CA2249562C - Certain fused pyrrolecarboxamides as gaba brain receptor ligands - Google Patents

Abstract

Diclosed are compounds of formula (I), or the pharmaceutically acceptable non-toxic salts thereof, wherein W represents substituted or unsubstituted phenyl; T is hydrogen, halogen, hydroxyl, amino or alkyl; X is hydrogen, hydroxy, or lower alkyl; m is 0, 1, or 2; n is 0, 1, or 2; and R3 and R4 represent substituted or unsubstituted organic residues. 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. These compounds are useful in the diagnosis and treatment of anxiety, sleep and seizure disorders, overdose with benzodiazepine drugs and for enhancement of memory.

Description

CERTAIN FUSED PYRROLECARBOXAMIDES AS GAGA BRAIN RECEPTOR LIGANDS.
BACKGROUND OF THE INVENTION
' 1 held of the Invention This invention relates to certain fused pvtrolecarboxanilides which selectively bind to GABAa receptors. This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating anxiety, sleep and seizure disorders. and overdoses of benzodiazepine-type drugs, and enhancing alermess.
Desctrilation of the Related Art -Aminobutvric acid lGABAI is regarded as one of the major inhibitory amino acid transmitters in the mammalian brain. Over 30 years have elapsed since its presence in the brain was demonstrated (Roberts & Frankel, J. Biol. Chem ~,$7: 55-63, 1950;
Udeniriend. J.
Biol. Chem. ~: 65-69, 1950). Since that time, an enormous amount of effort has been devoted to implicating GAGA in the etiology of seizure disorders, sleep, anxiety and cognition (Tallman and Gallager, Ann. Rev. Neuroscience 8_: 21-44, 1985).
Widely, although unequally, distributed through the mammalian brain, GAGA is said to be a transmitter at approximately 30% of the synapses in the brain. In most regions of the brain.
GABA is associated with local inhibitory neurons and only in two regions is GABA
associated with longer projections. GABA mediates many of its actions through a complex of proteins localized both on cell bodies and nerve endings; these are called GABAa receptors.
Postsvnaptic responses to GAGA are mediated through alterations in chloride conductance that generally, although not invariably, lead to hvperpolarization of the cell. Recent '_'~ investigations have indicated that the complex of proteins associated with postsvnaptic GABA
responses is a major site of action for a number of structurally unrelated compounds capable of modifying postsvnaptic responses to GABA. Depending on the mode of interaction, these compounds are capable of producing a spectrum of activities (either sedative.
anxiolvtic, and anticonvulsant. or wakefulness. seizures, and anxiety).
SUBSTITUTE SHEET (RULE 26) WO 97!34870 PCT/US97/04623 1,4-Benzodiazepines continue to be amone the most widely used drugs in the world.
Principal among the benzodiazepines marketed are chlordiazepoxide, diazepam.
flurazepam, and triazolam. These compounds are widely used as anxiolytics, sedative-hypnotics, muscle relaxants, and anticonvulsants. A number of these compounds are extremely potent drugs;
s such potency indicates a site of action with a high affinity and specificity for individual receptors. Early electrophysiological studies indicated that a major action of benzodiazepines was enhancement of GABAergic inhibition. The benzodiazepines were capable of enhancing presynaptic inhibition of a monosynaptic ventral root reflex, a GABA-mediated event (Schmidt et al., 1967, Arch. Exp. Path. Pharmakol. 258: 69-82). All subsequent electrophysiological studies (reviewed in Tallman et al. 1980, Science 207:
274-81, Haefley et al., 1981, Handb. Exptl. Pharmacol. 33: 95-102) have generally confirmed this finding, and by the mid-1970s, there was a general consensus among electrophysiologists that the benzodiazepines could enhance the actions of GABA.
With the discovery of the "receptor" for the benzodiazepines and the subsequent definition of the nature of the interaction between GABA and the benzodiazepines, it appears that the behaviorally important interactions of the benzodiazepines with different neurotransmitter systems are due in a large part to the enhanced ability of GABA itself to modify these systems. Each modified system, in turn, may be associated with the expression of a behavior.
Studies on the mechanistic nature of these interactions depended on the demonstration of a high-affinity benzodiazepine binding site (receptor). Such a receptor is present in the CNS of all vertebrates phylogenetically newer than the honey fishes {Squires &
Braestrup 1977, Nature 1~6: 732-34, Mohler & Okada, 1977, Science 198: 854-51, Mohler &
Okada, 1977, Br. J. Psychiatry 1~: 261-68). By using tritiated diazepam, and a variety of other compounds, it has been demonsuated that these benzodiazepine binding sites fulfill many of the criteria of pharmacological receptors; binding to these sites in vitro is rapid, reversible, stereospecific, and saturable. More importantly, highly significant cotrelations have been shown between the ability of benzodiazepines to displace diazepam from its binding site and activity in a number of animal behavioral tests predictive of benzodiazepine potency _2_ SUBSTITUTE SHEET (RULE 26) i Braestrup & Squires 1978, Br. J. Psychiatry 133: 249-60, Mohler & Okada, 1977, Science 198: 854-51, Mohler & Okada, 1977, Br. J. Psychiatry 133: 261-68). The average therapeutic doses of these drugs in man also correlate with receptor potency (Tallman et al. 1980, Science ' 07: 2 7 4-28 I ).
In 1978, it became clear that GABA and related analogs could interact at the low affinity ( 1 mM) GABA binding site to enhance the binding of benzodiazepines to the clonazepam-sensitive site (Tallman et al. 1978, Nature, 274: 383-85). This enhancement was caused by an increase in the affinity of the benzodiazepine binding site due to occupancy of the GABA site. The data were interpreted to mean that both GABA and benzodiazepine sites were allosterically linked in the membrane as part of a complex of proteins.
For a number of GABA analogs, the ability to enhance diazepam binding by 50% of maximum and the ability to inhibit the binding of GAGA to brain membranes by 50% could be directly correlated.
Enhancement of benzodiazepine binding by GABA agonists is blocked by the GABA
receptor antagonist (+) bicuculline; the stereoisomer (-) bicuculline is much less active (Tallman et al., 1978, Nature, 274: 383-85).
Soon after the discovery of high affinity binding sites for the benzodiazepines, it was discovered that a triazolopyridazine could interact with benzodiazepine receptors in a number of regions of the brain in a manner consistent with receptor heterogeneity or negative cooperativity. In these studies, Hill coefficients significantly less than one were observed in a number of brain regions, including cortex, hippocampus, and striatum. In cerebellum, triazolopyridazine interacted with benzodiazepine sites with a HiI1 coefficient of 1 (Squires et al., 1979, Phatma. Biochem. Behav. 1~: 825-30, Klepner et al. 1979, Phantlacol. Biochem.
Behav. 11: 457-62). Thus, multiple benzodiazepine receptors were predicted in the cortex, hippocampus, striatum, but not in the cerebellum.
Based on these studies, extensive receptor autoradiographic localization studies were carried out at a light microscopic level. Although receptor heterogeneity has been demonstrated (Young & Kuhar 1980, J. Phatmacol. Exp. Ther. 212: 337-46, Young et al., 1981 J. Pharmacol Exp. ther 2~: 425-430, Niehoff et al. 1982, J. Pharmacol.
Exp. Ther. 221:
670-75), no simple correlation between localization of receptor subtypes and the behaviors SUBSTITUTE SHEET (RULE 26) associated with the region has emerged from the early studies. In addition, in the cerebellum, where one receptor was predicted from binding studies, autoradiography revealed heterogeneity of receptors (Niehoff et al.. 1982. J. Pharmacol. Exp. Ther. ~, 2~: 670-75).
A physical basis for the differences in drug specificity for the two apparent subtypes of benzodiazepine sites has been demonstrated by Sieghart & Karobath, 1980, Nature ?8~: 285-87. Using gel electrophoresis in the presence of sodium dodecyl sulfate, the presence of several molecular weight receptors for the benzodiazepines has been reported.
The receptors were identified by the covalent incorporation of radioactive flunitrazepam, a benzodiazepine which can covalently label all receptor types. The major labeled bands have molecular weights of 50,000 to 53,000, 55,000, and 57,000 and the triazolopyridazines inhibit labeling of the slightly higher molecular weight forms (53,000, 55,000, 57,000) (Seighart et al. 1983, Eur. J. Phatmacol. 88: 291-99).
At that time, the possibility was raised that the multiple forms of the receptor represent "isoreceptors" or multiple allelic forms of the receptor (Tallinan & Gallager l 985, Ann. Rev.
Neurosci. $, 21-44). Although common for enzymes, genetically distinct forms of receptors have not generally been described. As we begin to study receptors using specific radioactive probes and electrophoretic techniques, it is almost certain that isoreceptors will emerge as important in investigations of the etiology of psychiatric disorders in people.
The GABAa receptor subunits have been cloned from bovine and human cDNA
libraries (SchofieId P R et al., Zentrum fur Molekulare Biologie, University of Heidelberg, FRG FEBS
letters (1989 Feb 2?), 244(2), 361-364; Garrett K M et al., Biochemical and biophysical research communications (1988 Oct 31), 156(2):1039-1045). A number of distinct cDNAs were identified as subunits of the GABAa receptor complex by cloning and expression. These are categorized into a, Vii, 'y, 8, E, and provide a molecular basis for the GABAa receptor heterogeneity and distinctive regional pharmacology (Shivers, Brenda D. et al, Cent. Mol. Biol., Univ. Heidelberg, Heidelberg, Fed. Rep. Ger. Neuron (1989), 3(3):327-337; Levitan, Edwin S. et al., MRC Mol.
Neurobiol. Unit, MRC Cent., Cambridge, UK. Nature (London, United Kingdom) (1988), 335(6185):76-?9). The y subunit appears to enable drugs like benzodiazepines to modify the GABA responses (Pritchett D B et al., ZMBH, Universitat Heidedberg, FRG Nature (1989 Apr 13), 338(6216), 582-S.). The presence of low Hill coefficients in the binding of ligands to the GABAa receptor indicates unique profiles of subtype specific pharmacological action.
Drugs that interact at the GABAa receptor can possess a spectrum of pharmacological activities depending on their abilities to modify the actions of GABA. For example, the beta-carbolines were first isolated based upon their ability to inhibit competitively the binding of diazepam to its binding site (Nielsen et al.. 1979, Life Sci. 25: 679-86). The receptor binding assay is not totally predictive about the biological activity of such compounds; agonists.
partial agonists, inverse agonists, and antagonists can inhibit binding. When the beta-carboline structure was determined, it was possible to synthesize a number of analogs and test these compounds behaviorally. It was immediately realized that the beta-carbolines could antagonize the actions of diazepam behaviorally (Tenen & Hirsch, 1980. Nature 288: 609-10).
In addition to this antagonism, beta-carbolines possess intrinsic activity of their own opposite to that of the benzodiazepines; they become known as inverse agonists.
l 0 In addition, a number of other specific antagonists of the benzodiazepine receptor were developed based on their ability to inhibit the binding of benzodiazepines.
The best studied of these compounds is an imidazodiazepine (Hunkeler et al., 1981, Nature 2~0: 514-516). This compound is a high affinity competitive inhibitor of benzodiazepine and beta-carboline binding and is capable of blocking the pharmacological actions of both these classes of 15 compounds. By itself, it possesses little intrinsic pharmacological activity in animals and humans (Hunkeler et al., 1981, Nature 290: S I4-16; Dan agh et al., 1983, Eur.
J. Clin.
Phalzrtacol. 14: 569-70). When a radiolabeled form of this compound was studied (Mohler &
Richards, 1981, Nature 294: 763-65), it was demonstrated that this compound would interact with the same number of sites as the benzodiazepines and beta-carbolines, and that the 20 interactions of these compounds were purely competitive. This compound is the ligand of choice for binding to GABAa receptors because it does not possess receptor subtype specificity and measures each state of the receptor.
The study of the interactions of a wide variety of compounds similar to the above has led to the categorizing of these compounds. Presently, those compounds possessing activity 25 similar to the benzodiazepines are called agonists. Compounds possessing activity opposite to benzodiazepines are called inverse agonists. and the compounds blocking both types of activity have been termed antagonists. This categorization has been developed to emphasize the fact that a wide variety of compounds can produce a spectrum of pharmacological effects, to indicate that compounds can interact at the same receptor to produce opposite effects, and -$-SUBSTITUTE SHEET (RULE 26) to indicate that beta-carbolines and antagonists with intrinsic anxiogenic effects are not svnonvmous.
A biochemical test for the pharmacological and behavioral properties of compounds that interact with the benzodiazepine receptor continues to emphasize the interaction with the s GABAergic system. In contrast to the benzodiazepines, which show an increase in their affinity due to GABA (Tallman et al., 1978, Nature 274: 383-85, Tallman et al., 1980, Science 207: 274-81 ), compounds with antagonist properties show little GABA shift (i.e., change in receptor affinity due to GABA) (Mohler & Richards 1981, Nature 294: 763-65), and the inverse agonists actually show a decrease in affinity due to GABA (Braestrup &
Nielson 1981, Nature 2~4: 472-474). Thus, the GABA shift predicts generally the expected behavioral properties of the compounds.
Various compounds have been prepared as benzodiazepine agonists and antagonists.
For Example, U.S. Patents Nos. 3,455,943, 4,435,403, 4,596,808, 4,623,649, and 4,719,210, German Patent No. DE 3,246,932, and Liebigs Ann. Chem. 1986, 1749 teach assorted 1 S benzodiazepine agonists and antagonists and related anti-depressant and central nervous system active compounds.
U.S. Patent No. 3,455,943 discloses compounds of the formula:
R~ ~ X
~ y wherein Rl is a member of the group consisting of hydrogen and lower alkoxy;
R2 is a member of the group consisting of hydrogen and lower alkoxy; R3 is a member of the group consisting of hydrogen and lower alkyl; and X is a divalent radical selected from the group consisting of SU85T1TUTE SHEET (RULE 26) ~NH \ 'N
~ lower alkyl lower alkyl lower alkyl and \/N
lowe~r'alkyl and the non-toxic acid addition salts thereof.
Other references, such as U.S. Patent No. 4,435,403 and German patent DE

3,246,932 disclose compounds containing the following structural skeleton:
A~
~N
I, 'N H
H
where A is carbon or nitrogen.
A variety of indole-3-carboxamides are described in the literature. For example, J.
Org. Chem., 42: 1883-1885 (1977) discloses the following compounds.
O
/ C-N.H / O ~H
\ \ I I C _N \
J \
N /
H C~ H Br O p /
\
/ C-NCH / C._N~H I
N / N
H I
H
J. Heterocylic Chem., 14: 519-520 ( 1977) discloses a compound of the following formula:
_7_ SUBSTtTUTE SHEET (RULE 26) / C-NCH
N
H
None of these indole-3-carboxamides includes an oxy substiuent at the 4-position of the indole ring.
U.S. Patent No. 5,484,944, discloses compounds of the general formula:
O
N
c ~ '' T H
~N
I
X
or the pharmaceutically acceptable non-toxic salts thereof wherein:
T is halogen, hydrogen, hydroxyl, amino or straight or branched chain Iower alkoxy having 1-6 carbon atoms;
X is hydrogen, hydroxyl or straight or branched chain lower alkyl having 1-6 carbon atoms;
W is phenyl, 2- or 3-thienyl, 2-, 3-, or 4-pyridyl or 6-quinolinyl, each of which may be mono or disubstituted with halogen, cyano, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, amino, mono or dialkylamino where each alkyl is independently straight or branched chain lower alkyl having 1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms, or NRl CORD, COR?, CONK 1 R2 or COZRZ where R 1 and R~ are the same or different and represent hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms; and C
represents -g_ R3 ~O O
O
Y \ R3 ~ N Ra w/ Nw R5 ( / arR \ ~ or ~ or Rs Rs Rs ~CH2)n wherein:
Y represents nitrogen or C-R4;
Z represents N-R7 or a carbon atom substituted with Rg and R9, i.~., C(Rg)(R9);
n is 1, 2, 3, or 4;
R3 is hydrogen, phenyl, 2-, 3-, or 4-pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms, or phenylalkyl or 2-, 3, or 4-pyridylalkyl where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms;
R4 is halogen or trifluoromethyl; or -OR10, -COR10, -C02R10, -OCOR10, or -R10, where R10 is hydrogen, phenyl, 2,- 3, or 4-pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms, or phenylalkyl or 2-, 3-, or 4-pyridylalkyl where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms; or -CONR11R12 or -(CH2)mNR11R12~ where m is 0, 1, or 2; R11 represents hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms; and R12 is hydrogen, phenyl, 2-, 3-, or 4-pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms, or phenylalkyl or 2-, 3-, or 4-pyridylalkyl where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms; or NR11R12 forms a heterocyclic group which is morpholinyl, piperidinyl, pyrrolidinyl, or N-alkyl piperazinyl;
R5 and Rb are the same or different and represent hydrogen, halogen, straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms;

SUBSTITUTE SHEET (RULE Z6) R7 is hydrogen. phenyl. .-. 3-. or 4-pyridy 1. straight or branched chain lower alkyl having 1-6 carbon atoms. or phenylalkyl or ?-. 3-, or 4-pyridylalkyl where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms;
Rg is hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms; and R9 is -COR13, -CO~R13 or -R13, where R13 is hydrogen, phenyl, 2-, 3-, or 4-pyridyl, straight or branched chain lower alkyl having l-6 carbon atoms, or phenylalkyl or 2-, 3-, or 4-pyridylalkyl where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms; or -CONR14R15 or -~~2)k~14R15~ where k is 0, 1, or 2; R14 represents hydrogen, straight or branched chain lower alkyl having I-6 carbon atoms; and R15 is hydrogen, phenyl, 2-, 3-, or 4-pyridyl, straight or branched chain lower alkyl having 1-6 carbon atoms, or phenylaikyl or 2-, 3-, or 4-pyridylalkyl where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms; or NR14R15 forms a heterocyclic group which is morpholinyl, piperidinyl, pyrrolidinyl, or N-alkyl piperazinyl.
International Publication No. W095/11885 , filed October 26, 1994 and published May 4, 1995, ~ also discloses pvcrole derivatives of the general formula described in U.S. Patent No.
5,484.944. i.e., y0 X
W
N
H
The substituents on this general formula are as defined in U.S. Patent No.
5,484,944. In addition. ! U.S. Patent No. 5,608,0?9, filed June 7, 1995 and issued on March 4, 199?, .
. discloses compounds of the general formula set forth in U.S. Patent No. 5.484,944.

SUMMARY OF THE INVENTION
An obj ect of the present invention is to provide certain fusedpyrrolecarboxamides as GABA
brainreceptor ligands. In accordance with an aspect of thepresent invention, there is provided a compound of the formula:
O O
,W
'N
H
3 rm ~ ~~T
R4 ~'3n _ N

X
or the pharmaceutically acceptable non-toxic salts thereof wherein:
W is aryl or heteroaryl, each of which is optionally substituted with up to five groups selected independently from halogen, cyano, hydroxy, alkyl or cycloalkyl having 3-7 carbon atoms, amino or mono- or dialkylamino where each alkyl is independently lower alkyl or cycloalkyl having 3-7 carbon atoms, alkoxy or cycloalkyl allcoxy having 3-7 carbon atoms, or NR1COR2, COR2, CONR1R2 or C02R2 where R1 and RZ are the same or different and represent hydrogen or alkyl or cycioalkyl having 3-7 carbon atoms; and T is halogen, hydrogen, hydroxyl, amino or alkoxy;
X is hydrogen, hydroxyl or alkyl;
mis0, l,or2;
n is 0, 1, or 2; and R3 and R4 are the same or different and represent hydrogen, alkyl, CORS or C02R5 where RS is alkyl or cycloalkyl having 3-7 carbon atoms, CONR6R~ where R6 and R~ are selected independently from hydrogen, alkyl, cycloalkyl having 3-7 carbon atoms, phenyl, 2-,3-, or 4-pyridyl , or NR6R7 forms a heterocyclic group which is mozpholinyl, piperidinyl, pyrrolidinyl, or N-alkyl piperazinyl; or R3-R4 together represent ,cyclic moiety having 3-7 carbon atoms.

In accordance with another aspect of the invention, there is provided a compound of the formula:
Re Rg O O
'N
H
R rt' I ~~H Rto R4 n N

H
wherein R3 and R4 are the same or different and represent hydrogen, alkyl, CORS or C02R5 where R5 is allyl or cycloalkyl having 3-7 carbon atoms, CONR6R7 where R6 and R7 are selected independently from hydrogen, alkyl, cycloalkyi having 3-7 carbon atoms, phenyl, 2-,3-, or 4-pyridyl , or NR6R7 forms a heterocyclic group which is morpholinyl, piperidinyl, pyrrolidinyl, or N-alkyl piperazinyl; or R3-R~ together represent a cyclic moiety having 3-7 carbon atoms;
Rg is hydrogen, halogen, hydroxyl, alkyl, allcoxy, cycloalkyl aikoxy having 3-7 carbon atoms, amino, mono- or diaikylamino; and Rg is hydrogen, halogen, cyano, hydroxy, alkyl, alkoxy, cycioalkyl alkoxy having 3-7 carbon atoms, amino, mono- or dialkyiamino, NR1COR2, COR2, or C02R2 where RI and RZ are the same or different and represent hydrogen, alkyl, or cycloalkyl having 3-7 carbon atoms; and RIO is hydrogen, halogen, hydroxyl, alkyl, alkoxy, amino, mono- or dialkylamino;
m is 0, I, or 2; and n is 0, I, or 2.
-lla-In accordance with another aspect of the invention, there is provided a compound of the formula:
O
O G
N~
H
~'' H

H
w here G represents thienyl, thiazolvl. pvridvl, napthyridinyi, quinolinyl, or phenyl, each of which is optionally mono-. dl- or trisubstituted with halogen. alkyl, alkoxy, or hydroxy; and R3 and R4 are the same or different and represent hydrogen or alkyl, provided that not both R3 and R4 are hydrogen.
This invention provides novel compounds of Formula I which interact with a GABAa binding site, the benzodiazepine receptor.
The invention provides pharmaceutical compositions comprising compounds of Formula I. The invention also provides compounds useful in the diagnosis and treatment of anxiety, sleep and seizure disorders, overdose with ben2odiazepine drugs and for enhancement of memory. Accordingly, a broad embodiment of the invention is directed to compounds of general Formula I:
O O
NEW
H
~~-T

N
Ra ~ 1 X
I
-11b-or the pharmaceutically acceptable non-toxic salts thereof wherein:
W is aryl or heteroaryl; and T is halogen, hydrogen, hydroxyl, amino or straight or branched chain lower alkoxy having 1-6 carbon atoms;
X is hydrogen, hydroxyl or straight or branched chain tower alkyl having 1-6 carbon atoms;
m is 0, l, or 2;
n is 0, 1, or 2; and R3 and R4 are the same or different and are selected from hydrogen, straight or branched lower alkyl having 1-6 carbon atoms, CORS or C02R5 where R5 is straight or branched lower alkyl having 1-6 carbon atoms or cycloalkyl having 3-7 carbon atoms, CONR6R7 where R( and R7 are selected independently from hydrogen, straight or branched chain lodver alkyl having 1-6 carbon atoms, cycloalkyl having 3-7 carbon atoms, phenyl, 2-,3-, or 4-pyridyl, or NRbR~ forms a heterocyclic group which is morpholinyl, piperidinyl, pyrrolidinyl, or N-alkyl piperazinyl; or R3-R4 together represent a cyclic moiety having 3-7 carbon atoms; and where each alkyl substituent in Formula 1 is optionally substituted with at least one group independently selected from hydroxv, mono- or dialkyl amino, phenyl or pytidyl.
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. In other words, while the compounds of the invention all interact with GABAa brain receptors, they do not display identical physiologic activity.
Thus, these compounds are useful in the diagnosis and treatment of anxiety, sleep and seizure disorders, overdose with benzodiazepine drugs and for enhancement of memory. For example, these compounds can be used to treat overdoses of benzodiazepine-type drugs as they would competitively bind to the benzodiazepine receptor.

WO 97/34870 PC'T/US97/04623 DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term "aryl" refers to aromatic carbocyclic groups having a single ring (e.g., phenvi), multiple rings (e.g., biphenyl), or multiple condensed rings in which at least one is aromatic. (e.g., l.?,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), which can optionally be substituted with e.g., halogen, lower alkyl, lower alkylthio.
trifluoromethyl, lower acyloxy, aryl, and heteroaryl.
A preferred aryl group is phenyl optionally substituted with up to five groups selected independently from halogen, cyano, hydroxy, straight or branched chain lower alkyl having I-b carbon atoms or cycloalkyl having 3-7 carbon atoms, amino, mono or dialkylamino where each alkyl is independently straight or branched chain lower alkyl having 1-6 carbon atoms or cycloalkyl having 3-7 carbon atoms, straight or branched chain lower alkoxy having 1-6 carbon atoms, cycloalkyl alkoxy having 3-7 carbon atoms, or NR1COR2, COR2, or C02R2 where R1 and R? are the same or different and represent hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms or cycloalkyl having 3-7 carbon atoms I S By heteroaryl is meant aromatic ring systems having at least one and up to four hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur.
Examples of heteroaryl groups are pytidyl, pyrimidinyl, pyrrolyl, pyrazolyl, pyrazinyl, pyridazinyl, oxazolyl, napthvridinyl, isoxazolyl, phthalazinyl, furanyl, quinolinyl, isoquinolinyl, thiazolyl, and thienyl, which can optionally be substituted with, e.g., halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, aryl, heteroaryl, and hydroxy.
The aryl and heteroaryl groups herein are systems characterized by 4n+2 n electrons, where n is an integer..
In addition to those mentioned above, other examples of the aryl and heteroaryl groups encompassed within the invention are the following:
/_~, - ~ , , w N~ ~~ C~'~ ~ y I ~J I
N N /
S

SUBSTITUTE SHEET {RULE 26) \ ~~ \ N~~ N~ N~~ \ /~
I / / I / / / / /~

Ny I , l .\
o~ o~ ' ~ o o N ,-'~

I/ ~I/

As noted above, each of these groups can optionally be mono- or polysubstituted with groups selected independently from, for example, halogen, lower alkyl, lower alkoxy, lower alkyithio, trifiuoromethyl, lower acyloxy, aryl, heteroaryl, and hydroxy.
Still other examples of various aryl and heteroaryl groups are shown in Chart D of published International Application WO 93/17025.
By "alkyl" and "lower alkyl" in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyi, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. Unless indicated otherwise, the alkyl group substituents herein are optionally substituted with at least one group independently selected from hydroxy, mono- or dialkyl amino, phenyl or pyridyl.
Where R, and R, are both alkyl, each alkyl is independently selected from Iower alkyl.
By "alkoxy" and "lower alkoxy" in the present invention is meant straight or branched chain alkoxy groups having 1-6 carbon atoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.
As used herein "cycloalkyi alkoxy" refers to groups of the formula SUBSTITUTE SHEET (RULE 26~

(CH 2~H -(CR'R")b0-where a is an integer of from 2 to 6; R' and R" independently represent hydrogen or alkyl; and b is an integer of from 1 to 6.
By the term "halogen" in the present invention is meant fluorine. bromine.
chlorine, and iodine.
By "N-alkylpiperazyl" in the invention is meant radicals of the formula:
-N N-R
U
where R is alkyl as defined above.
By "monoalkylamino" as used herein is meant an amino substitutent substituted with one ( 1 ) alkyl group where the alkyl group is lower alkyl as defined above or cycloalkyl having from 3-7 carbon atoms.
By "dialkylamino" as used herein is meant an amino substitutent substituted with two (2) alkyl groups where the alkyl groups are independently lower alkyl groups as defined above or cycloalkyl groups having from 3-7 carbon atoms.
The novel compounds encompassed by the instant invention can be described by general formula I set forth above or the pharmaceutically acceptable non-toxic salts thereof.
In addition, the present invention encompasses compounds of Formula II.

H~
Rio Rs H
Ra , H
II

SU85T1TUTE SHEET (RULE 26) wherein R3 and R4 are the same or different and represent hydrogen, alkyl, CORS or CO?RS where R5 is alkyl or cycloalkyl having 3-7 carbon atoms, CONR6R7 where R6 and R~ are selected independently from hydrogen, alkyl, cycloalkyl having 3-7 carbon atoms, phenyl, 2-,3-. or 4-pyridyi , or NR6R~ forms a heterocyclic group which is morpholinyl, piperidinyl, pyrrolidinyl, or N-alkyl piperazinyl; or R3-R4 together represent a cyclic moiety having 3-7 carbon atoms;
Rg is hydrogen, halogen, hydroxyl, alkyl, alkoxy, cycloalkyl alkoxy having 3-7 carbon atoms, amino, mono- or dialkylamino; and R9 is hydrogen, halogen, cyano, hydroxy, alkyl, alkoxy, cycloalkyl alkoxy having 3-7 carbon atoms, amino. mono- or dialkylamino. NR1COR2, COR2, or C02R~ where R1 and R2 are the same or different and represent hydrogen, alkyl, or cycloalkyl having 3-7 carbon atoms; and Rlp is hydrogen, halogen, hydroxyl, alkyl, alkoxy, amino, mono- or dialkylamino;
m is 0, 1, or 2; and nis0, l,or2.
Preferred compounds of Formula II are those where the phenyl group is mono-, dl-, or trisubstituted in the 2,4, and/or positions relative to the point of attachment of the phenyl ringto the amide nitrogen.
In addition, the present invention encompasses compounds of Formula III.

O O
~H R
~o N
H
III
wherein R3 and R4 are the same or different and represent hydrogen or alkyl;

SUBSTTTUTE SHEET (RULE 26) Rg is hydrogen. halogen. hydroxyl. alkyl. alkoxy, cvcioalkvi aikoxy having 3-7 carbon atoms.
amino. mono- or dialkvlamino: and R9 is hydrogen, haloeen, cyano. hydroxy, alkyl, alkoxy, cycloalkyl alkoxy having 3-7 carbon atoms, ammo, mono- or dialkylamino, NRI COR2, COR2, or C02R2 where R1 and R? are the same or different and represent hydrogen, alkyl, or cycloalkyl having 3-7 carbon atoms; and R10 is hydrogen, halogen, hydroxyl, alkyl, alkoxy, amino, mono- or dialkylamino.
Preferred compounds of Formula III are those where the phenyl group is mono-, dl-, or trisubstituted in the 2,4, and/or ~ positions relative to the point of attachment of the phenyl ring to the amide nitrogen. Particularly preferred compounds of Formula III
are those where the phenyl group in trisubstituted in the 2,4, and 5 postitons relative to the point of attachment of the phenyl ring to the amide nitrogen, and Rg, R,, and R,o are independently selected from hyrogen, halogen, hydroxy, alkoxy, and alkyl, provided that not all of Rg, R"
and R,o are hydrogen.
In addition, the present invention encompasses compounds of Formula IV.

O O
N
H I
Rio R ~N

H
IV
wherein R3 represents alkyl;
Rg is hydrogen, halogen, hydroxyl, alkyl, alkoxy, cycloalkyl alkoxy having 3-7 carbon atoms, amino, mono- or dialkylamino; and R9 is hydrogen, halogen, cyano. hydroxy, alkyl, alkoxy, cycioalkyi aikoxy having 3-7 carbon atoms, amino, mono- or dialkylamino, NRICOR2, COR2, or C02R2 where RI and SUBSTITUTE SHEET (RULE 26) R? are the same or different and represent hydrogen. alkyl, or cvcloalkyl having 3- i carbon atoms: and R10 is hydrogen, halogen. hydroxyl, alkyl, alkoxy, amino, mono- or dialkvlamino.
Prefen ed compounds of Formula IV are those where Rg, R" and R,o are independently selected from hydrogen. halogen, hydroxy, alkoxy, and alkyl, provided that not all of RQ, R4, and R,o are hydrogen.
In addition, the present invention encompasses compounds of Formula V.
R$

O O
_H R
R3 ~ ~~H ~o R4/~/ N
H
V
wherein R3 and R4 are the same or different and represent alkyl;
Rg is hydrogen, halogen, hydroxyl, alkyl, alkoxy, cycloalkyl alkoxy having 3-7 carbon atoms, amino, mono- or dialkylamino; and R9 is hydrogen, halogen, cyano, hydroxy, alkyl, alkoxy, cycloalkyl alkoxy having 3-7 carbon 1S atoms, amino, mono- or dialkylamino, NR1COR2, COR2, or C02R2 where R1 and R2 are the same or different and represent hydrogen, alkyl, or cycloalkyl having 3-7 carbon atoms; and Rl0 is hydrogen, halogen, hydroxyl, alkyl, alkoxy, amino, mono- or diaikylamino.
Preferred compounds of Formula V are those where Rg, Rq, and R,o are independently selected from hydrogen, halogen, hydroxy, alkoxy, and alkyl, provided that not all of Rs, R"
and R,o are hydrogen. Particularly preferred compounds of Formula V are those weree R, an R4 are both methyl, and Rs, R.,, and R,o are independently selected from hydrogen, halogen, hydroxy, alkoxy, and alkyl, provided that not all of Rs, Rq, and R,~ are hydrogen.
_18_ SUSST1TUTE SHEET (RULE 26) In addition. the present invention encompasses compounds of Formula VI

_ / Rg .. O
H~
Rio Ra .. , H
VI
wherein q is an integer of from 2-6;
Rg is hydrogen, halogen, hydroxyl, alkyl, alkoxy, cycloalkyl alkoxy having 3-7 carbon atoms, amino, mono- or dialkylamino; and R9 is hydrogen, halogen, cyano, hydroxy, alkyl, alkoxy, cycloalkyl alkoxy having 3-7 carbon atoms, amino, mono- or diallcylamino, NRICOR2, COR2, or C02R2 where R1 and R2 are the same or different and represent hydrogen, alkyl, or cycloalkyl having 3-7 carbon atoms; and RI0 is hydrogen, halogen, hydroxyl, alkyl, alkoxy, amino, mono- or dialkylamino;
m is 0, 1, or 2; and n is 0, 1, or 2.
Preferred compounds of Formula VI are those where Re, R9, and R,o are independently selected from hydrogen, halogen, hydroxy, alkoxy, and alkyl, provided that not all of Rg, R9, and R,o are hydrogen.
In addition, the present invention encompasses compounds of Formula VII.

SUBSTITUTE SHEET (RULE 26) WO 97/34870 PC'T/US97/04623 N~G
H
Rs H
Ra . i H
VII
where G represents aryl or heteroary such as, for example, thienyl, thiazolyl, pyridyl, napthvridinyl, quinolinyl, or phenyl, each of which is optionaly mono-, di- or trisubstituted with halogen alkyl alkoxy, or hydroxy; and R3 and R4 are the same or different and represent hydrogen or alkyl, provided that not both R3 and R4 are hydrogen.
Preferred compounds of Formula VII are those where R3 and R4 are C 1 _3 alkyl, and more preferably methyl. Other preferred compounds of Formula VII are those where R3 is hydrogen and R4 is C 1 _3 alkyl, and more preferably R4 is methyl.
Preferred compounds of Formula VII include a G group selected from the following:
/ Ra / Rb~Rc Ra ~ Ra Ra / /
Rc Ra Ra Ra / ~~ Rc ~I
Rc ~, Rb Ra~/ .~Rb Ra /~/Rc R , a SUBSTITUTE SHEET (RULE 26) /~Rd Rb\//\iRd Rb~~Rc \ I \ I
~~ Rb //~Rc S~~Re I
. ~\ , l Rb S //~~ / N'u N
l R9 l Re ~ ~ ~\ ~ ~ \ /
N N
/NUN\ / \
I ~/ \
\~ . / w N /
f \/~ ~~ S, ~~~ I/ R
I Nv~Re . ~N
N
In the above G groups, the following definitions apply.
Ra is halogen;
Rb is hydroxy;
Rc represents alkoxy;
Rd represents alkyl;
Re represents hydrogen or Rd;
Rf represents hydrogen, or R~; and Rg represents hydrogen, Ra or R~.
In those formulas where more than one of the same substituent appears. those substituents are the same or different.
Particularly preffered Ra groups in G are fluorine. Particularly preferred Rc groups in G are methoxy and ethoxy. Particularly preferred Rd groups in G are methyl and ethyl.

SUSST1TUTE SHEET (RULE 26) Representative compounds of the invention are shown below in Table 1.
Table 1 O O ~ ~ O O
N \ N \
H3C I H3C I ~ H F
'N ~N

Compound 1 Compound 2 O O \ ~ O O \
~N _N
H ~ ~ H

Compound 3 Compound 4 O O / ~ O / OCH3 \ O \
N N
H F I ~ H
F
H3C H HsC H
Compound S Compound 6 S

~N N N N
H ~ ~ H
HsC N HsC N

Compound 7 Compound 8 / ~ /
O O I O O
N wN ~ N N wN /
O H ~ O H
H3C 'H H3C 'H
Compound 9 Compound 10 SUBSTITUTE SHEET (RULE 26) The following numbering system is used to identify positions on the pyrrole ring portion of the compounds of the invention:
O
s N
s ~ ~ H
1 / z s N
H
Representative compounds of the present invention, which are encompassed by Formula l, include, but are not limited to the compounds in Table I and their pharmaceutically acceptable salts. Non-toxic pharmaceutically acceptable salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, 10 methanesulfonic, nitric, benzoic, citric, tartaric, malefic, hydroiodic, alkanoic such as acetic, HOOC-(CH2)n-COOH where n is 0-4, and the like. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.
The present invention also encompasses the prodrugs, preferably acyIated prodrugs, of the compounds of Formula I. Those skilled in the art will recognize various synthetic 1 S methodologies which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I.
The pharmaceutical utility of compounds of this invention are indicated by the following assay for GABAa receptor binding activity.
Assays are carried out as described in Thomas and Tallman (J. Bio. Chem. 156:

20 9842 , J. Neurosci. 3_: 433-440, 1983). Rat cortical tissue is dissected and homogenized in 25 volumes (w/v) of 0.05 M Tris HCl buffer (pH 7.4 at 4°C). The tissue homoeenate is centrifuged in the cold (4°C) at 20,000 x g for 20'. The supernatant is decanted and the pellet is rehomogenized in the same volume of buffer and again centrifuged at 20,000 x g. The supernatant is decanted and the pellet is frozen at -20°C overnight.
The pellet is then thawed 25 and rehomogenized in 25 volume (original wt/voI) of buffer and the procedure is carried out SU8ST1TUTE SHEET (RULE 26) twice. The pellet is tinallv resuspended in ~0 volumes ~wwol of 0.05 M Tris HCl buffer (pH
-.-i at 40°C).
Incubations contain 100 ml of tissue homogenate, I00 ml of radioligand 0.5 nM
(3H-ROI ~-1788 [3H-Flumazenil] specific activity 80 Ci/mmol), drug or blocker and buffer to a total volume of 500 ml. Incubations are carried for 30 min at 4oC then are rapidly filtered through GFB filters to separate free and bound ligand. Filters are washed twice with fresh 0.05 M Tris HCl buffer (pH 7.4 at 4oC) and counted in a liquid scintillation counter. 1.0 mM
diazepam is added to some tubes to determine nonspecific binding. Data are collected in triplicate determinations, averaged and % inhibition of total specific binding is calculated.
Total Specific Binding = Total - Nonspecific. In some cases, the amounts of unlabeled drugs is varied and total displacement curves of binding are carried out. Data are converted to Ki's;
results for compounds of this invention are listed in Table 2.

Compound Number K; (nM) 5 0.5 1 S 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. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrastemal injection or infusion techniques. In addition, there is provided a pharmaceutical SU85T1TlJTE SHEET (RULE 26) 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 which 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 giyceryl monosterate 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 carboxvmethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polvvinylpyrrolidone, gum tragacanth and gum acacia;
dispersing or wetting SU85T1TUTE SHEET (RULE 26) 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 monooieate, 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 cetyi 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 ?5 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 monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate.
The emulsions may also contain sweetening and flavoring agents.

SU85TiTUTE SHEET (RULE 26) Syrups and elixirs may be formulated with sweetening agents. for example glycerol, propylene glycol. sorbitor 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 for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which 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 anaesthetics, preservatives and buffering agents can be dissolved in the vehicle.
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 about 1 mg to about S00 mg of an active ingredient.

SUBSTffUTE SHEET (RULE 26) 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.
An illustration of the preparation of compounds of the present invention is given in Scheme I.

SUBSTITUTE 5liEET (RULE 26) Scheme I
O O OH
K.,CO;. BrCH,COCO,_Et ~.,-CO,Et R~ , ,n O R~~ i ~n O
MsCI, Et3N
CH.,CI.,, 0° C
r - -CO.,Et CO.,Et R3 { rt, ( ~ NH40Ac. DMF R3 {
R4 / ~ ~ n H 100° C R4 ~ ~ n O
SN NaOH, EtOH.
85o C W
O O HN
CO.,H ~ O
{ n, ~ \ EtgN, CIC02E~ ~ {
Rs l R3 R4 ~~ H DMF, 0° C R4 ~ N

CO,Et 1 N NaOH. -EtOH.
85 C ~ W
HN
O

R4 ..
where W, m, n, R3, and R4 are defined as above.
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 present invention, as demonstrated by the following examples. In some cases protection of certain reactive functionaiities may be necessary to achieve some of the above transformations.
In general the SUBST1TUTF SHEET tRULE 26) need for such protecting ?roups will be apparent to those skilled in the art of organic synthesis as well as the conditions necessary to attach and remove such groups.
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.

WO 97/34870 PC"T/US97/04623 Example 1 Preparation of starting materials and intermediates The starting materials and various intermediates may be obtained from commercial sources, prepared from commercially available organic compounds, or prepared using well known synthetic methods.
Representative examples of methods for preparing intermediates of the invention are set forth below.
1. Ethyl 3-hydroxy 4-oxo-6-methyl-2,3,4,5,6,7 hexahvdrobenzofuran-3-carboxvlate O OH
C02Et To a stirred mixture of 5-methyl-1,3-cyclohexanedione (10.25 g, 81 mmol) and potassium carbonate (22.46 g, 162 mmol) in dichloromethane (200 mL) at 0°C was added a solution of ethyl bromopyruvate ( 10.7 mL, 85 mmol) in dichloromethane (50 mL). The reaction was allowed to reach ambient temperature, stirred for 18 hours, then poured into saturated aqueous ammonium chloride. After adjusting to neutral pH with aqueous hydrochloric acid, the mixture was extracted 2X with dichloromethane, the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give ethyl 3-hydroxy 4-oxo-b-methyl-2,3,4,5,6,7-hexahydrobenzofi.trap-3-carboxylate ( 18.48 g).
'0 2. Ethyl4-oxo-6-methyl-4,5,6,7-tetrahvdrobenzofuran-3-carboxylate O
C02Et a 'O
A solution of methanesulfonyl chloride (6.1 mL, 78.5 mmol) in dichloromethane (50 mL) was added to a stirring solution of ethyl 3-hydroxy 4-oxo-b-methyl-2,3.4,5,6,7-?5 hexahydrobenzofuran-3-carboxylic acid (18.48 g, 76 mmol) and triethylamine (21.4 mL, 154 mmol) in dichloromethane ( 150 mL) at 0°C. The mixture was allowed to reach ambient SU85T1TUTE SHEET (RULE 26) temperature. stirred for 2 hours. then poured into aqueous 1 N sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate.
filtered. and concentrated in vacuo to give ethyl 4-oxo-6-methyl-4,5,6,7-tetrahydrobenzofuran-3-carboxylate ( 16.86 g).
3. 4-oxo-6-methyl-4,5,6,7-tetrahydro 1H-indole-3-carboxylic acid O

a 'N
H
A stirred mixture of ethyl 4-oxo-6-methyl-4,5,6,7-tetrahydrobenzofuran-3-carboxylate ( 15.7 g, 7I mmol) and ammonium acetate (9.54 g, 124 mmol) in N,N,-dimethylformamide 75 mL) was heated at 100°C for 2 hours. The reaction mixture was concentrated in vacuo, ice water was added, and the precipitate collected, rinsed with water then diethyl ether and dried to give ethyl 4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxylate (5.94 g). To this ester was added aqueous SN sodium hydroxide (50 mL) and ethyl alcohol ( 10 mL) and the mixture heated at reflux for 40 minutes. The reaction mixture was cooled in an ice water bath, acidified with aqueous hydrochloric acid, and the precipitate collected, rinsed with water then diethyl ether and dried to give 4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (5.2 g). m.p. 210-211°C.
4. 4-Oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (m.p. 231-232°C) was prepared essentially according to the procedures described in Parts 1-3 of this examples.

SUBSTITUTE SHEET (RULE 26) Example 2 O
O
~N
F
'N
H
To a stirred solution of 4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-IH-indole-3-carboxylic acid ( 155 mg, 0.75 mmol) and triethylamine (209 ~L, 1.5 mmol) in dimethylformamide (4 mL) at 0°C was added ethyl chloroformate ( 143 ~L, 1.5 mmol). After stirring an additional 45 minutes, 2-fluoroaniline ( 145 ~L, 1.5 mmol) was added. The reaction mixture was stirrred for 30 minutes, then poured into aqueous 3.6N 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 SN
sodium hydroxide (5 mL) and ethyl alcohol (1 mL), and the mixture was heated at reflux for 30 minutes. After cooling in an ice water bath, the reaction mixture was acidified with hydrochloric acid, the precipitate was collected, rinsed with water, and dried to give 55 mg of N-(2-fluorophenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 2).
Example 3 The following compounds are prepared essentially according to the procedures described in Examples 1 and 2.
(a) N-Phenyl-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-IH-indole-3-carboxamide (Compound 1 ).
(b) N-(2-Fluorophenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-IH-indo1e-3-carboxamide; mp 259-261 °C.
(c) N-(3-Fluorophenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-IH-indo1e-3-carboxamide; mp 268-270°C.

SUBSTTTUTE SHEET (RULE 26) (d) N-(2, 4- Diflurophenyl)-4-oxo-6.6-dimethvl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.
(e) N-(2,4-Difluorophenyl)-4-oxo-6.6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide .
N-(3Methoxyphenyl)-4-oxo-6,6-dimethyl-4,5,6, 7-tetrahydro-1 H-indole-3-carboxamide.
(g) N-(2-Hydroxy-4-methoxyphenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; mp 190-192°C.
(h) N-(3-Hydroxy-4-methoxyphenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; mp 282-284°C.
(i) N-(2-Fluoro-4-methoxyphenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; mp 213-215°C.
(j) N-(2-Fluoro-4-methoxyphenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.
(k) N-(2-Fluoro-~-methoxyphenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.
(1) N-(2-Fluoro-4-methoxyphenyl)-4-oxo-6,6-dimethyi-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; mp 225-227°C.

SU85T1TUTE SHEET (RULE Z6) (ml N-(2-Methoxphenyi)-:~-oxo-6,6-dimethvl-4.5,6.7-tetrahydro-1H-indole-3-carboxamide (Compound 3).
(n) N-(4-Ethoxvphenyl)-4-oxo-6,6-dimethyl-4.5,6,7-tetrahydro-1H-indo1e-3-carboxamide.
(o) N-(4-Methoxyphenyi)-4-oxo-6.6-dimethyi-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.
(p) N-(2-Hydroxy-~t.-methylphenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; mp 201-203°C.
(q) N-Phenyl-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 4); mp 278-279°C.
(r) N-(2-Fluorophenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 5); mp 264-265°C.
(s) N-{3-Fluorophenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; mp 302-303°C.
(t) N-(4-Fluorophenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; mp 262-264°C.
(u) N-(3-Methoxyphenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; mp 234-235°C.
(v) N-(4-Hydroxyphenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide: mp 320°C.

SU8ST1TUTE SHEET (RULE 2fi~

(w) N-(2-Fiuoro-4-hydroxvphenvl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-IH-indole-3-carboxamide; mp 330°C.
(x) N-(2-Hydroxy-4-methoxyphenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; mp 236-238°C.
(y) N-(4-Methoxyphenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; mp 260-261 °C.
(z) N-(2-Fluoro-4-methoxvphenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 6); mp 217-2I9°C.
(aa) N-(4-Ethoxyphenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-I S carboxamide; mp 269°C.
(bb) N-(2-Fluoro-4-ethoxyphenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; mp 224-225°C.
(cc) N-(3,4-Dihydroxyphenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; mp 267-269°C.
(dd) N-(2-Hydroxy-4-methylphenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; mp 258-260°C.

(ee) N-(3-Thienyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 7).
(ff) N-(2-Thiazoyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro- 1H-indole-3-carboxamide.

SUBSTITUTE SHEET (RULE 26) (ggj N-(5-Methyl-2-thiazolyl)-4-oxo-6.6-dimethyl-4.x,6,7-tetrahydro-1H-indole-carboxamide.
(hh) N-(3-Pvridyl)-4-oxo-6.6-dimethyl-4,5.6,7-tetrahydro-1H-indole-3-carboxamide; mp 237-239°C.
(ii) N-(4-Methoxy-3-pvridyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; mp 217-218°C.
(jj) N-(2-Chloro-1,8-napthyridin-7-yl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-indole-3-carboxamide; mp 278-280°C.
(kk) N-(1,8-Napthyridin-2y1)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (compound 8); mp 389-390°C.
{1l) N-(3-Pyridyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide;
mp 225-227°C.
(mm) N-(4-Pyridyl)-4-oxo-6-methyi-4,5,6,7-tetrahydro-1H-indoie-3-carboxamide;
mp 280-290°C.
(nn) N-(1,8-Napthyridin-2-yl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 9).
(oo) N-(6-Methyl-1,8-napthridin-2-yl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; mp 338-340°C(d).
(pp) N-(2-Quinolinyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 10); mp 273-275°C.
(qq) N-(4-Pyridyl)-4-oxo-b,6-dimethyl-4,5,6,7-tetrahydro-1H-indoie-3-carboxmide.
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 present invention and that modifications may be made therein without departing from the spirit or scope of the present 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.

SUBSTITUTE SHEET (RULE I6)

Claims (55)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A compound of the formula:

or a pharmaceutically acceptable non-toxic salt thereof wherein:
W is aryl or 2-, 3-, or 4-pyridyl, each of which is optionally substituted with up to five groups selected independently from halogen, cyano, hydroxy, alkyl, cycloalkyl having 3-7 carbon atoms, amino, mono- or dialkylamino where each alkyl is independently lower alkyl or cycloalkyl having 3-7 carbon atoms, alkoxy, cycloalkyl alkoxy where said cycloalkyl has 3-7 carbon atoms, NR1COR2, COR2, CONR1R2 and CO2R2 where R1 and R2 are the same or different and represent hydrogen or alkyl or cycloalkyl having 3-7 carbon atoms; and R3 and R4 are hydrogen or C1-3 alkyl, provided that not both R3 and R4 are hydrogen, wherein, unless otherwise specified, alkyl and lower alkyl represent straight or branched chain alkyl groups having 1-6 carbon atoms, alkoxy represents straight or branched chain alkoxy groups having 1-6 carbon atoms, and aryl is selected from phenyl, biphenyl, 1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, phenanthryl and biphenylenyl.

2. The compound according to claim 1, of the formula:

wherein R8 is hydrogen, halogen, hydroxyl, alkyl, alkoxy, cycloalkyl alkoxy where said cycloalkyl has3-7 carbon atoms, amino, mono- or dialkylamino where each alkyl is independently lower alkyl or cycloalkyl having 3-7 carbon atoms;
R9 is hydrogen, halogen, cyano, hydroxy, alkyl, alkoxy, cycloalkyl alkoxy where said cycloalkyl has 3-7 carbon atoms, amino, mono- or dialkylamino where each alkyl is independently lower alkyl or cycloalkyl having 3-7 carbon atoms, NR1COR2, COR2, or CO2R2 where R1 and R2 are the same or different and represent hydrogen, alkyl, or cycloalkyl having 3-7 carbon atoms; and R10 is hydrogen, halogen, hydroxyl, alkyl, alkoxy, amino, mono- or dialkylamino where each alkyl is independently lower alkyl or cycloalkyl having 3-7 carbon atoms.

3. The compound according to claim 1, of the formula:

where G represents pyridyl or phenyl, each of which is optionally mono-, di- or trisubstituted with halogen, alkyl, alkoxy, or hydroxy.

4. The compound according to claim 3, wherein R3 and R4 are methyl.

5. The compound according to claim 3, wherein R3 is methyl and R4 is hydrogen.

6. The compound according to claim 1, which is N-Phenyl-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

7. The compound according to claim 1, which is N-(2-Fluorophenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

8. The compound according to claim 1, which is N-(3-Fluorophenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

9. The compound according to claim 1, which is N-(4-Fluorophenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

10. The compound according to claim 1, which is N-(2,4-Difluorophenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

11. The compound according to claim 1, which is N-(2,6-Difluorophenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

12. The compound according to claim 1, which is N-(3-Methoxyphenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

13. The compound according to claim 1, which is N-(2-Hydroxy-4-methoxyphenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

14. The compound according to claim 1, which is N-(3-Hydroxy-4-methoxyphenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

15. The compound according to claim 1, which is N-(2-Fluoro-4-methoxyphenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

16. The compound according to claim 1, which is N-(2-Fluoro-4-ethoxyphenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

17. The compound according to claim 1, which is N-(2-Fluoro-5-methoxyphenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

18. The compound according to claim 1, which is N-(2-Fluoro-4-hydroxyphenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

19. The compound according to claim 1, which is N-(4-Methoxyphenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

20. The compound according to claim 1, which is N-(4-Ethoxyphenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

21. The compound according to claim 1, which is N-(4-Methylphenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

22. The compound according to claim 1, which is N-(2-Hydroxy-4-methylphenyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

23. The compound according to claim 1, which is N-Phenyl-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

24. The compound according to claim 1, which is N-(2-Fluorophenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

25. The compound according to claim 1, which is N-(3-Fluorophenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

26. The compound according to claim 1, which is N-(4-Fluorophenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

27. The compound according to claim 1, which is N-(3-Methoxyphenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

28. The compound according to claim 1, which is N-(4-Hydroxyphenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

29. The compound according to claim 1, which is N-(2-Fluoro-4-hydroxyphenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

30. The compound according to claim 1, which is N-(2-Hydroxy-4-methoxyphenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

31. The compound according to claim 1, which is N-(4-Methoxyphenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

32. The compound according to claim 1, which is N-(2-Fluoro-4-methoxyphenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

33. The compound according to claim 1, which is N-(4-Ethoxyphenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

34. The compound according to claim 1, which is N-(2-Fluoro-4-ethoxyphenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

35. The compound according to claim 1, which is N-(3,4-Dihydroxyphenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

36. The compound according to claim 1, which is N-(2-Hydroxy-4-methylphenyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

37. The compound according to claim 1, which is N-(3-Pyridyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

38. The compound according to claim 1, which is N-(4-Methoxy-3-pyridyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

39. The compound according to claim 1, which is N-(3-Pyridyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

40. The compound according to claim 1, which is N-(4-Pyridyl)-4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

41. The compound according to claim 1, which is N-(4-Pyridyl)-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

42. A pharmaceutical composition comprising the compound according to any one of claims 1 to 41, and at least one pharmaceutically acceptable carrier.

43. The compound according to claim 1, of the formula:
or a pharmaceutically acceptable salt thereof, wherein R8 is hydrogen, halogen, hydroxyl, alkyl, alkoxy, cycloalkyl alkoxy where said cycloalkyl has 3-7 carbon atoms, amino, mono- or dialkylamino where each alkyl is independently lower alkyl or cycloalkyl having 3-7 carbon atoms;
R9 is hydrogen, halogen, cyano, hydroxy, alkyl, alkoxy, cycloalkyl alkoxy where said cycloalkyl has 3-7 carbons atoms, amino, mono- or dialkylamino where each alkyl is independently lower alkyl or cycloalkyl having 3-7 carbon atoms; and R10 is hydrogen, halogen, hydroxyl, alkyl, alkoxy, amino, mono- or dialkylamino where each alkyl is independently lower alkyl or cycloalkyl having 3-7 carbon atoms.

44. The compound according to claim 1, of the formula:
or a pharmaceutically acceptable salt thereof, wherein:

G represents pyridyl which is optionally mono-, di- or trisubstituted with halogen, alkyl, alkoxy, or hydroxy.

45. The compound according to claim 1, of the formula:
wherein R3 and R4 are the same or different and represent hydrogen or alkyl, provided that not both R3 and R4 are hydrogen;
R8 is hydrogen, halogen, hydroxyl, alkyl, alkoxy, cycloalkyl alkoxy where said cycloalkyl has 3-7 carbon atoms, amino, mono- or dialkylamino where each alkyl is independently lower alkyl or cycloalkyl having 3-7 carbon atoms;
R9 is hydrogen, halogen, cyano, hydroxy, alkyl, alkoxy, cycloalkyl alkoxy where said cycloalkyl has 3-7 carbon atoms, amino, mono- or dialkylamino where each alkyl is independently lower alkyl or cycloalkyl having 3-7 carbon atoms, NR1COR2, COR2, or CO2R2 where R1 and R2 are the same or different and represent hydrogen, alkyl, or cycloalkyl having 3-7 carbon atoms; and R10 is hydrogen, halogen, hydroxyl, alkyl, alkoxy, amino, mono- or dialkylamino where each alkyl is independently lower alkyl or cycloalkyl having 3-7 carbon atoms.

46. The compound according to claim 45, of the formula:

47. The compound according to claim 46, wherein R8, R9, and R10 are independently selected from hydrogen, halogen, alkyl, alkoxy, amino, and mono-and dialkylamino where each alkyl is independently lower alkyl or cycloalkyl having 3-7 carbon atoms.

48. The compound according to claim 45, of the formula:

49. The compound according to claim 48, wherein R3 and R4 are both methyl, and R8, R9, and R10 are independently selected from hydrogen, halogen, hydroxy, alkoxy, and alkyl, provided that not all of R8, R9, and R10 are hydrogen.

50. Use of a therapeutic amount of the compound according to any one of claims 1 to 41 or 43 to 49, or the composition according to claim 42 to treat anxiety, sleep, or seizure disorders in a patient in need thereof.

51. Use of a therapeutic amount of the compound according to any one of claims 1 to 41 or 43 to 49, or the composition according to claim 42 to treat an overdose with benzodiazepine drugs in a patient in need thereof.

52. Use of a therapeutic amount of the compound according to any one of claims 1 to 41 or 43 to 49, or the composition according to claim 42 to enhance memory in a patient in need thereof.

53. Use of the compound according to any one of claims 1 to 41 or 43 to 49, in the manufacture of a pharmaceutical composition for the treatment of anxiety, sleep, or seizure disorders.

54. Use of the compound according to any one of claims 1 to 41 or 43 to 49, in the manufacture of a pharmaceutical composition for the treatment of an overdose with benzodiazepine drugs.

55. Use of the compound according to any one of claims 1 to 41 or 43 to 49, in the manufacture of a pharmaceutical composition for the enhancement of memory.