WO2006058338A2 - 4 - piperidinecarboxamide derivatives as modulators of vanilloid vr1 receptor - Google Patents

4 - piperidinecarboxamide derivatives as modulators of vanilloid vr1 receptor Download PDF

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WO2006058338A2
WO2006058338A2 PCT/US2005/043192 US2005043192W WO2006058338A2 WO 2006058338 A2 WO2006058338 A2 WO 2006058338A2 US 2005043192 W US2005043192 W US 2005043192W WO 2006058338 A2 WO2006058338 A2 WO 2006058338A2
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piperidine
carboxylic acid
amide
phenyl
benzo
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PCT/US2005/043192
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French (fr)
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WO2006058338A3 (en
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Raul R. Calvo
Cheung S. Wing
Mark R. Player
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Janssen Pharmaceutica N.V.
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    • C07—ORGANIC CHEMISTRY
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    • 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
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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    • 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
    • C07D417/12—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 chain containing hetero atoms as chain links
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    • C07D417/14—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 three or more hetero rings
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    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
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    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • This invention is directed to novel vanilloid receptor VR1 ligands. More particularly, this invention relates to novel 4-piperidincarboxamides that are potent modulators of VR1.
  • Noxious chemical, thermal and mechanical stimuli excite peripheral nerve endings of small diameter sensory neurons (nociceptors) in sensory ganglia (e. g., dorsal root, nodose and trigeminal ganglia) and initiate signals that are perceived as pain.
  • sensory ganglia e. g., dorsal root, nodose and trigeminal ganglia
  • These neurons are crucial for the detection of harmful or potentially harmful stimuli (heat) and tissue damage (local tissue acidosis and/or stretch) that arise from changes in the extracellular space during inflammatory or ischaemic conditions (Wall, P. D., and Melzack, R., Textbook of Pain. 1994, New York: Churchill Livingstone).
  • Nociceptors transduce noxious stimuli into membrane depolarization that triggers action potential, conducts the action potential from the sensory sites to the synapses in the CNS, and conversion of action potentials invokes a perception of pain, discomfort, and appropriate mechanical/physical protective reflexes.
  • nociception is carried out by ion channels or receptors.
  • Plant derived vanilloid compounds (capsaicin and its ultrapotent analog, resiniferatoxin, etc.) are known to selectively depolarize nociceptors and elicit sensations of burning pain — the sensation that is typically obtained by hot chili peppers. Therefore, capsaicin mimics the action of physiological/endogenous stimuli that activates the "nociceptive pathway”.
  • the present invention is directed to compounds of formula (II)
  • Ar is an aryl selected from the group consisting of benzo[b]thiophenyl, naphthyl, biphenyl, isoquinolinyl, thiophenyl, pyridazinyl, and benzothiazolyl;
  • Z is O or S;
  • R 2 is hydrogen or C h alky! optionally substituted with -OR 4 ; n is 1 or 2;
  • R 3 is independently hydrogen, Ci -6 alkyl, -COOR 4 , Or -CH 2 COOR 4 ; R 4 is hydrogen or C h alky!; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
  • the present invention is directed to compounds of formula (II) wherein Z is O and n is 1.
  • the present invention is directed to compounds of formula (M) wherein Z is O and R 2 is hydrogen.
  • the present invention is directed to compounds of formula (III):
  • R is independently selected from the group consisting of halogen; R 1 ; fluorinated C- M oalkyl; phenyl; amino; cyano; CF 3 O-; a 3 membered cyclic heteroalkyl containing 1 heteroatom that is N, O or S wherein said 3 membered cyclic heteroalkyl is optionally substituted with a substituent that is halogen, R 1 , fluorinated C- M oalkyl, amino, cyano, CF 3 O-, R 1 O-, R 1 S-, R 1 SO 2 -, R 1 S(O)-, R 1 SO 2 NH-, or -LCOY; a 4 to 5 membered cyclic heteroalkyl containing 1-3 heteroatoms that independently are N, O or S wherein said 4 to 5 membered cyclic heteroalkyl is optionally substituted with 1 to 2 substituents that independently are halogen, R 1 , fluorinated Ci- ioalkyl,
  • R 1 is Ci-i O alkyl;
  • L is -NH-, a direct bond, -O-, or -CH 2 -;
  • Y is H, R 1 , HO, R 1 O-, R 1 S-, -NH 2 , R 1 NH-, or (R 1 ) 2 N-;
  • Z is O or S
  • R 2 is hydrogen or C 1-6 alkyl optionally substituted with -OR 4 ; n is 1 or 2; R 3 is independently hydrogen, Ci -6 alkyl, -COOR 4 , Or-CH 2 COOR 4 ; R 4 is hydrogen or C 1-3 alkyl; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
  • the present invention is directed to compounds of formula (Ha):
  • Ar is an aryl selected from the group consisting of benzo[b]thiophenyl, naphthyl, biphenyl, isoquinolinyl, thiophenyl, pyridazinyl, and benzothiazolyl; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
  • the present invention is also drawn to compounds of formula (Ilia):
  • R is independently selected from the group consisting of halogen; R 1 ; fluorinated C- M oalkyl; phenyl; amino; cyano; CF 3 O-; a 3 membered cyclic heteroalkyl containing 1 heteroatom that is N, O or S wherein said 3 membered cyclic heteroalkyl is optionally substituted with a substituent that is halogen, R 1 , fluorinated Ci-i O alkyl, amino, cyano, CF 3 O-, R 1 O-, R 1 S-, R 1 SO 2 -, R 1 S(O)-, R 1 SO 2 NH-, or -LCOY; a 4 to 5 membered cyclic heteroalkyl containing 1-3 heteroatoms that independently are N, O or S wherein said 4 to 5 membered cyclic heteroalkyl is optionally substituted with 1 to 2 substituents that independently are halogen, R 1 , fluorinated Ci-ioalkyl, amino,
  • R 1 HO, R 1 O-, R 1 S-, -NH 2 , R 1 NH-, or (R 1 ) 2 N-; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
  • Ci ⁇ (where a and b are integers) refers to a radical containing from a to h carbon atoms inclusive.
  • Ci -3 denotes a radical containing 1 , 2 or 3 carbon atoms.
  • “Fluorinated alkyl” refers to a saturated branched or straight chain hydrocarbon radical derived by removal of 1 hydrogen atom from the parent alkane; the parent alkane contains from 1 to 6 carbon atoms with 1 or more hydrogen atoms substituted with fluorine atoms up to and including substitution of all hydrogen atoms with fluorine.
  • Preferred fluorinated alkyls include trifluoromethyl substituted alkyls and perfluorinated alkyls; more preferred fluorinated alkyls include trifluoromethyl, perfluoroethyl, 2,2,2- trifluoroethyl, perfluoropropyl, 3,3,3-trifluoroprop-1-yl, 3,3.3-trifluoroprop-2-yl, 1,1 ,1 ,3,3,3-hexafluoroprop-2-yl; a particularly preferred fluorinated alkyl is trifluoromethyl.
  • Fluorinated alkanyloxy refers to a radical derived from a fluorinated alkyl radical attached to an oxygen atom with the oxygen atom having one open valence for attachment to a parent structure.
  • Alkyl refers to a saturated or unsaturated, branched, straight-chain or cyclic monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene or alkyne.
  • Typical alkyl groups include, but are not limited to, methyl; ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl, propan-2-yl , cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl, cycloprop-1-en-1-yl; cycloprop- 2-en-1-yl, prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, but-1- en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, buta-1,3
  • alkanyl alkenyl
  • alkynyl alkynyl
  • alkanyl refers to a saturated branched, straight-chain or cyclic monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane.
  • Typical alkanyl groups include, but are not limited to, methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl, cyclopropan-1-yl, etc.; butyanyls such as butan-1-yl, butan-2-yl, 2-methyl- propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, etc.; and the like.
  • the alkanyl groups are (Ci -8 ) alkanyl, with (C 1 - 3 ) being particularly preferred.
  • Alkenyl refers to an unsaturated branched, straight-chain or cyclic monovalent hydrocarbon radical having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene.
  • the radical may be in either the cis or trans conformation about the double bond(s).
  • alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl, prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such as but- 1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1 ,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-i-en-3-yl, cyclobuta-1 ,3-dien-1-yl, etc.; and the like.
  • the alkenyl group is (C 2-S ) alkenyl, with (C
  • Alkvnyl refers to an unsaturated branched, straight-chain or cyclic monovalent hydrocarbon radical having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne.
  • Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.
  • the alkynyl group is (C 2-8 ) alkynyl, with (C-2- 3 ) being particularly preferred.
  • Alkyldiyl refers to a saturated or unsaturated, branched, straight-chain or cyclic divalent hydrocarbon radical derived by the removal of one hydrogen atom from each of two different carbon atoms of a parent alkane, alkene or alkyne, or by the removal of two hydrogen atoms from a single carbon atom of a parent alkane, alkene or alkyne.
  • the two monovalent radical centers can form bonds with the same or different atoms.
  • Typical alkyldiyls include, but are not limited to methandiyl; ethyldiyls such as ethan-1 ,1-diyl, ethan-1 ,2-diyl, ethen-1 ,1-diyl, ethen-1 ,2-diyl; propyldiyls such as propan-1 ,1-diyl, propan-1 ,2- diyl, propan-2,2-diyl, propan-1 ,3-diyl, cyclopropan-1 ,1-diyl, cyclopropan-1 ,2- diyl, prop-1-en-1 ,1-diyl, prop-1-en-1 ,2-diyl, prop-2-en-1 ,2-diyl, prop-1-en-1 ,3- diyl, cycloprop-1-en-1 ,2-diyl, cycloprop-1 ,2-diyl, prop-1-en-1
  • alkandiyl alkendiyl and/or alkyndiyl
  • the alkyldiyl group is (Ci- ⁇ ) alkyldiyl, with (Ci -8 ) being particularly preferred.
  • saturated acyclic alkandiyl radicals in which the radical centers are at the terminal carbons e.g., methandiyl; ethan-1 ,2-diyl; propan-1 ,3-diyl; butan-1 ,4-diyl; and the like (also referred to as alkylenos, as defined infra).
  • Vic Alkyldiyl refers to a saturated or unsaturated, branched, straight-chain or cyclic hydrocarbon radical having two adjacent monovalent radical centers derived by the removal of one hydrogen atom from each of two adjacent carbon atoms of a parent alkane, alkene or alkyne. The two monovalent radical centers can form bonds with the same or different atom(s).
  • Typical vie alkyldiyls include, but are not limited to vie ethyldiyls such as ethan-1 ,2-diyl, ethen-1 ,2-diyl; vie propyldiyls such as propan-1 ,2-diyl, cyclopropan-1 ,2-diyl, prop-1 -en-1 ,2-diyl, prop-2-en-1 ,2-diyl, cycloprop-1 -en-1 ,2-diyl, etc.; vie butyldiyls such as butan-1 ,2-diyl, 2-methyl-propan-1 ,2-diyl, cyclobutan-1 ,2- diyl, but-1 -en-1 ,2-diyl, cyclobut-1 -en-1 ,2-diyl, buta-1 ,3-dien-1 ,2-diyl, cyclobuta- 1 ,3-dien-1 ,2-d
  • vie alkandiyl vie alkendiyl and/or vie alkyndiyl
  • the vie alkyldiyl group is (C-2-8) vie alkyldiyl, with (C2-3) being particularly preferred.
  • Gem Alkyldiyl refers to a saturated or unsaturated, branched, straight-chain or cyclic hydrocarbon radical having one divalent radical center derived by the removal of two hydrogen atoms from a single carbon atom of a parent alkane, alkene or alkyne. The divalent radical center forms bonds with two different atoms.
  • Typical gem alkyldiyls include, but are not limited to gem methanyldiyl; gem ethyldiyls such as ethan-1 ,1-diyl,ethen-1 ,1-diyl; gem propyldiyls such as propan-1 ,1-diyl, propan-2,2-diyl, cyclopropan-1 ,1-diyl, prop-1-en-1 ,1-diyl, cycloprop-2-en-1 ,1-diyl, prop-2-yn-1 ,1-diyl, etc.; butyldiyls such as butan-1 ,1-diyl, butan-2,2-diyl, 2-methyl-propan-1 ,2-diyl, cyclobutan- 1 ,1-diyl, but-1-en-1 ,1-diyl, 2-methyl-prop-1-en-1 ,1-di
  • the nomenclature gem alkandiyl, gem alkendiyl and/or gem alkyndiyl is used.
  • the gem alkyldiyl group is (C-i-e) gem alkyldiyl, with (C 1 - 3 ) being particularly preferred.
  • Alkyleno refers to a saturated or unsaturated, straight-chain or branched acyclic bivalent hydrocarbon bridge radical derived by the removal of one hydrogen atom from each of the two terminal carbon atoms of an acyclic parent alkane, alkene or alkyne.
  • Typical alkyleno groups include, but are not limited to, methano; ethylenos such as ethano, etheno, ethyno; propylenos such as propano, propeno, prop-1,2-dieno, propyno, etc.; butylenos such as butano, 2-methyl-propano, but-1-eno, but-2-eno, 2-methyl-prop-1-eno, 2- methanylidene-propano, but-1 ,3-dieno, but-1-yno, but-2-yno, but-1 ,3-diyno, etc.; and the like.
  • alkano alkeno and/or alkyno
  • the alkyleno group is (d-s) alkyleno, with (C 1 - 3 ) being particularly preferred.
  • straight-chain saturated alkano radicals e.g., methano, ethano, propano, butano, and the like.
  • Alkylidene: refers to a saturated or unsaturated, branched, straight-chain or cyclic divalent hydrocarbon radical derived by removal of two hydrogen atoms from the same carbon atom of a parent alkane, alkene or alkyne.
  • Typical alkylidene radicals include, but are not limited to, methanylidene, ethylidenes such as ethanylidene, ethenylidene; propylidenes such as propan-1-ylidene, propan-2-ylidene, cyclopropan-1-ylidene, prop-1-en-1-ylidene, prop-2-en-1- ylidene, cycloprop-2-en-1-ylidene, etc.; butylidenes such as butan-1-ylidene, butan-2-ylidene, 2-methyl-propan-1-ylidene, cyclobutan-1-ylidene, but-1-en-1- ylidene, but-2-en-1-ylidene, but-3-en-1-ylidene, buta-1 ,3-dien-1-ylidene; cyclobut-2-en-1-yliden
  • alkanylidene alkenylidene and/or alkynylidene
  • the alkylidene group is (Ci -8 ) alkylidene, with (C- 1 - 3 ) being particularly preferred.
  • acyclic saturated alkanylidene radicals in which the divalent radical is at a terminal carbon e.g., methanylidene, ethan-1 -ylidene, propan-1-ylidene, butan-1- ylidene, 2-methyl-propan-1 -ylidene, and the like.
  • Alkylidvne refers to a saturated or unsaturated, branched or straight-chain trivalent hydrocarbon radical derived by removal of three hydrogen atoms from the same carbon atom of a parent alkane, alkene or alkyne.
  • the trivalent radical center forms a triple bond with a single atom.
  • Typical alkylidyne radicals include, but are not limited to, methanylidyne; ethanylidyne; propylidynes such as propan-1-ylidyne, prop-2-en-1-ylidyne, prop-2-yn-1-ylidyne; butylidynes such as butan-1-ylidyne, 2-methyl-propan-1 - ylidyne, but-2-en-1-ylidyne, but-3-en-1 -ylidyne, buta-2,3-dien-1-ylidyne, but-2- yn-1-ylidyne, but-3-yn-1 -ylidyne, etc.; and the like.
  • alkanylidyne alkenylidyne and/or alkynylidyne
  • alkylidyne group is (C-i-s) alkylidyne, with (C ⁇ 3 ) being particularly preferred.
  • saturated alkanylidyne radicals e.g., methanylidyne, ethanylidyne, propan-1- ylidyne, butan-1-ylidyne, 2-methyl-propan-1 -ylidyne, and the like.
  • Heteroalkyl Heteroalkanyl, Heteroalkenyl.
  • Parent aromatic ring system refers to an unsaturated cyclic or polycyclic ring system having a conjugated ⁇ electron system. Specifically included within the definition of "parent aromatic ring system” are fused ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as, for example, indane, indene, phenalene, etc.
  • Typical parent aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like
  • Aryl: refers to a monovalent aromatic
  • Typical aryl groups include, but are not limited to, radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like.
  • the aryl include,
  • Arylalkyl refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal carbon atom, is replaced with an aryl radical.
  • Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2- naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like.
  • the arylalkyl group is (C- 6 -26) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (Ci- ⁇ ) and the aryl moiety is (C 5 - 2 o)-
  • the arylalkyl group is (C 6 -i 3 ), e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (Ci- 3 ) and the aryl moiety is (C 5 - 10 ).
  • Even more preferred arylalkyl groups are phenylalkanyls.
  • alkanyloxy refers to a saturated branched, straight-chain or cyclic monovalent hydrocarbon alcohol radical derived by the removal of the hydrogen atom from the hydroxide oxygen of the alcohol.
  • Typical alkanyloxy groups include, but are not limited to, methanyl; ethanyloxy; propanyloxy groups such as propan-1 -yloxy (CH 3 CH 2 CH 2 O-), propan-2-yloxy ((CH 3 ) 2 CHO- -), cyclopropan-1 -yloxy, etc.; butyanyloxy groups such as butan-1 -yloxy, butan-2-yloxy, 2-methyl-propan-1-yloxy, 2-methyl-propan-2-yloxy, cyclobutan- 1-yloxy, etc.; and the like.
  • the alkanyloxy groups are (C-i-s) alkanyloxy groups, with (C 1 - 3 ) being particularly preferred.
  • Parent Heteroaromatic Ring System refers to a parent aromatic ring system in which one or more carbon atoms are each independently replaced with a heteroatom. Typical heteratoms to replace the carbon atoms include, but are not limited to, N, P, O, S, Si etc. Specifically included within the definition of "parent heteroaromatic ring systems" are fused ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as, for example, arsindole, chromane, chromene, indole, indoline, xanthene, etc.
  • Typical parent heteroaromatic ring systems include, but are not limited to, arsindole, carbazole, ⁇ -carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thi
  • Heteroaryl refers to a monovalent heteroaromatic radical derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system.
  • Typical heteroaryl groups include, but are not limited to, radicals derived from acridine, arsindole, carbazole, ⁇ -carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyri
  • the heteroaryl group is a 5-20 membered heteroaryl, with 5-10 membered heteroaryl being particularly preferred.
  • Specific preferred heteroaryls for the present invention are quinoline, isoquinoline, pyridine, pyrimidine, furan, thiophene and imidazole.
  • Substituted: refers to a radical in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).
  • each X is independently a halogen (preferably -F, -Cl or -Br) and each R is independently -H, alkyl, alkanyl, alkenyl, alkynyl, alkylidene, alkylidyne, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl or heteroaryl-heteroalkyl, as defined herein.
  • halogen preferably -F, -Cl or -Br
  • Preferred substituents include hydroxy ⁇ halogen, Ci -8 alkyl, Ci -8 alkanyloxy, fluorinated alkanyloxy, fluorinated alkyl, C-i-salkylthio, Cs-scycloalkyl, Ca- ⁇ cycloalkanyloxy, nitro i amino i Ci-salkylamino, C-i- ⁇ dialkylamino, C 3-8 cycloalkylamino i CyBnO 1 carboxy, Ci -7 alkanyloxycarbonyl, Ci -7 alkylcarbonyloxy, formyl, carbamoyl, phenyl, aroyl, carbamoyl, amidino, (Ci- 8 alkylamino)carbonyl, (arylamino)carbonyl and aryl(Ci- 8 alkyl)carbonyl,
  • Aroyl refers to arylacyl substituents.
  • Acyl refers to alkylcarbonyl substituents.
  • a "phenylCi- ⁇ alkanylaminocarbonylCi. 6 alkyl" substituent refers to a group of the formula alkanyl
  • the invention is directed to compounds of formula (I)
  • HET is a heteroaryl selected from the group consisting of 1 ,3-dihydro-benzoimidazol-2-one-5-yl, 3,4-dihydro-2h-benzo[1 ,4]oxazine, 1 ,2,3,4-tetrahydro-[1 ,8]naphthyridine, 1 h-pyrrolo[2,3-b]pyridine, benzo[b]thiophene-4-yl, benzo[b]thiophene-5-yl, benzo[b]thiophene-6-yl, benzo[b]thiophene-7-yl, benzo[b]furan-4-yl, benzo[b]furan-5-yl, benzo[b]furan-6-yl, benzo[b]furan-7-yl, 4h-quinazoline-1 -yl, 4h-quinazoline-2-yl, 4h-quinazoline-3-yl, quinazoline-2-
  • Ar is an aryl selected from the group consisting of benzo[b]thiophenyl, naphthyl, biphenyl, isoquinolinyl, thiophenyl, pyridazinyl, and benzothiazolyl; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
  • the present invention is directed to compounds of formula (I) wherein HET is a heteroaryl selected from the group consisting of 1 ,3-dihydro-benzoimidazol-2-one-5-yl,
  • Ar is an aryl selected from the group consisting of benzo[b]thiophenyl, naphthalenyl, biphenyl, quinolinyl, isoquinolinyl, thiophenyl, pyrimidinyl, pyridaziny
  • the present invention is directed to compounds of formula (I) wherein HET is a heteroaryl selected from the group consisting of 1,3-dihydro-benzoimidazol-2-one-5-yl, 3,4-dihydro-2h-benzo[1 ,4]oxazine,
  • Ar is an aryl selected from the group consisting of thiophenyl, pyrimidinyl, pyridazinyl, phenyl, benzothiazole, and pyridinyl;and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
  • the present invention is directed to compounds of formula (I) wherein
  • HET is a heteroaryl selected from the group consisting of 1 ,3-dihydro-benzoimidazol-2-one-5-yl, 3,4-dihydro-2h-benzo[1 ,4]oxazine, 1 ,2,3,4-tetrahydro-[1 ,8]naphthyridine, 1h-pyrrolo[2,3-b]pyridine, benzo[b]thiophene-4-yl, benzo[b]thiophene-5-yl, benzo[b]thiophene-6-yl, benzo[b]thiophene-7-yl, 4h-quinazoline-1 -yl, 4h-quinazoline-2-yl, 4h-quinazoline-3-yl, quinazoline-2-yl, quinoxaline-2-yl, pteridine, carbazole, acridine, phenazine, pyrrole, thiazole-2-yl, thi
  • Ar is an aryl selected from the group consisting of phenyl, benzothiazole, and pyridinyl; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
  • the present invention is directed to compounds of formula (I) wherein
  • HET is a phthalazine-4-yl, isoindole-4-yl, isoindole-5-yl, isoindole-6-yl, isoindole-7-yl, ih-indazole-4-yl, ih-indazole-5-yl, ih-indazole-6-yl, ih-indazole-7-yl, purine-2-yl, purine-6-yl, purine-8-yl, benzimidazole-4-yl, benzimidazole-5-yl, benzimidazole-6-yl, benzimidazole-7-yl, cinnoline-4-yl, cinnoline-7-yl, cinnoline-8-yl, quinoxaline-5-yl, quinoxaline-6-yl, 2,7-naphthyridine-2-yl, pyrazine-2-yl,
  • Ar is an aryl selected from the group consisting of benzo[b]thiophenyl, naphthyl, biphenyl, isoquinolinyl, thiophenyl, pyridazinyl, and benzothiazolyl; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
  • the present invention is directed to compounds of formula (I) wherein HET is a heteroaryl selected from the group consisting of quinoline-2-yl, quinoline-3-yl, quinoline-4-yl, indoline-4-yl, indoline-5-yl, indoline-6-yl, indoline-7-yl, isoquinoline-1-yl, isoquinoline-3-yl, isoquinoline-4-yl, cinnoline-3-yl, cinnoline-5-yl, cinnoline-6-yl, phthalazine-5-yl, phthalazine-6-yl, quinazoline-4-yl, quinazoline-5-yl, quinazoline-6-yl, quinazoline-8-yl, 1 ,6-naphthyridine-2-yl, 1 ,6-naphthyridine-3-yl, 1 ,6-naphthyridine
  • Ar is an aryl selected from the group consisting of benzo[b]thiophenyl, naphthyl, biphenyl, isoquinolinyl, thiophenyl, pyridazinyl, and benzothiazolyl; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
  • the present invention is directed to compounds of formula (I) wherein HET is a heteroaryl selected from the group consisting of 1 ,3-dihydro-benzoimidazol-2-one-5-yl,
  • Ar is an aryl selected from the group consisting of benzo[b]thiophenyl, naphthalenyl, biphenyl, quinolinyl, isoquinolinyl, thiophenyl, pyrimidinyl, pyridazinyl, phenyl, benzothiazolyl, and pyridinyl; provided that when HET is benzimidazolyl, Ar is not pyrimidinyl or phenyl; and provided that when HET is pyrazolyl, Ar is not phenyl; and provided that when het is benzofuranyl, Ar is not pyridinyl; and provided that when het is benzothiazolyl, Ar is not pyrimidinyl; and provided that when HET is isoquinolinyl, Ar is not pyridinyl; and provided that when HET is pyridinyl, Ar is not pyrimidinyl, pyridinyl, or phenyl
  • the present invention is directed to compounds of formula (I) wherein HET is a heteroaryl selected from the group consisting of 1 ,3-dihydro-benzoimidazol-2-one-5-yl, 3,4-dihydro-2h-benzo[1 ,4]oxazine,
  • Ar is an aryl selected from the group consisting of thiophenyl, pyrimidinyl, pyridazinyl, phenyl, benzothiazolyl, and pyridinyl; provided that when HET is benzimidazolyl, Ar is not pyrimidinyl or phenyl; and provided that when HET is pyrazolyl, Ar is not phenyl; and provided that when
  • HET is benzofuranyl, Ar is not pyridinyl; and provided that when HET is benzothiazolyl, Ar is not pyrimidinyl; and provided that when HET is isoquinolinyl, Ar is not pyridinyl; and provided that when HET is pyridinyl, Ar is not pyrimidinyl, pyridinyl or phenyl; and provided that when HET is pyridinyl, Ar is not phenyl, pyridinyl; and provided that when HET is quinolinyl, Ar is not pyrimidinyl; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
  • the present invention is directed to compounds of formula (I) wherein HET is a heteroaryl selected from the group consisting of 1 ,3-dihydro-benzoimidazol-2-one-5-yl, 3,4-dihydro-2h-benzo[1 ,4]oxazine, 1 ,2,3,4-tetrahydro-[1 ,8]naphthyridine, 1 h-pyrrolo[2,3-b]pyridine, benzo[b]thiophene-4-yl, benzo[b]thiophene-5-yl, benzo[b]thiophene-6-yl, benzo[b]thiophene-7-yl, benzo[b]furan-4-yl, benzo[b]furan-5-yl, benzo[b]furan-6-yl, benzo[b]furan-7-yl, 4h-quinazoline-1-yl, 4h-quinazoline-2-yl, 4h-quin
  • Ar is an aryl selected from the group consisting of phenyl, benzothiazole, and pyridine; provided that when HET is pyrazolyl, Ar is not phenyl; and provided that when HET is benzimidazolyl, Ar is not phenyl; and provided that when HET is benzofuranyl, Ar is not pyridinyl; and provided that when HET is isoquinolinyl, Ar is not pyridinyl; and provided that when HET is pyridinyl, Ar is not pyridinyl or phenyl
  • the present invention is directed to compounds of formula (I) wherein HET is a heteroaryl selected from the group consisting of phthalazine-4-yl, isoindole-4-yl, isoindole-5-yl, isoindole-6-yl, isoindole-7-yl, ih-indazole-4-yl, ih-indazole-5-yl, ih-indazole-6-yl, ih-indazole-7-yl, purine-2-yl, purine-6-yl, purine-8-yl, benzimidazole-4-yl, benzimidazole-5-yl, benzimidazole-6-yl, benzimidazole-7-yl, cinnoline-4-yl, cinnoline-7-yl, cinnoline-8-yl, quinoxaline-5-yl, quinoxaline-6-yl,
  • Ar is an aryl selected from the group consisting of benzo[b]thiophenyl, naphthalenyl, biphenyl, quinolinyl, isoquinolinyl, thiophenyl, pyrimidinyl, pyridazinyl, phenyl, benzothiazolyl, and pyridinyl;
  • the present invention is directed to compounds of formula (I) wherein
  • HET is a heteroaryl selected from the group consisting of phthalazine-4-yl, isoindole-4-yl, isoindole-5-yl, isoindole-6-yl, isoindole-7-yl, ih-indazole-4-yl, ih-indazole-5-yl, ih-indazole-6-yl, ih-indazole-7-yl, purine-2-yl, purine-6-yl, purine-8-yl, benzimidazole-4-yl, benzimidazole-5-yl, benzimidazole-6-yl, benzimidazole-7-yl, cinnoline-4-yl, cinnoline-7-yl, cinnoline-8-yl, quinoxaline-5-yl, quinoxaline-6-yl, 2,7-naphthyridine-2-yl,
  • Ar is an aryl selected from the group consisting of thiophenyl, pyrimidinyl, pyridazinyl, phenyl, benzothiazolyl, and pyridinyl; provided that when
  • HET is benzimidazolyl, Ar is not pyrimidinyl or phenyl; and provided that when HET is benzothiazolyl, Ar is not pyrimidinyl; and provided that when HET is isoquinolin-5-yl, Ar is not pyridinyl; and provided that when HET is pyridinyl, Ar is not pyrimidinyl, pyridinyl, or phenyl;and provided that when HET is quinolinyl, Ar is not pyrimidinyl; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
  • the present invention is directed to compounds of formula (I) wherein HET is a heteroaryl selected from the group consisting of phthalazine-4-yl, isoindole-4-yl, isoindole-5-yl, isoindole-6-yl, isoindole-7-yl, ih-indazole-4-yl, ih-indazole-5-yl, ih-indazole-6-yl, ih-indazole-7-yl, purine-2-yl, purine-6-yl, purine-8-yl, benzimidazole-4-yl, benzimidazole-5-yl, benzimidazole-6-yl, benzimidazole-7-yl, cinnoline-4-yl, cinnoline-7-yl, cinnoline-8-yl, quinoxaline-5-yl, quinoxaline-6-yl,
  • Ar is an aryl selected from the group consisting of phenyl, benzothiazole, and pyridine; provided that when HET is benzimidazolyl, Ar is not phenyl; and provided that when HET is isoquinolinyl, Ar is not pyridinyl; and provided that when HET is pyridinyl, Ar is not pyridinyl or phenyl; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
  • the present invention is directed to compounds of formula (I) wherein HET is a heteroaryl selected from the group consisting of quinoline-2-yl, quinoline-3-yl, quinoline-4-yl, indoline-4-yl, indoline-5-yl, indoline-6-yl, indoline-7-yl, isoquinoline-1-yl, isoquinoline-3-yl, isoquinoline-4-yl, cinnoline-3-yl, cinnoline-5-yl, cinnoline-6-yl, phthalazine-5-yl, phthalazine-6-yl, quinazoIine-4-yl, quinazoline-5-yl, quinazoline-6-yl, quinazoline-8-yl, 1 ,6-naphthyridine-2-yl, 1 ,6-naphthyridine-3-yl, 1 ,6-naph
  • Ar is an aryl selected from the group consisting of benzo[b]thiophenyl, naphthalenyl, biphenyl, quinolinyl, isoquinolinyl, thiophenyl, pyrimidinyl, pyridazinyl, phenyl, benzothiazolyl, and pyridinyl; provided that when HET is benzothiazolyl, Ar is not pyrimidiny; and provided that when HET is isoquinolinyl, Ar is not pyridinyl; and provided that when HET is pyridinyl, Ar is not pyrimidinyl, pyridinyl, or phenyl; and provided that when HET is quinolinyl, Ar is not pyrimidinyl; and provided that when HET is thiazolyl, Ar is not quinolinyl; and provided that when HET is thiazolyl, Ar is not quinolinyl; and enantiomers, diaste
  • the present invention is directed to compounds of formula (I) wherein
  • HET is a heteroaryl selected from the group consisting of quinoline-2-yl, quinoline-3-yl, quinoline-4-yl, indoline-4-yl, indoline-5-yl, indoline-6-yl, indoline-7-yl, isoquinoline-1-yl, isoquinoline-3-yl, isoquinoline-4-yl, cinnoline-3-yl, cinnoline-5-yl, cinnoline-6-yl, phthalazine-5-yl, phthalazine-6-yl, quinazoline-4-yl, quinazoline-5-yl, quinazoline-6-yl, quinazoline-8-yl, 1 ,6-naphthyridine-2-yl, 1 ,6-naphthyridine-3-yl, 1 ,6-naphthyridine-4-yl, 1 ,6-naph
  • Ar is an aryl selected from the group consisting of thiophenyl, pyrimidinyl, pyridazinyl, phenyl, benzothiazolyl, and pyridinyl; provided that when
  • HET is isoquinolinyl, Ar is not pyridinyl; and provided that when HET is pyridinyl, Ar is not pyridinyl, phenyl, 2-quinazolinyl, 5-quinoxalinyl or pyrimidinyl; and provided that when HET is quinolinyl, Ar is not pyrimidinyl; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
  • the present invention is directed to compounds of formula (I) wherein HET is a heteroaryl selected from the group consisting of quinoline-2-yl, quinoline-3-yl, quinoline-4-yl, indoline-4-yl, indoline-5-yl, indoline-6-yl, indoline-7-yl, isoquinoline-1-yl, isoquinoline-3-yl, isoquinoline-4-yl, cinnoline-3-yl, cinnoline-5-yl, cinnoline-6-yl, phthalazine-5-yl, phthalazine-6-yl, quinazoline-4-yl, quinazoline-5-yl, quinazoline-6-yl, quinazoline-8-yl, 1 ,6-naphthyridine-2-yl, 1 ,6-naphthyridine-3-yl,
  • Ar is an aryl selected from the group consisting of phenyl, benzothiazolyl, and pyridinyl; provided that when HET is isoquinolinyl, Ar is not pyridinyl; and provided that when HET is pyridinyl, Ar is not pyridinyl or phenyl; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
  • the present invention is directed to compounds of formula (II)
  • Ar is an aryl selected from the group consisting of benzo[b]thiophenyl, naphthyl, biphenyl, isoquinolinyl, thiophenyl, pyridazinyl, and benzothiazolyl;
  • Z is O or S;
  • R 2 is hydrogen or Ci -6 alkyl optionally substituted with -OR 4 ; n is 1 or 2;
  • R 3 is independently hydrogen, Ci -6 alkyl, -COOR 4 , Or -CH 2 COOR 4 ;
  • R 4 is hydrogen or Ci_ 3 alkyl; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
  • the present invention is directed to compounds of formula (II) wherein Z is O and n is 1. In another embodiment, the present invention is directed to compounds of formula (II) wherein Z is O and R 2 is hydrogen.
  • the present invention is directed to compounds of formula (III):
  • R is independently selected from the group consisting of halogen; R 1 ; fluorinated C- M oalkyl; phenyl; amino; cyano; CF 3 O-; a 3 membered cyclic heteroalkyl containing 1 heteroatom that is N, O or S wherein said 3 membered cyclic heteroalkyl is optionally substituted with a substituent that is halogen, R 1 , fluorinated Ci_i O alkyl, amino, cyano, CF 3 O-, R 1 O-, R 1 S-, R 1 SO 2 -, R 1 S(O)-, R 1 SO 2 NH-, or -LCOY; a 4 to 5 membered cyclic heteroalkyl containing 1-3 heteroatoms that independently are N, O or S wherein said 4 to 5 membered cyclic heteroalkyl is optionally substituted with 1 to 2 substituents that independently are halogen, R 1 , fluorinated C- I- l oalky
  • heteroaryl wherein said heteroaryl is cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, pthalazine, pteridine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinoline, quinolizine, quinazoline, quinoxaline, tetrazole, thiadiazole, triazine, or triazole wherein said heteroaryl
  • R 1 is C 1-10 alkyl
  • L is -NH-, a direct bond, -O-, or -CH 2 -;
  • Y is H, R 1 , HO, R 1 O-, R 1 S-, -NH 2 , R 1 NH-, or (R 1 ) 2 N-;
  • Z is O or S;
  • R 2 is hydrogen or C 1-6 alkyl optionally substituted with -OR 4 ; n is 1 or 2;
  • R 3 is independently hydrogen, Ci -6 alkyl, -COOR 4 , Or -CH 2 COOR 4 ;
  • R 4 is hydrogen or C h alky!; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
  • the present invention is directed to compounds of formula (III) wherein Z is O and n is 1.
  • the present invention is directed to compounds of formula (III) wherein Z is O and R 2 is hydrogen.
  • the present invention is directed to compounds of formula (Ha):
  • Ar is an aryl selected from the group consisting of benzo[b]thiophenyl, naphthyl, biphenyl, isoquinolinyl, thiophenyl, pyridazinyl, and benzothiazolyl; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
  • the present invention is directed to compounds of formula (Ilia):
  • R is independently selected from the group consisting of halogen; R 1 ; fluorinated C-i-ioalkyl; phenyl; amino; cyano; CF 3 O-; a 3 membered cyclic heteroalkyl containing 1 heteroatom that is N, O or S wherein said 3 membered cyclic heteroalkyl is optionally substituted with a substituent that is halogen, R 1 , fluorinated Ci_ioalkyl, amino, cyano, CF 3 O-, R 1 O-, R 1 S-, R 1 SO 2 -, R 1 S(O)-, R 1 SO 2 NH-, or -LCOY; a 4 to 5 membered cyclic heteroalkyl containing 1-3 heteroatoms that independently are N, O or S wherein said 4 to 5 membered cyclic heteroalkyl is optionally substituted with 1 to 2 substituents that independently are halogen, R 1 , fluorinated C- M oalkyl,
  • the present invention is directed to compounds of formula (Ilia) wherein X is CH.
  • the present invention is directed to compounds of formula (Ilia) wherein m is 1 or 2.
  • the present invention is directed to compounds of formula (Ilia) wherein R is independently Ci -4 alkanyl, CF 3 , or halo.
  • the present invention is directed to compounds of formula (Ilia) wherein X is CH, m is 1 or 2 and R is independently Ci -4 alkanyl, CF 3 , or halo.
  • HET is optionally substituted at 1-3 substitutable atoms with a substituent that is independently selected from the group consisting of hydroxyl; R 1 ; R 1 O-; R 1 S-; CF 3 O-; R 1 S(O)-; R 1 SO 2 -; -LCOY; C 6-10 aryl; a 3 to 7 membered cyclic heteroalkanyl containing from 1 to 3 heteroatoms wherein said heteroatoms independently are N, O or S; and a 5 to 10 membered heteroaryl selected from the group consisting of benzofuran, benzimidazole, benzisoxazole, benzthiazole, benzothiophene, benzoxazole, cinnoline, furan, imidazole, imidazoline, indazole, indole, indoline, indolizine, isobenzofuran, isoindole, isoindoline, isoquinoline, isothiazole, iso
  • the present invention is directed to a compound selected from the group consisting of
  • the present invention is directed to a compound selected from the group consisting of
  • the present invention is directed to a compound selected from the group consisting of 1 -(2,3-Dimethyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide;
  • the present invention is directed to a compound selected from the group consisting of 1 -(2,3-Dimethyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide;
  • the present invention is directed to a compound selected from the group consisting of
  • the compounds of the present invention may also be present in the form of pharmaceutically acceptable salts.
  • the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts" (Ref. International J. Pharm., 1986, 33, 201-217; J. Pharm.Sci., 1997 (Jan), 66, 1, 1 ).
  • Other salts well known to those in the art may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts.
  • organic or inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic ortrifluoroacetic acid.
  • Organic or inorganic bases include, but are not limited to, basic or cationic salts such as benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
  • basic or cationic salts such as benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
  • the present invention includes within its scope prodrugs of the compounds of this invention.
  • prodrugs will be functional derivatives of the compounds that are readily convertible in vivo into the required compound.
  • the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • the compounds according to this invention may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
  • the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers
  • these isomers may be separated by conventional techniques such as preparative chromatography.
  • the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • the compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base.
  • the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
  • any of the processes for preparation of the compounds of the present invention it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • the compounds of the present invention can be administered alone, they will generally be administered in admixture with a pharmaceutical carrier, excipient or diluent selected with regard to the intended route of administration and standard pharmaceutical or veterinary practice.
  • a pharmaceutical carrier excipient or diluent selected with regard to the intended route of administration and standard pharmaceutical or veterinary practice.
  • the present invention is directed to pharmaceutical and veterinary compositions comprising compounds of Formula (I) and one or more pharmaceutically acceptable carriers, excipients or diluents.
  • the compounds of the present invention may be admixed with any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), and/or solubilising agent(s). Tablets or capsules of the compounds may be administered singly or two or more at a time, as appropriate. It is also possible to administer the compounds in sustained release formulations.
  • the compounds of Formula (I) can be administered by inhalation or in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.
  • An alternative means of transdermal administration is by use of a skin patch.
  • they can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin. They can also be incorporated, at a concentration of between 1 and 10% by weight, into an ointment consisting of a white wax or white soft paraffin base together with such stabilizers and preservatives as may be required.
  • compositions are administered orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavoring or coloring agents.
  • excipients such as starch or lactose
  • capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavoring or coloring agents.
  • compositions can also be injected parenterally, for example intracavernosally, intravenously, intramuscularly or subcutaneously.
  • the compositions will comprise a suitable carrier or diluent.
  • compositions are best used in the form of a sterile aqueous solution which may contain other substances, for example enough salts or monosaccharides to make the solution isotonic with blood.
  • compositions may be administered in the form of tablets or lozenges which can be formulated in a conventional manner.
  • pharmaceutical and veterinary compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral).
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
  • Solid oral preparations may also be coated with substances such as sugars or be enteric-coated so as to modulate the major site of absorption.
  • the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation.
  • Injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives.
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those skilled in that art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • a therapeutically effective amount for use of the instant compounds or a pharmaceutical composition thereof comprises a dose range of from about 0.001 mg to about 1 ,000 mg, in particular from about 0.1 mg to about 500 mg or, more particularly from about 1 mg to about 250 mg of active ingredient per day for an average (70 kg) human.
  • a pharmaceutical composition is preferably provided in the form of tablets containing, 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
  • the therapeutically effective dose for active compounds of the invention or a pharmaceutical composition thereof will vary according to the desired effect. Therefore, optimal dosages to be administered may be readily determined and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the advancement of the disease condition.
  • compositions and dosage regimens may be administered in any of the foregoing compositions and dosage regimens or by means of those compositions and dosage regimens established in the art whenever use of the compounds of the invention as vanilloid receptor modulators is required for a subject in need thereof.
  • the invention also provides a pharmaceutical or veterinary pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical and veterinary compositions of the invention.
  • Optionally associated with such containers can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
  • the compounds of Formula (I) are useful in methods for treating or preventing a disease or condition in a mammal which disease or condition is affected by the modulation of one or more vanilloid receptors.
  • the compounds of Formula (I) are useful in methods for treating or preventing a disease or condition in a mammal which disease or condition is affected by the modulation of one or more vanilloid receptors. Such methods comprises administering to a mammal in need of such treatment or prevention a therapeutically effective amount of a compound, salt or solvate of Formula (I).
  • the compounds of Formula (I) are useful for in methods for preventing or treating a chronic- or acute-pain causing diseases or conditions and pulmonary dysfunction, and more particularly, in treating diseases or conditions that cause inflammatory pain, burning pain, itch or urinary incontinence, and chronic obstructive pulmonary disease.
  • the compounds of Formula (I) are useful for treating diseases and conditions selected from the group consisting of osteoarthritis, rheumatoid arthritis, fibromyalgia, migraine, headache, toothache, burn, sunburn, snake bite (in particular, venomous snake bite), spider bite, insect sting, neurogenic bladder, benign prostatic hypertrophy, interstitial cystitis, urinary tract infection, cough, asthma, chronic obstructive pulmonary disease, rhinitis, contact dermatitis/hypersensitivity, itch, eczema, anxiety, panic disorders, pharyngitis, mucositis, enteritis, cellulites, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, causalgia, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, bony fractures, post-operative
  • diseases and conditions selected
  • compositions comprising one or more of the compounds of Formula (I) While the present invention also comprises compositions comprising intermediates used in the manufacture of compounds of Formulae (I).
  • Example 1B Using the procedure outlined in Example 1B, the title compound was prepared from 3-aminoquinoline (0.087g, 0.60 mmol) and 1 -(3-trifluoromethyl-phenyl)- piperidine-4-carboxylic acid (0.055g, 0.2 mmol) as an off-white solid (0.024g).
  • Example 1 B Using the procedure outlined in Example 1 B, the title compound was prepared from 3-aminoquinoline (0.18, 1.3 mmol) and 1-biphenyl-3-yl-piperidine-4- carboxylic acid, (0.12g, 0.43 mmol) as an off-white solid (0.069g).
  • Example 1 B Using the procedure outlined in Example 1 B, the title compound was prepared from 3-aminoquinoline (0.15g , 1.0 mmol) and 1-(4-trifIuoromethyl-phenyl)- piperidine-4-carboxylic acid (0.095g, 0.35 mmol) as an off-white solid (0.075g).
  • Example 1B Using the procedure outlined in Example 1B, the title compound was prepared from 3-aminoquinoline (0.08g , 0.54 mmol) and 1-(2,3-dimethyl-phenyl)- piperidine-4-carboxylic acid (0.043g, 0.18 mmol) as an off-white solid (0.006g).
  • Example 1 B Using the procedure outlined in Example 1 B, the title compound was prepared from 3-aminoquinoline (0.193g, 1.3 mmol) and 1-(3,4-dimethyl-phenyl)- piperidine-4-carboxylic acid (0.104g, 0.45 mmol) as an off-white solid (O.OO ⁇ g).
  • Example 1B Using the procedure outlined in Example 1B, the title compound was prepared from 7-ethyladenine (0.119g , 0.73 mmol) and 1-(3-trifluoromethyl-phenyl)- piperidine-4-carboxylic acid (0.1Og, 0.40 mmol) as an off-white solid
  • Example 8 Using the procedure outlined in Example 8, the title compound was prepared from 6-aminobenzothiazole (0.008 g, 0.051 mmol) and 1-(3-trifluoromethyl- phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as an off-white solid.
  • Example 8 Using the procedure outlined in Example 8, the title compound was prepared from ethyl 3-amino-1H-indole-2-carboxylate (0.010 g, 0.051 mmol) and 1-(3- trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a light brown solid.
  • Example 8 Using the procedure outlined in Example 8, the title compound was prepared from 3,4-methylenedioxyaniline (0.006 g, 0.051 mmol) and 1-(3- trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a light brown solid.
  • Example 16 1-(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (1-acetyl-2,3-dihydro- 1 /-/-indol-6-yl)-amide
  • Example 1B Using the procedure outlined in Example 1B, the title compound was prepared from 1-acetyl-6-amino-2,3-dihydro(1H)-indole (0.009 g, 0.051 mmol) and 1-(3- trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as an off-white solid.
  • Example 1B Using the procedure outlined in Example 1B, the title compound was prepared from 5-aminooxindole (0.008 g, 0.051 mmol) and 1-(3-trifluoromethyl-phenyl)- piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as an off-white solid.
  • Example 1B Using the procedure outlined in Example 1B, the title compound was prepared from 3,4-ethylenedioxyaniline (0.008 g, 0.051 mmol) and 1-(3-trifluoromethyl- phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as an off-white solid.
  • Example 1 B Using the procedure outlined in Example 1 B, the title compound was prepared from 5-amino-2-methylbenzothiazole (0.008 g, 0.051 mmol) and 1-(3- trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a light brown solid.
  • Example 1B Using the procedure outlined in Example 1B, the title compound was prepared from 3-amino-5-nitrobenzoisothiazole (0.010 g, 0.051 mmol) and 1-(3- trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a light brown solid.
  • Example 1 B Using the procedure outlined in Example 1 B, the title compound was prepared from 4-aminoindole (0.007 g, 0.051 mmol) and 1 -(3-trifluoromethyl-phenyl)- piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a brown solid.
  • Example 1B Using the procedure outlined in Example 1B, the title compound was prepared from 5-aminoindole (0.007 g, 0.051 mmol) and 1 -(3-trifluoromethyl-phenyl)- piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a light brown solid.
  • Example 2 Using the procedure outlined in Example 1 , the title compound was prepared from 6-aminoindole (0.007 g, 0.051 mmol) and 1 -(3-trif luoromethyl-phenyl)- piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as an off-white solid.
  • Example 1 B Using the procedure outlined in Example 1 B, the title compound was prepared from 1 -methyl-1 H-indazol-5-amine (0.008 g, 0.051 mmol) and 1-(3- trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a light brown solid.
  • Example 1B Using the procedure outlined in Example 1B, the title compound was prepared from 5-amino-2-methoxypyridine (0.006 g, 0.051 mmol) and 1-(3- trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as an off-white solid.
  • Example 1B Using the procedure outlined in Example 1B, the title compound was prepared from 6-amino-2-mercaptobenzothiazole (0.009 g, 0.051 mmol) and 1-(3- trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as an off-white solid.
  • Example 1B Using the procedure outlined in Example 1B, the title compound was prepared from 3,4-dihydro-2H-1 ,5-benzodioxepin-7-amine (0.008 g, 0.051 mmol) and 1- (3-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a pale yellow solid.
  • Example 1B Using the procedure outlined in Example 1B, the title compound was prepared from 1-acetyl-5-amino-2,3-dihydro-(1H)indole (0.009 g, 0.051 mmol) and 1-(3- trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a white solid.
  • Example 1 B Using the procedure outlined in Example 1 B, the title compound was prepared from 7-aminoindole (0.007 g, 0.051 mmol) and 1 -(3-trifluoromethyl-phenyl)- piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a white solid.
  • Example 31 1 -(S-Trifluoromethyl-phenyO-piperidine ⁇ -carboxylic acid (1 ,4-dioxo-1 ,2,3,4- tetrahydro-phthalazin-6-yl)-amide
  • Example 1B Using the procedure outlined in Example 1B, the title compound was prepared from 6-phenoxy-3-pyridinamine (0.010 g, 0.051 mmol) and 1-(3- trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a brown solid.
  • Example 8 Using the procedure outlined in Example 8, the title compound was prepared from 6'-amino-3',4'-(methylenedioxy)acetophenone (0.009 g, 0.051 mmol) and 1-(3-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a yellow brown solid.
  • Example 8 Using the procedure outlined in Example 8, the title compound was prepared from 6-amino-2H-1 ,4-benzoxazin-3(4H)-one (0.008 g, 0.051 mmol) and 1-(3- trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a white solid.
  • Example 35 1 -(S-Trifluoromethyl-phenyO-piperidine- ⁇ carboxylic acid (4-dimethylamino-5- phenyl-pyrimidin-2-yl)-amide
  • Example 8 Using the procedure outlined in Example 8, the title compound was prepared from N 4 , N 4 -dimethyl-5-phenyl-2,4-pyrimidinediamine (0.011 g, 0.051 mmol) and 1-(3-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a pale yellow oil.
  • Example 8 Using the procedure outlined in Example 8, the title compound was prepared from ethyl 1 -(5-amino-2-pyridinyl)-3,5-dimethyl-1 H-pyrazole-4-carboxylate (0.013 g, 0.051 mmol) and 1-(3-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a pale brown solid.
  • Example 8 Using the procedure outlined in Example 8, the title compound was prepared from the above prepared amino product (0.008 g, 0.042 mmol) and 1-(3- trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.01 g, 0.038 mmol) as an off-white solid.
  • Example 8 Using the procedure outlined in Example 8, the title compound was prepared from 6-amino-2,3-dimethylpyrido(2,3-b)pyrazine (0.009 g, 0.051 mmol) and 1- (3-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as an yellow oil.
  • Example 8 Using the procedure outlined in Example 8, the title compound was prepared from 4,6-dimethyl-thieno[2,3 ⁇ b]pyridin-3-ylamine (0.009 g, 0.051 mmol) and 1- (3-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as an yellow oil.
  • Example 8 Using the procedure outlined in Example 8, the title compound was prepared from 5-(3,4-dimethoxyphenyl)-4-methyl-2-pyrimidinamine (0.013 g, 0.051 mmol) and 1-(3-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a white solid.
  • Example 8 Using the procedure outlined in Example 8, the title compound was prepared from 2-amino-4-phenoxy-6-methylpyrimidine (0.010 g, 0.051 mmol) and 1-(3- trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a white solid.
  • Example 8 Using the procedure outlined in Example 8, the title compound was prepared from 7-amino-2H-1 ,4-benzoxazin-3(4H)-one (0.008 g, 0.051 mmol) and 1-(3- trifluoromethyl-phenyI)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a white solid.
  • Example 8 Using the procedure outlined in Example 8, the title compound was prepared from 5-amino-6-methylaminoquinoxaline (0.009 g, 0.051 mmol) and 1-(3- trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a reddish yellow solid.
  • Example 8 Using the procedure outlined in Example 8, the title compound was prepared from 1-(4-amino-2,3-dihydro-indol-1-yl)-ethanone (0.009 g, 0.051 mmol) and 1-(3-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a white solid.
  • 1-(3-Trifluoromethyl-phenyl)-piperidine-4-carbonyl chloride was prepared from 1-(3-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid as described in Example 8A.
  • the title compound was prepared (0.012g) from thieno[2,3- d]pyrimidin-4-ylamine (0.33 mmol) and 1-(3-trifluoromethyl-phenyl)- piperidine-4-carbonyl chloride (0.33 mmol) using the procedure outlined in Example 8B.
  • 1-(3-Trifluoromethyl-phenyl)-piperidine-4-carbonyl chloride was prepared from 1-(3-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid as described in Example 8A.
  • the title compound was prepared (0.012g) from 3-methyl- benzo[d]isothiazol-5-ylamine (0.33 mmol) and 1 -(3-trifluoromethyl-phenyl)- piperidine-4-carbonyl chloride (0.33 mmol) using the procedure outlined in Example 8B.
  • Example 8B 1-(3-Trifluoromethyl-phenyl)-piperidine-4-carbonyl chloride was prepared from I ⁇ S-trifluoromethyl-phenyQ-piperidine ⁇ -carboxylic acid as described in Example 8A.
  • the title compound was prepared (0.012g) from 6-chloro-4- methyl-pyridazin-3-ylamine (0.33 mmol) and 1 -(3-trifluoromethyl-phenyl)- piperidine-4-carbonyl chloride (0.33 mmol) using the procedure outlined in Example 8B.
  • Example 8A The title compound was prepared (0.007g) from 1 H-indazol-7- ylamine (0.33 mmol) and 1-(3-trifluoromethyl-phenyl)-piperidine-4-carbonyl chloride (0.33 mmol) using the procedure outlined in Example 8B.
  • i-phenyl-piperidine-4-carboxylic acid is prepared from bromobenzene (4 mmol).
  • the title compound is prepared from 3-aminoquinoline (0.5 mmol) and i-phenyl-piperidine-4-carboxylic acid (0.18 mmol).
  • 1-benzothiazol-5-yl-piperidine-4- carboxylic acid is prepared from 5-bromobenzothiazole (4 mmol).
  • the title compound is prepared from 3- aminoquinoline (0.5 mmol) and 1-benzothiazol-5-yl-piperidine-4-carboxylic acid (0.20 mmol).
  • 1-benzothiazol-5-yl-piperidine-4- carboxylic acid is prepared from 5-bromobenzothiazole (4 mmol).
  • the title compound is prepared from 4- aminoindoline (0.5 mmol) and i-benzothiazol- ⁇ -yl-piperidine- ⁇ carboxylic acid (0.20 mmol).
  • i-phenyl-piperidine-4-carboxylic acid is prepared from bromobenzene (4 mmol).
  • the title compound is prepared from 4-aminoindoline (0.5 mmol) and 1-phenyl-piperidine-4-carboxylic acid (0.18 mmol).
  • i-phenyl-piperidine-4-carboxylic acid is prepared from bromobenzene (4 mmol).
  • the title compound is prepared from 1-aminoisoquinoline (0.5 mmol) and i-phenyl-piperidine ⁇ -carboxylic acid (0.18 mmol).
  • 1-phenyl-piperidine-4-carboxylic acid is prepared from bromobenzene (4 mmol).
  • the title compound is prepared from 3-aminocinnoline (0.5 mmol) and 1-phenyl-piperidine-4-carboxylic acid (0.18 mmol).
  • Example 1A 1-benzothiazol-5-yl-piperidine-4- carboxylic acid is prepared from 5-bromobenzothiazole (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 3- aminocinnoline (0.5 mmol) and i-benzothiazol- ⁇ -yl-piperidine ⁇ -carboxylic acid (0.20 mmol).
  • a solution of phthalazine (2.5g, 19.2 mmol) in concentrated sulfuric acid (30 ml_) is treated slowly with potassium nitrate (2g, 19.2 mmol). After 18 h the solution is cooled. Water (30 ml_) is added. The solution is basified using 10 M NaOH to pH 13 (litmus). The solution is cooled for 18 h, filtered to give 5-nitro-phthalazine (0.93 g).
  • i-phenyl-piperidine-4-carboxylic acid is prepared from bromobenzene (4 mmol).
  • the title compound is prepared from 4-aminoquinazoline (0.5 mmol) and i-phenyl-piperidine-4-carboxylic acid (0.18 mmol).
  • 1-benzothiazol-5-yl-piperidine-4- carboxylic acid is prepared from 5-bromobenzothiazole (4 mmol).
  • the title compound is prepared from 4- aminoquinazoline (0.5 mmol) and 1-benzothiazol-5-yl-piperidine-4-carboxylic acid (0.20 mmol).
  • Example 68 1-benzothiazol-5-yl-piperidine-4- carboxylic acid is prepared from 5-bromobenzothiazole (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 3- aminopyridine (0.5 mmol) and 1 ⁇ benzothiazol-5-yl-piperidine-4-carboxylic acid (0.20 mmoi).
  • Example 68
  • i-phenyl-piperidine-4-carboxylic acid is prepared from bromobenzene (4 mmol).
  • the title compound is prepared from benzo[d]isothiazol-3- ylamine (0.5 mmol) and i-phenyl-piperidine-4-carboxylic acid (0.18 mmol).
  • i-phenyl-piperidine-4-carboxylic acid is prepared from bromobenzene (4 mmol).
  • the title compound is prepared from benzothiazol-2-ylamine (0.5 mmol) and i-Phenyl-piperidine-4-carboxylic acid (0.18 mmol).
  • [1 ,3']bipyridinyl-4-carboxylic acid is prepared from 3-bromopyridine (4 mmol).
  • a solution of 3-chloro-pyridazine 2-oxide (0.5 mmol) and piperidine-4- carboxylic acid methyl ester (5 mmol) is heated to 80 D C for 18 h.
  • the solution is cooled to room temperature.
  • 2.5N NaOH (15 mmol) is added and the solution is heated to 6O 0 C for 18 h.
  • the reaction solution is cooled to room temperature and partitioned between EtOAc and water.
  • the aqueous layer is separated and acidified using 3N HCI.
  • the aqueous layer is extracted with EtOAc.
  • Example 8 Using the procedure outlined in Example 8, the title compound is prepared 1-aminophthalazine (0.5 mmol) and 1-pyridazin-3-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • 1-thiophen-2-yI-piperidine-4- carboxylic acid is prepared from 2-bromothiophene (4 mmol).
  • the title compound is prepared from 1- aminophthalazine (0.5 mmol) and 1-Thiophen-2-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • 1-thiophen-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromothiophene (4 mmol).
  • the title compound is prepared from TH ⁇ purin-6-ylamine (0.5 mmol) and 1-thiophen-2-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • 1-pyrimidin-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromopyrimidine (4 mmol).
  • the title compound is prepared from 7H- purin-6-ylamine (0.5 mmol) and 1-pyrimidin-2-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • Example 1A 1-pyrimidin-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromopyrimidine (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from cinnolin-4-ylamine (0.5 mmol) and 1-pyrimidin-2-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • Example 78 1-thiophen-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromothiophene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from cinnolin-4-ylamine (0.5 mmol) and 1-thiophen-2-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • Example 78
  • 1-thiophen-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromothiophene (4 mmol).
  • the title compound is prepared from quinoxalin-6-ylamine (0.5 mmol) and 1-thiophen-2-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • Example 80 Using the procedure outlined in Example 1A, 1-pyridazin-3-yl-piperidine-4- carboxylic acid (4 mmol) is prepared as in Example 120. Using the procedure outlined in Example 8, the title compound is prepared from quinoxalin-6- ylamine (0.5 mmol) and 1-pyridazin-3-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • Example 80
  • 1-pyrimidin-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromopyrimidine (4 mmol).
  • the title compound is prepared from quinoxalin-6-ylamine (0.5 mmol) and 1-pyrimidin-2-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • 1-pyrimidin-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromopyrimidine (4 mmol).
  • the title compound is prepared from pyrazin- 2-ylamine (0.5 mmol) and 1-pyrimidin-2-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • 1-thiophen-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromothiophene (4 mmol).
  • the title compound is prepared from pyrazin- 2-ylamine (0.5 mmol) and 1-thiophen-2-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • 1-thiophen-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromothiophene (4 mmol).
  • the title compound is prepared from quinazolin-7-ylamine (0.5 mmol) and 1-thiophen-2-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • 1-pyrimidin-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromopyrimidine (4 mmol).
  • the title compound is prepared from quinazolin-7-ylamine (0.5 mmol) and 1-pyrimidin-2-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • 1-pyrimidin-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromopyrimidine (4 mmol).
  • the title compound is prepared from pyridazin-3-ylamine (0.5 mmol) and 1-pyrimidin-2-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • Example 1 1-thiophen-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromothiophene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from pyridazin-3-ylamine (0.5 mmol) and 1-thiophen-2-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • Example 1A 1-benzo[b]thiophen-3-yl- piperidine-4-carboxylic acid is prepared from 3-bromo-benzo[b]thiophene (4 mmol).
  • Example 8 the title compound is prepared from 5-amino-1 ,3-dihydro-benzoimidazol-2-one (0.5 mmol) and 1- benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • 1-naphthaIen-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromo-naphthalene (4 mmol).
  • the title compound is prepared from 5- amino-1 ,3-dihydro-benzoimidazol-2-one (0.5 mmol) and 1-naphthalen-2-yl- piperidine-4-carboxylic acid (0.18 mmol).
  • Example 90 Using the procedure outlined in Example 1A, 1-naphthalen-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromo-naphthalene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 6- amino-4H-benzo[1 ,4]oxazin-3-one (0.5 mmol) and 1-naphthalen-2-yl- piperidine-4-carboxylic acid (0.18 mmol). Example 90
  • 1-biphenyl-3-yl-piperidine-4- carboxylic acid is prepared from 3-bromo-biphenyl (4 mmol).
  • the title compound is prepared from 6- amino-4H-benzo[1 ,4]oxazin-3-one (0.5 mmol) and 1-biphenyl-3-yl-piperidine- 4-carboxylic acid (0.18 mmol).
  • Example 92 1-biphenyl-3-yl-piperidine-4- carboxylic acid is prepared from 3-bromo-biphenyl (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from quinazolin-2-ylamine (0.5 mmol) and 1-biphenyl-3-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • Example 92
  • Example 1A 1-quinolin-3-yl-piperidine-4- carboxylic acid is prepared from 3-bromo-quinoline (4 mmol).
  • Example 8 the title compound is prepared from quinazolin-2-ylamine (0.5 mmol) and i-quinolin-S-yl-piperidine ⁇ -carboxylic acid (0.18 mmol).
  • Example 94 Using the procedure outlined in Example 1A, 1-quinolin-3-yl-piperidine-4- carboxylic acid is prepared from 3-bromo-quinoline (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from quinoxalin-2-ylamine (0.5 mmol) and 1-quinolin-3-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • Example 94 Using the procedure outlined in Example 1A, 1-quinolin-3-yl-piperidine-4- carboxylic acid is prepared from 3-bromo-quinoline (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from quinoxalin-2-ylamine (0.5 mmol) and 1-quinolin-3-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • Example 94 Using the procedure outlined in Example 1A, 1-quinolin-3-yl-piperidine-4- carboxylic acid is prepared from 3-bromo-quinoline
  • Example 1A 1-isoquinolin-5-yl-piperidine-4- carboxylic acid is prepared from 5-Bromo-isoquinoline (4 mmol).
  • Example 8 the title compound is prepared from quinoxalin-2-ylamine (0.5 mmol) and i-isoquinolin- ⁇ -yl-piperidine ⁇ -carboxylic acid (0.18 mmol).
  • Example 96 1-isoquinolin-5-yl-piperidine-4- carboxylic acid is prepared from 5-bromo-isoquinoline (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 9H- carbazol-3-ylamine (0.5 mmol) and 1-isoquinolin-5-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • Example 96
  • 1-benzo[b]thiophen-3-yl- piperidine-4-carboxylic acid is prepared from 3 ⁇ bromo-benzo[b]thiophene (4 mmol).
  • the title compound is prepared from 9H-carbazol-3-ylamine (0.5 mmol) and 1-benzo[b]thiophen-3- yl-piperidine-4-carboxylic acid (0.18 mmol).
  • Example 98 Using the procedure outlined in Example 1A, 1 -benzo[b]thiophen-3-yl- piperidine-4-carboxylic acid is prepared from 3-bromo-benzo[b]thiophene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from phenazin-2-ylamine (0.5 mmol) and 1-benzo[b]thiophen-3-yl- piperidine-4-carboxylic acid (0.18 mmol). Example 98
  • 1-naphthalen-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromo-naphthalene (4 mmol).
  • the title compound is prepared from phenazin-2-ylamine (0.5 mmol) and 1-naphthalen-2-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • 1-naphthalen-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromo-naphthalene (4 mmol).
  • the title compound is prepared from thiazol- 2-ylamine (0.5 mmol) and 1-naphthalen-2-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • 1-biphenyl-3-yl-piperidine-4- carboxylic acid is prepared from 3-bromobiphenyl (4 mmol).
  • the title compound is prepared from thiazol- 2-ylamine (0.5 mmol) and i-biphenyl-S-yl-piperidine ⁇ -carboxylic acid (0.18 mmol).
  • 1-biphenyl-3-yl-piperidine-4- carboxylic acid is prepared from 3-bromobiphenyl (4 mmol).
  • the title compound is prepared from 1 H- imidazol-2-ylamine (0.5 mmol) and 1-biphenyl-3-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • Example 1A 1-quinolin-3-yl-piperidine-4- carboxylic acid is prepared from 3-bromo-quinoline (4 mmol).
  • Example 8 the title compound is prepared from 1 H- imidazol-2-ylamine (0.5 mmol) and 1-quinolin-3-yl-piperidine ⁇ 4-carboxylic acid (0.18 mmol).
  • Example 1A 1-quinolin-3-yl-piperidine-4- carboxylic acid is prepared from 3-bromo-quinoline (4 mmol).
  • Example 8 the title compound is prepared from 2H- pyrazol-3-ylamine (0.5 mmol) and 1-quinolin-3-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • Example 1A 1-isoquinolin-5-yl-piperidine-4- carboxylic acid is prepared from 5-bromo-isoquinoline (4 mmol).
  • Example 8 the title compound is prepared from 2H- pyrazol-3-ylamine (0.5 mmol) and i-isoquinolin- ⁇ -yl-piperidine ⁇ -carboxylic acid (0.18 mmol).
  • 1-isoquinolin-5-yl-piperidine-4- carboxylic acid is prepared from 5-bromo-isoquinoline (4 mmol).
  • the title compound is prepared from isoxazol-3-ylamine (0.5 mmol) and 1-isoquinolin-5-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • Example 1A 1 -benzo[b]thiophen-3-yl- piperidine-4-carboxylic acid is prepared from 3-bromo-benzo[b]thiophene (4 mmol).
  • the title compound is prepared from 3-methyl-isothiazol-5-ylamine (0.5 mmol) and 1- benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • 1-naphthalen-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromo-naphthalene (4 mmol).
  • the title compound is prepared from 3- methyl-isothiazol-5-ylamine (0.5 mmol) and 1-naphthalen-2-yl-piperidine-4- carboxylic acid (0.18 mmol).
  • 1-benzo[b]thiophen-3-yI- piperidine-4-carboxylic acid is prepared from 3-bromo-benzo[b]thiophene (4 mmol).
  • the title compound is prepared from [1 ,6]naphthyridin-4-ylamine (0.5 mmol) and 1- benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • 1-naphthalen-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromo-naphthalene (4 mmol).
  • the title compound is prepared from [1 ,7]naphthyridin-8-ylamine (0.5 mmol) and 1-naphthalen-2-yl-piperidine-4- carboxylic acid (0.18 mmol).
  • Example 114 Using the procedure outlined in Example 1A, 1-naphthalen-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromo-naphthalene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from acridin- 9-ylamine (0.5 mmol) and 1-naphthalen-2-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • Example 1A 1-biphenyl-3-yl-piperidine-4- carboxylic acid is prepared from 3-biphenyl (4 mmol).
  • Example 8 the title compound is prepared from acridin-9-ylamine (0.5 mmol) and i-biphenyl-S-yl-piperidine ⁇ -carboxylic acid (0.18 mmol).
  • Example 116 Using the procedure outlined in Example 1A, 1-biphenyl-3-yl-piperidine-4- carboxylic acid is prepared from 3-biphenyl (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 1-methyl-4,5- dihydro-1 H-imidazol-2-ylamine (0.5 mmol) and 1-biphenyl-3-yl-piperidine-4- carboxylic acid (0.18 mmol).
  • Example 116 Using the procedure outlined in Example 1A, 1-biphenyl-3-yl-piperidine-4- carboxylic acid is prepared from 3-biphenyl (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 1-methyl-4,5- dihydro-1 H-imidazol-2-ylamine (0.5 mmol) and 1-biphenyl-3-yl-piperidine-4- carboxylic acid (0.18 mmol).
  • Example 116 Using the procedure outlined in Example 1A, 1-b
  • 1-quinolin-3-yl-piperidine-4- carboxylic acid is prepared from 3-bromo-quinoline(4 mmol).
  • the title compound is prepared from 1- methyl-4,5-dihydro-1 H-imidazol-2-ylamine (0.5 mmol) and 1-quinolin-3-yl- piperidine-4-carboxylic acid (0.18 mmol).
  • Example 1A 1-isoquinolin-5-yl-piperidine- 4-carboxylic acid is prepared from 5-bromo-isoquinoline (4 mmol).
  • 1-isoquinolin-5-yl-piperidine-4-carboxylic acid [1-(toluene-4-sulfonyl)-4,5-dihydro-1 H-pyrazol-3-yl]-amide is prepared from 1-(toluene-4-sulfonyl)-4,5-dihydro-1 H-pyrazol-3-ylamine (0.5 mmol) and 1-isoquinolin-5-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • Example 2 Using the procedure outlined in Example 1A, 1-isoquinolin-5-yl-piperidine- 4-carboxylic acid is prepared from 5-bromo-isoquinoline (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from [1 ,8]naphthyridin-2-ylamine (0.5 mmol) and 1-isoquinolin-5-yl-piperidine-4- carboxylic acid (0.18 mmol).
  • [2,6]Naphthyridin-1-ylamine is prepared from 1-bromo-[2,6]naphthyridine using the procedure given in Organic Letters. 3(17), 2729-2732 (2001).
  • 5-Nitro-benzo[d]isoxazole is prepared from benzo[d]isoxazole as described in Example 63A.
  • Benzo[d]isoxazol-5-ylamine is prepared from 5-nitro-benzo[d]isoxazole as described in Example 63B.
  • Example 124 Using the procedure outlined in Example 1A, 1-naphthalen-2-yl-piperidine- 4-carboxylic acid is prepared from 2-Bromo-naphthalene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from benzo[d]isoxazol-5-ylamine (0.5 mmol) and 1-naphthalen-2-yl-piperidine-4- carboxylic acid (0.18 mmol).
  • Example 124 Using the procedure outlined in Example 1A, 1-naphthalen-2-yl-piperidine- 4-carboxylic acid is prepared from 2-Bromo-naphthalene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from benzo[d]isoxazol-5-ylamine (0.5 mmol) and 1-naphthalen-2-yl-piperidine-4- carboxylic acid (0.18 mmol).
  • Example 124 Using the procedure outlined in Example 1A, 1-naphthalen-2
  • Example 1A 1-biphenyl-3-yl-piperidine-4- carboxylic acid is prepared from 3-bromo-biphenyl (4 mmol).
  • Example 8 the title compound is prepared from benzo[d]isoxazol-5-ylamine (0.5 mmol) (prepared as in Example 169b) and 1- biphenyl-S-yl-piperidine ⁇ -carboxylic acid (0.18 mmol).
  • Example 1A 1-biphenyl-3-yl-piperidine-4- carboxylic acid is prepared from 3-bromo-biphenyl (4 mmol).
  • the title compound is prepared from 1 H- pyrrol-3-ylamine (0.5 mmol) (prepared as in Example 172a) and 1-biphenyl-3- yl-piperidine-4-carboxylic acid (0.18 mmol).
  • Example 126 i-Quinolin-S-yl-piperidine- ⁇ carboxylic acid (1 H-pyrrol-3-yl)-amide
  • Example 1A 1-quinolin-3-yl-piperidine-4- carboxylic acid is prepared from 3-bromo-quinoIine (4 mmol).
  • Example 8 the title compound is prepared from 1 H- pyrrol-3-ylamine (0.5 mmol) and i-quinolin-S-yl-piperidine ⁇ -carboxylic acid (0.18 mmol).
  • Example 2 Using the procedure outlined in Example 1A, 1-quinolin-3-yl-piperidine-4- carboxylic acid is prepared from 3-bromo-quinoline (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 1 H- pyrroIo[2,3-b]pyridin-3-ylamine (0.5 mmol) and 1-quinolin-3-yl-piperidine-4- carboxylic acid (0.18 mmol).
  • Example 1A 1-isoquinolin-5-yl-piperidine-4- carboxylic acid is prepared from 3-bromo-quinoline (4 mmol).
  • Example 8 the title compound is prepared from 1 H- pyrrolo[2,3-b]pyridin-3-ylamine (0.5 mmol) (prepared as in Example 174a) and i-isoquinolin- ⁇ -yl-piperidine ⁇ -carboxylic acid (0.18 mmol).
  • Example 1A 1-isoquinolin-5-yl-piperidine- 4-carboxylic acid is prepared from 3-bromo-quinoline (4 mmol).
  • Example 8 the title compound is prepared from pteridin- 4-ylamine (0.5 mmol) (prepared as in Example 176b) and 1-isoquinolin-5-yl- piperidine-4-carboxylic acid (0.18 mmol).
  • Example 1A 1-benzo[b]thiophen-3-yl- piperidine-4-carboxy
  • Example 8 the title compound is prepared from pteridin-4-ylamine (0.5 mmol) (prepared as in Example 176b) and 1-benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • 1,4-Dihydro-quinazoline is prepared from 2-aminomethyl-phenylamine (1 mmol) following the procedure given in Journal of Organic Chemistry, 5, 133- 141 (1940).
  • 6-Nitro-1 ,4-dihydro-quinazoline is prepared from 1 ,4-dihydro-quinazoline (1 mmol) following the procedure given in Example 69A.
  • Example 1A 1-benzo[b]thiophen-3-yl- piperidine-4-carboxylic acid is prepared from 3-bromo-benzo[b]thiophene (4 mmol).
  • Example 8 the title compound is prepared from 1 ,4-dihydro-quinazolin-6-ylamine (0.5 mmol) (prepared as in Example 178c) and 1-benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • 1-naphthalen-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromo-naphthalene (4 mmol).
  • the title compound is prepared from 1 ,4- dihydro-quinazolin-6-ylamine (0.5 mmol) and 1-naphthalen-2-yl-piperidine-4- carboxylic acid (0.18 mmol).
  • Example 1A 1-naphthalen-2-yl-piperidine- 4-carboxylic acid is prepared from 2-bromo-naphthalene (4 mmol).
  • Example 8 the title compound is prepared from [1 ,7]naphthyridin-4-ylamine (0.5 mmol) (prepared as in Example 18Og) and 1- naphthalen-2-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • Example 1A 1-biphenyl-3-yl-piperidine-4- carboxylic acid is prepared from 3-bromo-biphenyl (4 mmol).
  • Example 8 the title compound is prepared from [1 ,7]naphthyridin-4-ylamine (0.5 mmol) (prepared as in Example 18Og) and 1- biphenyl-3-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • Example 1A 1-biphenyl-3-yl-piperidine-4- carboxylic acid is prepared from 3-Bromo-biphenyl (4 mmol).
  • Example 8 the title compound is prepared from [2,7]naphthyridin-4-ylamine (0.5 mmol) (prepared as in Example 182e) and 1- biphenyl-3-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • 1-quinolin-3-yl-piperidine-4- carboxylic acid is prepared from 3-Bromo-quinoline (4 mmol).
  • the title compound is prepared from [2,7]naphthyridin-4-ylamine (0.5 mmol) and 1-quinolin-3-yl-piperidine-4- carboxylic acid (0.18 mmol).
  • Example 1A 1-isoquinolin-5-yl-piperidine-4- carboxylic acid is prepared from 5-bromo-isoquinoline (4 mmol).
  • Example 8 the title compound is prepared from [2,6]naphthyridin-1-ylamine (0.5 mmol) (prepared as in Example 184e) and 1- lsoquinolin-5-yl-piperidine-4-carboxylic acid (0.18 mmol).
  • 6-amino-2H- 1 ,4-benzoxazine-3(4H)-one (0.02 g, 0.122 mmol) and triethylamine (0.03 mL, 0.183 mmol) were added sequentially into the acyl chloride solution at 0 0 C.
  • the reaction mixture was warmed to 25 0 C and stirred for 20 min. Concentration of the solvent provided the residue which was then purified by flash column chromatography with hexanes and ethyl acetate to afford 1-phenyl-piperidine-4-carboxylic acid (3-oxo-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-yl)-amide as white solid.
  • 1-m-tolyl-piperidine-4- carboxylic acid was prepared from 3-iodotoulene (2.08 g, 9.54 mmol) as a yellow solid.
  • Example 139B Using the procedure outlined in Example 139B, the title compound was prepared from 1-o-tolyl-piperidine-4-carboxylic acid (0.03 g, 0.122 mmol) as light brown solid.
  • Mass Spectrum (LCMS, ESI pos.) Calcd. for C 2 i H 23 N 3 O 3 : 365.4. Found: 366.0 (M + + 1 ).
  • Example 139B Using the procedure outlined in Example 139B, the title compound was prepared from 1-(2,3-dimethyl-phenyl)-piperidine-4-carboxylic acid (0.03 g, 0.122 mmol) as white solid.
  • Mass Spectrum (LCMS, ESI pos.) Calcd. for C 22 H 25 N 3 O 3 : 379.5. Found: 380.1 (M + ).
  • Example 139B Using the procedure outlined in Example 139B, the title compound was prepared from 1-(2-fluoro-phenyl)-piperidine-4-carboxylic acid (0.03 g, 0.122 mmol) as off-white solid.
  • Mass Spectrum (LCMS, ESI pos.) Calcd. for C 20 H 20 FN 3 O 3 : 369.4. Found: 370.1 (M + + 1 ).
  • Example 139B Using the procedure outlined in Example 139B, the title compound was prepared from 3'-methyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-4-carboxylic acid (0.03 g, 0.122 mmol) as light brown solid.
  • 1-benzothiazol-2-yl- piperidine-4-carboxylic acid was prepared from 2-bromo-benzothiazole (2.04 g, 9.54 mmol) as a yellow solid.
  • Example 139B Using the procedure outlined in Example 139B, the title compound was prepared from 3'-nitro-3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-4-carboxylic acid (0.03 g, 0.122 mmol) as yellow solid.
  • Example 164 1-(4-Bromo-2,3,5,6-tetrafluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-yl)-amide

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Abstract

This invention is directed to vanilloid receptor VR1 ligands. More particularly, this invention relates to hetero isonipecotic amides that are potent modulators of VR1 which are useful for the treatment and prevention of disease conditions in mammals.

Description

TITLE OF THE INVENTION
4-PIPERIDINECARBOXAMIDE MODULATORS OF VANILLOID VR1
RECEPTOR
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to United States Provisional Application Nos. 60/631 ,436, filed November 29, 2004, 60/732,035, filed November 1 , 2005 and 60/712,496 filed August 30, 2005, all of which are hereby incorporated by reference in its entirety.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR
DEVELOPMENT
The research and development of the invention described below was not federally sponsored.
BACKGROUND OF THE INVENTION
This invention is directed to novel vanilloid receptor VR1 ligands. More particularly, this invention relates to novel 4-piperidincarboxamides that are potent modulators of VR1.
Noxious chemical, thermal and mechanical stimuli excite peripheral nerve endings of small diameter sensory neurons (nociceptors) in sensory ganglia (e. g., dorsal root, nodose and trigeminal ganglia) and initiate signals that are perceived as pain. These neurons are crucial for the detection of harmful or potentially harmful stimuli (heat) and tissue damage (local tissue acidosis and/or stretch) that arise from changes in the extracellular space during inflammatory or ischaemic conditions (Wall, P. D., and Melzack, R., Textbook of Pain. 1994, New York: Churchill Livingstone). Nociceptors transduce noxious stimuli into membrane depolarization that triggers action potential, conducts the action potential from the sensory sites to the synapses in the CNS, and conversion of action potentials invokes a perception of pain, discomfort, and appropriate mechanical/physical protective reflexes. At the molecular level, nociception is carried out by ion channels or receptors. Plant derived vanilloid compounds (capsaicin and its ultrapotent analog, resiniferatoxin, etc.) are known to selectively depolarize nociceptors and elicit sensations of burning pain — the sensation that is typically obtained by hot chili peppers. Therefore, capsaicin mimics the action of physiological/endogenous stimuli that activates the "nociceptive pathway". Recent advances in pain biology have identified receptors for vanilloids, protons (i.e., acidic solutions), and for heat. Because nociceptors are involved with unwanted pain and inflammatory conditions in human beings and animals, modulation of their nociceptive pathway is important in palliative and other therapies.
Walpole and colleagues at Sandoz reported on the first competitive antagonist of the sensory neuron excitants capsaicin and resineriferatoxin (Walpole, C. S. J. et. al., J. Med. Chem. 1994, 37, 1942). Subsequently, capsazepine has been shown to be a vanilloid receptor antagonist.
SUMMARY OF THE INVENTION
The present invention is directed to compounds of formula (II)
Figure imgf000003_0001
(II) wherein
Ar is an aryl selected from the group consisting of benzo[b]thiophenyl, naphthyl, biphenyl, isoquinolinyl, thiophenyl, pyridazinyl, and benzothiazolyl; Z is O or S;
R2 is hydrogen or Chalky! optionally substituted with -OR4; n is 1 or 2;
R3 is independently hydrogen, Ci-6alkyl, -COOR4, Or -CH2COOR4; R4 is hydrogen or Chalky!; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
In another embodiment, the present invention is directed to compounds of formula (II) wherein Z is O and n is 1.
In another embodiment, the present invention is directed to compounds of formula (M) wherein Z is O and R2 is hydrogen.
In another embodiment, the present invention is directed to compounds of formula (III):
Figure imgf000004_0001
(III) wherein
X is CH or N; m is an integer from 0 to 4;
R is independently selected from the group consisting of halogen; R1; fluorinated C-Moalkyl; phenyl; amino; cyano; CF3O-; a 3 membered cyclic heteroalkyl containing 1 heteroatom that is N, O or S wherein said 3 membered cyclic heteroalkyl is optionally substituted with a substituent that is halogen, R1, fluorinated C-Moalkyl, amino, cyano, CF3O-, R1O-, R1S-, R1SO2-, R1S(O)-, R1SO2NH-, or -LCOY; a 4 to 5 membered cyclic heteroalkyl containing 1-3 heteroatoms that independently are N, O or S wherein said 4 to 5 membered cyclic heteroalkyl is optionally substituted with 1 to 2 substituents that independently are halogen, R1, fluorinated Ci- ioalkyl, amino, cyano, CF3O-, R1O-, R1S-, R1SO2-, R1S(O)-, R1SO2NH-, or -LCOY; a 6 to 7 membered cyclic heteroalkyl containing 1-3 heteroatoms that independently are N, O or S wherein said 6 to 7 membered cyclic heteroalkyl is optionally substituted with 1 to 3 substituents that independently are halogen, R1, fluorinated
Figure imgf000005_0001
amino, cyano, CF3O-, R1O-, R1S-, R1SO2-, R1S(O)-, R1SO2NH-, or -LCOY; a heteroaryl wherein said heteroaryl is cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, pthalazine, pteridine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinoline, quinolizine, quinazoline, quinoxaline, tetrazole, thiadiazole, triazine, or triazole wherein said heteroaryl is optionally substituted with 1 to 3 substituents that independently are halogen, R1, fluorinated C-Moalkyl, amino, cyano, CF3O-, R1O-, R1S-,
R1SO2-, R1S(O)-, R1SO2NH-, or -LCOY; hydroxyl; R1O-; R1S-; R1SO2-; R1S(O)-; R1SO2NH-; -LCOY; and C6-i0aryl; R1 is Ci-iOalkyl; L is -NH-, a direct bond, -O-, or -CH2-; Y is H, R1, HO, R1O-, R1S-, -NH2, R1NH-, or (R1)2N-;
Z is O or S;
R2 is hydrogen or C1-6alkyl optionally substituted with -OR4; n is 1 or 2; R3 is independently hydrogen, Ci-6alkyl, -COOR4, Or-CH2COOR4; R4 is hydrogen or C1-3alkyl; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
In another embodiment, the present invention is directed to compounds of formula (Ha):
Figure imgf000006_0001
(Ha)
wherein Ar is an aryl selected from the group consisting of benzo[b]thiophenyl, naphthyl, biphenyl, isoquinolinyl, thiophenyl, pyridazinyl, and benzothiazolyl; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
The present invention is also drawn to compounds of formula (Ilia):
Figure imgf000006_0002
(Ilia)
wherein X is CH or N; m is an integer from 0 to 4;
R is independently selected from the group consisting of halogen; R1; fluorinated C-Moalkyl; phenyl; amino; cyano; CF3O-; a 3 membered cyclic heteroalkyl containing 1 heteroatom that is N, O or S wherein said 3 membered cyclic heteroalkyl is optionally substituted with a substituent that is halogen, R1, fluorinated Ci-iOalkyl, amino, cyano, CF3O-, R1O-, R1S-, R1SO2-, R1S(O)-, R1SO2NH-, or -LCOY; a 4 to 5 membered cyclic heteroalkyl containing 1-3 heteroatoms that independently are N, O or S wherein said 4 to 5 membered cyclic heteroalkyl is optionally substituted with 1 to 2 substituents that independently are halogen, R1, fluorinated Ci-ioalkyl, amino, cyano, CF3O-, R1O-, R1S-, R1SO2-, R1S(O)-, R1SO2NH-, or -LCOY; a 6 to 7 membered cyclic heteroalkyl containing 1-3 heteroatoms that independently are N, O or S wherein said 6 to 7 membered cyclic heteroalkyl is optionally substituted with 1 to 3 substituents that independently are halogen, R1, fluorinated C-Moalkyl, amino, cyano, CF3O-, R1O-, R1S-, R1SO2-, R1S(O)-, R1SO2NH-, or -LCOY; a heteroaryl wherein said heteroaryl is cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, pthalazine, pteridine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinoline, quinolizine, quinazoline, quinoxaline, tetrazole, thiadiazole, triazine, or triazole wherein said heteroaryl is optionally substituted with 1 to 3 substituents that independently are halogen, R1, fluorinated C-i.-ioalkyl, amino, cyano, CF3O-, R1O-, R1S-, R1SO2-, R1S(O)-, R1SO2NH-, or -LCOY; hydroxyl; R1O-; R1S-; R1SO2-; R1S(O)-; R1SO2NH-; -LCOY; and C6-ioaryl; wherein R1 is C-i_iOalkyl; L is -NH-, a direct bond, -O-, or -CH2-; and Y is H,
R1, HO, R1O-, R1S-, -NH2, R1NH-, or (R1)2N-; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the following underlined terms are intended to have the following meanings:
"Ca^" (where a and b are integers) refers to a radical containing from a to h carbon atoms inclusive. For example, Ci-3 denotes a radical containing 1 , 2 or 3 carbon atoms.
"Fluorinated alkyl" refers to a saturated branched or straight chain hydrocarbon radical derived by removal of 1 hydrogen atom from the parent alkane; the parent alkane contains from 1 to 6 carbon atoms with 1 or more hydrogen atoms substituted with fluorine atoms up to and including substitution of all hydrogen atoms with fluorine. Preferred fluorinated alkyls include trifluoromethyl substituted alkyls and perfluorinated alkyls; more preferred fluorinated alkyls include trifluoromethyl, perfluoroethyl, 2,2,2- trifluoroethyl, perfluoropropyl, 3,3,3-trifluoroprop-1-yl, 3,3.3-trifluoroprop-2-yl, 1,1 ,1 ,3,3,3-hexafluoroprop-2-yl; a particularly preferred fluorinated alkyl is trifluoromethyl.
"Fluorinated alkanyloxy" refers to a radical derived from a fluorinated alkyl radical attached to an oxygen atom with the oxygen atom having one open valence for attachment to a parent structure.
"Alkyl:" refers to a saturated or unsaturated, branched, straight-chain or cyclic monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene or alkyne. Typical alkyl groups include, but are not limited to, methyl; ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl, propan-2-yl , cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl, cycloprop-1-en-1-yl; cycloprop- 2-en-1-yl, prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, but-1- en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1 ,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1 ,3-dien-1-yl, but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. Where specific levels of saturation are intended, the nomenclature "alkanyl", "alkenyl" and/or "alkynyl" is used, as defined below. In preferred embodiments, the alkyl groups are (Ci-8) alkyl, with (C1-3) being particularly preferred.]
"Alkanyl:" refers to a saturated branched, straight-chain or cyclic monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Typical alkanyl groups include, but are not limited to, methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl, cyclopropan-1-yl, etc.; butyanyls such as butan-1-yl, butan-2-yl, 2-methyl- propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, etc.; and the like. In preferred embodiments, the alkanyl groups are (Ci-8) alkanyl, with (C1-3) being particularly preferred.
"Alkenyl:" refers to an unsaturated branched, straight-chain or cyclic monovalent hydrocarbon radical having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene. The radical may be in either the cis or trans conformation about the double bond(s). Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl, prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such as but- 1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1 ,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-i-en-3-yl, cyclobuta-1 ,3-dien-1-yl, etc.; and the like. In preferred embodiments, the alkenyl group is (C2-S) alkenyl, with (C2-3) being particularly preferred.
"Alkvnyl:" refers to an unsaturated branched, straight-chain or cyclic monovalent hydrocarbon radical having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. In preferred embodiments, the alkynyl group is (C2-8) alkynyl, with (C-2-3) being particularly preferred.
"Alkyldiyl:" refers to a saturated or unsaturated, branched, straight-chain or cyclic divalent hydrocarbon radical derived by the removal of one hydrogen atom from each of two different carbon atoms of a parent alkane, alkene or alkyne, or by the removal of two hydrogen atoms from a single carbon atom of a parent alkane, alkene or alkyne. The two monovalent radical centers can form bonds with the same or different atoms. Typical alkyldiyls include, but are not limited to methandiyl; ethyldiyls such as ethan-1 ,1-diyl, ethan-1 ,2-diyl, ethen-1 ,1-diyl, ethen-1 ,2-diyl; propyldiyls such as propan-1 ,1-diyl, propan-1 ,2- diyl, propan-2,2-diyl, propan-1 ,3-diyl, cyclopropan-1 ,1-diyl, cyclopropan-1 ,2- diyl, prop-1-en-1 ,1-diyl, prop-1-en-1 ,2-diyl, prop-2-en-1 ,2-diyl, prop-1-en-1 ,3- diyl, cycloprop-1-en-1 ,2-diyl, cycloprop-2-en-1 ,2-diyl, cycloprop-2-en-1,1-diyl, prop-1-yn-1 ,3-diyl, etc.; butyldiyls such as, butan-1 ,1-diyl, butan-1 ,2-diyl, butan-1 ,3-diyl, butan-1 ,4-diyl, butan-2,2-diyl, 2-methyl-propan-1 ,1-diyl, 2- methyl-propan-1 ,2-diyl, cyclobutan-1 ,1-diyl; cyclobutan-1 ,2-diyl, cyclobutan- 1 ,3-diyl, but-1-en-1 ,1-diyl, but-1-en-1 ,2-diyl, but-1-en-1 ,3-diyl, but-1-en-1 ,4- diyl, 2-methyl-prop-1-en-1 ,1-diyl, 2-methylprop-2-en-1 ,1-diyl, buta-1 ,3-dien- 1 ,1 -diyl, buta-1 ,3-dien-1 ,2-diyl, buta-1 ,3-dien-1 ,3-diyl, buta-1 ,3-dien-1 ,4-diyl, cyclobut-1-en-1 ,2-diyl, cyclobut-1 -en-1 ,3-diyl, cyclobut-2-en-1 ,2-diyl, cyclobuta-1 ,3-dien-1 ,2-diyl, cyclobuta-1 ,3-dien-1 ,3-diyl, but-1-yn-1 ,3-diyl, but- 1-yn-1 ,4-diyl, buta-1 ,3-diyn-1 ,4-diyl, etc.; and the like. Where specific levels of saturation are intended, the nomenclature alkandiyl, alkendiyl and/or alkyndiyl is used. In preferred embodiments, the alkyldiyl group is (Ci-β) alkyldiyl, with (Ci-8) being particularly preferred. Also preferred are saturated acyclic alkandiyl radicals in which the radical centers are at the terminal carbons, e.g., methandiyl; ethan-1 ,2-diyl; propan-1 ,3-diyl; butan-1 ,4-diyl; and the like (also referred to as alkylenos, as defined infra).
"Vic Alkyldiyl:" refers to a saturated or unsaturated, branched, straight-chain or cyclic hydrocarbon radical having two adjacent monovalent radical centers derived by the removal of one hydrogen atom from each of two adjacent carbon atoms of a parent alkane, alkene or alkyne. The two monovalent radical centers can form bonds with the same or different atom(s). Typical vie alkyldiyls include, but are not limited to vie ethyldiyls such as ethan-1 ,2-diyl, ethen-1 ,2-diyl; vie propyldiyls such as propan-1 ,2-diyl, cyclopropan-1 ,2-diyl, prop-1 -en-1 ,2-diyl, prop-2-en-1 ,2-diyl, cycloprop-1 -en-1 ,2-diyl, etc.; vie butyldiyls such as butan-1 ,2-diyl, 2-methyl-propan-1 ,2-diyl, cyclobutan-1 ,2- diyl, but-1 -en-1 ,2-diyl, cyclobut-1 -en-1 ,2-diyl, buta-1 ,3-dien-1 ,2-diyl, cyclobuta- 1 ,3-dien-1 ,2-diyl, but-3-yn-1 ,2-diyl, etc.; and the like. Where specific levels of saturation are intended, the nomenclature vie alkandiyl, vie alkendiyl and/or vie alkyndiyl is used. In preferred embodiments, the vie alkyldiyl group is (C-2-8) vie alkyldiyl, with (C2-3) being particularly preferred.
"Gem Alkyldiyl:" refers to a saturated or unsaturated, branched, straight-chain or cyclic hydrocarbon radical having one divalent radical center derived by the removal of two hydrogen atoms from a single carbon atom of a parent alkane, alkene or alkyne. The divalent radical center forms bonds with two different atoms. Typical gem alkyldiyls include, but are not limited to gem methanyldiyl; gem ethyldiyls such as ethan-1 ,1-diyl,ethen-1 ,1-diyl; gem propyldiyls such as propan-1 ,1-diyl, propan-2,2-diyl, cyclopropan-1 ,1-diyl, prop-1-en-1 ,1-diyl, cycloprop-2-en-1 ,1-diyl, prop-2-yn-1 ,1-diyl, etc.; butyldiyls such as butan-1 ,1-diyl, butan-2,2-diyl, 2-methyl-propan-1 ,2-diyl, cyclobutan- 1 ,1-diyl, but-1-en-1 ,1-diyl, 2-methyl-prop-1-en-1 ,1-diyl, 2-methyl-prop-2-en- 1 ,1-diyl, cyclobut-2-en-1 ,1-diyl, buta-1 ,3-dien-1 ,1-diyl, etc.; and the like. Where specific levels of saturation are intended, the nomenclature gem alkandiyl, gem alkendiyl and/or gem alkyndiyl is used. In preferred embodiments, the gem alkyldiyl group is (C-i-e) gem alkyldiyl, with (C1-3) being particularly preferred.
"Alkyleno:" refers to a saturated or unsaturated, straight-chain or branched acyclic bivalent hydrocarbon bridge radical derived by the removal of one hydrogen atom from each of the two terminal carbon atoms of an acyclic parent alkane, alkene or alkyne. Typical alkyleno groups include, but are not limited to, methano; ethylenos such as ethano, etheno, ethyno; propylenos such as propano, propeno, prop-1,2-dieno, propyno, etc.; butylenos such as butano, 2-methyl-propano, but-1-eno, but-2-eno, 2-methyl-prop-1-eno, 2- methanylidene-propano, but-1 ,3-dieno, but-1-yno, but-2-yno, but-1 ,3-diyno, etc.; and the like. Where specific levels of saturation are intended, the nomenclature alkano, alkeno and/or alkyno is used. In preferred embodiments, the alkyleno group is (d-s) alkyleno, with (C1-3) being particularly preferred. Also preferred are straight-chain saturated alkano radicals, e.g., methano, ethano, propano, butano, and the like. "Alkylidene:" refers to a saturated or unsaturated, branched, straight-chain or cyclic divalent hydrocarbon radical derived by removal of two hydrogen atoms from the same carbon atom of a parent alkane, alkene or alkyne. The divalent radical center forms a double bond with a single atom. Typical alkylidene radicals include, but are not limited to, methanylidene, ethylidenes such as ethanylidene, ethenylidene; propylidenes such as propan-1-ylidene, propan-2-ylidene, cyclopropan-1-ylidene, prop-1-en-1-ylidene, prop-2-en-1- ylidene, cycloprop-2-en-1-ylidene, etc.; butylidenes such as butan-1-ylidene, butan-2-ylidene, 2-methyl-propan-1-ylidene, cyclobutan-1-ylidene, but-1-en-1- ylidene, but-2-en-1-ylidene, but-3-en-1-ylidene, buta-1 ,3-dien-1-ylidene; cyclobut-2-en-1-ylidene, etc.; and the like. Where specific levels of saturation are intended, the nomenclature alkanylidene, alkenylidene and/or alkynylidene is used. In preferred embodiments, the alkylidene group is (Ci-8) alkylidene, with (C-1-3) being particularly preferred. Also preferred are acyclic saturated alkanylidene radicals in which the divalent radical is at a terminal carbon, e.g., methanylidene, ethan-1 -ylidene, propan-1-ylidene, butan-1- ylidene, 2-methyl-propan-1 -ylidene, and the like.
"Alkylidvne:" refers to a saturated or unsaturated, branched or straight-chain trivalent hydrocarbon radical derived by removal of three hydrogen atoms from the same carbon atom of a parent alkane, alkene or alkyne. The trivalent radical center forms a triple bond with a single atom. Typical alkylidyne radicals include, but are not limited to, methanylidyne; ethanylidyne; propylidynes such as propan-1-ylidyne, prop-2-en-1-ylidyne, prop-2-yn-1-ylidyne; butylidynes such as butan-1-ylidyne, 2-methyl-propan-1 - ylidyne, but-2-en-1-ylidyne, but-3-en-1 -ylidyne, buta-2,3-dien-1-ylidyne, but-2- yn-1-ylidyne, but-3-yn-1 -ylidyne, etc.; and the like. Where specific levels of saturation are intended, the nomenclature alkanylidyne, alkenylidyne and/or alkynylidyne is used. In preferred embodiments, the alkylidyne group is (C-i-s) alkylidyne, with (C^3) being particularly preferred. Also preferred are saturated alkanylidyne radicals, e.g., methanylidyne, ethanylidyne, propan-1- ylidyne, butan-1-ylidyne, 2-methyl-propan-1 -ylidyne, and the like. "Heteroalkyl. Heteroalkanyl, Heteroalkenyl. Heteroalkvnyl, Heteroalkylidene. Heteroalkylidvne. Heteroalkyldiyl, Vic Heteralkyldiyl. Gem Heteroalkyldiyl. Heteroalkyleno and Heteroalkyldiylidene:" refer to alkyl, alkanyl, alkenyl, alkynyl, alkylidene, alkylidyne, alkyldiyl, vie alkyldiyl, gem alkyldiyl, alkyleno and alkyldiylidene radicals, respectively, in which one or more carbon atoms (and any necessary associated hydrogen atoms) are independently replaced with the same or different heteroatoms (including any necessary hydrogen or other atoms). Typical heteroatoms to replace the carbon atom(s) include, but are not limited to, N, P, O, S, Si, etc. Preferred heteroatoms are O, N and S. Thus, heteroalkyl, heteroalkanyl, heteroalkenyl, heteroalkynyl, heteroalkylidene, heteroalkylidyne, heteroalkyldiyl, vie heteroalkyldiyl, gem heteroalkyldiyl, heteroalkyleno and heteroalkyldiylidene radicals can contain one or more of the same or different heteroatomic groups, including, by way of example and not limitation, epoxy (-O-), epidioxy (-O-O-), thioether (-S-), epidithio (-SS-), epoxythio (-O-S-), epoxyimino (-O-NR1-), imino (-NR1-), biimmino (-NR'-NR1-), azino (=N-N=), azo (-N=N-), azoxy (-N-O-N- -), azimino (-NR'-N=N-), phosphano (-PH-), λ4-sulfano (-SH2-), sulfonyl (- -S(O)2-), and the like, where each R' is independently hydrogen or (C-i-Cβ) alkyl.
"Parent Aromatic Ring System:" refers to an unsaturated cyclic or polycyclic ring system having a conjugated π electron system. Specifically included within the definition of "parent aromatic ring system" are fused ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as, for example, indane, indene, phenalene, etc. Typical parent aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like "Aryl:" refers to a monovalent aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Typical aryl groups include, but are not limited to, radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like. In preferred embodiments, the aryl group is (C5. 2o) aryl, with (C5.10) being particularly preferred. Particularly preferred aryl groups are phenyl and naphthyl groups.
"Arylalkyl:" refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal carbon atom, is replaced with an aryl radical. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2- naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like. Where specific alkyl moieties are intended, the nomenclature arylalkanyl, arylakenyl and/or arylalkynyl is used. [In preferred embodiments, the arylalkyl group is (C-6-26) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (Ci-β) and the aryl moiety is (C5-2o)- In particularly preferred embodiments the arylalkyl group is (C6-i3), e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (Ci- 3) and the aryl moiety is (C5-10). Even more preferred arylalkyl groups are phenylalkanyls.
"Alkanyloxy:" refers to a saturated branched, straight-chain or cyclic monovalent hydrocarbon alcohol radical derived by the removal of the hydrogen atom from the hydroxide oxygen of the alcohol. Typical alkanyloxy groups include, but are not limited to, methanyl; ethanyloxy; propanyloxy groups such as propan-1 -yloxy (CH3CH2CH2O-), propan-2-yloxy ((CH3)2CHO- -), cyclopropan-1 -yloxy, etc.; butyanyloxy groups such as butan-1 -yloxy, butan-2-yloxy, 2-methyl-propan-1-yloxy, 2-methyl-propan-2-yloxy, cyclobutan- 1-yloxy, etc.; and the like. In preferred embodiments, the alkanyloxy groups are (C-i-s) alkanyloxy groups, with (C1-3) being particularly preferred.
"Parent Heteroaromatic Ring System:" refers to a parent aromatic ring system in which one or more carbon atoms are each independently replaced with a heteroatom. Typical heteratoms to replace the carbon atoms include, but are not limited to, N, P, O, S, Si etc. Specifically included within the definition of "parent heteroaromatic ring systems" are fused ring systems in which one or more rings are aromatic and one or more rings are saturated or unsaturated, such as, for example, arsindole, chromane, chromene, indole, indoline, xanthene, etc. Typical parent heteroaromatic ring systems include, but are not limited to, arsindole, carbazole, β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like.
"Heteroaryl:" refers to a monovalent heteroaromatic radical derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system. Typical heteroaryl groups include, but are not limited to, radicals derived from acridine, arsindole, carbazole, β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like. In preferred embodiments, the heteroaryl group is a 5-20 membered heteroaryl, with 5-10 membered heteroaryl being particularly preferred. Specific preferred heteroaryls for the present invention are quinoline, isoquinoline, pyridine, pyrimidine, furan, thiophene and imidazole.
"Substituted:" refers to a radical in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s). Typical substituents include, but are not limited to, -X, -R, -O', =O, -OR, -O-OR, -SR, -S-, =S, -NRR, =NR, -CX3, -CN, -OCN, -SCN, -NCO, -NCS, -NO, -NO2, =N2, -N3, -NHOH, -S(O)2O", -S(O)2OH, -S(O)2R, -P(O)(C)2, -P(O)(OH)2, -C(O)R, -C(O)X1 -C(S)R, -C(S)X, -C(O)OR, -C(O)O",
-C(S)OR, -C(O)SR, -C(S)SR, -C(O)NRR, -C(S)NRR and -C(NR)NRR, where each X is independently a halogen (preferably -F, -Cl or -Br) and each R is independently -H, alkyl, alkanyl, alkenyl, alkynyl, alkylidene, alkylidyne, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl or heteroaryl-heteroalkyl, as defined herein. Preferred substituents include hydroxyι halogen, Ci-8alkyl, Ci-8alkanyloxy, fluorinated alkanyloxy, fluorinated alkyl, C-i-salkylthio, Cs-scycloalkyl, Ca-βcycloalkanyloxy, nitroi aminoi Ci-salkylamino, C-i-βdialkylamino, C3-8cycloalkylaminoi CyBnO1 carboxy, Ci-7alkanyloxycarbonyl, Ci-7alkylcarbonyloxy, formyl, carbamoyl, phenyl, aroyl, carbamoyl, amidino, (Ci-8alkylamino)carbonyl, (arylamino)carbonyl and aryl(Ci-8alkyl)carbonyl,
"Aroyl" refers to arylacyl substituents.
"Acyl" refers to alkylcarbonyl substituents.
With reference to substituents, the term "independently" means that when more than one of such substituent is possible, such substituents may be the same or different from each other.
Throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. Thus, for example, a "phenylCi-βalkanylaminocarbonylCi. 6alkyl" substituent refers to a group of the formula alkanyl
Figure imgf000017_0001
Figure imgf000017_0002
The invention is directed to compounds of formula (I)
Figure imgf000017_0003
(I) wherein
HET is a heteroaryl selected from the group consisting of 1 ,3-dihydro-benzoimidazol-2-one-5-yl, 3,4-dihydro-2h-benzo[1 ,4]oxazine, 1 ,2,3,4-tetrahydro-[1 ,8]naphthyridine, 1 h-pyrrolo[2,3-b]pyridine, benzo[b]thiophene-4-yl, benzo[b]thiophene-5-yl, benzo[b]thiophene-6-yl, benzo[b]thiophene-7-yl, benzo[b]furan-4-yl, benzo[b]furan-5-yl, benzo[b]furan-6-yl, benzo[b]furan-7-yl, 4h-quinazoline-1 -yl, 4h-quinazoline-2-yl, 4h-quinazoline-3-yl, quinazoline-2-yl, quinoxaline-2-yl, pteridine, carbazole, acridine, phenazine, pyrrole, thiazole-2-yl, thiazole-4-yl, thiazole-5-yl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, 2-imidazoline-2-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, 2-pyrazoline-3-yl, isoxazole-3-yl, isoxazole-4-yl, isoxazole-5-yl, isothiazole-3-yl, isothiazole-4-yl, isothiazole-5-yl, benzisoxazole, phthalazine-4-yl, isoindole-4-yl, isoindole-5-yl, isoindole-6-yl, isoindole-7-yl, ih-indazole-4-yl, ih-indazole-5-yl, ih-indazole-6-yl, ih-indazole-7-yl, purine-2-yl, purine-6-yl, purine-8-yl, benzimidazole-4-yl, benzimidazole-5-yl, benzimidazole-6-yl, benzimidazole-7-yl, cinnoline-4-yl, cinnoline-7-yl, cinnoline-8-yl, quinoxaline-5-yl, quinoxaline-6-yl, 2,7-naphthyridine-2-yl, pyrazine-2-yl, pyrazine-3-yl, quinazoline-7-yl, 1 ,7-naphthyridine-2-yl, 1 ,7-naphthyridine-5-yl, 1 ,7-naphthyridine-6-yl, 1 ,7-naphthyridine-8-yl, 2,6-naphthyridine-3-yl, 2,6-naphthyridine-4-yl, 2,6-naphthyridine-5-yl, 2,6-naphthyridine-7-yl, 2,6-naphthyridine-8-yl, pyridazine-3-yl, pyridazine-4-yl, pyridazine-5-yl, quinoline-2-yl, quinoline-3-yl, quinoline-4-yl, indoline-4-yl, indoline-5-yl, indoline-6-yl, indoline-7-yl, isoquinoline-1-yl, isoquinoline-3-yl, isoquinoline-4-yl, cinnoline-3-yl, cinnoline-5-yl, cinnoline-6-yl, phthalazine-5-yl, phthalazine-6-yl, quinazoline-4-yl, quinazoline-5-yl, quinazoline-6-yl, quinazoline-8-yl, 1 ,6-naphthyridine-2-yl, 1 ,6-naphthyridine-3-yl, 1 ,6-naphthyridine-4-yl, 1 ,6-naphthyridine-5-yl,
1 ,6-naphthyridine-7-yl, 1 ,6-naphthyridine-8-yl, 1 ,8-naphthyridine-2-yl, 1 ,8-naphthyridine-3-yl, 1 ,8-naphthyridine-4-yl, 1 ,7-naphthyridine-3-yl, 1 ,7-naphthyridine-4-yl, 2,6-naphthyridine-1-yl, 2,7-naphthyridine-3-yl, 2,7-naphthyridine-4-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, benzisothiazolyl, and benzothiazolyl;
Ar is an aryl selected from the group consisting of benzo[b]thiophenyl, naphthyl, biphenyl, isoquinolinyl, thiophenyl, pyridazinyl, and benzothiazolyl; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
In another embodiment, the present invention is directed to compounds of formula (I) wherein HET is a heteroaryl selected from the group consisting of 1 ,3-dihydro-benzoimidazol-2-one-5-yl,
3,4-dihydro-2h-benzo[1 ,4]oxazine,
1 ,2,3,4-tetrahydro-[1 ,8]naphthyridine, 1 h-pyrrolo[2,3-b]pyridine, benzo[b]thiophene-4-yl, benzo[b]thiophene-5-yl, benzo[b]thiophene-6-yl, benzo[b]thiophene-7-yl, 4h-quinazoline-1 -yl, 4h-quinazoline-2-yl, 4h-quinazoline-3-yl, quinazoline-2-yl, quinoxaline-2-yl, pteridine, carbazole, acridine, phenazine, pyrrole, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, 2-imidazoline-2-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, 2-pyrazoline-3-yl, isoxazole-3-yl, isoxazole-4-yl, isoxazole-5-yl, isothiazole-3-yl, isothiazole-4-yl, isothiazole-5-yl, benzisoxazole, phthaIazine-4-yl, isoindole-4-yl, isoindole-5-yl, isoindole-6-yl, isoindole-7-yl, ih-indazole-4-yl, ih-indazole-5-yl, ih-indazole-6-yl, ih-indazole-7-yl, purine-2-yl, purine-6-yl, purine-8-yl, cinnoline-4-yl, cinnoline-7-yl, cinnoline-8-yl, quinoxaline-5-yl, quinoxaline-6-yl, 2,7-naphthyridine-2-yl, pyrazine-2-yl, pyrazine-3-yl, quinazoline-7-yl, 1 ,7-naphthyridine-2-yl, 1 ,7-naphthyridine-5-yl, 1 ,7-naphthyridine-6-yl, 1 ,7-naphthyridine-8-yl, 2,6-naphthyridine-3-yl, 2,6-naphthyridine-4-yl, 2,6-naphthyridine-5-yl, 2,6-naphthyridine-7-yl, 2,6-naphthyridine-8-yl, pyridazine-3-yl, pyridazine-4-yl, pyridazine-5-yl, indoline-4-yl, indo!ine-5-yl, indoline-6-yl, indoline-7-yl, cinnoline-3-yl, cinnoline-5-yl, cinnoline-6-yl, phthalazine-5-yl, phthalazine-6-yl, quinazoline-4-yl, quinazoline-5-yl, quinazoline-6-yl, quinazoline-8-yl, 1 ,6-naphthyridine-2-yl, 1,6-naphthyridine-3-yl, 1 ,6-naphthyridine-4-yl, 1,6-naphthyridine-5-yl,
1 ,6-naphthyridine-7-yl, 1 ,6-naphthyridine-8-yl, 1 ,8-naphthyridine-2-yl, 1 ,8-naphthyridine-3-yl, 1 ,8-naphthyridine-4-yl, 1 ,7-naphthyridine-3-yl, 1 ,7-naphthyridine-4-yl, 2,6-naphthyridine-1-yl, 2,7-naphthyridine-3-yl, 2,7-naphthyridine-4-yl, and benzisothiazole; Ar is an aryl selected from the group consisting of benzo[b]thiophenyl, naphthalenyl, biphenyl, quinolinyl, isoquinolinyl, thiophenyl, pyrimidinyl, pyridazinyl, phenyl, benzothiazole, and pyridinyl;and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
In another embodiment, the present invention is directed to compounds of formula (I) wherein HET is a heteroaryl selected from the group consisting of 1,3-dihydro-benzoimidazol-2-one-5-yl, 3,4-dihydro-2h-benzo[1 ,4]oxazine,
1 ,2,3,4-tetrahydro-[1 ,8]naphthyridine, 1h-pyrrolo[2,3-b]pyridine, benzo[b]thiophene-4-yl, benzo[b]thiophene-5-yl, benzo[b]thiophene-6-yl, benzo[b]thiophene-7-yl, 4h-quinazoline-1 -yl, 4h-quinazoline-2-yl, 4h-quinazoline-3-yl, quinazoline-2-yl, quinoxaline-2-yl, pteridine, carbazole, acridine, phenazine, pyrrole, thiazole-2-yl, thiazole-4-yl, thiazole-5-yl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, 2-imidazoline-2-yl, pyrazolθ-3-yl, pyrazole-4-yl, pyrazole-5-yl, 2-pyrazoline-3-yl, isoxazole-3-yl, isoxazole-4-yl, isoxazole-5-yl, isothiazole-3-yl, isothiazole-4-yl, isothiazole-5-yl, benzisoxazole, phthalazine-4-yl, isoindole-4-yl, isoindole-5-yl, isoindole-6-yl, isoindole-7-yl, ih-indazole-4-yl, ih-indazole-5-yl, ih-indazole-6-yl, ih-indazolθ-7-yl, purine-2-yl, purine-6-yl, purine-8-yl, cinnoline-4-yl, cinnoline-7-yl, cinnoline-8-yl, quinoxaline-5-yl, quinoxaline-6-yl, 2,7-naphthyridine-2-yl, pyrazine-2-yl, pyrazine-3-yl, quinazoline-7-yl, 1 ,7-naphthyridine-2-yl, 1 ,7-naphthyridine-5-yl, 1 ,7-naphthyridine-6-yl, 1 ,7-naphthyridine-8-yl, 2,6-naphthyridine-3-yl, 2,6-naphthyridine-4-yl, 2,6-naphthyridine-5-yl, 2,6-naphthyridine-7-yl, 2,6-naphthyridine-8-yl, pyridazine-3-yl, pyridazine-4-yl, pyridazine-5-yl, indoline-4-yl, indoline-5-yl, indoline-6-yl, indoline-7-yl, cinnoline-3-yl, cinnoline-5-yl, cinnoline-6-yl, phthalazine-5-yl, phthalazine-6-yl, quinazoline-4-yl, quinazoline-5-yl, quinazoline-6-yl, quinazoline-8-yl, 1 ,6-naphthyridine-2-yl, 1 ,6-naphthyridine-3-yl, 1 ,6-naphthyridine-4-yl, 1 ,6-naphthyridine-5-yl, 1 ,6-naphthyridine-7-yl, 1 ,6-naphthyridine-8-yl,
1 ,8-naphthyridine-2-yl, 1 ,8-naphthyridine-3-yl, 1 ,8-naphthyridine-4-yl, 1 ,7-naphthyridine-3-yl, 1 ,7-naphthyridine-4-yl, 2,6-naphthyridine-i-yl, 2,7-naphthyridine-3-yl, 2,7-naphthyridine-4-yl, and benzisothiazole; Ar is an aryl selected from the group consisting of thiophenyl, pyrimidinyl, pyridazinyl, phenyl, benzothiazole, and pyridinyl;and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
In another embodiment, the present invention is directed to compounds of formula (I) wherein
HET is a heteroaryl selected from the group consisting of 1 ,3-dihydro-benzoimidazol-2-one-5-yl, 3,4-dihydro-2h-benzo[1 ,4]oxazine, 1 ,2,3,4-tetrahydro-[1 ,8]naphthyridine, 1h-pyrrolo[2,3-b]pyridine, benzo[b]thiophene-4-yl, benzo[b]thiophene-5-yl, benzo[b]thiophene-6-yl, benzo[b]thiophene-7-yl, 4h-quinazoline-1 -yl, 4h-quinazoline-2-yl, 4h-quinazoline-3-yl, quinazoline-2-yl, quinoxaline-2-yl, pteridine, carbazole, acridine, phenazine, pyrrole, thiazole-2-yl, thiazole-4-yl, thiazole-5-yl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, 2-imidazoline-2-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, 2-pyrazoline-3-yl, isoxazole-3-yl, isoxazole-4-yl, isoxazole-5-yl, isothiazole-3-yl, isothiazoIe-4-yl, isothiazole-5-yl, benzisoxazole, phthalazine-4-yl, isoindole-4-yl, isoindole-5-yl, isoindole-6-yl, isoindole-7-yl, ih-indazole-4-yl, ih-indazole-5-yl, ih-indazole-6-yl, ih-indazole-7-yl, purine-2-yl, purine-6-yl, purine-8-yl, benzimidazole-4-yl, benzimidazole-5-yl, benzimidazole-6-yl, benzimidazole-7-yl, cinnoline-4-yl, cinnoline-7-yl, cinnoline-8-yl, quinoxaline-5-yl, quinoxaline-6-yl, 2,7-naphthyridine-2-yl, pyrazine-2-yl, pyrazine-3-yl, quinazoline-7-yl, 1 ,7-naphthyridine-2-yl, 1 ,7-naphthyridine-5-yl, 1 ,7-naphthyridine-6-yl, 1 ,7-naphthyridine-8-yl, 2,6-naphthyridine-3-yl, 2,6-naphthyridine-4-yl, 2,6-naphthyridine-5-yl, 2,6-naphthyridine-7-yl, 2,6-naphthyridine-8-yl, pyridazine-3-yl, pyridazine-4-yl, pyridazine-5-yl, indoline-4-yl, indoline-5-yl, indoline-6-yl, indoline-7-yI, cinnoline-3-yl, cinnoline-5-yl, cinnoline-6-yl, phthalazine-5-yl, phthalazine-6-yl, quinazoline-4-yl, quinazoline-5-yl, quinazoline-6-yl, quinazoline-8-yl, 1 ,6-naphthyridine-2-yl, 1 ,6-naphthyridine-3-yl, 1 ,6-naphthyridine-4-yl, 1 ,6-naphthyridine-5-yl, 1 ,6-naphthyridine-7-yl, 1 ,6-naphthyridine-8-yl, 1 ,8-naphthyridine-2-yl,
1 ,8-naphthyridine-3-yl, 1 ,8-naphthyridine-4-yl, 1 ,7-naphthyridine-3-yl, 1 ,7-naphthyridine-4-yl, 2,6-naphthyridine-1-yl, 2,7-naphthyridine-3-yl, 2,7-naphthyridine-4-yl, benzisothiazolyl, and benzothiazolyl; Ar is an aryl selected from the group consisting of phenyl, benzothiazole, and pyridinyl; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof. In another embodiment, the present invention is directed to compounds of formula (I) wherein
HET is a phthalazine-4-yl, isoindole-4-yl, isoindole-5-yl, isoindole-6-yl, isoindole-7-yl, ih-indazole-4-yl, ih-indazole-5-yl, ih-indazole-6-yl, ih-indazole-7-yl, purine-2-yl, purine-6-yl, purine-8-yl, benzimidazole-4-yl, benzimidazole-5-yl, benzimidazole-6-yl, benzimidazole-7-yl, cinnoline-4-yl, cinnoline-7-yl, cinnoline-8-yl, quinoxaline-5-yl, quinoxaline-6-yl, 2,7-naphthyridine-2-yl, pyrazine-2-yl, pyrazine-3-yl, quinazoline-7-yl, 1 ,7-naphthyridine-2-yl, 1 ,7-naphthyridine-5-yl, 1 ,7-naphthyridine-6-yl, 1 ,7-naphthyridine-8-yl,
2,6-naphthyridine-3-yl, 2,6-naphthyridine-4-yl, 2,6-naphthyridine-5-yl, 2,6-naphthyridine-7-yl, 2,6-naphthyridine-δ-yl, pyridazine-3-yl, pyridazine-4-yl, pyridazine-5-yl, quinoline-2-yl, quinoline-3-yl, quinoline-4-yl, indoline-4-yl, indoline-5-yl, indoline-6-yl, indoline-7-yl, isoquinoline-1-yl, isoquinoline-3-yl, isoquinoline-4-yl, cinnoline-3-yl, cinnoline-5-yl, cinnoline-6-yl, phthalazine-5-yl, phthalazine-6-yI, quinazoline-4-yl, quinazoline-5-yl, quinazoline-6-yl, quinazoline-8-yl, 1 ,6-naphthyridine-2-yl, 1 ,6-naphthyridine-3-yl, 1 ,6-naphthyridine-4-yl, 1 ,6-naphthyridine-5-yl, 1 ,6-naphthyridine-7-yl, 1 ,6-naphthyridine-8-yl, 1 ,8-naphthyridine-2-yl, 1 ,8-naphthyridine-3-yl, 1 ,8-naphthyridine-4-yl,
1 ,7-naphthyridine-3-yl, 1 ,7-naphthyridine-4-yl, 2,6-naphthyridine-1-yl, 2,7-naphthyridine-3-yl, 2,7-naphthyridine-4-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, benzisothiazolyl, and benzothiazolyl;
Ar is an aryl selected from the group consisting of benzo[b]thiophenyl, naphthyl, biphenyl, isoquinolinyl, thiophenyl, pyridazinyl, and benzothiazolyl; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
In another embodiment, the present invention is directed to compounds of formula (I) wherein HET is a heteroaryl selected from the group consisting of quinoline-2-yl, quinoline-3-yl, quinoline-4-yl, indoline-4-yl, indoline-5-yl, indoline-6-yl, indoline-7-yl, isoquinoline-1-yl, isoquinoline-3-yl, isoquinoline-4-yl, cinnoline-3-yl, cinnoline-5-yl, cinnoline-6-yl, phthalazine-5-yl, phthalazine-6-yl, quinazoline-4-yl, quinazoline-5-yl, quinazoline-6-yl, quinazoline-8-yl, 1 ,6-naphthyridine-2-yl, 1 ,6-naphthyridine-3-yl, 1 ,6-naphthyridine-4-yl, 1 ,6-naphthyridine-5-yl, 1 ,6-naphthyridine-7-yl,
1 ,6-naphthyridine-8-yl, 1 ,8-naphthyridine-2-yl, 1 ,8-naphthyridine-3-yl, 1 ,8-naphthyridine-4-yl, 1 ,7-naphthyridine-3-yl, 1 ,7-naphthyridine-4-yl, 2,6-naphthyridine-1-yl, 2,7-naphthyridine-3-yl, 2,7-naphthyridine-4-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, benzisothiazolyl, and benzothiazolyl;
Ar is an aryl selected from the group consisting of benzo[b]thiophenyl, naphthyl, biphenyl, isoquinolinyl, thiophenyl, pyridazinyl, and benzothiazolyl; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
In another embodiment, the present invention is directed to compounds of formula (I) wherein HET is a heteroaryl selected from the group consisting of 1 ,3-dihydro-benzoimidazol-2-one-5-yl,
3,4-dihydro-2h-benzo[1 ,4]oxazine,
1 ,2,3,4-tetrahydro-[1 ,8]naphthyridine, 1h-pyrrolo[2,3-b]pyridine, benzo[b]thiophene-4-yl, benzo[b]thiophene-5-yl, benzo[b]thiophene-6-yl, benzo[b]thiophene-7-yl, benzo[b]furan-4-yl, benzo[b]furan-5-yl, benzo[b]furan-6-yl, benzo[b]furan-7-yl,
4h-quinazoline-1-yl, 4h-quinazoline-2-yl, 4h-quinazoline-3-yl, quinazoline-2-yl, quinoxaline-2-yl, pteridine, carbazole, acridine, phenazine, pyrrole, thiazole-2-yl, thiazole-4-yl, thiazole-5-yl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, 2-imidazoline-2-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, 2-pyrazoline-3-yl, isoxazole-3-yl, isoxazole-4-yl, isoxazole-5-yl, isothiazole-3-yl, isothiazole-4-yl, isothiazole-5-yl, benzisoxazole, phthalazine-4-yl, isoindole-4-yl, isoindole-5-yl, isoindole-6-yl, isoindole-7-yl, ih-indazole-4-yl, ih-indazole-5-yl, ih-indazole-6-yl, ih-indazole-7-yl, purine-2-yl, purine-6-yl, purine-8-yl, benzimidazole-4-yl, benzimidazole-5-yl, benzimidazole-6-yl, benzimidazole-7-yl, cinnoline-4-yl, cinnoline-7-yl, cinnoline-8-yl, quinoxaline-5-yl, quinoxaline-6-yl, 2,7-naphthyridine-2-yl, pyrazine-2-yl, pyrazine-3-yl, quinazoline-7-yl, 1 ,7-naphthyridine-2-yl, 1 ,7-naphthyιϊdine-5-yl, 1 ,7-naphthyridine-6-yl, 1 ,7-naphthyridine-8-yl, 2,6-naphthyridine-3-yl, 2,6-naphthyridine-4-yl, 2,6-naphthyridine-5-yl, 2,6-naphthyridine-7-yl, 2,6-naphthyridine-8-yl, pyridazine-3-yl, pyridazine-4-yl, pyridazine-5-yl, quinoline-2-yl, quinoline-3-yl, quinoline-4-yl, indoline-4-yl, indoline-5-yl, indoline-6-yl, indoline-7-yl, isoquinoline-1-yl, isoquinoline-3-yl, isoquinoline-4-yl, cinnoline-3-yl, cinnoline-5-yl, cinnoline-6-yl, phthalazine-5-yl, phthalazine-6-yl, quinazoline-4-yl, quinazoline-5-yl, quinazoline-6-yl, quinazoline-8-yl, 1 ,6-naphthyridine-2-yl, 1 ,6-naphthyridine-3-yl, 1 ,6-naphthyridine-4-yl, 1 ,6-naphthyridine-5-yl,
1 ,6-naphthyridine-7-yl, 1 ,6-naphthyridine-8-yl, 1 ,8-naphthyrϊdine-2-yl, 1 ,8-naphthyridine-3-yl, 1 ,8-naphthyridine-4-yl, 1 ,7-naphthyιϊdine-3-yl, 1 ,7-naphthyridine-4-yl, 2,6-naphthyridine-1-yl, 2,7-naphthyιϊdine-3-yl, 2,7-naphthyridine-4-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, benzisothiazolyl, and benzothiazolyl;
Ar is an aryl selected from the group consisting of benzo[b]thiophenyl, naphthalenyl, biphenyl, quinolinyl, isoquinolinyl, thiophenyl, pyrimidinyl, pyridazinyl, phenyl, benzothiazolyl, and pyridinyl; provided that when HET is benzimidazolyl, Ar is not pyrimidinyl or phenyl; and provided that when HET is pyrazolyl, Ar is not phenyl; and provided that when het is benzofuranyl, Ar is not pyridinyl; and provided that when het is benzothiazolyl, Ar is not pyrimidinyl; and provided that when HET is isoquinolinyl, Ar is not pyridinyl; and provided that when HET is pyridinyl, Ar is not pyrimidinyl, pyridinyl, or phenyl; and provided that when HET is quinolinyl, Ar is not pyrimidinyl or pyridinyl; and provided that when HET is thiazolyl, Ar is not quinolinyl; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof. In another embodiment, the present invention is directed to compounds of formula (I) wherein HET is a heteroaryl selected from the group consisting of 1 ,3-dihydro-benzoimidazol-2-one-5-yl, 3,4-dihydro-2h-benzo[1 ,4]oxazine,
1 ,2,3,4-tetrahydro-[1 ,8]naphthyridine, 1 h-pyrrolo[2,3-b]pyridine, benzo[b]thiophene-4-yl, benzo[b]thiophene-5-yl, benzo[b]thiophene-6-yl, benzo[b]thiophene-7-yl, benzo[b]furan-4-yl, benzo[b]furan-5-yl, benzo[b]furan-6-yl, benzo[b]furan-7-yl, 4h-quinazoline-1-yl, 4h-quinazoline-2-yl, 4h-quinazoline-3-yl, quinazoline-2-yl, quinoxaline-2-yl, pteridine, carbazole, acridine, phenazine, pyrrole, thiazole-2-yl, thiazole-4-yl, thiazole-5-yl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, 2-imidazoline-2-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, 2-pyrazoline-3-yl, isoxazole-3-yl, isoxazole-4-yl, isoxazole-5-yl, isothiazole-3-yl, isothiazole-4-yl, isothiazole-5-yl, benzisoxazole, phthalazine-4-yl, isoindole-4-yl, isoindole-5-yl, isoindole-6-yl, isoindole-7-yl, ih-indazole-4-yl, ih-indazole-5-yl, ih-indazole-6-yl, ih-indazole-7-yl, purine-2-yl, purine-6-yl, purine-8-yl, benzimidazole-4-yl, benzimidazole-5-yl, benzimidazole-6-yl, benzimidazole-7-yl, cinnoline-4-yl, cinnoline-7-yl, cinnoline-8-yl, quinoxaline-5-yl, quinoxaline-6-yl, 2,7-naphthyridine-2-yl, pyrazine-2-yl, pyrazine-3-yl, quinazoline-7-yl, 1 ,7-naphthyridine-2-yl, 1 ,7-naphthyridine-5-yl,
1 ,7-naphthyridine-6-yl, 1 ,7-naphthyridine-8-yl, 2,6-naphthyridine-3-yl, 2,6-naphthyridine-4-yl, 2,6-naphthyridine-5-yl, 2,6-naphthyridine-7-yl, 2,6-naphthyridine-8-yl, pyridazine-3-yl, pyridazine-4-yl, pyridazine-5-yl, quinoline-2-yl, quinoline-3-yl, quinoline-4-yl, indoline-4-yl, indoline-5-yl, indoline-6-yl, indoline-7-yl, isoquinoline-1-yl, isoquinoline-3-yl, isoquinoline-4-yl, cinnoline-3-yl, cinnoline-5-yl, cinnoline-6-yl, phthalazine-5-yl, phthalazine-6-yl, quinazoline-4-yl, quinazoline-5-yl, quinazoline-6-yl, quinazoline-8-yl, 1 ,6-naphthyridine-2-yl, 1 ,6-naphthyridine-3-yl, 1 ,6-naphthyridine-4-yl, 1 ,6-naphthyridine-5-yl, 1 ,6-naphthyridine-7-yl, 1 ,6-naphthyridine-8-yl, 1 ,8-naphthyridine-2-yl, 1 ,8~naphthyridine-3-yl, 1 ,8-naphthyridine-4-yl, 1 ,7-naphthyridine-3-yl, 1 ,7-naphthyridine-4-yl, 2,6-naphthyridine-1-yl, 2,7-naphthyridine-3-yl, 2,7-naphthyridine-4-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, benzisothiazolyl, and benzothiazolyl;
Ar is an aryl selected from the group consisting of thiophenyl, pyrimidinyl, pyridazinyl, phenyl, benzothiazolyl, and pyridinyl; provided that when HET is benzimidazolyl, Ar is not pyrimidinyl or phenyl; and provided that when HET is pyrazolyl, Ar is not phenyl; and provided that when
HET is benzofuranyl, Ar is not pyridinyl; and provided that when HET is benzothiazolyl, Ar is not pyrimidinyl; and provided that when HET is isoquinolinyl, Ar is not pyridinyl; and provided that when HET is pyridinyl, Ar is not pyrimidinyl, pyridinyl or phenyl; and provided that when HET is pyridinyl, Ar is not phenyl, pyridinyl; and provided that when HET is quinolinyl, Ar is not pyrimidinyl; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
In another embodiment, the present invention is directed to compounds of formula (I) wherein HET is a heteroaryl selected from the group consisting of 1 ,3-dihydro-benzoimidazol-2-one-5-yl, 3,4-dihydro-2h-benzo[1 ,4]oxazine, 1 ,2,3,4-tetrahydro-[1 ,8]naphthyridine, 1 h-pyrrolo[2,3-b]pyridine, benzo[b]thiophene-4-yl, benzo[b]thiophene-5-yl, benzo[b]thiophene-6-yl, benzo[b]thiophene-7-yl, benzo[b]furan-4-yl, benzo[b]furan-5-yl, benzo[b]furan-6-yl, benzo[b]furan-7-yl, 4h-quinazoline-1-yl, 4h-quinazoline-2-yl, 4h-quinazoline-3-yl, quinazoline-2-yl, quinoxaline-2-yl, pteridine, carbazole, acridine, phenazine, pyrrole, thiazole-2-yl, thiazole-4-yl, thiazole-5-yl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, 2-imidazoline-2-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, 2-pyrazoline-3-yl, isoxazole-3-yl, isoxazole-4-yl, isoxazole-5-yl, isothiazole-3-yl, isothiazole-4-yl, isothiazole-5-yl, benzisoxazole, phthalazine-4-yl, isoindole-4-yl, isoindole-5-yl, isoindole-6-yl, isoindole-7-yl, ih-indazole-4-yl, ih-indazole-5-yl, ih-indazole-6-yl, ih-indazole-7-yl, purine-2-yl, purine-6-yl, purine-8-yl, benzimidazole-4-yl, benzimidazole-5-yl, benzimidazole-6-yl, benzimidazole-7-yl, cinnoline-4-yl, cinnoline-7-yl, cinnoline-8-yI, quinoxaline-5-yl, quinoxaline-6-yI, 2,7-naphthyridine-2-yl, pyrazine-2-yl, pyrazine-3-yl, quinazoline-7-yl, 1 ,7-naphthyridine-2-yl, 1 ,7-naphthyridine-5-yl, 1 ,7-naphthyridine-6-yl, 1,7-naphthyridine-8-yl, 2,6-naphthyridine-3-yl,
2,6-naphthyridine-4-yl, 2,6-naphthyridine-5-yl, 2,6-naphthyridine-7-yl, 2,6-naphthyridine-8-yl, pyridazine-3-yl, pyridazine-4-yl, pyridazine-5-yl, quinoline-2-yl, quinoline-3-yl, quinoline-4-yl, indoline-4-yl, indoline-5-yl, indoline-6-yl, indoline-7-yl, isoquinoline-1-yl, isoquinoline-3-yl, isoquinoline-4-yl, cinnoline-3-yl, cinnoline-5-yl, cinnoline-6-yl, phthalazine-5-yl, phthalazine-6-yl, quinazoline-4-yl, quinazoline-5-yl, quinazoline-6-yl, quinazoline-8-yi, 1 ,6-naphthyridine-2-yl, 1 ,6-naphthyridine-3-yl, 1 ,6-naphthyridine-4-yl, 1 ,6-naphthyridine-5-yI, 1 ,6-naphthyridine-7-yl, 1 ,6-naphthyridine-8-yl, 1 ,8-naphthyridine-2-yl, 1 ,8-naphthyridine-3-yl, 1 ,8-naphthyridine-4-yl, 1 ,7-naphthyridine-3-yl,
1 ,7-naphthyridine-4-yl, 2,6-naphthyridine-1-yl, 2,7-naphthyridine-3-yl, 2,7-naphthyridine-4-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, benzisothiazolyl, and benzothiazolyl; Ar is an aryl selected from the group consisting of phenyl, benzothiazole, and pyridine; provided that when HET is pyrazolyl, Ar is not phenyl; and provided that when HET is benzimidazolyl, Ar is not phenyl; and provided that when HET is benzofuranyl, Ar is not pyridinyl; and provided that when HET is isoquinolinyl, Ar is not pyridinyl; and provided that when HET is pyridinyl, Ar is not pyridinyl or phenyl; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof. In another embodiment, the present invention is directed to compounds of formula (I) wherein HET is a heteroaryl selected from the group consisting of phthalazine-4-yl, isoindole-4-yl, isoindole-5-yl, isoindole-6-yl, isoindole-7-yl, ih-indazole-4-yl, ih-indazole-5-yl, ih-indazole-6-yl, ih-indazole-7-yl, purine-2-yl, purine-6-yl, purine-8-yl, benzimidazole-4-yl, benzimidazole-5-yl, benzimidazole-6-yl, benzimidazole-7-yl, cinnoline-4-yl, cinnoline-7-yl, cinnoline-8-yl, quinoxaline-5-yl, quinoxaline-6-yl, 2,7-naphthyridine-2-yl, pyrazine-2-yl, pyrazine-3-yl, quinazoline-7-yl, 1 ,7-naphthyridine-2-yl, 1,7-naphthyridine-5-yl,
1 ,7-naphthyridine-6-yl, 1 ,7-naphthyridine-8-yl, 2,6-naphthyridine-3-yl, 2,6-naphthyridine-4-yl, 2,6-naphthyridine-5-yl, 2,6-naphthyridine-7-yl, 2,6-naphthyridine-8-yl, pyridazine-3-yl, pyridazine-4-yl, pyridazine-5-yl, quinoline-2-yl, quinoline-3-yl, quinoline-4-yl, indoline-4-yl, indoline-5-yl, indoline-6-yl, indoline-7-yl, isoquinoline-1-yl, isoquinoline-3-yl, isoquinoline-4-yl, cinnoline-3-yl, cinnoline-5-yl, cinnoline-6-yl, phthalazine-5-yl, phthalazine-6-yl, quinazoline-4-yl, quinazoline-5-yl, quinazoline-6-yl, quinazoline-8-yl, 1 ,6-naphthyridine-2-yl, 1 ,6-naphthyridine-3-yl, 1 ,6-naphthyridine-4-yl, 1 ,6-naphthyridine-5-yl, 1 ,6-naphthyridine-7-yl, 1 ,6-naphthyridine-8-yl, 1 ,8-naphthyridine-2-yl,
1 ,8-naphthyridine-3-yl, 1 ,8-naphthyridine-4-yl, 1 ,7-naphthyridine-3-yl, 1 ,7-naphthyridine-4-yl, 2,6-naphthyridine-1-yl, 2,7-naphthyridine-3-yl, 2,7-naphthyridine-4-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, benzisothiazolyl, and benzothiazolyl; Ar is an aryl selected from the group consisting of benzo[b]thiophenyl, naphthalenyl, biphenyl, quinolinyl, isoquinolinyl, thiophenyl, pyrimidinyl, pyridazinyl, phenyl, benzothiazolyl, and pyridinyl; provided that when HET is benzimidazolyl, Ar is not pyrimidinyl or phenyl; and provided that when HET is benzothiazolyl, Ar is not pyrimidinyl; and provided that when HET is isoquinolinyl, Ar is not pyridinyl; and provided that when HET is pyridinyl, Ar is not pyrimidinyl, pyridinyl or phenyl; and provided that when HET is quinolinyl, Ar is not pyrimidinyl; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
In another embodiment, the present invention is directed to compounds of formula (I) wherein
HET is a heteroaryl selected from the group consisting of phthalazine-4-yl, isoindole-4-yl, isoindole-5-yl, isoindole-6-yl, isoindole-7-yl, ih-indazole-4-yl, ih-indazole-5-yl, ih-indazole-6-yl, ih-indazole-7-yl, purine-2-yl, purine-6-yl, purine-8-yl, benzimidazole-4-yl, benzimidazole-5-yl, benzimidazole-6-yl, benzimidazole-7-yl, cinnoline-4-yl, cinnoline-7-yl, cinnoline-8-yl, quinoxaline-5-yl, quinoxaline-6-yl, 2,7-naphthyridine-2-yl, pyrazine-2-yl, pyrazine-3-yl, quinazoline-7-yl, 1 ,7-naphthyridine-2-yl, 1 ,7-naphthyridine-5-yl, 1 ,7-naphthyridine-6-yl, 1 ,7-naphthyridine-8-yl, 2,6-naphthyridine-3-yl,
2,6-naphthyridine-4-yl, 2,6-naphthyridine-5-yl, 2,6-naphthyridine-7-yl, 2,6-naphthyridine-8-yl, pyridazine-3-yl, pyridazine-4-yl, pyridazine-5-yl, quinoline-2-yl, quinoline-3-yl, quinoline-4-yl, indoline-4-yl, indoline-5-yl, indoline-6-yl, indoline-7-yl, isoquinoline-1-yl, isoquinoline-3-yl, isoquinoline-4-yl, cinnoline-3-yl, cinnoline-5-yl, cinnoline-6-yl, phthalazine-5-yl, phthalazine-6-yl, quinazoline-4-yl, quinazoline-5-yl, quinazoline-6-yl, quinazoline-8-yl, 1 ,6-naphthyridine-2-yl, 1 ,6-naphthyridine-3-yl, 1 ,6-naphthyridine-4-yl, 1 ,6-naphthyridine-5-yl, 1 ,6-naphthyridine-7-yl, 1 ,6-naphthyridine-8-yl, 1 ,8-naphthyridine-2-yl, 1,8-naphthyridine-3-yl, 1 ,8-naphthyridine-4-yl, 1 ,7-naphthyridine-3-yl,
1 ,7-naphthyridine-4-yl, 2,6-naphthyridine-1-yl, 2,7-naphthyridine-3-yl, 2,7-naphthyridine-4-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, benzisothiazolyl, and benzothiazolyl; Ar is an aryl selected from the group consisting of thiophenyl, pyrimidinyl, pyridazinyl, phenyl, benzothiazolyl, and pyridinyl; provided that when
HET is benzimidazolyl, Ar is not pyrimidinyl or phenyl; and provided that when HET is benzothiazolyl, Ar is not pyrimidinyl; and provided that when HET is isoquinolin-5-yl, Ar is not pyridinyl; and provided that when HET is pyridinyl, Ar is not pyrimidinyl, pyridinyl, or phenyl;and provided that when HET is quinolinyl, Ar is not pyrimidinyl; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
In another embodiment, the present invention is directed to compounds of formula (I) wherein HET is a heteroaryl selected from the group consisting of phthalazine-4-yl, isoindole-4-yl, isoindole-5-yl, isoindole-6-yl, isoindole-7-yl, ih-indazole-4-yl, ih-indazole-5-yl, ih-indazole-6-yl, ih-indazole-7-yl, purine-2-yl, purine-6-yl, purine-8-yl, benzimidazole-4-yl, benzimidazole-5-yl, benzimidazole-6-yl, benzimidazole-7-yl, cinnoline-4-yl, cinnoline-7-yl, cinnoline-8-yl, quinoxaline-5-yl, quinoxaline-6-yl, 2,7-naphthyridine-2-yl, pyrazine-2-yl, pyrazine-3-yl, quinazoline-7-yl, 1 ,7-naphthyridine-2-yl, 1 ,7-naphthyridine-5-yl, 1 ,7-naphthyridine-6-yl, 1 ,7-naphthyridine-8-yl, 2,6-naphthyridine-3-yl, 2,6-naphthyridine-4-yl, 2,6-naphthyridine-5-yl, 2,6-naphthyridine-7-yl, 2,6-naphthyridine-8-yl, pyridazine-3-yl, pyridazine-4-yl, pyridazine-5-yl, quinoline-2-yl, quinoline-3-yl, quinoline-4-yl, indoline-4-yl, indoline-5-yl, indoline-6-yl, indoline-7-yl, isoquinoline-1-yl, isoquinoline-3-yl, isoquinoline-4-yl, cinnoline-3-yl, cinnoline-5-yl, cinnoline-6-yl, phthalazine-5-yl, phthalazine-6-yl, quinazoline-4-yl, quinazoline-5-yl, quinazoline-6-yl, quinazoline-8-yl, 1 ,6-naphthyridine-2-yl, 1 ,6-naphthyridine-3-yl, 1 ,6-naphthyridine-4-yl, 1 ,6-naphthyridine-5-yl,
1 ,6-naphthyridine-7-yl, 1 ,6-naphthyridine-8-yl, 1 ,8-naphthyridine-2-yl, 1 ,8-naphthyridine-3-yl, 1 ,8-naphthyridine-4-yl, 1 ,7-naphthyridine-3-yl, 1 ,7-naphthyridine-4-yl, 2,6-naphthyridine-1-yl, 2,7-naphthyridine-3-yl, 2,7-naphthyridine-4-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, benzisothiazolyl, and benzothiazolyl;
Ar is an aryl selected from the group consisting of phenyl, benzothiazole, and pyridine; provided that when HET is benzimidazolyl, Ar is not phenyl; and provided that when HET is isoquinolinyl, Ar is not pyridinyl; and provided that when HET is pyridinyl, Ar is not pyridinyl or phenyl; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
In another embodiment, the present invention is directed to compounds of formula (I) wherein HET is a heteroaryl selected from the group consisting of quinoline-2-yl, quinoline-3-yl, quinoline-4-yl, indoline-4-yl, indoline-5-yl, indoline-6-yl, indoline-7-yl, isoquinoline-1-yl, isoquinoline-3-yl, isoquinoline-4-yl, cinnoline-3-yl, cinnoline-5-yl, cinnoline-6-yl, phthalazine-5-yl, phthalazine-6-yl, quinazoIine-4-yl, quinazoline-5-yl, quinazoline-6-yl, quinazoline-8-yl, 1 ,6-naphthyridine-2-yl, 1 ,6-naphthyridine-3-yl, 1 ,6-naphthyridine-4-yl, 1 ,6-naphthyridine-5-yl, 1,6-naphthyridine-7-yl,
1 ,6-naphthyridine-8-yl, 1 ,8-naphthyridine-2-yl, 1 ,8-naphthyridine-3-yl, 1 ,8-naphthyridine-4-yl, 1 ,7-naphthyridine-3-yl, 1 ,7-naphthyridine-4-yl, 2,6-naphthyridine-1 -yl, 2,7-naphthyridine-3-yl, 2,7-naphthyridine-4-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, benzisothiazolyl, and benzothiazolyl;
Ar is an aryl selected from the group consisting of benzo[b]thiophenyl, naphthalenyl, biphenyl, quinolinyl, isoquinolinyl, thiophenyl, pyrimidinyl, pyridazinyl, phenyl, benzothiazolyl, and pyridinyl; provided that when HET is benzothiazolyl, Ar is not pyrimidiny; and provided that when HET is isoquinolinyl, Ar is not pyridinyl; and provided that when HET is pyridinyl, Ar is not pyrimidinyl, pyridinyl, or phenyl; and provided that when HET is quinolinyl, Ar is not pyrimidinyl; and provided that when HET is thiazolyl, Ar is not quinolinyl; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
In another embodiment, the present invention is directed to compounds of formula (I) wherein
HET is a heteroaryl selected from the group consisting of quinoline-2-yl, quinoline-3-yl, quinoline-4-yl, indoline-4-yl, indoline-5-yl, indoline-6-yl, indoline-7-yl, isoquinoline-1-yl, isoquinoline-3-yl, isoquinoline-4-yl, cinnoline-3-yl, cinnoline-5-yl, cinnoline-6-yl, phthalazine-5-yl, phthalazine-6-yl, quinazoline-4-yl, quinazoline-5-yl, quinazoline-6-yl, quinazoline-8-yl, 1 ,6-naphthyridine-2-yl, 1 ,6-naphthyridine-3-yl, 1 ,6-naphthyridine-4-yl, 1 ,6-naphthyridine-5-yl, 1 ,6-naphthyridine-7-yl, 1 ,6-naphthyridine-8-yl, 1 ,8-naphthyridine-2-yl, 1 ,8-naphthyridine-3-yl, 1 ,8-naphthyridine-4-yl, 1 ,7-naphthyridine-3-yl, 1 ,7-naphthyridine-4-yl,
2,6-naphthyridine-1 -yl, 2,7-naphthyridine-3-yl, 2,7-naphthyridine-4-yl, pyridine-2-yl, pyridine-3-yI, pyridine-4-yl, benzisothiazolyl, and benzothiazolyl;
Ar is an aryl selected from the group consisting of thiophenyl, pyrimidinyl, pyridazinyl, phenyl, benzothiazolyl, and pyridinyl; provided that when
HET is isoquinolinyl, Ar is not pyridinyl; and provided that when HET is pyridinyl, Ar is not pyridinyl, phenyl, 2-quinazolinyl, 5-quinoxalinyl or pyrimidinyl; and provided that when HET is quinolinyl, Ar is not pyrimidinyl; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
In another embodiment, the present invention is directed to compounds of formula (I) wherein HET is a heteroaryl selected from the group consisting of quinoline-2-yl, quinoline-3-yl, quinoline-4-yl, indoline-4-yl, indoline-5-yl, indoline-6-yl, indoline-7-yl, isoquinoline-1-yl, isoquinoline-3-yl, isoquinoline-4-yl, cinnoline-3-yl, cinnoline-5-yl, cinnoline-6-yl, phthalazine-5-yl, phthalazine-6-yl, quinazoline-4-yl, quinazoline-5-yl, quinazoline-6-yl, quinazoline-8-yl, 1 ,6-naphthyridine-2-yl, 1 ,6-naphthyridine-3-yl,
1 ,6-naphthyridine-4-yl, 1 ,6-naphthyridine-5-yl, 1 ,6-naphthyridine-7-yl, 1 ,6-naphthyridine-8-yl, 1 ,8-naphthyridine-2-yl, 1 ,8-naphthyridine-3-yl, 1 ,8-naphthyridine-4-yl, 1 ,7-naphthyridine-3-yl, 1 ,7-naphthyridine-4-yl, 2,6-naphthyridine-1 -yl, 2,7-naphthyridine-3-yl, 2,7-naphthyridine-4-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, benzisothiazolyl, and benzothiazolyl;
Ar is an aryl selected from the group consisting of phenyl, benzothiazolyl, and pyridinyl; provided that when HET is isoquinolinyl, Ar is not pyridinyl; and provided that when HET is pyridinyl, Ar is not pyridinyl or phenyl; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
In another embodiment, the present invention is directed to compounds of formula (II)
Figure imgf000033_0001
(II) wherein
Ar is an aryl selected from the group consisting of benzo[b]thiophenyl, naphthyl, biphenyl, isoquinolinyl, thiophenyl, pyridazinyl, and benzothiazolyl; Z is O or S;
R2 is hydrogen or Ci-6alkyl optionally substituted with -OR4; n is 1 or 2;
R3 is independently hydrogen, Ci-6alkyl, -COOR4, Or -CH2COOR4;
R4 is hydrogen or Ci_3alkyl; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
In another embodiment, the present invention is directed to compounds of formula (II) wherein Z is O and n is 1. In another embodiment, the present invention is directed to compounds of formula (II) wherein Z is O and R2 is hydrogen.
In another embodiment, the present invention is directed to compounds of formula (III):
Figure imgf000034_0001
(III) wherein X is CH or N; m is an integer from 0 to 4;
R is independently selected from the group consisting of halogen; R1; fluorinated C-Moalkyl; phenyl; amino; cyano; CF3O-; a 3 membered cyclic heteroalkyl containing 1 heteroatom that is N, O or S wherein said 3 membered cyclic heteroalkyl is optionally substituted with a substituent that is halogen, R1, fluorinated Ci_iOalkyl, amino, cyano, CF3O-, R1O-, R1S-, R1SO2-, R1S(O)-, R1SO2NH-, or -LCOY; a 4 to 5 membered cyclic heteroalkyl containing 1-3 heteroatoms that independently are N, O or S wherein said 4 to 5 membered cyclic heteroalkyl is optionally substituted with 1 to 2 substituents that independently are halogen, R1, fluorinated C-I- loalkyl, amino, cyano, CF3O-, R1O-, R1S-, R1SO2-, R1S(O)-, R1SO2NH-, or -LCOY; a 6 to 7 membered cyclic heteroalkyl containing 1-3 heteroatoms that independently are N, O or S wherein said 6 to 7 membered cyclic heteroalkyl is optionally substituted with 1 to 3 substituents that independently are halogen, R1, fluorinated Ci.iOalkyl, amino, cyano,
CF3O-, R1O-, R1S-, R1SO2-, R1S(O)-, R1SO2NH-, or -LCOY; a heteroaryl wherein said heteroaryl is cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, pthalazine, pteridine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinoline, quinolizine, quinazoline, quinoxaline, tetrazole, thiadiazole, triazine, or triazole wherein said heteroaryl is optionally substituted with 1 to 3 substituents that independently are halogen, R1, fluorinated Ci.iOalkyl, amino, cyano, CF3O-, R1O-, R1S-, R1SO2-, R1S(O)-, R1SO2NH-, or -LCOY; hydroxyl; R1O-; R1S-; R1SO2-;
R1S(O)-; R1SO2NH-; -LCOY; and C6-10aryl;
R1 is C1-10alkyl;
L is -NH-, a direct bond, -O-, or -CH2-;
Y is H, R1, HO, R1O-, R1S-, -NH2, R1NH-, or (R1)2N-; Z is O or S;
R2 is hydrogen or C1-6alkyl optionally substituted with -OR4; n is 1 or 2;
R3 is independently hydrogen, Ci-6alkyl, -COOR4, Or -CH2COOR4;
R4 is hydrogen or Chalky!; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
In another embodiment, the present invention is directed to compounds of formula (III) wherein Z is O and n is 1.
In another embodiment, the present invention is directed to compounds of formula (III) wherein Z is O and R2 is hydrogen.
In another embodiment, the present invention is directed to compounds of formula (Ha):
Figure imgf000035_0001
(Ha) wherein Ar is an aryl selected from the group consisting of benzo[b]thiophenyl, naphthyl, biphenyl, isoquinolinyl, thiophenyl, pyridazinyl, and benzothiazolyl; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
In another embodiment, the present invention is directed to compounds of formula (Ilia):
Figure imgf000036_0001
(Ilia) wherein X is CH or N; m is an integer from 0 to 4;
R is independently selected from the group consisting of halogen; R1; fluorinated C-i-ioalkyl; phenyl; amino; cyano; CF3O-; a 3 membered cyclic heteroalkyl containing 1 heteroatom that is N, O or S wherein said 3 membered cyclic heteroalkyl is optionally substituted with a substituent that is halogen, R1, fluorinated Ci_ioalkyl, amino, cyano, CF3O-, R1O-, R1S-, R1SO2-, R1S(O)-, R1SO2NH-, or -LCOY; a 4 to 5 membered cyclic heteroalkyl containing 1-3 heteroatoms that independently are N, O or S wherein said 4 to 5 membered cyclic heteroalkyl is optionally substituted with 1 to 2 substituents that independently are halogen, R1, fluorinated C-Moalkyl, amino, cyano, CF3O-, R1O-, R1S-, R1SO2-, R1S(O)-, R1SO2NH-, or -LCOY; a 6 to 7 membered cyclic heteroalkyl containing 1-3 heteroatoms that independently are N, O or S wherein said 6 to 7 membered cyclic heteroalkyl is optionally substituted with 1 to 3 substituents that independently are halogen, R1, fluorinated Ci_iOalkyI, amino, cyano, CF3O-, R1O-, R1S-, R1SO2-, R1S(O)-, R1SO2NH-, or -LCOY; a heteroaryl wherein said heteroaryl is cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, pthalazine, pteridine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinoline, quinolizine, quinazoline, quinoxaline, tetrazole, thiadiazole, triazine, or triazole wherein said heteroaryl is optionally substituted with 1 to 3 substituents that independently are halogen, R1, fluorinated C-Moalkyl, amino, cyano, CF3O-, R1O-, R1S-, R1SO2-, R1S(O)-, R1SO2NH-, or -LCOY; hydroxyl; R1O-; R1S-; R1SO2-; R1S(O)-; R1SO2NH-; -LCOY; and C6-ioaryl; wherein R1 is Ci-10alkyl; L is -NH-, a direct bond, -O-, or -CH2-; and Y is H, R1, HO, R1O-, R1S-, -NH2, R1NH-, or (R1)2N-; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
In another embodiment, the present invention is directed to compounds of formula (Ilia) wherein X is CH.
In another embodiment, the present invention is directed to compounds of formula (Ilia) wherein m is 1 or 2.
In another embodiment, the present invention is directed to compounds of formula (Ilia) wherein R is independently Ci-4alkanyl, CF3, or halo.
In another embodiment, the present invention is directed to compounds of formula (Ilia) wherein X is CH, m is 1 or 2 and R is independently Ci-4alkanyl, CF3, or halo.
The compounds of Formulas (I), (II) and (Na) in the embodiments above are optionally substituted as follows:
HET is optionally substituted at 1-3 substitutable atoms with a substituent that is independently selected from the group consisting of hydroxyl; R1; R1O-; R1S-; CF3O-; R1S(O)-; R1SO2-; -LCOY; C6-10aryl; a 3 to 7 membered cyclic heteroalkanyl containing from 1 to 3 heteroatoms wherein said heteroatoms independently are N, O or S; and a 5 to 10 membered heteroaryl selected from the group consisting of benzofuran, benzimidazole, benzisoxazole, benzthiazole, benzothiophene, benzoxazole, cinnoline, furan, imidazole, imidazoline, indazole, indole, indoline, indolizine, isobenzofuran, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, pthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinoline, quinolizine, quinazoline, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine, and triazole; ptionally substituted with one to four substituents independently selected from the group consisting of halogen; R1; fluorinated d.-ioalkyl; phenyl; amino; cyano; CF3O-; a 3 membered cyclic heteroalkyl containing 1 heteroatom that is N, O or S wherein said 3 membered cyclic heteroalkyl is optionally substituted with a substituent that is halogen, R1, fluorinated Ci-iOalkyl, amino, cyano, CF3O-, R1O-, R1S-, R1SO2-, R1S(O)-, R1SO2NH-, or -LCOY; a 4 to 5 membered cyclic heteroalkyl containing 1-3 heteroatoms that independently are N, O or S wherein said 4 to 5 membered cyclic heteroalkyl is optionally substituted with 1 to 2 substituents that independently are halogen, R1, fluorinated Ci-iOalkyl, amino, cyano, CF3O-, R1O-, R1S-, R1SO2-, R1S(O)-, R1SO2NH-, or -LCOY; a 6 to 7 membered cyclic heteroalkyl containing 1-3 heteroatoms that independently are N, O or S wherein said 6 to 7 membered cyclic heteroalkyl is optionally substituted with 1 to 3 substituents that independently are halogen, R1, fluorinated C-i- Kjalkyl, amino, cyano, CF3O-, R1O-, R1S-, R1SO2-, R1S(O)-, R1SO2NH-, or -LCOY; a heteroaryl wherein said heteroaryl is cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, pthalazine, pteridine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinoline, quinolizine, quinazoline, quinoxaline, tetrazole, thiadiazole, triazine, or triazole wherein said heteroaryl is optionally substituted with 1 to 3 substituents that independently are halogen, R1, fluorinated C1-10alkyl, amino, cyano, CF3O-, R1O-, R1S-, R1SO2-, R1S(O)-, R1SO2NH-, or -LCOY; hydroxyl; R1O-; R1S-; R1SO2-; R1S(O)-; R1SO2NH-; -LCOY; and C6-i0aryl; wherein R1 is Ci-iOalkyl; L is -NH-, a direct bond, -O-, or -CH2-; and Y is H, R1, HO, R1O-, R1S-, -NH2, R1NH-, or (R1)2N-.
In another embodiment, the present invention is directed to a compound selected from the group consisting of
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid quinolin-3-ylamide; 1 -Biphenyl-S-yl-piperidine-^carboxylic acid quinolin-3-ylamide; 1 -^-Trifluoromethyl-phenyO-piperidine-^carboxylic acid quinolin-3-ylamide; 1 -(2,3-Dimethyl-phenyl)-piperidine-4-carboxylic acid quinolin-3-ylamide; 1-(3,4-Dimethyl-phenyl)-piperidine-4-carboxylic acid quinolin-3-ylamide;
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (9-ethyl-9H-purin-6- yl)-amide; 1-(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (1 H-indol-4-yl)- amide; 1-(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (1-acetyl-2,3-dihydro-
1 H-indol-7-yl)-amide; 1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid thieno[2,3- d]pyrimidin-4-ylamide;
1-(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (1 H-indazol-7-yl)- amide;
1 -(S-Trifluoromethyl-phenyO-piperidine^-carboxylic acid (3-methyl- benzo[d]isothiazol-5-yl)-amide; HS-Trifluoromethyl-phenyO-piperidine^-carboxylic acid benzothiazol-6- ylamide; 3-{[1 -(3-Trif luoromethyl-phenyl)-piperidine-4-carbonyl]-amino}-1 H-indole-2- carboxylic acid ethyl ester; 1-(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid benzo[1 ,3]dioxol-5- ylamide; 1 -(S-Trifluoromethyl-phenyO-piperidine-^carboxylic acid (1 -acetyl-2,3-dihydrc~
1H-indol-6-yl)-amide; 1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (1 -acetyl-2,3-dihydrc~
1 /-/-indol-7-yl)-amide; 1-(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (2-oxo-2,3-dihydro
1 H-indoi-4-yl)-amide; 1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (2,3-dihydro- benzo[1 ,4]dioxin-6-yl)-amide;
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (2-methyl- benzothiazol-5-yl)-amide;
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (5-nitro- benzo[d]isothiazol-3-yl)-amide; 1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (1 H-indol-4-yl)- amide; 1-(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (1H-indol-5-yl)- amide; 1 -(S-Trifluoromethyl-phenyO-piperidine^-carboxylic acid (1 H-indol-6-yI)- amide;
1 -(S-Trifluoromethyl-phenyO-piperidine^-carboxylic acid (1 -methyl-1 H- indazol-5-yl)-amide;
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (2-mercapto- benzothiazol-6-yl)-amide; 1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (8-hydroxy-quinolin-
5-yl)-amide; 1-(3-TrifluoromethyI-phenyl)-piperidine-4-carboxylic acid (3,4-dihydro-2H- benzo[b][1 ,4]dioxepin-7-yl)-amide; I^S-Trifluoromethyl-phenyO-piperidine^-carboxylic acid (1-acetyl-2,3-dihydrc-
1H-indol-5-yl)-amide ;
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (1 H-indol-7-yl)- amide; i-CS-Trifluoromethyl-phenyO-piperidine^-carboxylic acid (1 ,4-dioxo-1 ,2,3,4- tetrahydro-phthaIazin-6-yl)-amide; 1 -(S-Trifluoromethyl-phenyO-piperidine-Φcarboxylic acid (6-phenoxy-pyridin-3- yl)-amide; 1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (6-acetyl- benzo[1 ,3]dioxol-5-yl)-amide; 1-(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid [4-(4,6-dimethoxy- pyrimidin-2-yl)-phenyl]-amide; 1 -(3-TrifluoromethyI-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-
2H-benzo[1 ,4]oxazin-6-yl)-amide;
1 -(S-Trifluoromethyl-phenyO-piperidine^-carboxylic acid (4-dimethylamino-δ- phenyl-pyrimidin-2-yl)-annide; and
S^-Dimethyl-i^δ-lfi^S-trifluoromethyl-phenylJ-piperidine^-carbonyll-amino}- pyridin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester.
In another embodiment, the present invention is directed to a compound selected from the group consisting of
1-Phenyl-piperidine-4-carboxylic acid quinolin-3-ylamide;
1 -Benzothiazol-δ-yl-piperidine^-carboxylic acid quinolin-3-ylamide;
1-BenzothiazoI-5-yl-piperidine-4-carboxylic acid (2,3-dihydro-1 H-indol-4-yl)- amide; i-Phenyl-piperidine^-carboxylic acid (2,3-dihydro-1 H-indol-4-yl)-amide;
3,4,5,6-Tetrahydro-2H-[1 ,3']bipyridinyl-4-carboxylic acid isoquinolin-1-ylamide;
1-Phenyl-piperidine-4-carboxylic acid isoquinolin-1-ylamide;
1-Phenyl-piperidine-4-carboxylic acid cinnolin-3-ylamide;
1 -Benzothiazol-δ-yl-piperidine^-carboxylic acid cinnolin-3-ylamide; i-Benzothiazol-δ-yl-piperidine^-carboxylic acid phthalazin-5-ylamide;
3,4,5,6-Tetrahydro-2H-[1 ,4']bipyridinyl-4-carboxylic acid phthalazin-5-ylamide;
1-Phenyl-piperidine-4-carboxylic acid quinazolin-4-ylamide;
1 -Benzothiazol-δ-yl-piperidine^-carboxylic acid quinazolin-4-ylamide;
1 -Benzothiazol-δ-yl-piperidine-4-carboxylic acid pyridin-3-ylamide; 1-Phenyl-piperidine-4-carboxylic acid benzo[d]isothiazol-3-ylamide;
3,4,5,6-Tetrahydro-2H-[1 ,2']bipyridinyl-4-carboxylic acid benzo[d]isothiazol-3- ylamide; i-Phenyl-piperidine-4-carboxylic acid benzothiazol-2-ylamide; 3,4,5,6-Tetrahydro-2H-[1 ,3']bipyridinyl-4-carboxylic acid benzothiazol-2- ylamide;
1 -Pyridazin-S-yl-piperidine-^carboxylic acid phthalazin-1 -ylamide;
1 -Thiophen^-yl-piperidine^-carboxylic acid phthalazin-1 -ylamide; 1-Thiophen-2-yl-piperidine-4-carboxylic acid (7H-purin-6-yl)-amide;
1 -Pyrimidin^-yl-piperidine^-carboxylic acid (7H-purin-6-yl)-amide;
1 -Pyrimidin-Σ-yl-piperidine^-carboxylic acid cinnolin-4-ylamide;
1 -Thiophen^-yl-piperidine^-carboxylic acid cinnolin-4-ylamide;
1 -Thiophen^-yl-piperidine^-carboxylic acid quinoxalin-6-ylamide; 1-Pyridazin-3-yl-piperidine-4-carboxylic acid quinoxalin-6-ylamide;
1 -Pyrimidin-2-yl~piperidine-4-carboxylic acid quinoxalin-6-ylamide;
1 -Pyrimidin^-yl-piperidine^-carboxylic acid pyrazin-2-ylamide;
1-Thiophen-2-yl-piperidine-4-carboxylic acid pyrazin-2-ylamide;
1-Thiophen-2-yl-piperidine-4-carboxylic acid quinazolin-7-ylamide; 1-Pyrimidin-2-yl-piperidine-4-carboxylic acid quinazolin-7-ylamide;
1 -Pyrimidin^-yl-piperidine^-carboxylic acid pyridazin-3-ylamide;
1 -Thiophen^-yl-piperidine^-carboxylic acid pyridazin-3-ylamide;
1-Benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid (2-oxo-2,3-dihydro-1 H- benzoimidazol-5-yl)-amide; 1-Naphthalen-2-yl-piperidine-4-carboxylic acid (2-oxo-2,3-dihydro-1H- benzoimidazol-5-yl)-amide;
1-Naphthalen-2-yl-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide; i-Biphenyl-S-yl-piperidine^-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide;
1 -Biphenyl-S-yl-piperidine^-carboxylic acid quinazolin-2-ylamide;
1 -Quinolin-S-yl-piperidine^-carboxylic acid quinazolin-2-ylamide;
1 -Quinolin-S-yl-piperidine^-carboxylic acid quinoxalin-2-ylamide;
1 -Isoquinolin-δ-yl-piperidine^-carboxylic acid quinoxalin-2-ylamide; 1-lsoquinolin-5-yl-piperidine-4-carboxylic acid (9H-carbazol-3-yl)-amide;
1 -Benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid (9H-carbazol-3-yl)- amide;
1 -Benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid phenazin-2-ylamide; 1-Naphthalen-2-yl-piperidine-4-carboxylic acid phenazin-2-ylamide; 1 -Naphthalen^-yl-piperidine^-carboxylic acid thiazol-2-ylamide; i-Biphenyl-S-yl-piperidine^-carboxylic acid thiazol-2-ylamide; i-Biphenyl-S-yl-piperidine-^carboxylic acid (1 H-imidazol-2-yl)-annide; 1 -Quinolin-S-yl-piperidine-^carboxylic acid (1 H-imidazol-2-yl)-amide; i-Quinolin-S-yl-piperidine-^carboxylic acid (2H-pyrazol-3-yl)-amide; 1 -Isoquinolin-δ-yl-piperidine-^carboxylic acid (2H-pyrazol-3-yl)-amide; 1 -Isoquinolin-δ-yl-piperidine-^carboxylic acid isoxazol-3-ylamide; 1 -Benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid isoxazol-3-ylamide; 1-Benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid (3-methyl-isothiazol-5- yl)-amide; 1 -Naphthalen^-yl-piperidine^-carboxylic acid (3-methyl-isothiazol-5-yl)- amide;
1-lsoquinolin-5-yl-piperidine-4-carboxyiic acid [1 ,6]naphthyridin-4-ylamide; 1-Benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid [1 ,6]naphthyridin-4- ylamide; 1-Benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid [1 ,7]naphthyridin-8- ylamide;
1-Naphthalen-2-yl-piperidine-4-carboxylic acid [1 ,7]naphthyridin-8-ylamide; 1-Naphthalen-2-yl-piperidine-4-carboxylic acid acridin-9-ylamide; 1-Biphenyl-3-yl-piperidine-4-carboxylic acid acridin-9-ylamide; 1-Biphenyl-3-yl-piperidine-4-carboxylic acid (1-methyl-4,5-dihydro-1 H- imidazol-2-yl)-amide;
1-Quinolin-3-yl-piperidine-4-carboxylic acid (1-methyl-4,5-dihydro-1 H- imidazol-2-yl)-amide;
1-Quinolin-3-yl-piperidine-4-carboxylic acid (4,5-dihydro-1 H-pyrazol-3-yl)- amide; i-lsoquinolin-δ-yl-piperidine^-carboxylic acid (4,5-dihydro-1 H-pyrazol-3-yl)- amide; 1 -Isoquinolin-δ-yl-piperidine^-carboxylic acid [1 ,8]naphthyridin-2-ylamide; 1-Benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid [1 ,8]naphthyridin-2- ylamide; 1 -BenzofbJthiophen-S-yl-piperidine-^carboxylic acid [2,6]naphthyτϊdin-1 - ylamide;
1 -Naphthalen^-yl-piperidine^-carboxylic acid [2,6]naphthyridin-1 -ylamide; 1 -Naphthalen^-yl-piperidine^-carboxylic acid benzo[d]isoxazol-5-ylamide; i-Biphenyl-S-yl-piperidine^-carboxylic acid benzo[d]isoxazol-5-ylamide; i-Biphenyl-S-yl-piperidine^-carboxylic acid (1 H-pyrrol-3-yl)-amide; 1-Quinolin-3-yl-piperidine-4-carboxylic acid (1 H-pyrrol-3-yl)-amide; 1-Quinolin-3-yl-piperidine-4-carboxylic acid (1 H-pyrrolo[2,3-b]pyridin-3-yl)- amide; 1 -Isoquinolin-δ-yl-piperidine^-carboxylic acid (1 H-pyrrolo[2,3-b]pyridin-3-yl)- amide;
1 -Isoquinolin-δ-yl-piperidine^-carboxylic acid pteridin-4-ylamide; 1 -BenzotbJthiophen-S-yl-piperidine^-carboxylic acid pteridin-4-ylamide; 1-Benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid (1 ,4-dihydro-quinazolin- 6-yl)-amide;
1-Naphthalen-2-yl-piperidine-4-carboxylic acid (1 ,4-dihydro-quinazolin-6-yl)- amide;
1-Naphthalen-2-yl-piperidine-4-carboxylic acid [1 ,7]naphthyridin-4-ylamide; 1-Biphenyl-3-yl-piperidine-4-carboxylic acid [1 ,7]naphthyridin-4-ylamide; i-Biphenyl-S-yl-piperidine^-carboxylic acid [2,7]naphthyridin-4-ylamide; 1 -Quinolin-S-yl-piperidine^-carboxylic acid [2,7]naphthyridin-4-ylamide; 1-Quinolin-3-yl-piperidine-4-carboxylic acid [2,6]naphthyridin-1 -ylamide; and 1 -Isoquinolin-δ-yl-piperidine^-carboxylic acid [2,6]naphthyridin-1 -ylamide.
In another embodiment, the present invention is directed to a compound selected from the group consisting of 1 -(2,3-Dimethyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide;
1 -(2,5-Bis-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-yl)-amide;
1 -(2-Bromo-3-fluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro- 2H-benzo[1 ,4]oxazin-6-yl)-amide; 1 -(2-Bromo-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide; 1 -(2-Chloro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydrc-2H- benzo[1 ,4]oxazin-6-yl)-amide; 1-(2-Cyano-3-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-yl)-amide; 1 -(2-Cyano-5-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-yl)-amide;
1 -(2-Ethyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide;
1 -(2-Fluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide; 1 -(2-lsopropyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide; 1-(2-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-
2H-benzo[1 ,4]oxazin-6-yl)-amide; 1 -(3,4,5-Trifluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide;
1 -(3,4-Difluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide;
1 -(3,4-Dimethyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide; 1 -(3,5-Difluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydrc-2H- benzo[1 ,4]oxazin-6-yl)-amide; 1-(3-Bromo-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide; 1 -(3-Chloro-2-methyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-
2H-benzo[1 ,4]oxazin-6-yl)-amide;
1 -(3-Chloro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide;
1 -(3-Fluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide; 1 -(3-Methoxy-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide; 1 -(S-Trifluoromethyl-phenyO-piperidine^-carboxylic acid (2-oxo-2,3-dihydro-
1 H-pyrido[2,3-b][1 ,4]oxazin-7-yl)-amide; 1-(3-Trifluoromθthyl-phenyl)-piperidine-4-carboxylic acid [4-(2-hydroxy-ethyl)-
3-oxo-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-yl]-amide; 1 -(4-Bromo-2,3,5,6-tetrafluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-yl)-amide;
1 -(4-tert-Butyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide;
1 -Benzothiazol^-yl-piperidine^-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide; 1-m-Tolyl-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide; 1-o-Tolyl-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide; 1-Phenyl-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide;
3'-Methyl-3,4,5,6-tθtrahydro-2H-[1 ,2']bipyridinyl-4-carboxylic acid (3-oxo-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-yl)-amide; and
3'-Nitro-3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-4-carboxylic acid (3-oxc~3,4- dihydro-2H-benzo[1 ,4]oxazin-6-yl)-amide.
In another embodiment, the present invention is directed to a compound selected from the group consisting of 1 -(2,3-Dimethyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide;
1 -(2,5-Bis-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-yl)-amide;
1 -(2-Bromo-3-fluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro- 2H-[1 ,4]oxazin-6-yl)-amide; 1 -(2-Bromo-phenyl)-piperidine-4-carboxylic acid (3-oxc~3,4-dihydrc-2H- benzo[1 ,4]oxazin-6-yl)-amide; 1 ~(2-Chloro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide; 1-(2-Cyano-3-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-yl)-amide; 1 -(2-Cyano-5-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-yl)-amide;
1 -(2-Ethyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide;
1 -(2-Fluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro2H- benzo[1 ,4]oxazin-6-yl)-amide; 1 -(2-lsopropyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide; 1-(2-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-
2H-benzo[1 ,4]oxazin-6-yl)-amide; 1 -(3,4,5-Trifluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide;
1 -(3,4-Difluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide;
1 -(3,4-Dimethyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide; 1 -(3,5-Difluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide; 1-(3-Bromo-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide; 1 -(S-Chloro^-methyl-phenyO-piperidine^-carboxylic acid (3-oxo-3,4-dihydro-
2H-benzo[1 ,4]oxazin-6-yl)-amide;
1 -(3-Chloro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide;
1 -(3-Fluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro2H- benzo[1 ,4]oxazin-6-yl)-amide; 1 -(3-Methoxy-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide; 1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (2-oxo-2,3-dihydro-
1 H-pyrido[2,3-b][1 ,4]oxazin-7-yl)-amide; 1-(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid [4-(2-hydroxy-ethyl)-
3-oxo-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-yl]-amide; 1 -(4-Bromo-2,3,5,6-tetrafluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-yl)-amide;
1 -(4-tert-Butyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide;
1 -Benzothiazol^-yl-piperidine^-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide; 1-m-Tolyl-piperidine-4-carboxylic acid (3-oxo-3,4-dihydrc-2H- benzo[1 ,4]oxazin-6-yl)-amide; 1-o-Tolyl-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide; 1-Phenyl-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide;
S'-Methyl-S^.δ.β-tetrahydro^H-li ,2']bipyridinyl-4-carboxylic acid (3-oxo-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-yl)-amide; and
3'-Nitro-3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-4-carboxylic acid (3-oxo-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-yl)-amide.
In another embodiment, the present invention is directed to a compound selected from the group consisting of
1 -(3,4,5-Trifluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-5-yl)-amide; 1 -(3,4,5-Trif luoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-7-yl)-amide; 1 -(3,4,5-Trif luoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-8-yl)-amide;
1 -(3,4,5-Trifluoro-phenyl)-piperidine-4-carboxylic acid (4-methyl-3-oxo-3,4- dihydro-2H-benzo[1,4]oxazin-6-yl)-amide; 1 -(3,4,5-Trifluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4~dihydro-2H- benzo[1 ,4]thiazin-6-yl)-amide; 1 -(3,4,5-Trifluoro-phenyl)-piperidine-4-carboxylic acid [2-(2-hydroxy-ethyl)-3- oxo-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-yl]-amide; 2-Methyl-3-oxo-6-{[1-(3,4,5-trifluoro-phenyl)-piperidine-4-carbonyl]-amino}-
3,4-dihydro-2H-benzo[1 ,4]oxazine-2-carboxylic acid ethyl ester; 2-Methyl-3-oxo-6-{[1-(3,4,5-trifluoro-phenyl)-piperidine-4-carbonyl]-amino}-
3,4-dihydro-2H-benzo[1 ,4]oxazine-2-carboxylic acid;
S-Oxo-β-^I^S^.δ-trifluoro-phenyl^piperidine^-carbonylJ-aminoJ-S^-dihydro- 2H-benzo[1 ,4]oxazine-2-carboxylic acid ethyl ester;
S-Oxo-θ-^I^S^.δ-trifluoro-phenyO-piperidine^-carbony^-aminoJ-S^-dihydro-
2H-benzo[1 ,4]oxazine-2-carboxylic acid; (3-Oxo-6-{[1-(3,4,5-trifluoro-phenyl)-piperidine-4-carbonyl]-amino}-3,4- dihydro-2H-benzo[1 ,4]oxazin-2-yl)-acetic acid methyl ester; and (3-Oxo-6-{[1-(3,4,5-trifluoro-phenyl)-piperidine-4-carbonyl]-amino}-3,4- dihydro-2H-benzo[1 ,4]oxazin-2-yl)-acetic acid.
The compounds of the present invention may also be present in the form of pharmaceutically acceptable salts. For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts" (Ref. International J. Pharm., 1986, 33, 201-217; J. Pharm.Sci., 1997 (Jan), 66, 1, 1 ). Other salts well known to those in the art may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Representative organic or inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic ortrifluoroacetic acid.
Representative organic or inorganic bases include, but are not limited to, basic or cationic salts such as benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds that are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term "administering" shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
Even though the compounds of the present invention (including their pharmaceutically, acceptable salts and pharmaceutically acceptable solvates) can be administered alone, they will generally be administered in admixture with a pharmaceutical carrier, excipient or diluent selected with regard to the intended route of administration and standard pharmaceutical or veterinary practice. Thus, the present invention is directed to pharmaceutical and veterinary compositions comprising compounds of Formula (I) and one or more pharmaceutically acceptable carriers, excipients or diluents.
By way of example, in the pharmaceutical and veterinary compositions of the present invention, the compounds of the present invention may be admixed with any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), and/or solubilising agent(s). Tablets or capsules of the compounds may be administered singly or two or more at a time, as appropriate. It is also possible to administer the compounds in sustained release formulations.
Alternatively, the compounds of Formula (I) can be administered by inhalation or in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder. An alternative means of transdermal administration is by use of a skin patch. For example, they can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin. They can also be incorporated, at a concentration of between 1 and 10% by weight, into an ointment consisting of a white wax or white soft paraffin base together with such stabilizers and preservatives as may be required.
For some applications, preferably the compositions are administered orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavoring or coloring agents.
The compositions (as well as the compounds alone) can also be injected parenterally, for example intracavernosally, intravenously, intramuscularly or subcutaneously. In this case, the compositions will comprise a suitable carrier or diluent.
For parenteral administration, the compositions are best used in the form of a sterile aqueous solution which may contain other substances, for example enough salts or monosaccharides to make the solution isotonic with blood.
For buccal or sublingual administration the compositions may be administered in the form of tablets or lozenges which can be formulated in a conventional manner. By way of further example, pharmaceutical and veterinary compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral). Thus for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations, such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral preparations may also be coated with substances such as sugars or be enteric-coated so as to modulate the major site of absorption. For parenteral administration, the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation. Injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives. Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those skilled in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
A therapeutically effective amount for use of the instant compounds or a pharmaceutical composition thereof comprises a dose range of from about 0.001 mg to about 1 ,000 mg, in particular from about 0.1 mg to about 500 mg or, more particularly from about 1 mg to about 250 mg of active ingredient per day for an average (70 kg) human.
For oral administration, a pharmaceutical composition is preferably provided in the form of tablets containing, 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated. It is also apparent to one skilled in the art that the therapeutically effective dose for active compounds of the invention or a pharmaceutical composition thereof will vary according to the desired effect. Therefore, optimal dosages to be administered may be readily determined and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the advancement of the disease condition. In addition, factors associated with the particular subject being treated, including subject age, weight, diet and time of administration, will result in the need to adjust the dose to an appropriate therapeutic level. The above dosages are thus exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention. Compounds of this invention may be administered in any of the foregoing compositions and dosage regimens or by means of those compositions and dosage regimens established in the art whenever use of the compounds of the invention as vanilloid receptor modulators is required for a subject in need thereof.
The invention also provides a pharmaceutical or veterinary pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical and veterinary compositions of the invention. Optionally associated with such containers) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration. As modulators of the vanilloid VR1 ion channel, the compounds of Formula (I) are useful in methods for treating or preventing a disease or condition in a mammal which disease or condition is affected by the modulation of one or more vanilloid receptors.
As modulators of the vanilloid VR1 ion channel, the compounds of Formula (I) are useful in methods for treating or preventing a disease or condition in a mammal which disease or condition is affected by the modulation of one or more vanilloid receptors. Such methods comprises administering to a mammal in need of such treatment or prevention a therapeutically effective amount of a compound, salt or solvate of Formula (I). In particular, the compounds of Formula (I) are useful for in methods for preventing or treating a chronic- or acute-pain causing diseases or conditions and pulmonary dysfunction, and more particularly, in treating diseases or conditions that cause inflammatory pain, burning pain, itch or urinary incontinence, and chronic obstructive pulmonary disease.
By way of example only, the compounds of Formula (I) are useful for treating diseases and conditions selected from the group consisting of osteoarthritis, rheumatoid arthritis, fibromyalgia, migraine, headache, toothache, burn, sunburn, snake bite (in particular, venomous snake bite), spider bite, insect sting, neurogenic bladder, benign prostatic hypertrophy, interstitial cystitis, urinary tract infection, cough, asthma, chronic obstructive pulmonary disease, rhinitis, contact dermatitis/hypersensitivity, itch, eczema, anxiety, panic disorders, pharyngitis, mucositis, enteritis, cellulites, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, causalgia, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, bony fractures, post-operative ileus, irritable bowel syndrome, inflammatory bowel diseases such as Crohn's Disease and ulcerative colitis, cholecystitis, pancreatitis, postmastectomy pain syndrome, oral neuropathic pain, Charcot's pain, reflex sympathetic dystrophy, Guillain-Barre syndrome, meralgia paresthetica, burning-mouth syndrome, optic neuritis, postfebrile neuritis, migrating neuritis, segmental neuritis, Gombault's neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngial neuralgia, migrainous neuralgia, idiopathic neuralgia, intercostals neuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, red neuralgia, Sluder's neuralgia, splenopalatine neuralgia, supraorbital neuralgia, vidian neuralgia, sinus headache, tension headache, labor, childbirth, intestinal gas, menstruation, hot flash, cancer, and trauma.
While the present invention comprises compositions comprising one or more of the compounds of Formula (I), the present invention also comprises compositions comprising intermediates used in the manufacture of compounds of Formulae (I).
GENERAL SYNTHETIC METHODS
Compounds of formula (I) can be prepared by methods known to those who are skilled in the art. The following reaction schemes are only meant to represent examples of the invention and are in no way meant to be a limit of the invention.
Compounds of Formula (I) may be prepared generally according to the Scheme 1 and Scheme 2 below: Scheme 1
Figure imgf000056_0001
Scheme 2
Figure imgf000056_0002
EXAMPLES
Example 1 i-Biphenyl-Φyl-piperidine-Φcarboxylic acid quinoiin-3-ylamide
Figure imgf000056_0003
A. Sodium t-butoxide (0.211g, 2.2 mmol) was added to a solution of 4- bromobiphenyl (0.233g, 1.0 mmol), Pd(OAc)2 (0.002 g, 0.008 mmol), and 2- (di-t- butylphosphino)- biphenyl (0.006 g, 0.02 mmol) in THF (5 ml). After 5 minutes of stirring, isonipecotic acid (0.129 g, 1.0 mmol) was added to the solution. The solution was heated to 650C for 18 h under an argon atmosphere, then cooled to room temperature and partitioned between EtOAc and water. The aqueous layer was separated and acidified using 3N HCI and then extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give 1-biρhenyl-4-yl-piperidine-4- carboxylic acid as a light brown solid (0.10 g, 0.35 mmol).1H NMR (400MHz, DMSO) δ (ppm): 7.58 (d, 1 H), 7.53 (d, 2H), 7.40 (t, 1 H), 7.00 (d, 2H), 3.70 (d, 2H), 2.80 (m, 2H), 2.38-2.46 (m, 1 H)1 1.85-1.92 (m, 2H), 1.60-1.70 (m, 2H).
B. A solution of 3-aminoquinoline (0.077g, 0.54 mmol), 1 -biphenyl-4-yl- piperidine-4-carboxylic acid, (0.05Og, 0.18 mmol), Hydroxybenzotriazole (HOBt) (0.072g, 0.54 mmol) and triethylamine (0.075 ml, 0.54 mmol) in dimethylformamide (DMF) (1 ml) was treated with Ethyl-3-(3 dimethylaminopropyl)-carbodiimide (EDC) (0.102g, 0.54 mmol). The solution was stirred at room temperature for 18 h. 10% K2CO3 (5 ml) was added to the solution, which was then filtered. The solid was sequentially washed with water, MeOH and then dried in vacuo to give the title compound as an off- white solid (0.084g). 1H NMR (400MHz, CDCI3) δ (ppm): 9.77 (s, 1H), 8.55- 8.68 (m, 2H), 7.73 (d, 1 H), 7.50-7.55 (m, 1 H), 7.20-7.38 (m, 6H), 7.12-7.16 (m, 2H), 6.90-7.03 (m, 1 H), 6.79 (d, 2H), 3.55-3.62 (m, 2H), 2.52-2.62 (m, 2H), 2.30-2.40 (m, 1 H), 1.70-1.82 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C27H25N3O : 408.20 (M + H). Found: 408.3.
Example 2
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid quinolin-3-ylamide
Figure imgf000057_0001
Using the procedure outlined in Example 1A, 1-(3-trifluoromethyl-phenyl)- piperidine-4-carboxylic acid was prepared from 1-bromo-3- trifluoromethylbenzene (1.1 ml, 8 mmol) as an off-white solid (0.16g). 1H NMR (400MHz, CD3OD) δ (ppm): 7.40 (t, 1H), 7.18-7.24 (m, 2H), 7.09 (d, 1 H), 3.75 (d, 2H), 2.85 (t, 2H), 2.48-2.52 (m, 1 H), 2.00-2.10 (m, 2H), 1.78-1.88 (m, 2H).
Using the procedure outlined in Example 1B, the title compound was prepared from 3-aminoquinoline (0.087g, 0.60 mmol) and 1 -(3-trifluoromethyl-phenyl)- piperidine-4-carboxylic acid (0.055g, 0.2 mmol) as an off-white solid (0.024g). 1H NMR (400MHz, DMSO) δ (ppm): 10.50 (s, 1 H), 8.93 (d, 1 H), 8.75 (d, 1 H), 7.90-7.97 (m, 2H), 7.54-7.67 (m, 2H), 7.43 (t, 1 H), 7.25-7.30 (m, 1 H), 7.20- 7.22 (s, 1 H), 7.06 (d, 1 H), 3.93 (d, 2H), 2.85 (t, 2H), 2.60-2.70 (m, 1 H), 1.93- 2.00 (m, 2H), 1.70-1.85 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C22H20F3 N3O: 400.16 (M + H). Found: 400.3.
Example 3
1-Biphenyl-3-yl-piperidine-4-carboxylic acid quinolin-3-ylamide
Figure imgf000058_0001
Using the procedure outlined in Example 1A, 1-biphenyl-3-yl-piperidine-4- carboxylic acid was prepared from 3-bromobiphenyl (0.56 g, 2.0 mmol). 1H NMR (400MHz, CDCI3) δ (ppm): 9.10-9.70 (bs, 1 H), 7.60 (d, 2H), 7.45 (t, 2H), 7.35 (t, 2H), 7.16-7.20 (m, 1 H), 7.13 (d, 1 H), 6.97 (m, 1 H), 3.75 (d, 2H), 2.85- 2.90 (m, 2H), 2.49-2.52 (m, 1 H), 1.80-1.90 (m, 2H), 2.08-2.15 (m, 3H), 1.90- 2.05 (m, 2H).
Using the procedure outlined in Example 1 B, the title compound was prepared from 3-aminoquinoline (0.18, 1.3 mmol) and 1-biphenyl-3-yl-piperidine-4- carboxylic acid, (0.12g, 0.43 mmol) as an off-white solid (0.069g). 1H NMR (400MHz, DMSO) δ (ppm): 10.50-10.61 (s, 1H), 8.94 (d, 1H), 8.76 (d, 1H), 7.90-7.97 (m, 2H)1 7.51-7.54 (m, 4H), 7.42-7.47 (m, 2H), 7.27-7.38 (m, 2H), 7.19-7.21 (bs, 1 H), 6.97-7.05 (m, 2H), 3.91 (d, 2H), 2.80 (t, 2H), 2.60-2.70 (m, 1 H), 1.79-2.01 (m, 4H).
Example 4
1 -(4-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid quinolin-3-ylamide
Figure imgf000059_0001
Using the procedure outlined in Example 1A, 1-(4-tifluoromethyl-phenyl)- piperidine-4-carboxylic acid was prepared from 1-bromo-4-trifluoromethyl- benzene (0.560 ml, 4 mmol) as an off-white solid (0.10g). 1H NMR (400MHz, CD3CN) δ (ppm): 7.49 (d, 2H), 7.02 (d, 2H), 3.80 (d, 2H), 2.90 (t, 2H), 2.49- 2.56 (m, 1 H), 1.60-1.73 (m, 2H), 1.50-1.59 (m, 2H).
Using the procedure outlined in Example 1 B, the title compound was prepared from 3-aminoquinoline (0.15g , 1.0 mmol) and 1-(4-trifIuoromethyl-phenyl)- piperidine-4-carboxylic acid (0.095g, 0.35 mmol) as an off-white solid (0.075g). 1H NMR (400MHz, DMSO) δ (ppm): 10.60-10.62 (s, 1 H), 8.93 (d, 1 H), 8.74 (d, 1 H), 7.90-7.96 (m, 2H), 7.48-7.65 (m, 4H), 7.10 (d, 2H), 4.00 (d, 2H), 2.90 (t, 2H), 2.67-2.74 (m, 1 H), 1.90-1.99 (m, 2H), 1.70-1.80 (m, 2H).
Example 5
1 -(2,3-Dimethyl-phenyl)-piperidine-4-carboxylic acid quinolin-3-ylamide
Figure imgf000059_0002
Using the procedure outlined in Example 1A, 1-(2,3-dimethyl-phenyl)- piperidine-4-carboxylic acid was prepared from 1-bromo-2,3-dimethyl- benzene (0.542 ml, 4 mmol) as an off-white solid (0.06g). 1H NMR (400MHz, CD3CN) δ (ppm): 7.02 (t, 1 H), 6.85 (t, 2H), 3.00-3.05 (m, 2H), 2.60-2.68 (m, 2H), 2.24 (s, 3H), 2.19 (s, 3H), 1.78-1.90 (m, 5H).
Using the procedure outlined in Example 1B, the title compound was prepared from 3-aminoquinoline (0.08g , 0.54 mmol) and 1-(2,3-dimethyl-phenyl)- piperidine-4-carboxylic acid (0.043g, 0.18 mmol) as an off-white solid (0.006g). 1H NMR (400MHz, CD3OD) δ (ppm): 8.92 (s, 1 H), 8.75 (s, 1 H), 7.90 (d, 1 H), 7.88 (d, 1 H), 7.55-7.73 (m, 2H), 6.83-7.03 (m, 3H), 3.15 (d, 2H), 2.54- 2.75 (m, 3H), 2.50 (s, 6H), 1.95-2.10 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C23H25N3O: 360.20 (M + H). Found: 360.2.
Example 6
1 -(3,4-Dimethyl-phenyl)-piperidine-4-carboxylic acid quinolin-3-ylamide
Figure imgf000060_0001
Using the procedure outlined in Example 1A, 1-(3,4-dimethyl-phenyI)- piperidine-4-carboxylic acid was prepared from 1-bromo-3,4-dimethylbenzene (0.540 ml, 4 mmol) as an off-white solid (0.14g). 1H NMR (400MHz, CDCI3) δ (ppm): 7.93 (dd, 1 H), 7.50 (d, 1 H), 7.10 (d, 1 H), 4.00 (d, 2H), 2.92 (t, 2H), 2.67-2.73 (m, 1 H), 1.93-2.00 (m, 2H), 2.68-2.80 (m, 2H).
Using the procedure outlined in Example 1 B, the title compound was prepared from 3-aminoquinoline (0.193g, 1.3 mmol) and 1-(3,4-dimethyl-phenyl)- piperidine-4-carboxylic acid (0.104g, 0.45 mmol) as an off-white solid (O.OOβg). 1H NMR (400MHz, solvent) δ (ppm): 8.85 (bs, 1 H), 8.73 (bs, 1 H), 8.05 (d, 1 H), 7.80 (d, 1 H), 7.50-7.70 (m, 3H), 7.05 (d, 1 H), 6.70-6.80 (m, 2H), 3.74 (d, 2H), 2.75 (t, 2H)1 2.40-2.50 (m, 1 H), 2.25 (s, 3H), 2.20 (s, 3H), 2.00- 2.13 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C23H25N3O: 360.20 (M + H). Found: 360.2.
Example 7 1-(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (9-ethyl-9H-purin-6- yl)-amide
Figure imgf000061_0001
Using the procedure outlined in Example 1B, the title compound was prepared from 7-ethyladenine (0.119g , 0.73 mmol) and 1-(3-trifluoromethyl-phenyl)- piperidine-4-carboxylic acid (0.1Og, 0.40 mmol) as an off-white solid
(0.0023g). 1H NMR (400MHz, CDCI3) δ (ppm): 8.73 (s, 1H), 8.606 (bs, 1H), 8.00 (s, 1 H), 7.30-7.39 (m, 1 H), 7.04-7.17 (m, 3H), 4.35 (q, 2H), 3.80 (d, 2H), 3.18-3.34 (m, 1H), 2.85-2.98 (m, 2H), 1.97-2.22 (m, 4H), 1.58 (t, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C20H2IF3N6O: 419.17 (M + H). Found: 419.2.
Example 8 (04/072069)
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (1 /-/-indol-4-yl)-amide
Figure imgf000061_0002
A. Oxalyl chloride (0.262 ml, 3 mmol) was added to a solution of 1-(3- trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.273 g, 1 mmol) in methylene chloride (5 ml). After 1 h the solution was concentrated to yield 1- (3-trifluoromethyl-phenyl)-piperidine-4-carbonyl chloride, which was used as is for the next step.
B. To a solution of 4-aminoindole (0.066g, 0.5 mmol) and triethylamine (0.070 ml, 0.5 mmol) in methylene chloride (1 ml) was added a solution of 1-(3- trifluoromethyl-phenyl)-piperidine-4-carbonyl chloride, (0.145g, 0.5 mmol) in methylene chloride (1 ml). After 18 h the solution was washed with K2CO3 (10% in water). The methylene chloride layer was separated and concentrated. The residue was purified by preparative TLC (silica gel, 20 X 20 cm, 2000 microns, EtOAc/hexanes 4:6) to give the title compound (0.035g). 1H NMR (400MHz, CD3OD) δ (ppm): 7.51 (d, 1H), 7.22-7.33 (m, 1H), 6.96-7.19 (m, 6H), 6.39-6.46 (m, 1H), 3.71 (d, 2H), 2.71-2.83 (m, 2H), 2.43-2.56 (m, 1 H), 1.84-2.06 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C2IH20F3N3O: 388.16 (M + H). Found: 388.1.
Example 9 i-p-Trifluoromethyl-phenyO-piperidine^-carboxylic acid (1-acetyl-2,3-dihydro- 1H-indol-7-yl)-amide
Figure imgf000062_0001
Using the procedure outlined in Example 8, the title compound was prepared from 1-(7-amino-2,3-dihydro-indol-1-yl)-ethanone (0.059g , 0.33 mmol) as an off-white solid (0.056g). 1H NMR (400MHz, CDCI3) δ (ppm): 10.43 (s, 1H), 7.89-8.02 (m, 1H), 6.95-7.41 (m, 6H), 4.10 (t, 2H), 3.79 (d, 2H), 3.11 (t, 2H), 2.88 (t, 2H), 2.43-2.54 (m, 1H), 2.38 (s, 3H), 1.90-2.14 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C23H24F3N3O2: 432.18 (M + H). Found: 432.2.
Example 10
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid thieno[2,3- d]pyrimidin-4-ylamide
Figure imgf000062_0002
Using the procedure outlined in Example 8, the title compound was prepared from thieno[2,3-d]pyrimidin-4-ylamine (0.05Og , 0.33 mmol) as an off-white solid (0.012g). 1H NMR (400MHz, CDCI3) δ (ppm): 10.86 (s, 1 H), 10.72 (s, 1H), 9.68 (d, 1H), 9.56 (s, 1H), 9.39-9.46 (m, 1 H), 9.13-9.24 (m, 3H), 5.89 (d, 2H), 4.87-5.03 (m, 3H), 4.05-4.28 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for Ci9Hi7F3N4OS: 407.11 (M + H). Found: 407.1.
Example 11 (04/072069)
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (1 H-indazol-7-yl)- amide
Figure imgf000063_0001
Using the procedure outlined in Example 8, the title compound was prepared from 1/-/-indazol-7-ylamine (0.044g , 0.33 mmol) as an off-white solid (0.0068g). 1H NMR (400MHz, DMSO) δ (ppm): 8.01 (s, 1H), 7.62 (d, 1H), 7.50 (d, 1H), 7.40 (s, 1H), 7.34 (t, 1H), 7.01-7.15 (m, 4H), 2.78-2.92 (m, 2H), 2.55- 2.68 (m, 1H), 1.97-2.10 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C20Hi9F3N4O: 389.15 (M + H). Found: 389.2.
Example 12 (04/072069)
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (3-methyl- benzo[d]isothiazol-5-yl)-amide
Figure imgf000064_0001
Using the procedure outlined in Example 8, the title compound was prepared from 3-methyl-benzo[d]isothiazol-5-ylamine (0.055g , 0.33 mmol) as an off- white solid (0.011 g). 1H NMR (400MHz, solvent) δ (ppm): 8.47 (s, 1H), 7.87 (d, 1H), 7.34-7.48 (m, 3H), 7.08-7.12 (m, 3H), 3.87 (d, 2H), 2.83-2.96 (m, 2H), 2.76 (s, 3H), 2.43-2.55 (m, 1H), 1.99-2.20 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C2IH20F3N3OS: 420.13 (M + H). Found: 420.1.
Example 13
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid benzothiazol-6- ylamide
Figure imgf000064_0002
Using the procedure outlined in Example 8, the title compound was prepared from 6-aminobenzothiazole (0.008 g, 0.051 mmol) and 1-(3-trifluoromethyl- phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as an off-white solid. 1H NMR (300MHz, CDCI3) δ (ppm): 8.93 (s, 1 H), 8.62 (d, 1 H), 8.05 (d, 1 H), 7.43-7.39 (m, 1 H), 7.36-7.31 (m, 2H), 7.15-7.09 (m,.3H), 3.83 (d, 2H), 2.87 (td, 2H), 2.52-2.42 (m, 1H), 2.10-2.01 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C20Hi8F3N3OS : 405.4; Found: 406.3 (M + H). Example 14
3-{[1-(3-Trifluoromethyl-phenyl)-piperidine-4-carbonyl]-amino}-1H-indole-2- carboxylic acid ethyl ester
Figure imgf000065_0001
Using the procedure outlined in Example 8, the title compound was prepared from ethyl 3-amino-1H-indole-2-carboxylate (0.010 g, 0.051 mmol) and 1-(3- trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a light brown solid. 1H NMR (300MHz, CDCI3) δ (ppm): 8.27 (s, 1 H), 8.44 (s, 1H), 8.26 (d, 1 H), 7.33-7.26 (m, 3H), 7.16-7.08 (m, 4H), 4.44 (q, 2H), 3.84 (dt, 2H), 2.92 (t, 2H), 2.68-2.55 (m, 1 H)1 2.28-2.04 (m, 4H), 1.44 (t, 3H). Mass Spectrum (LCMS1 ESI pos.) Calcd. for C2-JH24F3N3O3 : 459.5; Found: 460.4 (M + H).
Example 15
1-(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid benzo[1 ,3]dioxol-5- ylamide
Figure imgf000065_0002
Using the procedure outlined in Example 8, the title compound was prepared from 3,4-methylenedioxyaniline (0.006 g, 0.051 mmol) and 1-(3- trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a light brown solid. 1H NMR (300MHz, CDCI3) δ (ppm): 7.35 (t, 1 H), 7.25 (d, 1H), 7.20 (S1 1 H), 7.13-7.07 (m, 3H), 6.80 (dd, 1 H), 6.74 (d, 1 H), 5.95 (s, 2H)1 3.80 (dt, 2H), 2.83 (td, 2H), 2.40-2.35 (m, 1 H), 2.05-1.95 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C20Hi9F3N2O3 : 392.4; Found: 393.3 (M + H).
Example 16 1-(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (1-acetyl-2,3-dihydro- 1 /-/-indol-6-yl)-amide
Figure imgf000066_0001
Using the procedure outlined in Example 1B, the title compound was prepared from 1-acetyl-6-amino-2,3-dihydro(1H)-indole (0.009 g, 0.051 mmol) and 1-(3- trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as an off-white solid. 1H NMR (300MHz, CDCI3) δ (ppm): 8.12 (d, 1 H), 7.75 (s, 1 H), 7.37-7.32 (m, 2H), 7.13-7.07 (m, 4H), 6.98 (dd, 1 H), 4.05 (t, 2H), 3.80 (d, 2H), 3.18 (t, 2H), 2.83 (td, 2H), 2.41-2.37 (m, 1 H), 2.22 (s, 3H), 2.05-1.96 (m, 4H).
Example 17
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (2-oxo-2,3-dihydro- 1H-indol-5-yl)-amide
Figure imgf000066_0002
Using the procedure outlined in Example 1B, the title compound was prepared from 5-aminooxindole (0.008 g, 0.051 mmol) and 1-(3-trifluoromethyl-phenyl)- piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as an off-white solid. 1H NMR (300MHz, CDCI3) δ (ppm): 7.50 (s, 1 H), 7.39-7.33 (m, 2H), 7.22-7.18 (m, 2H), 7.05 (d, 1H), 6.83 (d, 1 H), 3.85 (d, 2H), 3.52 (s, 2H), 2.88-2.78 (m, 2H), 2.58-2.48 (m, 1H)1 2.04-1.92 (m, 4H). Mass Spectrum (LCMS1 ESI pos.) Calcd. for C2IH20F3N3O2 : 403.4; Found: 388.3 (M - CH2).
Example 18
1 -(S-Trifluoromethyl-phenyO-piperidine^-carboxylic acid (2,3-dihydro- benzo[1 ,4]dioxin-6-yl)-amide
Figure imgf000067_0001
Using the procedure outlined in Example 1B, the title compound was prepared from 3,4-ethylenedioxyaniline (0.008 g, 0.051 mmol) and 1-(3-trifluoromethyl- phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as an off-white solid. 1H NMR (300MHz, CDCI3) δ (ppm): 7.35 (t, 1 H), 7.16 (d, 1 H)1 7.13-7.07 (m, 4H), 6.91 (dd, 1 H)1 6.80 (d, 1 H)1 4.24 (s, 4H)1 3.80 (d, 2H), 2.84 (td, 2H)1 2.44-2.36 (m, 1 H)1 2.05-1.95 (m, 4H). Mass Spectrum (LCMS1 ESI pos.) Calcd. for C2iH2i F3N2O3 : 406.4; Found: 407.4 (M + H).
Example 19 1-(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (2-methyl- benzothiazol-5-yl)-amide
Figure imgf000067_0002
Using the procedure outlined in Example 1 B, the title compound was prepared from 5-amino-2-methylbenzothiazole (0.008 g, 0.051 mmol) and 1-(3- trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a light brown solid. 1H NMR (300MHz1 CDCI3) δ (ppm): 10.16 (s, 1 H)1 8.30 (d, 1 H), 7.91 (d, 1H), 7.56 (del, 1 H), 7.42 (t, 1 H), 7.26 (d, 1 H), 7.19 (s, 1 H)1 7.05 (d, 1 H), 3.88 (d, 2H), 2.82 (s, 2H), 2.77 (s, 3H), 2.60-2.46 (m, 1 H), 1.96-1.84 (m, 2H), 1.80-1.65(m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C21H20F3N3OS : 419.5; Found: 419.7 (M+).
Example 20
1 -(S-Trifluoromethyl-phenyO-piperidine^-carboxylic acid (5-nitro- benzo[d]isothiazol-3-yl)-amide
Figure imgf000068_0001
Using the procedure outlined in Example 1B, the title compound was prepared from 3-amino-5-nitrobenzoisothiazole (0.010 g, 0.051 mmol) and 1-(3- trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a light brown solid. 1H NMR (300MHz, CDCI3) δ (ppm): 7.36 (t, 1 H), 7.17-7.07 (m, 4H), 6.55 (ddd, 1H), 6.46 (ddd, 1H), 6.41 (t, 1 H), 3.73 (dt, 2H), 2.94 (td, 2H), 2.76-2.67 (m, 1 H), 2.22-2.16 (m, 2H), 2.07-1.94 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C20Hi7F3N4O3S : 450.4; Found: 432.3 (M - 18).
Example 21 (04/072069)
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (1 H-indol-4-yl)-amide
Figure imgf000068_0002
Using the procedure outlined in Example 1 B, the title compound was prepared from 4-aminoindole (0.007 g, 0.051 mmol) and 1 -(3-trifluoromethyl-phenyl)- piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a brown solid. 1H NMR (300MHz, CDCI3) δ (ppm): 8.35 (s, 1H), 7.80 (d, 1 H)1 7.47 (s, 1 H), 7.36 (t, 1 H), 7.23-7.08 (m, 6H), 6.48 (s, 1 H), 3.83 (d, 2H), 2.88 (t, 2H), 2.59-2.47 (m, 1 H), 2.18-1.96 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C21H20F3N3O : 387.4; Found: 388.3 (M + H).
Example 22 (04/072069)
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (1 /-/-indol-5-yl)-amide
Figure imgf000069_0001
Using the procedure outlined in Example 1B, the title compound was prepared from 5-aminoindole (0.007 g, 0.051 mmol) and 1 -(3-trifluoromethyl-phenyl)- piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a light brown solid. 1H NMR (300MHz, CDCI3) δ (ppm): 7.75 (d, 1 H), 7.39 (t, 1 H), 7.31 (dd, 1 H), 7.22- 7.16 (m, 4H), 7.05 (d, 1 H), 6.39 (dd, 1 H), 3.86 (d, 2H)1 2.90-2.80 (m, 2H), 2.59-2.52 (m, 1H), 2.00-1.93 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C2-IH20F3N3O : 387.4; Found: 388.3 (M + H).
Example 23 (04/072069) 1 -(S-Trifluoromethyl-phenyO-piperidine^-carboxylic acid (1 H-indol-6-yl)-amide
Figure imgf000069_0002
Using the procedure outlined in Example 1 , the title compound was prepared from 6-aminoindole (0.007 g, 0.051 mmol) and 1 -(3-trif luoromethyl-phenyl)- piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as an off-white solid. 1H NMR (300MHz, CDCI3) δ (ppm): 10.99 (s, 1 H), 9.84 (s, 1 H), 7.98 (s, 1 H)1 7.41 (d, 2H), 7.27-7.19 (m, 3H), 7.04 (dt, 2H), 6.33 (t, 1 H), 3.89 (d, 2H), 2.81 (t, 2H), 2.62-2.48 (m, 1 H), 1.89 (d, 2H), 1.76 (td, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C2IH20F3N3O : 387.4; Found: 388.3 (M + H).
Example 24 (04/072069)
1 -(S-Trifluoromethyl-phenyO-piperidine^-carboxylic acid (1 -methyl-1 H- indazol-5-yl)-amide
Figure imgf000070_0001
Using the procedure outlined in Example 1 B, the title compound was prepared from 1 -methyl-1 H-indazol-5-amine (0.008 g, 0.051 mmol) and 1-(3- trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a light brown solid. 1H NMR (300MHz, CDCI3) δ (ppm): 8.01 (d, 1 H), 7.93 (s, 1 H), 7.42-7.32 (m, 4H), 7.14-7.08 (m, 3H), 4.06 (s, 3H), 3.82 (d, 2H), 2.85 (t, 2H), 2.50-2.39 (m, 1 H), 2.09-2.00 (m, 4H).
Example 25
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (6-methoxy-pyridin-3- yl)-amide
Figure imgf000070_0002
Using the procedure outlined in Example 1B, the title compound was prepared from 5-amino-2-methoxypyridine (0.006 g, 0.051 mmol) and 1-(3- trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as an off-white solid. 1H NMR (300MHz, CDCI3) δ (ppm): 8.14 (d, 1 H), 7.94 (dd, 1H), 7.35 (t, 1H), 7.13-7.07 (m, 4H), 6.74 (d, 1 H), 3.92 (s, 3H), 3.82 (dt, 2H), 2.85 (td, 2H), 2.44-2.39 (m, 1 H), 2.09-1.97 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C19H20F3N3O2 : 379.4; Found: 380.4 (M + H).
Example 26
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (2-mercapto- benzothiazol-6-yl)-amide
Figure imgf000071_0001
Using the procedure outlined in Example 1B, the title compound was prepared from 6-amino-2-mercaptobenzothiazole (0.009 g, 0.051 mmol) and 1-(3- trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as an off-white solid. 1H NMR (300MHz, CDCI3) δ (ppm): 7.91 (d, 1 H), 7.48 (dd, 1 H), 7.39 (t, 1 H), 7.24-7.18 (m, 4H), 7.05 (d, 1 H), 3.86 (d, 2H), 2.84 (td, 2H), 2.59-2.52 (m, 1H), 2.01-1.90 (m, 4H).
Example 27 1-(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (8-hydroxy-quinolin- 5-yl)-amide
Figure imgf000071_0002
Using the procedure outlined in Example 1 B, the title compound was prepared 5-amino-8-hydroxyquinoline (0.008 g, 0.051 mmol) and 1 -(3-trifluoromethyl- 43192
phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a white solid. 1H NMR (300MHz, CDCI3) δ (ppm): 8.87 (dd, 1H), 8.19 (d, 1H), 7.88 (s, 1H), 7.48-7.33 (m, 2H), 7.25 (d, 1H), 7.17-7.07 (m, 4H), 6.78 (d, 1H), 4.21 (s, 1H), 3.80 (d, 2H), 3.02 (t, 2H), 2.33 (d, 2H), 2.13 (t, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C22H20F3N3O2 : 415.4; Found: 416.3 (M + H).
Example 28
1 -(S-Trifluoromethyl-phenyO-piperidine^-carboxylic acid (3,4-dihydro-2H- benzo[b][1 ,4]dioxepin-7-yl)-amide
Figure imgf000072_0001
Using the procedure outlined in Example 1B, the title compound was prepared from 3,4-dihydro-2H-1 ,5-benzodioxepin-7-amine (0.008 g, 0.051 mmol) and 1- (3-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a pale yellow solid. 1H NMR (300MHz, CDCI3) δ (ppm): 7.35 (t, 1H), 7.21 (d, 1H)1 7.13-7.04 (m, 5H), 6.93 (d, 1H), 4.18 (dt, 4H), 3.81 (d, 2H), 2.85 (t, 2H), 2.39 (m, 1H), 2.18 (quin, 2H), 2.03-1.96 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C22H23F3N2O3 : 420.4; Found: 421.4 (M + H).
Example 29
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (1 -acetyl-2,3-dihydro-
1 H-indol-5-yl)-amide
Figure imgf000072_0002
Using the procedure outlined in Example 1B, the title compound was prepared from 1-acetyl-5-amino-2,3-dihydro-(1H)indole (0.009 g, 0.051 mmol) and 1-(3- trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a white solid. 1H NMR (300MHz, CDCI3) δ (ppm): 8.12 (d, 1H), 7.75 (s, 1H), 7.37-7.33 (m, 2H), 7.13-7.09 (m, 2H), 6.98 (d, 1 H), 4.05 (t, 2H), 3.81 (d, 2H), 3.18 (t, 2H), 2.84 (t, 2H), 2.41 (m, 1 H), 2.22 (s, 3H), 2.04-1.98 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C23H24F3N3O2 : 431.5; Found: 432.4 (M + H).
Example 30 (04/072069)
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (1 H-indol-7-yl)-amide
Figure imgf000073_0001
Using the procedure outlined in Example 1 B, the title compound was prepared from 7-aminoindole (0.007 g, 0.051 mmol) and 1 -(3-trifluoromethyl-phenyl)- piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a white solid. 1H NMR (300MHz, CDCI3) δ (ppm): 10.01 (s, 1H), 7.53 (s, 1H), 7.50 (d, 1H), 7.36 (t, 1 H), 7.24 (t, 1 H), 7.15 (s, 1 H), 7.11 (t, 1 H), 7.02 (t, 1 H), 6.73 (d, 1 H), 6.55 (t, 1 H), 3.84 (d, 2H), 2.88 (td, 2H), 2.56-2.52 (m, 1 H), 2.14-2.03 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C2IH20F3N3O : 387.4; Found: 388.3 (M + H).
Example 31 1 -(S-Trifluoromethyl-phenyO-piperidine^-carboxylic acid (1 ,4-dioxo-1 ,2,3,4- tetrahydro-phthalazin-6-yl)-amide
Figure imgf000074_0001
Using the procedure outlined in Example 1B, the title compound was prepared from isoluminol (0.009 g, 0.051 mmol) and 1 -(3-trif luoromethyl-phenyl)- piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a white solid. 1H NMR (300MHz, CDCI3) δ (ppm): 8.02 (d, 1 H), 7.47-7.38 (m, 3H), 7.25-7.22 (m, 3H), 7.10-7.06 (m, 2H), 6.71-6.70 (m, 1 H), 3.81 (m, 2H), 2.97 (t, 3H), 2.63 (m, 2H), 2.03 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C-21H19F3N4O3 : 432.4; Found: 433.3 (M + H).
Example 32
1 -(S-Trifluoromethyl-phenyO-piperidine^-carboxylic acid (6-phenoxy-pyridin-3- yl)-amide
Figure imgf000074_0002
Using the procedure outlined in Example 1B, the title compound was prepared from 6-phenoxy-3-pyridinamine (0.010 g, 0.051 mmol) and 1-(3- trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a brown solid. 1H NMR (300MHz, CDCI3) δ (ppm): 8.33 (s, 1 H), 8.07 (dd, 1 H), 7.44-7.34 (m, 4H), 7.22-7.14 (m, 3H), 7.09-7.06 (m, 3H), 6.92 (d, 1 H), 3.85 (d, 2H), 2.94 (t, 2H), 2.56-2.53 (m, 1 H), 1.97-1.89 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C24H22F3N3O2 : 441.5; Found: 442.3 (M + H).
Example 33
1 -(S-Trifluoromethyl-phenyO-piperidine^-carboxylic acid (6-acetyl- benzo[1 ,3]dioxol-5-yl)-amide US2005/043192
Figure imgf000075_0001
Using the procedure outlined in Example 8, the title compound was prepared from 6'-amino-3',4'-(methylenedioxy)acetophenone (0.009 g, 0.051 mmol) and 1-(3-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a yellow brown solid. 1H NMR (300MHz, CDCI3) δ (ppm): 12.29 (s, 1 H), 8.43 (S1 1 H), 7.34 (t, 1 H), 7.28 (s, 1 H), 7.14 (s, 1 H), 7.08 (t, 2H), 6.04 (s, 2H), 3.80 (dt, 2H), 2.88 (td, 2H), 2.59 (s, 2H), 2.50-2.46 (m, 1 H), 2.14 (d, 2H), 2.00 (dt, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C22H2IF3N2O4 : 434.4; Found: 434.7 (M+).
Example 34
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro- 2H-benzo[1 ,4]oxazin-6-yl)-amide
Figure imgf000075_0002
Using the procedure outlined in Example 8, the title compound was prepared from 6-amino-2H-1 ,4-benzoxazin-3(4H)-one (0.008 g, 0.051 mmol) and 1-(3- trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a white solid. 1H NMR (300MHz, CDCI3) δ (ppm): 7.78 (s, 1H), 7.54 (s, 1H), 7.36 (m, 1H), 7.22-7.06 (m, 4H), 6.92 (d, 1H), 6.77 (d, 1H), 4.59 (s, 2H), 3.81 (d, 2H), 2.87 (m, 2H), 2.42 (m, 1 H)1 2.05 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C2iH20F3N3O3 : 419.4; Found: 419.7 (M+).
Example 35 1 -(S-Trifluoromethyl-phenyO-piperidine-^carboxylic acid (4-dimethylamino-5- phenyl-pyrimidin-2-yl)-amide
Figure imgf000076_0001
Using the procedure outlined in Example 8, the title compound was prepared from N4, N4-dimethyl-5-phenyl-2,4-pyrimidinediamine (0.011 g, 0.051 mmol) and 1-(3-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a pale yellow oil. 1H NMR (300MHz1 CDCI3) δ (ppm): 8.13 (s, 1H), 7.44-7.31 (m, 6H), 7.11-7.07 (m, 4H), 3.75 (d, 2H), 2.97-2.94 (m, 1 H), 2.84 (s, 6H)1 2.79 (t, 2H), 2.11-1.99 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C25H26F3N5O : 469.5; Found: 469.9 (M+).
Example 36 3,5-Dimethyl-1-(5-{[1-(3-trifluoromethyl-phenyl)-piperidine-4-carbonyl]-amino}- pyridin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester
Figure imgf000076_0002
Using the procedure outlined in Example 8, the title compound was prepared from ethyl 1 -(5-amino-2-pyridinyl)-3,5-dimethyl-1 H-pyrazole-4-carboxylate (0.013 g, 0.051 mmol) and 1-(3-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a pale brown solid. 1H NMR (300MHz, CDCI3) δ (ppm): 8.41 (d, 1 H), 8.24 (dd, 1 H), 7.69 (d, 1 H), 7.62 (s, 1 H), 7.35 (t, 1 H), 7.13-7.08 (m, 3H), 4.32 (q, 2H)1 4.12 (d, 2H), 2.85 (t, 2H)1 2.79 (s, 3H), 2.49 (s, 3H), 2.47-2.44 (m, 1 H)1 2.06-1.99 (m, 4H), 1.38 (t, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C26H28F3N5O3 : 515.5; Found: 515.9 (M+).
Example 37 1-(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (1-acetyl-2-methyl- 2,3-dihydro-1 H-indol-6-yl)-amide
Figure imgf000077_0001
A mixture of 1-(2-Methyl-6-nitro-2,3-dihydro-indol-1-yl)-ethanone (0.010 g, 0.0454 mmol) and 10 % Pd/C (0.005 g, 0.00545 mmol) in 1 ml_ of MeOH was stirred under H2(g) for 1 hour. Catalyst was filtered off and the filtrate was concentrated to provide 1-(6-amino-2-methyl-2,3-dihydro-indol-1-yl)-ethanone as white solid, which is ready for the following amide coupling without further purification.
Using the procedure outlined in Example 8, the title compound was prepared from the above prepared amino product (0.008 g, 0.042 mmol) and 1-(3- trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.01 g, 0.038 mmol) as an off-white solid. 1H NMR (400MHz1 CDCI3) δ (ppm): 7.91 (s, 1 H)1 7.79 (d, 1 H)1 7.39 (s, 1 H)1 7.34 (t, 1 H), 7.16-7.09 (m, 4H)1 4.47 (s, 1 H)1 3.80 (d, 2H)1 3.45 (dd, 1 H)1 2.85 (t, 2H), 2.64 (d, 1 H)1 2.04 (s, 1 H), 2.28 (s, 3H)1 2.04-1.95 (m, 4H), 1.30 (d, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C24H26F3N3O2 : 445.5; Found: 446.2 (M + H).
Example 38
HS-Trifluoromethyl-phenyO-piperidine^-carboxylic acid (2-oxo-2,3-dihydro- 1 H-indol-6-yl)-amide
Figure imgf000078_0001
A mixture of 3,3-dichloro-6-nitro-1 ,3-dihydro-indol-2-one (0.020 g, 0.0809 mmol) and 10 % Pd/C (0.009 g, 0.00809 mmol) in 2 ml_ of MeOH was stirred under H2(g) for 1 hour. The catalyst was filtered off and the filtrate was concentrated to provide 6-amino-1 ,3-dihydro-indol-2-one as a white solid, which is ready for the following amide coupling without further purification.
Using the procedure outlined in Example 8, the title compound was prepared from the above prepared amino product (0.009 g, 0.061 mmol) and 1-(3- trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.01 g, 0.055 mmol) as an off-white solid. 1H NMR (400MHz, CDCI3) δ (ppm): 7.56 (s, 1 H), 7.50 (s, 1 H), 7.29 (t, 1 H), 7.14-6.98 (m, 4H), 6.74 (d, 1 H)1 3.75 (d, 2H), 3.42 (s, 2H), 2.80 (t, 2H), 2.36 (m, 1H), 2.04-1.88 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C2IH20F3N3O2 : 403.4; Found: 404.2 (M + H).
Example 39
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid quinazolin-4-ylamide
Figure imgf000078_0002
Using the procedure outlined in Example 8, the title compound was prepared from 4-quinazolinamine (0.007 g, 0.051 mmol) and 1-(3-trifluoromethyl- phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as an yellow solid. 1H NMR (400MHz, CDCI3) δ (ppm): 8.0-7.88 (m, 3H), 7.66 (s, 1 H), 7.36 (t, 2H), 7.24-7.12 (m, 4H), 3.80 (d, 2H), 2.98 (t, 2H), 2.86 (m, 1 H), 2.22 (m, 2H), 2.08 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C2i H19F3N4O : 400.4; Found: 401.2 (M + H).
Example 40
1 -(S-Trifluoromethyl-phenyO-piperidine^-carboxylic acid (2,3-dimethyl- pyrido[2,3-b]pyrazin-6-yl)-amide
Figure imgf000079_0001
Using the procedure outlined in Example 8, the title compound was prepared from 6-amino-2,3-dimethylpyrido(2,3-b)pyrazine (0.009 g, 0.051 mmol) and 1- (3-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as an yellow oil. 1H NMR (400MHz, CDCI3) δ (ppm): 8.66 (d, 1 H), 8.56 (bs, 1 H), 8.34 (d, 1 H), 7.35 (t, 1 H), 7.14 (s, 1 H), 7.09 (t, 2H), 3.81 (d, 2H), 2.88 (t, 2H), 2.76 (s, 3H), 2.74 (s, 3H), 2.56 (m, 1H), 2.15-2.12 (m, 2H), 2.06-1.99 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C22H22F3N5O : 429.4; Found: 430.2 (M + H).
Example 41
1 -(3-Trif luoromethyl-phenyl)-piperidine-4-carboxylic acid (4,6-dimethyl- thieno[2,3-b]pyridin-3-yl)-amide
Figure imgf000079_0002
Using the procedure outlined in Example 8, the title compound was prepared from 4,6-dimethyl-thieno[2,3~b]pyridin-3-ylamine (0.009 g, 0.051 mmol) and 1- (3-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as an yellow oil. 1H NMR (300MHz, CDCI3) δ (ppm): 7.80 (s, 1 H), 7.71 (bs, 1H), 7.36 (t, 1 H), 7.15 9s, 1H)1 7.10 (d, 2H), 6.93 (s, 1 H), 3.83 (d, 2H)1 2.88 (t, 2H), 2.72 (s, 3H), 2.61 (s, 3H), 2.51-2.45 (m, 1 H), 2.18-2.10 (m, 2H), 2.04- 1.94 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C22H22F3N3OS : 433.5; Found: 434.2 (M + H).
Example 42
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid [5-(3,4-dimethoxy- phenyl)-4-methyl-pyrimidin-2-yl]-amide
Figure imgf000080_0001
Using the procedure outlined in Example 8, the title compound was prepared from 5-(3,4-dimethoxyphenyl)-4-methyl-2-pyrimidinamine (0.013 g, 0.051 mmol) and 1-(3-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a white solid. 1H NMR (400MHz, CDCI3) δ (ppm): 8.41 (s, 1 H), 8.02 (bs, 1 H), 7.28 (m, 1 H), 7.02-7.24 (m, 3H), 6.98 (d, 1 H), 6.85 (dd, 1 H), 6.78 (d, 1 H), 3.94 (s, 3H), 3.90 (s, 3H), 3.84 (dd, 2H), 3.12 (m, 1 H), 2.93 (m, 2H), 2.47 (s, 3H), 2.24-1.96 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C25H26F3N5O : 469.5; Found: 501.3 (M + MeCN + H).
Example 43
1 -(3-Trif luoromethyl-phenyl)-piperidine-4-carboxylic acid (4-methyl-6-phenoxy- pyrimidin-2-yl)-amide
Figure imgf000081_0001
Using the procedure outlined in Example 8, the title compound was prepared from 2-amino-4-phenoxy-6-methylpyrimidine (0.010 g, 0.051 mmol) and 1-(3- trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a white solid. 1H NMR (400MHz, CDCI3) δ (ppm): 7.79 (bs, 1 H), 7.40 (t, 2H), 7.33 (t, 1 H), 7.19 (t, 1 H), 7.13 (dd, 2H), 7.05 (m, 3H), 6.41 (s, 1 H), 3.60 (d, 2H), 3.21 (m, 1 H), 2.47 (t, 2H), 2.43 (s, 3H), 1.94-1.82 (m, 4H). Mass
Spectrum (LCMS1 ESI pos.) Calcd. for C24H2SF3N4O2 : 456.5; Found: 457.3 (M + H).
Example 44 1-(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro- 2H-benzo[1 ,4]oxazin-7-yl)-amide
Figure imgf000081_0002
Using the procedure outlined in Example 8, the title compound was prepared from 7-amino-2H-1 ,4-benzoxazin-3(4H)-one (0.008 g, 0.051 mmol) and 1-(3- trifluoromethyl-phenyI)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a white solid. 1H NMR (400MHz, CDOD3) δ (ppm): 7.38 (t, 1 H), 7.30 (d, 1 H), 7.20 (dd, 1 H), 7.17 (bs, 1 H), 7.12 (dd, 1 H), 7.05 (d, 1 H), 6.83 (d, 1H), 4.55 (s, 2H), 3.84 (d, 2H), 2.83 (dt, 2H), 2.53-2.49 (m, 1H), 1.96-1.89 (m, 4H). Mass Spectrum (LCMS1 ESI pos.) Calcd. for C2IH20F3N3O3 : 419.4; Found: 420.2 (M + H).
Example 45 1-(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (6-methylamino- quinazolin-5-yl)-amide
Figure imgf000082_0001
Using the procedure outlined in Example 8, the title compound was prepared from 5-amino-6-methylaminoquinoxaline (0.009 g, 0.051 mmol) and 1-(3- trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a reddish yellow solid. 1H NMR (400MHz, CDOD3) δ (ppm): 8.92 (bs, 1 H), 8.63 (d, 1 H), 8.60 (d, 1 H), 7.92 (d, 1 H), 7.46 (d, 1 H), 7.37 (t, 1 H), 7.25-7.10 (m, 3H), 3.86 (d, 2H), 3.06 (s, 3H), 2.97 (t, 2H), 2.75 (m, 1H)1 2.32-2.22 (m, 2H), 2.18-2.06 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C22H22F3N5O : 419.4; Found: 420.2 (M + H).
Example 46
1 -(S-Trifluoromethyl-phenyO-piperidine^-carboxylic acid (1 -acetyl-2,3-dihydro- 1 H-indol-4-yl)-amide
Figure imgf000082_0002
Using the procedure outlined in Example 8, the title compound was prepared from 1-(4-amino-2,3-dihydro-indol-1-yl)-ethanone (0.009 g, 0.051 mmol) and 1-(3-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid, (0.013 g, 0.046 mmol) as a white solid. 1H NMR (400MHz, CDCI3) δ (ppm): 8.06 (d, 1 H), 7.36 (t, 1 H), 7.32-6.98 (m, 6H), 4.08 (t, 2H), 3.81 (d, 2H), 3.10 (t, 2H), 2.88 (t, 2H), 2.43 (m, 1 H), 2.14-1.94 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C23H24F3N3O2 : 431.5; Found: 432.2 (M + H).
Example 47
1 -(S-Trifluoromethyl-phenyO-piperidine^-carboxylic acid (5-furan-2-yl-2H- pyrazol-3-yl)-amide
Figure imgf000083_0001
A. To a solution of 1-(3-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (1.63 g, 5.96 mmol) in a mixed solvent (80 ml_, DCM : DMF = 3 : 1) was added PS-HOBT (4.41 g, 3.97 mmol), N,N'-diisopropylcarbodiimide (2.7 ml_, 17.5 mmol), and pyridine (0.19 ml_, 2.38 mmol) (Scheme 2). After stirring for 8 hours, the resin was filtered off and washed with DCM, DMF, DCM, and THF sequentially. The resin was dried under vacuum, ready for the next coupling step.
B. A mixture of resin bound material (0.040 g) and 5-furan-2-yl-2H-pyrazol-3- ylamine (0.010 g 0.067 mmol) in 1 ml_ of dioxane was heated to 100 0C for 14 hours. Resin was filtered off and the filtrate was concentrated to provide a crude product which was then purified by silica gel column chromatograph to afford the title compound as light brown solid. 1H NMR (400MHz, CD3CN) δ (ppm): 8.87 (bs, 1H), 7.56 (s, 1 H), 7.42 (t, 1 H)1 7.22-7.20 (m, 2H), 7.09 (d, 1 H), 6.73 (d, 1 H), 6.64 (bs, 1 H), 6.55 (dd, 1H), 3.70 (d, 2H), 2.86 (dt, 2H), 2.58-2.53 (m, 1 H), 2.02-1.80 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C20Hi9F3N4O2 : 404.4; Found: 405.2 (M + H). Example 48
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (5-thiophen-2-yl-2H- pyrazol-3-yl)-amide
Figure imgf000084_0001
Using the procedure outlined in Example 47, the title compound was prepared from resin bound material (0.050 g) and 5-thiophen-2-yl-2H-pyrazol-3-ylamine (0.011 g, 0.067 mmol) as a white solid (Scheme 2). 1H NMR (400MHz,
CDOD3) δ (ppm): 7.44 (m, 4H), 7.21 (d, 1 H), 7.18 (s, 1 H), 7.08 (t, 1 H), 7.05 (d, 1 H), 3.84 (d, 2H), 2.85 (dt, 2H), 2.62-2.56 (m, 1H), 2.00-1.89 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C20Hi9F3N4OS : 420.5; Found: 421.1 (M + H).
Example 49
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid thieno[2,3- d]pyrimidin-4-ylamide
Figure imgf000084_0002
1-(3-Trifluoromethyl-phenyl)-piperidine-4-carbonyl chloride was prepared from 1-(3-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid as described in Example 8A. The title compound was prepared (0.012g) from thieno[2,3- d]pyrimidin-4-ylamine (0.33 mmol) and 1-(3-trifluoromethyl-phenyl)- piperidine-4-carbonyl chloride (0.33 mmol) using the procedure outlined in Example 8B. 1H NMR (400MHz, CDCI3) δ (ppm): 10.86-10.89 (s, 1 H), 10.70- 10.75 (s, 1 H), 9.67-9.70 (m, 1 H), 9.55-9.59 (m, 1 H), 9.40-9.45 (m, 1 H), 9.10- 9.21 (m, 3H), 5.87-5.93 (in, 2H), 4.67-5.02 (m, 3H), 4.05-4.28 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C19H17F3N4OS: 406.11 (M + H). Found: 407.20.
Example 50 (04/072069)
1 -(S-Trifluoromethyl-phenyO-piperidine^-carboxylic acid (3-methyl- benzo[d]isothiazol-5-yl)-amide
Figure imgf000085_0001
1-(3-Trifluoromethyl-phenyl)-piperidine-4-carbonyl chloride was prepared from 1-(3-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid as described in Example 8A. The title compound was prepared (0.012g) from 3-methyl- benzo[d]isothiazol-5-ylamine (0.33 mmol) and 1 -(3-trifluoromethyl-phenyl)- piperidine-4-carbonyl chloride (0.33 mmol) using the procedure outlined in Example 8B. 1H NMR (400MHz, CDCI3) δ (ppm): 8.45-8.47 (s, 1 H), 7.85-7.88 (m, 1 H), 7.35-7.47 (m, 3H), 7.10-7.18 (m, 3H), 3.83-3.90(m, 2H), 2.87-2.94 (m, 2H), 2.48-2.53 (m, 1 H), 2.04-2.18 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C21H20F3N3OS: 419.13 (M + H). Found: 420.20.
Example 51
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (6-chloro-4-methyl- pyridazin-3-yl)-amide
Figure imgf000085_0002
A. A solution of 3,6-Dichloro-4-methyl-pyridazine (1.Og, 6.1 mmol) in concentrated ammonium hydroxide (40 ml_) was heated to 130 0C in a sealed reaction vessel. After 18 h the solution was cooled to room temperature. The solution was filtered. The solid was washed with water and dried in vacuo to give β-Chloro^-methyl-pyridazin-S-ylamine. 1H NMR (400MHz, CDCI3) δ (ppm): 2.18-2.20 (d, 3H), 4.80-4.90 (bs, 2H), 7.11-7.12 (s, 1 H).
B. 1-(3-Trifluoromethyl-phenyl)-piperidine-4-carbonyl chloride was prepared from I^S-trifluoromethyl-phenyQ-piperidine^-carboxylic acid as described in Example 8A. The title compound was prepared (0.012g) from 6-chloro-4- methyl-pyridazin-3-ylamine (0.33 mmol) and 1 -(3-trifluoromethyl-phenyl)- piperidine-4-carbonyl chloride (0.33 mmol) using the procedure outlined in Example 8B. 1H NMR (400MHz, CDCI3) δ (ppm): 9.77-9.85 (s, 1 H)1 7.43-7.48 (m, 1 H), 7.30-7.38 (m, 1 H), 7.00-7.17 (m, 3H), 3.59-3.78(m, 2H)1 2.70-2.98 (m, 3H), 2.32-2.40 (s, 3H), 1.93-2.18 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For Ci8H18CIF3N4O: 398.11 (M + H). Found: 399.1.
Example 52 (04/072069)
1-(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (1 H-indazol-7-yl)- amide
Figure imgf000086_0001
1-(3-Trifluoromethyl-phenyl)-piperidine-4-carbonyl chloride was prepared from 1-(3-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid as described in
Example 8A. The title compound was prepared (0.007g) from 1 H-indazol-7- ylamine (0.33 mmol) and 1-(3-trifluoromethyl-phenyl)-piperidine-4-carbonyl chloride (0.33 mmol) using the procedure outlined in Example 8B. 1H NMR (400MHz, CDCI3+ drops CD3OD and DMSO(d6)) δ (ppm): 8.00 (s, 1 H), 7.60- 7.66 (m, 1 H), 7.47-7.52 (m, 1 H), 7.40 (s, 1 H), 7.33-7.36 (m, 1 H), 7.04-7.13 (m, 4H), 2.80-2.90 (m, 2H), 2.58-2.63 (m, 1 H), 2.00-2.10 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. FOr C20H19F3N4O: 388.15 (M + H). Found: 389.2.
Example 53
1 -(2-Bromo-phenyl)-piperidine-4-carboxylic acid quinolin-3-ylamide
Figure imgf000087_0001
A. 1-(2-Bromo-phenyl)-piperidine-4-carboxylic acid was prepared from 1 ,2- dibromobenzene (0.483 ml_, 4 mmol) and ethylisonipecotate (0.615 ml, 4.0 mmol) as described in Example 1.
B. 1-(2-Bromo-phenyl)-piperidine-4-carbonyl chloride was prepared from 1- (2-bromo-phenyl)-piperidine-4-carboxylic acid (O.Oδg, 0.28 mmol) as described in Example 8A.
C. The title compound was prepared (0.025g) from 3-aminoquinoline (0.14 mmol) and 1-(2-Bromo-phenyl)-piperidine-4-carbonyl chloride (0.14 mmoi) using the procedure outlined in Example 8B. 1H NMR (400MHz, CD3OD) δ (ppm): 8.77-8.80 (m, 1H), 8.30- 8.33(s, 1H), 7.80-7.85 (m, 1H), 7.55-7.60 (m, 1H), 7.48-7.52 (m, 3H), 7.20-7.26 (m, 1H), 7.00-7.08 (m, 1H), 6.84-6.88 (m, 1 H), 3.40-3.46 (m, 2H), 2.65-2.75 (m, 2H), 2.48-2.56 (m, 1 H), 1.90-2.20 (4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C2i H20BrN3O: 409.08 (M + H). Found: 410.1.
Example 54 (04/072069)
1-(9-Methyl-9H-purin-6-yl)-piperidine-4-carboxylic acid (1 H-indol-4-yl)-amide
Figure imgf000088_0001
A. A solution of 6-Bromo-9H-purine (2g, 10 mmol) and potassium carbonate (2.9g, 22.1 mmol) in acetonitrile (20 ml_) was treated with methyl iodide (0.69 mL, 11 mmol). After 18 h solution was filtered. The filtrate was concentrated to give 6-bromo-9-methyl-9H-purine as a 2:1 mixture of regioisomers and was used as is for the next step.
B. 1-(9-Methyl-9H-purin-6-yl)-piperidine-4-carboxylic acid was prepared from 6-bromo-9-methyl-9H-purine (4 mmol) and ethylisonipecotate (0.615 ml, 4.0 mmol) using the procedure in Example 1.
C. The title compound was prepared (0.004g) from 1-(9-Methyl-9H-purin-6- yl)-piperidine-4-carboxylic acid (0.141 g, 0.5 mmol) and 1 H-indol-4-ylamine (0.214g, 1.5 mmol) as described in Example 8. 1H NMR (400MHz, CDCI3) δ (ppm): 8.30-8.42 (m, 2H), 7.72-7.81 (m, 2H), 7.40-7.47(s, 1 H), 7.15-7.20 (m, 2H), 6.50 (s, 1 H), 5.50-5.60 (bs, 2H), 3.81-3.84 (s, 3H), 3.23-3.37 (m, 2H), 2.70-2.80 (m, 1 H), 1.99-2.25 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C20H2IN7O: 375.18 (M + H). Found: 376.20.
Example 55 i-Phenyl-piperidine-4-carboxylic acid quinolin-3-ylamide
Figure imgf000088_0002
Using the procedure outlined in Example 1A, i-phenyl-piperidine-4-carboxylic acid is prepared from bromobenzene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 3-aminoquinoline (0.5 mmol) and i-phenyl-piperidine-4-carboxylic acid (0.18 mmol).
Example 56
1 -Benzothiazol-δ-yl-piperidine^-carboxylic acid quinolin-3-ylamide
Figure imgf000089_0001
Using the procedure outlined in Example 1 , 1-benzothiazol-5-yl-piperidine-4- carboxylic acid is prepared from 5-bromobenzothiazole (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 3- aminoquinoline (0.5 mmol) and 1-benzothiazol-5-yl-piperidine-4-carboxylic acid (0.20 mmol).
Example 57
1-Benzothiazol-5-yl-piperidine-4-carboxylic acid (2,3-dihydro-1 H-indol-4-yl)- amide
Figure imgf000089_0002
Using the procedure outlined in Example 1A, 1-benzothiazol-5-yl-piperidine-4- carboxylic acid is prepared from 5-bromobenzothiazole (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 4- aminoindoline (0.5 mmol) and i-benzothiazol-δ-yl-piperidine-Φcarboxylic acid (0.20 mmol).
Example 58 i-Phenyl-piperidine-4-carboxylic acid (2,3-dihydro-1 H-indol-4-yl)-amide
Figure imgf000090_0001
Using the procedure outlined in Example 1A, i-phenyl-piperidine-4-carboxylic acid is prepared from bromobenzene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 4-aminoindoline (0.5 mmol) and 1-phenyl-piperidine-4-carboxylic acid (0.18 mmol).
Example 59 3,4,5, 6-Tetrahydro-2H-[1 ,3']bipyridinyl-4-carboxylic acid isoquinolin-1-ylamide
Figure imgf000090_0002
Using the procedure outlined in Example 1A, 3,4,5,6-tetrahydro-2H- [1 ,3']bipyridinyl-4-carboxylic acid is prepared from 3-bromopyridine (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 1-aminoisoquinoline (0.5 mmol) and 3,4,5,6-tetrahydro-2H- [1 ,3']bipyridinyl-4-carboxylic acid (0.18 mmol). Example 60 i-Phenyl-piperidine-4-carboxylic acid isoquinolin-1-ylamide
Figure imgf000091_0001
Using the procedure outlined in Example 1 , i-phenyl-piperidine-4-carboxylic acid is prepared from bromobenzene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 1-aminoisoquinoline (0.5 mmol) and i-phenyl-piperidine^-carboxylic acid (0.18 mmol).
Example 61 i-Phenyl-piperidine-4-carboxylic acid cinnolin-3-ylamide
Figure imgf000091_0002
Using the procedure outlined in Example 1A, 1-phenyl-piperidine-4-carboxylic acid is prepared from bromobenzene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 3-aminocinnoline (0.5 mmol) and 1-phenyl-piperidine-4-carboxylic acid (0.18 mmol).
Example 62
1 -Benzothiazol-5-yl-piperidine-4-carboxylic acid cinnolin-3-ylamide
Figure imgf000092_0001
Using the procedure outlined in Example 1A, 1-benzothiazol-5-yl-piperidine-4- carboxylic acid is prepared from 5-bromobenzothiazole (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 3- aminocinnoline (0.5 mmol) and i-benzothiazol-δ-yl-piperidine^-carboxylic acid (0.20 mmol).
Example 63 i-Benzothiazol-δ-yl-piperidine^-carboxylic acid phthalazin-5-ylamide
Figure imgf000092_0002
A. A solution of phthalazine (2.5g, 19.2 mmol) in concentrated sulfuric acid (30 ml_) is treated slowly with potassium nitrate (2g, 19.2 mmol). After 18 h the solution is cooled. Water (30 ml_) is added. The solution is basified using 10 M NaOH to pH 13 (litmus). The solution is cooled for 18 h, filtered to give 5-nitro-phthalazine (0.93 g).
B. A solution of 5-nitro-phthalazine (0.175 g, 1 mmol) and SnCI2 (0.57g, 3 mmol) in concentrated HCI (10 ml_) is stirred at room temperature for 2 h. Ice is added to the solution. A solution of 25% NaOH is added to pH 14 (litmus). The solution is cooled for 18 h. The solution is filtered. Aqueous filtrate is extracted twice with EtOAc. EtOAc layers are combined, washed with water, brine, dried over Na2SO4, filtered and concentrated to give phthalazin-5- ylamine (0.05Og). C. Using the procedure outlined in Example 1A, 1 -benzothiazol-5-yl- piperidine-4-carboxylic acid is prepared from 5-bromobenzothiazole (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 5-aminophthalazine (0.5 mmol) and 1-benzothiazol-5-yl-piperidine-4- carboxylic acid (0.20 mmol).
Example 64
3,4,5,6-Tetrahydro-2H-[1 ,4']bipyridinyl-4-carboxylic acid phthalazin-5-ylamide
Figure imgf000093_0001
Using the procedure outlined in Example 1A, 3,4,5,6-tetrahydro-2H- [1 ,4']bipyridinyl-4-carboxylic acid is prepared from 4-bromopyridine (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 3,4,5, 6-tetrahydro-2H-[1 ,4']bipyridinyl-4-carboxylic acid (0.5 mmol) and 5-aminophthalazine (0.20 mmol).
Example 65 i-Phenyl-piperidine-4-carboxylic acid quinazolin-4-ylamide
Figure imgf000093_0002
Using the procedure outlined in Example 1A, i-phenyl-piperidine-4-carboxylic acid is prepared from bromobenzene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 4-aminoquinazoline (0.5 mmol) and i-phenyl-piperidine-4-carboxylic acid (0.18 mmol).
Example 66 i-Benzothiazol-δ-yl-piperidine-^carboxylic acid quinazolin-4-ylamide
Figure imgf000094_0001
Using the procedure outlined in Example 1A, 1-benzothiazol-5-yl-piperidine-4- carboxylic acid is prepared from 5-bromobenzothiazole (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 4- aminoquinazoline (0.5 mmol) and 1-benzothiazol-5-yl-piperidine-4-carboxylic acid (0.20 mmol).
Example 67
1 -Benzothiazol-δ-yl-piperidine^-carboxylic acid pyridin-3-ylamide
Figure imgf000094_0002
Using the procedure outlined in Example 1A, 1-benzothiazol-5-yl-piperidine-4- carboxylic acid is prepared from 5-bromobenzothiazole (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 3- aminopyridine (0.5 mmol) and 1~benzothiazol-5-yl-piperidine-4-carboxylic acid (0.20 mmoi). Example 68
1 -Phenyl-piperidine^-carboxylic acid benzo[d]isothiazol-3-ylamide
Figure imgf000095_0001
Using the procedure outlined in Example 1A, i-phenyl-piperidine-4-carboxylic acid is prepared from bromobenzene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from benzo[d]isothiazol-3- ylamine (0.5 mmol) and i-phenyl-piperidine-4-carboxylic acid (0.18 mmol).
Example 69
3,4,5, 6-Tetrahydro-2H-[1 ,2']bipyridinyl-4-carboxylic acid benzo[d]isothiazol-3- ylamide
Figure imgf000095_0002
Using the procedure outlined in Example 1A, 3,4,5, 6-tetrahydro-2H- [1 ,2']bipyridinyl-4-carboxylic acid is prepared from 2-bromopyridine (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from benzo[d]isothiazol-3-ylamine (0.5 mmol) and 3,4,5,6-tetrahydro-2H- [1 ,2']bipyridinyl-4-carboxylic acid (0.18 mmol).
Example 70 i-Phenyl-piperidine^-carboxylic acid benzothiazol-2-ylamide
Figure imgf000096_0001
Using the procedure outlined in Example 1A, i-phenyl-piperidine-4-carboxylic acid is prepared from bromobenzene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from benzothiazol-2-ylamine (0.5 mmol) and i-Phenyl-piperidine-4-carboxylic acid (0.18 mmol).
Example 71 3,4,5, 6-Tetrahydro-2H-[1 ,3']bipyridinyl-4-carboxylic acid benzothiazol-2- ylamide
Figure imgf000096_0002
Using the procedure outlined in Example 1A, 3,4,5,6-tetrahydro-2H-
[1 ,3']bipyridinyl-4-carboxylic acid is prepared from 3-bromopyridine (4 mmol).
Using the procedure outlined in Example 8, the title compound is prepared from benzothiazol-2-ylamine (0.5 mmol) and 3,4,5,6-tetrahydro-2H-
[1 ,3']bipyridinyl-4-carboxylic acid (0.18 mmol).
Example 72
1 -Pyridazin-S-yl-piperidine^-carboxylic acid phthalazin-1 -ylamide
Figure imgf000097_0001
A. A solution of 3-chloro-pyridazine 2-oxide (0.5 mmol) and piperidine-4- carboxylic acid methyl ester (5 mmol) is heated to 80DC for 18 h. The solution is cooled to room temperature. 2.5N NaOH (15 mmol) is added and the solution is heated to 6O0C for 18 h. The reaction solution is cooled to room temperature and partitioned between EtOAc and water. The aqueous layer is separated and acidified using 3N HCI. The aqueous layer is extracted with EtOAc. EtOAc layer is washed with brine, dried over MgSO4, filtered and concentrated to give 1-(2-oxy-pyridazin-3-yl)-piperidine-4-carboxylic acid (0.3 mmol). A suspension of 1-(2-oxy-pyridazin-3-yl)-piperidine-4-carboxylic acid (0.1 mmol) and iron powder (0.4 mmol) in 50% aqueous acetic acid (2 ml_) is stirred at room temperature for 2 h. The solution is filtered and the filtrate is concentrated to give 1-pyridazin-3-yl-piperidine-4-carboxylic acid (0.07 mmol).
B. Using the procedure outlined in Example 8, the title compound is prepared 1-aminophthalazine (0.5 mmol) and 1-pyridazin-3-yl-piperidine-4-carboxylic acid (0.18 mmol).
Example 73
1 -Thiophen^-yl-piperidine^-carboxylic acid phthalazin-1 -ylamide
Figure imgf000097_0002
Using the procedure outlined in Example 1A, 1-thiophen-2-yI-piperidine-4- carboxylic acid is prepared from 2-bromothiophene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 1- aminophthalazine (0.5 mmol) and 1-Thiophen-2-yl-piperidine-4-carboxylic acid (0.18 mmol).
Example 74
1 -Thiophen^-yl-piperidine^-carboxylic acid (7H-purin-6-yl)-amide
Figure imgf000098_0001
Using the procedure outlined in Example 1A, 1-thiophen-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromothiophene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from TH¬ purin-6-ylamine (0.5 mmol) and 1-thiophen-2-yl-piperidine-4-carboxylic acid (0.18 mmol).
Example 75 i-Pyrimidin^-yl-piperidine^-carboxylic acid (7H-purin-6-yl)-amide
Figure imgf000098_0002
Using the procedure outlined in Example 1A, 1-pyrimidin-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromopyrimidine (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 7H- purin-6-ylamine (0.5 mmol) and 1-pyrimidin-2-yl-piperidine-4-carboxylic acid (0.18 mmol).
Example 76 1-Pyrimidin-2-yl-piperidine-4-carboxylic acid cinnolin-4-ylamide
Figure imgf000099_0001
Using the procedure outlined in Example 1A1 1-pyrimidin-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromopyrimidine (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from cinnolin-4-ylamine (0.5 mmol) and 1-pyrimidin-2-yl-piperidine-4-carboxylic acid (0.18 mmol).
Example 77
1-Thiophen-2-yl-piperidine-4-carboxylic acid cinnolin-4-ylamide
Figure imgf000099_0002
Using the procedure outlined in Example 1A, 1-thiophen-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromothiophene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from cinnolin-4-ylamine (0.5 mmol) and 1-thiophen-2-yl-piperidine-4-carboxylic acid (0.18 mmol). Example 78
1 -Thiophen^-yl-piperidine^-carboxylic acid quinoxalin-6-ylamide
Figure imgf000100_0001
Using the procedure outlined in Example 1A, 1-thiophen-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromothiophene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from quinoxalin-6-ylamine (0.5 mmol) and 1-thiophen-2-yl-piperidine-4-carboxylic acid (0.18 mmol).
Example 79
1 -Pyridazin-3-yl-piperidine-4-carboxylic acid quinoxalin-6-ylamide
Figure imgf000100_0002
Using the procedure outlined in Example 1A, 1-pyridazin-3-yl-piperidine-4- carboxylic acid (4 mmol) is prepared as in Example 120. Using the procedure outlined in Example 8, the title compound is prepared from quinoxalin-6- ylamine (0.5 mmol) and 1-pyridazin-3-yl-piperidine-4-carboxylic acid (0.18 mmol). Example 80
1 -Pyrimidin^-yl-piperidine^-carboxylic acid quinoxalin-6-ylamide
Figure imgf000101_0001
Using the procedure outlined in Example 1A, 1-pyrimidin-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromopyrimidine (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from quinoxalin-6-ylamine (0.5 mmol) and 1-pyrimidin-2-yl-piperidine-4-carboxylic acid (0.18 mmol).
Example 81
1-Pyrimidin-2-yl-piperidine-4-carboxylic acid pyrazin-2-ylamide
Figure imgf000101_0002
Using the procedure outlined in Example 1A, 1-pyrimidin-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromopyrimidine (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from pyrazin- 2-ylamine (0.5 mmol) and 1-pyrimidin-2-yl-piperidine-4-carboxylic acid (0.18 mmol).
Example 82
1-Thiophen-2-yl-piperidine-4-carboxylic acid pyrazin-2-ylamide
Figure imgf000102_0001
Using the procedure outlined in Example 1A, 1-thiophen-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromothiophene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from pyrazin- 2-ylamine (0.5 mmol) and 1-thiophen-2-yl-piperidine-4-carboxylic acid (0.18 mmol).
Example 83
1 -Thiophen^-yl-piperidine^-carboxylic acid quinazolin-7-ylamide
Figure imgf000102_0002
Using the procedure outlined in Example 1A, 1-thiophen-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromothiophene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from quinazolin-7-ylamine (0.5 mmol) and 1-thiophen-2-yl-piperidine-4-carboxylic acid (0.18 mmol).
Example 84
1 -Pyrimidin^-yl-piperidine^-carboxylic acid quinazolin-7-ylamide
Figure imgf000103_0001
Using the procedure outlined in Example 1 , 1-pyrimidin-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromopyrimidine (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from quinazolin-7-ylamine (0.5 mmol) and 1-pyrimidin-2-yl-piperidine-4-carboxylic acid (0.18 mmol).
Example 85 1-Pyrimidin-2-yl-piperidine-4-carboxylic acid pyridazin-3-ylamide
Figure imgf000103_0002
Using the procedure outlined in Example 1A, 1-pyrimidin-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromopyrimidine (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from pyridazin-3-ylamine (0.5 mmol) and 1-pyrimidin-2-yl-piperidine-4-carboxylic acid (0.18 mmol).
Example 86
1 -Thiophen^-yl-piperidine^-carboxylic acid pyridazin-3-ylamide
Figure imgf000104_0001
Using the procedure outlined in Example 1A1 1-thiophen-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromothiophene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from pyridazin-3-ylamine (0.5 mmol) and 1-thiophen-2-yl-piperidine-4-carboxylic acid (0.18 mmol).
Example 87 1-Benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid (2-oxo-2,3-dihydro-1 H- benzoimidazol-5-yl)-amide
Figure imgf000104_0002
Using the procedure outlined in Example 1A, 1-benzo[b]thiophen-3-yl- piperidine-4-carboxylic acid is prepared from 3-bromo-benzo[b]thiophene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 5-amino-1 ,3-dihydro-benzoimidazol-2-one (0.5 mmol) and 1- benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid (0.18 mmol).
Example 88
1-Naphthalen-2-yl-piperidine-4-carboxylic acid (2-oxo-2,3-dihydro-1 H- benzoimidazol-5-yl)-amide
Figure imgf000105_0001
Using the procedure outlined in Example 1A, 1-naphthaIen-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromo-naphthalene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 5- amino-1 ,3-dihydro-benzoimidazol-2-one (0.5 mmol) and 1-naphthalen-2-yl- piperidine-4-carboxylic acid (0.18 mmol).
Example 89
1 -Naphthalen^-yl-piperidine^-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide
Figure imgf000105_0002
Using the procedure outlined in Example 1A, 1-naphthalen-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromo-naphthalene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 6- amino-4H-benzo[1 ,4]oxazin-3-one (0.5 mmol) and 1-naphthalen-2-yl- piperidine-4-carboxylic acid (0.18 mmol). Example 90
1 -Biphenyl-S-yl-piperidine-^carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide
Figure imgf000106_0001
Using the procedure outlined in Example 1A, 1-biphenyl-3-yl-piperidine-4- carboxylic acid is prepared from 3-bromo-biphenyl (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 6- amino-4H-benzo[1 ,4]oxazin-3-one (0.5 mmol) and 1-biphenyl-3-yl-piperidine- 4-carboxylic acid (0.18 mmol).
Example 91
1 -Biphenyl-S-yl-piperidine^-carboxylic acid quinazolin-2-ylamide
Figure imgf000106_0002
Using the procedure outlined in Example 1A, 1-biphenyl-3-yl-piperidine-4- carboxylic acid is prepared from 3-bromo-biphenyl (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from quinazolin-2-ylamine (0.5 mmol) and 1-biphenyl-3-yl-piperidine-4-carboxylic acid (0.18 mmol). Example 92
1 -Quinolin-S-yl-piperidine^-carboxylic acid quinazolin-2-ylamide
Figure imgf000107_0001
Using the procedure outlined in Example 1A, 1-quinolin-3-yl-piperidine-4- carboxylic acid is prepared from 3-bromo-quinoline (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from quinazolin-2-ylamine (0.5 mmol) and i-quinolin-S-yl-piperidine^-carboxylic acid (0.18 mmol).
Example 93
1 -Quinolin-S-yl-piperidine^-carboxylic acid quinoxalin-2-ylamide
Figure imgf000107_0002
Using the procedure outlined in Example 1A, 1-quinolin-3-yl-piperidine-4- carboxylic acid is prepared from 3-bromo-quinoline (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from quinoxalin-2-ylamine (0.5 mmol) and 1-quinolin-3-yl-piperidine-4-carboxylic acid (0.18 mmol). Example 94
1 -Isoquinolin-δ-yl-piperidine^-carboxylic acid quinoxalin-2-ylamide
Figure imgf000108_0001
Using the procedure outlined in Example 1A, 1-isoquinolin-5-yl-piperidine-4- carboxylic acid is prepared from 5-Bromo-isoquinoline (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from quinoxalin-2-ylamine (0.5 mmol) and i-isoquinolin-δ-yl-piperidine^-carboxylic acid (0.18 mmol).
Example 95
1 -lsoquinolin-δ-yl-piperidine-4-carboxylic acid (9H-carbazol-3-yi)-amide
Figure imgf000108_0002
Using the procedure outlined in Example 1A, 1-isoquinolin-5-yl-piperidine-4- carboxylic acid is prepared from 5-bromo-isoquinoline (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 9H- carbazol-3-ylamine (0.5 mmol) and 1-isoquinolin-5-yl-piperidine-4-carboxylic acid (0.18 mmol). Example 96
1 -Benzotbfthiophen-S-yl-piperidine^-carboxylic acid (9H-carbazol-3-yl)-amide
Figure imgf000109_0001
Using the procedure outlined in Example 1A, 1-benzo[b]thiophen-3-yl- piperidine-4-carboxylic acid is prepared from 3~bromo-benzo[b]thiophene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 9H-carbazol-3-ylamine (0.5 mmol) and 1-benzo[b]thiophen-3- yl-piperidine-4-carboxylic acid (0.18 mmol).
Example 97
1 -Benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid phenazin-2-ylamide
Figure imgf000109_0002
Using the procedure outlined in Example 1A, 1 -benzo[b]thiophen-3-yl- piperidine-4-carboxylic acid is prepared from 3-bromo-benzo[b]thiophene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from phenazin-2-ylamine (0.5 mmol) and 1-benzo[b]thiophen-3-yl- piperidine-4-carboxylic acid (0.18 mmol). Example 98
1 -Naphthalen^-yl-piperidine-^carboxylic acid phenazin-2-ylamide
Figure imgf000110_0001
Using the procedure outlined in Example 1A, 1-naphthalen-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromo-naphthalene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from phenazin-2-ylamine (0.5 mmol) and 1-naphthalen-2-yl-piperidine-4-carboxylic acid (0.18 mmol).
Example 99
1 -Naphthalen^-yl-piperidine^-carboxylic acid thiazol-2-ylamide
Figure imgf000110_0002
Using the procedure outlined in Example 1A, 1-naphthalen-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromo-naphthalene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from thiazol- 2-ylamine (0.5 mmol) and 1-naphthalen-2-yl-piperidine-4-carboxylic acid (0.18 mmol).
Example 100
1-Biphenyl-3-yl-piperidine-4-carboxylic acid thiazol-2-ylamide
Figure imgf000111_0001
Using the procedure outlined in Example 1 , 1-biphenyl-3-yl-piperidine-4- carboxylic acid is prepared from 3-bromobiphenyl (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from thiazol- 2-ylamine (0.5 mmol) and i-biphenyl-S-yl-piperidine^-carboxylic acid (0.18 mmol).
Example 101 i-Biphenyl-S-yl-piperidine^-carboxylic acid (1 H-imidazol-2-yl)-amide
Figure imgf000111_0002
Using the procedure outlined in Example 1A, 1-biphenyl-3-yl-piperidine-4- carboxylic acid is prepared from 3-bromobiphenyl (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 1 H- imidazol-2-ylamine (0.5 mmol) and 1-biphenyl-3-yl-piperidine-4-carboxylic acid (0.18 mmol).
Example 102
1-Quinolin-3-yl-piperidine-4-carboxylic acid (1 H-imidazol-2-yl)-amide
no
Figure imgf000112_0001
Using the procedure outlined in Example 1A, 1-quinolin-3-yl-piperidine-4- carboxylic acid is prepared from 3-bromo-quinoline (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 1 H- imidazol-2-ylamine (0.5 mmol) and 1-quinolin-3-yl-piperidine~4-carboxylic acid (0.18 mmol).
Example 103 i-Quinolin-S-yl-piperidine^-carboxylic acid (2H-pyrazol-3-yl)-amide
Figure imgf000112_0002
Using the procedure outlined in Example 1A, 1-quinolin-3-yl-piperidine-4- carboxylic acid is prepared from 3-bromo-quinoline (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 2H- pyrazol-3-ylamine (0.5 mmol) and 1-quinolin-3-yl-piperidine-4-carboxylic acid (0.18 mmol).
Example 104
1 -lsoquinolin-5-yl-piperidine-4-carboxylic acid (2H-pyrazol-3-yl)-amide
in
Figure imgf000113_0001
Using the procedure outlined in Example 1A, 1-isoquinolin-5-yl-piperidine-4- carboxylic acid is prepared from 5-bromo-isoquinoline (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 2H- pyrazol-3-ylamine (0.5 mmol) and i-isoquinolin-δ-yl-piperidine^-carboxylic acid (0.18 mmol).
Example 105
1 -Isoquinolin-δ-yl-piperidine^-carboxylic acid isoxazol-3-ylamide
Figure imgf000113_0002
Using the procedure outlined in Example 1A, 1-isoquinolin-5-yl-piperidine-4- carboxylic acid is prepared from 5-bromo-isoquinoline (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from isoxazol-3-ylamine (0.5 mmol) and 1-isoquinolin-5-yl-piperidine-4-carboxylic acid (0.18 mmol).
Example 106
1 -Benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid isoxazol-3-ylamide
Figure imgf000114_0001
Using the procedure outlined in Example 1A, 1 -benzo[b]thiophen-3-yl- piperidine-4-carboxylic acid is prepared from 3-bromo-benzo[b]thiophene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from isoxazol-3-ylamine (0.5 mmol) and 1-benzo[b]thiophen-3-yl- piperidine-4-carboxylic acid (0.18 mmol).
Example 107 1-Benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid (3-methyl- isothiazol-5-yl)-amide
Figure imgf000114_0002
Using the procedure outlined in Example 1A, 1 -benzo[b]thiophen-3-yl- piperidine-4-carboxylic acid is prepared from 3-bromo-benzo[b]thiophene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 3-methyl-isothiazol-5-ylamine (0.5 mmol) and 1- benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid (0.18 mmol). Example 108
1 -Naphthalen-2-yl-piperidine-4-carboxylic acid (3-methyl-isothiazol-5-yl)- amide
Figure imgf000115_0001
Using the procedure outlined in Example 1A, 1-naphthalen-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromo-naphthalene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 3- methyl-isothiazol-5-ylamine (0.5 mmol) and 1-naphthalen-2-yl-piperidine-4- carboxylic acid (0.18 mmol).
Example 109
1-lsoquinolin-5-yl-piperidine-4-carboxylic acid [1 ,6]naphthyridin-4-ylamide
Figure imgf000115_0002
Using the procedure outlined in Example 1A, 1-isoquinolin-5-yl-piperidine-4- carboxylic acid is prepared from 5-bromo-isoquinoline (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from
[1 ,6]naphthyridin-4-ylamine (0.5 mmol) and 1-isoquinolin-5-yl-piperidine-4- carboxylic acid (0.18 mmol). Example 110
1-Benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid [1 ,6]naphthyτidin-4- ylamide
Figure imgf000116_0001
Using the procedure outlined in Example 1A, 1-benzo[b]thiophen-3-yI- piperidine-4-carboxylic acid is prepared from 3-bromo-benzo[b]thiophene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from [1 ,6]naphthyridin-4-ylamine (0.5 mmol) and 1- benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid (0.18 mmol).
Example 111
1-Benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid [1 ,7]naphthyridin-8- ylamide
Figure imgf000116_0002
Using the procedure outlined in Example 1A, 1 -benzo[b]thiophen-3-yl- piperidine-4-carboxylic acid is prepared from 3-bromo-benzo[b]thiophene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from [1 ,7]naphthyridin-8-yIamine (0.5 mmol) and 1- benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid (0.18 mmol).
Example 112 1-Naphthalen-2-yl-piperidine-4-carboxylic acid [1 ,7]naphthyridin-8-ylamide
Figure imgf000117_0001
Using the procedure outlined in Example 1A, 1-naphthalen-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromo-naphthalene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from [1 ,7]naphthyridin-8-ylamine (0.5 mmol) and 1-naphthalen-2-yl-piperidine-4- carboxylic acid (0.18 mmol).
Example 113
1 -Naphthalen-2-yl-piperidine-4-carboxylic acid acridin-9-ylamide
Figure imgf000117_0002
Using the procedure outlined in Example 1A, 1-naphthalen-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromo-naphthalene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from acridin- 9-ylamine (0.5 mmol) and 1-naphthalen-2-yl-piperidine-4-carboxylic acid (0.18 mmol). Example 114
1-Biphenyl-3-yl-piperidine-4-carboxylic acid acridin-9-ylamide
Figure imgf000118_0001
Using the procedure outlined in Example 1A, 1-biphenyl-3-yl-piperidine-4- carboxylic acid is prepared from 3-biphenyl (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from acridin-9-ylamine (0.5 mmol) and i-biphenyl-S-yl-piperidine^-carboxylic acid (0.18 mmol).
Example 115 i-Biphenyl-S-yl-piperidine^-carboxylic acid (1-methyl-4,5-dihydro-1 H- imidazol-2-yl)-amide
Figure imgf000118_0002
Using the procedure outlined in Example 1A, 1-biphenyl-3-yl-piperidine-4- carboxylic acid is prepared from 3-biphenyl (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 1-methyl-4,5- dihydro-1 H-imidazol-2-ylamine (0.5 mmol) and 1-biphenyl-3-yl-piperidine-4- carboxylic acid (0.18 mmol). Example 116
1 -Quinolin-S-yl-piperidine^-carboxylic acid (1 -methyl-4,5-dihydro-1 H- imidazol-2-yl)-amide
Figure imgf000119_0001
Using the procedure outlined in Example 1A, 1-quinolin-3-yl-piperidine-4- carboxylic acid is prepared from 3-bromo-quinoline(4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 1- methyl-4,5-dihydro-1 H-imidazol-2-ylamine (0.5 mmol) and 1-quinolin-3-yl- piperidine-4-carboxylic acid (0.18 mmol).
Example 117
1-Quinolin-3-yl-piperidine-4-carboxylic acid (4,5-dihydro-1 H-pyrazol-3-yl)- amide
Figure imgf000119_0002
A. Using the procedure outlined in Example 1A, 1-quinolin-3-yl~piperidine-4- carboxylic acid is prepared from 3-bromo-quinoline(4 mmol). Using the procedure outlined in Example 8, 1-quinolin-3-yl-piperidine-4-carboxylic acid [1-(toluene-4-sulfonyl)-4,5-dihydro-1H-pyrazol-3-yl]-amide is prepared from 1- (toluene-4-sulfonyl)-4,5-dihydro-1H-pyrazol-3-ylamine (0.5 mmol) and 1- quinolin-3-yl-piperidine-4-carboxylic acid (0.18 mmol). B. A solution of i-quinolin-S-yl-piperidine^-carboxylic acid [1 -(toluene-4- sulfonyl)-4,5-dihydro-1 H-pyrazol-3-yl]-amide (0.2 mmol) in 30% HBr in acetic acid (1 mL) is stirred at 700C for 8 h. The solution is concentrated and the residue is chromatographed on a prep TLC plate (2000 microns, silica as stationary phase, methylene chloride/MeOH 9:1 ) to give the title compound.
Example 118 i-lsoquinolin-δ-yl-piperidine-Φ-carboxylic acid (4,5-dihydro-1 H-pyrazol-3-yl)- amide
Figure imgf000120_0001
A. Using the procedure outlined in Example 1A, 1-isoquinolin-5-yl-piperidine- 4-carboxylic acid is prepared from 5-bromo-isoquinoline (4 mmol). Using the procedure outlined in Example 8, 1-isoquinolin-5-yl-piperidine-4-carboxylic acid [1-(toluene-4-sulfonyl)-4,5-dihydro-1 H-pyrazol-3-yl]-amide is prepared from 1-(toluene-4-sulfonyl)-4,5-dihydro-1 H-pyrazol-3-ylamine (0.5 mmol) and 1-isoquinolin-5-yl-piperidine-4-carboxylic acid (0.18 mmol).
B. A solution of 1-isoquinolin-5-yl-piperidine-4-carboxylic acid [1 -(toluene-4- sulfonyl)-4,5-dihydro-1 H-pyrazol-3-yl]-amide (0.2 mmol) in 30% HBr in acetic acid (1 mL) is stirred at 700C for 8 h. The solution is concentrated and the residue is chromatographed on a prep TLC plate (2000 microns, silica as stationary phase, methylene chloride/MeOH 9:1 ) to give the title compound.
Example 119
1-lsoquinolin-5-yl-piperidine-4-carboxylic acid [1 ,8]naphthyridin-2-ylamide
Figure imgf000121_0001
A. A solution of [1 ,8]naphthyridine (0.2 mmol) and potassium amide (0.8 mmol) in liquid ammonia (20 ml_) is stirred at -400C for 3 h. The solution is concentrated. Residue is partitioned between EtOAc and water. EtOAc layer is separated and washed successively with water and brine. EtOAc layer is dried over sodium sulfate, filtered and concentrated to give [1 ,8]naphthyridin- 2-ylamine which is used as is for the next step.
B. Using the procedure outlined in Example 1A, 1-isoquinolin-5-yl-piperidine- 4-carboxylic acid is prepared from 5-bromo-isoquinoline (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from [1 ,8]naphthyridin-2-ylamine (0.5 mmol) and 1-isoquinolin-5-yl-piperidine-4- carboxylic acid (0.18 mmol).
Example 120
1-Benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid [1 ,8]naphthyridin-2- ylamide
Figure imgf000121_0002
Using the procedure outlined in Example 1 , 1 -benzo[b]thiophen-3-yl- piperidine-4-carboxylic acid is prepared from 3-bromo-benzo[b]thiophene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from [1 ,8]naphthyridin-2-ylamine (0.5 mmol) (prepared as in Example 165a) and 1-benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid (0.18 mmol).
Example 121
1 -Benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid [2,6]naphthyridin-1 - ylamide
Figure imgf000122_0001
A. 1-Bromo-[2,6]naphthyridine is prepared from 1-bromo-[2,6]naphthyridin-3- ylamine using the procedure from Vogel's Textbook of Practical Organic Chemistry p. 945, fifth ed., 1989.
B. [2,6]Naphthyridin-1-ylamine is prepared from 1-bromo-[2,6]naphthyridine using the procedure given in Organic Letters. 3(17), 2729-2732 (2001).
C. Using the procedure outlined in Example 1C, 1 -benzo[b]thiophen-3-yl- piperidine-4-carboxylic acid is prepared from 3-bromo-benzo[b]thiophene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from [2,6]naphthyridin-1-ylamine (0.5 mmol) (prepared as in Example 167b) and 1-benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid (0.18 mmol).
Example 122
1-Naphthalen-2-yl-piperidine-4-carboxylic acid [2, 6]naphthyridin-1 -ylamide
Figure imgf000123_0001
Using the procedure outlined in Example 1A, 1-naphthalen-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromo-naphthalene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from
[2,6]naphthyridin-1-ylamine (0.5 mmol) (prepared as in Example 167b) and 1- naphthalen-2-yl-piperidine-4-carboxylic acid (0.18 mmol).
Example 123 1-Naphthalen-2-yl-piperidine-4-carboxylic acid benzo[d]isoxazol-5-ylamide
Figure imgf000123_0002
A. 5-Nitro-benzo[d]isoxazole is prepared from benzo[d]isoxazole as described in Example 63A.
B. Benzo[d]isoxazol-5-ylamine is prepared from 5-nitro-benzo[d]isoxazole as described in Example 63B.
C. Using the procedure outlined in Example 1A, 1-naphthalen-2-yl-piperidine- 4-carboxylic acid is prepared from 2-Bromo-naphthalene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from benzo[d]isoxazol-5-ylamine (0.5 mmol) and 1-naphthalen-2-yl-piperidine-4- carboxylic acid (0.18 mmol). Example 124
1 -Biphenyl-S-yl-piperidine-^carboxylic acid benzo[d]isoxazol-5-ylamide
Figure imgf000124_0001
Using the procedure outlined in Example 1A, 1-biphenyl-3-yl-piperidine-4- carboxylic acid is prepared from 3-bromo-biphenyl (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from benzo[d]isoxazol-5-ylamine (0.5 mmol) (prepared as in Example 169b) and 1- biphenyl-S-yl-piperidine^-carboxylic acid (0.18 mmol).
Example 125 i-Biphenyl-S-yl-piperidine^-carboxylic acid (1 H-pyrrol-3-yl)-amide
Figure imgf000124_0002
A. 1 H-Pyrrol-3-ylamine is prepared from 3-nitro-1 H-pyrrole following the procedure from Example 63B.
B. Using the procedure outlined in Example 1A, 1-biphenyl-3-yl-piperidine-4- carboxylic acid is prepared from 3-bromo-biphenyl (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 1 H- pyrrol-3-ylamine (0.5 mmol) (prepared as in Example 172a) and 1-biphenyl-3- yl-piperidine-4-carboxylic acid (0.18 mmol). Example 126 i-Quinolin-S-yl-piperidine-^carboxylic acid (1 H-pyrrol-3-yl)-amide
Figure imgf000125_0001
Using the procedure outlined in Example 1A, 1-quinolin-3-yl-piperidine-4- carboxylic acid is prepared from 3-bromo-quinoIine (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 1 H- pyrrol-3-ylamine (0.5 mmol) and i-quinolin-S-yl-piperidine^-carboxylic acid (0.18 mmol).
Example 127 i-Quinolin-S-yl-piperidine^-carboxylic acid (1 H-pyrrolo[2,3-b]pyridin-3-yl)- amide
Figure imgf000125_0002
A. 3-Bromo-1 H-pyrrolo[2,3-b]pyridine and ammonia (0.5M in 1 ,4-dioxane) is heated to reflux. After 5 h the solution is concentrated. The residue is chromatographed on a silica gel plug to give 1 H-pyrrolo[2,3-b]pyridin-3- ylamine.
B. Using the procedure outlined in Example 1A, 1-quinolin-3-yl-piperidine-4- carboxylic acid is prepared from 3-bromo-quinoline (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 1 H- pyrroIo[2,3-b]pyridin-3-ylamine (0.5 mmol) and 1-quinolin-3-yl-piperidine-4- carboxylic acid (0.18 mmol).
Example 128 i-lsoquinolin-δ-yl-piperidine-Φ-carboxylic acid (1 H-pyrrolo[2,3-b]pyridin-3-yl)- amide
Figure imgf000126_0001
Using the procedure outlined in Example 1A, 1-isoquinolin-5-yl-piperidine-4- carboxylic acid is prepared from 3-bromo-quinoline (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 1 H- pyrrolo[2,3-b]pyridin-3-ylamine (0.5 mmol) (prepared as in Example 174a) and i-isoquinolin-δ-yl-piperidine^-carboxylic acid (0.18 mmol).
Example 129
1 -Isoquinolin-δ-yl-piperidine^-carboxylic acid pteridin-4-ylamide
Figure imgf000126_0002
A. A solution of pteridin-4-ol (1 mmol) in 10 ml_ of POCI3 is stirred at O0C for 10 min then at 1000C for 6 h. The solution is concentrated. The residue is partitioned between ethyl acetate and water. Ethyl acetate layer is separated, dried over sodium sulfate, filtered and concentrated to give 4-chloro-pteridine.
B. A solution of 4-chloro-pteridine (0.5 mmol) and ammonia (0.5M in 1 ,4- dioxane, 2 mmol) in DMF is heated to 1000C. After 5 h the solution is concentrated. Residue is chromatographed on a silica gel plug to give pteridin-4-ylamine.
C. Using the procedure outlined in Example 1A, 1-isoquinolin-5-yl-piperidine- 4-carboxylic acid is prepared from 3-bromo-quinoline (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from pteridin- 4-ylamine (0.5 mmol) (prepared as in Example 176b) and 1-isoquinolin-5-yl- piperidine-4-carboxylic acid (0.18 mmol).
Example 130
1 -Benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid pteridin-4-ylamide
Figure imgf000127_0001
Using the procedure outlined in Example 1A, 1-benzo[b]thiophen-3-yl- piperidine-4-carboxy|ic acid is prepared from 3-bromo-benzo[b]thiophene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from pteridin-4-ylamine (0.5 mmol) (prepared as in Example 176b) and 1-benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid (0.18 mmol).
Example 131
1-Benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid (1 ,4-dihydro-quinazolin-
6-yl)-amide
Figure imgf000128_0001
A. 1,4-Dihydro-quinazoline is prepared from 2-aminomethyl-phenylamine (1 mmol) following the procedure given in Journal of Organic Chemistry, 5, 133- 141 (1940).
B. 6-Nitro-1 ,4-dihydro-quinazoline is prepared from 1 ,4-dihydro-quinazoline (1 mmol) following the procedure given in Example 69A.
C. 1 ,4-Dihydro-quinazolin-6-ylamine is prepared from 6-nitro-1 ,4-dihydro- quinazoline (1 mmol) following the procedure given in Example 69B.
D. Using the procedure outlined in Example 1A, 1-benzo[b]thiophen-3-yl- piperidine-4-carboxylic acid is prepared from 3-bromo-benzo[b]thiophene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 1 ,4-dihydro-quinazolin-6-ylamine (0.5 mmol) (prepared as in Example 178c) and 1-benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid (0.18 mmol).
Example 132
1-Naphthalen-2-yl-piperidine-4-carboxylic acid (1 ,4-dihydro-quinazolin-6-yl)- amide
Figure imgf000129_0001
Using the procedure outlined in Example 1A, 1-naphthalen-2-yl-piperidine-4- carboxylic acid is prepared from 2-bromo-naphthalene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from 1 ,4- dihydro-quinazolin-6-ylamine (0.5 mmol) and 1-naphthalen-2-yl-piperidine-4- carboxylic acid (0.18 mmol).
Example 133 1-Naphthalen-2-yl-piperidine-4-carboxylic acid [1 ,7]naphthyridin-4-ylamide
Figure imgf000129_0002
A. To a solution of 2-bromo-3-hydroxypyridine (5.00 g, 0.029 mmol) in 40 ml_ of anhydrous Et2θ is added E.3N (4.4 ml_, 0.032 mmol) and trifluoromethanesulfonic anhydride (5.3 mL, 0.032 mmol) at 0 0C. The mixture is warmed to 25 0C and stirred 3 h. Brine is added and the aqueous layer is extracted with Et2θ. The combined organic solvent is washed with brine, dried under MgSO4, and concentrated to dryness. The residue is purified by silica gel column chromatography with hexanes : EtOAc = 10 : 1 as eluent to provide trifluoro-methanesulfonic acid 2-bromo-pyridin-3-yl ester as colorless oil.
B. To a solution of trifluoro-methanesulfonic acid 2-bromo-pyridin-3-yl ester (10.00 g, 0.033 mol) in 160 mL of anhydrous DMF is added (trimethylsilyl)acetylene (5.1 mL, 0.036 mol), Pd(PPh3)2Cl2 (1.15 g, 0.0016 mol), LiCI (3.33 g, 0.0785 mol), and Et3N (6.8 mL, 0.049 mol). A mixture is warmed to 55 0C and stirred 14 h. Water is added to quench the reaction mixture. The aqueous layer is extracted Et2O. The combined solvent is dried and concentrated to dryness. The residue is purified by silica gel column chromatography with hexanes : EtOAc = 10 : 1 as eluent to provide 2-bromo- 3-trimethylsilanylethynyl-pyridine as brown oil.
C. To a solution of 2-bromo-3-trimethylsilanylethynyl-pyridine (1.66 g, 6.53 mmol) in 35 mL of Et2O is added n-BuLi (4.5 mL, 7.18 mmol) at -78 0C. After stirring for an hour, DMF (0.7 mL, 7.49 mmol) is added at the same temperature. The reaction mixture is warmed to room temperature after 30 min. Stirring 20 min, the reaction is quenched by brine. The aqueous layer is extracted with Et2O. The combined solvent is dried and concentrated to dryness. The residue is purified by silica gel column chromatography with hexanes : EtOAc = 10 : 1 as eluent to provide 3-trimethylsilanylethynyl- pyridine-2-carbaldehyde as brown oil.
D. To a solution of S-trimethylsilanylethynyl-pyridine^-carbaldehyde (1.25 g, 6.15 mmol) in 40 ml of 2.0 M NH3 in EtOH. Heated to 80 0C for 9 h. Solvent is evaporated to give residue which is purified by silica gel column chromatography with hexanes : EtOAc = 2 : 1 as eluent to provide [1 ,7]naphthyridine as brown solid.
E. To a solution of [1 ,7]naphthyridine (2.36 g, 0.018 mol) in 5 mL of acetic acid is added 2.5 mL of 32% percacetic acid. A mixture is heated to 75 0C for 3 h. The mono- and dioxides are separated by fractional crystallization using methylcyclohexane to yield [1 ,7]naphthyridine 1 -oxide.
F. A mixture of [1 ,7]naphthyridine 1 -oxide (1.27 g, 8.69 mmol) in 5 mL of fuming nitric acid is heated to 550C for 5 h. Nitric acid is removed and the resulting residue is neutralized by aqueous NaHCO3. The aqueous layer is extracted by Et2O. The combined solvent is dried and concentrated to dryness. The residue is purified by silica gel column chromatography with hexanes : EtOAc = 1 : 1 as eluent to provide 4-nitro-[1 ,7]naphthyridine 1- oxide.
G. A mixture of 4-nitro-[1 ,7]naphthyridine 1 -oxide (0.82 g, 4.29 mmol) and Raney nickel (2.32 g) in 12 mL of MeOH is hydrogenated at 25 0C. The catalyst is filtered off and the filtrated is concentrated to dryness which is purified by silica gel column chromatography with EtOAc as eluent to provide [1 ,7]naphthyridin-4-ylamine.
H. Using the procedure outlined in Example 1A, 1-naphthalen-2-yl-piperidine- 4-carboxylic acid is prepared from 2-bromo-naphthalene (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from [1 ,7]naphthyridin-4-ylamine (0.5 mmol) (prepared as in Example 18Og) and 1- naphthalen-2-yl-piperidine-4-carboxylic acid (0.18 mmol).
Example 134
1-Biphenyl-3-yl-piperidine-4-carboxylic acid [1 ,7]naphthyridin-4-ylamide
Figure imgf000131_0001
Using the procedure outlined in Example 1A, 1-biphenyl-3-yl-piperidine-4- carboxylic acid is prepared from 3-bromo-biphenyl (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from [1 ,7]naphthyridin-4-ylamine (0.5 mmol) (prepared as in Example 18Og) and 1- biphenyl-3-yl-piperidine-4-carboxylic acid (0.18 mmol).
Example 135
1-Biphenyl-3-yl-piperidine-4-carboxylic acid [2,7]naphthyridin-4-ylamide
Figure imgf000132_0001
A. To a solution of diisopropylamine (5.3 ml_, 0.0380 mol) in 120 ml_ of anhydrous THF is added n-BuLi (21.8 mL, 0.0348 mol) at 0 0C. After stirring 20 minutes, 4-bromopyridine (5.00 g, 0.0316 mol) is added and the mixture is stirred for an hour. DMF (9.8 mL, 0.126 mol) is added. Stirring for 20 minutes, the mixture is warmed up to 25 0C and stirred for 30 minutes. Saturated aqueous NH4CI solution is added to quench the reaction and the aqueous layer is extracted with Et2O. The combined solvent is dried and concentrated to dryness. The residue is purified by silica gel column chromatography with hexanes : EtOAc = 10 : 1 as eluent to provide 4-bromo-pyridine-3- carbaldehyde.
B. To a solution of 4-bromo-pyridine-3-carbaldehyde (9.46 g, 0.0509 mol) in 150 mL of anhydrous DMF is added (trimethylsilyl)acetylene (7.9 mL, 0.0559 mol), Pd(PPh3)2Cl2 (1.79 g, 0.00255 mol), LiCI (5.18 g, 0.122 mol), and Et3N (10.6 mL, 0.0764 mol). A mixture is warmed to 55 0C and stirred 12 h. Water is added to quenched the reaction mixture. The aqueous layer is extracted Et2O. The combined solvent is dried and concentrated to dryness. The residue is purified by silica gel column chromatography with hexanes : EtOAc = 10 : 1 as eluent to provide 4-trimethylsilanylethynyl-pyridine-3-carbaldehyde.
C. To a solution of 4-trimethylsilanylethynyl-pyridine-3-carbaldehyde (1.07 g, 5.26 mmol) in 40 ml of 2.0 M NH3 in EtOH. Heated to 80 0C for 9 h. Solvent is evaporated to give residue which is purified by silica gel column chromatography with hexanes : EtOAc = 2 : 1 as eluent to provide [2,7]naphthyfldine. D. To a solution of dinitrogen pentoxide (1.16 g, 10.7 mmol) in 8 ml of liquid sulfur dioxide is added [2,7]naphthyridine (0.874 g, 6.72 mmol) at -380C. The mixture is stirred for 5 minutes and then poured onto ice (9 g). After overnight stirring, the mixture is extracted with CH2Cb. The combined solvent is dried and concentrated to dryness. The residue is purified by silica gel column chromatography with hexanes : EtOAc = 2 : 1 as eluent to provide 4-nitro- [2,7]naphthyridine.
E. A mixture of 4-nitro-[2,7]naphthyridine (0.52 g, 2.97 mmol) and Raney nickel (1.6 g) in 10 mL of MeOH is hydrogenated at 25 0C. The catalyst is filtered off and the filtrated is concentrated to dryness which is purified by silica gel column chromatography with EtOAc as eluent to provide [2,7]naphthyridin-4-ylamine.
F. Using the procedure outlined in Example 1A, 1-biphenyl-3-yl-piperidine-4- carboxylic acid is prepared from 3-Bromo-biphenyl (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from [2,7]naphthyridin-4-ylamine (0.5 mmol) (prepared as in Example 182e) and 1- biphenyl-3-yl-piperidine-4-carboxylic acid (0.18 mmol).
Example 136
1 -Quinolin-S-yl-piperidine^-carboxylic acid [2,7]naphthyridin-4-ylamide
Figure imgf000133_0001
Using the procedure outlined in Example 1A, 1-quinolin-3-yl-piperidine-4- carboxylic acid is prepared from 3-Bromo-quinoline (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from [2,7]naphthyridin-4-ylamine (0.5 mmol) and 1-quinolin-3-yl-piperidine-4- carboxylic acid (0.18 mmol).
Example 137 i-Quinolin-S-yl-piperidine^-carboxylic acid [2,6]naphthyridin-1-ylamide
Figure imgf000134_0001
A. A mixture of 3-methyl-pyridine 1 -oxide (20 g, 0.183 mol) and iodoethane (32 ml_, 0.403 mmol) is stirred 16 h. 200 ml_ water is added, the aqueous layer is separated and washed with Et2θ. The collected aqueous layer is warmed to 50 0C and a solution of KCN (24 g, 0.366 mol) in 60 ml. of water is added slowly in one hour. After an additional one hour stirring, the mixture is extracted with Et2O. The combined solvent is dried and concentrated to dryness. The residue is purified by silica gel column chromatography with hexanes : EtOAc = 4 : 1 as eluent to provide 3-methyl-isonicotinonitrile.
B. To a solution of 3-methyl-isonicotinonitrile (12.25 g, 0.104 mmol) in 100 mL of DMF is added dimethylformamide dimethyl acetal (22 ml_, 0.166 mol) portionwise in 5 days. The solvent is evaporated to dryness. The residue is purified by silica gel column chromatography with hexanes : EtOAc = 4 : 1 as eluent to provide 3-(2-dimethylamino-vinyl)-isonicotinonitrile.
C. To a solution of 3-(2-dimethylamino-vinyl)-isonicotinonitrile (5.26 g, 0.0304 mol) in 6 mL of glacial acetic acid is added 100 mL of 30 % hydrogen bromide in acetic acid at 40 0C. The mixture is then warmed up to 55 0C for an additional 2 hours. Solvent is evaporated to generate the residue which is poured onto ice, neutralized with NaHCO3, and extracted with CH2CI2. The combined solvent is dried and concentrated to dryness. The residue is purified by silica gel column chromatography with hexanes : EtOAc = 2 : 1 as eluent to provide 2H-isoquinolin-1-one.
D. A mixture of 2H-isoquinolin-1-one (3.46 g, 0.0238 mol) and 20 ml_ of phosphorous oxybromide is refluxed for 2 hours. The excess phosphorous oxybromide is evaporated off, the residue is treated with ice and neutralized by sodium bicarbonate. The combined solvent is dried and concentrated to dryness. The residue is purified by silica gel column chromatography with hexanes : EtOAc = 2 : 1 as eluent to provide 1-bromo-[2,β]naphthyridine.
E. A mixture of 1-bromo-[2,6]naphthyridine (1.26 g, 6.03 mol) and 10 mL of 2.0 M ammonia in 2-propanol is heated to 120 0C for 8h. Solvent is evaporated off to dryness. The residue is purified by silica gel column chromatography with EtOAc as eluent to provide [2,6]naphthyridin-1-ylamine.
F. Using the procedure outlined in Example 1 , 1-quinolin-3-yl-piperidine-4- carboxylic acid is prepared from 3-bromo-quinoline (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from [2,6]naphthyridin-1-ylamine (0.5 mmol) (prepared as in Example 184e) and 1- quinolin-S-yl-piperidine^-carboxylic acid (0.18 mmol).
Example 138
1 -Isoquinolin-δ-yl-piperidine^-carboxylic acid [2,6]naphthyridin-1 -ylamide
Figure imgf000135_0001
Using the procedure outlined in Example 1A, 1-isoquinolin-5-yl-piperidine-4- carboxylic acid is prepared from 5-bromo-isoquinoline (4 mmol). Using the procedure outlined in Example 8, the title compound is prepared from [2,6]naphthyridin-1-ylamine (0.5 mmol) (prepared as in Example 184e) and 1- lsoquinolin-5-yl-piperidine-4-carboxylic acid (0.18 mmol).
Compounds of Formulas (II), (Ha), (III) and (Ilia) may be prepared generally according to the Schemes 1 and 2 (vide supra) and also by Schemes 3, 4 or 5 below:
Scheme 3
Figure imgf000136_0001
Scheme 4
Figure imgf000136_0002
Scheme 5
Figure imgf000136_0003
Example 139 i-Phenyl-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide
Figure imgf000137_0001
A. To a solution of ethyl isonipecotate (1.00 g, 6.36 mmol) in 10 mL of anhydrous DME was added iodobenzene (1.95 g, 9.54 mmol), bis(tri-t- butylphosphine)palladium(O) (0.33 g, 0.636 mmol), and potassium phosphate (2.70 g, 12.7 mmol). The reaction mixture was heated to 100 0C and stirred for 14 hours. Solids were filtered off from the resulting mixture and the collected filtrate was concentrated under reduced pressure to provide the crude product, which was then redissolved into 10 mL of methanol. 2 mL of 1N lithium hydroxide was added to hydrolyze the ester at 80 0C for 3 hours. Solvent was evaporated off and the basic residue was acidified by 2N HCI. The aqueous mixture was extracted with EtOAc. The combined organic layers was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to afford the crude product which was then purified by flash column chromatography with CH2Cb and MeOH to yield i-phenyl-piperidine-4-carboxylic acid as yellow solid.
B. To a solution of i-phenyl-piperidine-4-carboxylic acid (0.03 g, 0.122 mmol) in 5 mL of CH2CI2 was added oxalyl chloride (0.02 mL, 0.244 mmol) and a catalytic amount of DMF. The reaction mixture was stirred for 2 hours. Solvent was evaporated to dryness under reduced pressure. The residue was redissolved in 5 mL of CH2CI2. 6-amino-2H- 1 ,4-benzoxazine-3(4H)-one (0.02 g, 0.122 mmol) and triethylamine (0.03 mL, 0.183 mmol) were added sequentially into the acyl chloride solution at 0 0C. The reaction mixture was warmed to 25 0C and stirred for 20 min. Concentration of the solvent provided the residue which was then purified by flash column chromatography with hexanes and ethyl acetate to afford 1-phenyl-piperidine-4-carboxylic acid (3-oxo-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-yl)-amide as white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.61-7.58 (m, 4H), 7.54-7.51 (m, 1 H), 7.39 (t, 1 H), 7.04-7.01 (m, 1H), 6.91 (d, 1 H), 4.54 (s, 2H), 3.84 (d, 2H), 3.66- 3.59 (m, 2H), 2.82-2.79 (m, 1 H), 2.28-2.23 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C20H2IN3O3 : 351.4. Found: 352.1 (M+ + 1).
Example 140 i-m-Tolyl-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide
Figure imgf000138_0001
Using the procedure outlined in Example 139A, 1-m-tolyl-piperidine-4- carboxylic acid was prepared from 3-iodotoulene (2.08 g, 9.54 mmol) as a yellow solid.
Using the procedure outlined in Example 139B, the title compound was prepared from 1-m-tolyl-piperidine-4-carboxylic acid (0.03 g, 0.122 mmol) as an off-white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.38 (d, 1 H), 7.01 (t, 1 H), 6.98 (dd, 1 H), 6.88 (dd, 1 H), 6.82-6.78 (m, 2H), 6.67 (d, 1 H), 4.53 (s, 2H), 3.73 (d, 2H), 2.76-2.69 (m, 2H), 2.49-2.45 (m, 1 H), 2.29 (s, 3H), 2.01- 1.90 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C2iH23N3O3 : 365.4. Found: 366.1 (M+ + 1).
Example 141 i-o-Tolyl-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide
Figure imgf000139_0001
Using the procedure outlined in Example 139A, 1-o-tolyl-piperidine-4- carboxylic acid was prepared from 3-iodotoulene (2.08 g, 9.54 mmol) as a yellow solid.
Using the procedure outlined in Example 139B, the title compound was prepared from 1-o-tolyl-piperidine-4-carboxylic acid (0.03 g, 0.122 mmol) as light brown solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.40 (d, 1H), 7.16-7.10 (m, 2H), 7.04 (d, 1 H), 7.00 (dd, 1 H), 6.95-6.91 (m, 1 H), 6.89 (d, 1 H), 4.55 (s, 2H), 3.16-3.12 (m, 2H), 2.70 (td, 2H), 2.47 (m, 1H), 2.30 (s, 3H), 2.01-1.93 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C2i H23N3O3 : 365.4. Found: 366.0 (M+ + 1 ).
Example 142
1 -(2-Ethyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide
Figure imgf000139_0002
Using the procedure outlined in Example 139A, 1-(2-ethyl-phenyl)-piperidine- 4-carboxylic acid was prepared from 1 -ethyl-2-iodobenzene (2.21 g, 9.54 mmol) as a yellow solid.
Using the procedure outlined in Example 139B, the title compound was prepared from 1-(2-ethyl-phenyl)-piperidine-4-carboxylic acid (0.03 g, 0.122 mmol) as white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.40 (d, 1 H), 7.20 (dd, 1 H), 7.13-7.08 (m, 2H), 7.03-6.99 (m, 2H), 6.89 (d, 1 H), 4.54 (s, 2H)1 3.10 (d, 2H), 2.77-2.69 (m, 4H), 2.49-2.43 (m, 1 H), 2.01-1.90 (m, 4H), 1.23 (t, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C22H25N3O3 : 379.5. Found: 380.1 (M+ + 1 ).
Example 143
1 -(2-lsopropyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide
Figure imgf000140_0001
Using the procedure outlined in Example 139A, 1-(2-isopropyl-phenyl)- piperidine-4-carboxylic acid was prepared from 2-iodoisopropylbenzene (2.35 g, 9.54 mmol) as a yellow solid.
Using the procedure outlined in Example 139B, the title compound was prepared from 1-(2-isopropyl-phenyl)-piperidine-4-carboxylic acid (0.03 g, 0.122 mmol) as off-white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.40 (d, 1H), 7.24 (d, 1 H), 7.12-7.10 (m, 2H), 7.07-7.04 (m, 1H), 7.00 (dd, 1H), 6.89 (d, 1 H), 4.53 (s, 2H), 3.54 (h, 1 H), 3.06 (d, 2H), 2.76 (td, 2H), 2.46 (m, 1 H), 2.01- 1.89 (m, 4H), 1.21 (s, 3H), 1.19 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C23H27N3O3 : 393.5. Found: 394.1 (M++ 1).
Example 144
1 -(3,4-Dimethyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide
Figure imgf000141_0001
Using the procedure outlined in Example 139A, 1-(3,4-dimethyl-phenyl)- piperidine-4-carboxylic acid was prepared from 4-iodo-o-xylene (2.21 g, 9.54 mmol) as a yellow solid.
Using the procedure outlined in Example 139B, the title compound was prepared from 1-(3,4-dimethyl-phenyl)-piperidine-4-carboxylic acid (0.03 g, 0.122 mmol) as white solid. 1H NMR (400MHz, CDCI3) δ (ppm): 7.61 (s, 1 H), 7.52 (d, 1 H), 7.14 (s, 1 H), 7.03 (d, 1 H), 6.91 (d, 1 H), 6.78-6.71 (m, 3H), 4.59 (s, 2H), 3.70 (d, 2H), 2.72 (t, 2H), 2.35 (m, 1H), 2.23 (s, 3H), 2.19 (s, 3H), 2.04-1.98 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C22H25N3O3 : 379.5. Found: 379.9 (M+).
Example 145
1 -(2,3-Dimethyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide
Figure imgf000141_0002
Using the procedure outlined in Example 139A, 1-(2,3-dimethyl-phenyl)- piperidine-4-carboxylic acid was prepared from 3-bromo-o-xylene (1.77 g, 9.54 mmol) as a yellow solid.
Using the procedure outlined in Example 139B, the title compound was prepared from 1-(2,3-dimethyl-phenyl)-piperidine-4-carboxylic acid (0.03 g, 0.122 mmol) as white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.39 (d, 1H), 7.03-6.99 (m, 2H), 6.92-6.84 (m, 3H), 4.53 (s, 2H), 3.49 (d, 2H), 2.67 (t, 2H), 2.46 (m, 1 H), 2.25 (s, 3H), 2.23 (s, 3H), 2.03-1.90 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C22H25N3O3 : 379.5. Found: 380.1 (M+).
Example 146
1 -(4-tert-Butyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide
Figure imgf000142_0001
Using the procedure outlined in Example 139A, 1-(4-tert-butyl-phenyl)- piperidine-4-carboxylic acid was prepared from 1 -t-butyl-4-iodobenzene (2.48 g, 9.54 mmol) as a yellow solid.
Using the procedure outlined in Example 139B, the title compound was prepared from 1-(4-tert-butyl-phenyl)-piperidine-4-carboxylic acid (0.03 g, 0.122 mmol) as white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.38 (s, 1 H), 7.28 (d, 2H), 6.99-6.87 (m, 4H), 4.53 (s, 2H), 3.70 (d, 2H), 2.75-2.68 (m, 2H), 2.47 (m, 1 H), 1.94 (m, 4H), 1.28 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C24H29N3O3 : 407.5. Found: 408.1 (M+).
Example 147
1-(3-Fluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide
Figure imgf000143_0001
Using the procedure outlined in Example 139A, 1-(3-fluoro-phenyl)-piperidine- 4-carboxylic acid was prepared from 3-bromochlorobenzene (2.12 g, 9.54 mmol) as a brown solid.
Using the procedure outlined in Example 139B, the title compound was prepared from 1-(3-fluoro-phenyl)-piperidine-4-carboxylic acid (0.03 g, 0.122 mmol) as white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.37 (d, 1H), 7.19 (q, 1 H), 6.98 (dd, 1 H), 6.88 (d, 1H), 6.76 (dd, 1 H), 6.68 (dt, 1 H), 6.49 (dt, 1 H), 4.53 (S, 2H), 3.80 (d, 2H), 2.82-2.75 (m, 2H), 2.50 (m, 1H), 1.93-1.90 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C20H20FN3O3 : 369.4. Found: 370.1 (M++ 1).
Example 148
1 -(3-Chloro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)~amide
Figure imgf000143_0002
Using the procedure outlined in Example 139A, 1-(3-chloro-phenyl)- piperidine-4-carboxylic acid was prepared from 3-bromochlorobenzene (1.83 g, 9.54 mmol) as a brown solid.
Using the procedure outlined in Example 139B, the title compound was prepared from 1-(3-chloro-phenyl)-piperidine-4-carboxylic acid (0.03 g, 0.122 mmol) as white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.38 (d, 1 H), 7.14 (t, 1H), 6.98 (dd, 1 H), 6.95 (t, 1H), 6.91-6.87 (m, 2H), 6.78 (dd, 1 H), 4.53 (s, 2H), 3.79 (d, 2H), 2.78 (td, 2H), 2.52-2.48 (m, 1 H), 1.93-1.87 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C20H20CIN3O3 : 385.8. Found: 386.0 (M+).
Example 149
1 -(3-Bromo-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide
Figure imgf000144_0001
Using the procedure outlined in Example 139A, 1 -(3-bromo-phenyl)- piperidine-4-carboxylic acid was prepared from 1 ,3-dibromobenzene (2.25 g, 9.54 mmol) as a brown solid.
Using the procedure outlined in Example 139B, the title compound was prepared from 1-(3-bromo-phenyl)-piperidine-4-carboxylic acid (0.03 g, 0.122 mmol) as white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 9.80 (s, 1H), 7.37 (d, 1 H), 7.25 (s, 1 H), 7.22-7.18 (m, 1 H)1 7.08 (dd, 2H), 6.99 (dd, 1 H), 6.89 (d, 1 H), 4.53 (s, 2H), 3.79 (d, 2H), 2.95 (m, 2H), 2.56 (m, 1H), 2.01-1.93 (m, 4H). Mass Spectrum (LCMS1 ESI pos.) Calcd. for C20H20BrN3O3 : 430.3. Found: 430.0 (M+).
Example 150
1 -(3-Methoxy-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide
Figure imgf000145_0001
Using the procedure outlined in Example 139A, 1 -(3-methoxy-phenyl)- piperidine-4-carboxylic acid was prepared from 3-iodoanisole (2.23 g, 9.54 mmol) as a yellow solid.
Using the procedure outlined in Example 139B, the title compound was prepared from 1-(3-methoxy-phenyl)-piperidine-4-carboxylic acid (0.03 g, 0.122 mmol) as off-white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.37 (d, 1 H), 7.12 (t, 1 H), 6.98 (dd, 1H), 6.88 (d, 1H), 6.58 (dd, 1H), 6.51 (t, 1 H), 6.23 (dd, 1H), 4.53 (s, 2H), 3.76 (s, 3H), 3.74 (m, 2H), 2.78-2.71 (m, 2H), 2.48-2.46 (m, 1 H), 1.93-1.89 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C2IH23N3O4 : 381.4. Found: 382.0 (M+ + 1).
Example 151
1 -(2-Fluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide
Figure imgf000145_0002
Using the procedure outlined in Example 139A, 1-(2-fluoro-phenyl)-piperidine- 4-carboxylic acid was prepared from 1-fluoro-2-iodobenzene (2.12 g, 9.54 mmol) as a yellow solid.
Using the procedure outlined in Example 139B, the title compound was prepared from 1-(2-fluoro-phenyl)-piperidine-4-carboxylic acid (0.03 g, 0.122 mmol) as off-white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.39 (d, 1 H), 7.08-6.95 (m, 5H), 6.89 (d, 1 H), 4.53 (s, 2H), 3.51 (d, 2H), 2.74 (td, 2H), 2.48 (m, 1 H), 2.01-1.95 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C20H20FN3O3 : 369.4. Found: 370.1 (M++ 1 ).
Example 152
1-(2-Chloro-phenyl)-piperidine-4-carboxyIic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide
Figure imgf000146_0001
Using the procedure outlined in Example 139A, 1-(2-chloro-phenyl)- piperidine-4-carboxylic acid was prepared from 1-chloro-2-iodobenzene (2.27 g, 9.54 mmol) as a yellow solid.
Using the procedure outlined in Example 139B, the title compound was prepared from 1-(2-chloro-phenyl)-piperidine-4-carboxylic acid (0.03 g, 0.122 mmol) as off-white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.40 (d, 1H), 7.35 (dd, 1 H), 7.25 (dd, 1 H), 7.14 (dd, 1 H), 7.01-6.97 (m, 2H), 6.89 (d, 1 H), 4.54 (s, 2H), 3.43 (d, 2H), 2.73 (td, 2H), 2.49 (m, 1 H), 2.05-1.94 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C20H20FN3O3 : 385.8. Found: 386.0 (M+).
Example 153 1-(2-Bromo-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide
Figure imgf000147_0001
Using the procedure outlined in Example 139A, 1 -(2-bromo-phenyl)- piperidine-4-carboxylic acid was prepared from 1-bromo-2-iodobenzene (2.70 g, 9.54 mmol) as a yellow solid.
Using the procedure outlined in Example 139B, the title compound was prepared from 1-(2-bromo~phenyl)~piperidine-4-carboxylic acid (0.03 g, 0.122 mmol) as white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.55 (dd, 1H), 7.40 (d, 1 H), 7.30 (td, 1 H), 7.14 (dd, 1 H), 7.00 (dd, 1 H), 6.93 (td, 1 H), 6.89 (d, 1 H), 4.51 (s, 2H), 3.40 (d, 2H), 2.73 (td, 2H), 2.49 (m, 1 H), 2.07-1.87 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C2OH2OBrN3O3 : 430.3. Found: 430.0 (M+).
Example 154
1-(3,5-Difluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide
Figure imgf000147_0002
Using the procedure outlined in Example 139A, 1-(3,5-difluoro-phenyl)- piperidine-4-carboxylic acid was prepared from 1-bromo-3,5-difluorobenzene (1.84 g, 9.54 mmol) as a yellow solid.
Using the procedure outlined in Example 139B, the title compound was prepared from 1-(3,5-difluoro-phenyl)-piperidine-4-carboxylic acid (0.03 g, 0.122 mmol) as off-white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.37 (d, 1 H), 6.98 (dd, 1 H), 6.88 (d, 1 H), 6.51 (dd, 2H), 6.28-6.23 (m, 1 H), 4.53 (s, 2H), 3.82 (d, 2H), 2.83 (td, 2H), 2.56-2.50 (m, 1 H), 1.93-1.84 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C20H19F2N3O3 : 387.4. Found: 388.0 (M+ + 1 ).
Example 155
1 -(3,4-Difluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide
Figure imgf000148_0001
Using the procedure outlined in Example 139A, 1-(3,5-difluoro-phenyl)- piperidine-4-carboxylic acid was prepared from 1-bromo-3,5-difluorobenzene (1.84 g, 9.54 mmol) as a yellow solid.
Using the procedure outlined in Example 139B, the title compound was prepared from 1-(3,5-difluoro-phenyl)-piperidine-4-carboxylic acid (0.03 g, 0.122 mmol) as white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.37 (d, 1 H), 7.08 (dt, 1 H), 6.98 (dd, 1 H), 6.88 (d, 1 H), 6.85 (ddd, 1 H), 6.75-6.71 (m, 1 H), 4.53 (s, 2H), 3.69 (d, 2H)1 2.77-2.70 (m, 2H), 2.49-2.45 (m, 1 H), 1.94-1.88 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C20Hi9F2N3O3 : 387.4. Found: 388.0 (M+ + 1).
Example 156
I^SAδ-Trifluoro-phenyO-piperidine^-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide
Figure imgf000149_0001
Using the procedure outlined in Example 139A, 1-(3,4,5-trifluoro-phenyl)- piperidine-4-carboxylic acid was prepared from 5-bromo-1 ,2,3- trifluorobenzene (2.01 g, 9.54 mmol) as a yellow solid.
Using the procedure outlined in Example 139B, the title compound was prepared from I^SAδ-trifluoro-phenyO-piperidine^-carboxylic acid (0.03 g, 0.122 mmol) as white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.38 (d, 1 H), 6.98 (dd, 1 H), 6.88 (d, 1 H), 6.67 (dd, 2H), 4.53 (s, 2H), 3.74 (d, 2H), 2.77 (td, 2H), 2.52-2.46 (m, 1 H), 1.94-1.84 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C20H20BrN3O3 : 405.4. Found: 406.0 (M++ 1 ).
Example 157 1-(3-Chloro-2-methyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro- 2H-benzo[1 ,4]oxazin-6-yl)-amide
Figure imgf000149_0002
Using the procedure outlined in Example 139A, 1-(3-chloro-2-methyl-phenyl)- piperidine-4-carboxylic acid was prepared from 2-chloro-6-iodotoluene (2.41 g, 9.54 mmol) as a yellow solid.
Using the procedure outlined in Example 139B, the title compound was prepared from 1-(3-chloro-2-methyl-phenyl)-piperidine-4-carboxylic acid (0.03 g, 0.122 mmol) as off-white solid. 1H NMR (400MHz1 CD3OD) δ (ppm): 9.79 (s, 1 H), 7.39 (d, 1 H), 7.11-7.08 (m, 2H), 7.00-6.98 (m, 2H), 7.07-7.04 (d, 1 H), 4.53 (s, 2H), 2.74 (t, 2H), 2.34 (m, 1H), 2.35 (s, 3H), 1.98 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C2IH22CIN3O3 : 399.9. Found: 399.9 (M+).
Example 158
3'-Methyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-4-carboxylic acid (3-oxo-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-yl)-amide
Figure imgf000150_0001
Using the procedure outlined in Example 139A, 3'-methyl-3,4,5,6-tetrahydro- 2H-[1 ,2']bipyridinyl-4-carboxylic acid was prepared from 2-bromo-3-methyl- pyridine (0.98 g, 5.73 mmol) as a yellow solid.
Using the procedure outlined in Example 139B, the title compound was prepared from 3'-methyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-4-carboxylic acid (0.03 g, 0.122 mmol) as light brown solid. 1H NMR (400MHz, CD3OD) δ (ppm): 9.82 (s, 1 H), 8.03 (d, 1 H), 7.91 (d, 1 H), 7.40 (t, 1 H), 7.17 (t, 2H), 7.00 (dd, 1 H), 6.74 (d, 1 H)1 4.53 (s, 2H), 3.74 (d, 2H), 3.16 (m, 2H), 2.65 (m, 1 H), 2.04-2.00 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C20H22N4O3 : 366.4. Found: 367.0 (M++ 1 ).
Example 159 1-Benzothiazol-2-yl-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide
Figure imgf000151_0001
Using the procedure outlined in Example 139A, 1-benzothiazol-2-yl- piperidine-4-carboxylic acid was prepared from 2-bromo-benzothiazole (2.04 g, 9.54 mmol) as a yellow solid.
Using the procedure outlined in Example 139B, the title compound was prepared from 1-benzothiazol-2-yl-piperidine-4-carboxylic acid (0.03 g, 0.122 mmol) as white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.73 (d, 1H), 7.50 (dd, 1 H), 7.41-7.37 (m, 2H), 7.21 (t, 1 H), 6.99 (dd, 1 H), 6.89 (d, 1 H), 4.53 (s, 2H), 4.19 (d, 2H), 3.45-3.32 (m, 2H), 2.73-2.65 (m, 1 H), 2.06-1.93 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C21H20N4O3S : 408.5. Found: 409.1 (M+ + 1 ).
Example 160
1 -(2-Bromo-3-fluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro- 2H-benzo[1 ,4]oxazin-6-yl)-amide
Figure imgf000151_0002
A. A mixture of ethyl isonipecotate (1.00 g, 6.36 mmol), 2-bromo-1 ,3- difluorobenzene (0.82 g, 4.24 mmol), and 4-(dimethylamino)pyridine (0.26 g, 2.12 mmol) was heated to 1000C and stirred for 2 hours. The resulting reaction mixture was subjected to flash chromatography with hexanes and ethyl acetate to provide the ester, which was then dissolved into 10 ml_ of methanol. 2 ml_ of 1 N lithium hydroxide was added to hydrolyze the ester at 80 0C for 3 hours. Solvent was evaporated off and the basic residue was acidified by 2N HCI. The aqueous mixture was extracted with EtOAc. The combined organic layers was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to afford the crude product which was then purified by flash column chromatography with CH2Cb and MeOH to yield 1-(2-bromo-3-fluoro-phenyl)-piperidine-4-carboxylic acid as yellow solid. B. Using the procedure outlined in Example 139B, the title compound was prepared from 1-(2-bromo-3-fluoro-phenyl)-piperidine-4-carboxylic acid (0.04 g, 0.122 mmol) as white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.40 (d, 1 H), 7.29 (td, 1 H), 7.00 (dd, 1 H), 6.95 (d, 1 H), 6.90-6.86 (m, 2H), 4.54 (s, 2H), 3.43 (d, 2H), 2.75 (td, 2H), 2.53-2.46 (m, 1 H), 2.10-1.92 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for
C20H19BrFN3O3 : 448.3. Found: 449.9 (M++ 1 ).
Example 161
3'-Nitro-3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-4-carboxylic acid (3-oxo-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-yl)-amide
Figure imgf000152_0001
Using the procedure outlined in Example 160A, 3'-nitro-3,4,5,6-tetrahydro-2H- [1 ,2']bipyridinyl-4-carboxylic acid was prepared from 2-bromo-3-nitropyridine (1.06 g, 4.24 mmol) as a yellow solid.
Using the procedure outlined in Example 139B, the title compound was prepared from 3'-nitro-3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-4-carboxylic acid (0.03 g, 0.122 mmol) as yellow solid. 1H NMR (400MHz, CD3OD) δ (ppm): 8.35 (dd, 1 H)1 8.18 (dd, 1 H)1 7.38 (d, 1 H), 6.98 (dd, 2H), 6.88 (d, 1 H), 6.84 (dd, 1 H), 4.53 (s, 2H), 3.89 (d, 2H), 3.13-3.05 (m, 2H), 2.63 (m, 1 H), 1.91-1.85 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for Ci9H19N5O5 : 397.4. Found: 398.0 (M++ 1 ).
Example 162
1 -(2-Cyano-3-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-yl)-amide
Figure imgf000153_0001
Using the procedure outlined in Example 160A, 1 -(2-cyano-3-trif luoromethyl- phenyl)-piperidine-4-carboxylic acid was prepared from 2-fluoro-6- (trifluoromethyl)benzonitrile (1.26 g, 4.24 mmol) as a yellow solid.
Using the procedure outlined in Example 139B, the title compound was prepared from 1 -(2-cyano-3-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (0.04 g, 0.122 mmol) as off-white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.71 (t, 1 H), 7.47 (d, 1 H), 7.43 (d, 1 H)1 7.40 (d, 1 H), 6.99 (dd, 1 H), 6.89 (d, 1 H), 4.54 (s, 2H), 3.65 (d, 2H), 2.98 (td, 2H), 2.55 (m, 1 H), 2.08-1.98 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C22H19F3N4O3 : 444.4. Found: 445.1 (M++ 1 ).
Example 163 1-(2-Cyano-5-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-yl)-amide
Figure imgf000154_0001
Using the procedure outlined in Example 160A, 1 -(2-cyano-5-trif luoromethyl- phenyl)-piperidine-4-carboxylic acid was prepared from 2-fluoro-4- (trifluoromethyl)benzonitrile (1.26 g, 2.42 mmol) as a yellow solid.
Using the procedure outlined in Example 139B, the title compound was prepared from 1 -(2-cyano-5-trifluoromethyl-phenyl)-piperidine-4-carboxyIic acid (0.04 g, 0.122 mmol) as white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.80 (d, 1 H), 7.40-7.32 (m, 3H), 6.99 (dd, 1 H), 6.89 (d, 1 H), 4.54 (s, 2H), 3.74 (d, 2H), 2.99 (td, 2H), 2.56 (m, 1 H), 2.06-2.00 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C22Hi9F3N4O3 : 444.4. Found: 445.0 (M++ 1 ).
Example 164 1-(4-Bromo-2,3,5,6-tetrafluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-yl)-amide
Figure imgf000154_0002
Using the procedure outlined in Example 160A, 1-(4-bromo-2,3,5,6- tetrafluoro-phenyl)-piperidine-4-carboxylic acid was prepared from bromo- pentafluorobenzene (1.51 g, 4.24 mmol) as a yellow solid.
Using the procedure outlined in Example 139B, the title compound was prepared from 1-(4-bromo-2,3,5,6-tetrafluoro-phenyl)-piperidine-4-carboxylic acid (0.04 g, 0.122 mmol) as white solid. 1H NMR (400MHz, DMSO-d6) δ (ppm): 10.71 (s, 1 H), 9.88 (s, 1 H), 7.56 (d, 1 H), 7.04 (del, 1 H), 6.85 (d, 1 H), 4.89 (s, 2H), 3.10 (td, 2H), 1.84-1.71 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C20Hi6F4N3O3 : 502.3. Found: 503.9 (M++ 1 ).
Example 165
1 -(2-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-
2H-benzo[1 ,4]oxazin-6-yl)-amide
Figure imgf000155_0001
A. To a solution of ethyl isonipecotate (0.42 g, 2.67 mmol) in 7 ml_ of anhydrous toluene was added bromobenzotrifluoride (0.50 g, 2.22 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.10 g, 0.109 mmol), 2-(di-t-butylphosphino)biphenyl (0.13 g, 0.437 mmol), and sodium t- butoxide (0.32 g, 3.33 mmol). The reaction mixture was heated to 80 0C and stirred for 12 hours. Solids were filtered off from the resulting mixture and the collected filtrate was concentrated under reduced pressure to dryness, which was then purified by flash column chromatography with hexanes and ethyl acetate to provide the ester.
Then, it was dissolved into 6 mL of methanol. 1 ml_ of 1 N lithium hydroxide was added to hydrolyze the ester at 80 0C for 2 hours. Solvent was evaporated off and the basic residue was acidified by 2N HCI. The aqueous mixture was extracted with EtOAc. The combined organic layers was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to afford the crude product which was then purified by flash column chromatography with CH2CI2 and MeOH to yield 1-(2-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid as yellow solid. B. Using the procedure outlined in Example 139B, the title compound was prepared from 1-(2-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (0.03 g, 0.122 mmol) as yellow solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.64-7.57 (m, 2H), 7.48 (d, 1 H), 7.40 (d, 1 H), 7.28 (t, 1 H), 6.99 (dd, 1 H), 6.88 (d, 1 H), 4.53 (s, 2H), 3.10 (d, 2H), 2.84 (t, 2H), 2.49-2.45 (m, 1 H), 2.01-1.88 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C21 H20F3N3O3 : 419.4. Found: 420.0 (M++ 1 ).
Example 166 1-(2,5-Bis-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-yl)~amide
Figure imgf000156_0001
Using the procedure outlined in Example 165A, 1-(2,5-bis-trifluoromethyl- phenyl)-piperidine-4-carboxylic acid was prepared from 2,5- bis(trifluoromethyl)bromobenzene (0.51 g, 2.23 mmol) as a yellow solid.
Using the procedure outlined in Example 139B, the title compound was prepared from 1-(2,5-bis-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (0.04 g, 0.122 mmol) as off-white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.86 (d, 1 H), 7.75 (s, 1 H), 7.60 (d, 1 H), 7.40 (d, 1 H), 6.99 (dd, 1 H), 6.89 (d, 1 H)1 4.53 (s, 2H), 3.16 (d, 2H), 2.89 (td, 2H), 2.51 (m, 1 H), 2.02-1.90 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C22Hi9F6N3O3 : 487.4. Found: 488.0 (M++ 1 ).
Example 167
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (2-oxo-2,3-dihydro-
1 H-pyrido[2,3-b][1 ,4]oxazin-7-yl)-amide
Figure imgf000157_0001
167
A. To a solution mixture of 2-hydroxy-3,5-dinitropyridine(2.00 g, 10.8 mmol) and rhodium(ll) trifluoroacetate dimmer (0.14 g, 2.16 mmol) in
40 mL of 1 ,2-dichloroethane was added ethyl diazoacetate (1.11 g, 9.72 mmol) in 8 mL of 1 ,2-dichloroethane slowly by spyring pump over 6 hours at 40 0C. The reaction was stirred for another 3 hours at 25 0C after addition. Solvent was evaporated off to give the residue, which was then purified by flash column chromatography with hexanes and ethyl acetate to afford the ester.
B. To a solution of the ester (0.34 g, 1.25 mmol) in 7 mL of solvent mixture (AcOH : EtOH = 1 : 2) was added iron powder (0.35 g, 6.27 mmol). The reaction mixture was refluxed for 10 hours. After simple filtration, the filtrate was concentrated under reduced pressure to provide the residue, which was then purified by flash column chromatography with hexanes and ethyl acetate to afford 7-amino-1 H- pyrido[2,3-b][1 ,4]oxazin-2-one.
C. Using the procedure outlined in Example 1A, 1 -(3-trifluoromethyl- phenyl)-piperidine-4-carboxylic acid was prepared from 3- bromobenzotrifluoride (0.21 g, 0.95 mmol) as a yellow solid.
D. To a solution of 1-(3-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (0.025 g, 0.0914 mmol) in 4 mL of CH2CI2 was added oxalyl chloride (0.02 mL, 0.183 mmol) and a catalytic amount of DMF. The reaction mixture was stirred for 2 hours. Solvent was evaporated to dryness under reduced pressure. The residue was redissolved in 4 mL of CH2CI2. 7-amino-1 H-pyrido[2,3-b][1 ,4]oxazin-2-one obtained in step B (0.017 g, 0.101 mmol) and triethylamine (0.02 mL, 0.137 mmol) were added sequentially into the acyl chloride solution at 0 0C. The reaction mixture was warmed to 25 0C and stirred for 20 min. Concentration of the solvent provided the residue which was then purified by flash column chromatography with hexanes and ethyl acetate to afford 1-(3- trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (2-oxo-2,3-dihydro- 1 H-pyrido[2,3-b][1 ,4]oxazin-7-yl)-amide. 1H NMR (400MHz, CD3OD) δ (ppm): 7.87 (d, 1 H), 7.83 (d, 1 H), 7.39 (t, 1H), 7.20 (d, 1 H), 7.17 (s, 1 H), 7.05 (d, 1 H), 4.78 (s, 2H), 3.85 (d, 2H), 2.84 (td, 2H), 2.58-2.52
(m, 1H), 2.01-1.90 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C20H19F3N4O3 : 420.4. Found: 421.0 (M++ 1).
Example 168 1-(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid [4-(2-hydroxy-ethyl)- 3-oxo-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-yl]-amide
Figure imgf000158_0001
A. To a solution of 6-nitro-2H-1 ,4-benzoxazin-3(4H)-one (0.50 g, 2.58 mmol) in 10 mL of MeCN was added potassium carbonate (0.53 g, 3.86 mmol) and (2-bromoethoxy)-t-butyldimethylsilane (0.55 mL, 2.58 mmol). The mixture was heated to 80 0C and stirred for 12 hours. The filtrate was collected from removing the solid and was concentrated under reduced pressure to residue, which was then purified by flash column chromatography with hexanes and ethyl acetate to afford the nitro compound.
B. To a solution of nitro compound (0.32, 0.908 mmol) in 10 mL of EtOH was added 10% palladium on charcoal (0.10 g, 0.0908 mmol). The mixture was hydrogenated under balloon pressure of hydrogen gas for one hour. The catalyst was removed and the filtrate was concentrated under reduced pressure to provide the amino compound.
C. Using the procedure outlined in Example 1A, 1-(3-trifluoromethyl- phenyl)-piperidine-4-carboxylic acid was prepared from 3- bromobenzotrifluoride (0.21 g, 0.95 mmol) as a yellow solid.
D. To a solution of 1-(3-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (0.026 g, 0.0951 mmol) in 4 mL of CH2CI2 was added oxalyl chloride
(0.02 mL, 0.190 mmol) and a catalytic amount of DMF. The reaction mixture was stirred for 2 hours. Solvent was evaporated to dryness under reduced pressure. The residue was redissolved in 4 mL of CH2CI2. The amino compound obtained in step B (0.031 g, 0.0951 mmol) and triethylamine (0.02 mL, 0.143 mmol) were added sequentially into the acyl chloride solution at 0 0C. The reaction mixture was warmed to 25 0C and stirred for 20 min. Concentration of the solvent provided the residue which was then purified by flash column chromatography with hexanes and ethyl acetate to afford the silyl protected compound.
E. To a solution of the silyl protected compound (0.023 g, 0.0398 mmol) in 4 mL of THF was added 1 M tetrabutylammonium fluoride in THF (0.05 mL, 0.0477 mmol) at 00C. The reaction mixture was warmed to 250C and stirred for 3 hours. Solvent was evaporated to dryness, which was then purified by flash column chromatography with hexanes and ethyl acetate to afford 1-(3-rifluoromethyl-phenyl)-piperidine-4-carboxylic acid [4-(2-hydroxy-ethyl)-3-oxo-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-yl]- amide as white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.67 (d, 1H), 7.39 (t, 1 H), 7.32 (dd, 1 H), 7.12 (s, 1H), 7.09 (dd, 1 H), 7.05 (d, 1H), 6.93 (d, 1 H), 4.57 (s, 2H), 4.03 (t, 2H), 3.60 (d, 2H), 3.79 (t, 2H), 2.84 (td, 2H), 2.55-2.50 (m, 1 H), 2.01-1.91 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C23H24F3N3O4 : 463.5. Found: 464.0 (M+).
Example 169
1 -(3,4,5-Trifluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-5-yl)-amide
Figure imgf000160_0001
A. A mixture of 2-amino-3-nitrophenol (3.00 g, 0.0195 mol), ethyl bromoacetate (6.0 ml_, 0.0545 mol), and diisopropylethylamine (4.8 ml_, 0.0273 mol) was heated to 140 0C for 5 hours. The reaction mixture was cooled down, diluted with EtOAc, and washed with brine. The organic layer was dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (silica, hexanes and ethyl acetate) to provide (2- amino-3-nitro-phenoxy)-acetic acid ethyl ester as a yellow oil.
B. To a solution of (2-amino-3-nitro-phenoxy)-acetic acid ethyl ester (2.57 g, 0.107 mol) in 120 ml_ of EtOH at rt was added potassium carbonate (2.96 g, 2.17 mol). The reaction mixture was refluxed for 72 hours. The reaction mixture was concentrated in vacuo, and the residue was purified chromatography (silica, hexanes and ethyl acetate) to provide 5~nitro-4H-benzo[1 ,4]oxazin-3-one as yellow solid.
C. To a solution of 5-nitro-4H-benzo[1 ,4]oxazin-3-one (0.314 g, 1.62 mmol) in 7 ml_ of MeOH was added 10 % palladium on charcoal (0.172 g, 0.162 mmol). The reaction mixture was stirred under balloon pressure of H2 gas for 2 hours. The catalyst was filtered and the filtrate was concentrated under reduced pressure to provide 5-amino-4H- benzo[1 ,4]oxazin-3-one as light brown solid.
D. Using the procedure outlined in Example 139A, 1-(3,4,5-trifluoro- phenyl)-piperidine-4-carboxylic acid was prepared from 5-bromo-1 ,2,3- trifluorobenzene (2.01 g, 9.54 mmol) as a yellow solid.
E. To a solution of 1-(3,4,5-trifluoro-phenyl)-piperidine-4-carboxylic acid (0.052 g, 0.201 mmol) in 4 ml_ of CH2CI2 was added oxalyl chloride (0.04 ml_, 0.402 mmol) and a catalytic amount of DMF. The reaction mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was redissolved in 4 mL of CH2CI2, and 5-Amino-4H-benzo[1 ,4]oxazin-3-one (obtained in step C) (0.033 g, 0.201 mmol) and triethylamine (0.06 mL, 0.402 mmol) were added sequentially to the acyl chloride solution at 0 0C. The reaction mixture was warmed to 25 0C and stirred for 20 min. The reaction mixture was concentrated, and the residue which was purified by chromatography (silica, hexanes and ethyl acetate) to afford 1- (3,4, 5-trifluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro- 2H-benzo[1 ,4]oxazin-5-yl)-amide as white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.6.99-6.94 (m, 2H), 6.89 (dd, 1 H), 6.69 (dd, 2H),
4.55 (s, 2H), 3.75 (d, 2H), 2.80 (td, 2H), 2.62-2.58 (m, 1 H), 2.05-2.01 (m, 2H), 1.90 (td, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C20Hi8F3N3O3 : 405.4. Found: 406.1 (M+ + 1 ).
Example 170
1 -(3,4,5-Trifluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-7-yl)-amide
Figure imgf000162_0001
1) Oxalyl chloride, DMF
Figure imgf000162_0002
E. To a solution of 5-nitro-4H benzo[1 ,4]oxazin-3-one (0.314 g, 1.62 mmol) in 7 mL of MeOH was added 10 % palladium on charcoal (0.172 g, 0.162 mmol). The reaction mixture was hydrogenated under balloon pressure of H2 gas for 2 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to provide 7- amino-4H-benzo[1 ,4]oxazin-3-one as light brown solid. F. To a solution of 1-(3,4,5-trifluoro-phenyl)-piperidine-4-carboxylic acid, prepared in Example 168D, (0.048 g, 0.185 mmol) in 4 mL of CH2CI2 was added oxalyl chloride (0.03 mL, 0.370 mmol) and a catalytic amount of DMF. The reaction mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was redissolved in 4 mL of CH2CI2. 7-Amino-4H- benzo[1 ,4]oxazin-3-one obtained in step A (0.030 g, 0.185 mmol) and triethylamine (0.05 mL, 0.370 mmol) were added sequentially to the acyl chloride solution at 0 0C. The reaction mixture was warmed to 25 0C and stirred for 20 min. The reaction mixture was concentrated, and the residue the residue was purified by chromatography (silica, with hexanes and ethyl acetate) to afford 1-(3,4,5-Trifluoro-phenyl)- piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H-benzo[1 ,4]oxazin-7- yl)-amide as white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.30 (d, 1 H), 7.11 (dd, 1 H), 6.82 (d, 1 H), 6.67 (dd, 2H), 4.56 (s, 2H), 3.74 (d, 2H), 2.76 (td, 2H), 2.52-2.46 (m, 1 H), 1.94-1.84 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C20H18F3N3O3 : 405.4. Found: 406.2 (M+ + 1 )
Example 171
1 -(3,4,5-Trifluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-8-yl)-amide
Figure imgf000163_0001
A. To a solution of 2-chloro-1 ,3-dinitrobenzene (1.00 g, 4.94 mmol) in 14 mL of DMF was added ethyl glycolate (0.5 mL, 5.43 mmol) and potassium carbonate (0.75 g, 5.43 mmol). The reaction mixture was stirred for 8 hours at 250C. It was then diluted with EtOAc and washed with water. The organic layer was dried over MgSO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by chromatography (silica with hexanes and ethyl acetate) to provide (2,6-dinitro-phenoxy)-acetic acid ethyl ester as yellow solid. B. To a solution of (2,6-dinitro-phenoxy)-acetic acid ethyl ester (0.262 g, 0.970 mmol) in 12 mL of MeOH was added 10% palladium on charcoal (0.103 g, 0.0970 mmol). The reaction mixture was hydrogenated under balloon pressure of H2(g) at 60 0C for 6 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to provide 8-amino-4H-benzo[1 ,4]oxazin-3-one as light brown solid.
C. To a solution of 1-(3,4,5-trifluoro-phenyl)-piperidine-4-carboxylic acid, prepared in Example 168D, (0.047 g, 0.181 mmol) in 4 mL Of CH2CI2 was added oxalyl chloride (0.03 mL, 0.362 mmol) and a catalytic amount of DMF. The reaction mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was redissolved in 4 mL of CH2CI2. 8-Amino-4H- benzo[1 ,4]oxazin-3-one obtained in step B (0.030 g, 0.181 mmol) and triethylamine (0.05 mL, 0.362 mmol) were added sequentially to the acyl chloride solution at 0 0C. The reaction mixture was warmed to 25 0C and stirred for 20 min. The reaction mixture was concentrated, and the residue which was purified by chromatography (silica, with hexanes and ethyl acetate) to afford 1-(3,4,5-trifluoro-phenyl)-piperidine-4- carboxylic acid (3-oxo-3,4-dihydro-2H-benzo[1 ,4]oxazin-8-yl)-amide as white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.38 (d, 1H), 6.98 (dd, 1H), 6.85 (d, 1H), 6.68 (dd, 2H), 4.53 (s, 2H), 3.74 (d, 2H), 2.77 (td, 2H), 2.53-2.46 (m, 1H), 1.91-1.81 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C20Hi8F3N3O3 : 405.4. Found: 406.1 (M+ + 1).
Example 172
1 -(3,4,5-Trifluoro-phenyl)-piperidine-4-carboxylic acid (4-methyl-3-oxo-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-yl)-amide
Figure imgf000165_0001
A. To a solution of 4-methyl-6-nitro-4H-benzo[1 ,4]oxazin-3-one (0.100 g, 0.480 mmol) in 7 ml_ of MeOH was added palladium on charcoal (0.051 g, 0.048 mmol). The reaction mixture was hydrogenated under balloon pressure of H2(g) 1 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to provide 6-amino-4-methyl-4H-benzo[1 ,4]oxazin-3-one as brown solid.
B. To a solution of 1-(3,4,5-trifluoro-phenyl)-piperidine-4-carboxylic acid, prepared in Example 168D, (0.048 g, 0.185 mmol) in 4 ml_ of CH2CI2 was added oxalyl chloride (0.03 ml_, 0.370 mmol) and a catalytic amount of DMF. The reaction mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was redissolved in 4 ml_ of CH2CI2. 8-Amino-4H- benzo[1 ,4]oxazin-3-one obtained in step A (0.030 g, 0.181 mmol) and triethylamine (0.05 ml_, 0.362 mmol) were added sequentially to the acyl chloride solution at 0 0C. The reaction mixture was warmed to 25 0C and stirred for 20 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified chromatography (silica, with hexanes and ethyl acetate) to afford 1-(3,4,5-trifluoro- phenyl)-piperidine-4-carboxylic acid (4-methyl-3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide as white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.56 (d, 1 H), 7.10 (dd, 1 H), 6.93 (d, 1 H), 6.68 (dd, 2H), 4.58 (s, 2H), 3.75 (d, 2H), 2.78 (td, 2H), 2.54-2.48 (m, 1H), 2.01- 1.82 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C2IH20F3N3O3 : 419.4. Found: 420.2 (M+ + 1 ).
Example 173
1 -(3,4,5-Trifluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]thiazin-6-yl)-amide
Figure imgf000166_0001
1) 0xalyI chloride, DMF
Figure imgf000166_0002
2) Et3N
Figure imgf000166_0003
A. A solution of 2,4-dinitrofluorobenzene (5.5 ml_, 0.0455 mol), ethyl mercaptoacetate (5.0 g, 0.0455 mol) and triethylamine (5.3 ml_, 0.0455 mol) in 14 ml_ of THF was stirred at O0C for 12 hours. Ice was added to quench the reaction and the reaction mixture was extracted with EtOAc. The combined organic fractions were dried over MgSO4, filtered and the filtrate was concentrated. The residue purified by chromatography (silica, with hexanes and ethyl acetate) to afford (2,4- dinitro-phenylsulfanyl)-acetic acid ethyl ester as brown oil.
B. A solution of (2,4-dinitro-phenylsulfanyl)-acetic acid ethyl ester (9.90 g, 0.0346 mol) in 40 ml_ EtOAc and 40 ml_ AcOH was added dropwise to a suspension at 6O0C prepared by mixing iron (25 g, 0.450 mol) with 40 ml_ H2O and 2 mL AcOH. After the addition was complete, the reaction mixture was heated at 8O0C for 9 hours. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified chromatography (silica with hexanes and ethyl acetate) to afford 6-amino-4H-benzo[1 ,4]thiazin-3- one as dark brown solid.
C. To a solution of 1-(3,4,5-Trifluoro-phenyl)-piperidine-4-carboxylic acid, prepared in Example 168D, (0.060 g, 0.231 mmol) in 5 mL of CH2CI2 was added oxalyl chloride (0.04 mL, 0.462 mmol) and a catalytic amount of DMF. The reaction mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was redissolved in 5 mL Of CH2CI2. 6-Amino-4H- benzo[1 ,4]thiazin-3-one obtained in step B (0.042 g, 0.231 mmol) and triethylamine (0.06 mL, 0.462 mmol) were added sequentially to the acyl chloride solution at 0 0C. The reaction mixture was warmed to 25 0C and stirred for 20 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography (silica, with hexanes and ethyl acetate) to afford 1- (3,4,5-trifluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-
2H-benzo[1 ,4]thiazin-6-yl)-amide as white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 4.74 (d, 1 H), 7.23 (d, 1 H), 7.08 (dd, 1 H), 6.68 (dd, 2H), 3.74 (d, 2H), 3.40 (s, 2H), 2.77 (td, 2H), 2.52-2.49 (m, 1 H), 1.91- 1.81 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C20Hi8F3N3O2S : 421.4. Found: 422.1 (M+ + 1 ).
Example 174
I^SAδ-Trifluoro-phenyO-piperidine^-carboxylic acid [2-(2-hydroxy-ethyl)-3- oxo-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-yl]-amide O
O2N NO2 \ /
OH Na2CO3
Figure imgf000168_0001
Figure imgf000168_0002
A. To a solution of 2-amino-5-nitrophenol (20.0 g, 0.109 mol) in 120 ml_ of DMF was added D-bromo-D-butyrolactone (11.1 ml_, 0.119 mol) and sodium carbonate (11.6 g, 0.109 mol). The reaction mixture was heated at reflux for 5 hours. Water was added to quench the reaction and the reaction mixture was extracted with EtOAc. The combined organic fractions were dried over MgSO4, filtered and the filtrate was concentrated under educed pressure. The residue was purified by chromatography (silica, with hexanes and ethyl acetate) to afford 2-(2- hydroxy-ethyl)-6-nitro-4H-benzo[1 ,4]oxazin-3-one as brown oil.
B. To a solution of 2-(2-hydroxy-ethyl)-6-nitro-4H-benzo[1 ,4]oxazin-3-one (1.09 g, 4.58 mmol) in 18 ml_ of DMF was added tert-butyldimethylsilyl chloride (0.83 g, 5.49 mmol) and imidazole (0.78 g, 2.5 mmol). The reaction mixture was stirred for 3 hours. Water was added to quench the reaction and the reaction mixture was extracted with EtOAc. The combined organic fractions were dried over MgSO4, filtered and the filtrate and concentrated to dryness. The residue was purified by chromatography (silica, with hexanes and ethyl acetate) to afford 2-[2- (tert-butyl-dimethyi-silanyloxy)-ethyl]-6-nitro-4H-benzo[1 ,4]oxazin-3- one.
C. To a solution of 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-6-nitro~4H- benzo[1 ,4]oxazin-3-one (0.137 g, 0.389 mmol) in 4 ml_ of MeOH was added palladium on charcoal (0.039 g, 0.048 mmol). The reaction mixture was hydrogenated under balloon pressure of H2(g) for 1 hour. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to provide 6-amino-2-[2-(tert- butyl-dimethyl-silanyloxy)-ethyl]-4H-benzo[1 ,4]oxazin-3-one as brown solid.
D. To a solution of 1-(3,4,5-trifluoro-phenyl)-piperidine-4-carboxylic acid, prepared in Example 168D, (0.056 g, 0.216 mmol) in 4 mL Of CH2CI2 was added oxalyl chloride (0.04 mL, 0.432 mmol) and a catalytic amount of DMF. The reaction mixture was stirred for 2 hours. The reaction mixture was evaporated to dryness under reduced pressure.
The residue was redissolved in 4 mL of CH2CI2. 6-Amino-2-[2-(tert- butyl-dimethyl-silanyloxy)-ethyl]-4H-benzo[1 ,4]oxazin-3-one obtained in step C (0.070 g, 0.216 mmol) and triethylamine (0.06 mL, 0.432 mmol) were added sequentially to the acyl chloride solution at 0 0C. The reaction mixture was warmed to 250C and stirred for 20 min. The reaction mixture was concentrated, and the residue was purified by chromatography (silica with hexanes and ethyl acetate) to afford 1- (3,4,5-trifluoro-phenyl)-piperidine-4-carboxylic acid {2-[2-(tert-butyl- dimethyl-silanyloxy)-ethyl]-3-oxo-3,4-dihydro-2H-benzo[1 ,4]oxazin-6- yl}-amide as white solid.
E. To a solution of 1-(3,4,5-trifluoro-phenyl)-piperidine-4-carboxylic acid {2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl}-amide (0.046 g, 0.0816 mmol) in 3 mL of THF was added a solution of 1 M tetrabutylammonium fluoride in THF (0.05 mL, 0.0898 mmol) at 00C. The reaction mixture was warmed to 25 0C and stirred for 1 hour. The reaction mixture was evaporated to dryness, and the residue was purified by chromatography (silica with hexanes and ethyl acetate) to afford 1-(3,4,5-rifluoro-phenyl)- piperidine-4-carboxylic acid [2-(2-hydroxy-ethyl)-3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl]-amide as white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.37 (d, 1H), 6.99 (dd, 1H), 6.90 (d, 1H), 6.82 (dd, 2H), 4.65 (dd, 1 H), 3.77 (m, 4H), 2.77 (td, 2H), 2.52-2.46 (m, 1H), 2.14 (m, 1 H), 2.01-1.81 (m, 5H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C22H22F3N3O4 : 499.4. Found: 450.2 (M+ + 1).
Examples 175 and 176
2-Methyl-3-oxo-6-{[1-(3,4,5-trifluoro-phenyl)-piperidine-4-carbonyl]-amino}- 3,4-dihydro-2H-benzo[1 ,4]oxazine-2-carboxylic acid ethyl ester (175) and 2-Methyl-3-oxo-6-{[1-(3,4,5-trifluoro-phenyl)-piperidine-4-carbonyl]- amino}-3,4-dihydro-2H-benzo[1 ,4]oxazine-2-carboxylic acid (176)
Figure imgf000170_0001
Figure imgf000170_0003
Figure imgf000170_0002
A. To a solution of 2-amino-5-nitrophenol (6.00 g, 0.0326 mol) in 80 ml_ of DMF was added diethyl 2-bromo-2-methyl malonate (6.2 ml_, 0.0326 mol) and potassium fluoride (4.74 g, 0.0815 mol). The reaction mixture was heated at 60 0C for 6 hours. Water was added to quench the reaction and the reaction mixture was extracted with EtOAc. The combined organic fractions were dried over MgSO4, filtered and the filtrate was concentrated to dryness. The residue was purified by chromatography (silica with hexanes and ethyl acetate) to afford 2- methyl-6-nitro-3-oxo-3,4-dihydro-2H-benzo[1 ,4]oxazine-2-carboxylic acid ethyl ester. B. To a solution of 2-methyl-6-nitro-3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazine-2-carboxylic acid ethyl ester (0.182 g, 0.649 mmol) in 4 ml_ of MeOH was added palladium on charcoal (0.069 g, 0.0649 mmol). The reaction mixture was hydrogenated under balloon pressure of H2(g) for 1 hour. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to provide 6- amino-2-methyl-3-oxo-3,4-dihydro-2H-benzo[1 ,4]oxazine-2-carboxylic acid ethyl ester as brown solid.
C. To a solution of 1-(3,4,5-trifluoro-phenyl)-piperidine-4-carboxylic acid, prepared in Example 168D, (0.052 g, 0.201 mmol) in 4 mL of CH2CI2 was added oxalyl chloride (0.04 mL, 0.402 mmol) and a catalytic amount of DMF. The reaction mixture was stirred for 2 hours, and the reaction mixture was concentrated under reduced pressure. The residue was redissolved in 4 mL of CH2CI2. 6-Amino-2-methyl-3-oxo- 3,4-dihydro-2H-benzo[1,4]oxazine-2-carboxylic acid ethyl ester obtained in step B (0.050 g, 0.201 mmol) and triethylamine (0.06 mL,
0.402 mmol) were added sequentially to the acyl chloride solution at 0 0C. The reaction mixture was warmed to 25 0C and stirred for 20 min. The reaction mixture was concentrated, and the residue was purified by chromatography (silica with hexanes and ethyl acetate) to afford 2- methyl-3-oxo-6-{[1-(3,4,5-trifluoro-phenyl)-piperidine-4-carbonyl]- amino}-3,4-dihydro-2H-benzo[1 ,4]oxazine-2-carboxylic acid ethyl ester as white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.40 (d, 1 H), 7. 00 (dd, 1 H), 6.94 (d, 1 H), 6.55 (dd, 2H), 4.12 (qd, 2H), 3.30 (d, 2H), 2.76 (td, 2H), 2.52-2.45 (m, 1H), 1.94-1.80 (m, 4H), 1.73 (s, 3H), 1.13 (t, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C24H24F3N3O5 :
491.5. Found: 492.2 (M+ + 1).
D. A mixture of 2-methyl-3-oxo-6-{[1-(3,4,5-trifluoro-phenyl)-piperidine-4- carbonyl]-amino}-3,4-dihydro-2H-benzo[1 ,4]oxazine-2-carboxylic acid ethyl ester (0.011 g, 0.0223 mmol) and 1 ml_ of potassium hydroxide solution, prepared by mixing KOH (1.98 g), MeOH (46 ml_), and H2O (6 ml_), was stirred for 2 hours. The reaction mixture was acidified to pH 1-2 and then extracted with EtOAc. The combined organic fractions were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated to provide 2-methyl-3-oxo-6-{[1-(3,4,5-trifluoro-phenyl)- piperidine-4-carbonyl]-amino}-3,4-dihydro-2H-benzo[1 ,4]oxazine-2- carboxylic acid as white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.40 (dd, 2H)1 7.38 (d, 1H), 7.05 (dd, 1H), 6.96 (d, I H), 3.82 (d, 2H), 3.44 (td, 2H), 2.81-2.73 (m, 1 H), 2.19-2.13 (m, 4H), 1.75 (s, 3H). Mass
Spectrum (LCMS, ESI pos.) Calcd. for C22H2OF3N3O5 : 463.4. Found: 464.2 (M+ + 1).
Examples 177 and 178 S-Oxo-e-fli-^Aδ-trifluoro-phenyO-piperidine^-carbonyll-aminoJ-S^-dihydro- 2H-benzo[1 ,4]oxazine-2-carboxylic acid ethyl ester (177) and 3-Oxo-6-{[1-(3,4,5-trifluoro-phenyl)-piperidine-4-carbonyl]-amino}-3,4- dihydro-2H-benzo[1 ,4]oxazine-2-carboxylic acid (178)
10% Pd/C, H2(g)
Figure imgf000173_0002
Figure imgf000173_0001
Figure imgf000173_0003
A. To a solution of diethyl 2-bromomalonate (9.3 ml_, 0.0543 mol) in 40 mL of DMF was added potassium fluoride (7.89 g, 0.136 mol). After stirring for an hour, 2,4-dinitrophenol (10.00 g, 0.0543 mol) was added. The reaction mixture was heated at 700C for 30 hours. Water was added to quench the reaction and the reaction mixture was extracted with EtOAc. The combined organic fractions were dried over MgSO4, filtered and the filtrate was concentrated to dryness. The residue was purified by chromatography (silica with hexanes and ethyl acetate) to afford 2-(2,4-dinitro-phenoxy)-malonic acid diethyl ester.
B. To a solution of 2-(2,4-dinitro-phenoxy)-malonic acid diethyl ester (0.346 g, 1.01 mmol) in 8 mL of MeOH was added palladium on charcoal (0.107 g, 0.101 mmol). The reaction mixture was hydrogenated under balloon pressure of H2(g) at 60 0C for 48 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to provide 6-amino-3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazine-2-carboxylic acid ethyl ester as brown solid. C. To a solution of 1-(3,4,5-trifluoro-phenyl)-piperidine-4-carboxylic acid, prepared in Example 168D, (0.057 g, 0.220 mmol) in 4 mL of CH2CI2 was added oxalyl chloride (0.04 mL, 0.442 mmol) and a catalytic amount of DMF. The reaction mixture was stirred for 2 hours. The reaction mixture was evaporated to dryness under reduced pressure. The residue was redissolved in 4 mL of CH2CI2. 6-Amino-3-oxo-3,4- dihydro-2H-benzo[1 ,4]oxazine-2~carboxylic acid ethyl ester obtained in step B (0.052 g, 0.220 mmol) and triethylamine (0.06 mL, 0.440 mmol) were added sequentially to the acyl chloride solution at 0 0C. The reaction mixture was warmed to 25 0C and stirred for 20 min. The reaction mixture was concentrated, and the residue was purified by chromatography (silica with hexanes and ethyl acetate) to afford 3-oxo- 6-{[1-(3,4,5-trifluoro-phenyl)-piperidine-4-carbonyl]-amino}-3,4-dihydro-
2H-benzo[1 ,4]oxazine-2-carboxylic acid ethyl ester as white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.40 (d, 1 H), 7.01 (dd, 1 H), 6.82 (d, 1 H), 6.68 (dd, 2H), 5.22 (s, 1 H), 4.20 (q, 2H), 3.74 (d, 2H), 2.77 (td, 2H), 2.52-2.45 (m, 1 H), 1.91-1.82 (m, 4H), 1.23 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C23H22F3N3O5 : 477.4. Found:
478.2 (M+ + 1).
D. A mixture of 3-oxo-6-{[1-(3,4,5-trifluoro-phenyl)-piperidine-4-carbonyl]- amino}-3,4-dihydro-2H-benzo[1 ,4]oxazine-2-carboxylic acid ethyl ester (0.013 g, 0.0272 mmol) and 1 mL of potassium hydroxide solution, prepared by mixing KOH (1.98 g), MeOH (46 mL), and H2O (6 mL), was stirred for 2 hours. The reaction mixture was acidified to pH 1-2 and extracted with EtOAc. The combined organic fractions were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated to provide 3-oxo-6-{[1-(3,4,5-trifluoro-phenyl)-piperidine- 4-carbonyl]-amino}-3,4-dihydro-2H-benzo[1 ,4]oxazine-2-carboxylic acid as white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.43 (dd, 2H), 7.39 (d, 1 H), 7.06 (dd, 1 H), 6.98 (d, 1 H), 5.18 (s, 1 H), 3.83 (d, 2H), 3.49-3.43 (m, 2H), 2.78-2.73 (m, 1 H), 2.22-2.02 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C2iHi8F3N3O5 : 449.4. Found: 450.2 (M+ + 1 ). Examples 179 and 180
(3-Oxo-6-{[1-(3,4,5-trifluoro-phenyl)-piperidine-4-carbonyl]-amino}-3,4- dihydro-2H-benzo[1 ,4]oxazin-2-yl)-acetic acid methyl ester (179) and (3-Oxo-6-{[1-(3,4,5-trifluoro-phenyl)-piperidine-4-carbonyl]-amino}-3,4- dihydro-2H-benzo[1 ,4]oxazin-2-yl)-acetic acid (180)
O2N
Figure imgf000175_0001
A. To a solution of 2-amino-5-nitrophenol (4.0 g, 0760 mol) in 180 ml_ of
MeOH was added maleic anhydride (7.5 g, 0.0760 mol) and triethylamine (10.6 mL, 0.760 mol). The reaction mixture was heated at reflux for 5 hours. The reaction mixture was concentrated, and the residue was partitioned between EtOAc and water. The aqueous layer was extracted by EtOAc. The combined organic fractions were dried over MgSO4, filtered and the filtrate was concentrated to dryness. The residue was purified by chromatography (silica with hexanes and ethyl acetate) to afford (6-nitro-3-oxo-3,4-dihydro-2H-benzo[1 ,4]oxazin-2-yl)- acetic acid methyl ester. B. To a solution of (6-nitro-3-oxo-3,4-dihydro-2H-benzo[1 ,4]oxazin-2-yl)- acetic acid methyl ester (0.294 g, 1.10 mmol) in 8 mL of MeOH was added palladium on charcoal (0.117 g, 0.110 mmol). The reaction mixture was hydrogenated under balloon pressure of H2(g) for 1 hour. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to provide (6-amino-3-oxo-3,4- dihydro-2H-benzo[1 ,4]oxazin-2-yl)-acetic acid methyl ester as brown solid. C. To a solution of 1-(3,4,5-trifluoro-phenyl)-piperidine-4-carboxylic acid, prepared in Example 168D, (0.055 g, 0.212 mmol) in 4 ml_ Of CH2CI2 was added oxalyl chloride (0.04 ml_, 0.424 mmol) and a catalytic amount of DMF. The reaction mixture was stirred for 2 hours. The reaction mixture was then evaporated to dryness under reduced pressure. The residue was redissolved in 4 ml_ of CH2CI2. (6-Amino-3- oxo-3,4-dihydro-2H-benzo[1 ,4]oxazin-2-yl)-acetic acid methyl ester obtained in step B (0.050 g, 0.212 mmol) and triethylamine (0.06 ml_, 0.424 mmol) were added sequentially to the acyl chloride solution at 0 0C. The reaction mixture was warmed to 25 0C and stirred for 20 min. The reaction mixture was concentrated, and the residue was purified by chromatography (silica with hexanes and ethyl acetate) to afford (3- oxo-6~{[1-(3,4,5-trifluoro-phenyl)-piperidine-4-carbonyl]-amino}-3,4- dihydro-2H-benzo[1 ,4]oxazin-2-yl)-acetic acid methyl ester as white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.39 (d, 1 H), 6.98 (dd, 1 H), 6.87 (d, 1 H), 6.68 (dd, 2H), 3.74 (d, 2H), 3.71 (s, 3H), 3.06-2.93 (m,
2H), 2.77 (td, 2H), 2.53-2.46 (m, 1 H), 1.93-1.78 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C23H22F3N3O5 : 477.4. Found: 478.2 (M+ + 1 ). D. A mixture of 3-oxo-6-{[1-(3,4,5-trifluoro-phenyl)-piperidine-4-carbonyl]- amino}-3,4-dihydro-2H-benzo[1 ,4]oxazine-2-carboxylic acid ethyl ester
(0.014 g, 0.0293 mmol) and 1 mL of potassium hydroxide solution, prepared by mixing KOH (1.98 g), MeOH (46 mL), and H2O (6 mL), was stirred for 2 hours. The reaction mixture was acidified to pH 1-2 and then extracted with EtOAc. The combined organic fractions were washed with brine, dried over MgSO4, filtered and the filtrate wass concentrated to provide (3-oxo-6-{[1-(3,4,5-trifluoro-phenyl)-piperidine- 4-carbonyl]-amino}-3,4-dihydro-2H-benzo[1 ,4]oxazin-2-yl)-acetic acid as white solid. 1H NMR (400MHz, CD3OD) δ (ppm): 7.73 (d, 1H), 7.21 (dd, 1 H)1 7.05 (d, 1 H), 6.74 (dd, 2H), 3.52 (d, 2H), 2.65 (td, 2H), 2.36- 2.25 (m, 1 H), 1.89-1.76 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. TOr C22H20F3N3O5 : 463.4. Found: 464.2 (M+ + 1 ).
BIOLOGICAL EXAMPLES
Example 1 Human VR1 Binding Assay
Compounds of the present invention were tested for their ability to inhibit the binding of [3H] RTX to hVR1 receptors in a [3H] RTX binding assay as previously described (Zhang, Sui-Po. Improved ligand binding assays for vanilloid receptors. PCT Int. Appl. (2002), WO 0233411 A1 20020425 AN 2002:315209, and Grant, Elfrida R., Dubin, Adrienne E., Zhang, Sui-Po, Zivin, Robert A., Zhong, Zhong Simultaneous intracellular calcium and sodium flux imaging in human vanilloid receptor 1 (VR1 )-transfected human embryonic kidney cells: a method to resolve ionic dependence of VR1 -mediated cell death. J. Pharmacol. Exp. Ther., 2002, 300(1 ), 9-17.)
HEK293 cells were transfected with human VR1 vanilloid receptors and washed with Hank's balanced Salt Solution, dissociated with cell dissociation buffer (Sigma), and then centrifuged at 1000 x g for 5 min. Cell pellets were homogenized in cold 20 mM HEPES buffer, pH 7.4, containing 5.8 mM NaCI, 320 mM sucrose, 2 mM MgCI2, 0.75 CaCI2 and 5 mM KCI and centrifuged at 1000 x g for 15 min. The resultant supernate was then centrifuged at 40000 x g for 15 min. The pelleted membranes were stored in a freezer at -80°C.
Approximately 120 μg protein/ ml from membranes were incubated with indicated concentrations of [3H]RTX in 0.5 ml of the HEPES buffer (pH 7.4) containing 0.25 mg/mL fatty acid-free bovine serum albumin at 370C for 60 min. The reaction mixture was then cooled to 40C, added 0.1 mg α,-acid glycoprotein to each sample and incubated at 4°C for 15 min. The samples were centrifuged at 18500 x g for 15 min. The tip of the microcentrifuge tube containing the pellet was cut off. Bound radioactivity was quantified by scintillation counting. Non-specific binding was tested in the presence of 200 nM unlabeled RTX.
Alternatively, a binding assay using rat tissue was used. Rat spinal cord was homogenized twice with a Polytron and centrifuged at 3000 rpm for 10 min in HEPES buffer containing 20 mM HEPES, pH 7.4, NaCI 5.8 mM, sucrose 320 mM, MgCl2 2 mM, CaCI2 0.75 mM and KCI 5 mM. The supernatant was then centrifuged at 40000 x g for 15 min. The pellet was saved in a tube and 10 ml assay buffer was added into the tube. The pellet and buffer were mixed with a Polytron. The assay contained 120 μg/ ml membrane protein and 0.3-0.6 nM [3H]-RTX (PerkinElmer, Boston) in a total volume of 0.5 ml HEPES buffer. Following incubation for 60 min at 37°C, the samples were cooled on ice, and 100 mg of α-acid glycoprotein were added into the samples. After centrifugation at 18500 x g for 15 min, the supernatant was aspirated and the tips of tubes were cut off and placed into 6 ml vials.
Data were calculated according to the equation:
% inhibition = (total binding-binding)*100/(total binding - non specific binding).
Kj values were calculated using a Prism program.
Example 2 (Protocol 1 ) Human VR1 Functional Assay Using FLIPR™
The functional activity of the test compounds was determined by measuring changes in intracellular calcium concentration using FLIPR™ Calcium-3 Assay Kit and FLIPR™ technology.
HEK 293 cells transfected with Human Vanilloid Receptor 1 were maintained at 370C and 5% CO2 in: Dulbecco's Modification of Eagle's Medium (high glucose, L-glutamine, pyridoxine HCI, No sodium pyruvate), 10% FBS, 1X Penicillin-Streptomycin-Amphotericin B, 200 ug/mL zeocin. Approximately 24 hours prior to assay, 30,000 cells/well were plated onto a 384-well black clear bottom poly-D-lysine-coated assay plate with a well volume of 25 DL using Titertek Multidrop. On the day of the assay, the medium was dumped and 50 μl_ 1X dye were loaded using Multidrop. Plates were incubated with dye at 37 0C for 30 minutes followed by 30 minutes incubation at room temperature. Then the plates were assayed by FLIPR™ with 2 additions: 12.5 μl_ test compound with 5 minutes data acquisition followed by 12.5 μl_ capsaicin at the ECso concentration.
The EC50 values of test compounds were calculated based on a test compound-induced calcium response at the 5-minute time point. The IC50 values of compounds were calculated based on a decreased capsaicin- induced calcium response in the presence of test compound. These values are tabulated in Table 1 , below.
Table 1
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Example 2 (Protocol 2) Human VR1 Functional Assay Using FLIPR™
The functional activity of the test compounds was determined by measuring changes in intracellular calcium concentration using FLIPR™ Calcium-3 Assay Kit and FLIPR™ technology.
HEK 293 cells stably transfected with Human Vanilloid Receptor 1 were maintained at 370C and 5% CO2 in: Dulbecco's Modification of Eagle's Medium (4.5g/L glucose, L-glutamine, sodium pyruvate), 10% FBS, 1X Penicillin-Streptomycin, 400 ug/mL G418 Sulfate. Approximately 24 hours prior to assay, 5,000 cells/well were plated onto a 384-well black clear bottom poly-D-lysine-coated assay plate with a well volume of 25 μL using Titertek Multidrop. On the day of the assay, the medium was dumped and 50 μL of dye (bulk kit vials diluted with 200 mL buffer) was loaded using Multidrop. Plates were incubated with dye at 37 0C for 30 minutes followed by 30 minutes incubation at room temperature. Then the plates were assayed by FLI PR™ with 2 additions: 12.5 μL test compound with 5 minutes data acquisition followed by 12.5 μL capsaicin at the EC8O concentration.
The EC50 values of test compounds were calculated based on a test compound-induced calcium response at the 5-minute time point. The IC50 values of compounds were calculated based on a decreased capsaicin- induced calcium response in the presence of test compound. These values are tabulated in Table 2, below.
Table 2
Figure imgf000183_0001

Claims

1. A compound of formula (H)
Figure imgf000184_0001
(II) wherein
Ar is an aryl selected from the group consisting of benzo[b]thiophenyl, naphthyl, biphenyl, isoquinolinyl, thiophenyl, pyridazinyl, and benzothiazolyl; Z is O or S;
R2 is hydrogen or C-ι-6alkyl optionally substituted with -OR4; n is 1 or 2;
R3 is independently hydrogen, C1-6alkyl, -COOR4, or -CH2COOR4; R4 is hydrogen or Chalky!; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
2. A compound according to claim 1 wherein Z is O and n is 1.
3. A compound according to claim 1 wherein Z is O and R2 is hydrogen.
4. A compound of formula (III)
Figure imgf000184_0002
(III) wherein X is CH or N; m is an integer from 0 to 4;
R is independently selected from the group consisting of halogen; R1; fluorinated Ci-ioalkyl; phenyl; amino; cyano; CF3O-; a 3 membered cyclic heteroalkyl containing 1 heteroatom that is N, O or S wherein said 3 membered cyclic heteroalkyl is optionally substituted with a substituent that is halogen, R1, fluorinated Ci-ioalkyl, amino, cyano, CF3O-, R1O-, R1S-, R1SO2-, R1S(O)-, R1SO2NH-, or -LCOY; a 4 to 5 membered cyclic heteroalkyl containing 1-3 heteroatoms that independently are N, O or S wherein said 4 to 5 membered cyclic heteroalkyl is optionally substituted with 1 to 2 substituents that independently are halogen, R1, fluorinated Ci-iOalkyl, amino, cyano, CF3O-, R1O-, R1S-, R1SO2-, R1S(O)-, R1SO2NH-, or -LCOY; a 6 to 7 membered cyclic heteroalkyl containing 1-3 heteroatoms that independently are N, O or S wherein said 6 to 7 membered cyclic heteroalkyl is optionally substituted with 1 to 3 substituents that independently are halogen, R1, fluorinated C-i.-ioalkyl, amino, cyano, CF3O-, R1O-, R1S-, R1SO2-, R1S(O)-, R1SO2NH-, or -LCOY; a heteroaryl wherein said heteroaryl is cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, pthalazine, pteridine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinoline, quinolizine, quinazoline, quinoxaline, tetrazole, thiadiazole, triazine, or triazole wherein said heteroaryl is optionally substituted with 1 to 3 substituents that independently are halogen, R1, fluorinated Ci-iOalkyl, amino, cyano, CF3O-, R1O-, R1S-, R1SO2-, R1S(O)-, R1SO2NH-, or -LCOY; hydroxyl; R1O-; R1S-; R1SO2-; R1S(O)-; R1SO2NH-; -LCOY; and C6-ioaryl; R1 is C-Moalkyl; L is -NH-, a direct bond, -O-, or -CH2-;
Y is H, R1, HO, R1O-, R1S-, -NH2, R1NH-, or (R1)2N-;
Z is O or S;
R2 is hydrogen or C1-6alkyl optionally substituted with -OR4; n is 1 or 2;
R3 is independently hydrogen, Ci-6alkyl, -COOR4, Or-CH2COOR4; R4 is hydrogen or Chalky!; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
5. A compound according to claim 4 wherein Z is O and n is 1.
6. A compound according to claim 4 wherein Z is O and R2 is hydrogen.
7. A a compound selected from the group consisting of
1 -(S-Trifluoromethyl-phenyO-piperidine^-carboxylic acid quinolin-3-ylamide; 1 -Biphenyl-S-yl-piperidine^-carboxylic acid quinolin-3-ylamide; 1-(4-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid quinolin-3-ylamide; 1 -(2,3-Dimethyl-phenyl)-piperidine-4-carboxylic acid quinolin-3-ylamide; 1 -(3,4-Dimethyl-phenyl)-piperidine-4-carboxylic acid quinolin-3-ylamide; 1 -(S-Trifluoromethyl-phenyO-piperidine^-carboxylic acid (9-ethyl-9H-purin-6- yl)-amide; 1-(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (1H-indol-4-yl)- amide; 1 -(S-Trifluoromethyl-phenyO-piperidine^-carboxylic acid (1 -acetyl-2,3-dihydro-
1H-indol-7-yl)-amide;
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid thieno[2,3- d]pyrimidin-4-ylamide;
1 -(S-Trifluoromethyl-phenyO-piperidine^-carboxylic acid (1 /-/-indazol-7-yl)- amide; 1 -(S-Trifluoromethyl-phenyO-piperidine^-carboxylic acid (3-methyl- benzo[d]isothiazol-5-yl)-amide; 1-(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid benzothiazol-6- ylamide; 3-{[1-(3-Trifluoromethyl-phenyl)-piperidine-4-carbonyl]-amino}-1H-indole-2- carboxylic acid ethyl ester; 1-(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid benzo[1 ,3]dioxol-5- ylamide; 1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (1 -acetyl-2,3-dihydro-
1/-/-indol-6-yl)-amide; i-CS-Trifluoromethyl-phenylJ-piperidine^-carboxylic acid (1-acetyl-2,3-dihydro
1 /-/-indol-7-yl)-amide; 1 -(S-Trifluoromethyl-phenyO-piperidine-^carboxylic acid (2-oxo-2,3-dihydro
1 H-indol-4~yI)-amide;
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (2,3-dihydro- benzo[1 ,4]dioxin-6-yl)-amide;
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (2-methyl- benzothiazol-5-yl)-amide; 1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (5-nitro- benzo[d]isothiazol-3-yl)-amide; 1 -(S-Trifluoromethyl-phenyO-piperidine^-carboxylic acid (1 /-/-indol-4-yl)- amide; 1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (1 H-indol-5-yl)- amide;
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (1 /-/-indol-6-yl)- amide;
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (1 -methyl-1 H- indazol-5-yl)-amide; 1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (2-mercapto- benzothiazol-6-yl)-amide; 1-(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (8-hydroxy-quinolin-
5-yl)-amide; 1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (3,4-dihydro-2H- benzo[b][1 ,4]dioxepin-7-yl)-amide;
1-(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (1-acetyl-2,3-dihydro- 1 H-indol-5-yl)-amide ;
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (1 H-indol-7-yl)- amide; 1-(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (1 ,4-dioxo-1 ,2,3,4- tetrahydro-phthalazin-6-yl)-amide; 1 -(S-Trifluoromethyl-phenyO-piperidine-^carboxylic acid (6-phenoxy-pyridin-3- yl)-amide;
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (6-acetyl- benzo[1 ,3]dioxol-5-yl)-amide;
1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid [4-(4,6-dimethoxy- pyrimidin-2-yl)-phenyl]-amide; 1 -(S-Trifluoromethyl-phenyO-piperidine^-carboxylic acid (3-oxo-3,4-dihydro-
2H-benzo[1 ,4]oxazin-6-yl)-amide; 1-(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (4-dimethylamino-5- phenyl-pyrimidin-2-yl)-amide; and S.S-Dimethyl-i^δ^ti-CS-trifluoromethyl-phenyO-piperidine^-carbonyl^amino}- pyridin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester.
8. A compound selected from the group consisting of i-Phenyl-piperidine-4-carboxylic acid quinolin-3-ylamide;
1 -Benzothiazol-δ-yl-piperidine^-carboxylic acid quinolin-3-ylamide;
1-Benzothiazol-5-yl-piperidine-4-carboxylic acid (2,3-dihydro-1 H-indol-4-yl)- amide; i-Phenyl-piperidine-4-carboxyIic acid (2,3-dihydro-1H-indol-4-yl)-amide;
3,4,5, 6-Tetrahydro-2H-[1 ,3']bipyridinyl-4-carboxylic acid isoquinolin-1-ylamide;
1-Phenyl-piperidine-4-carboxylic acid isoquinolin-1-ylamide;
1-Phenyl-piperidine-4-carboxylic acid cinnolin-3-ylamide;
1 -Benzothiazol-δ-yl-piperidine^-carboxylic acid cinnolin-3-ylamide; i-Benzothiazol-δ-yl-piperidine^-carboxylic acid phthalazin-δ-ylamide;
3,4,δ,6-Tetrahydro-2H-[1 ,4']bipyridinyl-4-carboxylic acid phthalazin-δ-ylamide;
1-Phenyl-piperidine-4-carboxylic acid quinazolin-4-ylamide;
1 -Benzothiazol-δ-yl-piperidine-4-carboxylic acid quinazolin-4-ylamide;
1 -Benzothiazol-δ-yl-piperidine-4-carboxylic acid pyridin-3-ylamide; 1-Phenyl-piperidine-4-carboxylic acid benzo[d]isothiazol-3-ylamide;
3,4,δ,6-Tetrahydro-2H-[1 ,2']bipyridinyl-4-carboxylic acid benzo[d]isothiazol-3- ylamide; i-Phenyl-piperidine-4-carboxylic acid benzothiazol-2-ylamide; 3,4,5, 6-Tetrahydro-2H-[1 ,3']bipyridinyl-4-carboxylic acid benzothiazol-2- ylamide;
1 -Pyridazin-S-yl-piperidine^-carboxylic acid phthalazin-1 -ylamide;
1 -Thiophen-2-yl-piperidine-4-carboxylic acid phthalazin-1 -ylamide; 1-Thiophen-2-yl-piperidine-4-carboxylic acid (7H-purin-6-yl)-amide; i-Pyrimidin^-yl-piperidine^-carboxylic acid (7H-purin-6-yl)-amide;
1-Pyrimidin-2-yl-piperidine-4-carboxylic acid cinnoIin-4-ylamide;
1 -Thiophen^-yl-piperidine^-carboxylic acid cinnolin-4-ylamide;
1 -Thiophen^-yl-piperidine^-carboxylic acid quinoxalin-6-ylamide; 1-Pyridazin-3-yl-piperidine-4-carboxylic acid quinoxalin-6-ylamide;
1 -Pyrimidin-2-yl~piperidine-4-carboxylic acid quinoxalin-6-ylamide; i-Pyrimidin^-yl-piperidine^-carboxylic acid pyrazin-2-ylamide;
1-Thiophen-2-yl-piperidine-4-carboxylic acid pyrazin-2-ylamide;
1 -Thiophen^-yl-piperidine^-carboxylic acid quinazolin-7-ylamide; 1-Pyrimidin-2-yl-piperidine-4-carboxylic acid quinazolin-7-ylamide;
1 -Pyrimidin^-yl-piperidine^-carboxylic acid pyridazin-3-ylamide;
1 -Thiophen^-yl-piperidine^-carboxylic acid pyridazin-3-ylamide;
1-Benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid (2-oxo-2,3-dihydro-1 H- benzoimidazol-5-yl)-amide; 1-Naphthalen-2-yl-piperidine-4-carboxylic acid (2-oxo-2,3-dihydro-1 H- benzoimidazol-5-yl)-amide;
1-Naphthalen-2-yl-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide;
1-Biphenyl-3-yl-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide;
1 -Biphenyl-S-yl-piperidine^-carboxylic acid quinazolin-2-ylamide;
1 -Quinolin-S-yl-piperidine^-carboxylic acid quinazolin-2-ylamide;
1 -Quinolin-S-yl-piperidine^-carboxylic acid quinoxalin-2-ylamide;
1 -Isoquinolin-δ-yl-piperidine^-carboxylic acid quinoxalin-2-ylamide; 1-lsoquinolin-5-yl-piperidine-4-carboxylic acid (9H-carbazol-3-yl)-amide;
1-Benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid (9H-carbazol-3-yl)- amide; i-Benzotbjthiophen-S-yl-piperidine^-carboxylic acid phenazin-2-ylamide; 1 -Naphthalen^-yl-piperidine^-carboxylic acid phenazin-2-yIamide; 1 -Naphthalen^-yl-piperidine^-carboxylic acid thiazol-2-ylamide; i-Biphenyl-S-yl-piperidine^-carboxylic acid thiazol-2-ylamide; i-Biphenyl-S-yl-piperidine-^carboxylic acid (1 H-imidazol-2-yl)-amide; 1 -Quinolin-S-yl-piperidine-^carboxylic acid (1 H-imidazol-2-yl)-amide; 1 -Quinolin-3-yl-piperidine-4-carboxylic acid (2H-pyrazol-3-yl)-amide; 1 -Isoquinolin-δ-yl-piperidine^-carboxylic acid (2H-pyrazol-3-yl)-amide; 1 -Isoquinolin-δ-yl-piperidine^-carboxylic acid isoxazol-3-ylamide; 1 -Benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid isoxazol-3-ylamide; 1-Benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid (3-methyl-isothiazol-δ- yl)-amide; 1 -Naphthalen^-yl-piperidine^-carboxylic acid (3-methyl-isothiazol-5-yl)- amide;
1-lsoquinolin-5-yl-piperidine-4-carboxylic acid [1 ,6]naphthyridin-4-ylamide; 1-Benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid [1 ,6]naphthyridin-4- ylamide; 1-Benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid [1 ,7]naphthyridin-8- ylamide;
1-Naphthalen-2-yl-piperidine-4-carboxylic acid [1 ,7]naphthyridin-8-ylamide; 1-Naphthalen-2-yl-piperidine-4-carboxylic acid acridin-9-ylamide; 1-Biphenyl-3-yl-piperidine-4-carboxylic acid acridin-9-ylamide; 1-Biphenyl-3-yl-piperidine-4~carboxylic acid (1-methyl-4,5-dihydro-1 H- imidazol-2-yl)-amide;
1-Quinolin-3-yl-piperidine-4-carboxylic acid (1-methyl-4,5-dihydro-1 H- imidazol-2-yl)-amide;
1-Quinolin-3-yl-piperidine-4-carboxylic acid (4,5-dihydro-1 H-pyrazol-3-yl)- amide; i-lsoquinolin-δ-yl-piperidine^-carboxylic acid (4,5-dihydro-1 H-pyrazol-3-yl)- amide; 1 -Isoquinolin-δ-yl-piperidine^-carboxylic acid [1 ,8]naphthyridin-2-ylamide; 1-Benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid [1 ,8]naphthyridin-2- ylamide; 1 -Benzofblthiophen-S-yl-piperidine^-carboxylic acid [2,6]naphthyridin-1 - ylamide;
1 -Naphthalen^-yl-piperidine^-carboxylic acid [2,6]naphthyridin-1 -ylamide; 1 -Naphthalen^-yl-piperidine-^carboxylic acid benzo[d]isoxazol-5-ylamide; i-Biphenyl-S-yl-piperidine-^carboxylic acid benzo[d]isoxazol-5-ylamide; 1-Biphenyl-3-yl-piperidine-4-carboxylic acid (1 H-pyrrol-3-yl)-amide; 1-Quinolin-3-yl-piperidine-4-carboxylic acid (1 H-pyrrol-3-yl)-amide; 1-Quinolin-3-yl-piperidine-4-carboxylic acid (1 H-pyrrolo[2,3-b]pyridin-3-yl)- amide; 1-lsoquinolin-5-yl-piperidine-4-carboxylic acid (1 H-pyrrolo[2,3-b]pyridin-3-yl)- amide;
1 -Isoquinolin-δ-yl-piperidine^-carboxylic acid pteridin-4-ylamide; 1 -Benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid pteridin-4-ylamide; 1-Benzo[b]thiophen-3-yl-piperidine-4-carboxylic acid (1 ,4-dihydro-quinazolin- 6-yl)-amide;
1-Naphthalen-2-yl-piperidine-4-carboxylic acid (1 ,4-dihydro-quinazolin-6-yl)- amide;
1-Naphthalen-2-yl-piperidine-4-carboxylic acid [1 ,7]naphthyridin-4-ylamide; 1-Biphenyl-3-yI-piperidine-4-carboxylic acid [1 ,7]naphthyridin-4-ylamide; i-Biphenyl-S-yl-piperidine^-carboxylic acid [2,7]naphthyridin-4-ylamide; 1 -Quinolin-S-yl-piperidine^-carboxylic acid [2,7]naphthyridin-4-ylamide; 1-Quinolin-3-yl-piperidine-4-carboxyIic acid [2, 6]naphthyridin-1 -ylamide; and 1 -Isoquinolin-δ-yl-piperidine^-carboxylic acid [2,6]naphthyridin-1 -ylamide.
9. A compound of formula (Ha)
Figure imgf000191_0001
(Ha) wherein Ar is an aryl selected from the group consisting of benzo[b]thiophenyl, naphthyl, biphenyl, isoquinolinyl, thiophenyl, pyridazinyl, and benzothiazolyl; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
10. A compound of formula (Ilia):
Figure imgf000192_0001
(Ilia) wherein
X is CH or N; m is an integer from 0 to 4;
R is independently selected from the group consisting of halogen; R1; fluorinated C-i.-ioalkyl; phenyl; amino; cyano; CF3O-; a 3 membered cyclic heteroalkyl containing 1 heteroatom that is N, O or S wherein said 3 membered cyclic heteroalkyl is optionally substituted with a substituent that is halogen, R1, fluorinated Ci_iOalkyl, amino, cyano, CF3O-, R1O-, R1S-, R1SO2-, R1S(O)-, R1SO2NH-, or -LCOY; a 4 to 5 membered cyclic heteroalkyl containing 1-3 heteroatoms that independently are N, O or S wherein said 4 to 5 membered cyclic heteroalkyl is optionally substituted with 1 to 2 substituents that independently are halogen, R1, fluorinated C-i-ioalkyl, amino, cyano, CF3O-, R1O-, R1S-, R1SO2-, R1S(O)-, R1SO2NH-, or -LCOY; a 6 to 7 membered cyclic heteroalkyl containing 1-3 heteroatoms that independently are N, O or S wherein said 6 to 7 membered cyclic heteroalkyl is optionally substituted with 1 to 3 substituents that independently are halogen, R1, fluorinated C-i.-ioalkyl, amino, cyano, CF3O-, R1O-, R1S-, R1SO2-, R1S(O)-, R1SO2NH-, or -LCOY; a heteroaryl wherein said heteroaryl is cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, pthalazine, pteridine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinoline, quinolizine, quinazoline, quinoxaline, tetrazole, thiadiazole, triazine, or triazole wherein said heteroaryl is optionally substituted with 1 to 3 substituents that independently are halogen, R1, fluorinated Ci-10alkyl, amino, cyano, CF3O-, R1O-, R1S-, R1SO2-, R1S(O)-, R1SO2NH-, or -LCOY; hydroxyl; R1O-; R1S-; R1SO2-; R1S(O)-; R1SO2NH-; -LCOY; and C6-i oary'; R1 is C1-10alkyl; L is -NH-, a direct bond, -O-, or -CH2-;
Y is H, R1, HO, R1O-, R1S-, -NH2, R1NH-, or (R1)2N-; and enantiomers, diastereomers, tautomers, solvates, and pharmaceutically acceptable salts thereof.
11. A compound according to claim 10 wherein X is CH.
12. A compound according to claim 10 wherein m is 1 or 2.
13. A compound according to claim 10 wherein R is independently Ci-4alkanyl, CF3, or halo.
14. A compound according to claim 10 wherein X is CH, m is 1 or 2 and R is independently Ci-4alkanyl, CF3, or halo.
15. A compound selected from the group consisting of
1 -(2,3-Dimethyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide; 1 -(2,5-Bis-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-yl)-amide; 1-(2-Bromo-3-fluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-
2H-benzo[1 ,4]oxazin-6-yl)-amide;
1 -(2-Bromo-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide; 1 -(2-Chloro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro2H- benzo[1 ,4]oxazin-6-yl)-amide; 1 -(2-Cyano-3-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (3~oxc-3,4~ dihydro-2H-benzo[1 ,4]oxazin-6-yl)-amide; 1-(2-Cyano-5-trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-yl)-amide; 1 -(2-Ethyl-phenyI)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide;
1 -(2-Fluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide;
1 -(2-lsopropyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide; 1 -(2-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-
2H-benzo[1 ,4]oxazin-6-yl)-amide; 1-(3,4,5-Trifluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide; 1 -(3,4-Difluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide;
1 -(3,4-Dimethyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide;
1 -(3,5-Difluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide; 1 -(3-Bromo-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide; 1-(3-Chloro-2-methyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-
2H-benzo[1 ,4]oxazin-6-yl)-amide; 1 -(3-Chloro-phenyl)-piperidine-4-carboxylic acid (3-oxc-3,4-dihydrc-2H- benzo[1 ,4]oxazin-6-yl)-amide;
1 -(3-Fluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide;
1 -(3-Methoxy-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide; 1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxylic acid (2-oxo-2,3-dihydro-
1 H-pyrido[2,3-b][1 ,4]oxazin-7-yl)-amide; 1 -(3-Trifluoromethyl-phenyl)-piperidine-4-carboxyIic acid [4-(2-hydroxy-ethyl)-
3-oxo-3,4-dihydro-2H-benzo[1 ,4]oxazin-6-yl]-amide; 1-(4-Bromo-2,3,5,6-tetrafluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-yl)-amide; 1 -(4-tert-Butyl-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide;
1 -Benzothiazol^-yl-piperidine^-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide;
1-m-Tolyl-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide; 1-o-Tolyl-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide; 1-Phenyi-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-amide; S'-Methyl-SAδ.δ-tetrahydro^l-KI ,2']bipyridinyl-4-carboxylic acid (3-oxo-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-yl)-amide; and
3'-Nitro-3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-4-carboxylic acid (3-oxo-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-yl)-amide.
16. A compound selected from the group consisting of 1 -(3,4,5-Trifluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-5-yl)-amide; 1-(3,4,5-Trifluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-7-yl)-amide; 1 -(3,4,5-Trifluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]oxazin-8-yl)-amide;
1 -(3,4,5-Trif luoro-phenyl)-piperidine-4-carboxylic acid (4-methyl-3-oxo-3,4- dihydro-2H-benzo[1 ,4]oxazin-6-yl)-amide;
1 -(3,4,5-Trifluoro-phenyl)-piperidine-4-carboxylic acid (3-oxo-3,4-dihydro-2H- benzo[1 ,4]thiazin-6-yl)-amide; 1 -(3,4>5-Trifluoro-phenyl)-piperidine-4-carboxylic acid [2-(2-hydroxy-ethyl)-3- oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-amide; 2-Methyl-3-oxo-6-{[1-(3,4,5-trifluoro-phenyl)-piperidine-4-carbonyl]-amino}-
3,4-dihydro-2H-benzo[1 ,4]oxazine-2-carboxylic acid ethyl ester; 2-Methyl-3-oxo-6-{[1-(3,4,5-trifluoro-phenyl)-piperidine-4-carbonyl]-amino}-
3,4-dihydro-2H-benzo[1 ,4]oxazine-2-carboxylic acid; S-Oxo-β-lti^S^.δ-trifluoro-phenyO-piperidine^-carbonyll-aminoJ-S^-dihydro-
2H-benzo[1 ,4]oxazine-2-carboxylic acid ethyl ester;
3-Oxo-6-{[1-(3,4,5-trifluoro-phenyl)-piperidine-4-carbonyl]-amino}-3,4-dihydro- 2H-benzo[1 ,4]oxazine-2-carboxylic acid;
(3-Oxo-6-{[1-(3,4,5-trifluoro-phenyl)-piperidine-4-carbonyl]-amino}-3,4- dihydro-2H-benzo[1 ,4]oxazin-2-yl)-acetic acid methyl ester; and (3-Oxo-6-{[1-(3,4,5-trifluoro-phenyl)-piperidine-4-carbonyl]-amino}-3,4- dihydro-2H-benzo[1 ,4]oxazin-2-yl)-acetic acid.
17. A pharmaceutical composition comprising a compound, salt or solvate according to any of claims 1-16 admixed with a pharmaceutically acceptable carrier, excipient or diluent.
18. A veterinary composition comprising a compound, salt or solvate according to any of claims 1-16 admixed with a veterinarily acceptable carrier, excipient or dilluent.
19. A kit comprising in one or more containers an amount of the composition of any of claims 1-16 effective to treat or prevent a disease or condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, fibromyalgia, migraine, headache, toothache, burn, sunburn, snake bite (in particular, venomous snake bite), spider bite, insect sting, neurogenic bladder, benign prostatic hypertrophy, interstitial cystitis, urinary tract infection, cough, asthma, chronic obstructive pulmonary disease, rhinitis, contact dermatitis/hypersensitivity, itch, eczema, anxiety, panic disorders, pharyngitis, mucositis, enteritis, cellulites, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, causalgia, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, bony fractures, post¬ operative ileus, irritable bowel syndrome, inflammatory bowel diseases such as Crohn's Disease and ulcerative colitis, cholecystitis, pancreatitis, postmastectomy pain syndrome, oral neuropathic pain, Charcot's pain, reflex sympathetic dystrophy, Guillain-Barre syndrome, meralgia paresthetica, burning-mouth syndrome, optic neuritis, postfebrile neuritis, migrating neuritis, segmental neuritis, Gombault's neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngial neuralgia, migrainous neuralgia, idiopathic neuralgia, intercostals neuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, red neuralgia, Sluder's neuralgia, splenopalatine neuralgia, supraorbital neuralgia, vidian neuralgia, sinus headache, tension headache, labor, childbirth, intestinal gas, menstruation, hot flash, cancer, and trauma.
PCT/US2005/043192 2004-11-29 2005-11-29 4 - piperidinecarboxamide derivatives as modulators of vanilloid vr1 receptor WO2006058338A2 (en)

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