ/-(4-(2-fluoropyridin-4-yl)-2-(trifluoromethoxy)benzyl)-2,6-dioxo-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; Λ/-(4-(6-aminopyridin-3-yl)-2-(trifluoromethoxy)benzyl)-l-benzyl-2,6-dioxo-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; l-benzyl-Λ/-(4-(3,5-dimethyl-lH-pyrazol-4-yl)-2-(trifluoromethoxy)benzyl)-2,6- dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; l-benzyl-Λ/-(4-(6-hydroxypyridin-3-yl)-2-(trifluoromethoxy)benzyl)-2,6-dioxo-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; l-benzyl-2,6-dioxo-Λ/-((3-(trifluoromethoxy)-4'-ureidobiphenyl-4-yl)methyl)-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; Λ/-(4-(benzo[c][l,2,5]oxadiazol-5-yl)-2-(trifluoromethoxy)benzyl)-l-benzyl-2,6- dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; Λ/-(4-(2-aminopyrimidin-5-yl)-2-(trifluoromethoxy)benzyl)-l-benzyl-2,6-dioxo-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; l-benzyl-2,6-dioxo-Λ/-(4-(2-oxoindolin-5-yl)-2-(trifluoromethoxy)benzyl)-l,2,3,6- tetrahydropyrimidine-4-carboxamide; Λ/-(4-(lH-pyrrolo[3,2-δ]pyridin-6-yl)-2-(trifluoromethoxy)benzyl)-l-benzyl-2,6- dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; 1 -benzyl-Λ/-(4-(furan-2-yl)-2-(trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3,6- tetrahydropyrimidine-4-carboxamide; Λ/-(4-(5-acetylthiophen-2-yl)-2-(trifluoromethoxy)benzyl)-l-benzyl-2,6-dioxo-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; l-benzyl-Λ/-(4-(2,4-dioxo-l,2,3,4-tetrahydropyrimidin-5-yl)-2-
(trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4- carboxamide; l-benzyl-Λ/-(4-(furan-3-yl)-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l, 2,3,6- tetrahydropyrimidine-4-carboxamide; 1 -benzyl-N-((4 ' -(methylsulfonamido)-3 -(trifluoromethoxy)biphenyl-4-yl)methyl)-
2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; 1 -benzyl-N-((3 ' -(methylsulfonamido)-3 -(trifluoromethoxy)biphenyl-4-yl)methyl)-
2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; l-benzyl-2,6-dioxo-Λ/-(4-(quinolin-3-yl)-2-(trifluoromethoxy)benzyl)-l, 2,3,6- tetrahydropyrimidine-4-carboxamide; l-benzyl-2,6-dioxo-Λ/-(4-(pyrimidin-5-yl)-2-(trifluoromethoxy)benzyl)-l,2,3,6- tetrahydropyrimidine-4-carboxamide; N-(4-(lH-indol-4-yl)-2-(trifluoromethoxy)benzyl)-l-benzyl-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide; l-benzyl-Λ/-(4-(5-methoxypyridin-3-yl)-2-(trifluoromethoxy)benzyl)-2,6-dioxo-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; 1 -benzyl-JV-(4-( 1 -methyl- lH-pyrazol-4-yl)-2-(trifluoromethoxy)benzyl)-2,6-dioxo-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; l-benzyl-Λ/-(4-(6-morpholinopyridin-3-yl)-2-(trifluoromethoxy)benzyl)-2,6-dioxo-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; l-benzyl-2,6-dioxo-Λ/-(4-(l-propyl-lH-pyrazol-4-yl)-2-(trifluoromethoxy)benzyl)-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; l-benzyl-2,6-dioxo-Λ/-((3'-sulfamoyl-3-(trifluoromethoxy)biphenyl-4-yl)methyl)-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; l-benzyl-Λ/-(4-(2-(dimethylamino)pyrimidin-5-yl)-2-(trifluoromethoxy)benzyl)-
2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; Λ/-(4-(lH-pyrazol-5-yl)-2-(trifluoromethoxy)benzyl)-l-benzyl-2,6-dioxo-l, 2,3,6- tetrahydropyrimidine-4-carboxamide; Λ/-(4-(lH-pyrazol-4-yl)-2-(trifluoromethoxy)benzyl)-l-benzyl-2,6-dioxo-l, 2,3,6- tetrahydropyrimidine-4-carboxamide; l-benzyl-2,6-dioxo-Λ/-(2-(trifluoromethoxy)-4-(3-(trifluoromethyl)-lH-pyrazol-4- yl)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; l-benzyl-Λ/-(4-(l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrimidin-5-yl)-2-
(trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4- carboxamide; Λ/-(4-(lH-pyrrolo[2,3-δ]pyridin-5-yl)-2-(trifluoromethoxy)benzyl)-l-benzyl-2,6- dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; 1 -benzyl-JV-(4-( 1 -(2-morpholinoethyl)- l/f-pyrazol-4-yl)-2-
(trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4- carboxamide; (E)- 1 -benzy \-N-((4 ' -(TV -hydroxycarbamimidoyl)-3 -(trifluoromethoxy)biphenyl-4- yl)methyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; l-benzyl-Λ/-(4-(6-(methylcarbamoyl)pyridin-3-yl)-2-(trifluoromethoxy)benzyl)-
2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; l-benzyl-Λ/-(4-(2-cyanopyrimidin-5-yl)-2-(trifluoromethoxy)benzyl)-2,6-dioxo-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; Λ/-(4-(6-acetamidopyridin-3-yl)-2-(trifluoromethoxy)benzyl)-l-benzyl-2,6-dioxo-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; methyl 5-(4-((l-benzyl-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4- carboxamido)methyl)-3-(trifluoromethoxy)phenyl)pyridin-2-ylcarbamate; l-benzyl-Λ/-(4-(6-(hydroxymethyl)pyridin-3-yl)-2-(trifluoromethoxy)benzyl)-2,6- dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; 5-(4-((l-benzyl-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxamido)methyl)-3-
(trifluoromethoxy)phenyl)picolinic acid; Λ/-(4-(l-(3-methoxypropyl)-lH-pyrazol-4-yl)-2-(trifluoromethoxy)benzyl)-2,6- dioxo- 1 -(pyridin-2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; Λ/-(4-(l-(3-hydroxypropyl)-lH-pyrazol-4-yl)-2-(trifluoromethoxy)benzyl)-2,6- dioxo- 1 -(pyridin-2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; l-benzyl-Λ/-(4-(cyclopropylsulfonyl)-2-(trifluoromethoxy)benzyl)-2,6-dioxo-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; Λ/-(4-(cyclopropylsulfonyl)-2-(trifluoromethoxy)benzyl)-l-(2-morpholinoethyl)-
2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; Λ/-(4-(cyclopropylsulfonyl)-2-(trifluoromethoxy)benzyl)-2,6-dioxo-l-(pyridin-2- ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; (5)-N-(4-(4-hydroxy-2-oxopyrrolidin-l-yl)-2-(trifluoromethoxy)benzyl)-2,6-dioxo-
1 -(pyridin-2-ylmethyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; (5)-N-(4-(4-hydroxy-2-oxopyrrolidin- 1 -yl)-2-(trifluoromethoxy)benzyl)- 1 -(2- morpholinoethyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; 1 -benzyl-Λ/-(4-cyano-2-(trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3,6- tetrahydropyrimidine-4-carboxamide; Λ/-(4-cyano-2-(trifluoromethoxy)benzyl)-2,6-dioxo- 1 -(pyridin-2-ylmethyl)- 1 ,2,3,6- tetrahydropyrimidine-4-carboxamide; Λ/-(4-cyano-2-(trifluoromethoxy)benzyl)- 1 -(2-morpholinoethyl)-2,6-dioxo- 1 ,2,3,6- tetrahydropyrimidine-4-carboxamide; l-benzyl-Λ/-((3-(4-fluorophenyl)pyridin-2-yl)methyl)-2,6-dioxo-l, 2,3,6- tetrahydropyrimidine-4-carboxamide; Λ/-((3-(4-fluorophenyl)pyridin-2-yl)methyl)-2,6-dioxo-l-(pyridin-2-ylmethyl)-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; l-benzyl-Λ/-((2-(4-fluorophenyl)pyridin-3-yl)methyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide; Λ/-((2-(4-fluorophenyl)pyridin-3 -yl)methyl)- 1 -(2-morpholinoethyl)-2,6-dioxo-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; Λ/-((2-(4-fluorophenyl)pyridin-3-yl)methyl)-2,6-dioxo-l-(pyridin-2-ylmethyl)-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; l-benzyl-Λ/-((4-(4-fluorophenyl)pyridin-3-yl)methyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide; l-benzyl-Λ/-((3-(4-fluorophenyl)furan-2-yl)methyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide; l-benzyl-N-((3-(4-fluorophenyl)thiophen-2-yl)methyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide; l-benzyl-N-((4-(4-fluorophenyl)thiophen-3-yl)methyl)-2,6-dioxo-l,2,3,6- tetrahydropyrimidine-4-carboxamide; 1 -benzyl-N-((4 ' -fluorobiphenyl-2-yl)methyl)-2,6-dioxo- 1 ,2,3,6- tetrahydropyrimidine-4-carboxamide; N-((4 ' -fluorobiphenyl-2-yl)methyl)-2,6-dioxo- 1 -(pyridin-2-ylmethyl)- 1 ,2,3,6- tetrahydropyrimidine-4-carboxamide; N-((4 ' -fluorobiphenyl-2-yl)methyl)- 1 -(2-morpholinoethyl)-2,6-dioxo- 1 ,2,3 ,6- tetrahydropyrimidine-4-carboxamide; 4-((l-benzyl-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxamido)methyl)-3-
(trifluoromethoxy)benzoic acid; l-benzyl-Λ/-(4-(cyclohexylcarbamoyl)-2-(trifluoromethoxy)benzyl)-2,6-dioxo-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; 1 -benzyl-JV- {4-[(cyclohexylmethyl)carbamoyl]-2-(trifluoromethoxy)benzyl} -2,6- dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; (S)- 1 -benzyl-Λ/-(4-(2-carbamoylpyrrolidine- 1 -carbonyl)-2-
(trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4- carboxamide; l-benzyl-Λ/-(4-(3-cyanophenylcarbamoyl)-2-(trifluoromethoxy)benzyl)-2,6-dioxo-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; l-benzyl-Λ/-(4-(4-methoxyphenylcarbamoyl)-2-(trifluoromethoxy)benzyl)-2,6- dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; l-benzyl-Λ/-(4-(benzyl(methyl)carbamoyl)-2-(trifluoromethoxy)benzyl)-2,6-dioxo-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; l-benzyl-Λ/-(4-(4-cyanobenzylcarbamoyl)-2-(trifluoromethoxy)benzyl)-2,6-dioxo-
1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; 1 -benzyl-JV-(4-(methyl( 1 -methylpyrrolidin-3 -yl)carbamoyl)-2-
(trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4- carboxamide; (R)- 1 -benzyl-2,6-dioxo-N-(4-( 1 -phenylethylcarbamoyl)-2-
(trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; (S)-N-(4-(3 -acetamidopyrrolidine- 1 -carbonyl)-2-(trifluoromethoxy)benzyl)- 1 - benzyl-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; l-benzyl-Λ/-(4-(2-(cyanomethyl)phenylcarbamoyl)-2-(trifluoromethoxy)benzyl)-
2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; (R)- 1 -benzy l-JV-(4-(3 -hydroxypyrrolidine- 1 -carbonyl)-2-
(trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4- carboxamide; (S)- 1 -benzyl-JV-(4-(3 -hydroxypyrrolidine- 1 -carbonyl)-2-
(trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4- carboxamide; l-benzyl-Λ/-(4-(3-hydroxybenzylcarbamoyl)-2-(trifluoromethoxy)benzyl)-2,6- dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; l-benzyl-Λ/-(4-(5-fluoropyridin-2-ylcarbamoyl)-2-(trifluoromethoxy)benzyl)-2,6- dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; l-benzyl-2,6-dioxo-Λ/-(4-(tetrahydro-2H-pyran-4-ylcarbamoyl)-2-
(trifluoromethoxy)benzyl)- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; 1 -benzyl-JV- [4- { [(5 -methylisoxazol-3 -yl)methyl] carbamoyl} -2-
(trifluoromethoxy)benzyl]-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4- carboxamide; N-(4-( 1 -acetylpiperidin-4-ylcarbamoyl)-2-(trifluoromethoxy)benzyl)- 1 -benzyl-2,6- dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4-carboxamide; 1 -benzyl-JV-(4-( 1 ,5 -dimethyl- lH-pyrazol-3 -ylcarbamoyl)-2-
(trifluoromethoxy)benzyl)-2,6-dioxo- 1 ,2,3 ,6-tetrahydropyrimidine-4- carboxamide; 1 -benzyl-JV- [4- { [( 1 -methylpiperidin-4-yl)methyl] carbamoyl} -2-
(trifluoromethoxy)benzyl]-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4- carboxamide; 1 -benzyl-JV-[4- {[(1 -methylpyrrolidin-3-yl)methyl]carbamoyl} -2-
(trifluoromethoxy)benzyl]-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4- carboxamide; l-benzyl-2,6-dioxo-Λ/-[4-{[(6-oxo-l,6-dihydropyridin-3-yl)methyl]carbamoyl}-2-
(trifluoromethoxy)benzyl]-l,2,3,6-tetrahydropyrimidine-4-carboxamide; tautomers of any one of the aforementioned compounds; stereoisomers of any one of the aforementioned compounds; and pharmaceutically acceptable salts of any one of the aforementioned compounds, tautomers, and stereoisomers.
13. A pharmaceutical composition comprising a compound, tautomer, or pharmaceutically acceptable salt as defined in any one of the preceding claims, and a pharmaceutically acceptable excipient.
14. A use of a compound, tautomer, or pharmaceutically acceptable salt as defined in any one of claims 1 to 12 as a medicament.
15. A use of a compound, tautomer, or pharmaceutically acceptable salt as defined in any one of claims 1 to 12 for the manufacture of a medicament for the treatment of conditions associated with sEH.
16. A method of treating conditions associated with sEH, comprising administering to a patient in need treatment an effective amount of a compound, tautomer, or pharmaceutically acceptable salt as defined in any one of claims 1 to 12.
PCT/US2010/034000 2009-05-08 2010-05-07 2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamides WO2010129848A2 (en)

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US17683809P 2009-05-08 2009-05-08
US61/176,838 2009-05-08

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9126944B2 (en) 2013-02-28 2015-09-08 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
US9828345B2 (en) 2013-02-28 2017-11-28 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2003281169A1 (en) * 2002-07-17 2004-02-02 Warner-Lambert Company Llc Combination of an allosteric carboxylic inhibitor of matrix metalloproteinase-13 with celecoxib or valdecoxib
EP1828144A2 (en) * 2004-11-12 2007-09-05 OSI Pharmaceuticals, Inc. Integrin antagonists useful as anticancer agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF PHARMACEUTICAL SCIENCE, vol. 66, 1977, pages 2 - 19

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9126944B2 (en) 2013-02-28 2015-09-08 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
US9458110B2 (en) 2013-02-28 2016-10-04 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
US9828345B2 (en) 2013-02-28 2017-11-28 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors

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