HYDROXYQUINOLIN-2(1H)-ONES AND DERIVATIVES THEREOF

_{Field of the Invention}

_{This invention relates to novel compounds useful for the treatment of cognitive-related disorders and neuropathic pain disorders in a mamma l e.g. , a human. The invention also relates to pharmaceutical compositions containing such compounds.}

_{Background of the Invention}

_{The enzyme D-amino acid oxidase (DAAO) meta bolizes D-amino acids, and in particular, metabolizes D-serine in vitro at physiological pH . DAAO is expressed in the mammalian bra in and periphery, D-Serine's role as a neurotransmitter is important in the activation of the N-methyl-D-aspartate (NMDA) selective subtype of the glutamate receptor, an ion channel expressed in neurons, here denoted as NM DA receptor. Small organic molecules, which inhibit the enzymatic cycle of DAAO, may control the levels of D-serine, and thus influence the activity of the NM DA receptor in the brain. NMDA receptor activity is important in a variety of disease states , such as schizophrenia, psychosis, ataxias, ischemia, several forms of pain including neuropathic pain, and deficits in memory and cognition.}

_{Small organic molecules that inhibit the enzymatic cycle of DAAO may also control prod uction of toxic metabolites of D-serine oxid ation , such as hydrogen peroxide and ammonia. Thus, these molecules may influence the progression of cell loss in neurodegenerative d isorders. Neurodegenerative d iseases are d iseases in which central nervous system (CNS) neurons a nd/or peripheral neurons undergo a progressive loss of function, usually accompanied by (and perhaps caused by) a physica l deterioration of the structure of either the neuron itself or its interface with other neurons . Such cond itions include Parkinson's d isease, Alzheimer's d isease, Huntington's d isease and neuropathic pain. N-methyl-D-aspartate (NMDA)-glutamate receptors are expressed at excitatory synapses throughout the CNS- These receptors med iate a wide range of brain processes, including syna ptic plasticity, that are associated with certain types of memory formation and learning. NM DA-glutamate receptors require bind ing of two agonists to effect neurotransmission. One of these agonists is the excitatory amino acid L- glutamate, while the second agonist, at the so-called "strychnine-insensitive glycine site", is now thought to be D-serine. In animals, D-serine is synthesized from L-senne by serine racemase and degraded to its correspond ing ketoacid by DAAO- Together, serine racemase and DAAO are thought to play a crucial role in modulating N MDA neurotransmission by regulating CNS concentrations of D-serine,}

_{Several DAAO inhibitors are known in the literature including aminopyrazolines such as WO 2007/093829, fused bicyclics such as VVO 2008/089453, WO 2008/005456, WO2007/039773 and US 7 ,1 66,725.}

_{Certain fused bicycϋc glycine receptor antagonists have also been d isclosed including VVO 98/04288 and US 5,597,922.}

_{The present inventors have now discovered a group of very potent small molecules with selective DAAO inhibitory activity}

_{Summary of the Invention}

_{The present invention relates to a method of treating a disorder or cond ition that can be treated by inhibiting D-amino acid oxidase ( DAAO) activity in a mammal, preferably a human , in need of such treatment comprising administering to said mammal an effective amount of a compound of formula}

_I w _{herein ring "A" is a 6 membered aryl or 5 or 6 membered heteroaryl ring; wherein said 6 membered heteroaryl ring has one nitrogen heteroatom and wherein said 5 membered heteroaryl ring has one or two heteroatoms selected from N, O or S;} e _{ach R is independently selected from the group consisting of hydrogen, chloro, fiuoro, bromo, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, and cyano (wherein R is a substituent on either ring of the hydroxy quinolinone nucleus);} n _{is an integer selected from the group consisting of zero, one, two or three; or a pharmaceutically acceptable salt thereof.} T _{he present invention further relates to a method of enhancing cognition in a mammal, preferably a huma n, comprising administering to said mammal an effective amount of a compound of formula I}

_{One embod iment of the methods of the invention relates to compounds of formula}

_{Another embod iment of the methods of the invention relates to compounds of the formula I wherein ring "A" is a 6 membered heteroa ry! ring; containing one nitrogen heteroatom.}

_{Another embod iment of the methods of the invention relates to compounds of the formula I wherein ring "A" is a 5 membered heteroa ryl ring; containing one heteroatom selected from N, O or S}

_{Another embod iment of the methods of the invention relates to compounds of the formula I wherein ring "A" is a 5 membereα heteroa ryl ring: containing two heteroatoms wherein the first heteroatom is selected from N , O or S and the second heteroatom is N,}

_{The present methods also relates to a group of compounds of formula I wherein said compound is selected from the group consisting of:} 6 _{-ch!oro-3-hyd roxyquino!in-2( 1 H )-one;} 3 _{-hyd røxy-6,8-d imethylquinαlin-2(1 H )-αne;} 3 _{-hydroxy-6-methylqυιnohn-2( 1 H )-one;}

_{3-hydroxy-8-methylquinolin-2(1 H )-one;} 6 _{-fluoro-3-hydroxyquinolin-2(1 H )-one;} 7 _{-ch!oro-3-hyd roxyquinσiin-2( 1 H )-one; 3-hydroxyquinolin-2(1H)-αne;} 8 _{-chloro-3-hycJroxyquino!in-2(1H)-one;}

_{3-hydroxy-1 ,8-naphthyridin-2(1 H)-one,}

_{3-hydroxy-4-methylquinolin-2(1H)-one;} 3 _{-hyαroxy-§-methoxyquinol!n-2(iH)-one;}

_{5,7-dichloro-3-hydroxyqυinoiιn-2(1 H)-one; and}

_{5,6-dichloro-3-hydroxyquinoNn-2(1H)-one:} a _{nd the pharmaceutically acceptable salts of such compounds.}

_{The present invention also relates to the following compounds per se and to the method of using said compounds for the treatment of a disorder or condition that can be treated by inhibiting D-amino acid oxidase (DAAO) activity in a mammal, perførably a human, in need of such treatment:}

_{7-fluoro-3-hydroxyqυinoHn-2(1H}-one;}

_{5-chloro-6-fluoro-3-hydroxyquiπolin-2(1H)-one;} 7 _{-ethy!-3-hydroxyquino!in-2(1H)-one;}

_{4-f!uoro-3-hydroxyquinolin-2(1H)-one;}

_{4,δ-dif!uoro-3-hydroxyquino!in»2(iH)-one;}

_{3-hydroxy-1,5-naphthyridιn-2(1H)-one;}

_{3-hydroxy-1>7-naphthyridin-2(1H)-ane;} 3 _{-hydroxy-1.6-naphthyndin-2(1H)-one;}

_{5-hydroxy-1-methyi-1,7-dihydro-6H-pyτazolo[3,4-έ)]pyr idin-6-one;} 6 _{-hydroxythiθno[3,2-ιb3pyπdiπ-5(4H)-one;} 8 _{-fluoro-3-hydroxyquinolin-2(1H)-one;}

_{3-hydroxy-7-methylquinolin-2(1H)-one;} 4 _{-bromo-7-ch!oro-3-hyciroxyqυinolin-2(1 H)-one;} 6 _{,7-dich!oro-3-hydroxyqυinolin-2(1H)-one;}

_{7,8-dichloro-3-hydroxyquιno!in-2(1H)-one;}

_{7-chloro-3-hydroxy-8-methylquinolin-2(1H)-one:}

_{3-hydroxy-4-methyl-158-naphthyπdin-2(1H)-one;} 6 _{-hydroxyfuro[3:2-b]pyridiπ-5(4H}-one:}

_{5-flLOro-3-hydroxyqυinolin-2(1H}-one; 3-hydroxy-5-methylquinolin-2(1tf)-one;}

_{5-chloro-3-hyclroxyquino!in-2(1H)-one;}

_{3-hydroxypyrrolo[1 ,2-b]pyridaz.in-2(1 H)-one;}

_{5-hyciroxyfuro[2:3-b]pyπdifv6(7H)-one;} 5 _{-hyaroxyi5Oxazolo[5,4-b]pyridirv6(7H)-one;} 6 _{-hydroxyisoxazoio[4,5-b]ρyridin-5(4H)-one;}

_{5-hydroxyisoxazolo[3r4-b]pyricJin-6{7H)-ane;} 6 _{-hydroxyisoxazolo[4,3-b]pyridin-5(4H)-one;} 6 _{-hydroxy[1,3]oxazolo[4,5-b]pyridin-5(4H)-one;} 6 _{-hydroxy[1,3]oxazolo[5,4-b]pyήdin-5(4H>-oπe;}

_{5-hydroxy-2-methylfuro[2,3-b]pyridin-6(7H)-one;} 6 _{-hydroxy-2-methylfuro[3,2-b]pyhdin-5(4H)-one;} 6 _{-hydroxy-2-methyi[1,3]oxazoio[4,5-b3pyπdJn-5(4H}-one;}

_{5-hydroxy-3-methylisoxazolo[3,4-b]pyndin-6(7H)-one; 6-hydroxy-2-methy![1,3]oxa2θlo[5,4-b3pyridin-5(4H)-one ; 6-hydroxy-3-methylisoxazolo[4,5-b]pyridiπ-5(4H)-one;}

_{5-hydroxy-3-methylisoxazolo[5,4-b]pyridin-6(7H)-one;}

_{5-hydroxythieno[2,3-b3pyridiπ-6(7H)-one;} 6 _{-hydroxy[1,3]thia2olo[514-b]pyridiri-5(4H)-one;} 6 _{-hydroxy[1 ,33thiazolo[4,5-b]pyτidin-5(4H)-onθ;}

_{2-fluoro-5-hydroxyfuro[2>3-b]pyridin-6(7H)-one;}

_{2-fluoro-6-hydroxyfuro[3>2-b)pyridiπ-5(4H)-one;} 6 _{-hydroxy-2-methylthieno[3,2-b]pyridiπ-5(4H)-oπe;}

_{5-hydroxy-2-methyithιeno[2,3-b]pyndιn-6(7H)-one;} 2 _{-fiuoro-6-hydroxythieno[3>2-b3pyridin-5(4H)-one;}

_{2-f!υoro-5-hydroxylhieno[2,3-b]pyridin-6(7H)-onθ;}

_{2-chloro-6-hydroxyfuro[3,2-b]pyridiπ-5{4H)-one;}

_{2-chloro-5-hydroxyfuro[2,3-b]pyridin-6(7H)-one;}

_{2-chloro-6-hydroxythieno[3,2-b3pyridin-5(4H)-one;} 7 _{-fluoro-3-hydroxy-1 ,5-naphthyridin-2(1 H)-one;} 8 _{-fluoro-3-hydroxy-1 ,6-naphthyridin-2(1 H)-one; 6-fluoro-3-hydroxy-1 >8-naphthyriclin-2(1 H)-one;} 8 _{-flυoro-3-hydroxy-1 ,5-naphthyridin-2(1 H)-one;}

_{5-fJuorø-3-hydrαxy-1 ,8-naρhtbyridin-2(1 H)-απe;} 6 _{-chloro-3-hydroxy-1l8-naphthyndin-2(1H)-one;} 8 _{-chioro-3-hydroxy-1 ,5-naph{hyπdιπ-2{1H)-one;}

_{7-ch!oro-3-hydroxy-1 ,5-naphthyridin-2(1 H)-one;}

_{5-ch!oro-3-hydroxy-1,8-naphthyridin-2(1H)-one;} 8 _{-chiorα-3-hydrαxy-1 ,6-naphthyridin-2(1 H)-one;}

_{5-ch!oro-8-fluoro-3-hydroxy-1 ,8-naphthyridin-2(1 H)-one; 4-fluoro-3-hydroxy-1>8-naphthyhdin-2(1H)-one;}

_{4-fluoro-3-hydroxy-1 ,5-naphthyridiπ-2(1 H)-one;}

_{4-fluoro-3-hydroxy-1 ,6-naphthyridin-2(1 H)-one;}

_{4-flLOro-3-hydroxy-5-methy!quino!in-2(iH)-one;}

_{4-fluoro-3-hydroxy-8-methy!quiπolin-2(1H)-onβ;} 4 _{7-difluoro-3-hydroxyquino!in-2(1H)-one;}

_{4,5-dif!uoro-3-hydroxyquinoiin-2(1H)-one;}

_{4,6-dif!uoro-3-hydroxyquinoiin-2(1H)-one;}

_{4,7-difluoro-3-hydroκy-1 ,5-HaPhIhVrIdIn^(I H)-one;}

_{4,8-difluoro-3-hydroxy-1 ,5-naphthyπdm-2{ 1 H)-one;} 4 _{,5-difluoro-3-hydroxy-1 ,8-πaphthyπdιn-2(1 H)-one:}

_{4,8-difluoro-3-hydroxy-1 ,6-naphthyridin-2(1 H)-one;}

_{4-fluoro-3-hydroxy-2-oxo-1,2-dihydroquino!ine-5-carboni tri!e;}

_{4-flϋoro-3-hydroxy-2-oxo-1!2-clihydroquinoiine-8-carbo nitrile,}

_{5-ethy!-4-fluoro-3-hydroxyquinolin-2(1H)-one;} 8 _{-ethyl-4-fluoro-3-hydroxyquino!in-2(1H)-one;}

_{4!5-difiuoro-3-hydroxy-8-methyiquinoiin-2( 1 H)-one;}

_{4,8-dif!uoro-3-hydroxy-5-methy!quinolin-2(1H)-one;}

_{4.6-dif!uorO-3-hydroxy-5-methylquinolin-2(1H)-one;}

_{4,7-difluoro-3-hydroxy-8-mθthy!quιnolin-2(1H)-one;} 8 _{-ch!oro-4-fluoro-3-hydroxyquinolin-2(1 H)-one;}

_{5-ch!oro-4-fluoro-3-hydroxyquinolin-2(1H)-one; 8-chloro-4-fluoro-3-hydroxy-1 ,5-naphthyridin-2(1 H>-one; 8-chloro-4-fluoro-3-hydroxy-156-naphthyndin-2(1 H)-one;}

_{4,5,6-trifluoro-3-hyclroxyquinolin-2(1H)-one;}

_{4t5(8-trifluoro-3-hydroxyquinolin-2(1H)-one;} 4 _{,7.8-trifluoro-3-hydroxyqυιnol!n-2(1 H)-one,}

_{4,6,7-trιfluoro-3-hydroxyquinolin-2(1HVone;}

_{5-ethyJ-4J-dif!uoro-3-hydroxyquinαiin-2(1 H )-αne;} 8 _{-ethyl-4t6-difluoro-3-hydroxyquinolin-2(1H)-one;}

_{5-ethy!-4,8-difluoro-3-hydroxyquinolin-2(1H)-one;} 5 _{-chloro-4-fluoro-3-hydroxy-8-methylquiDOlin-2(1 H)-ODe; 8-ch!oro-4-fiuoro-3-hydroxy-5-methylquinoiin-2(1H)-one;}

_{5-ch!oro-4,7-dif!uoro-3-hydroxyquinolin-2(1H)-one;}

_{5-chloro-4,6-dif!uoro-3-hydroxyquinolin-2(1H)-one;} 8 _{-chloro-4,6-dif!uoro-3-hydroxyqυinolin-2(1H)-one;} 8 _{-chloro-4,5-dif!uoro-3-hydroxyquinolin-2(1H)-one;} 8 _{-chloro-5-ethyl-4-f!uoro-3-hydroxyquino!in-2(iH)-one;}

_{S-chloro-8-ethy!-4-fluoro-3-hydroxyquino!in-2(1H)-one;}

_{4-f!ϋoro-3-hydroxy-5-(trifluoromethyl)quinoiιn-2(1H)- one;}

_{4-fluoro-3-hydroxy-8-(trif!uoromethyl)quino!irι-2(1H)- one; 5,8-dichloro-4-fluoro-3-hydroxyquinolin-2(1H)-on8;}

_{7-fluoro-3-hydroxy-8-methylquinolin-2(1 H)-one;} 8 _{-fluoro-3-hydroxy-5-methylquino!m-2(1H)-one;} 6 _{-flϋoro-3-hydroxy-8-methylquinoiin-2(1H)-one;} 6 _{-fluoro-3-hydroxy-5-methylquιnoiin-2(1H)-one;} 7 _{-fluoro-3-hydroxy-5-methy!quinolin-2{1 H)-one,}

_{5-fluoro-3-hydroxy-8-methy!qusnoHn-2(1H)-one;} 6 _{,7-dif!uoro-3-hydroxyqυinolin-2(1H)-one;}

_{5,8-dif!uoro-3-hydrDxyquinolin-2(1H)-one;}

_{7,8-difluoro-3-hydroxyquinoiin-2(1 H)-ODΘ;} S _{,6-difluoro-3-hydroxyqυiπolin-2(1 H)-ODe;}

_{5,7-difluoro-3-hydroxyquino!in-2(1 H)-one; 6,8-difluoro-3-hydroxyquino!in-2(1H)-one;}

_{3-hydroxy-2-oxo-1,2-dihydroquino!ine-8-carbonitri!e;}

_{3-hydroxy-2-oxo-1,2-dihydroquinoline-6-carbonitr!le;}

_{3-hydiOxy-2-oxo-1,2-dihydroquinoIine-5-carbonitriIe;} 3 _{-hyoroxy-2-oxo-1 ,2-d!hydroqumolιne-7-cart»onιtπ!e;}

_{7-fluoro-3-hydroxy-2-oxo-1:2-dihydroquino!ine-6-carboni tri!e:}

_{7-fluoro-3-hydroxy-2-oxo-1;2-dihydroquino!!ne-8-carboni tri!e:}

_{7-flLroro-3-hydroxy-2-oxo-1!2-dihydroquinoline-5-carbon itrile; 6-fluoro-3- hydroxy- 2-oxo-1 ^-dihydroquinoiine-T-carbonitrile, 5-fluoro-3-hydroxy-2-oxo-1,2-dihydroquinoline-7-carboni trile; 8-fluoro-3-hydroxy-2-oxo-1.2-dihydroquino!ine-5-carboni friie: 8-fluoro-3-hydroxy-2-oxo-12-d!hydroquino!Jne-8-carbonit rile: 6-ftuoro-3-hydroxy-2-oxo-1,2-dihydroquinoiine-5-carboni tri!e; 6-fluoro-3-hydroxy-2-oxo-1l2-dihydroquinoiine-8-carboni trile, 5-fluoro-3-hydroxy-2-oxo-1;2-dihydroquinoiine-8-carboni tri!e:}

_{5-f!uoro-3-hydroxy-2-oxo-1,2-dihydroquinoiine-6-carboni trile; 8-fiuoro-3-hydroxy-2-oxo-1.2-dihydroquinoi!ne-7-carboni trile; θ-chloro-S-hydroxy^-oxo-i^-dihydroquJnoline-S-carbonit rϋe;}

_{5-chioro-3-hydroxy-2-oxo-1,2-dihydroquinohne-7-carbonit rile; 7-chloro-3-hydroxy-2-oxo-1,2-dihydroquinoiιπe-5-carbo nitrile;}

_{5-chloro-3-hydroxy-2-oxo-1,2-dihydroqυinoiine-8-carbon itrile;}

_{7-chbro-3-hydroxy-2-oxo-1:2-dihydroquinoline-8-carbonit ri!e; 8-chlorx>-3-hydroxy-2-oxo-1.2-dihydroQuinoiine-7-car bonitrile;}

_{5-chloro-3-hydroxy-2-oxo-1,2-dihydroquinoiιne-6-carbon itrile; 8-ch!oro-3-hydroxy-2-oxo-1!2-αihydroqυino!iπe-5-carb oπitrile; 6-ch!oro-3-hydroxy-2-oxo-1:2-dihydroqυinoline-5-carbon itri!e; 8-ch!oro-3-hydroxy-2-oxo-1.2-dihydroquinoline-6-carboni tri!e; 8-ethyl»7-fluoro-3-hyclraxyquιnolin-2(1H)-onβ;}

_{5-ethy!-8-fluoro-3-hydroxyquιno!in-2(1H)-one;} S _{-ethyl-6-fluoro-3-hydroxyquinolin-2(1 H)-one:}

_{5-ethyl-7-fluoro-3-hydroxyquinohn-2(1H)-one; 8-ethyl-6-fluoro-3-hydroxyquιnolin-2(1H)-one;} 6 _{-ch!oro-3-hycJroxy-8-methylquiπolin-2(1H)-one;}

_{5-ch!oro-3-hydroxy-δ-methylqυinolin-2(1H)-oπθ;}

_{5-chloro-3-hydroxy-7-methylquinolin-2(1H)-one;} 8 _{-chloro-3-hydroxy-5-methy!quιπolin-2(1 H)-one;} 6 _{-chloro-3-hydroxy-5-methyiquinolιn-2(1H)-one;}

_{7-chloro-3-hydroxy-5-methylquinolin-2(1H)-αne;} 8 _{-chloro-7-fluoro-3-hydroxyquinolin-2(1H)-one;} 8 _{-chloro-6-fIuoro-3-hydroxyqυinolin-2(1H)-one;} 6 _{-chloro-5-fluoro-3-hydroxyqυinolin-2(1H)-one;} 8 _{-chloro-5-fluoro-3-hydroxyquinolin-2(1H)-one;}

_{5-ch!oro-8-fluoro-3-hydroxyquinolin-2(1H)-one;}

_{7-chioro-8-fluoro-3-hydroxyquino!in-2(1H)-one;}

_{7-chloro-5-fiuoro-3-hydroxyqυinolin-2(1H)-one;} 6 _{-chloro-8-fluoro-3-hydroxyquinolin-2(1H)-one;}

_{5-chloro-7-fluoro-3-hydroxyqυinolin-2(1H)-one;}

_{7-ch!orO-5-ethyl-3-hydroxyquinolin-2(1H)-one;}

_{5-chloro-8-ethy!-3-hydroxyquinolin-2(1H)-one;} 6 _{-chloro-8-ethy!-3-hyciiOxyquinolιn-2(1H)-one;} 8 _{-chloro-5-θthyl-3-hydroxyquinolin-2(1 H)-oπe;} 6 _{-chloro-5-ethyl-3-hydroxyqυinolin-2(1H)-one;}

_{3-hydroxy-5-(trifluoromethyl)qυino!in-2(1H)-one;}

_{3-hydroxy-8-(trifluoromethyl)qυinolin-2(1H)-one;}

_{5>8-dichloro-3-hydroxyquino!in-2(1H)-one;} 6 _{,8-dichioro-3-hydroxyquinoiin-2(1 H)-oπe;} 6 _{-flυoro-3-hydroxy-8-(tr!fiuoromefhyl)qui'noHn-2(1H)-on e; 8-fluoiO-3-hydroxy-5-(trif!uorornethyI)quinoiin-2(1H)-o ne;}

_{5-fluorO-3-hydroxy-8-(trifluoramethyl)quinolin-2(1H)-on e; 6-fluoro-3-hydroxy-5-(trifluoromethyl)quinoi!n-2(1H)-on e; 7-fluoro-3-hydroxy-5-(trifiuoromethyl)quiπo!in-2(1H)-o ne;}

_{7-flLOro-3-hydroxy-8-(tπf!uoromelhyl)quino!ιn-2(iH)-o ne; 6-chloro-3-hydroxy-8-(trιfluoromethyl)quinoiιn-2(1H)-one;}

_{5-ch!oro-3-hydroxy-6-(trifluoromethyl)quinolin-2(1H)-on e;}

_{5-ch!oro-3-hydroxy-8-(trifluoromethyl)quinoiin-2(1H)-on e;} 8 _{-chloro-3-hydroxy-5-(trifluoromethyl)quinoiin-2(1H)-one ;} 8 _{-chloro-3-hydroxy-6-(trif!uoromethyljqυιnoiiπ-2(1 Hj-one. and}

_{7-chloro-3-hydroxy-5-(trifiUforomethyl)quinoiιn-2(1H)- one;}

_{5,6J4rifluoro-3-hydroxyquinolin-2( 1 H)-one;}

_{5>7,8-trifluoro-3-hydroxyquinolin-2(1 H)-one; and}

_{5,6,7.8-tetraf!uoro-3-hydroxyquinolin-2(1H)-one; or} p _{harmaceutically acceptable salts of said compounds.}

_{An embodiment of the present invention of particular interest relates to the 3-hydrαxyquinαlin-2(1H)-απe compounds:}

_{7-fiuorø-3-hydroxyquino!in-2(iHH>ne;}

_{5-chloro-6-fluoro-3-hydroxyquinolirv2(1H)-one;} 7 _{-ethy!-3-hydroxyquino!in-2(1H)-one;}

_{4-f!uoro-3-hydroxyquinolin-2(1H)-one;}

_{4,δ-dif!uoro-3-hydroxyquino!in»2(i H)-one;} 8 _{-f!ϋoro-3-hydroxyquiDθ!m-2(1H)-one;}

_{3-hydroxy-7-methylquinolirι-2(1H)-one;} 4 _{-bromo-7-ch!oro-3-hydroxyquinoliD-2(1 H)-one;} 6 _{,7-dichloro-3-hydroxyquiDoiiD-2(1H)-one;}

_{7,8-dichloro-3-hydroxyqυιnolin-2(1H)-one;}

_{7-chloro-3-hydroxy-8-methylquinolin-2(1 H)-one,}

_{5-fluoro-3-hydroxyquιno!!n-2(1H)-one;} 3 _{-hydroxy-5-methy!qυino!in-2(1H)-one; or}

_{5-chloro-3-hydroxyquinolis>2(1H)-onβ; including the pharmaceutically acceptable salts thereof.}

_{Another embodiment of the present invention of particular interest relates to a group of 6-membered heteroarylfused-pyridin-2(1 H)-ODe compounds selected from the group consisting of.}

_{3-hydroxy-1,5-naphthyridin-2(1H)-one; 3-hydroxy-1,7-naphthyrιdin-2(1H)-one;}

_{3-hydroxy-1,6-naphthyridin-2(1H)-one; and}

_{3-hydroxy-4-methyl-1 ,8-naphthyridin-2(1 H)-one; or pharmaceutically acceptable salts of each of the foregoing.} A _{nother embodiment of the present invention of particular interest relates to the 5-membered heteroarylfused-pyridin-2(1H)-ones:}

_{5-hydroxy-1-methyl-1,7-dihydro-8H-pyrazolo[3,4-ό]ρyri din-6-one;} 6 _{-hydroxythieno[312--?3pyridin-5(4H)-one; or} 6 _{-hydroxyfuro[3,2-b]pyridin-5(4H)-one;} i _{ncluding pharmaceutically acceptable salts of each of the foregoing.}

_{Another embodiment of the present invention of interest to the inventors relates to a group of (5-membered heteroaryifused)-pyrϊdin-2(1H)- ones selected from the group consisting of:}

_{3-hydroxypyrrolo[i ,2-b]pyridazin-2(1 H)-one;} 5 _{-hydroxyfuro[2,3-b]pyridin-6(7H)-one;}

_{5-hydroxyisoxazolot5,4-b]pyridin-6{7H)-one;}

_{S-hydroxyisoxazolo[4,5-b]pyπdin-5(4H)-one;}

_{5-hydroxyisoxazolo[3}4-b]pyridiπ-6(7H)-one;} 6 _{-hydroxyisoxazolo[4,3-b]pyridin-5(4H)-one;} 6 _{-hydroxy[1 ,3]oxazolo[4,5-b]pyτidin-5(4H)-one;} 6 _{-hydroxy[1,3]oxazolo[5,4-b]pyridin-5(4H)-one;}

_{5-hydroxy-2-methylfuro[213-b]pyridm-6(7H)-one;} 6 _{-hydroxy-2-methylfuro[3,2-b]pyridin-5(4H)-one;} 6 _{-hydroxy-2-methy![1,3]oxazolo[4,5-b3pyridin-5(4H)-one;} 5 _{-hyciroxy-3-methy!isoxazolo[3.4-b]pyridiπ-6(7H)-oπe;} 6 _{-hydroxy-2-methy![1(3]oxazolo[5(4-b3pyridin-5(4H)-one;} 6 _{-hydiOxy-3-methylisoxazolo[4,5-b]pyridin-5(4H)-one;}

_{5-hydrOxy-3-methylιsoxazolo[5,4-b]pyridin-6(7H)-onβ;}

_{5-hydroxythieno[2,3-b]pyridin-6(7H)-one;} 6 _{-hydroxy[1 ,3]thiazolo[5:4-b]pyhdin-5(4H)-one;} 6 _{-hydroxy[1,3]thiazolo[4:5-b]pyrid!n-5(4H)-one; 2-fluoro-5-hydroxyfuro[2,3-b]pyridin-6(7H)-one;}

_{2-fluoro-6-hydroxyfυro[3,2-b]pyricliπ-5(4H)-one;} 6 _{-hydroxy-2-methyitbieno[3,2-b]pyridin-5(4H)-one;}

_{5-hydiOxy-2-methy!thieno[2,3-b]pyridin-8(7H)-one;} 2 _{-fluoro-6-hydroxythieno[3!2-b]pyπdin-5(4H)-one;}

_{2-flυoro-5-hydroxythιeno[2!3-b]pyridin-6(7H)-one;}

_{2-ch!oro-6-hydroxyfuro[3,2-b]pyridiπ-5(4H)-one;}

_{2-chloro-5-hydroxyfuro[2}3-b]pyridin-6(7H)-one; and}

_{2-chloro-6-hydroxythieno[3,2-b]pyridin-5(4H)-one; or} p _{harmaceutically acceptable salts of each of the foregoing.}

_{Another embodiment of the present invention of interest to the inventors relates to a group of (6-membered heteroaryl fused)-pyridin-2(1H}- ones selected from:}

_{7-fluoro-3-hydroxy-1 ,5-naphthyridin-2(1 H)-one;} 8 _{-flϋoro-3-hydroxy-1 ,β-naphthyπdin-2{1 H)-αne;} 6 _{-f!uoro-3-hydroxy-1 ,8-naphthyridin-2(1 H)-one;} 8 _{-fiuoro-3-hydroxy-1 ,5-naρhthyridin-2(1 H)-one;}

_{5-f!uoro-3-hydroxy-1 l8-naphthyridin-2(1 H)-one;} 6 _{-chloro-3-hydroxy-1,8-naphthyridin-2(1H)-one;} 8 _{-chloro-3-hydroxy-1 ,5-naphthyridin-2(1H)-one;}

_{7-chloro-3-hydroxy-1,5-naphthyridin-2(1H)-one;}

_{5-ch!oro-3-hydroxy-1,8-naphthynd!n-2(1H)-one;} 8 _{-chloro-3-hydroxy-1 ,6-naphthyricJin-2(1 H)-one; and}

_{5-chloro-6-fluoro-3-hydroxy-1 s8-naphthyridin-2(1 H)-one; or} p _{harmaceutically acceptable salts of each of the foregoing,}

_{A group of particularly interesting 4-fiuoro-(6-membered heteroaryl fused)-pyridin-2(1 H)-ones include:}

_{4-fluoro-3-hydroxy-1 ,8-naphthyridin-2(1 H)-one;}

_{4-fluoro-3-hydroxy-1 ,5-naρhthyridιπ-2{1 H)-one;} 4 _{-fluoro-3-hydroxy-1 ,6-naρhthyridin-2(1 H)-one; and} p _{harmaceutically acceptable salts of each of the foregoing. Another group of 4-f!uoro-(aryl fused)-pyrιdin-2(1H)-ones (i.e. quinolm- 2(1 H)-ones) of particular interest includes:}

_{4-fiuoro-3-hydroxy-5-methylqutinolin-2(1H)-one;}

_{4-flLOro-3-hydroxy-8-methy!quinolin-2(1H)-one;} 4 _{,7-clιf!υoro-3-hydroxyquinoiin-2(i H)-oπe;}

_{4!5-difiuoro-3-hydroxyquino!in-2(1H)-one;}

_{4,6-difluoro-3-hydroxyquino!in-2(1H)-one;}

_{4-f!uoro-3-hydroxy-2-oxo-1!2-dihydroquino!ine-5-carboni trile;}

_{4-fluoro-3- hydroxy- 2-oxo-1 ^-dihydroquinoiine-δ-carbonitrile;} 5 _{-ethyl-4-fluoro-3-hydroxyquinoiin-2{1 H)-one;} 8 _{-ethy!-4-fluoro-3-hydroxyquinolin-2(1H)-one;}

_{4>5-difiuoro-3-hydroxy-8-methylquinolin-2(1H)-one;}

_{4I8-diflυoro-3-hydroxy-5-methylquinolin-2(1H)-one;}

_{4.6-dif!υoro-3-hydroxy-5-methy!quinolin-2(1H)-one;} 4 _{J-difluoro-3-hydroxy-8-methylquinolin-2(1 H)-one;} 8 _{-chloro-4-fluoro-3-hydroxyqυinolin-2(1H)-one;}

_{5-chloro-4-fluoro-3-hydroxyquinoiin-2(1H)-one; and} p _{harmaceutically acceptable salts thereof.}

_{Other 4-f!uoro-(aryl fused)-pyridiπ-2(1H)-ones (i.e. quinolin-2(1H)-ones) of interest include:}

_{4,5,8-trifluoro-3-hydroxyquinoijn-2(1H)-one;}

_{4,5>8-trifluoro-3-hydroxyquino!in-2(1H)-one;}

_{4I7,8-trifluoro-3-hydroxyquinolin-2(1H)-one;}

_{4>6,7-trifluoro-3-hydroxyquinolin-2( 1 H)-one;} S _{-ethyi-4r7-cJifluoro-3-hycJroxyqυiπolin-2(1 H)-one;} 8 _{-ethyl-4t6-difluoro-3-hydroxyquino!in-2(1H)-one:}

_{5-ethy!-4,8-difluoro-3-hydroxyquinolin-2(1H)-one;}

_{5-chloro-4-fluoro-3-hydroxy-8-methyiquinolin-2(1H)-one;} 8 _{-chloro-4-fluoro-3-hydroxy-5-methylquinolin-2(1H)-one;} S _{-chloro-4,7-diflυoro-3-hyσroxyquino!in-2(1H)-one;}

_{5-chloro-4,6-d!fluoro-3-hydroxyquino!in-2(1H)-one; 8-chioro-4,8-dif!uoro-3-hydroxyqυino!iπ-2(1H)-one;}

_{8-chloro^^-difiuoro-S-hydroxyquinolin^CIHVone;}

_{8-chiorø-5-ethyi-4-fluoro-3-hydroxyquinolin-2(1H)-oπ� �;} 6 _{-chloro-8-ethyi-4-fluoro-3-hydroxyquino!in-2(1H)-one;} 4 _{-f!υoro-3-hydroxy-5-(tπf!uoromethyl)quinol!n-2(iH)-o� �e;}

_{4-fluoro-3-hydroxy-8-(trifiuoromethyl)quino!!n-2(1H)-on e;}

_{5.S-dichloro^-fluoro-3-hydroxyquinoiin^CIHj-one; and} p _{harmaceutically acceptable salts thereof.}

_{A group of 4-fluoro-6-membered-heteroary! fused pyridin-2(1H)-ones of particular interest include;}

_{4,7-dif!uαro-3-hydroxy-1 ^-naphthyπdin^i H)-one;}

_{4i8-difluoro-3-hydroxy-1 s5-naphthyridin-2(1 H)-one;}

_{4,5-difluoro-3-hydroxy-1 !8-naphthyridin-2(1 H)-one;}

_{4,8-difluort>3-hydroxy-1 ,8-naphthyridin-2(1 H)-one;} 8 _{-chloro-4-fiuoro-3-hydroxy-1 ;5-πaphthyτidin-2(1 H)-one;}

_{8-chioro-4-fluoro-3-hydroxy-1,6-naphthyridin-2(1H)-one; and} p _{harmaceutically acceptable salts of each of the foregoing.}

_{Other fluoroquinolin-2(1 H)-ones of interest to the inventors include;}

_{7-fluoro-3-hydroxy-8-methylquinolin-2(1H)-one;} 8 _{-fluoro-3-hydroxy-5-methylqumoiin-2(1 H)-one;} 6 _{-fluOro-3-hydroxy-8-methylquinolin-2(1H)-one;} 6 _{-fluoro-3-hydroxy-5-methy!quino!in-2(1H) one;}

_{7-fluoro-3-hydroxy-5-methylquinoHn-2(1H)-one;}

_{5-fluoro-3-hydroxy-8-methylqufno!in-2(1H)-one;} 6 _{;7-d}fluoro-3-hydroxyqυinolin-2(1H)-one;}

_{5,8-difluoro-3-hydroxyquisiolin-2(1H)-one;}

_{7,8-difluoro-3-hydroxyqu}noiin-2(1H)-one;}

_{5,8-difluoro-3-hydroxyquinolin-2(1H)-one;}

_{5,7-difluoro-3-hydroxyquinoi!fv2{1H)-one;} 6 _{,8-difluoro-3-hydroxyquiπolin-2(1H)-one;}

_{8-ethyl-7-fluoro-3-hydroxyquinolfn-2(1H)-αne; 5-ethyl-8-fluoro-3-hydroxyquιnolin-2(1H)-one;}

_{5-ethy!-6-fluoro-3-hyclroxyquinoiin-2(1H)-one;}

_{5-ethyl-7-fluoro-3-hydroxyquinolin-2(1H)-one:} 8 _{-ethyl-6-fluoro-3-hydroxyquinolin-2(1 H)-one; and} p _{harmaceutically acceptable salts of each of the foregoing.}

_{Mitriie qυino!in-2(1H)-ones of interest to the inventors include:}

_{3-hydraxy-2-oxo-1,2-dihydroquinoiinβ-8-carbonitriie;}

_{S-hydroxy^-oxQ-i^-dihydroquinoline-β-carbonitrile,}

_{3-hyϋroxy-2-oxo-1,2-dihydroqυinoline-5-carbonitrile;} 3 _{-hyαroxy-2-oxo-1,2-dihydroquinoline-7-carbonitrile;}

_{7-fluoro-3-hydroxy-2-oxo-1.2-dihydroquino!ine-6-carboni friie:}

_{7-fluoro-3-hydroxy-2-oxo-1!2-dihydroquiπo!ine-8-carbo� �itrile:}

_{7-ftuoro-3-hydroxy-2-oxo-1,2-dihydroquinoiine-5-carboni tri!e; 6-fluoro-3-hydroxy-2-oxo-1l2-dihydroquinoiine-7-carboni trile, 5-flϋoro-3-hydroxy-2-oxo-1!2-dihydroquinoiine-7-carbon itrile: 8-f!uoro-3-hydroxy-2-oxo-1,2-dihydroquinoiine-5-carboni trile; 8-fiuoro-3-hydroxy-2-oxo-1.2-dihydroquinoi!ne-6-carboni trile; θ-fluoro-S-hydroxy^-oxo-i^-dihydroquinoline-δ-carboni trile; 6-fluoro-3-hydroxy-2-oxo-1.2-dihydroquino!ine-8-carbon� �trile; 5-flαoro-3-hydroxy-2-oxo-1.2-dιhydroquinoiine-8-carbo nitrile:}

_{5-fluoro-3-hydroxy-2-oxo-1.2-dihydroquino!ine-6-carboni trile; 8-fluoro-3-hydroxy-2-oxo-1,2-dihydroquino!ine-7-carboni tri!e; 6-chlorO-3-hydroxy-2-oxo-1.2-dihydroQuinoiine-8-carboni trile;}

_{5-chloro-3-hydroxy-2-oxo-1,2-dihydroquinoiιne-7-carbon itrile; 7-ch!oro-3-hydroxy-2-oxo-1!2-αihydroqυino!iπe-5-carb oπitrile;}

_{5-ch!oro-3-hydroxy-2-oxo-1:2-dihydroquinoline-8-carboni trile;}

_{T-chloro-S-hydroxy^-oxo-i^-dihydroquinoline-S-carbonifr ile; 8-chbro-3-hydroxy-2-oxo-1,2-dihydroquinolinβ-7-carboπ itrile;}

_{5-chloro-3-hydroxy-2-oxo-1.2-dihydroquino!ιnθ-6-carbo nιtrilθ; 8-chloro-3-hydroxy-2-oxo-1:2-dihydroquinoiine-5-carboni trite; 6-chloro-3-hydroxy-2-oxo-1:2-dfhydroquinal!ne-5-carbani tri!e; and 8-chloro-3-hydroxy-2-oxo»1.2-dihydroquinoiine-6-carbonitri! e; and} p _{harmaceutically acceptable salts thereof.}

_{A group of chloro-quinolin-2(1H)-one$ of interest to the present inventors includes:} 6 _{-chloro-3-hydroxy-8-methy!quιπolin-2(1 H)-one.}

_{5-chloro-3-hydroxy-8-methylquinolin-2(1H)-one:}

_{5-chloro-3-hydroxy-7-methy!quinolin-2{1H)-αnβ:} 8 _{-chloro-3-hydroxy-5-methy!quinαlin-2(1H)-one;} 6 _{-chloro-3-hydroxy-5-methyiquinolin-2(1H)-one,} 7 _{-chloro-3-hydroxy-δ-methyiquinolin-2(1 H)-one;} 8 _{-chloro-7-fiuoro-3-hydroxyquinolin-2(1H)-one;} 8 _{-ch!oro-6-fluoro-3-hydroxyquinolin-2(1H)-one;} 6 _{-chioro-5-fluoro-3-hydroxyquinolin-2(1H)-one;} 8 _{-chloro-5-fiuoro-3-hydroxyqυinolin-2(1H)-one;} 5 _{-chloro-8-fluoro-3-hydroxyquinolin-2(1H)-one;}

_{7-chloro-8-fluoro-3-hydroxyqυinolin-2(1H)-one;}

_{7-chloro-5-fluoro-3-hydroxyquinohn-2(1H)-one;} 6 _{-chloro-8-fluoro-3-hydroxyquinolin-2(1H)-one;}

_{5-chloro-7-fluoro-3-hydroxyquinolin-2(1H)-one;} 7 _{-chloro-5-θthyl-3-hydroxyquιnolιn-2(1 H)-oπe;}

_{5-chloro-8-ethyl-3-hyύroxyqυinolin-2(1H)-one;} 6 _{-chbro-8-ethy!-3-hydroxyquino!in-2(1H)-one;} 8 _{-chloro-5-ethyl-3-hyrfroxyquinolin-2(1H)-one;} 6 _{-chloro-5-ethy!-3-hydroxyquinolin-2(1H)-one;} 5 _{,8-dichloro-3-hydroxyquinoiin-2(1 H)-oπe;} 6 _{,8-dichlOfO-3-hydroxyQuinolirj-2(1 H)-one; and} p _{harmaceutically acceptable salts thereof.}

_{A group of trifluoro-quinolin-2(1H)-ones of interest to the present inventors includes1} 3 _{-hydroxy-5-(trifluoromethyl)quinolin-2(1H)-one;}

_{3-hydroxy-8-(trifluoromethyl)quino!in-2(1H)-one; 6-fluoro-3-hydroxy-8-(trifluoronnethyl)quinoiin-2(1 H )-one;} 8 _{-fluoro-3-hyd roxy-5-(trif!uoromethyl)quinoiin-2(1 H)-one;}

_{5-fiuoro-3-hydroxy-8-(trifluoromethyl)quinoiin-2(1 H)-one;} 6 _{-flLOiO-3-hydroxy-5-(trifluoromethyl)quinoiin-2(1 H )-one;} 7 _{-fluoro-3-hyd roxy-5-(trιf!υoromethyl)quinoiιn-2ti H )-oπe;}

_{7-flυoro-3-hyd roxy-8-(trifiuoromethyI)quinoiin-2(1 H )-one;} 6 _{-chloro-3-hyd roxy-8-(trifluoromethyl )quinoiin-2( 1 H)-one;}

_{5-chloro-3-hyd roxy-6-(trtf!ϋoromethyl)quinoiin-2( 1 H)-one;}

_{5-chloro-3-hyd roxy-8-(trifluoromethyl)quinoiin-2( 1 H)-one;} 8 _{-chloro-3-hyd roxy-δ-(trifiuoromethyljquino!in-2( 1 H )-one;} 8 _{-chloro-3-hyd roxy-6-(trifluoromethyl)quino!in-2( 1 H)-one; a nd}

_{7-ch!oro-3-hyd roxy-5-(thf!uoromethyl)quinoiin-2( 1 H)-one; a nd} p _{harmaceutica lly acceptable salts thereof.}

_{As used herein, the phrase "the compounds of the invention" includes the general and specific compounds, including examples d iscussed herein and pharmaceutically acceptable salts thereof. If will aiso be understood that the phrase "compounds of the invention and pharmaceutically acceptable sait(s) thereof aiso encompasses the pharmaceutically acceptable hydrates, solvates, and tautomers of the compounds described herein and below and pharmaceutically acceptable salts thereof.}

_{The phrase "pharmaceutically acceptable SaIt(S)", as used herein, unless otherwise indicated , includes salts of acidic or basic groups which may be present in the compounds of the present invention. The compounds of the present invention that are basic in nature are capable of form ing a wide variety of salts with various inorganic and organic acids, The acids that may be used to prepare pharmaceutically acceptable acid add ition salts of such basic compounds are those that form non-toxic acid add ition salts, i.e., salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobrσmide, hydroiod ide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isαnicøtinate, acetate, lactate, sa licylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinste, fυmarate, gluconate, giucυronai e, saccharate, formate, benzoate, glutamate, methanesuifonate, ethanesulfonate, benzenesulfonate, p-to!uenesuifonate and pamoate [i.e. , 1 ,1 '-methyiene-bis-(2-hydroxy-3-naphthoate)] salts, The compounds of the present invention that include a basic moiety, such as an amino group, may form pharmaceutically acceptable salts with various amino acids, in add ition to the acids mentioned above.}

_{The invention also relates to base add ition salts of the compounds of the invention. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of the compounds of the invention that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmaceutically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolamrnonium and other base salts of pharmaceutically acceptable organic amines.}

_{Suitable base salts are formed from bases which form non-toxic salts. Non-limiting examples of suitable base salts include the a luminum, arginine, benzathine, calcium, choline, d iethylamine, d iolamme. glycine, lysine, magnesium, meglumine, oiamine, potassium , sod ium, fromefha mine and zinc salts.}

_{Hemisaits of acids and bases may also be formed , for example, hemisulphate and hemicalcium salts.} F _{or a review on suitable salts, see Ha nd book of Pharmaceutical Salts:}

_{Properties, Selection, and Use by Stahl and Wermuth (Wiley- VCH 1 2002). Methods for making pharmaceutically acceptable salts of compounds of the invention are known to one of skill in the a rt.}

_{The compounds of the invention may also exist in unsoivated and solvated forms. Thus, it will be understood that the compounds of the invention (and pharmaceutica lly acceptable salts thereof) also include hydrates and solvates of said compounds of the invention (and pharmaceutically acceptable salts thereof) as d iscussed below.}

_{The term "solvate" is used herein to describe a noncovalent or easily reversible combination between solvent and solute, or dispersion mea ns and d isperse phase. It will be und erstood that the solvate can be in the form of a solid , slurry (e.g., a suspension or d ispersion), or solution. Non-limiting examples of solvents include ethanol , metha nol , propanol , acetαnitrile, d imethyl ether, d iethyl ether, tetrahydrofuran. methylene chlorid e, and water.}

_{The term 'hydrate' is employed when said solvent is water.} A _{currently accepted classification system for orga nic hyd rates is one that defines isolated site, channel or meta l-ion coordinated hydrates - see}

_{Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed , H , G. Bhttain, Marcel Dekker, 1995). isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hyd rates , the water molecules lie in lattice channels where they are next to other wafer molecules , In metai-ion coordinated hydrates, the water molecules are bonded to the metal ion.}

_{When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independ ent of humid ity. When, however, the solvent or water is weakly bound , as in channel solvates a nd hygroscopic compounds, the water/solvent content will be dependent on humidity and d rying cond itions. In such cases, non-stoichiometry will be the norm.}

_{Also included within the scope of the invention are metabolites of compounds of the invention, that is, compounds formed in vivo upon administration of the drug. Some examples of metabolites in accordance with the invention include;} ( _{i) where the compound of the invention contains a methyl group, an hyd roxy rnethyi derivative thereof (e.g., -CHs -> --CH2QΗ);}

_{(ii ) where the compound of the invention contains a n alkoxy group, an hyd roxy derivative thereof (e.g,, -OR: -> -OH );} ( _{iii ) where the compound of the inventions is an N-oxid e, e.g.;} wherein R is as defined above.

The compounds of the invention may exist in several tautomeric forms, including the enol and imine form, and the keto and enamine form and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of the present invention, Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautαmer predominates, Even though one tautomer may be described, the present invention includes all tautomers of the present compounds. By way of example, the compound 7-fluoro-3-hydroxyquino)irv2(1H)-one (1 ). which is exemplified in Example 1 , may exist in the following tautomeric forms:

The present invention also includes isotopically-labeled compounds, which are identical to those recited in formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to, ² H. ³ H ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ¹⁸ F, and ³⁶ Ci, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.

Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as ³ H and ¹⁴ C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, Le., _{Η and carbon-14 , i.e.. '4C, isotopes are particularly preferred for their ease of preparation and detectabiiity. Further, substitution with heavier isotopes such as deuterium, i.e. , 2H , can afford certain therapeutic adva ntages resulting from greater metabolic stability, for example increased in vivo ha If- life or red uced dosage requirements and , hence, may be preferred in some circumstances. Isotopically-iabeled compounds of this invention and prod rugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically-iabeled reagent for a non-isotopically-iabeled reagent.} I _{n one embod iment, the invention relates to compositions comprising a compound of the invention and at least one additional ingredient (hereinafter "the compositions of the invention"). It will be understood that the compositions of the invention will encompass any combination of the compound of the invention and the at least one add itional ingred ient. Non- limiting examples of the at least one add itional ingredient include impurities (e.g. , intermed iates present in the unrefined compounds of the invention), active ingred ients as discussed herein (e.g., a n additional d rug or active agent), pharmaceutically acceptable excipients, or one or more solvents (e.g. , a pharmaceutically acceptable carrier as d iscussed herein).} T _{he term "solvent" as it relates to the compositions of the invention includes organic solvents (e.g., methanol, etha nol, isopropanol, ethyl acetate, methylene chloride, and tetrahyd rofυran ) a nd water. The one or more solvents may be present in a non-stoichiometric amount, e.g ., as a trace impurity, or in sufficient excess to d issolve the compound of the invention. Alternatively, the one or more solvents may be present in a stoichiometric amount, e.g. , 0.5: 1 , 1 : 1 , or 2: 1 molar ratio , based on the amount of compound of the invention.}

_{Sn one embod iment, at least one add itional ingred ient that is present in the composition of the invention is an organic solvent.} I _{n another embod iment, at least one additional ingred ient that is present in the composition of the invention is water. In one embod iment, at least one add itional ingred ient that is present in the composition of the invention is a pharmaceutica lly acceptable carrier.}

_{Sn another embod iment, at least one additional ingred ient that is present in the composition of the invention is a pharmaceutically acceptable excipient.}

_{Sn one embodiment, the composition of the invention is a solution .} S _{n another embod iment, the composition of the invention is a suspension.}

_{Sn another embod iment, the composition of the invention is a solid .} S _{n yet another embod iment, the invention relates to a composition comprising an effective amount of the compound of the invention, and a pharmaceutically acceptable carrier.}

_{Sn another embodiment, the invention relates to a composition comprising a therapeutically effective amount of the compound the invention as defined above, a pharmaceutically acceptable carrier and , optionally, at least one add itional med icinal or pharmaceutica l agent.}

_{Detailed Description of the Invention}

_{The compounds of the invention can be prepa red by one or more of the proced ures generally described in Schemes 1 to 7 below and in the Examples section.}

_{Compounds of formula i s wherein ring "A" is a n optiona lly substituted fused phenyl rad ical or an optionally substituted 5 or 6 membered heteroaryl rad ical; R is hyd rogen, (C rC2)alkyl, (C rCs)alkoxy, trifiuoromethyl or halo; and n is an integer from zero to three; may be prepared from aromatic (i.e. ring '-A" is optionally substituted phenyl) or heteroaromatic (i.e. ring "A" is optionally substituted heteroaryl) aminoaldehydes IH as shown in Scheme 1 . Scheme 1}

_{The anion of ethyi methoxyacetate, prepared by treatment with a base. for instance lithium bis(thmethylsilyl)amide or lithium d iisopropylamide. can be reacted with a compound of Formula HI to generate a compound of formula il .}

_{In some cases it is advantageous to treat the crude reaction prod uct with acid , for example hyd rochloric acid, at temperatures ranging from about 250C to reflux. Demethylation of the compound of Formula i l provides the compound of Formula I; this can be effected by a variety of method s fa miliar to those skilled in the art, and is frequently carried out through the action of boron tribromide.}

_{The requisite aminoaidehydes IH are often commercially available, or can be prepares in a straightforward manner from rβlateα materials such as the correspond ing carboxylic acid , carboxylic ester or alcohol a s shown in Scheme 3 below.}

_{Substituted isatins can also be used to prepare certain compounds of formula I (i.e. l(a) wherein ring "A" is the fused optionally substituted phenyl rad ical), as depicted in Scheme 2.}

_{Scheme 2}

_Ia

_{Treatment of isatin V {e.g. , a substituted 1 H-indoie-2,3-d ione wherein R is independently selected from hydrogen, chloro, fluoro, aikyl, trifluoromethyl or alkoxy and n is an integer from zero to three) with ethyl diazoaeetate and an amine base, generally d iethylamine, followed by subjection to acid , generally hydrochloric acid , provides a compound of formula IV, as described in S-Y. Sit et al.r Bioorganic Medicinal Chemistry Letters 1996. 6, 499-504. An alternative proced ure employs ethyl diazoacetate and zinc chloride, as detailed in MJ. Fray et a!,, Medicinal Chemistry Research 1996, 6, 581 -592. Hydrolysis of the compound of formula JV, for instance with lithium hyd roxide or sod ium hyd roxide, can be carried out under therma l or microwave cond itions, resulting in decarboxylation and formation of a compound of Formula i (a). See S-Y. Sit et a!. , op. cif. and M J. Fray et a!. , op. cit. The compound of formula V can also be converted to a compound of Formula I(a) through treatment with (tnrnethylsιryl)d iazomethane, as described in Example 2 below.} M _{any isatins are commercially available. Those that a re not may be prepared by literature methods. See P. Hewawasa m and N . A. Meanwell, Tetrahedron Letters 1994, 35, 7303-7306, and references conta ined therein. Scheme 3 refers to the preparation of certain intermediates useful in the preparation of compounds of Formula I in Scheme 1 above}

R _{eferring to Scheme 3, red uction of a compound of Formula VII, wherein ring "A" is an optionally substituted phenyl rad ical or a n optionally substituted 5 or 8 membered heteroaryl rad ical; R is hydrogen , (C rCsJalkyL (C rC2)alkoxy, trifiuoromethy! or halo; and n is an integer from zero to three to an alcohol of Formula Vl , wherein ring "A" is an optionally substituted phenyl rad ical or an optionally substituted 5 or 6 membered heteroaryl rad ical: R is hydrogen, (C rC*)alky!, (CrC -)a!koxy, trifluorσmethy! or halo; a nd n is an integer from zero to three can be carried out with numerous reagents known to those skilled in the art; the choice of reagent d epends on what other functionality is present in the molecule. One useful reagent for this transformation is lithium aluminum hyd ride. Oxidation of the alcohol of Formula VI to the aldehyde of Formula IiI, wherein ring "A" is an optionally substituted phenyl radical or an optionally substituted 5 or 6 membered heteroaryl radical; R is hyd rogen, (Ci-Cϊ)a lky! , (C rCiOalkoxy, trifiuoromethy! or halo; and n is an integer from zero to three can a lso be carried out via a number of methods, for instance treatment with manganese(iV) oxide.}

_{Aromatic or heteroaromatic ottho-bromo aldehydes can also be used to prepare compounds of Formula I. as outlined in Scheme 4, Scheme 4}

_{Referring to Scheme 4, replacement of the bromine atom in a compound of Formula Xl , wherein ring "A" is an optionally substituted phenyl rad ical or an optionally substituted 5 or 6 memberecl heteroaryl rad ical: R is hydrogen, (C rC2)alkyl. (CrC^)a Ikoxy, trifluoromethyl or halo; a nd n is an integer from zero to three, by a protected amine equivalent, such as terf-butyl carbamate, can be carried out through a coupling reaction , for "instance employing a palladium catalyst, such as tr!s(dibenzylideneacetone)d ipa!lad ium(0>-chioroform adduct, a nd a ligand such as Xantphos. See, for example, J. Yin and S. L. Buchwald , Organic Letters 2000. 2, 1 101 -1 104. Reaction of the prod uct aldehyde of Formula X with ethyl methoxyacetate, as described a bove for Scheme 2, affords a compound of Formula IX, which can be dehydrated and deprαtected to form a compound of Formula VIIl 1 for instance by mild treatment with boron tribromide, as described in Example 19 below. Ring closure to the compound of Form ula H occurs upon exposure to base, for example lithium bis(trimethyisilyl)amide.}

_{Alternatively, a compound of Formula Xi , wherein ring "A" is an optionally substituted phenyl radical or an optionally substituted 5 or 6 membered heteroaryi radical; R is hyd rogen, (C-rCsJalkyl, (C rC^Jalkoxy, trifluoromethy! or halo; and n is an integer from zero to three, can be reacted with 2-methoxyacetamide under coupling cond itions similar to those described for synthesis of Formula X above, to afford a compound of Formula XH; see also PJ , Manley and M.T. Bilodeaυ, Organic Letters 2004, β, 2433-2435, Ring closure to a compound of Formula I! is carried out through exposure to base, for instance use of potassium ferf-butoxide at about 700C. Conversion of a compound of formula SI to a compound of formula I can be ca rried out as described above.} B _{romoaldehydes of formula Xl can be prepared from the corresponding carboxylic acid , ester or alcohol, in similar fashion to the chemistry depicted in Scheme 3.}

_{Construction of compounds of Formula ia (i.e. ring "A" is fused phenyl) can also be achieved from an ortho-n'Λro toluene sta rting material , as depicted in Scheme 5.}

_{Scheme 5}

_{Referring to Scheme 5, reaction of a nitrotoluene of Formula XVi With d iethyl oxalate and sod ium ethoxide provides a compound of Formula XV, which can be protected with ethylene glycol under acid ic conditions, such as with para-toluenesulfonic acid , to give a compound of Formula XIV. Red uction of the nitro group, for instance with Raney nickel, tin(lf ) chloride or iron/hyd rochloric acid , is followed by intramolecular cyclization to afford a compound of Formula XIII. Subjection of a compound of Formula XIH to acidic cond itions, generally hyd rochloric acid at temperatures of 60-900C, then provides a compound of formula Ia.}

_{Introd uction of substituents at the 4-positιon of the hyd roxypyridone ring into a compound of Formula I (i .e. wherein one of said R is a substituent on the pyrid ine ring) can be effecteα in several ways, depending on the identity of the 4-substιtuent. as shown in Scheme 6.}

_{Referring to Scheme 6, where the desired 4-substιtυent is a n a!ky! group, a compound of Formula l (b) can be prepared from the aminoketone of Formula XVi H , in s manner analogous to preparation from aminoaldehyde of}

_{Formula III in Scheme 1 . A compound of this type is exemplified in Example}

_{1 8.}

_{4-Fluoro compounds of the formula 1 (C) can be generated from the correspond ing trifluoromethyl starting materia l of Formula XX, following the general method of A.S. Kiselyov et a!., Organic Letters 2004, 6, 4061 -4063. Once again, as in Scheme 1 . the anion of ethyl methoxyacetate is employed , reaction with a compound of Formula XX provides fiuoro-substituted intermed iate of Formula XIX, which is then transformed into a compound of Formula l(c). Where a chlorine or bromine atom is d esired at the 4-posιtιon, a d ifferent approach is employed , using the methodology of S-Y. Sit et a!.. Bioorganic Medicinal Chem. Lett. 1996, 6, 499-504. Treatment of a des-halo congener of Formula I (i.e. the pyridone ring is unsubstituted at the 4 position) with W-chlorosuccinimide or Λ/-bromosuccιnimide provides the corresponding halogenated material l (d ), wherein R1 is ehloro or bromo.}

_{Introd uction of substituents on the fused aryl or heteroa ryl ring can be effected after preparation of compounds of formula I (and Ia , Ib, Ic and Id ) as described herein above and in the Examples describee herein below by using a protecting group for the alpha-hyd roxy carbonyl system, as shown in Scheme 7,}

_{Scheme 7}

C _{ompounds of formula J, wherein at least one R is bromine ana the remaining R radicals are H . (C 5-Cs)alky!, trifiuorαmethyl, chloro or (C 3- C?)alkoxy; can be protected by reaction with d ibromomethane or (d ibromomethyl)benzene. m the presence of a base, for instance potassium carbonate or cesium fluoride, to provide a compound of formula XXi , wherein R^ is hydrogen or phenyl. The bromine substituent of XXI can then be converted to a number of other functional groups through methods known to those skilled in the art. Replacement of bromine by a cyano group can be effected through pallad ium-catalyzed cyanation; see J . Ramna uth et al.. Synlett 2003, 2237-2239 and references cited therein . The bromine substftuent can be replaced by methyl or ethyl through a Negishi-type coupling with d imethylzinc or d iethylzinc. according to the general proced ure of JΛ1 Herbert, Tetrahedron Letters 2004, 45, 817-819. Introd uction of an aldehyde can be carried out by lithium-halogen exchange using an organolithium reagent such as n-butyllrthium or ferf-butyllithium, followed by reaction with dimethylformamide. Compounds of the Formula XXI can then be converted to the compound of Formula I, wherein one R is -CN . methyl , Ethyl and -CHO by deproteciion using, for exa mple, boron iribromide or an acid such as hydrochloric acid .}

_{Introd uction of functional groups onto the phenyl ring of compound of Formula I can also be accomplished in the absence of a bromine. Nitration of the aryl or heteroary! ring in a compound of Formula XXI is earned out, for instance through reaction with nitric acid and sulfuric acid . Conversion of the nitro group to a halogen atom can be effected through reduction of the πstro group Xo an amino group, followed by, for exa mple, d iazotization and subsequent Sandmeyer reaction to provide a compound of Formula XXI, wherein one of said R is chlorine or bromine. Diazotization in the presence of fluoroboratβ, followed by thermal decomposition (the Balz-Schiemann reaction) yields a compound of Formula XXI wherein one of said R is fluorine, As noted above, the compounds of the invention are useful for treating d isorders in a patient such as a mammal, preferably a human. Non-limiting examples of d isorders that may be treated with a compound of the invention include cognitive-related disorders and disorders associated with neuropathic pain.}

_{In one embod iment, the invention relates to a method of treating a cognitive-related d isorder comprising administering a therapeutically effective amount of a compound of the invention to a patient in need thereof.}

_{This invention also relates to a method of treating a disorder or cond ition selected from psychosis, -schizophrenia , cond uct disord er, d isruptive behavior d isorder, bipolar d isorder, psychotic episod es of a nxiety, anxiety- associated with psychosis, psychotic mood disorders such as severe major depressive d isorder; mood d isord ers associated with psychotic d isorders such as acute mania or depression associated with bipolar d isorder and mood d isorders associated with schizophrenia, behavioral manifestations of mental retardation, conduct d isorder and autistic disorder; movement disorders such as Tourette's syndrome, akinetic-rigid syndrome, movement d isorders associated with Parkinson's disease, tard ive dyskinesia and other d rug induced and neurodegeneratson based d yskinesias; attention deficit hyperactivity disorder, cognitive d isorders such as dementias ( including age related dementia, and senile dementia of the Alzheimer's type) and memory d isorders in a mammal, includ ing a human , comprising ad ministering to a mammal sn need of such trestment an amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, that is effective in treating such cond ition or disorder.}

_{Sn another embod iment, the invention relates to a methoα of treating a d isorder or condition selected from psychosis , schizophrenia , bipola r disorder, psychotic episodes of anxiety, anxiety associated with psychosis , psychotic mood disorders such as severe major depressive disorder; mood d isorders associated with psychotic d isorders such as acute ma nia or depression associated with bipolar disorder and mood d isorders associated with schizophrenia, cognitive d isorders such as dementias (including age related dementia, and senile dementia of the Alzheimer's type), memory d isord ers and any combination thereof.}

_{In another embodiment, the compounds of the invention are useful for a treating child hood learning d isorders such as Developmental a rticulation d isorder. Developmental expressive language d isorder, Developmental receptive language disorder. Developmental reading d isorder (such as dyslexia). Developmental writing disorder. Developmental arithmetic disorder and Attention d isorders (such as ADH D),}

_{In another embod iment, the compounds of the invention are useful for treating benign forgetfuiness .}

_{Sn another embod iment, the invention relates to a method of treating a d isorder associated with neuropathic pain comprising ad ministering a therapeutically effective amount of a compound of the invention to a patient in need thereof.}

_{The term "treating", as used herein, unless otherwise ind icated , means reversing, alleviating, inhibiting the progress of, or preventing the d isord er or cond ition to which such term applies, or one or more symptoms of such d isorder or condition. The term "treatment", as used herein, unless otherwise indicated , refers to the act of treating as "treating" is defined immediately above. The term "treating" aiso includes adjuvant and neoadjuvant treatment of a subject.}

_{As used herein, the phrase "neuropathic pain" refers to pa in , typically chronic in d uration, initiated or caused by a primary lesion or dysfunction in the nervous system . Nerve damage can be caused by trauma and d isease and thus the term 'neuropathic pain' encompasses many d isorders with d iverse etiologies. These include, but are not limited to, peripheral neuropathy, diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia , back pain, cancer neuropathy, H IV neuropathy, pha ntom limb pa in , carpal tunnel synd rome, central post-stroke pa in and pain associated with chronic alcoholism , hypothyroid ism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy and vitamin deficiency. Neuropathic pain is pathological as it has no protective role. It is often present well after the original ca use has d issipated , commonly lasting for yea rs, significa ntly decreasing a patient's quality of life. The symptoms of neuropathic pain include spontaneous pain, which can be continuous, and paroxysma l or abnormal evoked pain, such as hyperalgesia (increased sensitivity to a noxious stimulus), ailodynia (sensitivity to a normally innocuous stimulus), shooting burning pain, and tingling a nd numbness. The diagnosis of neuropathic pain generally requires a complete med ical history that includes a careful description of symptoms and a physical examination .}

_{JJlVI?IQAssay, s.}

_{The in vitro activity of the compounds of the invention may be determined by the following proced ures.} D _AAO;

_{DAAO assays are known in the literature. One DAAO assay that can be used to demonstrate the activity of the compound s of the invention is based on the measurement of H5Oj1 one of the products of the action of DAAO on the amino acid substrate of interest, serine. Amplex Red (f nvitrαgen Life Science # A- 1 2222) is used in a coupled reaction a long with horseradish peroxidase (Sigma # P-8250) to produce a product, Resorυfin, which ca n be monitored via fluorescence.} i _{nhibitor compound s are d iluted in 100% DMSO starting at 4 mM in half log increments to create an 1 1 -point dose response by the Pfizer Material Management Group. Each d ilution is spotted in d uplicate, 0,5 microliters/well, into black 384 well plates (Costar #3573). No inhibition control wells (ZPE) are spotted with 0.5 microliters of 100% DMSO and 1 00% inhibition control wells (H PE) are spotted with 0.5 microliters of 4 mM 3-hydroxyquinolin-2(1 H)- one in 1 00% DMSO. Twenty microliters of assay buffer (10OmM Tris-HCL, pH 8.5) containing 4 nM human DAAO enzyme expressed in sfθ insect cells (produced and purified in-house), 80 uM flavin adenine d inucleotide (Sigma #F8625), 0.8 units horserad ish peroxidase (Sigma #P8250), and 100 uM Amplex Red (Molecular Probes #A12222) were added to each well of the plate using a Titertek MuitiDrop-384 reagent addition device, Next, twenty microliters of assay buffer containing 200 uM D-Serine (Sigma #84250) was added using the MυitiDrop. The plates are spun at 1 ,000 rpm to ensure ail liquid is coalesced to the bottom of the well. Exposure of Amplex Red to light must be kept to a minimum . The reaction is then incubated in the dark at ambient temperature for 30 - 60 minutes before read ing the plates on a PerkinElmer Envision 21 03 Mυitiiabe! Reader using the following settings: 1 0 flashes of the flash lamp, excitation filter 530 nm, emission filter 590 nm. The mean of the plate HPE and ZPE control values a re used to calculate % inhibition values for each compound well in SIGHTS (an in-house data analysis software package) and non-linear curve fitting is used to calculate an IC50 value for each compound .}

_{Applying the above assay to the compou nds of the invention provid es the data reported in Table 1 .}

_{The compounds of this invention can be ad ministered via either the oral, parenteral (such as subcutaneous, intravenous, intramuscular, intrasternal and infusion techniques), rectal, intranasal or topicai routes to mammals. In general, these compounds are most desirably administered to humans in doses ranging from about 1 mg to about 2000 mg per day, although variations will necessarily occur depend ing upon the weight and condition of the subject being treated and the particular route of administration chosen. However, a dosage level that is in the range of from about 0 1 mg to about 20 mg per kg of body weight per day is most desirably employed . Nevertheless, variations may still occur depending upon the species of animal being treated and its individual response to sa id med icament, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects provided that such higher dose levels are first divided into several small doses for administration throughout the day. The pharmaceutical composition may, for example, be in a form suitable for oral ad ministration such as a tablet, capsule, pill, powder, sustained release formulations, solution, or suspension: for parenteral injection such as a sterile solution, suspension or emulsion; for topical ad ministration such as an ointment or cream; or for rectal administration such as a suppository. The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages. The pha rmaceutical compo sition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingred ient, in addition, it may include other med icinal or pharmaceutical agents, carriers, adjuvants, etc.}

_{In one embodiment, the pharmaceutical composition of the invention is in a form suitable for oral administration.}

_{Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered , if desired .}

_{Suitable pharmaceutical carriers include inert d iluents or fillers, water and various organic solvents. The pharmaceutical compositions may, if desired , contain add itional ingredients such as flavorings, binders, excipients and the like. Thus for oral administration, tablets containing various excipients, such as citric acid may be employed together with various disiπtegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate. sod ium lauryl sulfate and talc a re often useful for tabieting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Preferred materials, therefore, include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and , if desired , emulsifying agents or suspend ing agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.} M _{ethods of preparing various pharmaceutical compositions with a specific amount of active compound are known, or will be apparent, to those skilled in this art. For examples, see Remington's Pharmaceutical Sciences} M _{ack Publishing Company, Easter, Pa., 1 5th Ed ition ( 1375).}

_{The compounds of the invention may be ad ministered in combination with one or more add itional medicinal or pharmaceutical agents ("the additional active agent"). Such use of compound s of the invention in combination with an add itional active agent may be for simulta neous, separate or sequential use.}

_{In one embodiment, the compounds of this invention are administered as adjunctive therapy with antipsychotics such as Ziprasidone (Geodon), molindone, loxapine, risperidone, olanzapine, quetiapine, aripiprazole, paliperidone, 2yrrexa, bifeprunox, vabicaserin, ispronicline, sertindole, amisulpride, prochlorperazine, fluphenazine, trifluoroperazine, thioridazine, haioperidoi, chioropromazine, flupentixoi, pipotiazine, clozapine, ana pimozide. In another embodiment, the compounds of the present invention may also be used in combination with CNS agents such as antidepressants (such as sertraline), antiparkinsonian drugs (such as deprenyi, L-dopa , Requip, Mirapex, MAOB inhibitors such as seiegine a nd rasagiiine, com P inhibitors such as Tasmar. A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, Nicotine agonists, Dopamine agonists and inhibitors of neuronal nitric oxide synthase), anti-Alzheimer's drugs such as donepeziϊ, tacrine. α.2δ inhibitors, COX-2 inhibitors, gaba pentenoids, prαpentofylline or metryfonate, and antipyschotics such as PDE1 0 inhibitors, 5HT2C agonists , a lpha 7 nicotinic receptor agonists, CB 1 antagonists and compounds having activity antagonizing dopamine D2 receptors.} I _{n another embod iment the compounds of the invention are administered as adjunctive therapy with Alzheimer's thera peutics includ ing donepezil, rivastigmine, galantamine, memantine; d imebon, immunotherapeutics (such as bapineuzumata. LY 2062430. gammagard , ACC-001 , R 1450, GSK 9337785 and CAD 106); secretase inhibitors (such as LY 4501 39, tarenfiurbii, fvi -0752 (Merck); S-1 953 (VVyeth)) and Rage inhibitors (such as PF-04499742 and PF-04494700). In one embodiment, the one or more add itiona l active agents, when used , are administered prior to administration of the compounds of the invention. In another embod iment, the one or more add itional active agents, when used , are administered after administration of the compounds of the invention. In another embodiment, the one or more additional active agents, when used , are ad ministered at about the same time as administration of the compounds of the invention- The additional active agent may be administered by any route useful to administer said add itional active agent} I _{n one embodiment, the one or more additional active agents are present in the pharmaceutical composition of the invention. Accordingly, in another embodiment, the invention relates to a method of treating a patient with a pharmaceutical composition of the invention further comprising one or more additional active agents.} T _{he examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations.} A _{ll patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference in their entireties.}

_{Exam ples} E _{xperiments were generally carried out under inert atmosphere (nitrogen or argon), particularly in cases where oxygen- or moisture-sensitive reagents or intermed iates were employed . Commercial solvents and reagents were generally used without further purification . Chemical shifts for nuclear magnetic resonance (NMR) data are expressed in parts per million (ppm, 6) referenced to resid ual peaks from the deuterated solvents employed . Exampie 1} 7 _{-fluoro-3-hvdroxvquinolin-2{1H)-one}

T _{he title compound was prepared by the procedure depicted Sn}

_{Scheme 1 and described in detail below, using the general method of S-Y. Sit et al., Bioorqanic Medicinal Chem Lett.1996, β, 499.}

_{Step 1. 6-Fluoro-1H-indo!e-2,3-dione (6-fluoroisatin, 200 mg, 1.2 mMoi), diethylamide (0.24 ml. 2.3 mMol), and ethyl diazoacetate (0,24 mL 2.3 mMol) were dissolved in ethanoi (15 mL) and stirred at room temperature for 64 hours. Removal of solvent in vacuo then provided the diazo intermediate as an Oil (LCMS m/z 278.0 [M-1]); this was treated with hydrochloric acid (1N, 75 rnL), and allowed to react for 40 hours at room temperature Filtration of the reaction mixture yielded ethyl 7-f!uoro-3- hydroxy-2-oxo-1.2-dihyo'roquinoiine-4-carboxylate as an orange solid (144 mg, 0.57 mMol). LCMS m/z 252.1 (M+1). 1H NMR (400 MHz, CD3OD) δ 1.42 (t, J^7,0 Hz13H), 4.48 (q, J =7.0 Hz, 2H)8 7.02 (m, 2H), 7.87 (del. J =5.6. 8.9 Hz, 1H).}

_{Step 2. Methanol (7.5 ml), water (7.5 ml) and the compound from step 1 (100 mg, 0.4 mMoi) were combined in a 30 mL microwave tube and treated with lithium hydroxide (86 mg, 3.6 mMol), The reaction was subjected to microwave conditions (Biotage Advancer, 15O0C, high power) for 2 hours, with 30 seconds of prestirήng. A white solid was removed via filtration, and the filtrate was acidified to pH 0 with 1N hydrochloric acid. Filtration of the resulting precipitate provided the title compound as a beige solid (70 mg, 0.39 mMoi). MS (APCI) m/z 180.0 (M+1). 1H NMR (400 MHz, CD3OD) 66.98 (m, 2H), 7.13 (br s, 1H), 7.51 (dd, J=6.0t 8.5 Hz, 1H). Example ..2} 5 _{-chloro-6-fluoro-3-hvciroxvαuinolin-2j'iH)-one}

_{Step 1. Ethyl 5-chloro-64luorα-3-hydroxy-2-oκo-1,2-d!hydroqumolιne- 4-carboxy!ate was prepared according to the genera! procedure for the synthesis of intermediate in Step 1 of Example 1, except that 4-chloro-5- fluoro-1H-indole-2,3-dione was used in place of 6-f!uorα-1H-indo!e-2,3-diαne, and that the acfueous filtrate after the hydrochloric acid treatment was extracted with dichloromethane (2 x 15 rnL) and the combined organic layers concentrated in vacuo to provide additional aliquots of intermediate (total: 220 mg.0.77 mMol, 77%). LCMS m/z 284,1 (M-1).}

_{Step 2, The title compound was prepared according to the general procedure for the synthesis of Example 1 , except the microwave reaction was carried out for 5 hours, to provide the title compound as a beige solid (9 mg, 0042 mMol, 9%). LCMS m/z 2121 (M-1). 1H NMR (400 MHz, DMSO-Gfe) C> 7 19 (S1 1H): 7.24 {tin, J^46, 9.1 Hz1 1H), 735 (dd, J^9.1, 91 Hz, 1H), 10.27 (brs, 1H)112.27 (brs, 1H).}

_{Example 3}

_{Step 1. Preparation of ethyl 7-ethyl-3-hydroxy-2-oxo-1 ,2- dihydroqϋino!ιne-4-carboxylate.} 6 _{-Ethyl-1H-ιπdole-2.3-dιone (200 mg, 1.1 mMol), diβthylaminβ (0.24 mL 2.3 mMol), and ethyl diazoacetate (0,24 mL.2.3 mMol) were dissolved in ethanol (15 ml) and stirred at room temperature for 64 hours. Removal of solvent in vacuo provided the dsazo intermediate as an oil (LCMS m/z 288.2 [M-1]}; this was treated with hydrochloric aciα (1N, 75 ml), and allowed to react for 18 hours at room temperature. The reaction mixture was extracted twice with dichioromethane, and solvent was removed in vacuo to provide 0,27 g crude product. Purification was earned out via silica gel chromatography (Gradient: 50% ethyl acetate/heptane to 100% ethyl acetate) to provide ethyl 7-ethyl-3-hydroxy-2-oxo-1,2-dihydrαquinoline-4-carboxy!ate (130 mg, <0.5 mfviσi), still contaminated with some of the indole-2,3-dione starting material, LCMS nv'z 260.2 (M-1).} S _{tep 2. Methanol (7,5 rnL), water (7,5 ml) and the product from step 1 (130 mg, <05 mMoi) were combined, treated with lithium hydroxide (100 mg, 4.7 mMoi) and heated to reflux for 18 hours. The reaction was filtered, and the filtrate was acidified with 1N hydrochloric acid, then extracted twice with ethyl acetate, and twice with dichloromethane. The combined dichloromethane layers were concentrated in vacuo. The residue was purified by silica gel chromatography (Gradient; 5% ethyl acetate/heptane to 50% to 100% ethyl acetate), followed by two sequential preparative siϋca gel thin layer chromatographic separations (Eluant: 50% ethyl acetafe/hexanes), providing the title compound as s brown solid (1 9 mg. 001 mMoi). LCMS m/z 1882 (M-1). 1H NMR (400 MHz, CDCkO «51.28 (t, 3H. presumed - obscured by solvent).2.74 (q, J-7,5 Hz, 2H), 6.87 (s, 1H).7.11 fm, 2H), 7.20 (s, 1H), 7.43 (d, J=8.1 Hz, 1H), 11.15 (br s, 1H).}

_{Example 4} 4 _{-f!uorα-3-hγdroxyquιnαlin-2(1H)-αne}

_{Step 1. Preparation of 4-fiuoro-3-methoxyquinoiin-2(1H)-one.} T _{he general method of A. S. Kiselyov et a!.. Organic Letters, 2004, 6, 4061 was employed to prepare the title compound. Ethyl methoxyacetate (0,59 ml, 5.0 rnfvioi) was added to a freshly prepared solution of lithium diisopropylamide (13 mMol) in tetrahydrofuran (5 mL) at -780C. After 30 minutes, 2-(trif!uoromethyl)aniline (0.15 ml, 1.2 mMol) was added and the reaction mixture was allowed to warm to room temperature and stir for 16 hours. Volatiles were removed in vacuo, and the remaining material was treated with saturated aqueous ammonium chloride solution. The resulting mixture was extracted twice with ethyl acetate, and the combined organic layers were washed With saturated aqueous sodium chloride solution, and dried over sodium sulfate. Concentration in vacuo provided a residue that was purified by silica gel chromatography (Gradient; 100% heptane to 100% ethyl acetate). The resulting orange oil was triturated with diethyl ether to provide the title intermediate as a white solid (20 mg, 0,10 mMol), LCMS m/i 134.1 (M+1). 1H NMR (400 MHz, CDCI3) δ 4.14 (d, J=U Hz, 3H), 7.30 (m, 1H), 7.35 (br d, J~8.3 Hz, 1H)1 7.51 (m, 1H), 7.77 (dd, J~1.2, 7.9 Hz, 1H), 10.88 (br s, 1H).}

_{Step 2. The product from Step 1 (18 mg, 0.093 mMol) was mixed with dichioromethane (0.5 ml) and the mixture was cooled to -780C. Boron tribromide (1M in dichioromethane, 0.28 mL, 0.28 mMol) was added, and the reaction was allowed to stir for 1 hour at the same temperature. Methanol (3 mL) was then added to the cold reaction mixture, volatiles were removed in vacuo,, and the residue was re-evaporated with dichioromethane. Addition of ether was followed by filtration to give the title compound as a yellow-white solid (5 mg, 0.028 mMol) LCMS m/z 180.1 (M+1). 1H NMR (400 MHz, CD5OD)S 7.30 (m, 1H), 7.34 (br d, J=8.3 Hz, 1H), 7.45 (m, 1H), 7.71 (m, 1H).} E _{xample 5}

_{4.,8-difJuoro-3-hydTpxY.quinpjin-2(iH/)-pne}

_{Step 1. Preparation of 4,8-difluoro-3-methoxyquinolin-2(1 H)-one, 4,8-Difluoro-3-methoxyquιnolin-2(1H)-one was prepared according to the general procedure for the synthesis of the intermediate in Step 1 of Example 4. except that 2-flυoro-6-(trifluoromethyi)aniline was used in place of 2-(trifluoromethyl)sni!ine. 4t8-Difluoro-3-methoxyquinolin-2(1H)-one was obtained as an off-white, fluffy solid (9 mg, 0.043 mMol, 3%), LCMS m/z 212.1 (M+1). 1H NMR (400 MHz1 CD3OD) δ 4.04 (d, J=1.7 Hz, 3H)1 7.30 (ddd, J=8.1.8.1, 5.0, 1H), 7.37 (ddd, J=10.9.8.3, 1.2 Hz. 1H), 7.59 (bd, J=7.9 Hz, 1H).}

_{Step 2. The title compound was prepared according to the general procedure for the synthesis of product in Example 4, except that 4,8-difluoro-}

_{3-methoxyquinolin-2(1H)-one was used as the rβactant to provide the title compound as a white/pinkish solid (3.5 mg, 0.018 mMol. 38%). LCMS m/z}

_{198.0 (M+1). 1H NMR (400 MHz, CD3OD) o 7.25 (in, 2H), 7.51 (m, 1H).}

_{Example 8} 3 _{-hγdroxy-1 ,5-naphthyhtiin-2(1 ffs-one hvdrobromide}

_{Step 1. Preparation of 3-methoxy-1,5-naphthyridin-2(1H)-αne,}

_{Ethyl methoxyacetate (0.71 rnL, 8.0 mMol) was added to a -780C solution of lithium bis(trimethy!silyl)amide (1.0 M solution in tetrahydrofuran, 6.0 mL, 8.0 mMol) in tetrahydrofuran (6 mL). After 20 minutes, a solution of 3- arninopyridine-2-carbaidehyde (244 mg, 2.00 mMol) in tetrahydrofuran (3 mL) was added drop-wise from a syringe. The resulting light orange solution was allowed to come slowly to room temperature as the dry ice/acetone bath warmed up. After 18 hours, the reaction was quenched with 6N hydrochloric acid (1.1 mL, 6.6 mMol), providing a precipitate; this mixture was heated to reflux for 2 hours. The reaction was then concentrated in vacuo, and the residue was dissolved in methanol. Product was precipitated out over time as a lsght gray solid (18 mg). The mother liquor from this filtration was loaded onto dry silica gel and solvent was removed under reduced pressure. Additional product was then obtained through dry column vacuum chromatography [DCVC: See D. S. Pedersen and C. Rosenbohm, Synthesis 2001, 16, 2431] of this material (Eluant: 100% dichloromethaπe to 10:2 dιchloromethane:methanol). The product obtained from the DCVC was triturated with methanol to yield product as an off-white solid (78 mg). A final DCVC of mixed fractions and the second mother liquor provided more product as a white solid (97 mg; total recovery: 193 mg, 1.1 mMol). LCMS m/z 175.1 (M-1). 1H NMR (400 MHz, CD3OD) 53.98 <$, 3H), 7.26 (S1 1H), 7.41 (dd, .7=4.6, 8.3 Hz1 1H), 7.70 (brd, J=8.3 Hz: 1H)18.45 (dd, J=1.2, 4.6 Hz, 1H).}

_{Step 2. In a microwave vial equipped with a stir bar, finely ground product from Step 1 (10 mg, 0,06 mMol) was mixed with anhydrous dichloromethane (1 mL) and cooled in a dry ice/acetone bath. After addition of boron trifarαmidβ (1.0 M solution in dichlαromethane, 0.38 mL.0,38 mMol), the reaction was left in the cold bath for 5 minutes, then stirred at room temperature for 20 minutes, and finally heated in a microwave reactor for 10 minutes at 1000C. The tightly capped reaction was then subjected to conventional heating at 6O0C for 65 hours. After being quenched with methanol (3 ml), approximately half of the reaction mixture was concentrated in vacuo, and the residue was triturated with dichloromethane to provide the title compound as a gray solid (5.4 mg: 0.022 mMol). LCMS m/z 161.0 (M-1 ). 1H NMR (400 MHz, CD3OD) δ 7.23 (s, 1H), 7.79 (dd, J=5.7, 8.4 Hz, 1H). 8.20 (d, ,7=8.0 Hz, 1H), 8.53 (dd, J=1.2,57 Hz7 1H),} E _{xample 7}

_{3-hγdrqχγ J j-naρ.hthγ.rø}

_{Step 1. Preparation of 3-methoxy-1 ,7-naphthyridin-2(1 H)-one. 3-Methoxy-1,7-naphthyridin-2(1tf)-one was prepared according to the genera! procedure for the synthesis of the intermediate from Step 1 of Example 8, except that 3-aminoisonicQtinaldehyde was used in place of 3- aminopyridine-2-carbaidehyde. Product was obtained as white and light yellow solids (88 mg, 0.50 mMol, 25%), LCMS m/z 175,1 (M-"! ). !H NMR (400 MHz1 CD3OD) 33.97 (s, 3H), 7.25 (s, IH), 7.60 (d, J^5Λ Hz, 1H), 8.27 (d. J=5.4 Hz, 1H), 8.54 (s, 1H).}

_{Step 2, The product from Step 1 (10.9 mg. 0.062 mMol) was mixed with anhydrous dichlorαmethanβ (2 ml) and cooled in a dry ice/acetone bath. After addition of boron tribromide (1.0 M solution in dichloromethane.0.32 mL. 0.32 mMol), the reaction was left in the cold bath for 30 minutes, then allowed to warm to room temperature and stir for 18 hours. The reaction was cooled to -78°C again, and additional boron tribromide (1 mL, 1 mMol) was added. The mixture was allowed to reach ambient temperature, and stirred for 7 days; after which it was cooled in an ice bath and quenched with methanol (4 mL). The mixture was warmed to room temperature, solvents were removed under reduced pressure, and the residue was triturated with dichloromethane, and then with 20:1 dichloromethane.methanαl, to provide the title compound as a light gray solid (8 mg, 0.033 mMol), LCMS m/z 161.1 (M-1). 1H NMR (400 MHz1 CD3OD) o 7.28 (S, 1H), 8.02 (d( J=6.2 Hz, 1H), 8.36 (d, J=6.2 Hz, 1H), 8.61 (S1 1H).}

_{Example 8}

_{3"MdJS^y.'li&:DlBM!lMdiQ-21IHl^n^^hM^r!Ml!dl}

S _{tep L Preparation of 3-methoxy-1,6-naphthyridin-2(1H)-one.}

_{Ethyl methoxyacetate (0,71 mL. 6.0 mMol) was added to a -780C solution of lithium bis(trimethy!silyl)amide (1.0 M solution in tetrahydrofuran, 6.0 mL, 6,0 mMol) in tetrahydrofuran (6 mL). After 20 minutes, a solution of 4- arninonicotinaidehyde (244 mg, 2.00 mMol) in tetrahydrofuran (4 ml) was added drop-wise from a syringe. The resulting light orange solution was allowed to come slowly to room temperature as the dry ice/acetone bath warmed up. After 16 hours, the reaction was quenched with 6N hydrochloric acid (1.1 mL, 6.8 mMol), providing a precipitate; this mixture was heated to reflux for 2 hours. The reaction was then concentrated in vacuo, and the residue was triturated with dichloromethaπe, then methanol. A solid was removed via filtration, and the filtrate was concentrated in vacuo. The residue was triturated with ether to provide a tan solid; approximately one-third of this solid was subjected to DCVC over silica gel (Eluant, 100% dichloromethane to 100:10:1 clichloromethane:methano!;triethylamine), yielding 3-methoxy-1 ,6- naphthyridin-2(1H)-one as a white solid contaminated with triethylamine. A second DCVC was carried out on this material (Eluant; 100% dichloromethane to 10:1 dichioromethane:methanol) to provide additional intermediate as a white solid (85 mg, 0.37 mMol). APCI m/z 175.1 (M-1). 1H NMR (400 MHz, CD3OD) 63.96 (s, 3H), 7.37 (S1 1H), 7.39 (m. apparent br d, J-6.0 Hz11H), 8.40 (d, J=6.0 Hz, 1H), 8.86 (s, 1H).}

_{Step 2. 3-Methoxy-1,6-naphthyridin-2(1H)-oπe from Step 1 (25 mg, 0.14 mMol) was mixed with anhydrous dichloromethane (2 mL) and cooled in a dry ice/acetone hath. After addition of boron tribromide (1,0 M solution in dichloromethane, 0.57 mL, 0,57 mMol), the reaction was left in the cold bath for 30 minutes, then allowed to warm to room temperature and stir for 18 hours. Additional dichioromethane (2 mL) was added, the reaction was cooled in a dry ice/acetone bath, and then treated with additional boron tribromide (0.57 mL, 0.57 mMol). The reaction mixture was allowed to come to ambient temperature and was stirrec for 4 days, after which it was cooled to -780C and quenched with methanol (5 mL). The mixture was warmed to room temperature, solvents were removed under reduced pressure, and the residue was triturated with dichloromethane, then with ethyl acetate, and finally with hot methanol to provide the title compound as an off-white solid (13,2 mg.0.054 mMol). APCI m/z 161.1 (M-I), 1H NMR (400 MHz, CD3OD) δ 7,27 (s, 1H)t 7.62 (d, J=6.6 Hz. 1H). 8,46 (m, apparent br d, J=6.6Hz, 1H), 8.98 (S1 1H).}

_{Example 9}

_{Step 1, Preparation of 5-methoxy-1 -methyl- 1,7-dihyd rα-6H- pyra2o!o[3,4-6]pyriclfin-6-one.}

_{Ethyl methoxyacetate (0.35 ml, 3,0 rriMoi) was added to a -780C solution of lithium bis{tπmethyisilyl)amide (1.0 M solution in tetrahydrofuran, 3.0 mL, 3.0 rnMol) in tetrahydrofuran (3 ml_). After 20 minutes, a solution of S- amιno-1-mβthyl-1H-pyrazole-4-carbaidehyde (125 mg, 1.00 mMolj in tetrahydrαfuran (3 mL, necessary to warm this to achieve a solution) was added drop-wise from a syringe. The resulting yellow solution was allowed to come slowly to room temperature as the dry ice/acetone bath warmed up. After 18 hours, the reaction was quenched with 6N hydrochloric acid (1 mL, 8 rπMoi), and the mixture was allowed to stir for 18 hours. The solids were collected by filtration and washed with ethyl acetate to provide 5-methoxy-1- methyl-1,7-dihydro-6H-pyrazolo[3,4-jb]pyridin-6-one as an off-white solid (110 mg. 0,61 mMol}. APC! m/z 178.1 (M-1). 1H NMR (400 MHz, CD3OD) 63.85 (S, 3H), 3.93 (S, 3H), 7.26 (S, 1 H), 7,84 c's, 1 H).}

_{Step 2. 5-Methoxy-1 -methyl- 1 ,7-dihydrQ-6H-pyra2θlo[3,4-£>]pyπdin-S- one from Step 1 (32 mg, 0.18 mMol) was mixed with anhydrous dichloromethane (2 mL) and cooled in a dry ice/acetone bath. After addition of boron tribromide (1.0 M solution in dichloromethane, 0.72 ml, 0.72 mMol), the reaction was left in the cold bath for 15 minutes, then allowed to warm to room temperature and stir for 18 hours. It was then cooled to -7S0C and quenched with methanol (5 mL). The mixture was warmed to room temperature, solvents were removed under reduced pressure, and the residue was triturated with dichloromethane, then with ethyl acetate to provide the title compound as a tan solid (20 mg, 0.12 mMol). LCMS m/z 184.1 (M-1 ). 1 H NMR (400 MHz, CD3OD) o 3.94 (s, 3H ), 7, 1 1 (S1 1 H)1 7.80 (S, 1 H).}

_{6-hvαroxythjenof3,2:bipγτ!djn-5(4H ).-onβ}

_{Step 1 . Preparation of 3-aminothiαphene-2-carbaldehyde.}

_{A. Preparation of (3-arnino-2-fhieny! )rnethanol .}

_{A solution of methyl 3-aminothiophene-2-carboxy!ate (4.0 g, 25 mMol) in tetrahydrofuran ( 10 mL) was added drop-wise to a O0C solution of lithium aluminum hyd ride in tetrahyd rofuran ( 1 M1 51 mL, 51 mMol). After completion of the add ition, the reaction was allowed to warm to room temperature, and then stirred for 1 hour. The reaction was ca refully quenched with saturated aqueous sod ium sulfate solution (40 mL); the resulting solid was removed by filtration and the filtrate was concentrated under red uced pressure to provide roughly 50 mL of an aqueous mixture. This was extracted with ethyl acetate (3 x 1 50 mL), and the combined organic layers were concentrated in vacuo to provide (3-amιno-2-thieny!)methano! as a yellow solid (2.37 g, 18.3 mMol) which was carried on to the next step without purification. LCMS m/z 130.0 (M+1 ). B. A solution of (3-amino-2-thienyl)methanoI (2.37 g, 18.3 mMo!) in d ichloromethana (20 ml) was treated with a ctivated manganese d ioxide (8.0 g. 92 mMol) and stirred vigorously at room temperature for 18 hours. The mixture was then filtered through ceiite to provide an orange solution, which was concentrated in vacuo to yield 3-a m!nothiophene-2-carbaidehyde as a brown oil ( 1 .58 g, 12.4 mMol) that was ta ken on to the next step without purification. LCMS m/z 128.0 (M+1 ).}

_{Step 2. Preparation of 6-methoxythieno[312-6]pyridin-5(4H )-one.} E _{thyl methoxyacetate (2.7 ml, 23 mMol) was added to a -780C solution of lithium bis(trimethylsilyi)amide (1 .0 M solution in tetra hyd rofuran , 23.0 ml, 23.0 mMol). After 30 minutes, a solution of 3-aminathioph.ene-2-carbaldeh.yde (480 mg, 3.8 mMol) in tetrahyd rofuran (10 ml) was added , a nd the resulting dark brown mixture was allowed to come slowly to room temperature. A portion of the reaction mixture was purified by silica gel chromatography (Eluant: ethyl acetate, then 10% methanol in ethyl acetate, then 1 5% methanol in ethyl acetate). The material obtained from this column was titurated with 10% methanol in DCM and then filtered to provide 8- methoxythieno[312-fc]pyπd!n-5(4H )-one as a brown solid { 12 mg, 0.066 mMol). LCMS m/z 1 80.1 (M-1 ). 1 H NMR (400 MHz, CDCb with 2 drops CD3OD) .5 3.88 (S, 3H ), 7.03 (d . J^5.4 Hz, 1 H), 7.14 (s, 1 H ), 7.33 (d , J^5.4 Hz. 1 H).} S _{tep 3. Preparation of 6-hydroxythieno[3,2-b]pyπd in-S{4W)-one.} T _{he product from the previous step (10.5 mg, 0.058 mMol) was mixed with anhydrous dichioromethane (1 .5 ml) and cooled in a d ry ice/acetone bath. After addition of boron tribromide ( 1 ,0 M solution in d ichiorometha ne, 0. 174 ml, 0.174 mMol), the reaction was allowed to wa rm to room temperature and stirred for 3 hours. It was then carefully quenched with methanol (1 mL), and the reaction volume was brought to 1 0 mL with d ichioromethane. This organic layer was washed with wafer ( 10 mL), dried over sod ium sulfate, filtered and concentrated in vacuo to provide a light brown solid, which was resuspended in d ichioromethane. Filtration of this mixture provided the title compound as a beige solid (2.3 mg, 0.014 mMol). LCMS rn/z 166.0 (M-1). 1H NMR (400 MHz1 CD3OD) S 7.00 (dd. J=0.6, 5.4 Hz, 1H)17.33 (Ci1 J=0.6 Hz11H), 7.47 Cd, J=5.4 Hz5 IH).}

_{Example 11}

_{St^p 1, Preparation of ethy! δ-fiuoro-3-hyαroxy-2-oxo-1 ,2- dihydroquinoiine-4-carboxylate.}

_{Ethyl 8-f!uoro-3-hydroxy-2-oxo-1 ^-dihycJroαuinoline-Λ-carboxylate was prepared according to the general procedure for the synthesis of the intermediate of Step 1 of Example 1. except that 7-fluoro-1H-indole-2,3-dione was used in place of 6-fiLiθro-1H-iπGθie»2,3-dione. Ethyl 8-fluoro-3-hydroxy-2- oxo-1.2-dihydroquinoline-4-carboxylate was obtained as an orange solid (1.03 g, 4.1 mMol, 68%). LCMS m/z 250.1 (M-1). 1H NMR (400 MHz1 CD3OD) 5 1.42 (t J=7.1 Hz.3H).4.49 (q..7=7.1 Hz.2H), 7.19 (m, 2H).7.41 (m. 1H).} S _{tep 2. Methanol (1 ml), water (1 ml) and compound ethyl S-fluoro-S- hydroxy-2-oxo-1.2-dihydroquino!ine-4-carboxylate (100 mg, 0,40 mMol) were combined in a microwave vial and treated with lithium hydroxide (20 mg, 0.84 mMol). The reaction was subjected to microwave conditions (15O0C) for 15 minutes, then cautiously acidified with 1N hyαrochloπc aαα (0.84 mL 0.84 ITiMoI), and filtered. The collected solid was rinsed with pH 7 buffer, then methanol, to provide the title compound as a tan solid (40 mg, 0.22 mfviol). LCMS m/z 178.0 (M-1). !H NMR (400 MHz. DMSOds) o 7.10 (ddα, J=Q, 8, 5.2 Hz: 1H), 7.13 (d. J=1.6 Hz, 1H). 7.18 (ddd, J-10.3.8.1, 1.4 Hz, 1H)< 7,32 (br d, J-7.8 Hz. 1H), 9.74 (br s, 1H). 1206jbrs. 1H). Example 12}

_{3-hydroxy-7-methylquinoiin-2fiH)-one}

_{3-Hydroxy-7-methylquinolin-2(1H)-αne was prepared according to the genera! procedure for the synthesis of the intermediate of Step 1 of Example 11, except that ethyl 3-hydroxy-7-mθthyi-2-oxo-1,2-dihydroquinoliπθ'4- earfaαxyiate [see MJ. Fray et a!., Medicinal Chem. Research 1996, 6, 581] was used in place of ethyl 8-flυoro-3-hydroxy-2-oxo-1s2-dihydfoquinoline-4- carboxyiate. The title compound was obtained as a tan solid (49 mg, 0,28 mMol, 88%). LCMS rn/z 174.1 (M-1) Η NMR (400 MHz, DMSO-CZ6) S 2.32 (s, 3H), 6.94 (d. J=8,0 Hz, 1H), 6.98 (s, 1H), 7,04 (s, 1H), 7.34 (d, J=8.0 Hz, 1H).}

_{.ExarQBlg.J.3}

4 _{-bromo-7-chloro-3-hvdroxvquinolin-2(1H)-oπe}

_{The title compound can be prepared according to the procedure of S-Y. Sit et a!., Bioorganic Medicinal Chem. Lett. 1996, 6, 499. Specifically, A- bromo-7-chloro-3-hydroxyquino!in-2(1H)-one was obtained as a white solid, LCMS tWz 274.2 (M-1, largest ion of halogen pattern). 1H NMR (400 MHz, DMSOtfe) δ 7.31 (dd. J=SJ, 2,1 Hz, 1H), 7.34 (d, J=2.2 Hz1 1H), 7.72 (d: J-8,8 Hz, 1H), 10.64 (br S, 1H), 12.4 (br S, 1H). Example 14} 6 _{.7-dichloro-3-hydroxyquinolin-2(1H)-one}

6 _{,7-Dichloro-3-hydroxyquinolin-2 (1H)-one was prepared according to the general procedure for the synthesis of Example 12, except that ethyl 6,7- dichloro-3-hydroxy-2-oxo-1 ,2-dihydroqυinoline-4-carboxylate [see MJ. Fray et a!.. Medicinal Chem. Research 1996, 6, 581] was used as the starting material. The title compound was obtained as a tan solid. Yield: 36 mg, 0.16 mmol, 94%. LCMS m/z 230.0 (M+1). 1H NMR (400 MHz, CD3OD).δ 7.07 (s, 1H), 7.42 (s. 1H), 7.67 (S, 1H).}

_{Example 15} 7 _{,8-dichloro-3-hydroxyquinolin-2(1H)-one}

7 _{,8-dichloro-3-hydroxyquinolin-2(1H)-one was prepared according to the general procedure for the synthesis of Example 12. except that ethyl 7,8- dichloro-3-hydroxy-2-oxo-1,2-dihyclroquinoiine-4-carbox yIate [see MJ. Fray et al.; Medicinal Chem. Research 1996, 6, 581] was used as the starting material. The title compound was obtained as an off-white solid. Yield: 34 mg, 0.15 mmol, 87%. LCMS m/z 230.0 (M+1). 1H NMR (400 MHz, CD3OD) <5 7.02 (S5 1H)17.29 (d, J=8,4 Hz, 1H), 7.33 (G, J=8.β Hz: 1H). Example 16} 7 _{-chloro-3-hvdroxy-8-methylquinolin-2(1H)-one}

_{Step 1. Ethyl 7-chioiO-3-hydroxy-8-methy!-2-oxo-1,2-dihydroquino!ine- 4-carboxylate.}

_{Ethyl 7-chlαrQ-34iydrOxy-8-methyJ-2<)xo-1.2^!hyd!Oquinolinβ-4 - carboxylase can be prepared according to the procedure of MJ. Fray et a!.. Medicine! Chem Research 1996, 6, 581 and was obtained as a beige solid.}

_{LCMS m/z * (M-V). 1H NMR (400 MHz, CD3OD) ό 1.42 (t, J=7.1 Hz. 3H), 2.54 (s, 3H), 4.48 (q, J-7.1 Hz, 2H), 7.26 (d, J-8.8 Hz, 1H), 7.39 <br d, J=8,7 Hz,}

_1H).

_{Step 2. The title compound was prepareα according to the general procedure for the synthesis of Example 12, except that ethy! 7-ch!oro-3- hydroxy-8-methy!-2-oxo-1,2-dihydroquinoline-4-carboxy!a te was used as the starting material. The title compound was obtained as an off-white solid.}

_{Yield: 36 mg, 0.17 mmol, 94%. LCMS m/z 210.1 (M+1 J. 1H NMR (400 MHz,}

_{CD1OD) δ 2.49 (S13H)16.76 fs, 1H), 7.09 (d, J^BΛ Hz, 1H), 7.16 (d, >8.6 Hz,}

_1H),

_Exam|jjfeJL7 3 _{-hvdroxy-4-methyl-1,8-naphthyridin-2(1H)-onβ}

_{Step 1. Preparation of 3-methoxy-4-methyl-1.8-naphthyridin-2(1H)- one.}

_{3-methoxy-4-ιτiθthyl-1 ,8-naphthyridin-2(1H)-one was prepared according to the general procedure for the synthesis of the intermediate of}

_{Step 1 of Example 7, except that 1-(2-amiπopyhdin-3-yl)ethanαne [see TJ. Murray et al., Tetrahedron 1995, 51, 635] was used in place of 3- aminopyπdiπe-2-carbaldβhyde. After the addition of hydrochloric acid, the beige precipitate was filtered, then resuspended in 1N hydrochloric acid and heated at reflux for about 66 hours. The cooled reaction mixture was extracted with ethyl acetate (3 x 50 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. Filtration and removal of solvent in vacuo provided a roughly 1:1 mixture of compound 3-methoxy-4-methyl-1 ,8-naphthyridin-2(1H)-one and desired final product, 3-hydroxy-4-methyi-1,8-naphthyridin-2(1H)-one, as a beige solid. Yield: 50 mg, about 0,136 mmol each compound, 25%, LCMS m/z 191.1 (M+ 1 for 3-rnethoxy-4-methyl-1,8-naphthyridin-2(1H)-one) and 175.2 (M-1 for 3-hydroxy-4-methyl-1,8-naphthyridin-2(1H)-one). 1H NMR (400 MHz, CD5OD) δ 2.39 (s, 3H), 2.46 (s, 3H), 3.90 (s, 3H), 7.28 (dd, J=8.0.4.9 Hz, 1H)1 7.31 (dd, J=7.9, 4.8 Hz, 1H), 8.0S (dd, J~8.0, 1.5 Hz1 1H), 8.17 (dd, J=8.1, 1,7 Hzt 1 H)18.37 (dd,>4.7, 1.5 Hz, 1H), 8.47 (dd, J=4.6, U Hz, 1H). Step 2. Preparation of compound 3-hydrαxy-4-methyl-1,8- naphthyridin-2( 1 H)-one.}

_{The title compound was prepared according to the general procedure for the synthesis of Example 5, except that the mixture of products obtained in the previous step was used as the starting material. Additionally, the crude product was triturated with a 20; 1 mixture of dichloromethane and methanol, to provide the title compound as a beige solid. Yield: 8 mg, 0.045 mmol, 35%. LCMS m/z 175.1 (M-1). 1H NMR (400 MHz. CD3OD) δ 246 (s. 3H), 7.64 (dd, J-8.1, 5.6 Hz; 1H), 8.47 (dd, J~5,S, 1.4 H2. 1H), 8.63 (dd, J~B 0, 1.5 Hz: 1 H). Example 18} 6 _{-hvdroxyfuro[3,2-b]pyridin-5{4Hj-onβ}

_{Step 1. Preparation of tert-butyl (2-formy!-3-fυryl)carbamate.} t _{erf-Butyl carbamate (1.51 g, 12.9 mmol), cesium carbonate (4.89 g,}

_{15.0 mmol), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (99.4 mg; 0.098 mmoi), 415-bis(diphenylphαsphino)-9,9-dimethylxanthβπe (Xantphos, 180 mg. 0.311 mmoi) and 3-bromo-2-furaldehyde (1.87 g. 10.7 mmol) were combined in toluene (50 mL), and degassed by carrying out three cycles of a vacuum/ nitrogen introduction procedure. The reaction mixture was then heated to 1000C for about 18 hours, after which it was cooled, diluted with dichioromethane and filtered through Ceiite. The yellow filtrate was washed with saturated aqueous ammonium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting dark oil was purified via silica gel chromatography (Gradient1 100% heptane to 100% ethyl acetate) to provide terf-butyl (2-formyl-3-furyi)carbamate as a light yellow solid. Yield: 1.88 g, 8.90 mmol.83%. LCMS m/z 210.1 (M-1). 1H NMR (400 MHz, CD3OD) ό 1.54 (s. 9H), 7.17 (br s, 1H), 7.72 (d. J=1.9 Hz. 1H).9.68 (s, 1H).} S _{tep 2. Preparation of ethyl 3-{3-[(terf-butoxycarbonyl)amino]-2-furyl}-}

_{3-hydroxy-2-methoxypropanoate. Ethyi methoxyacetate (97%, 2,80 mL, 23,1 mmol) in tetrahydrofuran (25 mL) was added to a -780C solution of lithium bis(trimethy!si!yl)amicle (1.0M solution in tetrahydrofuran, 23.1 ml, 23.1 mmol). After 30 minutes, a solution of the product from Step 1 (1.88 g, 8.90 mmol) in tetrahydrofuran (15 mL) was adαeα drop-wise. After 1 hour at -780C, the reaction was quenched with water, and extracted with dichiorαmethane. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo The resulting yellow oil was subjected to silica gel chromatography (Gradient 100% heptane to 100% ethyl acetate) to provide ethyl 3-{3-[(tert-butoxycarbonyl)amino3-2-furyl}- 3-hydroxy-2-methoxypropanoate as a colorless oil, which by !H NfVlR was a roughly 3:1 mixture of diastereorners. Yield- 2.77 g, 8,41 mmol, 94%. LCMS m/z 328.1 (M-1). 1H NMR (400 MHz1 CD3OD) S 1.19 and 1,25 (two triplets, J=7.1 Hz, 3H), 1.50 (s, 9H)1 3.37 and 3.41 (2 singlets, 3H).4.08 and 4.14 (2 doublets. J=5.8, 6.6 Hz, 1H)1 4.12 and 4.20 (2 multiplets, apparent broad quartets, J=7 Hz, 2H)14.96 and 5.01 (2 br doublets, J=6.6, 5.8 Hz, 1H), 6,72 (brs, 1H), 7.33 and 7.34 (2 doublets, J-1.9, 2.1 Hz1 1H).}

_{Step 3. Preparation of ethyl <2Z)-3-(3-amino-2-furyl)-2- methoxyacryiate.}

_{The product from Step 2 (2.3 g, 7.0 mmol) was mixed with dichloromethane (15 mL) and cooled to -1O0C. After addition of boron tnbromide (1.0M solution in dichiorαmethane, 6.28 mL, 8.28 mmol), the reaction was stirred at -1O0C for 1 hour, then carefully quenched with methanol (5 mL), and partitioned between wafer and dichloromethane (50 mL). The aqueous layer was extracted five times with dichloromethane, and the combined organic layers were driec over magnesium sulfate, filtered and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 100% heptane to 100% ethyl acetate, followed by flushing with a gradient of 100% ethyl acetate to 10% methanol in ethyl acetate) provided ethyl {2Z)-3- (3-amina-2-furyi)-2-methaxyacrylate as an orange oil. Yield: 310 mg, 1.4 mmol, 20%. 1H NMR (400 MHz, CDAOD) 61.33 (t, J-7.1 Hz, 3H), 3.66 (S1 3H), 4,24 (q, J~7 Hz, 2H).6.17 (s, 1H).7.10 (s, 1H).7.37 (br s. 1H). Step 4. Preparation of 6-methoxyfuro[3,2-b]pyπdin-5(4H)-one.}

_{The product from Step 3 (0.31 g, 1.4 mmo!) was dissolved in 5 ml of}

_{THF and added drop-wise to a -780C solution of lithium bis(trimethy!silyl)amide (1.0M solution in tetrahydrofuran, 4.4 mL, 4.4 mmo!). The reaction was allowed to warm to about 25''C. After 3 hours, it was again cooled to -780C and treated with additional lithium bιs(trimethylsiiyi)amide (1.0M solution in tetrahydrofuran, 1.5 mL, 1.5 mmol). After 1 h the reaction was quenched With saturated aqueous ammonium chloride solution (2 mL}, and solvents were removed in vacuo. The resulting material was mixed with dichloromethane and filtered; the solid was washed with 10% methanol in dichloromethane and filtered to obtain 6-methoxyfuro[3,2-b3pyridin-5(4H)-one as a beige solid. Yield: 74 mg, 045 mmol, 32%. LCMS m/z 168.0 (M+1), 'H NMR (400 MHz, CD3OD) 63.87 (s, 3H).6.60 (br s, 1H), 7.43 (s, 1H)17.70 id, J~2Λ Hz, 1H).} S _{tep 5. Preparation of compound 8-hydrαxyfurα[3,2-b]pyπdin-5{4/-/)- one.}

_{The product from Step 4 (29 mg, 0,18 mmol) was combined with dichloromethane (2 mL), and the heterogeneous mixture was cooled to -1O0C and treated crop- wise with boron tribromide (1.0M solution in dichloromethane, 0.54 mL, 0,54 mmol). After 10 minutes, the reaction was warmed to about 250C, at which point the reaction had proceeded to less than 50% completion, by LCMS analysis. Additional dichloromethane (12 mL) was added, and the flask was recooied to -10°C and again treated with boron tribromide (1.0M solution in dichloromethane, 1.4 mL, 14 mmol). After warming to about 250C and stirring for an hour, the reaction was quenched with methanol (1 mL) and filtered. The filtrate was allowed to stand for several hours while a precipitate formed; the supernatant was then removed and concentrated in vacuo. The resulting residue was triturated with 10% methanol in dichloromethane, to provide the title compound as a beige solid. Yield: 4 mg. 0.026 mmol, 14%. MS (APCI) m/z 152.0 (M+1). 1H NMR (400 MHz, CD3OD) a 6.73 (del, J=2.2.0.9 Hz. 1H)17.50 (d, J=LO Hz, 1H), 7.83 (d, J=2.3 Hz, 1H).}

_{Example 19}

_{Step 1. Preparation of (2-amino-6-fluorophenyi)rnethanol.}

_{A solution of lithium aluminum hydride (1.0M solution in tetrahydrofυran, 18 mL, 18 mmoi) was cooled in an ice bath, and treated drop- wise with a solution of 2-amino-6-f!υorobenzoic acid (2.00 g, 12.9 mrnol) in tetrahydrofuran (30 mL). The ice bath was allowed to melt over the following 18 hours and the reaction mixture warmed to about 250C. The reaction was then quenched by the addition of sodium sulfate cieca hydrate (2 g) and saturated aqueous sodium chloride solution (6 mL). The resulting mixture was stirred for 1.5 hours, and then filtered through Celite. The filter pad was rinsed with diethyl ether (2 x 10 mL), and the filtrates were concentrated in vacuo. The resulting material was loaded onto silica gel by dissolution in tetrahydrofuran, treatment -with silica gel and removal of solvent under reduced pressure. Purification by dry column vacuum chromatography (Elυant: 100% heptane to 2:1 ethyl acetate;heptane) provided {2-amino-B- fiuorophenyl)methanol as a light yellow solid. Yield: 549 mg, 3.89 mmol, 30%. MS (APC!) m/z 139.8 (M-1). 1H NMR (400 MHz, CDCb) o 1.59 (br s. 1H), 4.33 (br s, 2H)14.79 (s, 2H), 6,48 (m, 2H)1 7,05 (add, J-B.2, 8.2, 6,4 Hz, 1H).}

_{Step 2, Preparation of 2-amiπo-6-fluorobenzaldehyde.}

_{The product from the previous step (250 mg, 1.77 mmo!) was mixed with dichloromethane (1 mL) and treated with manganese(IV) oxide (770 mg, 8,9 mmol). Additional dichloromethane (1 ml_) was used to rinse the sides of the reaction vessel. The heterogeneous reaction mixture was vigorously stirred for about 18 hours, then filtered through a 1.5 cm plug of silica gel, which was rinsed with additional dichloromethane (3 x 8 ml). The filtrates were concentrated in vacuo to afford 2-amino-6-fiuorαbenzaidehyαe as a waxy yellow solid. Yield; 187 mg, 1.34 mmoi, 76%, 1H NMR (400 UHz, CDCb) 06.33 (ddd, J=11.0, 8.0, 0.9 Hz, 1H), 8.40 (del, J=S.5, 0.7 Hz, 1H), 7,24 (ddd. J^B.X 8.3, 6.2 Hz, 1H)1 10.31 (s, 1H).}

_{Step 3. Preparation of 5-fluoro-4-hydroxy-3-methoxy-3,4- dihydroquinoiin-2{1H)-one,}

_{Ethyl mβthoxyacetate (253 uL. 2.15 mmol) was added to a -780C solution of lithium bis(trimethylsilyl)amide (1.0M solution in tetrahydrofuran, 2,2 mL 2.2 mmol) in tetrahydrofuran (2 mL). After 20 minutes, a solution of the product from the previous step (100 mg, 0.719 mmoi) in tetrahydrofuran (2 mL) was added drop-wise from a syringe. The resulting yellow solution was kept at -780C for 15 minutes, then the cooling bath was removed and the reaction mixture allowed to warm to about 250C. The reaction was quenched with 6N hydrochloric acid (360 uL 2.2 mmoi), providing a precipitate, which was collected by filtration. Purification via silica gel chromatography (Gradient: dichioromethane to 10:2 dichiαromβthanernβthanol) provided compound 5-fiuoro-4-hydroxy-3-methoxy-3,4-dihydroquinoiin-2(iH)-one as a white solid, characterized by 1H NMR as one major product containing a small amount of its diastereomβr Yield: 100 mg, 0.47 mmoi.65%. MS (ARC!) m/z 209.8 (M-1). 1H NMR (400 MHz, CD-5OD) o 3.64 (s, 3H), 4.11 (d, J=3.7 Hz, 1H), 5.24 (d, J^3.7 Hz, 1H), 6.73 (d, J=8.0 Hz, 1H), 6.80 (br dd; apparent t, J-9, 9 Hz, 1H). 7.29 (dddr apparent td. J~8.2, 8.2, 6.0 Hz. 1H). Partial Η NMR of minor diastereomer: 63,45 (S13H)1 377 (d, J=3.1 Hz, 1H), 5,02 (d, J-2.9 HZ, 1H).}

_{Step 4, Preparation of compound 5-flυoro-3-hydroxyquinoiin-2(1H)- one.}

_{The title compound was prepared according to the genera! procedure for the synthesis of Example 10, except that 5-f!uorα-4-hydroxy-3-methαxy- 3.4-dihydroquinoiin-2(1H)-one was used as the starting material. The title compound was obtained as a tan solid Yield: 23 mg, 0.13 rnmo!. 91%. LCMS m/z 180.1 (M+1). 1H NMR (400 MHz. CD3OD) δ 6.95 (dd, J-10.18.0 Hz. 1H), 7.12 (d, J=8.4 Hz. 1H), 7.27 (S1 1H), 7,32 (ddd, apparent td, J=8.2, 8,2, 5.8 Hz1 1H).}

_{Example 20} 3 _{:hγdroxy:5-methγjgynplιn-2ilH);pne}

_{Step 1. Preparation of (2-amino-6-methylphenyl)methanol.}

_{A solution of hthium aluminum hydride (94%, 1.07 g. 28.5 mmol) was cooled in an ice bath, and treated drop-wise with a solution of 2-amino-6- methylbenzoic acid (200 g. 13.2 mmol) in tetrshydrofuraπ (30 mL) The ice bath was allowed to melt and the reaction mixture warmed to about 25ϋC. It was allowed to stir for 1 hour, then heated at reflux for 2.5 hours. The reaction was then cooled in an ice bath and carefully quenched by the addition of sodium sulfate decahydrate (3 g) and saturated aqueous sodium chloride solution (10 mL). The resulting mixture was stirred for 30 minutes at O0C, 15 minutes at 250C, and was then filtered through Celite. The filter pad was rinsed with tetrahydrofuran (2 x 10 ml), and the filtrates were concentrated in vacuo: the resulting material was loaded onto silica gel and purified via dry column vacuum chromatography (Eluant: 100% heptane to 100% ethyl acetate), to afford (2-amino-6-methyiphenyl)methanol as a tan solid. Yield: 1.33 g, 9.69 mmol, 73%. MS (APCl) m/z 135.8 (M-1). 1H NMR (400 MHz, CDCIrO 52.34 (s, 3H), 4.75 (s, 2H), 6.59 (m, 2H), 7.02 (dd, apparent t, J-7.7, 7.7 Hz, 1H)} S _{tep 2. Preparation of 2-amino-6-methylbenzaldehyde.}

_{2-Amino-6-methylbβnzaldehyde was prepared according to the general procedure for the synthesis of Example 19, except that 2-amino-6- methylbenzaldehyσe was used as the starting material. The solid obtained in this way was recrystaϊhzed from heptane, to afford 2-amino-6- methylbenzaldehyde as bright yellow crystals. Yield; 258 mg, 1.89 mmol, 52%. 1H NMR (400 MHz, CDCi3) δ 2.58 (s, 3H), 6.39 (br s, 2H), 6.48 (m, 2H), 7.17 (dd, J=8: 8 Hz, 1H), 10.38 (s, 1H).}

_{Step 3. Preparation of 3-methσxy-5-methyiquiπolin-2(1H)-σne.}

_{Ethyl methoxyacetate (0,35 ml, 3,0 mmol) was added to a -780C solution of lithium bis(trimethylsily!)amide (1.0M solution in tetrahydrofuran, 3.0 mL 3.0 mmol) in tetrahydrofuran (3 mL). Ater 20 minutes, a solution of the product from the previous step (135 mg, 1,00 mmol) in tetrahydrofuran (3 mL) was added drop-wise from a syringe. The resulting yellow solution was allowed to come slowly to about 250C as the dry ice/acetone bath warmed up. After 18 hours, the reaction was quenched with 6N hydrochloric acid (0.36 mL 2.2 mmol), and the resulting precipitate was removed by filtration. The filtrate was concentrated in vacuo and purified by silica gel chromatography (Gradient: dichloromethane to 10:2 dichloromethane:methanol). The product crystallized out of one of the fractions, and was collected by filtration, to afford 3-methoxy-5-methy!quinolin-2(1H)-one as a white crystalline solid. Yield: 33 mg. 0,17 mmoi, 17%. MS (APCl) m/z 187.8 (M-1). 1H NMR (400 MHz, CD-iOD) 82.56 (s, 3H), 3.95 (s.3H), 7,09 (d, J=7.2 Hz, 1 H), 7,16 (d, J=8.2 Hz, 1H), 7.27 (m, 1H)17.29 (S11H).}

_{Step 4. Preparation of compound 3-hydroxy-5-rnethylquinolin-2(1W)- one.} T _{he title compound was prepared according to the genera! procedure for the synthesis of Example 10, except that 3-methoxy-5-methylquιnolin- 2(1H)-one was used as the starting materia!. The title compound was obtained as a tan solid. Yield: 34 mg, 0.19 mmol, quantitative LCMS m/z 176.1 (M+1). !H NMR (400 MHz, CD3OD) 52.55 (s. 3H). 7.20 (d; J-7.0 Hz1 1H), 7,30 (el, J=7.8 Hz, 1H)17.36 (dd, J=7.2S 7,2 Hz, 1H), 7,57 (S, 1H).}

_.JxajDPM-21. > _{.Φ.[Q[0:.3.:b.y.drpMQiJ.iD.PJ!n:2(1H):0.n.e}

_{Step 1 Preparation of 5-chloro-3-methoxyquinoiin-2(1H)-one.} 4 _{-Ch!αro-1H-indole-2,3-dione (182 mg, 1.00 mmol), diethylamine (0.207 ml, 2.0 mmol}, and (thmethyl$ilyl)dlazomethane (2M solution in hexanes, 1.0 mL, 2.0 mmol} were dissolved in ethanol (5 mL) ana stirred at about 250C for about 18 hours. Filtration of the heterogeneous reaction provided a solid, which was rinsed with ethanol (2 x 1 mL) to provide 5-chlαro- 3-methoxyquinolin-2(1H)-one as a gray solid. Yield; 125 mg, 0.60 mmol, 60%. LCMS m/z 210.1 (M+1).}

_{Step 2. Preparation of 5-ch!oro-3-hydroxyquιnolin-2(1H)-σne.}

_{The title compound was prepared according to the genera! procedure for the synthesis of Example 11, except that 5-chloro-3-hydroxyquιnolin- 2(i/-/)-one was used as the starting material, and that the crude product was slurried with hot methanol rather than triturated with dichloromethane. The slurry was cooled to about 250C and filtered to provide the title compound as a gray solid. Yield: 67 mg, 0.34 mmol, 70%. LCMS m/z 194.0 (M-1). 1H NMR (400 MHz, DMSOd6) 37.22 (s. 1H), 7.2? (m, 3H), 10.03 (br s. IH), 12.24 (br s, 1H).}

_{Example 22}

_{5 The titie compound was prepared from 2-amιno-5-bromo-3- pyridinβcarboxaldehyde using the procedure described in Example 8. APC! m/z 239 (M-1). 1H NMR (400 MHz, DMSO) δ 12.57 (s, 1H), 10.11 (S, 1H), 8.37 (s, 1H).8.20 (s, 1H).7.01 (S. 1H).}

_{Example 23} 1 _{0 7,8-difluorα-3-hydroxyquinolin-2(i H )-one}

_{The WIe compound was prepared from 6,7-difluoro-1H-indole-2,3-dione using the procedure described in Example 21. APCI m/z 196.1 (M-1). 1H NMR (400 MHz, CD3OD) δ 7.30-7.26 (m, 1H), 7.11-7.04 (m.2H).} ^ _{5 Example 24}

_{5.7-dif!υoro-3-hydroxyquιnolin-2(1H)-one}

_{The title compound was prepared from 4,6-difluoro-1H-indo!e-2,3-dione using the procedure described in Example 21. APCI m/z 196.1 (M-1). 1H 20 NMR (400 MHz1 DMSO) o 12.28 (s, 1H), 9.93 ^s, 1H)17.08-7.02 (m, 1H)16.99 (S, 1H), 6,84 (m, 1H). Example 25}

_{3-hvdroxv-2-oxo-1,2-dihvdroαuino!ine-8-carbonitriie}

_{Step 1. Preparation of 8-iodo-3-methoxyquinαlin-2(1H)-one.} 8 _{-fodo-3-methoxyqi!inolin-2(1H)-one was prepared from 7-iodo-1H- indo!e-2,3-clione using the same procedure as described in step 1 of Example 21. APCI m/z 301.9 (M+1). 1H NMR (400 MHz, CD3OD) S 7.87 (m, 1 H), 7.62 (m, 1H), 7.21 (m, 1H), 6.99 (m, 1H), 392 (S13H).}

_{Step 2. Preparation of 3-methoxyquinolin-2(1H)-one-8-carbonιtrile.} 8 _{-iodo-3-methoxyquinolin-2(1W)-one (90mg, 0.30 mmoi), zinc cyanide (41.8 mg, 0.356 mmol), xanthphos (3.50 rng: 0.0060 mmol), Pd2(dba)3 (2.80 mg; 0.0180 mmol) and TMEDA (14,5 mg, 0.125 mmol) were loaded into a 10 mL microwave tube (under nitrogen) with a stirring bar. DfVIF (2 mL) was added to the reaction mixture to produce a pale purple/pink homogeneous reaction mixture, and the tube was heated to 1800C for 20 minutes using microwave irradiation. The reaction mixture was partitioned between water and ethyl acetate, and the brown-yellow ethyl acetate layer was collected. The aqueous layer was washed 3 times with ethyl acetate, and the combined organics were dried over sodium sulfate, filtered and concentrated to afford 20 mg of a brown solid. APCl m/z 201 (M+1). 1H NMR (400 MHz, CD3OD)}

_{57.87 (m, 1H), 7.73 (m, 1H), 7.32-7.28 (m, 2H), 3.93 (s, 3H).}

_{Step 3. Preparation of 3-hydroxy-2-oxo-1,2-ciihydroquinoline-8- carbonitrile.}

_{The title compound was prepared from 3-methoxyqυinolin-2(1H)-one-8- carbonitrile using the procedure described in Example 10, step 3. APC! m/z 185,1 (M-1). 1H NMR (400 MHz, CD3OD) 67.81 (d, IH), 7.72 (d, 1H), 7.31 (dd, 1H), 7.19 (s, 1H). Example 26} 3 _{-hvdroxy-2-oxo-1,2-dihvdroquinoline-5-carbonitriie}

_{The title compound was prepared from 4-bωmo-1H-iπdole-2,3-dione using the procedure described in Example 25. APCI m/z 185,1 (M-1). !H NMR (400 MHz, CD3OD) 67.60 (d, 1H), 7.54 (d. 1H), 7.46-7.42 (dd, 1H), 7.32 (S1 1H).}

_{Example 27} 3 _{-hydroxy-2-oxo-1r2-dihydroquinoline-7-carbQnitrile}

_{The title compound was prepared from 6-bromo-1H-indo!e-2(3-dioπe using the procedure described in Example 25. APCl m/z 185.0 (M-1). 1H NMR (400 MHz, CD3OD) 67.64 (m, 1H).7.58 (rn, 1H).7.44 (m, 1H). 7,18 (s, 1H).} E _{xample 28}

_{5-chloro-3-hydroxy-8-methylquinolin-2(1H)-one}

_{The title compound was prepared from 4-cbioro-7-methyi-1H-lndo!e- 2,3-dione using the procedure described in Example 21. APCi m/z 208,1 (M- 1). 1H NMR (400 MHz. DMSO) 611.32 (S, 1H), 9.99 fs. 1H),. 7.21 (s, 1H), 7.15-7.09 (m, 2H), 2.36 (S, 3H). Example 29}

_{5-chloro-3-hvdroxy-6-methylquinoiin-2(1H}-one} T _{he title compound was prepared from 4-chloro-5-methyl-1H-indote- 2,3-dione using the procedure described in Example 21. APCi m/z 208.1 (M- 1). Η NMR (400 MHz1 DMSO) d 12.11 (S, 1H), 9.90 (S, 1H), 7.24-7,22 (m, 2H), 7.12 (m, 1H)12.33 (s, 3H).}

_{Example 30} 5 _{-chioro-7-fluoro-3-hvdroχyquinoiirι-2(1H)-one}

T _{he title compound was prepared from 4-chloro-6-f!uoro-1H-iπdolθ-2:3- dione using the procedure described in Example 21, step 1, except that only 0.8 equivalents of the TMS diazomethane reagent was added to the reaction mixture. The product was taken up into alcohol and treated with 1N HCI in dioxane and then concentrated to give the title compound as a hydrochloride salt. APC! m/z 212.1 (M-1). 1H NMR (400 MHz. DMSO) δ 12.27 (S1 1H), 10.03 (S1 1H): 7.27 (m, 1H), 7.16 (s, 1H), 6.39 (m, 1H),}

_{Example 31} 3 _{-hydroxy-5-(trifluoroniethyl)quinQlin-2(1H)-one}

T _{he title compound was prepared from 4-(trifluoromethyl)-1H-ιπdo!e-}

_{2,3-dione using the procedure described in Example 21. APCi m/z 228.1 (M- 1). 1H NMR (400 MHz, DMSO) ύ 12.34 (s, 1H)1 10.20 is, 1H)1 7,49 (m, 2H), 7,40 (m, 1H), 7.10 (s, 1H), Example 32}

_{5-bromo-3-hytiroxyquinolin-2(1H)-one}

_{The title compound was prepared from 4-bromo-1H-indote-2,3-dione using the procedure described in Example 21. APCI m/z 240, 242 (M+1). ^H NMR (400 MHz, DMSO) δ 12,18 (S, 1H), 7.39 (m, 1H), 7,24 (m. 1H), 7.19-7.15 (m, 2H).}

_{Example 33} 5 _{.8-άichloro-3-hvdroxyquinolιn-2{1H)-one}

T _{he title compound was prepared from 4,7-dichloro-1H-indαle-2,3- dione using the procedure described in Example 21, APCI m/z 228. 230, 232 (M-1). 1H NMR (400 MHz, DMSO) δ 11.52 (s, 1H), 10.39 (s, 1H)1 7.41 (d, 1H), 7.28 (d, 1H)17.21 (s, 1H).}

_Example.3.4

_{The title compound was prepared from 4!5-dichloro-1H-iπdole-2,3- dioπe using the procedure described in Example 21. APCl m/z 228; 230, 232 (M-1). 1H NMR (400 MHz1 DMSO) o 12.30 (S5 1H), 10.25 (broad s, 1H), 7,47 (m, IH)17.21 (m, 2H).} E _{xample 35}

_{The title compound was prepared from 4,6,7-trifluoro-1H-indole-2,3- dione using the procedure described in Example 21. APC! m/z 216.2 (M+1), 1H NMR (400 MHz, DMSO) δ 6.99 (S, 1 H) 7.29 (td, J=10.55, 6,06 Hz, 1 H) 10.13 (s, 1 H) 12.49 (br, s.,1 H).} E _{xample 36}

_{.5.6.7-trifluoro-3-hydroxyquinolin-2(1H)-one}

_{The title compound was prepared from 4,5,8-tπflυαro-1H-indole-2,3- dione using the procedure described in Example 21. APCl m/z 216.2 (M+1). 1H NMR (400 MHz, DMSO-dβ) 36.98 (s, 1 H) 7.01 (dd. J=6.55. 1.66 Hz, 1 H) 10.13 (S1 1 H) 12.24 (s, 1 H).}

_Exampje.37 . _{5,6,7,8-tetrafluoro-3-hydroxyquinolin -2(1H)-one}

T _{he title compound was prepared from 4,5,6,7-tetrafluoro-1H-indole-}

_{2,3-dione using the procedure described in Example 21. APCI m/z 234.1 (M+1). 1H NMR (400 MHz, METHANOL-d4) δ 7,12 (d, J= 1.37 Hz, 1 H).}

_{The compounds of Table 1 may be prepared according to methods analogous to those described above for Examples 1-37.}