SUBSTITUTED FUSED PYRROLEIMINES AND PYRAZOLEIMINES

Abstract: Disclosed are compounds of Formula (I) and the pharmaceutically acceptable salts thereof wherein R, Ar, A, n, R1 and R2 are defined herein. These compounds are highly selective agonists, antagonists or inverse agonists for GABAA brain receptors or prodrugs of agonists, antagonists or inverse agonists for GABAA brain receptors and are therefore useful in the diagnosis and treatment of anxiety, depression, Down Syndrome, sleep and seizure disorders, overdose with benzodiazepine drugs and for enhancement of memory. Pharmaceutical compositions, including packaged pharmaceutical compositions, are also disclosed.

Description: Substituted Fused Pyrrolei ines and Pyrazoleimines BACKGROUND OF THE INVENTION This application claims priority from U.S. Provisional Application S.N. 60/230,498, filed September 6, 2000, which is hereby incorporated by reference in its entirety. Field of the Invention This invention relates to novel fused pyrroleoximes and fused pyrazoleoximes and other such compounds, and more specifically to preferred fused pyrroleoximes and fused pyrazoleoximes that bind with high selectivity and high affinity to the benzodiazepine site of GABA A receptors. This invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in treatment of central nervous system (CNS) diseases. Description of the Related Art ', f The GABA A receptor superfamily represents one of the classes of receptors through which the major inhibitory neurotransmitter, γ-aminobutyric acid, or GABA, acts. Widely, although unequally, distributed through the mammalian brain, GABA mediates many of its actions through a complex of proteins called the GABA A receptor, which causes alteration in chloride conductance and membrane polarization. A number of cDNAs for GABA A receptor subunits have been characterized. To date at least 6α, 3β, 3γ, lε, lδ and 2p subunits have been identified. It is generally accepted that native GABA A receptors are typically composed of 2α, 2β, and lγ subunits (Pritchett & Seeburg Science 1989; 245:1389-1392 and Knight et . al . , Recept . Channels 1998; 6:1-18). Evidence such as message distribution, genome localization and biochemical study results suggest that the major naturally occurring receptor combinations are ιβ 2 γ 2 , 2 β 3 γ , α 3 β 3 γ 2 , and 5 β 3 γ 2 (Mohler et. al., Neuroch . Res . 1995; 20(5): 631 - 636). Benzodiazepines exert their pharmacological actions by interacting with the benzodiazepine binding sites associated with the GABA A receptor. In addition to the benzodiazepine site, the GABA A receptor contains sites of interaction for several other classes of drugs. These include a steroid binding site, a picrotoxin site, and the barbiturate site. The benzodiazepine site of the GABA A receptor is a distinct site on the receptor complex that does not overlap with the site of interaction for GABA or for other classes of drugs that bind to the receptor (see, e.g., Cooper, et al . , The Biochemical Basis of Neuropharmacology, 6 th ed. , 1991, pp. 145-148, Oxford University Press, New York) . Early electrophysiological studies indicated that a major action of the benzodiazepines was enhancement of GABAergic inhibition. Compounds that selectively bind to the benzodiazepine site and enhance the ability of GABA to open GABA A receptor channels are agonists of GABA receptors. Other compounds that interact with the same site but negatively modulate the action of GABA are called inverse agonists. Compounds belonging to a third class bind selectively to the benzodiazepine site and yet have little or no effect on GABA activity, but can block the action of GABA A receptor agonists or inverse agonists that act at this site. These compounds are referred to as antagonists. The important allosteric modulatory effects of drugs acting at the benzodiazepine site were recognized early and the distribution of activities at different receptor subtypes has been an area of intense pharmacological discovery. Agonists that act at the benzodiazepine site are known to exhibit anxiolytic, sedative, and hypnotic effects, while compounds that act as inverse agonists at this site elicit anxiogenic, cognition enhancing, and proconvulsant effects. While benzodiazepines have a long history of pharmaceutical use as anxiolytics, these compounds often exhibit a number of unwanted side effects. These may include cognitive impairment, sedation, ataxia, potentiation of ethanol effects, and a tendency for tolerance and drug dependence. GABA A selective ligands may also act to potentiate the effects of other CNS active compounds. For example, there is evidence that selective serotonin reuptake inhibitors (SSRIs) may show greater antidepressant activity when used in combination with GABA A selective ligands than when used alone. SUMMARY OF THE INVENTION This invention provides fused pyrroleoximes and pyrazoleoximes that bind, preferably with both high affinity and high selectivity, to the benzodiazepine site of the GABA A receptor, including human GABA A receptors. Thus, the invention provides compounds of Formula I, and pharmaceutical compositions comprising compounds of Formula I. The invention further comprises methods of treating patients suffering from CNS disorders with an effective amount of a compound of the invention. The patient may be a human or other mammal. Treatment of humans, domesticated companion animals (pet) or livestock animals suffering from CNS disorders with an effective amount of a compound of the invention is encompassed by the invention. In a separate aspect, the invention provides a method of potentiating the actions of other CNS active compounds. This method comprises administering an effective amount of a compound of the invention with another CNS active compound. Additionally this invention relates to the use of the compounds of the invention as probes for the localization of GABA A receptors in tissue sections. Accordingly, a broad aspect of the invention is directed to compounds of Formula I and the pharmaceutically acceptable salts thereof, wherein: R is hydroxy, hydrocarbyl or -O-hydrocarbyl , where each hydrocarbyl is optionally substituted with oxo, haloalkyl, haloalkoxy, halogen, cyano, hydroxy, alkyl, nitro, azido, alkanoyl, carboxamido, alkoxy, aryloxy, alkylthio, alkylsulfinyl , alkylsulfonyl, amino, mono or dialkylamino, aryl, arylalkyl, arylalkoxy, heteroaryl or heterocycloalkyl ; or R is -0-aryl, aryl, -O-heteroaryl , or heteroaryl, each of which is optionally substituted with halogen, cyano, hydroxyl, nitro, azido, alkanoyl, carboxamido, hydrocarbyl, -O-hydrocarbyl, aryloxy, haloalkyl, haloalkoxy, hydrocarbylthio hydrocarbylsulfinyl , hydrocarbylsulfonyl , amino, mono or dihydrocarbylamino, aryl, arylhydrocarbyl , arylalkoxy, heteroaryl or heterocycloalkyl; wherein each hydrocarbyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of oxo, halogen, cyano, nitro, haloalkyl, haloalkoxy, hydroxy, amino, alkyl substituted with 0-2 R A , alkoxy substituted with 0-2 R A , -NH (alkyl) substituted with 0-2 R A , -N (alkyl) (alkyl) where each alkyl is independently substituted with 0-2 R A , phenyl substituted with 0-3 R A , -XR B , and R c ; wherein R A is independently selected at each occurrence from the group consisting of halogen, hydroxy, alkyl, alkoxy, -NH (alkyl), -N (alkyl) (alkyl) , heterocycloalkyl, -S (0) m (alkyl) , where m is 0, 1, or 2, haloalkyl, haloalkoxy, -CO (alkyl), -CONH (alkyl) , -CON (alkyl) (alkyl), -XR B , and Y; X is independently selected at each occurrence from the group consisting of -CH 2 -, -CHR C -, -0-, -S(0) g -, -NH-, -NR C -, -C(=0)-, -C(=0)0-, -C(=0)NH-, -C(=0)NR c -, -S(0) g NH-, -S(0) g NR c -, NHC(=0)-, -NR c C(=0)-, -NHS(0) g -, and -NR c S(0) g -; where g is 0, 1, or 2; R B and R c are independently hydrocarbyl which may be further substituted with one or more substituents independently selected from oxo, hydroxy, halogen, amino, -NH(alkyl), -N (alkyl) (alkyl), cyano, nitro, haloalkyl, haloalkoxy, -O (alkyl), -NHC (O) (alkyl) , -N (alkyl) C(O) (alkyl) , -NHS (0) m (alkyl ) , -S (0) m (alkyl) , -S (0) m NH (alkyl) , and -S (O) m N (alkyl) (alkyl) ; where each m is 0, 1, or 2; Y is independently selected at each occurrence from 5- to 8-membered carbocycles or heterocycles, which are saturated, partially unsaturated, or aromatic and contain zero, one or two hetero atoms selected from N, 0, and S, and which may be further substituted with one or more substituents independently selected from the group consisting of halogen, oxo, hydroxy, amino, mono- or di (Cι-C 6 ) alkylamino, nitro, cyano, Ci- C_ alkyl, Cι-C 3 alkoxy, and -SO a (alkyl); where a is 0, 1 , or 2; Ri and R 2 are independently selected at each occurrence from hydrogen, halogen, hydroxy, hydrocarbyl, -O-hydrocarbyl, alkoxy, haloalkyl, haloalkoxy, nitro, cyano, amino, mono or dihydrocarbylamino; n is 0, 1, or 2 ; A is N or CR 3 , wherein R 3 is hydrogen or hydrocarbyl; Ar is aryl or heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, haloalkyl, haloalkoxy, halogen, cyano, hydroxy, nitro, azido, alkanoyl, carboxamido, hydrocarbyl substituted with 0-2 R A , -O-hydrocarbyl substituted with 0-2 R A , aryloxy, alkylthio hydrocarbylsulfinyl, hydrocarbylsulfonyl , amino, -NH (hydrocarbyl) substituted with 0-2 R A , -N (hydrocarbyl) (hydrocarbyl) wherein each hydrocarbyl is substituted with 0-2 R A , aryl, arylhydrocarbyl , arylalkoxy, heteroaryl and heterocycloalkyl; and R 40 is hydrogen, alkyl, arylalkyl or arylalkanoyl . The invention also provides intermediates and methods of making the compounds of the invention. DETAILED DESCRIPTION OF THE INVENTION In a specific aspect, the invention provides compounds of Formula I where A is nitrogen and n is 0. In another specific aspect, the invention provides compounds of Formula I where A is CR 3 , where R 3 is defined above, and n is 0. In another specific aspect, the invention provides compounds of Formula I where A is nitrogen and n is 1. In yet another specific aspect, the invention provides compounds of Formula I where A is CR 3 , where R 3 is defined above, and n is 1. In a yet further specific aspect, the invention provides compounds of Formula I where A is nitrogen and n is 2. In yet another specific aspect, the invention provides compounds of Formula I where A is CR 3 ,. where R 3 is defined above, and n is 2. More preferably the invention relates to compounds of Formula I and the pharmaceutically acceptable salts thereof, where R is hydroxy, alkyl, cycloalkyl, alkoxy, or cycloalkyloxy each of which is optionally substituted with oxo, haloalkyl, haloalkoxy halogen, cyano, hydroxy, alkyl, nitro, azido, alkanoyl, carboxamido, alkoxy, aryloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, mono or dialkylamino, aryl, arylalkyl, arylalkoxy, heteroaryl or heterocycloalkyl ; or R is phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridizinyl, benzimidazolyl, naphthyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo [b] thiophenyl , benz [d] isoxazolyl , quinolinyl , isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which is optionally mono-, di-, or trisubstituted with substituents independently chosen from halogen, cyano, nitro, haloalkyl, haloalkoxy, hydroxy, amino, alkyl substituted with 0-2 R A , alkoxy substituted with 0-2 R A , -NH (alkyl) substituted with 0-2 R A , -N (alkyl) (alkyl) where each alkyl is independently substituted with 0-2 R A , phenyl substituted with 0-3 R A , -XR B , and R c ; Ar is phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, benzimidazolyl, naphthyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo [b] thiophenyl, benz [d] isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which is optionally mono-, di-, or trisubstituted with substitutents independently chosen from oxo, halogen, cyano, nitro, haloalkyl, haloalkoxy, hydroxy, amino, alkyl substituted with 0-2 R A , alkoxy substituted with 0-2 R A , -NH (alkyl) substituted with 0-2 R A , -N (alkyl) (alkyl) where each alkyl is independently substituted with 0-2 R A , -XR B , and R c ; R A is independently selected at each occurrence from the group consisting of halogen, hydroxy, alkyl, alkoxy, -NH(alkyl), -N (alkyl) (alkyl) , morpholinyl, pyrrolidinyl , piperidinyl , thiomorpholinyl, piperazinyl, -S (O) m (alkyl) , where m is 0, 1, or 2, haloalkyl, haloalkoxyoxy, -CO(alkyl), CONH(alkyl), CON (alkyl) (alkyl) , -XR B , and Y, where X, Y, R A , R B , and R c are as defined with respect to Formula I. Such compounds are referred to hereinafter as compounds of Formula la. Preferred compounds of Formula la are those compounds where each alkyl is C ! -C 6 alkyl and each alkoxy is Cx-C . alkoxy. Such compounds are referred to hereinafter as compounds of Formula lb. Preferred compounds of Formula I include those where Ar is phenyl, pyridyl, pyrimidinyl, pyrazolyl, or pyridizinyl, each of which is unsubstituted or substituted with up to three groups selected from halogen, cyano, nitro, Ci-Cghaloalkyl , Cι-C 3 haloalkoxy, hydroxy, amino, and Ci- C 6 alkyl substituted with 0-2 R A , Cι-C 6 alkoxy substituted with 0-2 R A , -NH(Cι-C 6 alkyl) substituted with 0-2 R A , and - N(Cι-C 6 alkyl) ( Cι-C 6 alkyl) where each alkyl is independently substituted with 0-2 R A , -XR B , and R C; R A is independently selected at each occurrence the group consisting of halogen, hydroxy, Cι-C 6 alkyl, Ci- C.alkoxy, -NH(C 1 -C 6 alkyl) , -N (d-Cβalkyl) (d-C 6 alkyl) , Cι-C 6 haloalkyl, Cι-C 6 haloalkoxy, -XR B and Y; X is independently selected at each occurrence from the group consisting of -CH 2 -, -CHR C -, -O- , -NH- , -NR C - , and -C(=0) - ; R B and R c are independently Cι-C 3 alkyl, C 3 -C 7 cycloalkyl, or C 3 -C 7 cycloalkyl (Cι-C 6 ) alkyl, each of is optionally substituted with one or more substituents independently selected from oxo, hydroxy, halogen, amino, cyano, nitro, Cι-C 6 haloalkyl, Cι-C 6 haloalkoxy, Cι-C 6 alkyl, Cι-C 6 alkoxy, mono- or di (Ci- C s ) alkylamino, -NHC (O) (Cι_ s alkyl), and -N(Cι-C 6 alkyl)C(O) (Cι-C 6 alkyl) , where m is 0, 1, or 2; and Y is morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl , piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl , or imidazolidinyl . More preferred compounds and pharmaceutically acceptable salts of Formula I include those where R is hydroxy, Cι-C 6 alkyl, cycloalkyl, Cι-C 3 alkoxy, or cycloalkyloxy each of which ' is optionally substituted with oxo, Cι-C 6 haloalkyl, Cx-Cεhaloalkoxy halogen, cyano, hydroxy, Cι-C 6 alkyl, nitro, azido, Cι-C 6 alkanoyl, carboxamido, Cι-C 6 alkoxy, aryloxy, Cι-C 6 alkylthio, C x - C 6 alkylsulfinyl, Cι-C 6 alkylsulfonyl, amino, mono or di (Ci- Cg) alkylamino, aryl, aryl (Cχ-C 4 ) alkyl, aryl (Cχ-C 4 ) alkoxy, heteroaryl or heterocycloalkyl ; or R is phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridizinyl, benzimidazolyl, naphthyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo [b] thiophenyl, benz [d] isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl , or quinoxalinyl , each of which is optionally mono-, di-, or trisubstituted with substituents independently chosen from halogen, cyano, nitro, Cι-C e haloalkyl, Cι-C 6 haloalkoxy, hydroxy, amino, Cx-Cgalkyl substituted with 0-2 R A , Cι-C 6 alkoxy substituted with 0-2 R A , -NH (Cι-C 6 alkyl) substituted with 0-2 R A , -N(Cι-C . alkyl) (Cx-Cgalkyl) where each alkyl is independently substituted with 0-2 R A , phenyl substituted with 0-3 R A , -XR B , and R c ; i and R are independently selected at each occurrence from hydrogen, halogen, hydroxy, Cι-C 6 alkyl, Cι-C 3 alkoxy, Ci- C s haloalkyl, Cx-Cghaloalkoxy, nitro, cyano, amino, mono- or di- (Cι-C 6 ) alkylamino; Ar is phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, benzimidazolyl, naphthyl, indolyl, isoindolyl, . benzofuranyl, isobenzofuranyl, benzo [b] thiophenyl, ■ benz [d] isoxazolyl, quinolinyl, isoquinolinyl, ciiinblinyl, quinazolinyl, or quinoxalinyl, each of which is optionally mono,-, di-, or trisubstituted with substitutents, ' independently, chosen from oxo, halogen, cyano, nitro, Cι-C 6 haloalkyl , C ! -C e haloalkoxy, hydroxy, amino, Cι-C 6 alkyl substituted with 0-2 R A , Cι-C 6 alkoxy substituted with 0-2 R A , -NH (Cι-C δ alkyl) substituted with 0-2 R A , -N(Cι-C 6 alkyl) (Cι-C 6 alkyl) where each Cι-C 6 alkyl is independently substituted with 0-2 R A , -XR B , and R C; R A is independently selected at each occurrence from the group consisting of halogen, hydroxy, Cι-C 6 alkyl, Ci- C . alkoxy, -NH (Cι-C 6 alkyl) , -N(Cι-C 6 alkyl) ( Cι-C 6 alkyl) , morpholinyl, pyrrolidinyl , piperidinyl, thiomorpholinyl, piperazinyl, -S (O) m (alkyl) , where m is 0, 1, or 2, Cι-C 6 haloalkyl, Cι-C 6 haloalkoxy, -CO(Cι-C 3 alkyl) , CONH (Cι-C 6 alkyl) , CON(C 1 -C 6 alkyl) (Cx- C 6 alkyl) , -XR B / and Y; and R B and R c are independently Cx-Cεhydrocarbyl which may be further substituted with one or more substituents independently selected from oxo, hydroxy, halogen, amino, -NH(C 1 -C 6 alkyl) , -N (Cι-C 6 alkyl) (d-C 6 alkyl) , cyano, nitro, Cι-C 6 haloalkyl, Cι-C 6 haloalkoxy, -0(Cχ- C 6 alkyl) , -NHC (0) (d-C 6 alkyl) , -N (d-C 6 alkyl) C (0) ( C x - C 6 alkyl), -NHS (0) m (Ci-C 6 alkyl) , -S (0) ra (d-Cgalkyl) , -S(0) m NH(Cι-C 6 alkyl) , and -S (0) m N (Cι-C 6 alkyl) ( Cx- Cgalkyl); where each m is 0, 1, or 2. Particularly, the invention includes compounds where A is nitrogen, i.e. compounds of Formula II (below) Formula II and the pharmaceutically acceptable salts thereof, wherein n, R, Ri, R 2; and Ar are as defined for Formula I. Preferred compounds of Formula 'II are compounds wherein n is 1 (hereinafter compounds of Formula Ila) . Particularly preferred compounds of Formula Ila are those compounds wherein Ri and R 2 are d-C 6 alkyl, d-C 6 alkoxy, hydrogen, cyano, amino, amino (Ci-Cg) alkyl, halo (Ci-Cg) alkyl, or halo (Ci-C 6 ) alkoxy; and Ar is phenyl, pyridyl, pyrimidinyl, pyrazolyl, or pyridizinyl, each of which is unsubstituted or substituted with up to three groups selected from halogen, cyano, nitro, Ci- Cghaloalkyl, d-Cghaloalkoxy, hydroxy, amino, and d- Cgalkyl substituted with 0-2 R A , Ci-Cgalkoxy substituted with 0-2 R A/ -NH(d-Cgalkyl) substituted with 0-2 R A , and - N(d-C 3 alkyl) ( d-C 6 alkyl) where each alkyl is independently substituted with 0-2 R A , -XR B ; and R C; R A is independently selected at each occurrence the group consisting of halogen, hydroxy, Cι-C 6 alkyl, d- C 6 alkoxy, -NH (Ci-Cgalkyl ) , -N (d-Cgalkyl ) (C x -Cgalkyl ) , C x - Cghaloalkyl, d-Cghaloalkoxy, -XR B and Y; X is independently selected at each occurrence from the group consisting of -CH 2 -, -CHR C -, -O- , -NH- , -NR C - , and -C(=0) - ; R B and R c are independently d-C 6 alkyl, C 3 -C 7 cycloalkyl , or C 3 -C 7 cycloalkyl (Ci-Cg) alkyl, each of is optionally substituted with one or more substituents independently selected from oxo, hydroxy, halogen, amino, cyano, nitro, Cι-C 3 haloalkyl, Ci-Cg haloalkoxy, Ci-C alkyl, Ci-Cg alkoxy, mono- or di (d- C s ) alkylamino, -NHC(0) (d_ 6 alkyl), and -N(d-C 6 alkyl)C(O) (d-C 6 alkyl), where m is 0, 1, or 2; and Y is morpholinyl, homopiperazinyl , piperazinyl, homopiperidinyl , piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl . Such compounds are referred to hereinafter as compounds of Formula lie. Preferred compounds of Formula lie are those compounds wherein Ri and R 2 are defined as for Formula lie and R is Ci-C alkyl or -0-Cχ-Cgalkyl , wherein Cι-C 6 alkyl is straight or branched and may contain double or triple bonds; or R is C 3 -C 7 cycloalkyl or -0-C 3 -C 7 alkyl or R is phenyl or pyridyl, wherein each phenyl or pyridyl is unsubstituted or mono-, di-, or trisubstituted with halogen, cyano, nitro, halo (Cχ-Cg) alkyl, halo (Ci-Cg) alkoxy, hydroxy, amino, Cι-C 6 alkyl substituted with 0-2 R A , d- Cgalkoxy substituted with 0-2 R A , -NH(Cι_ 6 alkyl) substituted with 0-2 R A , -N (d-C 6 alkyl) ( Cι-C 3 alkyl) where each d-C 6 alkyl is independently substituted with 0-2 R A , phenyl substituted with 0-3 R A , -XR B , and R c . , wherein X, R A , R B , and R c are defined as for Formula I. Such compounds are referred to hereinafter as compounds of Formula lid. Also preferred are compounds of Formula II, Ila, lie, and lid wherein Ri and R 2 are independently selected at each occurrence from hydrogen, halogen, methyl and ethyl. As noted above, preferred compounds of Formula II include those where n is 1. Other preferred compounds of Formula II are those where n is 0, or where n is 2. Other preferred compounds and pharmaceutically acceptable salts of Formula I are those wherein: Ar is phenyl, pyridyl, or pyridizinyl each of which is optionally mono-, di-, or tri-substituted with substituents independently chosen from halogen, Cι-C 6 alkyl, d-C 6 alkoxy, amino, mono- or di (Ci- C 6 ) alkylamino, d-C 6 alkoxy (Ci-Cg) alkoxy, Ci-C alkylamino (Ci-Cg) alkoxy, amino (Ci-Cg) alkoxy, di (Ci- C 6 ) alkylamino (Ci-Cg) alkoxy, Ci- C 5 alkoxy (Cι-C 6 ) alkylamino, alkyl substituted with morpholinyl, homopiperazinyl , piperazinyl, homopiperidinyl , piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl, and Ci-Cg alkoxy substituted with morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, and imidazolidinyl. The invention also includes compounds and pharmaceutically acceptable salts of Formula II wherein Ar is phenyl, pyridyl, or pyridinzyl, each of which is substituted with one of i) halogen, Ci-Cg alkyl, Ci-Cg alkoxy, mono- or di- (Ci- Cg) alkylamino, Cι-C 6 alkoxy (Ci-Cg) alkoxy, mono or di- (Ci- C e ) alkylamino (Ci-Cg) alkoxy, or ii) Ci-Cg alkoxy substituted with morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl and Ar is optionally further substituted with one or two substitutuents independently chosen from halogen, Cι-C alkyl, C 1 -C 4 alkoxy, amino, Ci-Cg alkylamino, C 1 -C 3 alkoxy (C 1 -C 3 ) alkoxy, Cι-C 3 alkylamino (C 1 -C 3 ) alkoxy, amino (Cι-C 3 ) alkoxy, Cι-C 3 alkylamino (C 1 -C 3 ) alkoxy, and Ci-Cg alkoxy (Cι-C 6 ) alkylamino . Particularly preferred definitions for the variables Ri and R 2 of Formula II include hydrogen, Cι-C 2 alkyl, Cι-C 2 alkoxy, cyano, amino, and halogen. It is also preferred that not more than three of R x and R 2 are other than hydrogen. More preferred compounds and salts of Formula II are those wherein one, two, or three of R x and R 2 are independently chosen from hydrogen, halogen, methyl and ethyl, and the remaining R x and R 2 substituents are hydrogen. The invention is further directed to compounds and salts of Formula II, wherein R is Ci-Cgalkyl, Ci-Cgalkoxy, phenyl (Ci-Cg) alkyl , pyridyl (C x - C 6 ) alkyl, phenyl or pyridyl, wherein each phenyl or pyridyl is unsubstituted or mono-, di-, or trisubstituted with halogen, cyano, nitro, halo (Ci-Cg) alkyl, halo(Cι- C 6 ) alkoxy, hydroxy, amino, Ci-Cgalkyl substituted with 0-2 R A , Ci-Cgalkoxy substituted with 0-2 R A , -NH(Cι_ s alkyl) substituted with 0-2 R A , -N (Ci-Cgalkyl) ( Ci-Cgalkyl) where each Ci-Cgalkyl is independently substituted with 0-2 R A , phenyl substituted with 0-3 R A , -XR B , and R c . Furthermore the invention is directed to compounds and pharmaceutically acceptable salts of Formula II wherein R is Ci- alkyl, Cι_ 6 alkoxy, or phenyl (Ci-Cg) alkyl, pyridyl (Ci-Cg) alkyl , phenyl or pyridyl, where the aromatic portion of each is unsubstituted or mono-, di-, or trisubstituted with halogen, cyano, nitro, Ci-Cghaloalkyl, Ci-Cghaloalkoxy, hydroxy, amino, Ci-Cg alkoxy, or Ci- alkyl. The invention is also directed to compounds and pharmaceutically acceptable salts of Formula II wherein R is Cι-C 4 alkyl, Cι-C 4 alkoxy, or phenyl, where the phenyl is mono- or di-substituted with substituents independently chosen from halogen, cyano, nitro, Ci-Cghaloalkyl, Ci- Cghaloalkoxy, hydroxy, amino, Ci-Cg alkoxy, Cι_ s alkyl, amino (Ci-Cg) alkyl, mono- or di (Ci-Cg) alkylamino (Ci-Cg) alkyl , and mono- or di (Ci-Cg) alkylamino (Ci-Cg) alkoxy. Particularly included in the invention are compounds and pharmaceutically acceptable salts of Formula II wherein: Ar is phenyl, pyridyl, pyrimidinyl, pyrazolyl, or pyridizinyl, each of which is unsubstituted or substituted with up to three groups independently selected from halogen, cyano, nitro, d-C 6 haloalkyl, Ci-Cghaloalkoxy, hydroxy, amino, and Ci-Cgalkyl substituted with 0-2 R A , Ci-Cgalkoxy substituted with 0-2 R A , -NH(Cι-Cgalkyl) substituted with 0-2 R A , - N(Cι-Cgalkyl) (Cι-C 6 alkyl) where each alkyl is independently substituted with 0-2 R A , -XR B , and R c ; R A is independently selected at each occurrence the group consisting of halogen, hydroxy, d-C 6 alkyl, Ci- C 6 alkoxy, -NH (Ci-Cgalkyl ) , -N(Cι-C 6 alkyl) ( Ci-Cgalkyl), C x - Cghaloalkyl, Cι-C 6 haloalkoxy, CO (d-Cgalkyl) , CONH(Cι- Cgalkyl) , CON (d-Cgalkyl) (Ci-Cgalkyl) , -XR B and Y; X is independently selected at each occurrence from the group consisting of -CH 2 -, -CHR C -, -0-, -S(0) g -, -NH- , -NRc-, -C(=0)-, -C(=0)0-, -C(=0)NH-, -C(=0)NR c -, -S(0) g NH-, -S(0)gNR c -, NHC(=0)-, -NR c C(=0)-, -NHS(0) g - , and -NRcS (0) g - ;where g is 0, 1, or 2; R B and R c are independently alkyl groups which may be further substituted with one or more substituent (s) selected from oxo, hydroxy, halogen, amino, cyano, nitro, Ci-Cghaloalkyl, Ci-Cghaloalkoxy, -0 (Cι-C 6 alkyl) , -NH(Cι-g alkyl), -N (Ci-Cgalkyl) (C_ . - 6 alkyl), -NHC (0) (d- Cgalkyl) , -N (alkyl) C (O) (d-C 6 alkyl) , -NHS(0) m (C_.- Cgalkyl) , -S (0) m (d-C 6 alkyl) , -S (O) m NH (Ci-Cgalkyl) , and -S (0) m N(Cι-C 6 alkyl) (Ci-Cgalkyl) ; where m is 0, 1, or 2 ; and Y is morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl, each of which is unsubstituted or further substituted with one or more substituents independently chosen from halogen, oxo, hydroxy, amino, mono- or di (C x - C s ) alkylamino, nitro, cyano, Ci-Cg alkyl, Ci-Cg alkoxy. Particularly preferred compounds and pharmaceutically acceptable salts of Formula II are those Where Ar is phenyl, 2-pyridyl, 3 -pyridyl or pyridinzyl, each of which is substituted at the position para to the point of attachment of Ar with one of: i) halogen, Ci-C alkyl, Ci-Cg alkoxy, mono- or di- (Ci- C 6 ) alkylamino, d-C 3 alkoxy (Ci-Cg) alkoxy, mono or di- (Ci- C δ ) alkylamino (Ci-Cg) alkoxy, or ii) Ci-Cg alkoxy substituted with morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl; and Ar is optionally further substituted with one or two substituents independently chosen from: halogen, C 1 -C 4 alkyl, d-C 4 alkoxy, amino, Ci-Cg alkylamino, Cι-C 3 alkoxy (Cι-C 3 ) alkoxy, d-C 3 alkylamino (Cι-C 3 ) alkoxy, amino (Cι-C 3 ) alkoxy, C 1 -C 3 alkylamino (C 1 -C 3 ) alkoxy, and Cι-C 6 alkoxy (Ci-Cg) alkylamino; R is Cι-C 4 alkoxy; and one, two, or three of R x and R 2 are independently hydrogen, halogen, methyl or ethyl, and the remaining R x and R 2 substituents are hydrogen. Other particularly preferred compounds and pharmaceutically acceptable salts of Formula II are those wherein Ar is phenyl or 2-pyridyl, each of which is substituted at the position meta to the point of attachment of Ar with one of i) halogen, Ci-C alkyl, d-C 6 alkoxy, mono- or di- (C x - C 6 ) alkylamino, Ci-C 6 alkoxy (Cι-C 6 ) alkoxy, mono or di- (Ci- C 6 ) alkylamino (Ci-Cg) alkoxy, or ii) Ci-Cg alkoxy substituted with morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl , tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl; and Ar is optionally further substituted with one or two substituents independently chosen from: halogen, Cι-C 4 alkyl, C1-C4 alkoxy, amino, d-C 6 alkylamino, Cι-C 3 alkoxy (Cι-C 3 ) alkoxy, C1-C3 alkylamino (C 1 -C 3 ) alkoxy, amino (C 1 -C 3 ) alkoxy, C 1 -C 3 alkylamino (C 1 -C 3 ) alkoxy, and Cι-C 6 alkoxy (Ci-Cg) alkylamino; R is C 1 -C 4 alkoxy; and one, two, or three of R x and R 2 are independently hydrogen, halogen, methyl or ethyl, and the remaining Ri and R 2 substituents are hydrogen. The invention further includes compounds where A is C-R 3 , i.e. compounds of Formula III Formula III and the pharmaceutically acceptable salts thereof, wherein n, R, Ri, R 2 , R 3 , and Ar are as defined for Formula I. Preferred compounds of Formula III are compounds wherein n is 1 (hereinafter compounds of Formula Ilia) . The invention is particularly directed to compounds and pharmaceutically acceptable salts of Formula III wherein Ar is phenyl, pyridyl, pyrimidinyl, pyrazolyl, or pyridizinyl, each of which is unsubstituted or substituted with up to three groups independently selected from halogen, cyano, nitro, Cι-C 6 haloalkyl, Ci-Cghaloalkoxy, hydroxy, amino, and Ci-Cgalkyl substituted with 0-2 R A , Ci-C 5 alkoxy substituted with 0-2 R A , -NH(Cι-Cgalkyl) substituted with 0-2 R A , and -N(Cι-Cgalkyl) ( Ci-Cgalkyl) where each alkyl is independently substituted with 0-2 R A , -XR B , and R C; R A is independently selected at each occurrence the group consisting of halogen, hydroxy, Cι-C 6 alkyl, Ci- Cgalkoxy, -NH (Ci-Cgalkyl ) , -N (C x -Cgalkyl ) (d-Cgalkyl ) , Ci-Cghaloalkyl, Ci-Cghaloalkoxy, -XR B and Y; X is independently selected at each occurrence from the group consisting of -CH 2 -, -CHR C -, -0-, -NH- , -NR C -, and -C(=0) -; R B and R c are independently Ci-Cg alkyl, C 3 -C 7 cycloalkyl , or C 3 -C 7 cycloalkyl (Ci-Cg) alkyl , each of is optionally substituted with one or more substituents independently selected from oxo, hydroxy, halogen, amino, cyano, nitro, Ci-Cg haloalkyl, Ci-C haloalkoxy, Ci-Cg alkyl, Ci-C alkoxy, mono- or di (d- C 6 ) alkylamino, -NHC (O) (Ci-Cgalkyl) , and -N(d-C 6 alkyl)C(O) (Ci-Cgalkyl) , where m is 0, 1, or 2; and Y is morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl. More preferably Ar in Formula III is phenyl, pyridyl, or pyridizinyl each of which is optionally mono-, di-, or tri- substituted with substituents independently chosen from halogen, Ci-Cg alkyl, Cι-C 6 alkoxy, amino, mono- or di (Ci- C 6 ) alkylamino, Ci-C 6 alkoxy (Ci-Cg) alkoxy, Ci-Cg alkylamino (Ci-Cg) alkoxy, amino (Ci-Cg) alkoxy, - di (Ci- Cg) alkylamino (d-C 6 ) alkoxy, C x -C 6 alkoxy (Ci- C 6 ) alkylamino, alkyl substituted with morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl, or Ci-Cg alkoxy substituted with morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl. The invention is also directed to compounds of Formula III in which R, R x , R 2 , R 3 and n are as defined for Formula III and Ar is phenyl, pyridyl, or pyridinzyl, each of which is substituted with one of i) halogen, Ci-Cg alkyl, Ci-Cg alkoxy, mono- or di- (Ci- C 6 ) alkylamino, Ci-C 6 alkoxy (Ci-Cg) alkoxy, mono or di- (Ci- C 6 ) alkylamino (Ci-Cg) alkoxy, or ii) Ci-C alkoxy substituted with morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl and Ar is optionally further substituted with one or two substitutuents independently chosen from: halogen, C 1 -C4 alkyl, Cι-C 4 alkoxy, amino, Ci-Cg alkylamino, Cι-C 3 alkoxy (Cι-C 3 ) alkoxy, Cι-C 3 alkylamino (C 1 -C 3 ) alkoxy, amino (C 1 -C 3 ) alkoxy, C 1 -C 3 alkylamino (C 1 -C 3 ) alkoxy, and Ci-Cgalkoxy (Ci-Cg) alkylamino . Such compounds are referred to hereinafter as compounds of Formula IIlb. Particularly preferred definitions for the variables Ri and R 2 of Formula III include hydrogen, Cι-C 2 alkyl, Cι-C 2 alkoxy, cyano, amino, and halogen. It is also preferred that not more than three of Ri and R 2 are other than hydrogen. More preferred compounds and salts of Formula III are those wherein one, two, or three of Ri and R 2 are independently chosen from hydrogen, halogen, methyl and ethyl, and the remaining Ri and R 2 substituents are hydrogen. Other preferred compounds and pharmaceutically acceptable salts of the invention are those wherein Ar is as defined for compounds of Formula 11lb; n and R 3 are as defined for Formula III; R is Cι-C 6 alkyl, Cι-C 6 alkoxy, phenyl (Ci-Cg) alkyl, pyridyl (Ci- C 6 ) alkyl, phenyl or pyridyl, wherein each phenyl or pyridyl is unsubstituted or mono-, di-, or tri-substituted with halogen, cyano, nitro, halo (Ci-Cg) alkyl, halo (Ci- C 6 ) alkoxy, hydroxy, amino, Ci-Cgalkyl substituted with 0-2 R A , Ci-Cgalkoxy substituted with 0-2 R A , -NH(Cι- e alkyl) substituted with 0-2 R A , -N (Ci-Cgalkyl) (Ci-Cgalkyl) where each Ci-Cgalkyl is independently substituted with 0-2 R A , phenyl substituted with 0-3 R A , -XR B/ and R c (X, R B , and R c are defined as for Formula III) and one, two, or three of Ri and R 2 are independently chosen from hydrogen, halogen, methyl and ethyl, and the remaining Ri and R 2 substituents are hydrogen. Such compounds are referred to as compounds of Formula IIIc. Particularly preferred compounds and salts of Formula IIIc are those wherein R is Ci- alkyl, Ci- alkoxy, or phenyl (Ci-Cg) alkyl, pyridyl (d-C 6 ) alkyl , phenyl or pyridyl, wherein each phenyl or pyridyl is unsubstituted or mono-, di-, or trisubstituted with substitutents independently chosen from halogen, cyano, nitro, Ci- Cghaloalkyl, Ci-Cghaloalkoxy, hydroxy, amino, Ci-Cg alkoxy, and Cι_ 6 alkyl. Other preferred compounds and pharmaceutically acceptable salts of Formula III are those wherein Ar is phenyl, pyridyl, pyrimidinyl, pyrazolyl, or pyridizinyl, each of which is unsubstituted or substituted with up to three groups independently selected from: halogen, cyano, nitro, Ci-Cghaloalkyl, Ci-Cghaloalkoxy, hydroxy, amino, and Ci-Cgalkyl substituted with 0-2 R A , Ci- Cgalkoxy substituted with 0-2 R A , -NH (Cι-C 6 alkyl) substituted with 0-2 R A , -N (Ci-Cgalkyl) (Cι-C 6 alkyl) where each alkyl is independently substituted with 0-2 R A , -XR B , and Rc,- R A is independently selected at each occurrence the group consisting of halogen, hydroxy, Cι-C 6 alkyl, Ci- C s alkoxy, -NH(Cι-Cgalkyl) , -N(d-C 6 alkyl) (d-C 6 alkyl) , _- Cghaloalkyl, Ci-Cghaloalkoxy, CO (Ci-Cgalkyl) , CONH(Cι- Cgalkyl) , CON (Ci-Cgalkyl) (Ci-Cgalkyl) , -XR B and Y; X is independently selected at each occurrence from the group consisting of -CH 2 -, -CHR C -, -0-, -S(0) g -, -NH- , -NRc-, -C(=0)-, -C(=0)0-, -C(=0)NH-, -C(=0)NR c -, -S(0) g NH-, -S(0)gNR c -, NHC(=0)-, -NR c C(=0)-, -NHS(0) n - , and -NR C S (0) n - ;where g is 0, 1 , or 2 ; R B and R c are independently alkyl groups which may be further substituted with one or more substituent (s) selected from oxo, hydroxy, halogen, amino, cyano, nitro, Ci-Cghaloalkyl, Ci-Cghaloalkoxy, -0 (Cι-C 6 alkyl) , -NH(Cι-g alkyl), -N (Ci-Cgalkyl) (Ci-g alkyl), -NHC (0) (Ci- Cgalkyl) , -N (alkyl) C (0) (Ci-Cgalkyl) , -NHS (0) m (Cι- Cgalkyl) , -S (0) m (Ci-C 5 alkyl) , -S (0) m NH (Ci-Cgalkyl) , and -S (0) m N(Cι-C 6 alkyl) (Ci-Cgalkyl) ; where m is 0, 1, or 2 ; and Y is morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl, each of which is unsubstituted or further substituted with one or more substituents independently chosen from halogen, oxo, hydroxy, amino, mono- or di (Ci- C 6 ) alkylamino, nitro, cyano, d-C 6 alkyl, d-C 6 alkoxy. Such compounds are referred to hereinafter as compounds of Formula Hid. Preferred compounds and pharmaceutically acceptable salts of Formula 11Id are those wherein R is Cι-C 4 alkyl, Cι-C 4 alkoxy, or phenyl, where the phenyl is mono- or di-substituted with substituents independently chosen from halogen, cyano, nitro, Ci-Cghaloalkyl, Ci-Cghaloalkoxy, hydroxy, amino, d-C 6 alkoxy, Ci-g alkyl, amino (Ci-Cg) alkyl , mono- or di (Ci-Cg) alkylamino (Ci- C 6 ) alkyl, and mono- or di (d-C 6 ) alkylamino (Cι-C 6 ) alkoxy. The invention specifically embraces compounds of Formulae IV, V, VI, VII, VIII, and IX. IV V In each of Formulae IV-IX, Zi and Z 2 are independently CH or nitrogen, each R, Ri and R 2 independently carries the same definition assigned with respect to Formula I, and R 2 _ and R 2i are independently hydrogen, halogen, Ci-C alkyl, Ci-C alkoxy, amino, mono- or di (Ci-Cg) alkylamino, Ci-Cg alkoxy (Cι-C 6 ) alkoxy, Ci-Cg alkylamino (Ci-Cg) alkoxy, amino (Ci-Cg) alkoxy, di (Ci- Cg) alkylamino (Ci-Cg) alkoxy, Cι-C 3 alkoxy (Ci-Cg) alkylamino, or (C 5 -C 7 ) heterocycloalkyl (Ci-Cg) alkoxy. Preferred heterocycloalkyl groups in Formulae IV-IX are morpholinyl, piperidinyl, and piperazinyl. Preferably one of R 20 and R 2i is hydrogen, Cι-C 2 alkyl, halogen, or Cι-C 2 alkoxy and the other is morpholinyl- or piperidinyl- (C 2 -C 4 ) alkoxy, or mono- or di (C 1 -C 3 ) alkylamino (C 2 -C 4 ) alkoxy. More preferably, one of R 20 and Rι is hydrogen or halogen and the other is mono- or di (C 1 -C 3 ) alkylamino (C 2 - C 3 ) alkoxy or morpholinyl- or piperidinyl- (C 2 -C 4 ) alkoxy . Preferred R groups in Formulae IV to IX include hydroxy and C 1 -C 3 alkoxy. More preferred R groups are methoxy and ethoxy. Particularly preferred compounds of Formulae IV to IX are those where one of R 20 and R 2i is hydrogen or halogen in the 2- or 3- position with respect to the point of attachment of the 6- membered aromatic ring to the amide nitrogen and the other is in the 3- or, more preferably, in the 4 -position with respect to the point of attachment to the amide nitrogen. In Formulae IV to IX, preferably one of Zi and Z is CH and the other is CH or both of Zi and Z 2 are CH. More preferred compounds of IV to IX are those where both Z x and Z 2 are CH . Preferably, Ri and R 2 are independently selected at each occurrence from hydrogen, halogen, hydroxy, Cι- 6 alkyl, Cι_ 6 alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, amino, mono- or di (Cι- 6 ) alkylamino . More preferably, R x and R 2 are independently selected at each occurrence from hydrogen, methyl and ethyl . Preferred R groups in Formulae IV-IX are R is Ci-g alkyl, Ci-g alkoxy, or phenyl (Ci-Cg) alkyl, pyridyl (Ci-Cg) alkyl , phenyl or pyridyl, where the aromatic portion of each is unsubstituted or mono-, di-, or trisubstituted with halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, hydroxy, amino, Ci-Cg alkoxy, or Ci-g alkyl. This invention provides fused pyrroleoxime and pyrazoleoxime derivatives. Preferred examples of the invention bind with high affinity to the benzodiazepine site of GABA A receptors, including human GABA A receptors. Particularly preferred compounds are those that bind with high selectivity to the benzodiazepine site of GABA A receptors, including human GABA A receptors. Without wishing to be bound to any particular theory, it is believed that the interaction of the compounds of Formula I with the benzodiazepine site results in the pharmaceutical utility of these compounds. The invention further comprises methods of treating patients in need of such treatment with an amount of a compound of the invention sufficient to alter the symptoms of a CNS disorder. Compounds of the inventions that act as agonists at c 2 β 3 γ 2 and 0^ 3 7 2 receptor subtypes are useful in treating anxiety disorders such as panic disorder, obsessive compulsive disorder and generalized anxiety disorder; stress disorders including post-traumatic stress, and acute stress disorders. Compounds of the inventions that act as agonists at c. 2 β 3 γ 2 and c. 3 β 3 γ 2 receptor subtypes are also useful in treating depressive or bipolar disorders and in treating sleep disorders. Compounds of the invention that act as inverse agonists at the c. 5 β 3 γ 2 receptor subtype or c_ιβ 2 γ 2 and c. 5 β 3 γ 2 receptor subtypes are useful in treating cognitive disorders including those resulting from Down Syndrome, neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, and stroke related dementia. Compounds of the invention that act as agonists at the c_ιβ 2 γ 2 receptor subtype are useful in treating convulsive disorders such as epilepsy. Compounds that act as antagonists at the benzodiazepine site are useful in reversing the effect of benzodiazepine overdose and in treating drug and alcohol addiction. The diseases and/or disorders that can also be treated using compounds and compositions according to the invention include: Depression, e.g. depression, atypical depression, bipolar disorder, depressed phase of bipolar disorder. Anxiety, e.g. general anxiety disorder (GAD), agoraphobia, panic disorder +/- agoraphobia, social phobia, specific phobia, Post traumatic stress disorder, obsessive compulsive disorder (OCD) , dysthymia, adjustment disorders with disturbance of mood and anxiety, separation anxiety disorder, anticipatory anxiety acute stress disorder, adjustment disorders, cyclothymia. Sleep disorders, e.g. sleep disorders including primary insomnia, circadian rhythm sleep disorder, dyssomnia NOS, parasomnias, including nightmare disorder, sleep terror disorder, sleep disorders secondary to depression and/or anxiety or other mental disorders, substance induced sleep disorder. Cognition Impairment, e.g. cognition impairment, Alzheimer's disease, Parkinson's disease, mild cognitive impairment (MCI), age-related cognitive decline (ARCD) , stroke, traumatic brain injury, AIDS associated dementia, and dementia associated with depression, anxiety or psychosis. Attention Deficit Disorder, e.g. attention deficit disorder (ADD) , and attention deficit and hyperactivity disorder (ADHD) . The invention also provides pharmaceutical compositions comprising compounds of the invention, including packaged pharmaceutical compositions for treating disorders responsive to GABA A receptor modulation, e.g., treatment of anxiety, depression, sleep disorders or cognitive impairment by GABA A receptor modulation. The packaged pharmaceutical compositions include a container holding a therapeutically effective amount of at least one GABA A receptor modulator as described supra and instructions (e.g., labeling) indicating the contained GABA A receptor ligand is to be used for treating a disorder responsive to GABA A receptor modulation in the patient. In a separate aspect, the invention provides a method of potentiating the actions of other CNS active compounds, which comprises administering an effective amount of a compound of the invention in combination with another CNS active compound. Such CNS active compounds include, but are not limited to the following: for anxiety, serotonin receptor (e.g. 5-HT 1A ) agonists and antagonists; for anxiety and depression, neurokinin receptor antagonists or corticotropin releasing factor receptor (CRFi) antagonists; for sleep disorders, melatonin receptor agonists; and for neurodegenerative disorders, such as Alzheimer's dementia, nicotinic agonists, muscarinic agents, acetylcholinesterase inhibitors and dopamine receptor agonists. Particularly the invention provides a method of potentiating the antidepressant activity of selective serotonin reuptake inhibitors (SSRIs) by administering an effective amount of a GABA agonist compound of the invention in combination with an SSRI . Combination administration can be carried out in a fashion analogous to that disclosed in Da-Rocha, et al . , J " . Psychopharmacology (1997) 11(3) 211-218; Smith, et al . , Am . J. Psychiatry (1998) 155(10) 1339-45; or Le, et al . , Alcohol and Alcoholism (1996) 31 Suppl . 127-132. Also see, the discussion of the use of the GABA A receptor ligand 3- (5-methylisoxazol-3- yl) -6- (l-methyl-l,2,3-triazol-4-yl) methyloxy-1 , 2 , 4-triazolo [3 , 4-a] phthalazine in combination with nicotinic agonists, muscarinic agonists, and acetylcholinesterase inhibitors, in PCT International publications Nos. WO 99/47142, WO 99/47171, and WO 99/47131, respectively. Also see in this regard PCT International publication No. WO 99/37303 for its discussion of the use of a class of GABA A receptor ligands, 1,2,4- triazolo [4, 3-b] pyridazines, in combination with SSRIs. The invention also pertains to methods of inhibiting the binding of benzodiazepine compounds, such as Rol5-1788, to the GABA A receptors which methods involve contacting a compound of the invention with cells expressing GABA A receptors, wherein the compound is' present at a concentration sufficient to inhibit benzodiazepine binding to GABA A receptors in vi tro . This method includes inhibiting the binding of benzodiazepine compounds to GABA A receptors in vivo, e.g., in a patient given an amount of a compound of Formula I that would be sufficient to inhibit the binding of benzodiazepine compounds to GABA A receptors in vi tro . In one embodiment, such methods are useful in treating benzodiazepine drug overdose. The amount of a compound that would be sufficient to inhibit the binding of a benzodiazepine compound to the GABA A receptor may be readily determined via an GABA A receptor binding assay, such as the assay described in Example 5. The GABA A receptors used to determine in vi tro binding may be obtained from a variety of sources, for example from preparations of rat cortex or from cells expressing cloned human GABA A receptors. The invention also pertains to methods for altering the signal-transducing activity, particularly the chloride ion conductance of GABA A receptors, said method comprising exposing cells expressing such receptors to an effective amount of a compound of the invention. This method includes altering the signal-transducing activity of GABA A receptors in vivo, e.g., in a patient given an amount of a compound of Formula I that would be sufficient to alter the signal -transducing activity of GABA A receptors in vi tro . The amount of a compound that would be sufficient to alter the signal-transducing activity of GABA A receptors may be determined via a GABA A receptor signal transduction assay, such as the assay described in Example 6. The GABA A receptor ligands provided by this invention and labeled derivatives thereof are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the GABA A receptor. Labeled derivatives of the GABA A receptor ligands provided by this invention are also useful as radiotracers for positron emission tomography (PET) imaging or for single photon emission computerized tomography (SPECT) . The compounds herein described may have one or more asymmetric centers . Compounds of the invention containing an asymmetrically substituted atom may be isolated in enantiomerically enriched or racemic form. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms (racemates) , by asymmetric synthesis, or by synthesis from optically active starting materials. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent; derivatizing with an enantiomerically enriched resolving reagent, separating the resulting diastereomers through means well known in the art, and removing the enantiomerically enriched resolving reagent through ordinary chemical means such as, for example, hydrolysis or hydrogenation; or chromatography, using, for example a chiral HPLC column. Many geometric isomers of olefins, carbon-nitrogen double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the invention. Cis and trans geometric isomers, as well as E and Z isomers of the compounds of the invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral (enantiomeric and diastereomeric), and racemic forms, as well as all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. Some compounds of the invention exist as tautomers . Unless otherwise specified, any description or claim of one tautomeric form is intended to encompass the other tautomer. The term "substituted", as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., =0), then 2 hydrogens on the atom are replaced. Unless otherwise specified, when a group is substituted with more than one substituent, it is understood that the substituents are the same or different. The invention includes all isotopes of atoms occurring in the compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include l C, 13 C, and 1 C. When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R * , then said group may optionally be substituted with up to two R * groups and each R * is selected independently from the definition of R * . Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. Also, for example, dialkylamino groups are understood to contain two alkyl, preferably d-C 6 alkyl, groups that may be the same or different. Thus, dialkylamino encompasses N-ethyl-N- methylamino, N, N-diethylamino, N,N-dimethylamino, N-methyl-N- propylamino, and the like. Where the term "alkyl" is used, either alone or within other terms such as "haloalkyl" and "alkylsulfonyl", it embraces linear and branched radicals having one to about twelve carbon atoms. Preferred alkyl radicals are "lower alkyl" radicals having one to about ten carbon atoms. More preferred are lower alkyl radicals having one to about six carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, and sec-pentyl and the like. Preferred alkyl groups are Cι-C 6 alkyl groups. Especially preferred alkyl groups are methyl, ethyl, propyl, butyl, 3 -pentyl. The term d-C 6 alkyl as used herein includes alkyl groups having from 1 to 6 carbon atoms. Preferred examples are methyl and ethyl . "Alkylsulfonyl" embraces alkyl groups attached to a sulfonyl radical, where alkyl is defined as above, i.e., a group of the formula -S0 a (alkyl) . More preferred alkylsulfonyl radicals are "lower alkylsulfonyl" radicals having one to six carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl . The term "alkylsulfinyl" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent -S(=0)- atom. The terms "N-alkylamino" and "N,N-dialkylamino" denote amino groups which have been substituted with one alkyl radical and with two alkyl radicals, respectively. More preferred alkylamino radicals are "lower alkylamino" radicals having one or two alkyl radicals of one to six carbon atoms, attached to a nitrogen atom. Suitable "alkylamino" may be mono or dialkylamino such as N-methylamino, N-ethylamino, N,N- dimethylamino, N,N-diethylamino or the like. The term "alkylthio" embraces groups containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. An example of "alkylthio" is methyl hio, (CH3-S-) . The term "cycloalkyl" embraces radicals having three to ten carbon atoms. More preferred cycloalkyl radicals are "lower cycloalkyl" radicals having three to seven carbon atoms, i.e., C 3 -C 7 cycloalkyl. Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl . In the term "C 3 -C 7 cycloalkylalkyl" , the C 3 _ 7 cycloalkyl group is attached to the parent molecular moiety through the alkyl, preferably a Ci-Cg, more preferably a C 1 -C 4 alkyl, group. This term encompasses, but is not limited to, eye1opropy1methy1 , and eye1ohex 1meth 1. By "carboxamido" as used herein is meant groups of the formula -C(0)NR'R'' where R' and R' ' are the same or different and represent hydrogen or alkyl . Preferred carboxamido groups are those where both of R' and R' ' are hydrogen. The term "alkenyl" embraces unsaturated straight and branched chain radicals having two to about ten carbon atoms. Such radicals contain at least one carbon-carbon double bond which may occur at any stable point along the chain. Examples of alkenyl groups include, but are not limited to such groups as ethenyl and propenyl . The term "alkynyl" embraces straight and branched chain radicals having two to about ten carbon atoms and at least one carbon-carbon triple bond. The carbon-carbon triple bond may occur at any stable point along the chain. Examples of alkynyl groups include, but are not limited to such groups as ethynyl and propynyl . "Alkoxy" represents an alkyl group as defined above attached to the parent molecular moiety through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, 2-butoxy, tert-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy . More preferred alkoxy groups include methoxy, ethoxy, isopropoxy, and isobutoxy. As used herein, "alkanoyl" refers to an alkyl group as defined above attached through a carbonyl bridge, i.e., -CO (alkyl). Examples include acetyl, propionyl, and butyryl . The term "aryl" is used to indicate aromatic groups that contain only carbon atoms in the ring structure. Thus, the term "aryl" refers to an aromatic hydrocarbon ring system containing at least one aromatic ring. The aromatic ring may optionally be fused or otherwise attached to other aromatic hydrocarbon rings or non-aromatic hydrocarbon rings. Examples of aryl groups are, for example, phenyl, naphthyl, 1,2,3,4- tetrahydronaphthalene, indanyl, and biphenyl . Preferred aryl groups include phenyl, naphthyl, including 1-naphthyl and 2- naphthyl, and acenaphthyl . More preferred aryl groups include phenyl and napthyl . The aryl groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups. Thus, such aryl groups are optionally substituted with, for example, Ci-Cg alkyl, Cι-C 6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- or di- (Ci- C 6 ) alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Cι-C 6 haloalkyl, Cι-C 6 haloalkoxy, amino (Ci-Cg) alkyl , mono- or di (Ci-Cg) alkylamino (C x - C 6 ) alkyl. The term "haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example -C V F W where v = 1 to 3 and w = 1 to (2v+l) . Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl , and pentachloroethyl . Preferred haloalkyl groups are halo(Cι- C s ) alkyl groups; particularly preferred are trifluoromethyl, perfluoropropyl, and difluoromethyl . By "haloalkoxy" as used herein is meant represents a haloalkyl group, as defined above, attached through an oxygen bridge to a parent group. Preferred haloalkoxy groups are halo (Ci-Cg) alkoxy groups. Examples of haloalkoxy groups are trifluoromethoxy, 2 , 2-difluoroethoxy, 2 , 2 , 3-trifluoropropoxy and perfluoroisopropoxy . Where the term "hydrocarbyl" is used, either alone or within other terms such as "hydrocarbylthio" and "hydrocarbylsulfinyl" , it embraces straight, branched, and cyclic hydrocarbon groups having from 1 to about 12 carbon atoms. The hydrocarbyl groups are saturated or unsaturated, i.e., they contain one or more carbon-carbon double or triple bonds. Examples of hydrocarbyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert- butyl, pentyl, 2 -pentyl, isopentyl, neopentyl, hexyl, 2 -hexyl, 3 -hexyl, 3-methylpentyl, vinyl, isobutenyl, 2-pentenyl, 3- undecenyl, 4-nonenyl, acetylenyl, 2 -methyl -pent-3 -ynyl , 1- methyl -hex-2 -ynyl, cyclopropylmethyl , cyclopropyl, cyclohexylmethyl , cyclohexyl and propargyl . When reference is made herein to Ci-Cg hydrocarbyl containing one or two double or triple bonds it is understood that at least two carbons are present in the group for one double or triple bond, and at least four carbons for two double or triple bonds. As used herein, the term "heteroaryl" means stable monocyclic, bicylclic and tricyclic ring systems which contain at least one aromatic ring where the aromatic ring contains from 5-7 members and from 1 to 4 hetero atoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; the remaining rings contain from 5-7 members selected from carbon, oxygen, nitrogen, and sulfur. The- aromatic ring containing a hetero atom is the "heteroaromatic ring." In bicyclic and tricyclic ring systems, the heteroaromatic ring may be fused to a carbocyclic ring that may be aromatic, such as benzo, or to a heteroaromatic ring, such as pyrido or pyrrolidino, or to heteroaromatic and one carbocyclic ring. Thus, "heteroaryl" includes ring systems having from one to three rings of from 5-7 ring members in each ring and where at least one ring is aromatic and contains from one to four hetero atoms . Any of the rings in the heteroaryl groups may be further fused to another ring forming a spiro ring system. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on any substitutable carbon or nitrogen atom that results in a stable compound. Examples of suitable heteraryl substituents are d-C 6 alkyl, Ci-Cg alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- or di- (Ci-Cg) alkylamino, C 2 - Cgalkenyl, C 2 -C 6 alkynyl , d-C 6 haloalkyl, Ci-Cg haloalkoxy, amino (Ci-Cg) alkyl, and mono- or di (Ci-Cg) alkylamino (Cι-C 6 ) alkyl . Examples of heteroaryl groups include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl , benzothiophenyl , benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl , benzisoxazolyl , benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1, 5 , 2-dithiazinyl, dihydrofuro [2 , 3 -b] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl , octahydroisoquinolinyl, oxadiazolyl, 1 , 2 , 3-oxadiazolyl, 1, 2 , 4-oxadiazolyl ; 1,2,5- oxadiazolyl, 1, 3 , 4-oxadiazolyl, oxazolidinyl , oxazolyl, oxazolidinyl , pyrimidinyl, phenanthridinyl , phenanthrolinyl, phenazinyl, phenothiazinyl , phenoxathiinyl , phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl , 6H-1, 2 , 5-thiadiazinyl, 1 , 2 , 3-thiadiazolyl , 1, 2 , 4-thiadiazolyl , 1, 2 , 5-thiadiazolyl, 1 , 3 , 4thiadiazolyl , thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1, 2 , 3 -triazolyl , 1, 2 , 4-triazolyl , 1, 2, 5-triazolyl, 1 , 3 , 4-triazolyl, and xanthenyl . Preferred heteroaryl groups include, but are not limited to, pyridinyl, pyrimidinyl, furanyl, and thienyl. As used herein, the term "heterocycloalkyl" is intended to mean a stable 5-to 7-membered monocyclic or 7-to 10-membered bicyclic ring system which contains at least one non-aromatic ring wherein said ring consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S. The heterocycloalkyl ring or heterocycloalkyl bicyclic ring system may be fused to a benzene ring. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and 0 atoms in the heterocycloalkyl group exceeds 1, then these heteroatoms are not adjacent to one another. It is also preferred that the total number of S and 0 atoms in the heterocycloalkyl is not more than 1. Examples of heterocycloalkyl groups include but are not limited to tetrahydroquinolinyl , tetrahydroisoquinolinyl, pyrrolyl, piperazinyl, piperidinyl, tetrahydrofuranyl , morpholinyl, azetidinyl, 2H-pyrrolyl . The term "halogen" indicates fluorine, chlorine, bromine, and iodine . The term "-0-" represents an oxygen linker. Thus, the terms -0-aryl" and "-O-heteroaryl" refer to aryl and heteroaryl groups as defined above connected though an oxygen atom to a parent molecular group. The terms "aryloxy" and "-0- aryl" are equivalent as used herein. In addition, the terms "heteroaryloxy" and "-O-heteroaryl" -are equivalent as used herein. Non-toxic pharmaceutically acceptable salts include, but are not limited to salts of inorganic acids such as hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic, and nitric or salts of organic acids such as formic, citric, malic, maleic, fumaric, tartaric, succinic, acetic, lactic, methanesulfonic, p-toluenesulfonic, 2 -hydroxyethylsulfonic, salicylic and stearic. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts. The invention also encompasses prodrugs of the compounds of Formula I . The invention also encompasses the acylated prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies, which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I . Pharmaceutical Preparations Those skilled in the art will recognize various synthetic methodologies that may be employed to prepare non-toxic pharmaceutically acceptable prodrugs of the compounds encompassed by Formula I. Those skilled in the art will also recognize a wide variety of non-toxic pharmaceutically acceptable solvents that may be used to prepare solvates of the compounds of the invention, such as water, ethanol, mineral oil, vegetable oil, and dimethylsulfoxide. The compounds of general Formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Oral administration in the form of a pill, capsule, elixir, syrup, lozenge, troche, or the like is particularly preferred. The term parenteral as used herein includes subcutaneous injections, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intrathecal injection or like injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier. One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations . These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1, 3-butanediol . Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides . In addition, fatty acids such as oleic acid find use in the preparation of injectables. The compounds of general Formula I may also be administered in the form of suppositories, e.g., for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols . Compounds of general Formula I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle. For administration to non-human animals, the composition may also be added to the animal feed or drinking water. It may be convenient to formulate these animal feed and drinking water compositions so that the animal ingests an appropriate quantity of the composition during a meal or throughout the course of the day. It may also be convenient to present the composition as a premix for addition to the feed or drinking water. Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day) . The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from abqut 1 mg to about 500 mg of an active ingredient. Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most disorders, a dosage regimen of 4 times daily or less is preferred. For the treatment of anxiety, depression, or cognitive impairment a dosage regimen of 1 or 2 times daily is particularly preferred. For the treatment of sleep disorders a single dose that rapidly reaches effective concentrations is desirable. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of. the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy. Preferred compounds of the invention will have pharmacological properties that include, but are not limited to oral bioavailability, low toxicity, low serum protein binding and desirable in vi tro and in vivo half-lives. Penetration of the blood brain barrier for compounds used to treat CNS disorders is necessary, while low brain levels of compounds used to treat peripheral disorders are often preferred. Assays may be used to predict these desirable pharmacological properties. Assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. Toxicity to cultured hepatocytes may be used to predict compound toxicity. Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals given the compound intravenously. Serum protein binding may be predicted from albumin binding assays . Such assays are described in a review by Oravcova, et al . (Journal of Chromatography B (1996) volume 677, pages 1-27) . Compound half-life is inversely proportional to the frequency of dosage of a compound. In vi tro half-lives of compounds may be predicted from assays of microsomal half-life as described by Kuhnz and Gieschen (Drug Metabolism and Disposition, (1998) volume 26, pages 1120-1127) . Preparation of compounds A general illustration of the preparation of compounds of Formula I in the invention is given in Scheme I . Scheme I R, Ri, R 2 , n, A and Ar are as defined in Claim 1. With respect to the preparation of the oximes of the invention (Scheme I) , an appropriately substituted amine (RNH 2 ) is added to a suspension of the pyrrole or pyrazole carboxamide starting material in ethanol or other suitable solvent. The reaction mixture is heated for approximately 16 hours and the solvent is removed in vacuo to yield the oxime product (formula I) ■ The preparation of pyrrole carboxamides (formula A where A=CR 3 ) can be accomplished according to the procedures set forth in U.S. Patent No. 5,804,686, which is hereby incorporated by reference. Suitable procedures are also described in U.S. Patent Application S.N. 09/387,311, filed August 31, 1999, and U.S. Patent Application S.N. 09/651,207, filed August 30, 2000, the disclosures of which are incorporated herein in their entirety. The preparation of such compounds is generally depicted in Scheme II. Also, see International Applications WO 97/2624 and WO 01/16103. The preparation of pyrazole carboxamides (Formula A where A is nitrogen) can be accomplished according to the procedures set forth in International Application WO 00/40565. Scheme II 3 The preparation of representative Ar-NH groups 1S depicted below in Schemes III (1) , (2) and (3) . Scheme III (1) TFAA (2) CS 2 C0 3 , DMF, 75 10% Pd/C, H 2 EtOH (3 ) R 18 R 19 NH, i-PrOH sealed tube , 100°C 19 ~ ] Pyridine , TFAA, R 19 = COCF 3 CH 2 C1 2 , 0°C ( for R 19 = H) In Schemes III (1) and (2) , R 9 and R i4 represent hydrogen or alkyl, preferably hydrogen or Cι-C 6 alkyl. In Scheme 111(3), Ri 8 and Rι 9 independently represent hydrogen or alkyl, preferably hydrogen or d-C 6 alkyl, or Rι 8 i 9 represents a heterocycloalkyl group such as morpholinyl, piperidinyl, or piperazinyl . The preparation of representative substituted pyridylamines useful as Ar-NH 2 groups for preparing compounds of Formula I as shown in Scheme II is depicted below in Scheme IV. In Scheme IV, R 30 represents hydrogen or hydrocarbyl substituted with up to two R A groups, preferably hydrogen or alkyl substituted with up to two R A groups. Scheme IV Scheme V The preparation of other representative substituted anilines useful as Ar-NH 2 groups for preparing compounds of Formula I as shown in Scheme II is depicted below in Scheme V. In Scheme V, R 35 represents hydrogen or Cι-C 6 alkyl, preferably ethyl . Those skilled in the art will recognize that it may be necessary to utilize different solvents or reagents to achieve some of the above transformations. Unless otherwise specified all reagents and solvent are of standard commercial grade and are used without further purification. The disclosures in this _ application of all articles and references, including patents, are incorporated herein by reference in their entirety. The invention is illustrated further by the following examples, which are not to be construed as limiting the invention in scope or spirit to the specific procedures described in them. Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the invention, as demonstrated by the following examples. In some cases, protection of reactive functionalities may be necessary to achieve some of the above transformations. In general, such need for protecting groups, as well as the conditions necessary to attach and remove such groups, will be apparent to those skilled in the art of organic synthesis. EXAMPLES Intermediates Example A. 4-Oxo-4 , 5 , 6, 7, 4-tetrahydro-lH-indazole-3-carboxylic acid ethyl ester A solution of 2-ethyloxalylcyclohexan-1, 3-dione ( Synthesis, 1976, 722) (9.50 g, 45 mmol) , hydrazine monohydrate (2.2 mL, 45 mmol), and acetic acid (2.6 mL, 45 mmol) in ethanol (100 mL) is stirred at room temperature for 6 hours. The solvent is evaporated under reduced pressure and the resulting residue is dissolved in acetic acid (100 mL) , heated to 120 °C and stirred under nitrogen for 3 hours. The reaction mixture is then cooled to about room temperature and concentrated. The concentrate is dissolved in chloroform (200 mL) , treated with 10% NaCI (100 mL) , and neutralized with 1 M sodium carbonate. The organic layer is separated, dried over Na 2 S0 4 , filtered and the solvent is evaporated to give 4-oxo-4, 5, 6, 7, 4-tetrahydro- lH-indazole-3-carboxylic acid ethyl ester (7.65 g, purity 90%, yield 73%). 2 H NMR (CDC1 3 ) δ 0.95 (t, J=7.1 Hz, 3 H) , 2.17 (quintet, J=6.4 Hz, 2 H) , 2.58 (t, J=6.8 Hz, 2 H) , 3.00 (t, J=6.2 Hz, 2 H) , 4.44 (q, J=7.3 Hz, 2 H) . MW (Calc'd) 208.220; MS (M + H) + 209. Example B. 4-0xo-4, 5, 6, 7, 4 -tetrahydro-lH-indazole-3 -carboxylic acid A solution of 4-oxo-4, 5, 6, 7-4-tetrahydro-lH-indazole-3- carboxylic acid ethyl ester (purity 90%, 1.84 g, 8.0 mmol) in methanol (20 L) is treated with 10 N NaOH (4 L) and stirred under nitrogen at 60 °C for 90 minutes. The reaction mixture is cooled to approximately room temperature and the solvent is evaporated under reduced pressure. The resulting residue is dissolved in water (30 mL) , treated with brine (30 mL) , and acidified to pH 2 with cone, hydrochloric acid to produce copious precipitate. The mixture is cooled to 0°C, filtered, the solid is washed with water (5 mL) , and dried in a vacuum oven to give 4-oxo-4 , 5 , 6, 7 , 4-tetrahydro-lH-indazole-3- carboxylic acid (0.99 g, 66%) . X H NMR (DMS0-d 6 ) δ 2.18 (quintet, J=6.2 Hz, 2 H) , 2.66 (t, J=6.4 Hz, 2 H) , 2.95 (t, J=6.2 Hz, 2 H) . Example C. 4-Oxo-4 , 5 , 6, 7 , 4 -tetrahydro-lH-indazole-3 -carboxylic acid 4- [2- (propylamino) ethoxy] phenylamide Ethyl chloroformate (0.24 mL, 2.5 mmol) is added to a -5 3 C solution of 4-oxo-4 , 5, 6, 7-4-tetrahydro-lH-indazole-3- carboxylic acid (180 mg, 1.0 mmol) and triethylamine (0.56 mL, 4.0 mmol) in anhydrous DMF (3.0 mL) . The mixture is stirred at 0 °C for 2 hours. [2- (4-Amino-phenoxy) -ethyl] -propyl-carbamic acid tert-butyl ester (294 mg, 1.0 mmol) is then added. The resulting mixture is stirred at room temperature for 16 hours and then at 50 °C for one hour. Methanol (2 mL) and 4 M KOH (1 mL) are then added, and the stirring at 50 °C is continued for an additional one hour. The reaction mixture is then poured into water (30 mL) , neutralized with 1 M HCI, treated with 5% sodium bicarbonate (30 mL) , and extracted with ethyl acetate (50 mL) . The ethyl acetate layer is washed with water (50 mL) , dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is dissolved in chloroform (3 mL) , treated with trifluoroacetic acid (2 L) , and stirred at room temperature for 3 hours . The reaction mixture is diluted with ethyl acetate (100 L) , washed with 1 M sodium carbonate (100 mL) , dried over anhydrous sodium carbonate, filtered and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography using chloroform-methanol-acetic acid (80:16:4, v/v/v) as the eluent to give 95 mg (26%) of 4-oxo-4 , 5, 6, 7, 4-tetrahydro-lH-indazole- 3-carboxylic acid 4- [2- (propylamino) ethoxy] phenylamide . 1 H NMR (CDC1 3 ) δ 0.95 (t, J=7.3 Hz, 3 H) , 1.68 (quintet, J=7.5 Hz, 2 H) , 2.19 (m, 2 H) , 2.65 (m, 2 H) , 2.94 (t, J=7.5 Hz, 2 H) , 3.00 (m, 2 H) , 3.24 (m, 2 H) , 4.28 (m, 2 H) , 6.50 (bs, 2 H) , 6.92 (d, J=9.0 Hz, 2 H) , 7.69 (d, J=9.0 Hz, 2 H) , 12.3 (s, 1 H) . MW (calculated) 356.429; MS (M + H) + 357. Example P. 4-0xo-4 , 5, 6, 7, 4-tetrahydro-lH-indazole-3-carboxylic acid [3-fluoro-4- (2- (morpholin-4-yl-ethoxy) phenyl] -amide A mixture of 4-oxo-4 , 5, 6, 7, 4-tetrahydro-lH-indazole-3- carboxylic acid (188 mg, 1.0 mmol), anhydrous DMF (4 mL) , anhydrous dichloromethane (8 mL) , 1- [3- (dimethylamino) propyl] - 3-ethylcarbondiimide hydrochloride (287 mg, 1.5 mmol, DMAP (183 mg, 1.5 mmol), and 3-fluoro-4- (2 -morpholin-4-yl-ethoxy) - phenylamine (288 mg, 1.2 mmol) is stirred under nitrogen at room temperature for 3 days. The reaction mixture is poured into 10% NaCI (50 mL) and extracted with chloroform (2 x 50 mL) . The combined chloroform extracts are dried over Na 2 C0 3 , filtered and the solvent is evaporated under reduced pressure. The resulting residue is chromatographed on preparative silica gel plates using chloroform-methanol -acetic acid (70:24:6, v/v/v) as the eluent to give 130 mg (32%) of pure 4-oxo- 4 , 5, 6, 7, -tetrahydro-lH-indazole-3-carboxylic acid [3-fluoro-4- (2- (morpholin-4-yl-ethoxy) phenyl] -amide, as a white solid. ^ " H NMR (CD 3 OD) δ 2.19 (quintet, J=6.0 Hz, 2 H) , 2.65 (m, 6 H) , 2.86 (t, J=5.5 Hz, 2 H) , 2.95 (t, J=6.2 Hz, 2 H) , 3.77 (t, J=4.6 Hz, 4 H) , 4.20 (t, J=5.5 Hz, 2 H) , 7.01 (t, J=9.0 Hz, 1 H) , 7.36 (m, 1 H) , 7.83 (dd, J=13.2 and 2.4 Hz, 1 H). MW 402.432 (calculated); MS (M + H) + 403. Example E. 4-Oxo-4 , 5 , 6, 7-tetrahydro-lH-indazole-3-carboxylic acid [6- (2-propylamino-ethoxy) -pyridin-3-yl] -amide A mixture of 4-oxo-4 , 5, 6, 7, 4-tetrahydro-lH-indazole-3- carboxylic acid (188 mg, 1.0 mmol), anhydrous DMF (4 mL) , anhydrous dichloromethane (8 mL) , 1- [3- (dimethylamino) propyl] - 3-ethylcarbondiimide hydrochloride (287 mg, 1.5 mmol), DMAP (183 mg, 1.5 mmol), and [2- (5-amino-pyridin-2-yloxy) -ethyl] - propyl-carbamic acid tert-butyl ester (354 mg, 1.2 mmol) is stirred under nitrogen at room temperature for 3 days. The reaction mixture is then poured into 10% aqueous NaCI (50 mL) and extracted with chloroform (2 x 50 mL) . The combined chloroform extracts are dried over Na 2 C0 3 , filtered and concentrated to afford a residue. The residue is dissolved in chloroform (10 mL) , treated with trifluoroacetic acid (5 mL) , and stirred under nitrogen at room temperature for 5 hours. The reaction mixture is evaporated under reduced pressure and the resulting residue is partitioned between chloroform (80 mL) and 1 M Na 2 C0 3 (50 mL) . The layers are separated and the chloroform layer is dried over anhydrous Na 2 C0 3 , filtered and concentrated. The concentrate was purified by preparative thin layer chromatography using 2000 μm silica gel plates and chloroform-methanol-acetic acid (70:24:6, v/v/v) as the eluent to give 150 mg (42%) of 4-oxo-4 , 5, 6, 7-tetrahydro-lH-indazole-3- carboxylic acid [6- (2-propylamino-ethoxy) -pyridin-3-yl] -amide as a white solid. X H NMR (CDC1 3 ) δ 0.95 (t, J=7.3 Hz, 3 H) , 1.70 (quintet, J=7.7 Hz, 2 H) , 2.22 (t, J=6.1 Hz, 2 H) , 2.67 (t, J=6.0 Hz, 2 H) , 2.92 (t, J=7.5 Hz, 2 H) , 3.06 (t, J=6.0 Hz, 2 H) , 3.29 (t, J=4.9 Hz, 2 H) , 4.51 (t, J=4.8 Hz, 2 H) , 6.49 (d, J=8.8 Hz, 1 H) , 7.80 (dd, J=8.8 and 2.6 Hz, 1 H) , 8.62 (d, J=2.6 Hz, 1 H) . MW 357.417 (calculated); MS (M + H) + 358, m.p. 120 °C. Example F. 4-Oxo-4 , 5 , 6, 7-tetrahydro-lH-indazole-3-carboxylic acid [6- (2-ethylamino-ethoxy) -pyridin-3-yl] -amide The title compound is obtained from a reaction of 4-oxo- 4, 5, 6, 7, 4-tetrahydro-lH-indazole-3 -carboxylic acid (188 mg, 1.0 mmol) with [2- (5-amino-pyridin-2-yloxy) -ethyl] -ethyl-carbamic acid tert-butyl ester (338 mg, 1.2 mmol) in the presence of 1- [3- (dimethylamino) propyl] -3-ethylcarbondiimide hydrochloride (287 mg, 1.5 mmol) and DMAP (183 mg, 1.5 mmol) using the procedure described above in Example 4. Yield: 120 mg (35%) of the desired product as a white solid. X H NMR (CD 3 OD) δ 1.17 (t, J=7.1 Hz, 3 H) , 2.24 (quintet, J=6.4 Hz, 2 H) , 2.70 (t, J=6.4 Hz, 2 H) , 2.75 (q, J=7.0 Hz, 2 H) , 2.98 (t, J=6.2 Hz, 2 H) , 3.03 (t, J=5.1 Hz, 2 H) , 4.41 (t, J=5.3 Hz, 2 H) , 6.82 (d, J=9.0 Hz, 1 H) , 8.11 (dd, J=8.8 and 2.4 Hz, 1 H) . MW 343.390 (calc'd); MS (M + H) + 344. Example G. 4 -oxo-4, 5,6, 7-tetrahydrobenzofuran-3 -carboxylic acid 4-0x0-4, 5, 6, 7-tetrahydrobenzofuran-3 -carboxylic acid is prepared according to the following procedure. Potassium hydroxide (345 g, 6.15 mol) is dissolved in methyl alcohol (1.2 L) then cooled in an ice water bath. A solution of cyclohexanedione (714 g, 6.15 mol) in methyl alcohol (1.2 L) , dissolved using gentle heat, is added dropwise to the cold, stirred KOH solution over 2 h. A solution of ethyl bromopyruvate (1200 g, 6.15 mol) in methyl alcohol (1.5 L) is then added dropwise over 3 h. The reaction mixture is allowed to reach ambient temperature and stirred an additional 14.5 h. While cooling the reaction mixture via a water bath, a solution of sodium hydroxide (492 g, 12.4 mol) in water (984 mL) is added dropwise over 2.5 h. After stirring at ambient temperature for 15.5 h, the reaction mixture is cooled in an ice water bath, 500 g of ice added, and the resulting mixture is then acidified with concentrated hydrochloric acid ( ca IL) to pH 1. The reaction mixture is concentrated in vacuo, IL of ice is added, and the precipitate filtered, washed with ice water (3 X 200 mL) , and then dried in a vacuum oven at 75° C to afford 4-oxo-4 , 5, 6, 7-tetrahydrobenzofuran-3 -carboxylic acid (560 g) . m.p. 137-138° C. Example H. 4-oxo-4 ,5,6, 7-tetrahydroindole-3-carboxylate To a stirred mixture of 4-oxo-4 , 5 , 6, 7- tetrahydrobenzofuran-3 -carboxylic acid (640 g, 3.55 mol), potassium carbonate (1.7 kg, 10.65 mol) and cesium carbonate (100 g, 0.32 mol) in N,N-dimethylformamide (9 . 0 L) is added iodoethane (1250 g, 8.01 mol) . The mixture is heated at 60° C for 2 h. After cooling to ambient temperature, the mixture is filtered, the solid is rinsed with ethyl acetate, and the filtrate concentrated in vacuo . Water (2 L) is added then extracted with ethyl acetate (2 X 2L) ; the combined organic extracts are washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give ethyl 4-oxo- 4, 5, 6, 7-tetrahydrobenzofuran-3-carboxylic acid (642 g) . A mixture of this ester (640 g, 3.07 mol) and ammonium acetate (426 g, 5.53 mol) in N,N-dimethylformamide (320 mL) is heated to 100° C for 2 h. The reaction mixture is concentrated in vacuo , ice water (2.5L) is added, and extracted with dichloromethane (2 X 3L) ; the combined organic extracts are washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give ethyl 4-oxo-4 , 5 , 6, 7- tetrahydroindole-3-carboxylate (357 g) . A mixture of this ester (170 g, 0.82 mol) in ethyl alcohol (250 mL) and a solution of sodium hydroxide (165 g, 4.1 mol) in water (1 L) is heated at reflux for 1 h, then cooled in an ice water bath. Concentrated hydrochloric acid (350 mL) is added dropwise, the precipitate collected by filtration, rinsed with ice water (3 X) , and dried in a vacuum oven at 75° C to afford 4-oxo- 4,5, 6, 7-tetrahydroindole-3-carboxylate (125 g) . m.p. 269-270° C. Example I . 4- [N-trifluoroacetyl- (methylaminomethyl) aniline A solution of p-nitrobenzylbromide (5.40 g, 25 mmol) in acetonitrile (60 ml) is added dropwise to a stirred solution of aqueous methylamine (65 mL, 40 wt.%, 0.75 mol) in acetonitrile (50 mL) at 0°C. After stirring an additional 15 minutes, the solution is poured into brine and extracted 2X with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 4- (methylaminomethyl) nitrobenzene (4.04g). A solution of trifluoracetic anhydride (4.46 mL, 31.6 mmol) in dichloromethane (10 mL) is added dropwise to a stirred solution of 4- (methylaminomethyl) nitrobenzene (4.04g, 24.3 mmol) and pyridine (2.16 mL, 26.7 mmol) in dichloromethane (25 mL) at 0°C. After stirring an additional 30 minutes, the solution is poured into aqueous 3.6N hydrochloric acid and extracted with dichloromethane. The organic layer is washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 4- [N-trifluoroacetyl- (methylaminomethyl) ] nitrobenzene (6.55 g) . Crude 4- [N-trifluoroacetyl- (methylaminomethyl) ] nitrobenzene (6.55 g) is dissolved in ethyl alcohol (75 mL) , added tol0% Pd/C (655 mg) in a Parr bottle and shaken under Hydrogen (50 PSI) for 4 hours. The mixture is filtered through Celite and concentrated in vacuo to give 4- [N- trifluoroacetyl- (methylaminomethyl) aniline (5.75 g) . Example J. 4 -amino- (N-trifluoroacetyl-2 - methylaminoethoxy) benzene A mixture of p-nitrophenol (1.39 g, 10 mmol), 2- chloroethoxytrimethylsilane (3.2 ml, 20 mmol), potassium carbonate (4.15 g, 30 mmol), cesium carbonate (163 mg, 0.5 mmol) , and sodium iodide (149 mg, 1 mmol) in N,N- dimethylformamide ( 10 ml) is heated at 75°C for 19.5 hours. After cooling to ambient temperature, the mixture is diluted with ethyl acetate and filtered. The filtrate is washed with saturated aqueous sodium bicarbonate, then washed 2X with water, dried over magnesium sulfate, filtered, concentrated in vacuo, and purified on Silica gel (1:1 ethyl acetate/hexanes) to give 4 -nitro- (2 -Hydroxyethoxy) benzene (1.25 g) . 4-Nitro- (2 -Hydroxyethoxy) benzene (1.13 g, 6.2 mmol) in thionyl chloride (10 mL) is heated at reflux for 3 hours then concentrated in vacuo . After cooling the residue in an ice water bath, saturated aqueous sodium bicarbonate is added and the precipitate collected, rinsed with water, and dried to give 4-nitro- (2 -chloroethoxy) benzene (909 mg) . A mixture of 4-nitro- (2 -chloroethoxy) benzene (781 mg, 3.9 mmol) and aqueous methylamine (15 mL, 40 wt . %) in isopropyl alcohol (15 mL) is heated in a sealed tube at 100° for 4 hours. After cooling in an ice water bath, the mixtured is poured into brine and extracted 2X with dichloromethane, dried over sodium sulfate, filtered, and concentrated in vacuo to give 4 -nitron-methylaminoethoxy) benzene (697 mg) . To a solution of 4-nitro- (2 -methylaminoethoxy) benzene (766 mg, 3.9 mmol) and pyridine (0.35 mL, 4.29 mmol) in dichloromethane (5 mL) at 0° C is added dropwise trifluroacetic anhydride (0.72 mL, 5.08 mmol). After stirring at 0° C for 3.5 hours, the mixture is poured into aqueous 1.2 N hydrochloric acid and extracted with dichloromethane. The organic layer is washed with saturated aqueous sodium bicarbonate then brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 4-nitro- (N-trifluoroacetyl-2 -methylaminoethoxy) benzene (1.06 g) . Treatment of this nitro compound with 10% Palladium on carbon in ethyl alcohol (18 mL) in a Parr bottle under Hydrogen (55 PSI) for 2.25 hours affords 4-amino- (N- trifluoroacetyl-2 -methylaminoethoxy) benzene (709 mg) . Example K To a stirred solution of 4-oxo-4 , 5 , 6, 7-tetrahydro-lH- indole-3 -carboxylic acid (100 mg, 0.6 mmol) and triethylamine (0.15 mL, 1.1 mmol) in N,N-dimethylformamide (5 mL) at 0° C is added ethyl chloroformate (0.1 mL, 1.1 mmol). After stirring an additional 1 hour, 3- (N-trifluoroacetyl- (methylaminomethyl) aniline (0.3 g, 1.3 mmol ) is added. The reaction mixture is stirrred for 4 hours, then poured into saturated aqueous ammonium chloride and extracted 2X with ethyl acetate. The combined organic layers are washed sequentially with brine, aqueous 2N hydrochloric acid, then brine, dried over sodium sulfate, filtered, and concentrated in vacuo . To the residue is added 15% aqueous potassium bicarbonate (5 mL) and methyl alcohol (3 mL) , then heated at reflux for 3 hours. After cooling, the reaction mixture is extracted with ethyl acetate, the organic layer dried over sodium sulfate, filtered, and concentrated in vacuo to give N-[3- (methylaminomethyl) phenyl] -4-oxo-4, 5,6, 7-tetrahydro-lH-indole- 3-carboxamide . m.p. 130-132°C. Example L A mixture of 4-oxo-4 , 5, 6, 7-tetrahydro-lH-indole-3- carboxylic acid (179 mg, 1 mmol) , p-anisidine (616 mg, 5 mmol) , and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride [EDCI] (959 mg, 5 mmol) in 50% aqueous 1,4-dioxane (10 mL) was stirred at ambient temperature for 17 h. After concentrating in vacuo, the residue was taken up in 10% methanol in ethyl acetate, washed with 1.3M hydrochloric acid then with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo . Recrystallization from ethyl acetate afforded N- (4-methoxyphenyl) -4-oxo-4 , 5, 6, 7-tetrahydro-lH- indole-3-carboxamide (Compound 1); mp 219-220°C. Example M N- (2-Fluoro-4-methoxyphenyl) -4-benzyloxy-lH-indole-3- carboxamide (1.34 g, 3.4 mmol), prepared using the method above, was slurried with 10% palladium on carbon (134 mg) in ethanol (35 mL) in a Parr bottle and placed under a hydrogen atmosphere (50 psi) for 5 h. Methanol (5 ml) was added and the mixture returned to the Hydrogen atmosphere for an additional 18 h. The solution was filtered through Celite, concentrated in vacuo, and the residue purified by flash chromatography to afford N- (2-fluoro-4-methoxyphenyl) -4-hydroxy-lH-indole-3- carboxamide (Compound 2) as a beige solid; mp 259-261°C (d). Example N A mixture of 4-oxo-4 , 5 , 6, 7-tetrahydro-lH-indole-3- carboxylic acid (179 mg, 1 mmol), aniline (0.46 mL, 5 mmol), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (959 mg, 5 mmol) in 50% aqueous dioxane (10 mL) was allowed to stir at ambient temperature for 17.5 hours, then concentrated in vacuo . The residue was cooled in an ice water bath, aqueous 3.6 N hydrochloric acid was added, and the precipitate collected, rinsed with aqueous 3.6 N hydrochloric acid then water and dried. Recrystallization from ethyl alcohol afforded N-phenyl-4-oxo-4, 5,6, 7-tetrahydro-lH-indole-3-carboxamide (Compound 35) (164 mg) . mp 225-226° C. Example O To a solution of 4-oxo-4 , 5 , 6, 7-tetrahydro-lH-indole-3- carboxylic acid (538 mg, 3 mmol) and triethylamine (0.88 mL, 6.3 mmol) in N,N-dimethylformamide (15 mL) at 0° C was added ethyl chloroformate (0.57 L, 6 mmol) . After stirring at 0° C for 45 minutes, 2-fluoroaniline (0.58 mL, 6 mmol) wad added. The mixture was stirred for an additional 45 minutes, then allowed to stir at ambient temperature for 14 hours. The mixture was poured into aqueous 1.2 N hydrochloric acid and extracted 2X with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo . To the residue was added aqueous IN sodium hydroxide (10 mL) and ethyl alcohol (2 mL) and the mixture heated at reflux for 4.5 hours. After cooling in an ice water bath, the mixture was acidified with aqueous hydrochloric acid, the precipitate collected, rinsed with water and dried. Recrystallization from ethyl alcohol afforded N- (2- fluorophenyl ) -4-oxo-4, 5,6, 7-tetrahydro-lH-indole-3-carboxamide (Compound 46) (530 mg) . mp 238-240° C. Example 1 . Preparation of 4-methoxyimino-4 / 5, 6, 7-tetrahydro-lH-indole-3- carboxylic acid (2 -fluoro-phenyl) -amide 4-OXO-4, 5, 6, 7-tetrahydro-lH-indole-3-carboxylic acid (2- fluoro-phenyl) -amide (0.73 mmol), pyridine (2.2 mmol), EtOH (10 ml) and methoxylamine hydrochloride (2.2 mmol) are combined in a sealed tube and heated at 120 °C for 16 hours. The reaction mixture is cooled to room temperature, the solvent is removed in vacuo and the residue is treated with 10 ml of H 2 0 for 5 minutes. The resulting solid is collected by vacuum filtration to yield 160 mg (72%) of 4-methoxyimino-4 , 5, 6 , 7-tetrahydro-lH- indole-3 -carboxylic acid (2-fluoro-phenyl) -amide as a white solid. X H NMR (DMS0-d s ) δ 1.80-1.86 (m, 2H) , 2.62-2.73 (m, 4H) , 3.81 (s, 3H) , 7.10-7.29 (m, 3H) , 7.48 (d, 1H) , 8.01 (t, 1H) , 11.70 (s, 1H) , 11.81 (s, 1H) . Example 2 The following compounds (shown in Table 1) are prepared essentially according to the procedures shown in Schemes I-V and further illustrated in the Examples. Table 1 Exampl R A Ar Compound Name X H NMR e chemical shift Number 4- (4-Propyl-phenylimino) - 4,5,6,7-tetrahydro-lH- indazole-3 -carboxylic acid (4- op 1- hen l) -amide (CH 3 ) 2 CH- N 4-Isopropylimino-4, 5, 6, 7- tetrahydro-lH-indazole-3- carboxylic acid (3-fluoro-4- methoxy-phenyl) -amide CH 3 CH 2 0- CH 4-Ethoxyimino-4, 5,6,7- (CDC1 3 ) 1.22 (t, 3H) , tetrahydro-lH-indole-3- 1.91-1.95 (m, 2H) , carboxylic acid (2 -fluoro2.63 (t, 2H) , 2.80 (t, phenyl) -amide 2H) , 4.20 (q, 2H) , 7.10-7.18 (m, 3H) , 7.60 (s, 1H) , 8.03 (t, 1H) , 9.82 (s, 1H) , 12.20 (s, 1H) (CH 3 ) 2 CHO- CH 4- (2-propoxy) imino-4, 5,6,7- (CDC1 3 ) 1.21 (d, 6H) , tetrahydro-1H-indole-3- 1.87-1.94 (m, 2H) , carboxylic acid (2-fluoro2.63 (t, 2H) , 2.77 (t, phenyl) -amide 2H) , 4.42-4.49 (m, 1H) , 7.09-7.16 (m, 3H) , 7.59 (d, 1H) , 7.94 (t, 1H) , 9.88 (s, 1H0, 12.20 (s, 1H) (CH 3 )0- N 4-Methoxyimino-4, 5,6,7- -NH tetrahydro-lH-indazole-3- 7.46 (d, IH) , 7.75 (d, IH) , 11.67 (s, IH) , 11.90 (s, IH) 6.62 (d, IH) , 7.18 (d, IH) , 7.21 (t, IH) , 7.41 (s, IH) , 7.47 (S, IH) , 11.68 (s, IH) , 10 (CH 3 )0- N 11 CH 3 CH 2 0- N 4-Ethoxyimino-4, 5,6,7- tetrahydro-lH-indazole-3- carboxylic acid (3-fluoro-4- methoxy-phenyl) -amide 12 (CH 3 )0- N 4-Methoxyimino-4, 5,6,7- tetrahydro-lH-indazole-3- carboxylic acid [6- (2- propylamino-ethoxy) -pyridin- 3-yl] -amide 13 CH 3 CH 2 0- N 4-Ethoxyimino-4 ,5,6,7- tetrahydro-IH-indazole-3 - carboxylic acid [6-(2- propylamino-ethoxy) -pyridin- 3-yl] -amide 14 (CH 3 )0- N 15 CH 3 CH 2 0- N 16 (CH 3 )0- N 4-Methoxyimino-4, 5,6,7- tetrahydro-lH-indazole-3- carboxylic acid [4- (2- propylamino-ethoxy) -3- ON fluoro-phenyl] -amide 17 CH 3 CH 2 0- N 4-Ethoxyimino-4, 5,6,7- tetrahydro-lH-indazole-3- carboxylic acid [4- (2- propylamino-ethoxy) -3- fluoro-phenyl] -amide CH 3 CH 2 0- N - pyridin-3-yl] -amide 20 (CH 3 )0- N 4-Methoxyimino~4, 5,6,7- tetrahydro-lH-indazole-3- carboxylic acid [6- (3- dimethylamino-propoxy) - pyridin-3-yl] -amide 21 CH 3 CH 2 0- N 4-Ethoxyimino-4, 5,6,7- tetrahydro-lH-indazole-3- carboxylic acid [6- (3- dimethylamino-propoxy) - pyridin-3-yl] -amide 22 CH 3 0- N 4-Methoxyimino-4, 5,6,7- tetrahydro-lH-indazole-3- carboxylic acid [6- (2- ethoxy-ethoxy) -pyridin-3- yl] -amide 23 CH 3 CH 2 0- N 4-Ethoxyimino-4, 5,6,7- 4-Methoxylimino-4, 5,6,7- tetrahydro-lH-indazole-3- carboxylic acid (6- propylamino-pyridazin-3-yl) amide 4-Ethoxylimino-4,5, 6,7- tetrahydro-lH-indazole-3- carboxylic acid (6- propylamino-pyridazin-3 -yl) amide 26 CH 3 CH 2 0- N 27 CH 3 CH 2 0- N 28 CH 3 0- N 4-Methoxyimino-4, 5,6,7- tetrahydro-lH-indazole-3- carboxylic acid [6- (3- diethylamino-propoxy) - pyridin-3 -yl] -amide 29 CH 3 CH 2 0- N 4-Ethoxyimino-4, 5,6,7- tetrahydro-lH-indazole-3 ■ carboxylic acid [6-(3- diethylamino-propoxy) - pyridin-3 -yl] -amide 30 HO- N 31 CH 3 0- N 32 CH 3 0- N 4-Methoxyimino-4,5, 6, 7- tetrahydro-lH-indazole-3- carboxylic acid [6- (3- dimethylamino-propoxy) - pyridin-2-yl] -amide -4 Example 3 Preparation of radiolabeled probe compounds of the invention The compounds of the invention are prepared as radiolabeled probes by carrying out their synthesis using precursors comprising at least one atom that is a radioisotope. The radioisotope is preferably selected from of at least one of carbon (preferably 1 C) , hydrogen (preferably 3 H) , sulfur (preferably 35 S) , or iodine (preferably 125 I) . Such radiolabeled probes are conveniently synthesized by a radioisotope supplier specializing in custom synthesis of radiolabeled probe compounds. Such suppliers include Amersham Corporation, Arlington Heights, IL; Cambridge Isotope Laboratories, Inc. Andover, MA; SRI International, Menlo Park, CA; Wizard Laboratories, West Sacramento, CA; ChemSyn Laboratories, Lexena, KS; American Radiolabeled Chemicals, Inc., St. Louis, MO; and Moravek Biochemicals Inc., Brea, CA. Tritium labeled probe compounds are also conveniently prepared catalytically via platinum-catalyzed exchange in tritiated acetic acid, acid-catalyzed exchange in tritiated trifluoroacetic acid, or heterogeneous-catalyzed exchange with tritium gas. Such preparations are also conveniently carried out as a custom radiolabeling by any of the suppliers listed in the preceding paragraph. In addition, tritium may also be introduced by tritium-halogen exchange with tritium gas, transition metal catalyzed tritium gas reduction of unsaturated bonds, or sodium borotritide reduction of ketones, aldehydes, and imines . Example 4 Receptor autoradiography Receptor autoradiography (receptor mapping) is carried out in vitro as described by Kuhar in sections 8.1.1 to 8.1.9 of Current Protocols in Pharmacology (1998) John Wiley & Sons, New York, using radiolabeled compounds of the invention prepared as described in the preceding Example. Example 5 Binding Assay This assay is a standard assay for GABA A binding affinity. The high affinity and high selectivity of compounds of this invention for the benzodiazepine site of the GABA A receptor is confirmed using the binding assay described in Thomas and Tallman (J. Bio . Chem . 1981; 156_: 9838-9842 , and J. Neurosci . 1983; 3:433-440) . Rat cortical tissue is dissected and homogenized in 25 volumes (w/v) of Buffer A (0.05 M Tris HCI buffer, pH 7.4 at 4 °C) . The tissue homogenate is centrifuged in the cold (4 °C) at 20,000 x g for 20 minutes. The supernatant is decanted, the pellet rehomogenized in the same volume of buffer, and centrifuged again at 20,000 x g. The supernatant of this centrifugation step is decanted and the pellet stored at -20 °C overnight. The pellet is then thawed, resuspended in 25 volumes of Buffer A (original wt/vol), centrifuged at 20,000 x g and the supernatant is then decanted. This wash step is repeated once. The pellet is finally resuspended in 50 volumes of .Buffer A. Incubations containing 100 μl of tissue homogenate, 100 μl of radioligand, (0.5 nM 3 H-Rol5-1788 [ 3 H-Flumazenil] , specific activity 80 Ci/mmol) , and test compound or control (see below) , and are brought to a total volume of 500 μl with Buffer A. Incubations are carried for 30 min at 4°C and then rapidly filtered through Whatman GFB filters to separate free and bound ligand. Filters are washed twice with fresh Buffer A and counted in a liquid scintillation counter. Nonspecific binding (control) is determined by displacement of 3 H Rol5-1788 with 10 μM Diazepam (Research Biochemicals International, Natick, MA) . Data were collected in triplicate, averaged, and percent inhibition of total specific binding (Total Specific Binding = Total - Nonspecific) was calculated for each compound . A competition binding curve is obtained with up to 11 points spanning the compound concentration range from 10 "12 M to 10 "5 M obtained per curve by the method described above for determining percent inhibition. Ki values are calculated according the Cheng-Prussof equation. When tested using this assay, preferred compounds of Formula I exhibit Ki values of less than 1 uM, more preferred compounds of the invention have i values of less than 500 nM, and particularly preferred compounds have Ki values of less than 100 nM. Compounds 11-32 exhibit Ki values of less than 1 uM. Example 6 Electrophysiology The following assay is used to determine if a compound of the invention act as an agonist, an antagonist, or an inverse agonist at the benzodiazepine site of the GABA A receptor. Assays are carried out as described in White and Gurley (NeuroReport 6: 1313-1316, 1995) and White, Gurley, Hartnett, Stirling, and Gregory (Receptors and Channels 3 : 1-5, 1995) with modifications. Electrophysiological recordings are carried out using the two electrode voltage-clamp technique at a membrane holding potential of -70 mV. Xenopus Laevis oocytes are enzymatically isolated and injected with non- polyadenylated cRNA mixed in a ratio of 4:1:4 for α, β and γ subunits, respectively. Of the nine combinations of α, β and γ subunits described in the White et al . publications, preferred combinations are αιβ 2 γ 2 , α 2 β 3 γ 2/ α 3 β 3 γ 2 , and 5 β 3 γ 2 . Preferably all of the subunit cRNAs in each combination are human clones or all are rat clones. The sequence of each of these cloned subunits is available from GENBANK, e.g., human α l f GENBANK accession no. X14766, human α 2 , GENBANK accession no. A28100; human α 3 , GENBANK accession no. A28102; human α 5 , GENBANK accession no. A28104; human β 2 , GENBANK accession no. M82919; human β 3 , GENBANK accession no. Z20136; human β 2 , GENBANK accession no. X15376; rat αi, GENBANK accession no. L08490, rat α 2 , GENBANK accession no. L08491; rat α 3 , GENBANK accession no. L08492; rat α 5 , GENBANK accession no. L08494; rat β 2 , GENBANK accession no. X15467; rat β 3 , GENBANK accession no. X15468; and rat γ 2 , GENBANK accession no. L08497. For each subunit combination, sufficient message for each constituent subunit is injected to provide current amplitudes of >10 nA when 1 μM GABA is applied. Compounds are evaluated against a GABA concentration that evokes <10% of the maximal evokable GABA current (e.g. 1 μM - 9 μM) . Each oocyte is exposed to increasing concentrations of compound in order to evaluate a concentration/effect relationship. Compound efficacy is calculated as a percent- change in current amplitude: 100* ( (Ic/I) -1) , where Ic is the GABA evoked current amplitude observed in the presence of test compound and I is the GABA evoked current amplitude observed in the absence of the test compound. Specificity of a compound for the benzodiazepine site is determined following completion of a concentration/effect curve. After washing the oocyte sufficiently to remove previously applied compound, the oocyte is exposed to GABA + 1 μM R015-1788, followed by exposure to GABA + 1 μM R015-1788 + test compound. Percent change due to addition of compound is calculated as described above. Any percent change observed in the presence of R015-1788 is subtracted from the percent changes in current amplitude observed in the absence of 1 μM R015-1788. These net values are used for the calculation of average efficacy and EC 50 values by standard methods. To evaluate average efficacy and EC 50 values, the concentration/effect data are averaged across cells and fit to the logistic equation. The invention and the manner and process of making and using it, are now described in such full, clear, concise and exact terms as to enable any person skilled in the art to which it pertains, to make and use the same. It is to be understood that the foregoing describes preferred embodiments of the invention and that modifications may be made therein without departing from the spirit or scope of the invention as set forth in the claims. To particularly point out and distinctly claim the subject matter regarded as invention, the following claims conclude this specification.

Claims: What is claimed is: 1. A compound of the formula: or a pharmaceutically acceptable salt thereof, wherein: R is hydroxy, hydrocarbyl or -O-hydrocarbyl, where each hydrocarbyl is optionally substituted with oxo, haloalkyl, haloalkoxy, halogen, cyano, hydroxy, alkyl, nitro, azido, alkanoyl, carboxamido, alkoxy, aryloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, mono or dialkylamino, aryl, arylalkyl, arylalkoxy, heteroaryl or heterocycloalkyl; or R is -O-aryl, aryl, -O-heteroaryl, or heteroaryl, each of which is optionally substituted with halogen, cyano, hydroxyl, nitro, azido, alkanoyl, carboxamido, hydrocarbyl, -O-hydrocarbyl, aryloxy, haloalkyl, haloalkoxy, hydrocarbylthio hydrocarbylsulfinyl , hydrocarbylsulfonyl, amino, mono or dihydrocarbylamino, aryl, arylhydrocarbyl , arylalkoxy, heteroaryl or heterocycloalkyl ; wherein each hydrocarbyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of oxo, halogen, cyano, nitro, haloalkyl, haloalkoxy, hydroxy, amino, alkyl substituted with 0-2 R A , alkoxy substituted with 0-2 R A , -NH (alkyl) substituted with 0-2 R A , -N (alkyl) (alkyl) where each alkyl is independently substituted with 0-2 R A , phenyl substituted with 0-3 R A , -XRB, and R c ; wherein R A is independently selected at each occurrence from the group consisting of halogen, hydroxy, alkyl, alkoxy, -NH (alkyl), -N (alkyl) (alkyl) , heterocycloalkyl, -S (0) m (alkyl) , where m is 0, 1, or 2, haloalkyl, haloalkoxy, -CO (alkyl), -CONH (alkyl) , -CON (alkyl) (alkyl), -XR B , and Y; X is independently selected at each occurrence from the group consisting of -CH 2 -, -CHR C -, -0-, -S(0) g -, -NH-, -NRc-, -C(=0)-, -C(=0)0-, -C(=0)NH-, -C(=0)NR c -, -S(0) g NH-, -S(0) g NR c -, NHC(=0)-, -NR c C(=0)-, -NHS(0) g -, and -NR c S(0) g -; where g is 0, 1, or 2; R B and R c are independently hydrocarbyl which may be further substituted with one or more substituents independently selected from oxo, hydroxy, halogen, amino, -NH (alkyl), -N(alkyl) (alkyl), cyano, nitro, haloalkyl, haloalkoxy, -O(alkyl), -NHC (0) (alkyl) , -N (alkyl) C(O) (alkyl), -NHS (0) m (alkyl) , -S (0) m (alkyl) , -S (O) m NH (alkyl) , and -S (0) m N (alkyl) (alkyl); where each m is 0, 1, or 2; Y is independently selected at each occurrence from 5- to 8-membered carbocycles and heterocycles, which are saturated, partially unsaturated, or aromatic and contain zero, one or two hetero atoms selected from N, 0, and S, and which may be further substituted with one or more substituents independently selected from the group consisting of halogen, oxo, hydroxy, amino, mono- or di (Ci-Cg) alkylamino, nitro, cyano, Ci-Cg alkyl, Ci-Cg alkoxy, and -SO a (alkyl); where a is 0 , 1 , or 2 ; d R 2 are independently selected at each occurrence from hydrogen, halogen, hydroxy, hydrocarbyl, -O-hydrocarbyl, alkoxy, haloalkyl, haloalkoxy, nitro, cyano, amino, mono or dihydrocarbylamino; n is 0 , 1 , or 2 ; A is N or CR 3 , wherein R 3 is hydrogen or hydrocarbyl; and Ar is aryl or heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, haloalkyl, haloalkoxy, halogen, cyano, hydroxy, nitro, azido, alkanoyl, carboxamido, hydrocarbyl substituted with 0-2 R A , -O-hydrocarbyl substituted with 0-2 R A , aryloxy, alkylthio hydrocarbylsulfinyl, hydrocarbylsulfonyl , amino, -NH (hydrocarbyl) where the hydrocarbyl is substituted with 0-2 R A , -N (hydrocarbyl) (hydrocarbyl) where each hydrocarbyl is substituted with 0-2 R A , aryl, arylhydrocarbyl , arylalkoxy, heteroaryl and heterocycloalkyl . 2. A compound or salt according to Claim 1, wherein R is hydroxy, alkyl, cycloalkyl, alkoxy, or cycloalkyloxy each of which is optionally substituted with oxo, haloalkyl, haloalkoxy halogen, cyano, hydroxy, alkyl, nitro, azido, alkanoyl, carboxamido, alkoxy, aryloxy, alkylthio, alkylsulfinyl , alkylsulfonyl, amino, mono or dialkylamino, aryl, arylalkyl, arylalkoxy, heteroaryl or heterocycloalkyl ; or R is phenyl, pyrrolyl, f ranyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridizinyl, benzimidazolyl, naphthyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl , benzo [b] thiophenyl , benz [d] isoxazolyl , quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which is optionally mono-, di-, or trisubstituted with substituents independently chosen from halogen, cyano, nitro, haloalkyl, haloalkoxy, hydroxy, amino, alkyl substituted with 0-2 R A , alkoxy substituted with 0-2 R A , -NH (alkyl) substituted with 0-2 R A , -N (alkyl) (alkyl) where each alkyl is independently substituted with 0-2 R A , phenyl substituted with 0-3 R A , -XR B , and R c ; Ar is phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, benzimidazolyl, naphthyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl , benzo [b] thiophenyl , benz [d] isoxazolyl , quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which is optionally mono-, di-, or trisubstituted with substitutents independently chosen from oxo, halogen, cyano, nitro, haloalkyl, haloalkoxy, hydroxy, amino, alkyl substituted with 0-2 R, alkoxy substituted with 0-2 R A , -NH (alkyl) substituted with 0-2 R A , -N (alkyl) (alkyl) where each alkyl is independently substituted with 0-2 R A , -XR B , and R c ; R A is independently selected at each occurrence from the group consisting of halogen, hydroxy, alkyl, alkoxy, -NH(alkyl), - (alkyl) (alkyl) , morpholinyl, pyrrolidinyl, piperidinyl, thiomorpholinyl , piperazinyl, -S (O) m (alkyl) , where m is 0, 1, or 2, haloalkyl, haloalkoxyoxy, -CO(alkyl), CONH(alkyl), CON (alkyl) (alkyl) , -XR B , and Y. 3. A compound or salt according to Claim 1, wherein R is hydroxy, d-C 6 alkyl, cycloalkyl, Ci-Cgalkoxy, or cycloalkyloxy each of which is optionally substituted with oxo, Ci-Cghaloalkyl , Ci-Cghaloalkoxy halogen, cyano, hydroxy, Cι-C 3 alkyl, nitro, azido, Ci-Cgalkanoyl, carboxamido, Ci-Cgalkoxy, aryloxy, Ci-Cgalkylthio, Ci- C 6 alkylsulfinyl, d-Cgalkylsulfonyl, amino, mono or di (Ci- C 6 ) alkylamino, aryl, aryl (Cι-C 4 ) alkyl , aryl (Cι-C 4 ) alkoxy, heteroaryl or heterocycloalkyl ; or R is phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl , pyrazinyl, pyridizinyl, benzimidazolyl, naphthyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl , benzo [b] thiophenyl , benz [d] isoxazolyl , quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which is optionally mono-, di-, or trisubstituted with substituents independently chosen from halogen, cyano, nitro, Ci-Cghaloalkyl , Ci- Chaloalkoxy, hydroxy, amino, Ci-Cgalkyl substituted with 0-2 R A , Ci-Cgalkoxy substituted with 0-2 R A , -NH(Cι- Cgalkyl) substituted with 0-2 R A , -N (C x -Cgalkyl) (C .. - Cgalkyl) where each alkyl is independently substituted with 0-2 R A , phenyl substituted with 0-3 R A , -XR B , and R c ; Ri and R 2 are independently selected at each occurrence from hydrogen, halogen, hydroxy, Ci-Cg alkyl, Ci-C alkoxy, Ci- Cghaloalkyl, Ci-Cghaloalkoxy, nitro, cyano, amino, and mono- and di- (Cι-C 3 ) alkylamino; Ar is phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, benzimidazolyl, naphthyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo [b] thiophenyl, benz [d] isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, each of which is optionally mono-, di-, or trisubstituted with substitutents independently chosen from oxo, halogen, cyano, nitro, Ci-Cghaloalkyl, Ci- Cghaloalkoxy, hydroxy, amino, Ci-Cgalkyl substituted with 0-2 R A , Ci-Cgalkoxy substituted with 0-2 R A , -NH(C X - Cgalkyl) substituted with 0-2 R A , -N (Cι-C 6 alkyl) (Ci- Cgalkyl) where each Ci-Cgalkyl is independently substituted with 0-2 R A , -XR B , and R C; R A is independently selected at each occurrence from the group consisting of halogen, hydroxy, Ci-Cgalkyl, Ci- Cgalkoxy, -NH (Ci-Cgalkyl) , -N(d-C 6 alkyl) ( Cι-C 6 alkyl) , morpholinyl, pyrrolidinyl, piperidinyl, thiomorpholinyl, piperazinyl, --S (0) m (alkyl) , where m is 0, 1, or 2, Ci-Cghaloalkyl, Ci-Cghaloalkoxy, -CO(Cι-Cgalkyl) , CONH (C x -Cgalkyl) , CON (Ci-Cgalkyl) (C x - C e alkyl) , -XR B , and Y; and R B and R c are independently Ci-Cghydrocarbyl which may be further substituted with one or more substituents independently selected from oxo, hydroxy, halogen, amino, -NH(d-C 6 alkyl) , -N(d-C 6 alkyl) (C_.-C 6 alkyl) , cyano, nitro, d-C 6 haloalkyl, Cι-C 3 haloalkoxy, -0(C X - C s alkyl) , -NHC (O) (Ci-Cgalkyl) , -N(d-Cgalkyl) C (0) ( d- Cgalkyl), -NHS (O) m (Cι-C 6 alkyl) , -S (O) m (Cι-C 6 alkyl) , -S(0) m NH(Ci-Cgalkyl) , and -S (O) m N (Ci-Cgalkyl) (d- C 6 alkyl) ; where each m is 0, 1, or 2. 4. A compound or salt, according to Claim 1, wherein A is nitrogen. 5. A compound or salt according to claim 4, wherein n is 1. 6. A compound or salt according to claim 5, wherein Ar is phenyl, pyridyl, pyrimidinyl, pyrazolyl, or pyridizinyl, each of which is unsubstituted or substituted with up to three groups selected from halogen, cyano, nitro, Ci- Cghaloalkyl, Ci-Cghaloalkoxy, hydroxy, amino, and Ci- Cgalkyl substituted with 0-2 R A , Ci-Cgalkoxy substituted with 0-2 R A , -NH(Cι-Cgalkyl) substituted with 0-2 R A , and - -N(Cι-Cgalkyl) ( Ci-Cgalkyl) where each alkyl is independently substituted with 0-2 R A , -XR B , or R c R A is independently selected at each occurrence the group consisting of halogen, hydroxy, d-C 6 alkyl, Ci- C 6 alkoxy, -NH (C x -Cgalkyl ) , -N (Ci-C 6 alkyl) (Ci-Cgalkyl) , Ci-Cghaloalkyl, Ci-Cghaloalkoxy, -XR B and Y; X is independently selected at each occurrence from the group consisting of -CH 2 -, -CHR C -, -0- , -NH- , -NR C - , and -C(=0) -; R B and R c are independently Cι-C 6 alkyl, C 3 -C 7 cycloalkyl, or C 3 -C cycloalkyl (Ci-Cg) alkyl, each of is optionally substituted with one or more substituents independently selected from oxo, hydroxy, halogen, amino, cyano, nitro, Ci-Cg haloalkyl, Ci-C haloalkoxy, Ci-Cg alkyl, Ci-C alkoxy, mono- or di (C x - C 6 ) alkylamino, -NHC(0) (d-β alkyl), and -N(d-C 6 alkyl)C(O) (Ci-Cg alkyl), where m is 0, 1, or 2; and Y is morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl. 7. A compound or salt according to claim 6, wherein phenyl, pyridyl, pyrimidinyl, pyrazolyl, or pyridizinyl, each of which is unsubstituted or substituted with up to three groups selected from halogen, nitro, Ci-Cghaloalkyl , C x -C 6 haloalkoxy, hydroxy, amino, and Cι- 6 alkyl substituted with 0-2 R A , Ci-g alkoxy substituted with 0-2 R A , -NH(Cι- Cgalkyl) substituted with 0-2 R A , and -N (d-Cgalkyl) (Ci- Cgalkyl) where each alkyl is independently substituted R A is independently selected at each occurrence from the group consisting of halogen, hydroxy, Cι-C 6 alkyl, C - Cgalkoxy, -NH (d-Calkyl) , -N (d-C 3 alkyl) (d-C 3 alkyl) , C -C 3 haloalkyl, Cι-C 3 haloalkoxy, -XR B/ and Y; X is independently selected at each occurrence from the group consisting of -CH 2 -, -CHR C -, -0-, -NH- , -NR C - , and -C(=0) -; R B and R c are independently Cι-C 6 alkyl or C 3 -C 7 cycloalkyl, each of is optionally substituted with one or two substituents independently selected from hydroxy, halogen, amino, cyano, nitro, Ci-Cghaloalkyl, Ci- Cghaloalkoxy, Ci-C alkyl, Ci-Cg alkoxy, and mono- or di (Ci-Cg) alkylamino; and Y is morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl. 8. A compound or salt according to claim 5, wherein Ar is phenyl, pyridyl, or pyridizinyl each of which is optionally mono-, di-, or tri-substituted with substituents independently chosen from halogen, Ci-Cg alkyl, Ci-C alkoxy, amino, mono- or di (Ci- C 6 ) alkylamino, Ci-C 5 alkoxy (Ci-Cg) alkoxy, Ci-C alkylamino (Cι-C 6 ) alkoxy, amino (Ci-Cg) alkoxy, di (C x - C 6 ) alkylamino (Ci-Cg) alkoxy, Ci-Cg alkoxy (Ci-Cg) alkylamino, alkyl substituted with morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, imidazolidinyl, and Ci-Cg alkoxy substituted with morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl. 9. A compound or salt according to claim 5, wherein Ar is phenyl, pyridyl, or pyridinzyl, each of which is substituted with one of i) halogen, Ci-Cg alkyl, d-C 6 alkoxy, mono- or di- (Ci- C 6 ) alkylamino, Cι-C 6 alkoxy(Cι-C 6 ) alkoxy, mono or di- (Ci- C 6 ) alkylamino (Ci-Cg) alkoxy, or ii) Ci-Cg alkoxy substituted with morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl ; and optionally further substituted with one or two substitutuents independently chosen from: halogen, Cι-C 4 alkyl, Cι-C 4 alkoxy, amino, Ci-Cg alkylamino, C 1 -C 3 alkoxy (Cι-C 3 ) alkoxy, C 1 -C 3 alkylamino (Ci- C 3 ) alkoxy, amino (Cι-C 3 ) alkoxy, C -C 3 alkylamino (Ci- C 3 ) alkoxy, and Cι-C 6 alkoxy (d-C 6 ) alkylamino . 10. A compound or salt according to claim 9, wherein each Ri and each R 2 is independently hydrogen, halogen, d-C 6 alkyl, Cι-C 6 alkoxy, halo (Cι-C 3 ) alkyl , halo (d-C 6 ) alkoxy, cyano, amino, or amino (Cι-C 6 ) alkyl . 11. A compound or salt according to claim 10, wherein each Ri and R 2 is independently selected from hydrogen, C x -C 2 alkyl, Cι-C 2 alkoxy, cyano, amino, and halogen. 12. A compound or salt according to claim 11, wherein no more than three of Ri and R 2 are other than hydrogen. 13. A compound or salt according to claim 12 , wherein one, two, or three of R x and R 2 are independently chosen from hydrogen, halogen, methyl and ethyl, and the remaining Ri and R 2 substituents are hydrogen. 14. A compound or salt according to Claim 13, wherein R is Cι-C 6 alkyl, Cι-C 6 alkoxy, phenyl (Cι-C 6 ) alkyl, pyridyl ( - C 6 ) alkyl, phenyl or pyridyl, wherein each phenyl or pyridyl is unsubstituted or mono-, di-, or trisubstituted with halogen, cyano, nitro, halo (Ci-Cg) alkyl, halo(Cι- C 6 ) alkoxy, hydroxy, amino, Ci-C 3 alkyl substituted with 0-2 R A. Ci-Cgalkoxy substituted with 0-2 R A , -NH(Cι- 6 alkyl) substituted with 0-2 R A , -N (Ci-Cgalkyl) ( Ci-Cgalkyl) where each Ci-Cgalkyl is independently substituted with 0-2 R A , phenyl substituted with 0-3 R A , -XR B , and R c . 15. A compound according to Claim 14, wherein R is Ci-Cg alkyl, Cι-C 6 alkoxy, or phenyl (Ci-Cg) alkyl, pyridyl (Ci-Cg) alkyl , phenyl or pyridyl, where the aromatic portion of each is unsubstituted or mono-, di-, or trisubstituted with halogen, cyano, nitro, Ci-Cghaloalkyl, Ci-Cghaloalkoxy, hydroxy, amino, Cι-C 6 alkoxy, or Cι_ 6 alkyl . 16. A compound, according to Claim 5, wherein Ar is phenyl, pyridyl, pyrimidinyl, pyrazolyl, or pyridizinyl, each of which is unsubstituted or substituted with up to three groups selected from halogen, cyano, nitro, d-C 6 haloalkyl, C x - Cghaloalkoxy, hydroxy, amino, and Ci-Cgalkyl substituted with 0-2 R A , Ci- Cgalkoxy substituted with 0-2 R A , -NH (Ci-Cgalkyl) substituted with 0-2 R A , -N(d-C 6 alkyl) (d-C 6 alkyl) where each alkyl is independently substituted with 0-2 R A , -XR B , or Rc,. R A is independently selected at each occurrence the group consisting of halogen, hydroxy, Cι-C 6 alkyl, Ci- C s alkoxy, -NH (Ci-Cgalkyl) , -N (d-C 6 alkyl) ( Ci-Cgalkyl) , d- Cghaloalkyl, d- Cghaloalkoxy, CO (d-C 6 alkyl) , CONH(Cι- C 6 alkyl) , CON (Ci-Cgalkyl) (Ci-Cgalkyl) , -XR B and Y; X is independently selected at each occurrence from the group consisting of -CH 2 -, -CHR C -, -O- , -S(0) g -, -NH- , -NRc-, -C(=0)-, -C(=0)0-, -C(=0)NH-, -C(=0)NR c -, -S(0) g NH-, -S(0)gNR c -, NHC(=0)-, -NR c C(=0)-, -NHS (O) g - , and -NR C S (0) g - ; where g is 0, 1, or 2; R B and R c are independently alkyl groups which may be further substituted with one or more substituent (s) selected from oxo, hydroxy, halogen, amino, cyano, nitro, Ci-Cghaloalkyl, Ci-Cghaloalkoxy, -0(Cι- Cgalkyl), -NH(Cι_ 6 alkyl), -N(d-C 6 alkyl) (d_ 6 alkyl), -NHC(O) (Ci-Cgalkyl) , -N (alkyl) C (O) (Ci-Cgalkyl) , -NHS (0) m (Ci-Cgalkyl) , -S (0) m (d.-C 6 alkyl) , -S(0) ra NH(Cι- Cgalkyl) , and -S (O) m N (Ci-Cgalkyl) (Ci-Cgalkyl ) ; where m is 0, 1, or 2; and Y is morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl, each of which is unsubstituted or substituted with one or more substituents independently chosen from halogen, oxo, hydroxy, amino, mono- or di (Ci-Cg) alkylamino, nitro, cyano, Ci-Cg alkyl, and Ci-Cg alkoxy. 17. A compound or salt according to Claim 6, wherein: R is Cι-Calkyl, Cι-C 4 alkoxy, or phenyl, where the phenyl is mono- or di-substituted with substituents independently chosen from halogen, cyano, nitro, Ci-Cghaloalkyl , Ci- Cghaloalkoxy, hydroxy, amino, Ci-Cg alkoxy, Ci-g alkyl, amino (Ci-Cg) alkyl, mono- or di (Ci-Cg) alkylamino (Ci- C 5 ) alkyl, and mono- or di (d-C 6 ) alkylamino (Ci-Cg) alkoxy. 18. A compound or salt according to Claim 1, wherein A is CR 3 19. A compound or salt according to claim 18, wherein n is 1. 20. A compound according to claim 19, wherein Ar is phenyl, pyridyl, pyrimidinyl, pyrazolyl, or pyridizinyl, each of which is unsubstituted or substituted with up to three groups independently selected from halogen, cyano, nitro, Ci-Cghaloalkyl, Ci-Cghaloalkoxy, hydroxy, amino, and Ci-Cgalkyl substituted with 0-2 R A , Ci-C 6 alkoxy substituted with 0-2 R A , -NH(Cι-Cgalkyl) substituted with 0-2 R A , -N(Cι-Cgalkyl) ( Ci-Cgalkyl) where each alkyl is independently substituted with 0-2 R A/ -XR B , and R C; R A is independently selected at each occurrence the group consisting of halogen, hydroxy, Cι-C 6 alkyl, Ci- C 6 alkoxy, -NH (Ci-Cgalkyl ) , -N (Cι-C 6 alkyl) (Cι-C 6 alkyl) , d- Cghaloalkyl, Ci-Cghaloalkoxy, -XR B and Y; X is independently selected at each occurrence from the group consisting of -CH 2 -, -CHR C -, -0-, -NH- , -NR C - , and -C(=0) - ; R B and R c are independently Cι-C 6 alkyl, C 3 -C 7 cycloalkyl , or C 3 -C 7 cycloalkyl (Ci-Cg) alkyl, each of is optionally substituted with one or more substituents independently selected from oxo, hydroxy, halogen, amino, cyano, nitro, Ci-Cg haloalkyl, Ci-Cg haloalkoxy, Ci-Cg alkyl, Ci-Cg alkoxy, mono- or di (Ci- C 6 ) alkylamino, -NHC (0) (Ci-Cgalkyl) , and -N (Ci-Cg alkyl)C(O) (Ci-C 3 alkyl) , where m is 0, 1, or 2; and Y is morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl. 21. A compound according to claim 20, wherein Ar is phenyl, pyridyl, pyrimidinyl, pyrazolyl, or pyridizinyl, each of which is unsubstituted or substituted with up to three groups selected from halogen, nitro, Ci-Cghaloalkyl , Ci-Cghaloalkoxy, hydroxy, amino, and Cι_ 6 alkyl substituted with 0-2 R A , Ci-g alkoxy substituted with 0-2 R A , -NH(C X - Cgalkyl) substituted with 0-2 R A , --N (Ci-C 6 alkyl) (Ci- Cgalkyl) where each alkyl is independently substituted with 0-2 R A , -XR B , or R C; R A is independently selected at each occurrence the group consisting of halogen, hydroxy, Cι-C 5 alkyl, Ci- C 6 alkoxy, -NH (d-C alkyl) , -N(d-C 3 alkyl) (d-C 3 alkyl) , Cι-C 3 haloalkyl, Cι-C 3 haloalkoxy, -XR B , and Y; X is independently selected at each occurrence from the group consisting of -CH 2 -, -CHR C -, -0-, -NH- , -NR C - , and -C(=0) -; R B and R c are independently Cι-C 3 alkyl or C 3 -C 7 cycloalkyl, each of is optionally substituted with one or two substituents independently selected from hydroxy, halogen, amino, cyano, nitro, Ci-Cghaloalkyl, d- Cghaloalkoxy, Ci-C alkyl, Ci-Cg alkoxy, and mono- or di (Ci-Cg) alkylamino; and Y is morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl. 22. A compound or salt according to claim 18, wherein Ar is phenyl, pyridyl, or pyridizinyl each of which is optionally mono-, di-, or tri-substituted with substituents independently chosen from halogen, Ci-Cg alkyl, Ci-Cg alkoxy, amino, mono- or di (C x - C 6 ) alkylamino, Ci-C 3 alkoxy (Ci-Cg) alkoxy, C x -Cg alkylamino (Cι-C 6 ) alkoxy, amino (Ci-Cg) alkoxy, di (Ci- C 6 ) alkylamino (Ci-Cg) alkoxy, Ci-Cg alkoxy (Ci- C 6 ) alkylamino, alkyl substituted with morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl, and Ci-C alkoxy substituted with morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl. 23. A compound or salt according to claim 18, wherein Ar is phenyl, pyridyl, or pyridinzyl, each of which is substituted with one of: i) halogen, d-C 6 alkyl, Cι-C 3 alkoxy, mono- or di- (Ci- C 6 ) alkylamino, Ci-C 6 alkoxy (d-C 6 ) alkoxy, mono or di- (Ci- Cg) alkylamino (Ci-Cg) alkoxy, or ii) Ci-Cg alkoxy substituted with morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl and optionally further substituted with one or two substitutuents independently chosen from: halogen, Cι-C alkyl, Cι-C alkoxy, amino, d-C 6 alkylamino, Cι-C 3 alkoxy (Cι-C 3 ) alkoxy, Cι-C 3 alkylamino (Ci- C 3 ) alkoxy, amino (Cι-C 3 ) alkoxy, C 1 -C 3 alkylamino (Ci- C 3 ) alkoxy, and Cι-C 6 alkoxy (Cι-C 6 ) alkylamino . 24. A compound according to claim 23, wherein each R x and each R 2 is independently hydrogen, Ci-Cg alkyl, halo (Ci- Cg) alkyl, cyano, amino, or amino (d-C 6 ) alkyl . 25. A compound according to claim 24, wherein each Ri and R 2 is independently selected from hydrogen, Cι-C 2 alkyl, Cι-C 2 alkoxy, cyano, amino, and halogen. 26. A compound according to claim 25, wherein no more than three of R x and R 2 are other than hydrogen. 27. A compound according to claim 26, wherein one, two, or three of Ri and R 2 are independently selected from, hydrogen, halogen, methyl and ethyl, and the remaining Ri and R 2 substituents are hydrogen. 28. A compound or salt according to Claim 27, wherein R is Ci-Cgalkyl, or Ci-Cgalkoxy, or phenyl (Ci-Cg) alkyl, pyridyl (Cι-C 6 ) alkyl , phenyl or pyridyl, wherein each phenyl or pyridyl is unsubstituted or mono-, di-, or tri-substituted with halogen, cyano, nitro, halo (Ci-Cg) alkyl, halo (Ci-Cg) alkoxy, hydroxy, amino, Ci- Cgalkyl substituted with 0-2 R A , Ci-Cgalkoxy substituted with 0-2 R A , -NH(Ci- 6 alkyl) substituted with 0-2 R A , -N(Cι-Cgalkyl) (Ci-Cgalkyl) where each Ci-Cgalkyl is independently substituted with 0-2 R A , phenyl substituted with 0-3 R A , -XR B , or R c . 29. A compound or salt according to Claim 28, wherein R is Cι_g alkyl, Cι_ 6 alkoxy, or phenyl (Ci-Cg) alkyl, pyridyl (Ci-Cg) alkyl , phenyl or pyridyl, wherein each phenyl or pyridyl is unsubstituted or mono-, di-, or trisubstituted with substitutents independently chosen from halogen, cyano, nitro, Ci-Cghaloalkyl , Ci- Cghaloalkoxy, hydroxy, amino, Ci-Cg alkoxy, and Ci-g alkyl. 30. A compound or salt, according to Claim 19, wherein Ar is phenyl, pyridyl, pyrimidinyl, pyrazolyl, or pyridizinyl, each of which is unsubstituted or substituted with up to three groups independently selected from halogen, cyano, nitro, Ci-Cghaloalkyl , Ci-Cghaloalkoxy, hydroxy, amino, and Ci-Cgalkyl substituted with 0-2 R A , Cι-C 3 alkoxy substituted with 0-2 R A , -NH(Cι-Cgalkyl) substituted with 0-2 R A , -N(Cι-Cgalkyl) (Ci-Cgalkyl) where each alkyl is independently substituted with 0-2 R A , -XR B , and R C; R A is independently selected at each occurrence from the group consisting of halogen, hydroxy, Cι-C 3 alkyl, C x - Cgalkoxy, -NH (Ci-Cgalkyl) , -N (Ci-Cgalkyl) (d-C 6 alkyl) , Cι-C 6 haloalkyl, Ci-Cghaloalkoxy, CO (Ci-C 6 alkyl) , CONH (Ci-Cgalkyl) , CON (d-C 6 alkyl) (d-C 6 alkyl) , -XR B and Y; X is independently selected at each occurrence from the group consisting of -CH 2 -, -CHR C -, -0-, -S(0) g -, -NH-, -NRc-, -C(=0)-, -C(=0)0-, -C(=0)NH-, -C(=0)NR c - , -S(0) g NH-, -S(0)gNR c -, NHC(=0)-, -NR c C(=0)-, -NHS(0) n -/ and -NR c S(0) n -; where g is 0, 1, or 2;p R B and R c are independently alkyl groups which may be further substituted with one or more substituent (s) selected from oxo, hydroxy, halogen, amino, cyano, nitro, Ci-Cghaloalkyl , Ci-Cghaloalkoxy, -0(d- Cgalkyl) , -NH(Cι_ 6 alkyl), -N(Cι-C 6 alkyl) (Cι- 6 alkyl), -NHC(O) (Ci-Cgalkyl) , -N (alkyl) C (0) (Ci-Cgalkyl) , -NHS (0) m (Ci-Cgalkyl ) , -S (0) m (d-C 6 alkyl) , -S(0) m NH(C x - Cgalkyl) , and -S (O) m N (Ci-Cgalkyl) (Ci-C 6 alkyl) ; where m is 0, 1, or 2; and Y is morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl, each of which is unsubstituted or substituted with one or more substituents independently chosen from halogen, oxo, hydroxy, amino, mono- or di (Ci-Cg) alkylamino, nitro, cyano, Ci-Cg alkyl, and Ci-Cg alkoxy. 31. A compound or salt according to Claim 30, wherein: R is Cι-C 4 alkyl, Cι-C 4 alkoxy, or phenyl, where the phenyl is mono- or di-substituted with substituents independently chosen from halogen, cyano, nitro, Ci-Cghaloalkyl , Ci- Cghaloalkoxy, hydroxy, amino, Ci-C alkoxy, Ci-g alkyl, amino (Ci-Cg) alkyl, mono- or di (Ci-Cg) alkylamino (Ci- C s )alkyl, and mono- and di (Ci-Cg) alkylamino (Cι-C 6 ) alkox . 32. A compound or salt according to Claim 1 of the formula: wherein each R x and R 2 are independently hydrogen, methyl or ethyl ; and R is Ci- alkyl or Ci-g alkoxy, or R is phenyl or pyridyl each of which is unsubstituted or mono- , di-, or trisubstituted independently with halogen, cyano, nitro, Ci-Cghaloalkyl, C x -Cghaloalkoxy, hydroxy, amino, and Cι-C 6 alkyl substituted with 0-2 R A , Ci-C 5 alkoxy substituted with 0-2 R A , -NH (C x -Cgalkyl) substituted with 0-2 R A , -N(Cι-Cgalkyl) ( Cι-C 6 alkyl) where each Ci-Cgalkyl is independently substituted with 0-2 R A , phenyl substituted with 0-3 R A , -XR B , or R c . 33. A compound or salt according to claim 1, wherein n is 2. 34. A compound, according to Claim 33, wherein A is CR 3 , 35. A compound according to claim 34, wherein Ar is phenyl, pyridyl, pyrimidinyl, pyrazolyl, or pyridizinyl, each of which is unsubstituted or substituted with up to three groups independently selected from halogen, cyano, nitro, Ci-Cghaloalkyl, Ci-Cghaloalkoxy, hydroxy, amino, Ci-Cgalkyl substituted with 0-2 R A , Cι-C 6 alkoxy substituted with 0-2 R A , -NH(Cι-Cgalkyl) substituted with 0-2 R A , and -N(Cι-Cgalkyl) ( Cχ-C 6 alkyl) where each alkyl is independently substituted with 0-2 R A , -XR B , and R C; R A is independently selected at each occurrence the group consisting of halogen, hydroxy, Cι-C 6 alkyl, Ci- C 6 alkoxy, -NH(Cι-Cgalkyl) , -N (d-C 6 alkyl) (Ci-Cgalkyl) , Ci- Cghaloalkyl, Ci-Cghaloalkoxy, -XR B and Y; X is independently selected at each occurrence from the group consisting of -CH 2 -, -CHR C -, -0-, -NH- , -NR C - , and -C(=0) - ; R B and R c are independently Cι-C 6 alkyl, C 3 -C 7 cycloalkyl , or C 3 -C 7 cycloalkyl (Ci-Cg) alkyl, each of is optionally substituted with one or more substituents independently selected from oxo, hydroxy, halogen, amino, cyano, nitro, Ci-Cg haloalkyl, Ci-Cg haloalkoxy, d-C 5 alkyl, Ci-C alkoxy, mono- or di (d- C 6 ) alkylamino, -NHC(O) (Cι- 6 alkyl), and -N(Cι-C 3 alkyl) C (O) (Ci-Cg alkyl); and Y is morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl. 36. A compound or salt according to claim 35, wherein Ar is phenyl, pyridyl, pyrimidinyl, pyrazolyl, or pyridizinyl, each of which is unsubstituted or substituted with up to three groups independently selected from halogen, nitro, Ci-Cghaloalkyl , Ci-Cghaloalkoxy, hydroxy, amino, and Cι_ 6 alkyl sustituted with 0-2 R A , Cι_g alkoxy substituted with 0-2 R A , -NH(Cι-Cgalkyl) substituted with 0-2 R A , and -N(Ci-C 6 alkyl) (Ci-C 6 alkyl) where each alkyl is independently substituted with 0-2 R A , -XR B , and R C; R A is independently selected at each occurrence the group consisting of halogen, hydroxy, Cι-C ε alkyl, Ci- C 6 alkoxy, -NH (d-Calkyl) , -N (d-C 3 alkyl) (d-C 3 alkyl) , Cι-C 3 haloalkyl, Cι-C 3 haloalkoxy, -XR B , and Y; X is independently selected at each occurrence from the group consisting of -CH 2 -, -CHR C -, -0-, -NH- , -NR C - , and -C(=0) R B and R c are independently Cι-C e alkyl or C 3 -C 7 cycloalkyl, each of is optionally substituted with one or two substituents independently selected from hydroxy, halogen, amino, cyano, nitro, Ci-Cghaloalkyl, C ± - Cghaloalkoxy, Ci-Cg alkyl, Ci-Cg alkoxy, and mono- or di (Ci-Cg) alkylamino; and Y is morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl. 37. A compound or salt according to claim 34, wherein Ar is phenyl, pyridyl, or pyridizinyl each of which is optionally mono-, di-, or tri-substituted with substituents independently chosen from halogen, Ci-Cg alkyl, Ci-Cg alkoxy, amino, mono- or di (Ci- C 6 ) alkylamino, Ci-C 6 alkoxy (Ci-Cg) alkoxy, Ci-Cg alkylamino (Ci-Cg) alkoxy, amino (Ci-Cg) alkoxy, di (Ci- C s ) alkylamino (Ci-Cg) alkoxy, Cι-C 6 alkoxy (Ci- Cg) alkylamino, alkyl substituted with morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl, and Ci-Cg alkoxy substituted with morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl , tetrahydropyridyl , imidazolyl , imidazolinyl, and imidazolidinyl. 38. A compound or salt according to claim 34, wherein Ar is phenyl, pyridyl, or pyridinzyl , each of which is substituted with one of i) halogen, d-C 6 alkyl, Cι-C 3 alkoxy, mono- or di- (Ci- C 6 ) alkylamino, Ci-C 6 alkoxy (Ci-Cg) alkoxy, mono or di- (Ci- C 6 ) alkylamino (Ci-Cg) alkoxy, or ii) Ci-Cg alkoxy substituted with morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl and optionally further substituted with one or two substituents independently chosen from: halogen, Cι-C 4 alkyl, Cι-C 4 alkoxy, amino, d-C 6 alkylamino, Cι-C 3 alkoxy (Cι-C 3 ) alkoxy, Cι-C 3 alkylamino (Ci- C 3 ) alkoxy, amino (C 1 -C 3 ) alkoxy, Cι-C 3 alkylamino (Ci- C 3 ) alkoxy, and Ci-Cg alkoxy (Cι-C 6 ) alkylamino. 39. A compound or salt according to claim 38, wherein each R x and each R 2 is independently hydrogen, Cχ-C 6 alkyl, halo (Ci-Cg) alkyl, halo (d-C 6 ) alkoxy, cyano, amino, or amino (Ci- C 6 ) alkyl. 40. A compound or salt according to claim 39, wherein each R ± and R 2 are independently selected from hydrogen, Cι-C 2 alkyl, Cι-C 2 alkoxy, cyano, amino, and halogen. 41. A compound or salt according to claim 40, wherein no more than three of R x and R 2 are other than hydrogen. 42. A compound or salt according to claim 41, wherein one, two, or three of Ri and R 2 are independently selected from hydrogen, halogen, methyl, and ethyl, and the remaining Ri and R 2 substituents are hydrogen. 43. A compound or salt according to Claim 42, wherein: R is Ci-Cgalkyl, Ci-Cgalkoxy, phenyl (Ci-Cg) alkyl, pyridyl (Ci- Cg) alkyl, phenyl or pyridyl, wherein each phenyl or pyridyl is unsubstituted or mono-, di-, or trisubstituted independently with halogen, cyano, nitro, halo(Cι- C 6 ) alkyl, halo (Ci-Cg) alkoxy, hydroxy, amino, Cι-C 6 alkyl substituted with 0-2 R A , Cι-C 6 alkoxy substituted with 0-2 R A , -NH(Ci_g alkyl) substituted with 0-2 R A , -N(C_ . - Cgalkyl) (d-C 6 alkyl) where each Ci-Cgalkyl is independently substituted with 0-2 R A , phenyl substituted with 0-3 R A , -XR B , or Rc. 44. A compound according to Claim 43, wherein R is Ci- alkyl, Ci-g alkoxy, or phenyl (Cι-C 6 ) alkyl, pyridyl (d-C 6 ) alkyl , phenyl or pyridyl, where the aromatic portion of each is unsubstituted or mono-, di-, or trisubstituted with substituents independently chosen from halogen, cyano, nitro, Ci- Cghaloalkyl, Ci-Cghaloalkoxy, hydroxy, amino, Cι-C 6 alkoxy, and Ci- alkyl . 45. A compound, according to Claim 34, wherein Ar is phenyl, pyridyl, pyrimidinyl, pyrazolyl, or pyridizinyl, each of which is unsubstituted or substituted with up to three groups independently selected from halogen, cyano, nitro, Ci-Cghaloalkyl , Ci-Cghaloalkoxy, hydroxy, amino, and Ci-Cgalkyl substituted with 0- 2 R A , Ci-Cgalkoxy substituted with 0-2 R A , -NH(Cι-Cgalkyl) substituted with 0-2 R A , - N(Cι- Cgalkyl) (Ci- Cgalkyl) where each alkyl is independently substituted with 0-2 R A , -XR B , and R C; R A is independently selected at each occurrence from the group consisting of halogen, hydroxy, Ci-Cgalkyl, Ci-C 6 alkoxy, -NH (Ci-Cgalkyl) , -N (Ci-Cgalkyl) ( Ci-Cgalkyl) , C x - Cghaloalkyl, Ci-Cghaloalkoxy, CO (Ci-Cgalkyl) , CONH(Cι- Cgalkyl) , CON (Ci- Cgalkyl) (Cι-C 6 alkyl) , -XR B and Y; X is independently selected at each occurrence from the group consisting of -CH -, -CHR C -, -0-, -S(0) g -, -NH- , -NRc-, -C(=0)-, -C(=0)0-, -C(=0)NH-, -C(=0)NR c -, -S(0) g NH-, -S(0) n NR c -, NHC(=0)-, -NR c C(=0)-, -NHS(0) g - , and -NR C S (O) g - ;where g is 0, 1, or 2; R B and R c are independently alkyl groups which may be further substituted with one or more substituent (s) selected from oxo, hydroxy, halogen, amino, cyano, nitro, C x -Cghaloalkyl, C x -Cghaloalkoxy, -0(Cι- Cgalkyl) , -NH(Cι- 6 alkyl), -N(d-C 6 alkyl) (Cι_6 alkyl), -NHC(O) (Ci-Cgalkyl) , -N (alkyl) C (O) (Cι-C 6 alkyl) , -NHS (0) m (Cι-Cgalkyl) , -S (O) m (d-C 6 alkyl) , -S(0) m NH(Cι- Cgalkyl), and -S (O) m N (Ci-Cgalkyl) (Ci-C 6 alkyl) ; where m > is 0, 1, or 2; and Y is morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl, each of which is unsubstituted or further substituted with one or more substituents independently chosen from halogen, oxo, hydroxy, amino, mono- or di (Ci- C 6 ) alkylamino, nitro, cyano, Cι-C 6 alkyl, and Ci-Cg alkoxy. 46. A compound or salt according to Claim 45, wherein R is Cι-C 4 alkyl, d-C 4 alkoxy, or phenyl, where the phenyl is mono- or di-substituted with substituents independently chosen from halogen, cyano, nitro, d-C 6 haloalkyl, d- Cghaloalkoxy, hydroxy, amino, d-C 6 alkoxy, Cι_ 6 alkyl, amino (Ci-Cg) alkyl , mono- and di (d-C 6 ) alkylamino (Ci- C 6 ) alkyl, and mono- and di (d-C 6 ) alkylamino (Cι-C 6 ) alkoxy . 47. A compound or salt according to claim 1, wherein n is 2 48. A compound or salt according to Claim 47, wherein A is nitrogen. 49. A compound or salt according to claim 48, wherein Ar is phenyl, pyridyl, pyrimidinyl, pyrazolyl, or pyridizinyl, each of which is unsubstituted or substituted with up to three groups independently selected from halogen, cyano, nitro, Ci-Cghaloalkyl , Ci-Cghaloalkoxy, hydroxy, amino, Ci-Cgalkyl substituted with 0-2 R A , Ci-C 6 alkoxy substituted with 0-2 R A , -NH(Cι-Cgalkyl) substituted with 0-2 R A , -N(Cι-Cgalkyl) ( d-C 6 alkyl) where each alkyl is independently substituted with 0-2 R A , -XR B , or R C; R A is independently selected at each occurrence the group consisting of halogen, hydroxy, d-C 6 alkyl, Ci- C 6 alkoxy, -NH (Ci-Cgalkyl) , -N(d-C 6 alkyl) (d-C 6 alkyl) , Ci- Cghaloalkyl, Ci-Cghaloalkoxy, -XR B and Y; X is independently selected at each occurrence from the group consisting of -CH 2 -, -CHR C -, -O- , -NH- , -NR C - , and -C(=0) -; R B and R c are independently d-C 6 alkyl, C 3 -C 7 cycloalkyl, or C 3 -C 7 cycloalkyl (Ci-Cg) alkyl, each of is optionally substituted with one or more substituents independently selected from oxo, hydroxy, halogen, amino, cyano, nitro, Cι-C 6 haloalkyl, d-C 6 haloalkoxy, d-C 6 alkyl, Cι-C 6 alkoxy, mono- and di (Ci-Cg) alkylamino, -NHC (0) (Cι_ s alkyl), and -N(d-C 6 alkyl)C(O) (Cι-C 6 alkyl); and Y is morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl. 50. A compound or salt according to claim 49, wherein Ar is phenyl, pyridyl, pyrimidinyl, pyrazolyl, or pyridizinyl, each of which is unsubstituted or substituted with up to three groups independently selected from halogen, nitro, Ci-Cghaloalkyl, Ci-Cghaloalkoxy, hydroxy, amino, Cι- 6 alkyl substituted with 0-2 R A , Cι_ 6 alkoxy substituted with 0-2 R A , -NH(Ci-C 6 alkyl) substituted with 0-2 R A , -N(Cι- Cgalkyl) (d-C 6 alkyl) where each alkyl is independently substituted with 0-2 R A , -XR B , and R c ; R A is independently selected at each occurrence the group consisting of halogen, hydroxy, Cι-C 3 alkyl, Ci- Cgalkoxy, -NH (Cι-C 4 alkyl) , -N (d-C 3 alkyl) (d-C 3 alkyl) , Cι-C 3 haloalkyl, Cι-C 3 haloalkoxy, -XR B , and Y; X is independently selected at each occurrence from the group consisting of -CH 2 -, -CHR C -, -0-, -NH- , -NR C - , and -C(=0) - ; R B and R c are independently Ci-Cg alkyl or C 3 -C 7 cycloalkyl, each of is optionally substituted with one or two substituents independently selected from hydroxy, halogen, amino, cyano, nitro, Ci-Cghaloalkyl , Ci- Cghaloalkoxy, d-C 6 alkyl, Cι-C 6 alkoxy, and mono- and di (Ci-Cg) alkylamino; and Y is morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl. 51. A compound or salt according to claim 48, wherein Ar is phenyl, pyridyl, or pyridizinyl each of which is optionally mono-, di-, or tri-substituted with substituents independently chosen from halogen, d-C 6 alkyl, Ci-Cg alkoxy, amino, mono- and di (C x - C 6 ) alkylamino, Ci-Cgalkoxy (d-C 6 ) alkoxy, Cι-C 6 alkylamino (Ci-Cg) alkoxy, amino (d-C 6 ) alkoxy, di (Ci- C δ ) alkylamino (Cι-C 6 ) alkoxy, Ci-Cg alkoxy (Ci-Cg) alkylamino, alkyl substituted with morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl, and Ci-Cg alkoxy substituted with morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl. 52. A compound or salt according to claim 48, wherein Ar is phenyl, pyridyl, or pyridinzyl , each of which is substituted with one of i) halogen, d-C 6 alkyl, d-C 6 alkoxy, mono- or di- (C x - C s ) alkylamino, Ci-C 6 alkoxy (Ci-Cg) alkoxy, mono or di- (Ci- C 6 ) alkylamino (Ci-Cg) alkoxy, or ii) Ci-Cg alkoxy substituted with morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl or optionally further substituted with one or two substituents independently chosen from halogen, Cι-C 4 alkyl, Cι-C alkoxy, amino, Ci-C alkylamino, Cι-C 3 alkoxy (C x -C 3 ) alkoxy, Cι-C 3 alkylamino (Cι-C 3 ) alkoxy, amino (Cι-C 3 ) alkoxy, C 1 -C 3 alkylamino (Cι-C 3 ) alkoxy, and d-C 6 alkoxy (Ci-Cg) alkylamino. 53. A compound or salt according to claim 52, wherein each Ri and each R 2 is independently hydrogen, Ci-C alkyl, halo (Ci-Cg) alkyl, halo (Ci-Cg) alkoxy, cyano, amino, or amino (Ci- C 6 ) alkyl. 54. A compound or salt according to claim 53 , wherein each Ri and R 2 is independently selected from hydrogen, Cι-C 2 alkyl, Cι-C 2 alkoxy, cyano, amino, and halogen. 55. A compound or salt according to claim 54, wherein no more than three of Ri and R 2 are other than hydrogen. 56. A compound or salt according to claim 55, wherein one, two, or three of Ri and R 2 are independently hydrogen, halogen, methyl or ethyl, and the remaining Ri and R 2 substituents are hydrogen. 57. A compound or salt according to Claim 56, wherein: R is Ci-Cgalkyl, Ci-Cgalkoxy, or phenyl (Ci-Cg) alkyl, pyridyl (Ci-Cg) alkyl , phenyl or pyridyl, wherein each phenyl or pyridyl is unsubstituted or mono-, di-, or trisubstituted with halogen, cyano, nitro, halo (Ci-Cg) alkyl, halo (Ci-Cg) alkoxy, hydroxy, amino, Ci-Cgalkyl substituted with 0-2 R A , Ci-Cgalkoxy substituted with 0-2 R A , -NH(Cι_g alkyl) substituted with 0-2 R A , -N(Cι-Cgalkyl) ( Ci-Cgalkyl) where each Ci-Cgalkyl is independently substituted with 0-2 R A , phenyl substituted with 0-3 R A , -XR B , or R c . 58. A compound or salt according to Claim 57, wherein R is Ci- alkyl, Cι_g alkoxy, or phenyl (Ci-Cg) alkyl, pyridyl (Ci-Cg) alkyl , phenyl or pyridyl, where the aromatic portion of each is unsubstituted or mono-, di-, or trisubstituted with halogen, cyano, nitro, Ci-Cghaloalkyl, Ci-Cghaloalkoxy, hydroxy, amino, Ci-Cg alkoxy, or Cι_g alkyl. 59. A compound, according to Claim 48, wherein Ar is phenyl, pyridyl, pyrimidinyl, pyrazolyl, or pyridizinyl, each of which is unsubstituted or substituted with up to three groups selected from halogen, cyano, nitro, Ci-Cghaloalkyl, d-Cghaloalkoxy, hydroxy, amino, Ci-C 6 alkyl substituted with 0-2 R A , C x - Cgalkoxy substituted with 0-2 R A , -NH (Ci-Cgalkyl) substituted with 0-2 R A , -N (Cι-C 6 alkyl) (Ci-C 6 alkyl) where each alkyl is independently substituted with 0-2 R A , -XR B , and R C; R A is independently selected at each occurrence from the group consisting of halogen, hydroxy, Cι-C 6 alkyl, d- C 6 alkoxy, -NH (Ci-Cgalkyl) , -N (Ci-Cgalkyl) ( Ci-Cgalkyl) , Ci-Cghaloalkyl, Ci-Cghaloalkoxy, CO (d-Cgalkyl) , CONH (Ci-Cgalkyl ) , CON (Ci-Cgalkyl) (Cι-C 6 alkyl) , -XR B and Y; X is independently selected at each occurrence from the group consisting of -CH 2 -, -CHR C -, -0-, -S(0) g -, -NH- , -NRc-, -C(=0)-, -C(=0)0-, -C(=0)NH-, -C(=0)NR c -, -S(0) g NH-, -S(0) g NR c -, NHC(=0)-, -NR c C(=0)-, -NHS(0) g - , and -NR C S (O) g -;where g is 0, 1, or 2; Rβ and R c are independently alkyl groups which may be substituted with one or more substituent (s) selected from oxo, hydroxy, halogen, amino, cyano, nitro, Ci- Cghaloalkyl, Cι-C 6 haloalkoxy, -0 (Cι-C 6 alkyl) , -NH(Cι_ 6 alkyl), -N(Cι-C 6 alkyl) (Ci-g alkyl), -NHC(0) (Cι- Cgalkyl), -N (alkyl) C (O) (Ci-Cgalkyl) , -NHS (0) m (Cι- Cgalkyl) , -S (O) m (Cι-Cgalkyl) , -S (O) m NH (Cι-C 6 alkyl) , and -S (0) m N(Cι-C 6 alkyl) (Ci-Cgalkyl) ; where m is 0, 1, or 2 ; and Y is morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl , piperidinyl , tetrahydropyridyl , imidazolyl, imidazolinyl, or imidazolidinyl, each of which is unsubstituted or substituted with one or more substituents independently chosen from halogen, oxo, hydroxy, amino, mono- and di (d-C 6 ) alkylamino, nitro, cyano, Ci-Cg alkyl, and Ci-Cg alkoxy. 60. A compound or salt according to Claim 59, wherein R is Cι-C 4 alkyl, Cι-C 4 alkoxy, or phenyl, where the phenyl is mono- or di-substituted with substituents independently chosen from halogen, cyano, nitro, Ci-Cghaloalkyl , Ci- Cghaloalkoxy, hydroxy, amino, Ci-Cg alkoxy, d_g alkyl, amino (Ci-Cg) alkyl, mono- and di (Ci-Cg) alkylamino (Ci- Cg) alkyl, and mono- and di (Ci-Cg) alkylamino (Ci-Cg) alkoxy. 61. A compound or salt according to claim 9, wherein Ar is phenyl, 2-pyridyl, 3 -pyridyl or pyridinzyl , each of which is substituted at the position para to the point of attachment of Ar with one of i) halogen, Ci-C alkyl, Ci-Cg alkoxy, mono- or di- (Ci-Cg) alkylamino, Ci-Cgalkoxy (Ci-Cg) alkoxy, mono or di- (Ci-Cg) alkylamino (Ci-Cg) alkoxy, or ii) Ci-Cg alkoxy substituted with morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl; and optionally further substituted with one or two substituents independently chosen from halogen, Cι-C 4 alkyl, Cι-C 4 alkoxy, amino, Ci-Cg alkylamino, Cι-C 3 alkoxy (Cι-C 3 ) alkoxy, Cι-C 3 alkylamino (Cι-C 3 ) alkoxy, amino (Cι-C 3 ) alkoxy, Cι-C 3 alkylamino (Cι-C 3 ) alkoxy, and Ci-Cg alkoxy (Ci-Cg) alkylamino; R is Ci_C 4 alkoxy; and one, two, or three of R and R 2 are independently hydrogen, halogen, methyl or ethyl, and the remaining Ri and R 2 substituents are hydrogen. 62. A compound or salt according to claim 9, wherein Ar is phenyl or 2-pyridyl, each of which is substituted at the position meta to the point of attachment of Ar with one of i) halogen, Cι-C 6 alkyl, Ci-Cg alkoxy, mono- or di- (Ci-Cg) alkylamino, Ci-C 3 alkoxy (Ci-Cg) alkoxy, mono or di- (Ci-Cg) alkylamino (Ci-Cg) alkoxy, or ii) Ci-Cg alkoxy substituted with morpholinyl, homopiperazinyl, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridyl, imidazolyl, imidazolinyl, or imidazolidinyl; and optionally further substituted with one or two substituents independently chosen from halogen, Cι-C 4 alkyl, Cι-C 4 alkoxy, amino, Cι-C 6 alkylamino, Cι-C 3 alkoxy (Cι-C 3 ) alkoxy, C1-C 3 alkylamino (Cι-C 3 ) alkoxy, amino (Cι-C 3 ) alkoxy, C 1 -C 3 alkylamino (C 1 -C 3 ) alkoxy, and Ci-C alkoxy (Cι-C 3 ) alkylamino; R is Cι-C 4 alkoxy; and one, two, or three of R x and R 2 are independently hydrogen, halogen, methyl or ethyl, and the remaining R and R 2 substituents are hydrogen. 63. A compound or salt according to Claim 1, which is: 4- (4 -Propyl -phenylimino) -4,5,6, 7-tetrahydro-lH-indazole- 3-carboxylic acid (4 -propyl-phenyl) -amide, 4-Isopropylimino-4 ,5,6, 7-tetrahydro-lH-indazole-3- carboxylic acid (3-fluoro-4-methoxy-phenyl) -amide; 4-Methoxyimino-4 ,5,6, 7-tetrahydro-lH-indole-3-carboxylic acid (2-fluoro-phenyl) -amide ; 4-Ethoxyimino-4, 5,6, 7-tetrahydro-IH-indole-3 -carboxylic acid (2-fluoro-phenyl) -amide; 4- (2-propoxy) imino-4 ,5,6; 7-tetrahydro-lH-indole-3- carboxylic acid (2-fluoro-phenyl) -amide; 4-Methoxyimino-4, 5,6, 7-tetrahydro-IH-indazole-3- carboxylic acid [4- (2-propylamino-ethoxy) -phenyl] -amide; 4-Methoxyimino-4, 5,6, 7-tetrahydro-IH-indole-3 -carboxylic acid (3-fluoro-4-methoxy-phenyl) -amide; 4 -Ethoxyimino-4, 5,6, 7-tetrahydro-lH-indole-3-carboxylic acid (3-fluoro-4-methoxy-phenyl) -amide; 4-Methoxyimino-4, 5,6, 7-tetrahydro-lH-indole-3-carboxylic acid [4- (2-ethoxy-ethoxy) -phenyl] -amide; 4-Methoxyimino-4, 5,6, 7-tetrahydro-lH-indazole-3- carboxylic acid (3-fluoro-4-methoxy-phenyl) -amide, or a pharmaceutically acceptable salt thereof. 64. A compound or salt according to Claim 1, which is: 4-Ethoxyimino-4, 5,6, 7-tetrahydro-lH-indazole-3 -carboxylic acid (3-fluoro-4-methoxy-phenyl) -amide, 4-Methoxyimino-4, 5,6, 7-tetrahydro-lH-indazole-3- carboxylic acid [6- (2-propylamino-ethoxy) -pyridin-3 -yl] -amide, 4-Ethoxyimino-4 ,5,6, 7-tetrahydro-lH-indazole-3 -carboxylic acid [6- (2-propylamino-ethoxy) -pyridin-3 -yl] -amide, 4-Methoxyimino-4, 5,6, 7-tetrahydro-lH-indazole-3- carboxylic acid [4- (2 -morpholin-4-yl-ethoxy) -3-fluorophenyl] - amide, or a pharmaceutically acceptable salt thereof; 4-Ethoxyimino-4 ,5,6, 7-tetrahydro-lH-indazole-3-carboxylic acid [4- (2-morpholin-4-yl-ethoxy) -3-fluorophenyl] -amide, 4-Methoxyimino-4, 5, 6, 7-tetrahydro-lH-indazole-3- carboxylic acid [4- (2-propylamino-ethoxy) -3-fluoro-phenyl] - amide , 4-Ethoxyimino-4,5,6,7-1etrahydro-IH-indazole-3 -carboxylic acid [4- (2-propylamino-ethoxy) -3-fluoro-phenyl] -amide, 4-Ethoxyimino-4 ,5,6, 7-tetrahydro-lH-indazole-3-carboxylic acid [4- (2-dimethylamino-ethoxy) -phenyl] -amide, 4-Hydroxyimino-4, 5,6, 7-tetrahydro-lH-indazole-3- carboxylic acid [6- (3-dimethylamino-propoxy) -pyridin-3 -yl] - amide, 4-Methoxyimino-4, 5,6, 7-tetrahydro-lH-indazole-3- carboxylic acid [6- (3-dimethylamino-propoxy) -pyridin-3 -yl] - amide, or a pharmaceutically acceptable salt thereof; 65. A compound or salt according to Claim 1, which is: 4-Ethoxyimino-4 ,5,6, 7-tetrahydro-lH-indazole-3-carboxylic acid [6- (3-dimethylamino-propoxy) -pyridin-3 -yl] -amide, 4-Methoxyimino-4, 5,6, 7-tetrahydro-IH-indazole-3- carboxylic acid [6- (2 -ethoxy-ethoxy) -pyridin-3 -yl] -amide, 4-Ξthoxyimino-4, 5,6, 7-tetrahydro-lH-indazole-3-carboxylic acid [6- (2-ethoxy-ethoxy) -pyridin-3-yl] -amide, 4-Methoxylimino-4 ,5,6, 7-tetrahydro-IH-indazole-3- carboxylic acid (6-propylamino-pyridazin-3-yl) -amide, 4-Ethoxylimino-4, 5,6, 7-tetrahydro-IH-indazole-3- carboxylic acid (6-propylamino-pyridazin-3-yl) -amide, or a pharmaceutically acceptable salt thereof. 66. A compound or salt according to Claim 1, which is: -Ethoxyimino-4 ,5,6, 7-tetrahydro-lH-indazole-3 -carboxylic acid [6- (2-dimethylamino-ethoxy) -pyridin-2-yl] -amide, 4-Ethoxyimino-4 ,5,6, 7-tetrahydro-IH-indazole-3 -carboxylic acid [6- (3-dimethylamino-propoxy) -pyridin-2-yl] -amide, 4 -Methoxyimino-4, 5,6, 7-tetrahydro-lH-indazole-3- carboxylic acid [6- (3 -diethylamino-propoxy) -pyridin-3 -yl] - amide, 4 -Ethoxyimino-4, 5,6, 7-tetrahydro-IH-indazole-3 -carboxylic acid [6- (3 -diethylamino-propoxy) -pyridin-3 -yl] -amide, 4-Hydroxyimino-4 ,5,6, 7-tetrahydro-IH-indazole-3- carboxylic acid [6- (3-diethylamino-propoxy) -pyridin-3-yl] - amide, 4-Methoxyimino-4, 5,6, 7-tetrahydro-lH-indazole-3- carboxylic acid [6- (3-dimethylamino-ethoxy) -pyridin-2-yl] - amide, 4-Methoxyimino-4 ,5,6, 7-tetrahydro-lH-indazole-3- carboxylic acid [6- (3-dimethylamino-propoxy) -pyridin-2-yl] - amide, or a pharmaceutically acceptable salt thereof. 67. A compound of salt according to Claim 1 for use in therapeutic treatment of a disease or disorder associated with pathogenic agonism, inverse agonism or antagonism of the GABA A receptor. 68. A pharmaceutical composition comprising a compound or salt according to Claim 1 combined with at least one pharmaceutically acceptable carrier or excipient. 69. A method for the treatment of a disease or disorder associated with pathogenic agonism, inverse agonism or antagonism of the GABA A receptor, said method comprising administering to a patient in need of such treatment or prevention an effective amount of a compound or salt of Claim 1. 70. A method according to Claim 66 wherein the disease or disorder associated with pathogenic agonism, inverse agonism or antagonism of the GABA A receptor is anxiety, depression, a sleep disorder, or cognitive impairment. 71. The use of a compound or salt according to Claim 1 for the manufacture of a medicament for the treatment of a disease or disorder associated with pathogenic agonism, inverse agonism or antagonism of the GABA A receptor. 72. The use of a compound or salt according to Claim 1 for the manufacture of a medicament for the treatment of anxiety, depression, sleep disorders, or cognitive impairment. 73. A method for localizing GABA A receptors in a tissue sample comprising contacting with the sample a detectably- labeled compound or salt of Claim 1 under conditions that permit binding of the compound to GABA A receptors, washing the sample to remove unbound compound, and detecting the bound compound . 74. A method of inhibiting the binding of a benzodiazepine compound to a GABA A receptor, said method comprising contacting a compound or salt of claim 1 with cells expressing such a receptor in the presence of the benzodiazepine, wherein the compound is present at a concentration sufficient to inhibit the binding a benzodiazepine compound to a GABA A receptor in vi tro . 75. A method for altering the signal-transducing activity of GABA A receptors, said method comprising exposing cells expressing such receptors to a compound or salt according to claim 1 at a concentration sufficient to inhibit R015-1788 binding to cells expressing a cloned human GABA A receptor in vi tro . 76. A packaged pharmaceutical composition comprising the pharmaceutical composition of Claim 65 in a container and instructions for using the composition to treat a patient suffering from a disorder responsive to agonism, inverse agonism or antagonism of the GABA A receptor . 77. The packaged pharmaceutical composition of claim 73, wherein said patient is suffering from anxiety, depression, a sleep disorder, or cognitive impairment. 78. A compound or salt according to claim 1 wherein in a assay ^of GABA A receptor binding the compound exhibits an Ki of 1 micromolar or less. 79. A compound or salt according to claim 1 wherein in a assay of GABA A receptor binding the compound exhibits an Ki of 100 nanomolar or less. 80. A compound or salt according to claim 1 wherein in a assay of GABA A receptor binding the compound exhibits an Ki of 10 nanomolar or less. 81. A method for preparing a compound according to claim

Inventors: MAYNARD GEORGE, RACHWAL STANISLAW, XIE LINGHONG, MAYNARD, GEORGE, RACHWAL, STANISLAW, XIE, LINGHONG
Applicants: MAYNARD GEORGE, NEUROGEN CORP, RACHWAL STANISLAW, XIE LINGHONG, MAYNARD, GEORGE, NEUROGEN CORPORATION, RACHWAL, STANISLAW, XIE, LINGHONG
Application year: 2001
Main classification: C07D209
IPC codes: A61K31, A61P25, C07D209, C07D231, C07D401