ZA200201649B

ZA200201649B - Fused pyrrolecarboxamides: GABA brain receptor ligands.

Info

Publication number: ZA200201649B
Application number: ZA200201649A
Authority: ZA
Inventors: Pamela Albaugh; Kenneth Shaw; Alan Hutchison
Original assignee: Neurogen Corp
Priority date: 1999-08-31
Filing date: 2002-02-27
Publication date: 2003-05-28
Also published as: PE20010533A1; SV2002000161A; PA8501901A1; GT200000146A; CO5180633A1; UY26322A1; AR040397A1; ECSP003641A; TNSN00178A1

Description

FUSED PYRROLECARBOXAMIDES: [4

GABA BRAIN RECEPTOR LIGANDS

BACKGROUND OF THE INVENTION Field of the Invention

This invention relates to fused pyrrolecarboxamides. This invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in treatment of certain central nervous system (CNS) diseases.

This invention also relates to the use of these fused pyrrolecarboxamide compounds in combination with one or more other CNS agents to potentiate the effects of the other CNS agents. Additionally this invention relates to the use such compounds as probes for the localization of GABA, receptors in tissue sections.

Description of the related art

The GABA, receptor superfamily represents one of the classes of receptors through which the major inhibitory neurotransmitter, y-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, receptor, which causes alteration in chloride conductance and membrane polarization.

A number of cDNAs for GABA, receptor subunits have been characterized. To date at least 6a, 3B, 3y, le, 18 and 2p

» a .

WO 01/16103 PCT/USN0/2386G2 subunits have been identified. It is generally accepted that native GABA, receptors are typically composed of 2a, 2B, and ly subunits (Pritchett & Seeburg Science 1989; 245:1389-1392 and

Knight et. al., Recept. Channels 1998; €:1-18). Evidence such as message distribution, genome localization and biochemical study results suggest that the major naturally occurring receptor combinations are aif.y2, ®2B3v2, @3Bsy2, and assy. (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, receptor. In addition to the benzodiazepine site, the GABA, 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, 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" ed., 1991, pp. 145-148, Oxford 20. University . Press, New York). Early electrophysioclogical - 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, receptor channels are agonists of

GABA receptors. Other compounds that interact with the same site but negatively modulate the action of GABA are called

CC « . J 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, receptor agonists or 1nverse 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, selective ligands may also act to potentiate the effects of certain 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, selective ligands than when used alone.

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,

h WO 01/16103 PCT/US00/23862

German Patent No. DE 3,246,932, and Liebigs Ann. Chem. 1986, 1749 teach assorted benzodiazepine agonists and antagonists and related anti-depressant and central nervous system active compounds .

U.S. Patent No. 3,455,943 discloses indole derivatives.

Other references, such as U.S. Patent No. 4,435,403 and

German patent DE 3,246,932 disclose pyrimidinol[5,4-b)indoles and beta-carboline derivatives.

A variety of indole-3-carboxamides is described in the literature. See, for example, J. Org. Chem., 42: 1883-1885 (1977); J. Heterocylic Chem., 14: 519-520 (1977). Also, U.S.

Patent Nos. 5,804,686 and 6,080,873 and PCT International

Publication WO 97/26243, all of which are assigned to Neurogen

Corporation, disclose fused pyrrolecarboxamides. - 15

SUMMARY OF THE INVENTION

In a preferred aspect, this invention provides pyrrolecarboxamides that bind with high affinity and high selectivity to the benzodiazepine site of the GABA, receptor, including human GABA, receptors.

Thus, the invention provides compounds of Formula I (shown below), 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, receptors in tissue sections.

Accordingly, a broad aspect of the invention is directed to compounds of the formula

Ry 0 Oo Pe

Rs N

Saal:

Re ~ ~N T x

I and the pharmaceutically acceptable salts thereof wherein:

T is halogen, hydrogen, hydroxyl, amino, alkyl or alkoxy;

X is hydrogen, hydroxy, amino, benzyl, t-butoxycarbonyl, benzyloxycarbonyl, alkyl, or alkoxy;

G represents

Ra, z ™n where

Q is an optionally substituted aryl or optionally substituted heteroaryl group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms;

W is chosen from hydrogen, -0-, -NH-, -NR,-, -S(0)y-2-, -C(=0)-, -0C(=0)-, -C(=0)0-, -C(=0)NH-, -NHC (=0) -, _-NR,C(=0) -, -NHS (0) g-2-, -NR,S (0) ¢-2-, ~S (0) o-;NH-, ] -S(0)-2NR7~, and CR7Rg where R7 and Rg are the same or different and represent hydrogen, alkyl, or CR7Rg represents a cyclic moiety having 3-7 carbon atomg, wherein W may not be hydrogen when Q is phenyl, 2- or s 3-thienyl, or 2-, 3-, or 4 pyridyl, indolyl, imidazolyl, or pyridazinyl;

Z is hydrogen, hydroxy, cycloalkyl (alkoxy), amino, mono - or dif{alkyl,)amino, azacycloalkyl, -0O(alkyl,), -S(0O),. 2(alkyl,), -C(=0) (alkyl,), -0C(=0) (alkyl,), -0OC(=0)H, -C(=0)0(alkyl,), -C(=0)O0H, -C(=0)NH (alkyl,), -C(=0)N(alkyl;) 2, -C (=0) NH, -NHC (=0) (alkyl,), -NHC (=O) H, -N(alkyl,)C(=0) (alkyl;), -NHS(0),.;(alkyl,), -N(alkyl;) S(0)q-2(alkyl,), -5(0) 0-2NH (alkyl,), -8(0) 0-2 (alkyl,)N(alkyl,), wherein each alkyl, is independently straight, branched, or cyclic, may contain one or two double and/or triple bonds or combinations thereof, and is unsubstituted or substituted with one or more substituents independently . selected from hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy, or

Z is -N(Ry)28(0)g¢-2 (Rs) where each Ry is independently hydrogen or alkyl where the alkyl is straight, branched, or cyclic, may contain one or two double and/or triple bonds, and is unsubstituted or substituted with one or more substituents independently selected from hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy,

Rs is hydroxy, alkoxy, heteroaryl, aryl, or alkyl where each aryl and heteroaryl is optionally substituted with one or two of alkyl, hydroxy, alkoxy, triflouromethyl, halogen, amino, or mono- or dialkylamino; and each alkyl is optionally substituted with hydroxy, alkoxy, triflouromethyl, halogen, amino, mocno- or di- alkylamino, aryl, or heteroaryl; or

Z is phenyl or phenylalkyl where the phenyl portion is optionally substituted with alkyl, hydroxy, alkoxy, triflouromethyl, halogen, amino, or mono- or di- alkylamino, or

Z i8 2-, 3-, or 4-pyridyl, 1- or 2-imidaZzolyl, 1-, 2-, or 3-pyrrolyl, azeditinyl, norborn-2-yl, or adamantan-2- : 15 vl; each of which may be substituted on a tertiary carbon or a secondary nitrogen with C;-Cgalkyl, or

Z is NRgCORjg where Rg and Rig are the same or different and represent hydrogen or alkyl or cycloalkyl, or

Z is connected, optionally through W, to Q to from a 1-6

CT20 -membered ring; or

Z represents a group of the formula:

Ho

N o

ZN, where p is 1, 2, or 3;

k

D and D’ independently represent oxygen, NR, or CHR, provided that only one of D and D’ may be NR,, and only one of D and D’ may be oxygen, where each Ry is hydrogen or alkyl; and

R. is hydrogen or alkyl, or

Z represents a group of the formula:

R,

EN

Jr 24 )q where p is 1, 2, or 3; gq is 0, 1, or 2; each R; is independently hydrogen or alkyl; or

Z represents a group of the formula: le Ro ©) where } s is 0, 1, 2 or 3, and the sum of s and m is not less than 1;

Ro, is hydroxy, C;-Ce¢alkoxy, amino, mono- or di- alkylamino where each alkyl is independently optionally substituted with amino, or wmono- or dialkylamino, or

Ro 1s a group of the formula

R, ro

D

A “4 where p, D, D’, and R, are as defined above;

A and Ag independently reprecent a carbon chain optionally substituted with halogen, oxo, cyano, nitro, amino, mono or dialkylamino, alkyl, alkenyl, alkynyl, trifluoromethyl, trifluoromethoxy, or cycloalkyl; wherein k is 0, 1, 2, or 3; mis 0, 1, 2, or 3; and }

A represents a carbon chain optionally substituted with Rg and R¢ and n is 0, 1, 2, or 3; and

Ri, Rg, Rg, and Rg are the same or different and are independently selected at each occurrence from hydrogen, alkyl, -CORj3 or -CO2Rj1 where Rij is alkyl . or cycloalkyl having 3-7 carbon atoms; or -CONRj]2R13 where R12 and R13 are selected independently from hydrogen, alkyl, cycloalkyl having 3-7 carbon atoms, phenyl, 2-, 3-, or 4-pyridyl, or NRji2Ri13 forms a heterocyclic group which is morpholinyl, piperidinyl, _pyrrolidinyl, or N-alkyl piperazinyl; ox oo

R3 and Rg together with the carbon atom to which they are attached form a cyclic moiety having 3-7 carbon atoms; or x . s

Rs and Rg together with the carbon atom to which they are attached form a cyclic moiety having 3-7 carbon atoms; where each alkyl group forming an R3, R4, Rs, or Rg substituent or portion thereof may be substituted independently with hydroxy or mono- or dialkylamino where each alkyl is independently alkyl or cycloalkyl.

In another aspect, the invention provides intermediates useful for preparing compounds of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

In addition to compounds of Formula I described above, the invention also encompasses compounds of the same general formula and the pharmaceutically acceptable salts thereof, wherein:

T is halogen, hydrogen, hydroxyl, C;-C¢ amino, alkyl or C;-Cs alkoxy;

X is hydrogen, hydroxy, amino, C;-Cs alkyl, or C,-Cs alkoxy;

G represents pa, z a where 0 is phenyl, 2- or 3-thienyl, or 2-, 3-, or 4 pyridyl, 2-, 4-, or 5-pyrimidinyl, indolyl, imidazolyl, pyridazinyl, 1,4-benzodioxazinyl, 1,3-benzodioxolyl or imidazo[1l,2-alpyridinyl, all of which may be substituted by one or more of hydroxy, halogen, C;-Cg alkyl, C;-Cs alkoxy, cyano, nitro, amino, and mono- _or dialkyl {(Cy-Cg¢)amino; B

W is chosen from hydrogen, -0-, -NH-, -NR,;-, -S(0)p.2-, -C(=0) -, -0C (=0), -C (=0)0-, -C{(=0)NH-, -NHC (=0) -, -NR,C (=0) -, -NHS (0) g-2-, -NRyS (0) 9-2-, -S{0)p-2NH-, -S5(0)6.2R/H-, and CR7Rg where R37 and Rg are the same or different and represent hydrogen, alkyl, or R7-Rg

. taken together represents a cyclic moiety having 3-7 carbon atoms, wherein W may not be hydrogen when Q is phenyl, 2- or 3-thienyl, or 2-, 3-, or 4 pyridyl, indolyl, imidazolyl, or pyridazinyl;

Z is hydrogen, hydroxy, C;-C; cycloalkyl (C;-C¢ alkoxy), amino, mono- or di(C;~C¢ alkyl;)amino, or C;3-C, azacycloalkyl, -0(C;-Cs alkyl;), -S(0),-2(Cy-Cs alkyl,), -C(=0) (C3-Cs alkyli), -0OC(=0)(C;-Cs alkyl,), -0OC(=0)H, -C(=0)0(Cy-Cs alkylis), -C(=O)OH, -C(=0)NH (C;-Cs alkyl,), -C (=0) NH, -NHC (=0) (C1-Cs alkyl,), -NHC (=O) H, -N(C,-C¢ alkyl;)C(=0) (C1-Cs¢ alkyl,), -NHS (0) 0-2 (C1-C¢ alkyli), -N(C1-C¢ alkyl;)S(0)o-2(C1-Ce alkyl,), -S8(0)-2NH(C;-C¢ alkyl;), or -8(0)0-2(C1-C¢ alkyl )N(C;-Cs alkyl,), wherein C;-C¢ alkyl, is independently chosen at - each occurrence and is straight, branched, or cyclic, may contain one or two double and/or triple bonds, and is unsubstituted or substituted with one or more substituents selected from hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy, or

Z is -N(Ryn)2S5(0)s.2(Rg) where each Ry is independently hydrogen or alkyl where the alkyl is straight, branched, or cyclic, may contain one or two double and/or triple bonds, and is unsubstituted or substituted with one or more substituents independently selected from hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy,

Rs 1s hydroxy, alkoxy, or alkyl where the alkyl is optionally substituted with hydroxy, alkoxy, triflouromethyl, halogen, amino, mono- or di- alkylamino, aryl or heteroaryl,

Z is phenyl or phenyl (C;-C¢) alkyl where the phenyl portion is optionally substituted with C;-C¢ alkyl, hydroxy,

C1-Ce¢ alkoxy, trifluoromethyl, trifluoromethoxy, halogen, amino, or mono- or diC;-C¢ alkylamino, or

Z is 2-, 3-, or 4-pyridyl, 1- or 2-imidazolyl, 1-, 2-, or 3-pyrrolyl, or adamantane-2-yl; each of which may be substituted on a tertiary carbon or a secondary nitrogen with C,-Cgalkyl, or - 15 Z is NR9COR1p where Rg and Rjp are the same or different and represent hydrogen or C;-Cs alkyl or C;-C, cycloalkyl, or

Z is connected, optionally through W, to Q toc from a 1-6 membered ring; or

Z represents a group of the formula:

R p 3 where p is 1, 2, or 3;

D and D’ independently represent oxygen, NRy or CHR,

Sy v provided that only one of D and D’ may be NR, where each R, is hydrogen or C;-Cs alkyl; or and

R, is hydrogen or C;-C¢ alkyl, or

Z2 represents a group of the formula: [+]

NH q where p is 1, 2, or 3; q is 0, 1, or 2;

R; is hydrogen or C,-Cs alkyl; or a group of the formula:

Le

Oo where s is 0, 1, 2 or 3, and the sum of s and m is not less than 1;

Ro 1s hydroxy, C;-Csalkoxy, amino, mono- or diC,-

Cealkylamino where each alkyl is independently : optionally substituted with amino, mono- or diC;~Csalkylamino, or

R, is a group of the formula

R,

My

N D

3M, where p, D, D’, and R, are as defined above;

Ad ard Ada independently represent a carbon chain optionally substituted with hydrogen, halogen, oxo, cyano, nitro, amino, mono or di(C,-Cglalkylamino, straight or branched chain C;-Cg alkyl, C,-C¢ alkenyl,

C,-C¢ alkynyl, trifluoromethyl, trifluoromethoxy, or cycloC;-C¢ alkyl; wherein k is 0, 1, 2, or 3; : m is 0, 1, 2, or 3; and

A represents a carbon chain optionally substituted with Rg and R¢ and n is 0, 1, 2, or 3;

R3, Rg, Rg, and Rg are the same or different and are independently selected at each occurrence from . hydrogen, C;-C¢ alkyl, -CORj131 or -CO2R1] where Rij is

C,;-Cgalkyl or C3-C; cycloalkyl; or -CONR12R13 where R12 and R13 are selected independently from hydrogen, C,-Cs alkyl, Cy-Cy cycloalkyl, phenyl, 2-, 3-, or 4-pyridyl, or NRj2R13 _. . forms a heterocyclic group which is morpholinyl, ~ piperidinyl, pyrrolidinyl, or N-alkyl piperazinyl; or

R3 and Rg together with the carbon atom to which they are attached form a cyclic moiety having 3-7 carbon atoms; or vy

Rg and Re together with the carbon atom to which they are attached form a cyclic moiety having 3-7 carbon atoms; and where each alkyl group forming an R3, R4, R5, or Rg substituent or portion thereof may be substituted independently with hydroxy or mono- or dialkylamino where each alkyl is independently C;-C; alkyl or cycloalkyl having 3-7 carbon atoms.

Such compounds will be referred to as compounds of Formula

Ia. Particular compounds of the invention also include compounds of Formula I where Q is phenyl or pyridyl (compounds of Formula Ib) and compounds of Formula I wherein Q is phenyl or pyridyl; and either the group A or the group Ag is substituted by oxo (compounds of Formula Ic).

When W is hydrogen, m is 0 and 2 is absent resulting in Q . groups that are optionally substituted with alkyl where the alkyl is optionally substituted as defined above.

In addition, the present invention encompasses compounds of Formula II: rR, © 1 ow, 7

Ry N” Ha

Re m~N T x

*

Formula II and the pharmaceutically acceptable salts thereof: wherein n, k, m, R3-Rg¢, X, T, W, and Z are defined as for Formula I;

Q is phenyl or pyridyl substituted by up to 4 groups Y, where Y is independently selected at each occurrence from hydrogen, hydroxy, halogen, C;-Cs alkyl, C;-C¢ alkoxy, cyano, nitro, amino, and mono- or dialkyl (C;-C¢)amino. Compounds of Formula

II, include compounds of Formula IIa, Formula IIb, Formula IIc, and Formula IXd shown below kW Zz 0]

Rj; 7 a" Ha

Rs N

Rs IR H Y

Re (a) N T

H

Formula lla : Y 0 RW, 2 . Ry [7 ort Ma

Ra N

Rs fi AN H

Re ~N T

H

Formula lib

Y

—y- _k “4 KW z

O

0 !

R N

‘ H

Rs IR Y

Re ~N 7

I

X Formula lic v = KW Zz 9 0

Ra or ut

R, N

Rs | A\

Rs ry N T

X Formula hid

The present invention also encompasses compounds of

Formula IIL rR, £ 3 A WZ

Re NTN

Rs IN

Re NT

X

Formula III and the pharmaceutically acceptable salts thereof: wherein . =n, k, m, R3-R¢, X, T, W, and Z are defined as for Formula I;

Q is phenyl or pyridyl substituted by up to 4 groups Y, where Y is independently selected at each occurrence from hydrogen, hydroxy, halogen, C;-C¢ alkyl, C;-C¢ alkoxy, cyano, nitro, amino, and mono- or dialkyl(C,-Cg¢)amino. Particular compounds of Formula III include compounds of Formula IIIa and Formula

IIIb shown below.

Y oo Y. 0 Q § ” Ry 2 i w_ _Z

Ra N 4 4 H k m

Rs TN Hy Rs | \

Rg N T Rg n N T

X H

Formula IIIa Formula IIIb

The present invention also encompasses compounds of

Formula IV

Y

Y. ©) Z o © “Ma

Rs

R, N Y

H

Rs A\ Y

Re n N T . 5 X

Formula IV : and the pharmaceutically acceptable salts thereof: wherein n, m, Ri3~-Rg¢, X, T, W, and Z are defined as for Formula I;

OQ is phenyl or pyridyl substituted by up to 4 groups ¥Y, where Y is independently selected at each occurrence from hydrogen,— - hydroxy, halogen, C;-Cs alkyl, C;-C¢ alkoxy, cyano, nitro, amino, and mono- or dialkyl (C,-Cg)amino. Particularly included as compounds of Formula IV are compounds of Formula 1IV-1,

Formula IV-2, and Formula IV-3, shown below.

vo o

V4 3,

Rs

R, N

H-

Rg n N T } ) .

H

Formula IV-1

Y

Oo 4

Sen

Rs

Rs N

Rs | \

Re n N T

H

Formula IV-2 o . a Zz

PBSh

Rj ™ N

R N

4 H

Rs | N : Re A N T

H

Formula IV-3 :

Preferred compounds of Formula IV, IV-1, IV-2, and IV-3 are those compounds where Z is a group -OR and R is hydrogen or alkyl wherein the alkyl is straight, branched, or cyclic, may contain one or two double and/or triple bonds, and is unsubstituted or substituted with one or more substituents selected from: hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy.

Other preferred compounds of Formula IV, IV-1, IV-2, and

IV-3 are those compounds where Z is a group -NR.Rp wherein

Ra and Rp are independently hydrogen or alkyl wherein each alkyl is independently straight, branched, or cyclic, may contain one or two double and/or triple bonds, and is unsubstituted or substituted with one or more substituents selected from: hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy; or

Rs and Rp may be joined to form a heterocycloalkyl ring.

Further included as compounds of Formula IV are compounds of Formula IVa and IVb: o Y 0 0

R 0

Ry N 0 Ra J He 4 H R N 0] Zz

R AN 4 H 5 | Y

R Rs | \ © n N R

H 6 n N

H

Formula IVa

Formula IVb : 10

The present invention also encompasses compounds of

Formula V. oO Oo yA

Rj oY

Ry N

Rs TN

Re SN TT

X

Formula V wherein n, m, Ri-R¢, X, T, W, and Z are defined as for Formula I;

Q is phenyl or pyridyl substituted by up to 4 groups Y, where Y is independently selected at each occurrence from hydrogen,

hydroxy, halogen, C,-C¢ alkyl, C;-C¢ alkoxy, cyano, nitro, amino, and mono- or dialkyl (C,-C¢)amino. Particularly included as compounds of Formula V are compounds of Formula Va, Formula

Vb z 0)

Ra ff IA

Rs N

Rs | \ Hv

Re n N T

H

Formula Va

Y z 0

Ry, "

R, N

Rs | A\ H

Rs ~~ T

H

Formula Vb

Y .

Y. Zz 0 0] Zz | m

R, na N

Ry N

Rs | \ Y

Rs ~N OT

X

Formula Vc

Especially preferred compounds of Formula V, Va, Vb, and

Vc are compounds of wherein Z is a groups -NR,R, wherein R, and

Rp are independently hydrogen or alkyl wherein each alkyl is independently straight, branched, or cyclic, may contain one or two double and/or triple bonds, and is unsubstituted or substituted with one or more substituents selected from: hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy; or

R; and Rp may be joined to form a heterocycloalkyl ring.

The present invention also encompasses compounds of

Formula VI. 0 oO

Ry as _H

Rs N Zz

Rs | \ HM

Rg n N T

X

Formula VI and the pharmaceutically acceptable salts thereof: wherein n, m, Ri-Rg¢, ¥X, T, and Z are defined as for Formula I;

Q is phenyl or pyridyl substituted by up to 4 Y groups, where Y is independently selected at each occurrence from hydrogen, . hydroxy, halogen, C,-Cs alkyl, C;-C¢ alkoxy, cyano, nitro, amino, and mono- or dialkyl (C;-Cg¢)amino. Particularly included as compounds of Formula VI are compounds of Formula VIa and

Formula VIb (shown below). y © - tr Y. N Y =

Oo Y. Y

R; Oo JGR o o =

Ry n Z Rs x,

Rs | A Rs N N z

Re n N T Rs | A\

H Re "SN T x

Formula VIa

Formula VIb

The present invention also encompasses compounds of Formula

VII. 0 w

Ry, 9 Hi

Ry N

Rs | \

Rg - N

H

VII wherein W, Z, m, n, R3, Rg, Rs, and Rg are defined as for

Formula I.

The present invention also encompasses compounds of

Formula VIII.

Zz . o OQ Dim

Rj

N ld

Ry H

Rs | \

Rg TN

H

VIII wherein W, Z, m, n, R3, Rg, Rg, and Rg are defined for

Formula I.

The present invention also encompasses compounds of

Formula IX.

Zz 0 Q Dr

Rj N w

Ry k

H

Rs | \

Re TSN

H

IX wherein W, Z, k, m, n, R3, Ra, Rs, and Rg are defined as for Formula I.

The present invention also encompasses compounds of

Formula X.

Ww 0 0

Re N Z

Rs | \

Rg "NN

H

X wherein W, Z, k, m, n, R3, Rg, Rg, and Rg are defined as for Formula I. .

Preferred compounds of the invention are those where n is 1 _or--2. Particularly preferred are those where X and T are both hydrogen. Thus, preferred compounds of the invention have formulas Al or Bl.

Rs ? i .G Ry 1 G

Rs I \ R BR

Re N ° N

H H

Al B1

Preferred compounds of Formulas Al and Bl are those where

Riz, Rs, Rs and Re are independently hydrogen or alkyl. More 5 preferably, Ris, Ry, Rs and R¢ are independently hydrogen, methyl, or ethyl. Even wore preferably, R;, Rs, Rs and Ry are hydrogen or methyl, where not more than 2 of R3;-Rs are methyl.

Particularly preferred are compounds where R; and R; are C;-C; alkyl, most preferably methyl, when Rs and Res are hydrogen or . 10 where Rs and R¢ are (C;-C; alkyl, most preferably methyl, when R; and Rs; are hydrogen. Other particularly preferred compounds are those where R; is methyl and Rs-R¢ are hydrogen or Re is : methyl and R3-Rs are hydrogen.

Preferred G substituents of the invention include the following:

Cy on =

A where Ra represents hydrogen or alkyl where the alkyl is optionally halogenated; and e is an integer of 1-3.

More preferred G substituents of formula A include those where e is 1, 2, or 3, and Ry is hydrogen, methyl, ethyl, isopropyl, or cyclopropyl. Particularly preferred G substituents of formula A include those where e is 1, 2, or 3, and Ry is hydrogen or methyl.

Another preferred G substituent is the following formula:

Cy em 4

B where Ry represents hydrogen or alkyl where the alkyl is optionally halogenated; and e 1s an integer of 1-3.

More preferred G substituents of formula B include those : where e is 1, 2, or 3; and Ry is hydrogen, methyl or ethyl.

Particularly preferred G substituents of formula B include those where e is 1 or 2, and Ry is hydrogen or methyl.

Another preferred G substituent is the following formula:

Cee 2 Hal

Cc where

Hal represents a halogen, preferably fluoro, bromo, or chloro;

Ra and Rp independently represent hydrogen, C,-Cg alkyl, C3-Cycycloalkyl, C3~-CycycloalkylC,-Cealkyl where the cycloalkyl group may be substituted with halogen, C;-C¢ alkyl, C;-Cs alkoxy, or mono- or diC;-C¢ alkylamino; and e 1s an integer of 2-3.

Preferred compounds having formula C as the ¢ group include those where Hal is fluoro and e is 2, 3, or 4.

More preferred G substituents of formula C include those where Ra 1s hydrogen, methyl or ethyl; and Rp is hydrogen.

Particularly preferred G substituents of formula C include those where e is 2; Ra is hydrogen or methyl; and Rp is hydrogen.

Another preferred G substituent is the following formula:

OY To NR,R,

Hal

C-1 where

Hal represents a halogen, preferably fluoro, bromo, or chloro;

Ra and Rp independently represent hydrogen, C;-Cg alkyl, C;-C,cycloalkyl, C;-CicycloalkylC,-Cealkyl where the cycloalkyl group may be substituted with halogen, C;-C¢ alkyl, C;-C¢ alkoxy, or mono- oY diC;-C¢ alkylamino; and e is an integer of 2-3.

Preferred compounds having formula C-1 as the G group include those where Hal is fluoro and e is 2, 3, or 4.

Another preferred G substituent is the following formula:

Y. (CHy)e N-Ra

JL Y' R,

D where Ry represents hydrogen, alkyl, or C3-7 cycloalkyl, or a group of the formula: i Pr

N+, where p is 1, 2, or 3;

D and D’ independently represent oxygen, NRy or

CHRy, provided that only one of D and D’ may be - NRy, where each R, is hydrogen or C;-C¢ alkyl; __ } and

R, is hydrogen or C;-C¢ alkyl; and

Rp represents hydrogen, alkyl, or acyl;

Y and Y’ independently represent hydrogen or halogen; and e is an integer of 1-3.

More preferred G substituents of formula D are those where

Y is hydrogen or fluorine; and e is 1 or 2. Particularly preferred G substituents of formula D are those where Y is hydrogen or fluorine; e is 1 or 2; Ry is hydrogen, Ci-3 alkyl, or cyclopropyl, and Rp is hydrogen, methyl, or acyl. Other particularly preferred G substituents of formula D are those where Y is hydrogen and Y’ is fluorine. Still other particularly preferred G groups of Formula D are those where e is 1 or 2; Ra is hydrogen, C3.3 alkyl, cyclopropyl or cyclopropylmethyl, and Rp is hydrogen, methyl, or acyl.

Another preferred G substituent is the following formula: i

Y v Ro

D-1 ) where Ry represents hydrogen, alkyl, or C3-7 cycloalkyl; 1S and

Rp represents hydrogen, alkyl, or acyl; or

Ra and Ry independently represent hydrogen, C;-C¢ alkyl,

C3-7cycloalkylC;-Cgalkyl; and

More preferred G substituents of formula D are those where

Y is hydrogen or fluorine; and e is 1 or 2. Particularly preferred G substituents of formula D are those where Y is hydrogen or fluorine; e is 1 or 2; Ra is hydrogen, Cj.3 alkyl, or cyclopropyl, and Rp is hydrogen, methyl, or acyl. Other particularly preferred G substituents of formula D are those where. Y is hydrogen and Y’ is fluorine. Still other particularly preferred G groups of Formula D are those where e is 1 or 2; Ra is hydrogen, Cj-3 alkyl, cyclopropyl or cyclopropylmethyl, and Rp is hydrogen, methyl, or acyl.

Another preferred G substituent is the following formula: 0) jg Dl is z

E

: where Z is oxygen, nitrogen, or methylene; and m is 1 or 2.

Particularly preferred G substituents of formula E are those where Z is oxygen, and m is 1 or 2. Other particularly preferred G substituents of formula E are those where 2Z is nitrogen, and m is 1 or 2.

Another preferred G substituent is the following formula: y z

F where Z 1s oxygen or nitrogen; and m is 1 or 2.

Particularly preferred G substituents of formula F are those where Z is nitrogen, and m is 1 or 2.

Another preferred G substituent is the following formula:

Zz

Cr Om v fo

H where Z is oxygen, nitrogen, or methylene; and m is 1 or 2.

Particularly preferred G substituents of formula H are those where Z is nitrogen, and m is 1 or 2.

Another preferred G substituent is the following formula:

Y (CHae. _R,

TL Y R, yy

J where Ra represents hydrogen, alkyl, or C3-7 cycloalkyl;

Rp represents hydrogen, alkyl, or acyl;

More preferred G substituents of formula J are those where

Y and Y’ are independently hydrogen or fluorine; and e is 1 or 2. Particularly preferred G substituents of formula J are those where and Y’ are independently hydrogen or fluorine; e is 1 or 2; Rg is hydrogen, Cj;-3 alkyl, or cyclopropyl, and Rp is hydrogen, methyl, or acyl.

Another preferred G substituent is the following formula:

Cr Och NReRe

Rk x N

KX

: where

Ra and Rp independently represent hydrogen, C,;-Cg alkyl, C;-Cycycloalkyl, C3-CycycloalkylC;-Cgalkyl where the cycloalkyl group may be substituted with halogen, C;-C¢ alkyl, C;-C¢ alkoxy, or mono- or diC;-C¢ alkylamino; and e is an integer of 2-3.

Another preferred G substituent is represented by the following formula:

R;, R,

HO"

M where : Rp, 1s hydrogen, halogen, C;-Cealkyl, on

Cgalkoxy, or trifluoromethyl; s is 0, 1, 2 or 3, and the sum of s and m is not less than 1;

Ro is hydroxy, C;-Csalkoxy, amino, mono- or diC,-C¢alkylamino where each alkyl is independently optionally substituted with amino, mono- or diC;-Cesalkylamino, or

Ro 1s a group of the formula

RLY

AN,

S p is 1, 2, or 3;

D and D’' independently represent oxygen,

NR, or CHR, provided that only one of D and D’ may be NR, where each R, is hydrogen or C;-C¢ alkyl; or and

R; is hydrogen or C;-C¢ alkyl.

Preferred M groups are those where Ry, is hydrogen or halogen, most preferably fluoro, and R, is a group of the formula: }

Ris

Ris JN,

N— Ry i’ Ris . where

Ris is hydrogen or C;-Cgalkyl;

R;s is hydrogen or C,;-Cesalkyl;

Ris is hydrogen, ethyl, or methyl;

R17 is Ci1-Csalkyl; and

J is a C;-C, alkylene group, preferably methylene, ethylene, or propylene.

Particularly preferred groups of Formula M include those where s is 1 and R, 1s ethoxy, hydroxy, ethylamino, diethylamino, morpholinyl, piperazinyl, 4-methylpiperazinyl,

N— “\

N N

— TN — “N = ~ aN. MN ~

J NH \ { SN : DN g LN

Ee Ne 3€ don no y ) or H ;

Other preferred compounds of the invention are those of

Formula N-1.

Oo 0)

R, Ra G

NH

Rs A

Rs n N

X

N-TI wherein: n is 1 or 2;

X is hydrogen, or alkyl; -

R3, R4, Rg, and Rg are the same or different and are independently selected at each occurrence from hydrogen or alkyl; and

G represents phenyl or pyridyl, each of which is substituted with a group wz and optionally with halogen, alkyl, alkoxy, hydroxy, amino, or mono- or dialkylamino; where

S K and M independently represent a bond or C;-Cg alkylene;

W represents -0-, -NH-, -NR,- where R7 represents hydrogen or alkyl, or C;-Ci alkylene; and

Z is hydrogen, hydroxy, cycloalkyl (alkoxy), amino, mono- or dif{alkyl,)amino, or azacycloalkyl, -0O(alkyl,;), -5{0)g¢-2(alkyl;}, -C(=0) (alkyl,)., -0C(=0) (alkyl,), -0C(=0}H, -C(=0)0(alkyl,), -C(=0) OH, -C(=0O)NH(alkyl,), -C(=0)N(alkyl,) 2, -C (=O) NH,, -NHC (=0) (alkyl,), -NHC (=O) H, -N(alkyl,) C(=0) (alkyl,), -NHS (O}.2 (alkyl,), -N{alkyl,) 8(0)o-2{alkyl,), -S(0)o-2NH(alkyl,), . -S(0)-2 (alkyl;)N(alkyl,), wherein each alkyl, is independently straight, branched, or cyclic, may contain one or two double and/or triple bonds, and is unsubstituted or substituted with one or more substituents independently selected from hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy, or

Z is -N(Ry)2S(0) 4-2 (Rg) where each Ry is independently hydrogen or alkyl where the alkyl is straight, branched, or cyclic, may contain one or two double and/or triple bonds, and is unsubstituted or substituted with one or more substituents independently selected from hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy, and

Rg is hydroxy, alkoxy, alkyl where the alkyl is optionally substituted with hydroxy, alkoxy, triflouromethyl, halogen, amino, mono- or di- alkylamino, or

Rs is heteroaryl unsubstituted or substituted with alkyl, hydroxy, alkoxy, triflouromethyl, halogen, amino, or mono- Or dialkylamino;

Z is 2~, 3-, or 4-pyridyl, 1- or 2-imidazolyl, 1-, . 2-, or 3-pyrrolyl, azeditinyl, norborn-2-yl, or adamantan-2-yl; each of which may be substituted on a tertiary carbon or a secondary nitrogen with C;-Cgsalkyl, or

Z represents a group of the formula:

Ho

D" 3th where p is 1, 2, or 3;

D and D’ independently represent oxygen, NR, or

CHRy provided that only one of D and D’ may be NR, where each R, is hydrogen or alkyl; and

R, is hydrogen or alkyl, or

Z represents a group of the formula:

Pp

NH

A; : 10 where p is 1, 2, or 3; and qg is 0, 1, or 2; or

Z represents a group of the formula: ) wy 0 where s is 0, 1, 2 or 3, and the sum of s and m is not less than 1;

Ro, is hydroxy, C;-Csalkoxy, amino, wmono- or di- alkylamino where each alkyl is independently optionally substituted with amino, mono- or dialkylamino, or

Ro is a group of the formula

R

RL

3h where p, D, D’, and R, are as defined above.

Preferred compounds of formula N-I include those where X is hydrogen. Other preferred compounds of formula N-I are those where X is C;-C¢ alkyl, most preferably, methyl.

More preferred compounds of N-I are those where K is a bond and W is oxygen. In other more preferred compounds of formula N-I, K is a bond and W is a bond or methylene.

Still more preferred compounds of N-I are those where M is

C, or CC; alkylene. In other more preferred compounds of formula N-I, M is C, or Ci; alkylene. In these more preferred compounds of formula N-I, G is phenyl. Alternatively, G is pyridyl in more preferred compounds of formula N-I.

In preferred compounds of formula N-I, pA is amino, mono - or dil{alkyl)amino, or azacycloalkyl, -O(alkyl), -S({0)p-2(alkyl), -C(=0) (alkyl), -oc (=0) (alkyl), -0C(=0)H, oT -C(=0)0 (alkyl), -C(=0) CH, -C(=0O)NH (alkyl), ~-C(=0)N(C;-Csq alkyl,) a, -C(=0)NH,, -NHC (=0) (alkyl), -NHC (=O) H, ~N (alkyl) C(=0} (alkyl), -NHS (0) 9-2 (alkyl),

-N(alkyl)S(O)o.2 (alkyl), -8(0)o-2NH (alkyl), -5(0)¢-2(alkyl)N(alkyl), or

Z is -N(Ry)28(0).; (Rs) where each Ry is independently hydrogen or alkyl, and

Rs is hydroxy, alkoxy, or alkyl where the alkyl is optionally substituted with hydroxy, alkoxy, triflouromethyl, halogen, amino, or mono- or di- alkylamino, or

Rs 1s phenyl, imidazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl, each of which is optionally substituted with alkyl, hydroxy, alkoxy, triflouromethyl, halogen, amino, or mono-~- or dialkylamino. :

Preferred compounds of Formula I ~- X above (including all subformulae such as IIb, IIC etc), exhibit K; values of less than 100 nM at the GABA, receptor as determined by an assay of

GABA, receptor binding, especially preferred compounds of

Formula I - X exhibit K; values of less than 10 nM at the GABA, receptor as determined by an assay of GABA, receptor binding.

Representative compounds of the invention are shown below in Table 1.

Oo \ NHMe ©

N OCH

H 3

A\ \ H

N

H N

Compound 1 Compound 2 0 NHCH, 0 ? \ 2 N NHCH, \ Hf \

N N

H H

Compound 3 Compound 4 0 NH 0 NH 7 Ly i rr

N N

H H

Compound 5 Compound 6 fo) NHMe 0] 7 <r 7 lo

N N

N\ H \ H

N TN

3

Compound 7

Compound 8 oO oO 0 oS 0 $Y

N N 0 oo

N

HaC N H

Compound 9 Compound 10

0) 0] 0} Oo

O J § ) o IX )

N Oo N 0]

N

H N

Compound 11 Compound 12

Oo

PRON, 5. 0]

N N N oN

AN H N H HO

N

H H

Compound 13 Compound 14 0 NN

HO

N

\ H H ON.

N

H Compound 47

Compound 15

ON

H oN 0 TL oO N 07 NA Pa \ N” “CF, @ NH NH H

NH

Compound 95

Compound 86

H oO N

H

Og NA o | ON o N N FZ VN

NH P [

N. ~

Compound 115 Compound 145 i WO 01/16103 PCT/UGS00/23862

H H

H Ox LN N 0) N Oo le) Oo

Compound 149

Compound 148

H oO N

H F be 3 i TL

AN (0) ol

Nn LY ~N

NH fe)

NH H d222

Compound 179 Compoun 0] H oH o} N

N F J

3 LO s OQ

AN N N Y oY N OTN

NH (0) °

Compound 226 NTN

Compound 227 o NN oO H . 0 N { Ur Ia ® \ ] N

N

A NN N ~ )

N ~ H 0 NH

H © N

N @)

Oo

Compound 235

Compound 229 “The following numbering conventions are used to identify - - positions on the ring systems in the compounds of the invention: 6) 0)

O Oo 4 3 NY s * 3 NY 1 2 8 1 2 6 N N 7 H Te H

Representative compounds of the present invention, which are encompassed by Formula I, include, but are not limited to the compounds in Table I and their pharmaceutically acceptable salts. Non-toxic pharmaceutically acceptable salts include

S salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC- (CH2)p-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.

Representative compounds of the present invention, which are encompassed by Formula I, include, but are not limited to the compounds in Table 1 and their pharmaceutically acceptable salts. The present 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.

This invention relates to fused pyrrolecarboxamide compounds that bind with high affinity to the benzodiazepine site of GABA, receptors, including human GABA, receptors. This invention also includes such compounds that bind with high selectivity to the benzodiazepine site of GABA, receptors, including human GABA, 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 wmwethods of treating patients in need of such treatment with an amount of a compound

S of the invention sufficient to alter the symptoms of a CNS disorder. Compounds of the inventions that act as agonists at ozB3y2 and osf3y; 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 a,fs:y, and a3f;y. 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 assy; receptor subtype or a,fB:y2 and osPiy: 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 oaf:y. receptor subtype are useful in treating convulsive disorders - a such as epilepsy. Compounds that act as antagonists at the benzodiazepine site are useful in reversing the effect of benzodiazepine overdose and 1in treating drug and alcohol addiction. - 4 6 -

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 Disorders, e.g. Attention Deficit Disorder (ADD), Attention Deficit and Hyperactivity Disorder (ADHD).

The invention also provides pharmaceutical compositions comprising compounds of the invention, including packaged -4 7 -

pharmaceutical compositions for treating disorders responsive to GABA, receptor modulation, e.g., treatment of anxiety, depression, sleep disorders or cognitive impairment by GABAa receptor modulation. The packaged pharmaceutical compositions include a container holding a therapeutically effective amount of at least one GABA, receptor modulator as described supra and instructions (e.g., labeling) indicating the contained GABA, receptor ligand is to be used for treating a disorder responsive to GABA, 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-HTia) agonists and antagonists; for anxiety and depression, neurokinin receptor antagonists or corticotropin releasing factor receptor (CRF.) 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. - 4 8 -

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, receptor ligand 3- (5-methylisoxazol-3- yl) -6-(1-methyl-1,2,3-triazol-4-yl) methyloxy-1,2,4-triazolo [3,4-alphthalzine 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, receptor ligands, 1,2,4- triazolo[4,3-blpyridazines, in combination with SSRIs.

The present invention also pertains to methods of : inhibiting the binding of benzodiazepine compounds, such as

Rol5-1788, to the GABA, receptors which methods involve contacting a compound of the invention with cells expressing

GABA, receptors, wherein the compound is present at a concentration sufficient to inhibit benzodiazepine binding to

GABA, receptors in vitro. This method includes inhibiting the binding of benzodiazepine compounds to GABA, 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 GABAx receptors in vitro. 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, receptor may be readily determined via an GABAa receptor binding assay, such as the assay described in Example 8. The GABA, receptors used to determine in vitro binding may be obtained from a variety of sources, for example from preparations of rat cortex or from cells expressing cloned human GABA, receptors.

The present invention also pertains to methods for altering the signal-transducing activity, particulary the chloride ion conductanc of GABA, 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, receptors im 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 GABAx receptors in vitro. The amount of a compound that would be sufficient to alter the signal-transducing activity of GABA, receptors may be : -20___determined via a GABA, receptor signal transduction assay, such as the assay described in Example 5. oo

The GABA, 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, receptor.

Labeled derivatives the GABA, 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).

Definitions

If the compounds of the present invention have asymmetric centers, then this invention includes all of the optical isomers and mixtures thereof.

In addition, compounds with carbon-carbon double bonds may occur in cis, trans, Z- and E- forms, with all isomeric forms of the compounds being included in the present invention.

A dashed line (---) in a Formula indicates an optional bond. Thus the Formula o 9

Rs G

R, n

Rs : \ :

Re n N T l

X represents either oO Oo R lo) Oo

Rs _G 3 G

N

OR, N R, H

Rs \ or Rs | \ !

X X .

When any variable (e.g. C;.Cs alkyl, alkyli, Ri, Ra, Rs, Rs,

X, T, G, W, 2, k, or m) occurs more than one time in Formula I,

its definition on each occurrence is independent of its definition at every other occurrence.

By "alkyl" or "lower alkyl" in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon

S atoms, such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.

By "alkoxy" or "lower alkoxy" in the present invention is meant straight or branched chain alkyl group having 1-6 carbon atoms, attached to the parent molecular moiety through an oxygen atom. Examples of alkoxy groups include, 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.

The term "alkenyl" is intended to include either straight or branched hydrocarbon chains containing at least one carbon- carbon double bond which may occur in any stable point along the chain. Examples of alkenyl groups include ethenyl and propenyl. —20— The term "alkynyl" is intended to include either a straight or branched hydrocarbon chain containing at least one carbon-carbon triple bond which may occur in any stable point along the chain, such as ethynyl and propynyl.

By “diC,-Cgalkylamino” is meant an amino group carrying two C;-Cgalkyl groups that are the same or different. _go-

By “benzoxazinyl” as used herein is meant a moiety of the formula:

Oo )

LL,

A benzoxazin-6-yl group is depicted.

By "halogen" in the present invention is meant fluorine, bromine, chlorine, and iodine.

By "“2-hydroxyethoxy” is meant a group of the formula: -OCH2CH20H. .

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 include, for example, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalene and biphenyl. Preferred examples of aryl groups include phenyl and naphthyl. The aryl groups of the invention are unsubstituted or may be substituted as provided herein. Examples of suitable substituents include hydroxy, halogen, C,-C¢ alkyl, C;-C¢ alkoxy, cyano, nitro, amino, mono- or dialkyl (C;-C¢)amino, carboxamide, and N-mono- or N,N-disubstituted carboxamide.

The term "heteroaryl" refers to an aromatic ring system containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. The heteroaryl ring may be fused or otherwise attached to one or more heteroaryl rings, aromatic or non-aromatic hydrocarbon rings or heterocycloalkyl rings.

Examples of heteroaryl groups include, for example, pyridine, furan, thiophene, 5,6,7,8-tetrahydroisoquinoline and pyrimidine. Preferred examples of heteroaryl groups include 5S thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidinyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, thiazolyl, thiadiazolyl, benzothiazolyl, imidazo(1,2- alpyridinyl, isoxazolyl, oxadiazolyl, igsothiazolyl, benzisothiazolyl, triazolyl, tetrazolyl, pyrrolyl, indolyl, pyrazolyl, and benzopyrazolyl. These heteroaryl groups can be unsubstituted or may be substituted as provided herein.

Examples of suitable substituents include hydroxy, halogen, C;-

C¢ alkyl, C:-Cs alkoxy, cyano, nitro, amino, mono- or dialkyl (C;-C¢) amino, carboxamide, and N-mono- or N,N- disubstituted carboxamide.

By a 2-, 3-, or 4-pyridyl, 1- or 2-imidazolyl, 1-, 2-, or 3-pyrrolyl, or adamantane-2-yl group that is substituted on a tertiary carbon or a secondary nitrogen with C;-C¢ alkyl is meant any such group in which a hydrogen atom is replaced with. _. an appropriate alkyl group. By way of example, such groups _ . __. include the following: — N N ry $c I Y and I Dam 24 ju N 24 i TC N CH,

By “heterocycloalkyl” is meant a non-aromatic ring system comprising one or two rings of 4-, 5-, 6-, or 7- atoms per ring wherein at least one ring contains at least one and up to 4 hetercatoms selected from nitrogen, oxygen, or sulfur. Such heterocycloalkyl groups include, for example, tetrahydropyridyl, morpholinyl, thiomorpholinyl, pyrrolidinyl,

S piperazinyl, and tetrahydrofuryl. The heterocycloalkyl group can be attached to the parent molecular moiety through the heteroatom or through a carbon atom. These groups may be substituted with from one to four groups independently selected from alkyl, alkoxy, halogen, hydroxy, amino and mono- Or dialkylamino groups. Preferred substituents are hydroxy, methoxy, ethoxy, chloro, fluoro, bromo, methyl and ethyl. More preferred heterocycloalkyl groups are those that are independently substituted with two of hydroxy, methoxy, ethoxy, chloro, fluoro, bromo, methyl or ethyl. Particularly preferred heterocycloalkyl groups are those that are substituted with one of hydroxy, methoxy, ethoxy, chloro, fluoro, bromo, methyl or ethyl.

By "N-alkylpiperazyl" in the invention is meant radicals of the formula: /\ —N N—R / where R is a straight or branched chain lower alkyl as defined above.

By "acyclic moiety having 3-7 carbon atoms" is meant a cytobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Each of these groups may be substituted with alkyl, alkoxy, hydroxy, halcgen, amino or mono- or dialkylamino. Preferred substituents are alkyl and alkoxy. Particularly preferred are alkyl with methyl and ethyl being most preferred.

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, i0 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 present invention also encompasses prodrugs of the compounds of Formula I.

The present invention also encompasses the acylated prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies, which may } 20 be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I.

Pharmaceutical Compositions

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 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 ul 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 i | ) as glyceryl 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 - 5 8 -

active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Agueous 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 monocoleate, 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 clive 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 monoleate. The emulsions may also contain sweetening and flavoring agents. - 6 0-

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 ; 5 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 c water, Ringer's solution and isotonic sodium chloride sclution.

In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed o0il 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 will be cgnvenient to formulate these animal feed and drinking water compositions so that the animal takes in an appropriate quantity of the composition along with its diet. It will 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 _ 20 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 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 desirable pharmacological properties. Such properties include, but are : not limited to oral bioavailability, low toxicity, low serum protein binding and desirable in vitro and in vivo half-lifes.

Penetration of the blood brain barrier for compounds used to treat CNS disorders is necessary, while low brain levels of compounds used to treat periphereal disorders are often preferred.

Assays may be used to predict these desirable pharmacological properties. Assays used to predict bicavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. Toxicity to cultured hepatocyctes may be used to predict compound toxicity. - 6 3 -

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

S 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 vitro half-lifes 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 present invention is given in Scheme I.

Claims

What is claimed is:

1. A compound of the formula: Rs 2 1 _G R, N Sat Re NT x or a pharmaceutically acceptable salt thereof wherein: T is halogen, hydrogen, hydroxyl, amino, alkyl or alkoxy; X is hydrogen, hydroxy, amino, benzyl, t-butoxycarbonyl, benzyloxycarbonyl, alkyl, or alkoxy; G represents pa, z a where Q is an optionally substituted aryl or optionally substituted heteroaryl dgroup having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms; W is chosen from hydrogen, -0-, -NH-, -NR;-, -S{(0)o-2-, -c(=0)-, -0C(=0)-, -C(=0)0-, -C(=O)NH-, -NHC(=0)-, -NR,C (=0) -, -NHS (0) ¢g-2-, -NR;8 (0) ¢-2-, -S (0) ¢-2NH-, -S(0)¢-2NR7-, and CR7Rg where R7 and Rg are the same or different and represent hydrogen, alkyl, or CR7Rg represents a cyclic moiety having 3-7 carbon atoms, wherein W may not be hydrogen when Q is phenyl, 2- or

3-thienyl, or 2-, 3-, or 4 pyridyl, indolyl, imidazolyl, or pyridazinyl; 2 is hydrogen, hydroxy, cycloalkyl (alkoxy), amino, wono- or di (alkyl;)amino, azacycloalkyl, -O(alkyl;), -S(O),- ,(alkyl,), -C(=0)(alkyli), -0C(=0) (alkyl), -OC(=O)H, -C(=0)0O(alkyli), -C(=0) OH, -C(=0)NH(alkyl,), -C(=0)N(alkyl,)., -C (=0)NH;, -NHC (=0) (alkyli), -NHC (=O)H, -N(alkyl,;)C(=0) (alkyli), -NHS(O)o-2(alkyl,), -N(alkyli) S(0)e-2(alkyl,) , -5(0)o-2NH(alkyl,), -5(0)o¢-2 (alkyl) N{alkyl,), wherein each alkyl; is independently straight, branched, or cyclic, may contain one or two double and/or triple bonds or combinations thereof, and is unsubstituted or substituted : with one or more substituents independently selected from hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy, or 7 is -N(Ry)2S(0)o-2 (Rs) where each Ry is independently hydrogen or alkyl where the alkyl is straight, branched, or cyclic, may contain one or two double and/or triple bonds, and is unsubstituted or substituted with one or more substituents independently selected from hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy, Rg is hydroxy, alkoxy, heteroaryl, aryl, or alkyl where each aryl and heteroaryl is optionally substituted with one or two of alkyl, hydroxy, alkoxy, triflouromethyl, halogen, amino, or mono- or dialkylamino; and each alkyl is optionally substituted with hydroxy, alkoxy, triflouromethyl, halogen, amino, mono- or di- alkylamino, aryl, or heteroaryl; or Z is phenyl or phenylalkyl where the phenyl portion is optionally substituted with alkyl, hydroxy, alkoxy, triflouromethyl, halogen, amino, or wmono- or di- alkylamino, or Z is 2-, 3-, or 4-pyridyl, 1- or 2-imidazolyl, 1-, 2-, or 3-pyrrolyl, azeditinyl, norborn-2-yl, or adamantan-2- ’ 15 yl; each of which may be substituted on a tertiary carbon or a secondary nitrogen with C;-Cgalkyl, or Z is NRgCOR30 where Rg and Rig are the same or different and represent hydrogen or alkyl or cycloalkyl, or Z is connected, optionally through W, to Q to from a 1-6 membered ring; or Z represents a group of the formula: R A x where p is 1, 2, or 3;

D and D’ independently represent oxygen, NR, or CHR,

provided that only one of D and D’' may be NR, and only one of D and D’ may be oxygen, where each Ry is hydrogen or alkyl; and R, is hydrogen or alkyl, or Z represents a group of the formula: R, VE

N—R,

oo,

where p is 1, 2, or 3; qg is 0, 1, or 2; : each R, is independently hydrogen or alkyl; or Z represents a group of the formula: yk Re O where s is 0, 1, 2 or 3, and the sum of s and m is not less ’ than 1;

Ro, is hydroxy, C1-C¢alkoxy, amino, wmono- or di- alkylamino where each alkyl is independently optionally substituted with amino, or mono- or dialkylamino, or

Ro, is a group of the formula R %, h where p, D, D’, and R, are as defined above;

A and Ag independently represent a carbon chain optionally substituted with halogen, oxo, cyano, nitro, amino, mono or dialkylamino, alkyl, alkenyl, alkynyl, trifluoromethyl, trifluoromethoxy, or cycloalkyl; wherein k is 0, 1, 2, or 3; m is 0, 1, 2, or 3; and A represents a carbon chain optionally substituted with R; and Rg and n is 0, 1, 2, or 3; and R3, Ra, Rs, and Rg are the same or different and are independently selected at each occurrence from hydrogen, alkyl, -CORj13i or -CO2Rj11 where Rj] is alkyl or cycloalkyl having 3-7 carbon atoms; or -CONRj2R13 where R12 and R13 are selected independently £rom hydrogen, alkyl, cycloalkyl having 3-7 carbon atoms, phenyl, 2-, 3-, or 4-pyridyl, or NR12R13 forms a heterocyclic group which is morpholinyl, piperidinyl, pyrrolidinyl, or N-alkyl piperazinyl; or R3 and R4 together with the carbon atom to which they are attached form a cyclic moiety having 3-7 carbon atoms; or

R5 and Rg together with the carbon atom to which they are attached form a cyclic moiety having 3-7 carbon atoms; where each alkyl group forming an R3, R4, Rs, or Rg substituent or portion thereof may be substituted independently with hydroxy or mono- or dialkylamino where each alkyl is independently alkyl or cycloalkyl.

2. A compound of the formula: Rs 2? 1 _G Ry N Re nN T x or a pharmaceutically acceptable salt thereof wherein: T is halogen, hydrogen, hydroxyl, C;-C¢ amino, alkyl or C;-Cs : alkoxy; X is hydrogen, hydroxy, amino, C;-C¢ alkyl, or C;-C¢ alkoxy; G represents Sal z ™a where Q is phenyl, 2- or 3-thienyl, or 2-, 3-, or 4 pyridyl, 2-, 4-, or 5-pyrimidinyl, indolyl, imidazolyl, pyridazinyl, 1,4-benzodioxazinyl, 1,3-benzodioxolyl or imidazol[l,2-alpyridinyl, all of which may be substituted by one or more of hydroxy, halogen, C1-Ce alkyl, C,-C¢ alkoxy, cyano, nitro, amino, and mono- or dialkyl (C;-C¢) amino; W is chosen from hydrogen, -0-, -NH-, -NRy-, -S(0O)o-2-, -C(=0) -, -0C (=0), -C(=0)0-, -C(=O)NH-, -NHC (=0) -, -NR,C(=0) -, ~-NHS (0) g-2-., -NR-S (0) g-2-, -S{0)q-2NH-, -S(0)y-2NR;, and CR7Rg where Ry and Rg are the same or different and represent hydrogen, alkyl, or CR7Rg represents a cyclic moiety having 3-7 carbon atoms, wherein W may not be hydrogen when Q is Phenyl, 2- or 3-thienyl, or 2-, 3-, or 4 pyridyl, indolyl, imidazolyl, or pyridazinyl; Z is hydrogen, hydroxy, C3-C; cycloalkyl(C,-C¢ alkoxy), amino, mono- or di(C;-C¢ alkyl,)amino, or C3-C, azacycloalkyl, -0(C,-C¢ alkyl;), -S{0)4-2(C1-C¢ alkyl), -C(=0) (C;-Ce¢ alkyl;), -0C(=0) (C1-C¢ alkyli), -0C(=0)H, -C(=0)0(C1-C¢ alkyl,), -C(=0) 0H, -C(=0O)NH (C;-Cs alkyl), -C(=0)N(C,-Cs alkyl,),,

20. -C (=O) NH,, -NHC (=0) (C;-C¢ alkyli), -NHC (=0)H,—-- -N(C,-Cgalkyl,) C(=0) (C;-Csalkyl,), ~-NHS (0) 0-2 (Cy - Cealkyl;:) , -N(C,-Cs alkyl) S(0)o-2(C1-Cg alkyl,), -5(0)4-2NH(C,-Cs alkyli), or -S(0).2(C1-Cs alkyl )N(C1-C¢ alkyl,), wherein C;-C¢ alkyl; is independently chosen at each occurrence and is straight, branched, or cyclic, may contain one or two double and/or triple bonds, and is unsubstituted or substituted with one or more substituents selected from: hydroxy, oxo, halogen, amino,

cyano, nitro, and alkoxy, or Z is phenyl or phenyl(C;-Cs¢)alkyl where the phenyl portion is optionally substituted with C;-C¢ alkyl, hydroxy, C1-Cs alkoxy, trifluoromethyl, trifluoromethoxy, halogen, amino, or mono- or diC;-C¢ alkylamino, or Z is 2-, 3-, or 4-pyridyl, 1- or 2-imidazolyl, 1-, 2-, or 3-pyrrolyl, or adamantan-2-yl; each of which may be substituted on a tertiary carbon or a secondary nitrogen with C;-Cgalkyl, or Z is NRgCORjgp where Rg and Rjg are the same or different and represent hydrogen or C;-Cs alkyl or C;3-C, cycloalkyl, or Z is connected, optionally through W, to Q to form a 1-6 membered ring; or Z represents a group of the formula: R 1% 2 cht where p is 1, 2, or 3; : D and D’ independently represent oxygen, NR, or CHR, provided that only one of D and D’ may be NR,

where each R, is hydrogen or C;-Cs alkyl; or and R, is hydrogen or C;-Cs; alkyl, or Z represents a group of the formula: I; N—R, 2 Ja where p is 1, 2, or 3; q is 0, 1, or 2; R; is hydrogen or C;-Cg alkyl; or a group of the formula: wR oO where s is 0, 1, 2 or 3, and the sum of s and m is not less than 1; Ro, is hydroxy, C;-C¢alkoxy, amino, mono- or diC,- Csalkylamino where each alkyl is independently optionally substituted with amino, mono- or diC,-Csalkylamino, or Ro, i8 a group of the formula R: Moy 3 where p, D, D’, and R, are as defined above; Ad and Ada independently represent a carbon chain optionally substituted with hydrogen, halogen, oxo,

cyano, nitro, amino, mono or di (C;-C¢)alkylamino, straight or branched chain C;-Cg alkyl, C,-Cg alkenyl, C2-C¢ alkynyl, trifluoromethyl, trifluoromethoxy, or cycloC;-Cs alkyl;

S wherein k is 0, 1, 2, or 3; mis 0, 1, 2, or 3; and A represents a carbon chain optionally substituted with Rs and Rgand n is 0, 1, 2, or 3;

R3, R4, Rg, and Rg are the same or different and are independently selected at each occurrence from hydrogen, C;-C¢ alkyl, -COR11 or -CO2R3131 where Rjj is C;-Cgalkyl or C;-C; cycloalkyl; or -CONR12R13 where Rio and R13 are selected independently from hydrogen, C;-Cs alkyl, C3-Cy cycloalkyl, phenyl, 2-, 3-, or 4-pyridyl, or NRi2R13 : forms a heterocyclic group which is morpholinyl, piperidinyl, pyrrolidinyl, or N-alkyl piperazinyl; or

R3-R4 may be taken together to form a cyclic moiety having

3-7 carbon atoms; or

Rs-Rg may be taken together to form a cyclic moiety having 3-7 carbon atoms; and where each alkyl group forming an R3, Rg, Rs, or Rg substituent or portion thereof may be substituted independently with hydroxy or mono-

or dialkylamino where each alkyl is independently C;-C; alkyl or cycloalkyl having 3- 7 carbon atoms.

3. A compound according to Claim 1, wherein Q is phenyl or pyridyl.

4. A compound according to Claim 1, wherein Q is phenyl or pyridyl; and either the group A or the group Arle is substituted by oxo.

5. A compound according to claim 1, of the formula: Y Y kW Zz O R, a R, N Y H Rs | A\ Y Re n N T I X wherein each Y is independently selected from hydrogen, hydroxy, halogen, C;-Cs alkyl, C;-C¢ alkoxy, cyano, nitro, amino, and mono- or dialkyl (C;-Cg) amino.

6. A compound according to claim 1, of the formula:

kW Zz 0) rR, ™ Rs n Rs IN Y Re n N T H wherein Y is selected from hydrogen, hydroxy, halogen, C;-C¢ alkyl, C:-C¢ alkoxy, cyano, nitro, amino, and mono- or dialkyl (C;-C¢) amino.

7. A compound according to claim 1, of the formula: Y kW Zz 0) a © ort 7 R, n Rs | \ Re n N T

H . wherein Y is selected from hydrogen, hydroxy, halogen, C:-Cs alkyl, Ci1-C¢ alkoxy, cyano, nitro, amino, and mono- or ’ dialkyl (C,-C¢)amino.

8. A compound according to claim 1, of the formula: Y Y = KW yd o © I R; x. Bo m R N A Y" 4 H 3 Rs IN Y Re n N T ! X wherein: one of A and B is nitrogen and the other is carbon; when A is nitrogen, Y' is an electron pair; when B is nitrogen, Y" is an electron pair; Y is independently selected at each occurrence from hydrogen, hydroxy, halogen, C;-Cs alkyl, C,-Cs alkoxy, cyano, nitro, amino, and mono- or dialkyl (C;-Cg¢)amino, with the proviso that when A is carbon, Y’' is hydrogen, hydroxy, halogen, C;-Cs alkyl, C;-C¢ alkoxy, cyano, nitro, amino, Or mono- or dialkyl (C;-C¢) amino; and when B is carbon, Y’’ is hydrogen, hydroxy, halogen, C;-Ce alkyl, ¢C;-C¢ alkoxy, cyano, nitro, amino, or mono- or dialkyl (C;-Cg) amino. ’ 15

9. A compound according to claim 1, of the formula:

Y

Y. re © 0 be At: x oN R, N } Sel Y Re mn N T x wherein each Y is independently selected from hydrogen, hydroxy, halogen, C;-C¢ alkyl, C;-C¢ alkoxy, cyano, nitro, amino, and mono- or dialkyl (C;-Cg)amino.

WQO 01/16103 PCT/US00/23862

10. A compound according to claim 1, of the formula: ~ KW Z rR, P00 I. 3 x N R, n Rs | A\ Re n N T ) X :

11. A compound according to claim 1, of the formula: Y Y Y fo) O Rj AY Zz R, n k ™, Rs IR Y Re n N T X wherein each Y is independently selected from hydrogen, i hydroxy, halogen, C;-Cs alkyl, C;-Cs alkoxy, cyano, nitro, amino, and mono- or dialkyl (C;-C¢)amino.

12. A compound according to claim 1, of the formula:

Y. Rs W Zz Rs n k as Rs IN Re n N T H wherein Y is selected from hydrogen, hydroxy, halogen, C;-Cg alkyl, C1-C¢ alkoxy, cyano, nitro, amino, and mono- Or dialkyl (C1-C¢) amino. S 13. A compound according to claim 1, of the formula:

Y

Y. O_ 7 o © “HM Ri R, N Y Rs | A\ H vy Rs n N T “X wherein each Y is independently selected from hydrogen, hydroxy, halogen, C;-Cs alkyl, C,-Ce¢ alkoxy, cyano, nitro, amino, and mono- or dialkyl (C;-Cs) amino.

14. A compound according to claim 1, of the formula:

0 .Z o © “HM Rs R, N Rs [ AN Y Rs n N T - H wherein Y is selected from hydrogen, hydroxy, halogen, C;-Cg alkyl, C:-C¢ alkoxy, cyano, nitro, amino, and mono- or dialkyl (C,-Cs) amino.

15. A compound according to claim 1, of the formula:

Y 0,2 o © “Ma Rs Rs n Rs | N Rs n N T H wherein Y is selected from hydrogen, hydroxy, halogen, C;-Cg alkyl, C;-C¢ alkoxy, cyano, nitro, amino, and mono- or dialkyl (C;-C¢) amino.

16. A compound according to claim 1, of the formula:

Y

Y. oO ZZ 4 o © I Ha R N A Y" 4 H i Rs | A\ Y' Rs nN T . X wherein: one of A and B is nitrogen and the other is carbon; when A is nitrogen, Y’ is an electron pair; when B is nitrogen, Y’'‘’ is an electron pair; Y is independently selected at each occurrence from hydrogen, hydroxy, halogen, C;-C¢ alkyl, C,-C¢ alkoxy, cyano, nitro, amino, and mono- or dialkyl (C;-Cg¢)amino; provided that when A is carbon, Y’ is hydrogen, hydroxy, halogen, C;-Cg alkyl, C;-C¢ alkoxy, cyano, nitro, amino, or mono- or dialkyl (C,-C¢) amino; and when B is carbon, Y'’ is hydrogen, hydroxy, halogen, C;-Cg alkyl, C,-C¢ alkoxy, cyano, nitro, amino, or mono- Or dialkyl (C;-C4) amino.

17. A compound according to claim 1, of the formula: 1) = Z « o © OM 3 x UN R, N Rs | \ Rg n N T

H .

18. A compound according to claim 1, of the formula:

Y

Y. z O m Ry [7 R, N Y Rs 1 Re n N T X wherein each Y is independently selected from hydrogen, hydroxy, halogen, C-C¢ alkyl, C;-C¢ .alkoxy, cyano, nitro, ] amino, and mono- or dialkyl (C;-Cg) amino.

19. A compound according to claim 1, of the formula: Zz 0 m Re [7 Ry, N Rs | AN Y Rg NT H wherein Y is selected from hydrogen, hydroxy, halogen, C,-Cq alkyl, C1-Cs; alkoxy, cyano, nitro, amino, and mono- or dialkyl (C;-Cs) amino.

20. A compound according to claim 1, of the formula: Y Zz 0 m R, R, N Rs IN Re n N T H wherein Y is selected from hydrogen, hydroxy, halogen, C,-Cs alkyl, C;-C¢ alkoxy, cyano, nitro, amino, and mono- or dialkyl (C;-C¢) amino.

21. A compound according to claim 1, of the formula: : Y Y Zz : =z ® NT Sa Beye R, H Rs | A\ Y Rg N T U X wherein: one of A and B is nitrogen and the other is carbon; when A is nitrogen, Y’ is an electron pair; when B is nitrogen, Y’’ is an electron pair;

Y is independently selected at each occurrence from hydrogen, hydroxy, halcgen, C:;-C¢ alkyl, C;-Cs alkoxy, cyano, nitro, amino, and mono- or dialkyl (C;-C¢)amino; provided that when A is carbon, Y’ is hydrogen, hydroxy, halogen, C;-Cs alkyl, C,;-C¢ alkoxy, cyano, nitro, amino, or mono- Or dialkyl (C;-C¢) amino; and when B is carbon, Y’’ is hydrogen, hydroxy, halogen, C;-Cs alkyl, C;-C¢ alkoxy, cyano, nitro, amino, or mono- or dialkyl (C,~Cg¢) amino.

22. A compound according to claim 1, of the formula:

Y

Y. = v4 o 9 m Ra =~ _N R, N Rs | A\ Y Re n N T I X wherein each Y is independently selected from hydrogen, hydroxy, halogen, C;-C¢ alkyl, C,-C¢ alkoxy, cyano, nitro, amino, and mono- or dialkyl (C,-C¢) amino.

23. A compound according to claim 1,which is:

Y

Y. Y 0) R, [7 R, N Zz Rs | NH oy Re n N T X wherein each Y is independently selected from hydrogen, hydroxy, halogen, ©€;-C¢ alkyl, C;-C¢ alkoxy, cyano, nitro, amino, and mono- or dialkyl (C,-Cg)amino. Ss

24. A compound according to claim 1, which is:

Y. Oo Rs, 2 To R, N Zz H Rs | A Re n N T H wherein each Y is independently selected from hydrogen, hydroxy, halogen, C;-Cs¢ alkyl, C;-Cs alkoxy, cyano, nitro, amino, and mono- or dialkyl (Ci-C¢)amino.

25. A compound according to claim 1,which is:

Y

Y. o VN Re [7 3 NS R, N N Zz H Rs | A\ Re (oy N T X wherein Y is independently selected at each occurrence from hydrogen, hydroxy, halogen, C,-C¢ alkyl, C:;-C¢ alkoxy, cyano, nitro, amino, and mono- or dialkyl (C;-Cg)amino.

26. A compound according to claim 1, of the formula: 0 gs’ Zz Rg N Rs | A\ Rg p N

H .

27. A compound according to claim 1, of the formula: 0 0) jg w N R4 H Rs | AN R¢ - N

H .

28. A compound according to claim 1, of the formula: 0 oO ~ tm R w Rg N k Rs | AN R n N H

29. A compound according to claim 1, of the formula:

0 w vy _. R H Rs | AN R n N

H .

30. A compound according to claim 1, of the formula: Y Y @) OR o © “Mo Rs R, N Y Rs | \ Hv Re n N T X wherein: R is hydrogen or alkyl wherein the alkyl is straight, branched, or cyclic, may contain one or two double and/or triple bonds, and is unsubstituted or substituted with one or more substituents selected from hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy; and each Y 1s independently selected from hydrogen, hydroxy, halogen, C;-Cs alkyl, C;-Cs alkoxy, cyano, nitro, amino, and mono- or dialkyl (C;-C¢)amino.

31. A compound according to claim 1, of the formula:

0 Ry N Rs | A Rg n N H where R3, Rs, and Rg independently represent hydrogen or alkyl; Ra represents hydrogen or alkyl where the alkyl is optionally halogenated; and e is an integer of 1-3.

32. A compound according to claim 1, of the formula:

Y

Y. O a OR o © I Ha . Rs x, B~ R N A Y” 4 H Rs | \ Y' Re n N T X wherein one of A and B is nitrogen and the other is carbon; -when--A- is nitrogen, ¥’' is an electron pair; when B is nitrogen, Y'’ is an electron pair; R is hydrogen or alkyl wherein the alkyl is straight, branched, or cyclic, may contain one or two double and/or triple bonds, and is unsubstituted or substituted with one or more substituents selected from hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy; | : Y is independently selected at each occurrence from hydrogen, hydroxy, halogen, C;-Cs¢ alkyl, C,-Cs alkoxy, cyano, nitro, amino, and mono- or dialkyl (C;-Cs)amino; provided that when A is carbon, Y’ is hydrogen, hydroxy, halogen, ©€;-Ce¢ alkyl, C;-C¢ alkoxy, cyano, nitro, amino, or mono- or dialkyl (C;-Cg¢)amino; and when B is carbon, Y’’ is hydrogen, hydroxy, halogen, C,-Cg alkyl, C;-C¢ alkoxy, cyano, nitro, amino, or mono- or dialkyl (C;-Cg¢)amino.

33. A compound according to claim 1, of the formula: Y R, N Snel H Rg = N H wherein R is hydrogen or alkyl wherein the alkyl is straight, branched, or cyclic, may contain one or two double and/or triple bonds, and is unsubstituted or substituted with one or more substituents selected from: hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy; and each Y is independently selected from hydrogen, hydroxy, halogen, C3-Cs alkyl, Ci1-C¢ alkoxy, cyano, nitro, amino, and mono- or dialkyl (C;-Cg¢)amino.

34. A compound according to claim 1, of the formula:

Y

Y. O Ra N Y Shel Hoy Rs - N T X wherein: Ra and Ry, are independently hydrogen or alkyl wherein each alkyl is independently straight, branched, or cyclic, may contain one or two double and/or triple bonds, and is unsubstituted or substituted with one or more substituents : selected from: hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy; or NR,Rp represent a heterocycloalkyl ring; and each Y is independently selected from hydrogen, hydroxy, “halogen, C,-C¢ alkyl, C,-C¢ alkoxy, cyano, nitro, amino, and mono- or dialkyl (C;-Cg¢) amino.

35. A compound according to claim 1, of the formula:

Y OL NR.R b o O I Rs R, N Rs | A\ Rs - N H wherein: Ra and Rp, are independently hydrogen or alkyl wherein each alkyl is independently straight, branched, or cyclic, may contain one or two double and/or triple bonds, and is unsubstituted or substituted with one or more substituents selected from: hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy; or

NR.Ry, represents a heterocycloalkyl ring; and Y is selected from hydrogen, hydroxy, halogen, C;-C¢ alkyl, C;- Ce alkoxy, cyano, nitro, amino, and mono- or dialkyl (C,- : Cs) amino.

36. A compound according to Claim 1, of the formula: ON _NR,R a'‘b o © or (CH,Jq R3 b R | AN Rg o H where R3, Rs, and Rg independently represent hydrogen, or alkyl; Raz and Rp independently represent hydrogen or alkyl; and e 1s an integer of 2-3.

37. BA compound according to claim 1, of the formula: Y Rs x, B~ Rs | \ Y' Rs IN X wherein: one of A and B is nitrogen and the other is carbon; when A is nitrogen, Y' 1s an electron pair; when B is nitrogen; ¥Y’'’ is an electron pair;

Ra. and Rp are independently hydrogen or alkyl wherein each alkyl is independently straight, branched, or cyclic, may contain one or two double and/or triple bonds, and is unsubstituted or substituted with one or more substituents selected from hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy; each Y is independently selected from hydrogen, hydroxy, oo halogen, C;-C¢ alkyl, C1-Cs alkoxy, cyano, nitro, aming, and mono- or dialkyl (Ci-C¢) amino; provided that when A is carbon, Y’ is hydrogen, hydroxy, halogen, C;-C¢ alkyl, C;-C¢ alkoxy, cyano, nitro, amino, or mono- or dialkyl (C1-Ce) amino; and when B is carbon , Y’’ is hydrogen, hydroxy, halogen, C1-Cs alkyl, C;-C¢ alkoxy, cyano, nitro, amino, or mono- or dialkyl (C;-Cg) amino.

38. A compound according to claim 1, of the formula:

Y

Y. 0) R, 2 0 OX He h : Rs N Rs ied Hy Re SN H wherein: R, and Rp, are independently hydrogen or alkyl wherein each alkyl is independently straight, branched, or cyclic, way contain one or two double and/or triple bonds, and is unsubstituted or substituted with one or more substituents selected from: hydroxy, oxo, halogen, amino, cyano, nitro, } and alkoxy; or Ra, and Rp, may be joined to form a heterocycloalkyl ring; and each Y is independently selected from hydrogen, hydroxy, halogen, C,-C¢ alkyl, C,-C¢ alkoxy, cyano, nitro, amino, and mono- or dialkyl (C;-C¢)amino.

39. A compound according to claim 1, of the formula:

Y Zz Opp NRaRs 0 0 m Rs; SN N R, N Rs | \ Re "ON H wherein: R, and R,, are independently hydrogen or alkyl wherein each alkyl is independently straight, branched, or cyclic, may contain one or two double and/or triple bonds, and is unsubstituted or substituted with one or more substituents selected from: hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy; or

NR.Rp together form a heterocycloalkyl ring; and Y is selected from hydrogen, hydroxy, halogen, C;-C¢ alkyl, C;- . Cs alkoxy, cyano, nitro, amino, and mono- or dialkyl (C;- Cg) amino.

40. A compound according to Claim 1, of the formula: (CHp)e (0) 0 OR, N R | AN Re n N H where R3, Rs, and Rg independently represent hydrogen, or alkyl;

Ra represents hydrogen or alkyl where the alkyl is optionally halogenated; and e 1s an integer of 1-3. 5S 41. A compound according to claim 1, of the formula:

Y

Y. = NRaR, 0 0 Ra Xx, Be R N A Y" 4 H Rs | A\ Y' Re n N T U X wherein: one of A and B is nitrogen and the other is carbon; when A is nitrogen, ¥Y’ is an electron pair; when B is nitrogen, Y’'’ is an electron pair; Ra and Ry, are independently hydrogen or alkyl wherein each alkyl is independently straight, branched, or cyclic, may contain one or two double and/or triple bonds, and is unsubstituted or substituted with one or more substituents selected from: hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy; or

NR.R;, forms a heterocycloalkyl ring; each Y is independently selected from hydrogen, hydroxy, halogen, C;-C¢ alkyl, C;-Cs alkoxy, cyano, nitro, amino, and mono- or dialkyl (C;-Cg)amino; provided that when A is carbon, Y’ is hydrogen, hydroxy, halogen, C;-Cs alkyl, C;-C¢ alkoxy, cyano, nitro, amino, or mono- Or dialkyl (C;-Cs)amino; and when B is carbon, Y’‘’ is hydrogen, hydroxy, halogen, C;-Cs alkyl, C;-C¢ alkoxy, cyano, nitro, amino, or mono- or dialkyl (C;-Cs)amino.

42. A compound according to Claim 1, of the formula: oO 0) R © Rg n N H where G represents: : 0) V, gn gat Ion bi Vv Rls VA o! where V is oxygen, nitrogen, or methylene; and m is 1 or 2.

43. A compound according to claim 1, which is : 15 -N- [4- (2-Pyrrolidinylethoxy) phenyl} -4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide; N- [3-(2-Dimethylaminoethoxy) phenyl) -4-ox0-4,5,6,7- tetrahydro-1H-indole-3-carboxamide; N- [3-(2-n-Propylaminoethoxy) phenyl] -4-ox0-4,5,6,7- tetrahydro-1H-indole-3-carboxamide;

N-[3-(2-n-Butylaminoethoxy) phenyl] -4-oxo0-4,5,6,7- tetrahydro-1H-indole-3 -carboxamide; N- [3- (2-Isobutylaminoethoxy)phenyl] -4-oxo0-4,5,6,7- tetrahydro-1H-indole-3 -carboxamide; N-[3-(2-Cyclobutylaminoethoxy) phenyl] -4-ox0-4,5,6,7- tetrahydro-1H-indole-3-carboxamide; N-[3- (2-t-Butylaminoethoxy) phenyl) -4-oxo0-4,5,6,7- tetrahydro-1H-indole-3-carboxamide; N-[3-(2-Cyclopropylmethylaminoethoxy) phenyl] -4-oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide; N-{3-[2- (4-Methylcyclohexyl)aminoethoxy] phenyl }-4-oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide; or N-{3-[2- (3-Trifluoromethylbenzylamino) ethoxy} phenyl }-4- Ooxo0-4,5,6,7-tetrahydro-1H-indole-3-carboxamide. :

44. A compound according to claim 1, which is N-{3-[3-(3-Trifluoromethylbenzylamino)propoxylphenyl}-4- oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; N-[4-(2-Dimethylaminoethyl) phenyl] -4-oxo0-4,5,6,7- tetrahydro-1H-indole-3 -carboxamide; N-[4-(2-Pyrrolidin-1-ylethyl)phenyl] -4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide; N-[4-(2-Diisopropylaminoethoxy) phenyl] -4-o0x0-4,5,6,7- tetrahydro-1H-indole-3-carboxamide; N-{4-(2-Methylaminoethoxy) phenyl] -4-oxo0-4,5,6,7- tetrahydro-1H-indole-3-carboxamide;

N- {4-(2-Ethylaminoethoxy) phenyl] -4-oxc-4,5,6, 7-tetrahydro- 1H-indole-3-carboxamide; N- [2-Fluoro-4- (2-ethylaminoethoxy) phenyl] -4-oxc-4,5,6, 7- tetrahydro-1H-indole carboxamide; N- [4- (2-n-Propylaminoethoxy) phenyl} -4-ox0-4,5,6,7- tetrahydro-1H-indole-3-carboxamide; N- [2-Fluoro-4- (2-n-propylaminoethoxy) phenyl] -4-oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide; or N- [3-Fluoro-4- (2-n-propylaminoethoxy) phenyl] -4 -oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

45. A compound according to claim 1 which is N- [3-Fluoro-4- (2-n-propylaminoethoxy) phenyl] -4-oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide hydrochloride; N- [4- (2-Cyclopropylaminoethoxy) phenyl] -4-oxo0-4,5,6,7-~ tetrahydrc-1H-indole-3-carboxamide; N- [4- (2- Isopropylaminoethoxy) phenyl] -4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide; N- [4- (2-Cyclopropylmethylaminoethoxy) phenyl] -4 -oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide; N- [4- (2-Cyclopropylmethylaminoethoxy) phenyl] -4-oxo- 4,5,6,7-tetrahydro-1H-indole-3-~carboxamide hemifumarate; N- [2-Fluoro-4- (2-Cyclopropylmethylaminoethoxy) phenyl] -4- oxo-4,5,6,7-tetrahydro-1H-indole-3 -carboxamide; N- [3-Fluoro-4- (2-Cyclopropylmethylaminoethoxy) phenyl] -4- 0ox0-4,5,6,7-tetrahydro-1H-indole-3 -carboxamide;

N- [3-Fluoro-4-(2-Cyclopropylmethylaminoethoxy) phenyl] -4- oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide tosylate; N- [4- (2-Isobutylaminoethoxy)phenyl] -4-oxo0-4,5,6, 7- tetrahydro-~1H-indole-3-carboxamide; or N- [2-Fluoro-4- (2-Isobutylaminoethoxy) phenyl] -4-oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

46. A compound according to claim 1, which is N- [3-Fluoro-4- (2-Isobutylaminoethoxy) phenyl] -4-oxo- 4,5,6,7-tetrahydro-~1H-indole-~3-carboxamide; N- [4-(2-n-Butylaminoethoxy) phenyl] -4-ox0-4,5,6,7- tetrahydro-1H-indole-3-carboxamide; N- [4- (2-n-Butylaminoethoxy) phenyl] -4-oxo0-4,5,6,7- tetrahydro-1H-indole-3-carboxamide hydrochloride; N- [3-Fluoro-4-(2-n-butylaminoethoxy) phenyl] -4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide; . N-[4-(2-t-Butylaminoethoxy) phenyl) -4-ox0-4,5,6,7- tetrahydro-1H-indole-3 -carboxamide; N- [3-Fluoro-4-(2-t-butylaminoethoxy) phenyl] -4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide; N- [4- (2-adamant-2-ylaminoethoxy) phenyl] -4-ox0-4,5,6,7- tetrahydro-1H-indole-3 -carboxamide; N-{4-[(R)-Pyrrolidin-2-ylmethoxy]phenyl}-4-oxo0-4,5,6,7- tetrahydro-1H-indole-3 -carboxamide; N-{4-[(S)-Pyrrolidin-2-ylmethoxylphenyl}-4-oxo0-4,5,6,7- tetrahydro-1H-indole-3-carboxamide; or

N- [4- (Piperidin-3-ylmethoxy) phenyl] -4-oxo0-4,5,6,7- tetrahydro-1H-indole-3-carboxamide.

47. A compound according to claim 1, which is N- [4- (Piperidin-3-ylmethoxy) phenyl] -4-0x0-4,5,6,7- tetrahydro-1H-indole-3-carboxamide hydrochloride; N-[4- (2-Dimethylaminoethoxy) phenyl] -4-0x0-4,5,6,7- tetrahydro-1H-indole-3-carboxamide; N-[3-Fluoro-4-(2-dimethylaminoethoxy) phenyl} -4-oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide; N-[4-(2-Pyrrolidin-1-ylethoxy) phenyl] -4-o0x0-4,5,6,7- tetrahydro-1H-indole-3-carboxamide; N-[4- (2-Imidaz-1l-ylethoxy) phenyl] -4-oxo0-4,5,6,7- tetrahydro-1H-indole-3-carboxamide; N- [3-Fluoro-4- (2-moropholin-1-ylethoxy) phenyl] -4-oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide; N- (3-Fluoro-4- (2-pyrrolidin-1-ylethoxy)phenyl] -4-oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide; N-[4-(2-Piperidin-2-ylethoxy) phenyl] -4-oxo0-4,5,6,7- tetrahydro-1lH-indole-3-carboxamide; N-{4-[3- (2,2,2, ~Trifluorethyl) aminopropoxy] phenyl} - 4 -oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide; or N- [4- (3-Isopropylaminopropoxy) phenyl] -4-0x0-4,5,6,7- tetrahydro-1H-indole-3-carboxamide.

48. A compound according to claim 1, which is

N-{4-[3- (2-Methylpropyl) aminopropoxy] phenyl} -4-oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide ; N- [(4- (3-Isobutylaminopropoxy)phenyl] -4-oxo0-4,5,6,7- tetrahydro-1H-indole-3-carboxamide; S N-[4-(3-Cyclopropylmethylaminopropoxy) phenyl] -4-oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide; N-{4-[3- (3-Ethylpropyl)aminopropoxy] phenyl }-4-oxo-4,5,6, 7- tetrahydro-lH-indole-3-carboxamide; N-[4-(3-Cyclopentylaminopropoxy) phenyl] -4-oxo0-4,5,6, 7- tetrahydro-1H-indole-3-carboxamide; N-{4-[3- (N-Cyclopropylmethyl, N- propyl) aminopropoxy) phenyl }-4-oxo-4,5,6,7-tetrahydro-1H-indole- 3-carboxamide; N-[4- (2-Methylaminocethoxy)pyrid-3-yl]-4-ox0-4,5,6,7- tetrahydro-1H-indole-3-carboxamide; N- [4-(2-Ethylaminoethoxy)pyrid-3-yl] -4-oxo0-4,5,6,7~ tetrahydro-1H-indole-3 -carboxamide; N-[4- (2-Ethylaminoethoxy)pyrid-3-yl]-4-ox0-4,5,6,7- tetrahydro-1H-indole-3-carboxamide hydrochloride; or N-[4-(2-n-Propylaminoethoxy)pyrid-3-yl]-4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide.

48. A compound according to claim 1, which is N-[4- (2-n-Propylaminoethoxy)pyrid-3-yl}-4-oxo-4,5,6,7- tetrahydro-lH-indole-3-carboxamide hydrochloride;

N-{4-(2-Isopropylaminoethoxy)pyrid-3-yl}-4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide; N- {(4-(2-Isopropylamincethoxy)pyrid-3-yl]}-4-oxo0-4,5,6,7- tetrahydro-1H-indole-3-carboxamide hydrochloride; N-[4-(2-n-Butylaminoethoxy)pyrid-3-yl]-4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide; N-{4- (2-n-Butylaminoethoxy)pyrid-3-yl}-4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide hydrochloride; N-[4-(2-t-Butylaminoethoxy)pyrid-3-yl]-4-0ox0-4,5,6,7- tetrahydro-1H-indole-3-carboxamide; N- [4- (2-Benzylaminoethoxy) pyrid-3-yl]-4-oxo0-4,5,6,7- tetrahydro-1H-indole-3-carboxamide; N- [4- (2-Benzylaminoethoxy)pyrid-3-yl) -4-ox0-4,5,6,7- tetrahydro-1H-indole-3-carboxamide hydrochloride; : 15 N- [4- (Pyrid-3-ylmethoxy)pyrid-3-yl]-4-oxo0-4,5,6,7- tetrahydro-1H-indole-3-carboxamide; or N- [4- (Pyrid-3-ylmethoxy)pyrid-3-yl}-4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide hydrochloride.

50. A compound according to claim 1, which is N- [4- (Pyrid-4-ylmethoxy)pyrid-3-yl]-4-ox0-4,5,6,7- tetrahydro-1H-indole-3-carboxamide; N-[4- (Pyrid-4-ylmethoxy)pyrid-3-yl)] -4-ox0-4,5,6,7- tetrahydro-1H-indole-3-carboxamide hydrochloride; N-{4- [(R) -Pyrrolidn-2-ylmethoxylpyrid-3-yl}-4-ox0-4,5,6,7- tetrahydro-1H-indole-3-carboxamide;

oo 2 N-{4- [(R) -Pyrrolidn-2-ylmethoxy]pyrid-3-yl}-4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide hydrochloride; N-{4-[(S)-Pyrrolidn-2-ylmethoxy]pyrid-3-yl}-4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide; N- [4- (2-Dimethylaminoethoxy)pyrid-3-yl]-4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide; N- [4~ (3-Dimethylaminopropoxy)pyrid-3-yl] -4-oxo-4,5,6, 7- tetrahydro-1H-indole-3-carboxamide; N- [4-(2-Pyrrolidin-1-ylethoxy)pyrid-3-yl]-4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide; N-{4-(2-Pyrrolidin-1-ylethoxy)pyrid-3-yl] -4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide hydrochloride: or N- [4- (2~-Dimethylaminoethoxy)pyrid-3-yl] -4-oxo0-4,5,6,7- tetrahydro-1H-indole-3-carboxamide. : :

51. A compound according to claim 1, which is N-{4-[2- (4-Methyl-piperazin-1-yl)ethoxylpyrid-3-yl}-4-oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide; N-{4-[2-Morpholin-1-ylethoxy)pyrid-3-yl}-4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide; N-({4-[2-Piperidin-1-ylethoxylpyrid-3-yl}-4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide; N-{4-[2-Piperidin-1-ylethoxy)pyrid-3-yl}-4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide hydrochloride; N-{4-[(1-Methyl-pyrrolidin-3-yl)methoxy]pyrid-3-yl}-4-oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide;

N-{4- [(1-Ethyl-pyrrolidin-3-yl)methoxylpyrid-3-yl}-4-oxo- 4,5,6,7-tetrahydro-1H~-indole-3-carboxamide; N-{4- [2- (1-Methyl-pyrrolidin-2-yl) ethoxy] pyrid-3-yl}-4- oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; N-{4-[2-(1-Methyl-pyrrolidin-2-yl)ethoxy]lpyrid-3-yl}-4- oxo0-4,5,6,7-tetrahydro-1H-indole-3 -carboxamide hydrate; N-[4- (3-n-Propylaminopropoxy) pyrid-3-yl]-4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide; or N-{4- (3-Cyclopropylmethylaminopropoxy)pyrid-3-yl) -4-oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

52. A compound according to claim 1, which is N-{4-[3-(2-Ethylbutyl)aminopropoxylpyrid-3-yl}-4-oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide; N- [4- (3-Cyclohexylaminopropoxy)pyrid-3-yl] -4-oxo0-4,5,6,7- tetrahydro-1H-indole-3-carboxamide; N- {4-(3-Cyclohexylmethylaminopropoxy)pyrid-3-yl] -4-oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide; N-{4-[3- (Pyrid-4-ylmethyl)aminopropoxylpyrid-3-yl}-4-oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide; N-[4- (2-Pyrrolidin-1-ylethoxy)pyrid-3-yl] -4-0x0-4,5,6,7- tetrahydro-1H-indole-3-carboxamide; N-[4- (3-Di-n-propylaminopropoxy)pyrid-3-yl}-4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide; N-{4-[3-Di (cyclopropylmethyl)aminopropoxy) pyrid-3-yl}-4- oxo0-4,5,6,7-tetrahydro-1H-indole-~3-carboxamide;

N-{4-[3-Di(2-ethylbutyl)aminopropoxy)pyrid-3-yl}-4-oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide; N-{4-[3-Di(pyrid-4-ylmethyl)aminopropoxyl pyrid-3-yl}-4- oxo0-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; or N-{4-[2-(2-Pyrrolidin-1-ylethoxy) ethoxy] pyrid-3-yl}-4-oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide.

53. A compound according to claim 1, ‘which is N-{4-[2-(2,2-Dimethylaminoethylamino) -2-oxoethyl]l phenyl} - 4-0ox0-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; N-{4-[2-(4-Methylaminopiperizin-1yl) -2-oxoethyl) phenyl }-4- 0x0-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; N-{4-[7-azabicyclo(2.2.1)hept-2-yloxylphenyl}-4-oxo- 1,4,5,6,7,8-hexahydro-cyclohepta [b] pyrrole-3-carboxamide; N- [3-(2-Diethylaminoethoxy) phenyl] -4-oxo0-1,4,5,6,7,8- hexahydro-cyclohepta (bl pyrrole-3-carboxamide; N-[3- (2-Pyrrolidin-1-ylethoxy) phenyl] -4-ox0-1,4,5,6,7,8-~ hexahydro-cyclohepta [b] pyrrole-3-carboxamide; N-[3-(2-Di-i-propylaminoethoxy) phenyl) -4-oxo-1,4,5,6,7,8- hexahydro-cyclohepta [b] pyrrole-3-carboxamide; N- [3- (2-n~Propylaminoethoxy) phenyl] -4-oxo-1,4,5,6,7,8- hexahydro-cyclohepta [b] pyrrole-3-carboxamide; N- [3- (2-n-Butylaminoethoxy)phenyl] -4-oxo-1,4,5,6,7,8- hexahydro-cyclohepta[b] pyrrole-3-carboxamide; N- [3- (Methylaminopropoxy) phenyl] -4-oxo0-1,4,5,6,7,8- hexahydro-cyclohepta [b] pyrrole-3-carboxamide; or

N-{3-[3- (N-Ethyl,N-Methyl)aminopropoxy] phenyl }-4-oxo- 1,4,5,6,7,8-hexahydro-cyclohepta (bl pyrrole-3-carboxamide.

54. A compound according to claim 1, which is N-{3-[3-(N-Cyclopropylmethyl, N-n- propyl) aminopropoxy)] phenyl }-4-oxo-1,4,5,6,7, 8-hexahydro- cyclohepta [bl pyrrole-3-carboxamide ; N-[3-(Azeditinylpropoxy)phenyl] -4-ox0-1,4,5,6,7,8- hexahydro-cyclohepta[blpyrrole-3-carboxamide; N-[3- (3-Ethylaminopropoxy) phenyl) -4-o0x0-1,4,5,6,7, 8- hexahydro-cyclohepta [bl pyrrole-3-carboxamide; N-{3-{3-(2,2,2-Trifluoroethyl)aminopropoxy] phenyl }-4-oxo- 1,4,5,6,7,8-hexahydro-cyclohepta([b]pyrrole-3-carboxamide; N- [3- (3-n-Propylaminopropoxy) phenyl] -4-oxo-1,4,5,6,7,8- hexahydro-cyclohepta[blpyrrole-3-carboxamide; N- [3- (3-Isopropylaminopropoxy) phenyl] -4-oxo-1,4,5,6,7,8- hexahydro-cyclohepta [bl pyrrole-3-carboxamide; N-[3-({3-Cyclopropylaminopropoxy)phenyl}-4-oxo-1,4,5,6,7,8- hexahydro-cyclohepta [bl pyrrole-3-carboxamide; —20— — N-{3-(3-Cyclopropylmethylaminopropoxy) phenyl] -4-oxo- 1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide; or N- [3-(3-Cyclobutylaminopropoxy) phenyl] -4-o0xo0-1,4,5,6,7, 8- hexahydro-cyclohepta [b] pyrrole-3-carboxamide.

55. A compound according to claim 1, which is

N- [3- (3-Cyclohexylaminopropoxy) phenyl] -4-oxo0-1,4,5,6,7,8- hexahydro-cyclohepta [blpyrrole-3-carboxamide; N-{3-[3-(3-Ethylpropyl)aminopropoxyl phenyl }-4-oxo-

1,4.5,6,7,8-hexahydro-cyclohepta [b]pyrrole-3-carboxamide; N-{3-[3-(2-Methylpropyl)aminopropoxy] phenyl }-4-oxo- 1,4,5,6,7,8-hexahydro-cyclohepta (b]pyrrole-3-carboxamide; N- [3- (3-Isobutylaminopropoxy) phenyl] -4-o0x0-1,4,5,6,7,8- hexahydro-cyclohepta [bl pyrrole-3-carboxamide; N- [3- (3-t-Butylaminopropoxy) phenyl] -4-oxo-1,4,5,6,7,8~ hexahydro-cyclohepta[blpyrrole-3-carboxamide; N-{3-[3-(2-Methylbutyl)aminopropoxyl phenyl }-4-oxo- 1,4,5,6,7,8-hexahydro-cycloheptalblpyrrole-3-carboxamide; N-[3-(3-Isoamylaminopropoxy) phenyl] -4-oxo0-1,4,5,6,7,8- hexahydro-cyclohepta [b] pyrrole-3-carboxamide; N-{3-[3- (4-Methylpentyl)aminopropoxy] phenyl }-4-oxo- : 1,4,5,6,7,8-hexahydro-cyclohepta [b] pyrrole-3-carboxamide; N-{3-[3-(1,1-Dimethylpropyl)aminopropoxy) phenyl} -4-oxo- 1,4,5,6,7,8-hexahydro-cyclohepta [b] pyrrole-3-carboxamide; or N-{3-[3-(3,3,-Dimethylbutyl)aminopropoxy] phenyl} -4-oxo- 1,4,5,6,7,8-hexahydro-cyclohepta [bl pyrrole-3-carboxamide.

56. A compound according to claim 1, which is N-{3-{3-(2,4-Dimethylpent-3-yl)aminopropoxy) phenyl }-4-oxo- 1,4,5,6,7,8-hexahydro-cycloheptal[b]pyrrole-3-carboxamide; N-{3-([3-(4-Methylcyclohexyl)aminopropoxy] phenyl}-4-oxo- 1,4,5,6,7,8-hexahydro-cyclohepta [bl pyrrole-3-carboxamide;

N-{3-[3- (4-t-Butylcyclohexyl)aminopropoxy] phenyl }-4-oxo- 1,4,5,6,7,8-hexahydro-cyclchepta [bl pyrrole-3-carboxamide; N-{3-(3-(2,6-Dimethylcyclohexyl)aminopropoxy}phenyl}-4- oxo-1,4,5,6,7,8-hexahydro-cyclohepta [b]lpyrrole-3-carboxamide; N-{3-[3- (1-Phenylethyl)aminopropoxyl phenyl }-4-oxo- 1,4,5,6,7,8-hexahydro-cyclohepta [blpyrrole-3-carboxamide; N- [3- (3-Norborn-2-ylaminopropoxy) phenyl] -4-oxo- 1,4,5,6,7,8-hexahydro-cyclohepta [b]pyrrole-3-carboxamide; N- [3- (3~Adamant-1l-ylaminopropoxy) phenyl] -4-oxo- 1,4,5,6,7,8-hexahydro-cyclohepta [b] pyrrole-3-carboxamide; N- [3- (3-Norborn-2-ylmethylaminopropoxy) phenyl] -4-oxo- 1,4,5,6,7,8-hexahydro-cyclohepta [bl pyrrole-3-carboxamide; N- [3-(3-Adamant-2-ylaminopropoxy) phenyl] -4 -oxo- 1,4,5,6,7,8-hexahydro-cyclohepta [bl pyrrole-3-carboxamide; or N-[4- (2-Ethylaminoethoxy) phenyl] -4-oxo0-1,4,5,6,7,8- hexahydro-cyclohepta [bl pyrrole-3-carboxamide.

57. A compound according to claim 1, which is N- [4- (2-Ethylaminoethoxy) phenyl] -4-o0x0-1,4,5,6,7,8- hexahydro-cyclohepta[blpyrrole-3-carboxamide hydrochloride; N- [2-Fluoro-4-(2-Ethylaminoethoxy) phenyl] -4-oxo- 1,4,5,6,7,8-hexahydro-cyclohepta [bl pyrrole-3-carboxamide; N-[4-(2-n-Propylaminoethoxy) phenyl) -4-oxo0-1,4,5,6,7,8- hexahydro-cyclohepta [b]pyrrole-3-carboxamide; N- [4- (2-Cyclopropylaminoethoxy) phenyl] -4-oxo-1,4,5,6,7,8- hexahydro-cyclohepta [blpyrrole-3-carboxamide; :

N-4- (2-n-Butylaminoethoxy) phenyl] -4-oxo-1,4,5,6,7,8- hexahydro-cycloheptalb] pyrrole-3-carboxamide; N- (4~- (3-Ethylaminopropoxy) phenyl) -4-oxo0-1,4,5,6,7, 8- hexahydro-cycloheptalblpyrrole-3-carboxamide; N-{4-[3-(1-Phenyl-1-methylethyl)aminopropoxy]phenyl}-4- oxo-1,4,5,6,7,8-hexahydro-cyclohepta([blpyrrole-3-carboxamide; N- {4- (Pyrid-3-ylmethoxy)pyrid-3-yl)-4-ox0-1,4,5,6,7,8- hexahydro-cycloheptal[b]pyrrole-3-carboxamide; N- [4- (Pyrid-4-ylmethoxy) pyrid-3-yl]-4-oxo0-1,4,5,6,7,8- hexahydro-cyclohepta[b]pyrrole-3-carboxamide; or N- [4- (Pyrid-4-ylmethoxy)pyrid-3-yl}-4-oxo-1,4,5,6,7,8- hexahydro-cyclohepta [b]l pyrrole-3-carboxamide hydrochloride. . 58. A compound according to claim 1, which is N- [4- (2-Dimethylaminoethoxy)pyrid-3-yl]-4-oxo-1,4,5,6,7, 8- hexahydro-cyclohepta [bl pyrrole-3-carboxamide; n N- [4- (2-Diethylaminoethoxy)pyrid-3-yl]l-4-oxo-1,4,5,6,7,8- hexahydro-cyclohepta [bl pyrrole-3-carboxamide; N-[4- (2-Pyrrolidin-1-ylethoxy)pyrid-3-yl]-4-oxo- 1,4,5,6,7,8-hexahydro-cyclohepta [b]pyrrole-3-carboxamide; N-[4- (2-Pyrrolidin-1-ylethoxy)pyrid-3-yl]-4-oxo- 1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxamide hydrochloride; N- [4- (2-Piperidin-1-ylethoxy)pyrid-3-yl]-4-oxo- 1,4,5,6,7,8-hexahydro-cyclohepta[blpyrrole-3-carboxamide;

N-{4-[2- (1-Methyl-pyrrolidin-2-yl)ethoxylpyrid-3-yl}-4- oxo-1,4,5,6,7,8-hexahydro-cyclohepta [b] pyrrole-3-carboxamide; N-{4-[(1-BEthyl-pyrrolidin-3-yl)methoxylpyrid-3-yl}-4-oxo- 1,4,5,6,7,8-hexahydro-cyclohepta [b] pyrrole-3-carboxamide; N- [4- (2-Morpholin-1l-ylethoxy)pyrid-3-yl]-4-oxo- 1,4,5,6,7,8-hexahydro-cyclohepta [b]lpyrrole-3-carboxamide; N-[4- (2-Diethylaminoethoxy)pyrid-3-yl]-4-oxo0-1,4,5,6,7,8- hexahydro-cyclohepta [b] pyrrole-3-carboxamide; or N-[4-(2-n-Propylaminoethoxy) pyrid-3-yl]-4-oxo-1,4,5,6,7,8- hexahydro-cyclohepta[blpyrrole-3-carboxamide.

59. A compound according to claim 1, which is N- [4- (2-n-Propylaminoethoxy) pyrid-3-yl]-4-oxo0-1,4,5,6,7,8- hexahydro-cyclohepta [bl pyrrole-3-carboxamide hydrochloride; N- [4- (2-Isopropylaminoethoxy) phenyl] -4-0x0-1,4,5,6,7,8- hexahydro-cyclohepta[blpyrrole-3-carboxamide; N- [4- (3-Isopropylaminopropoxy) phenyl) -4-oxo-1,4,5,6,7,8- hexahydro-cyclohepta [b] pyrrole-3-carboxamide; N-{4-(3-Cyclopropylaminopropoxy) phenyl] -4-oxo0-1,4,5,6,7,8- hexahydro-cyclohepta[blpyrrole-3-carboxamide; N-[4- (3-Cyclobutylaminopropoxy) phenyl] -4-o0x0-1,4,5,6,7,8- hexahydro-cyclohepta [bl pyrrole-3-carboxamide; N-[4- (3-Cyclopropylmethylaminopropoxy) phenyl] -4-oxo- 1,4,5,6,7,8-hexahydro-cyclohepta{b]pyrrole-3-carboxamide; N-[4- (3-Isobutylaminopropoxy) phenyl) -4-oxo0-1,4,5,6,7,8- hexahydro-cyclohepta [bl pyrrole-3-carboxamide;

N-{4-(3-(2,2-Dimethylpropyl)aminopropoxy] phenyl }-4 -oxo- 1,4,5,6,7,8-hexahydro-cyclohepta [b] pyrrole-3-carboxamide; N-{4-[3-(3-Ethylpropyl) aminopropoxyl phenyl} -4-oxo- 1,4,5,6,7,8-hexahydro-cyclohepta [bl] pyrrole-3-carboxamide; or N-{4-[3-(2-Methylbutyl) aminopropoxy) phenyl }-4-oxo- 1,4,5,6,7,8-hexahydro-cyclohepta [b] pyrrole-3-carboxamide.

60. A compound according to claim 1, which is N-{4- [3~ (2-Methylpropyl) aminopropoxy] phenyl} -4-oxo- 1,4,5,6,7,8-hexahydro-cyclohepta [b] pyrrole-3-carboxamide; N-[4-(3-i-Pentylaminopropoxy) phenyl] -4-oxo-1,4,5,6,7,8- hexahydro-~cyclohepta [b] pyrrole-3-carboxamide; N- [4-~ (3-Cyclohexylaminopropoxy) phenyl] -4-oxo-1,4,5,6,7, 8- hexahydro-cyclohepta [bl] pyrrole-3-carboxamide; N-{4-[3- (N-Cyclopropylmethyl,N-n- : propyl) aminopropoxylphenyl}-4-oxo-1,4,5,6,7,8-hexahydro- cyclohepta [bl pyrrole-3-~carboxamide; N-[4-(3-Indan-2-ylaminopropoxy) phenyl] -4-oxo-1,4,5,6,7,8- hexahydro-cyclohepta [bl pyrrole-3-carboxamide; N- (3-Fluoro-4- (2-ethoxy-2-oxoethoxy) phenyl} -4-oxo-4,5,6,7- tetrahydro-1H-indole-3-carboxamide; N- [3-Fluoro-4- (2-hydroxy-2-oxoethoxy) phenyl) -4-oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide; N- [3-Fluoro-4-(2-ethylamino-2-oxoethoxy) phenyl] -4-oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide;

N- (3-Fluoro-4- (2-diethylamino-2-oxoethoxy) phenyl] -4-0oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide; or N-{3-Fluoro-4-[(2- (4-methylpiperizin-1-yl)-2- oxoethoxy] phenyl }-4-oxo0-4,5,6,7-tetrahydro-1H-indole-3- carboxamide.

61. A compound according to claim 1, which is N-ethyl-N- [2- (ethylamino) ethyl] -2-{4-~[(4-0ox0-(4,5,6,7- tetrahydroindol-3-yl) )carbonylamino] phenoxy }acetamide; N- [2- (dipropylamino) ethyl] -2-{4-[(4-0ox0-(4,5,6,7- tetrahydroindol-3-yl) ) carbonylamino] phenoxy }acetamide; N- [2- (diethylamino) ethyl] -N-methyl-2-{4- [{(4-0ox0-(4,5,6,7- tetrahydroindol-3-yl))carbonylamino] phenoxy }acetamide; N-{2- (diethylamino) ethyl] -N-ethyl-2-{4-[(4-0ox0o-(4,5,6,7- tetrahydroindol-3-yl))carbonylamino]phenoxy}acetamide; N- (4- (2-morpholin-4-yl-2-oxoethoxy) phenyl] (4-oxo-(4,5,6,7- tetrahydroindol-3-yl) ) carboxamide; N- [3-fluoxro-4-(2-morpholin-4-yl-2-oxoethoxy) phenyl] (4-oxo- (4,5,6,7-tetrahydroindol-3-yl)) carboxamide; -20- - {4-0x0-(4,5,6,7-trihydroindol-3-yl))-N-[4- (2-0ox0-2- piperazinylethoxy) phenyl) carboxamide; N- [3- (diethylamino) propyl] -2-{4-[(4-oxo-(4,5,6,7- tetrahydroindol-3-yl) )carbonylamino) phenoxy}acetamide; N-[3- (diethylamino) propyl) -2-{2-fluoro-4-[(4-oxo-(4,5,6,7- tetrahydroindol-3-yl))carbonylamino)] phenoxy }acetamide;

N- (4- (diethylamino) -1-methylbutyl] -2-{4- [(4-oxo- (4,5,6,7- tetrahydroindol-3-yl)) carbonylamino] phenoxy }acetamide; N- [4- (diethylamino) -1-methylbutyl] -2-{2-fluoro-4- [ (4-oxo- } (4,5,6,7-tetrahydroindol-3-yl) )carbonylamino] phenoxy }acetamide; S N- (2-{[2- (N-methylacetamido) ethyl] amino}pyrid-5-yl) -4-oxo- 4,5,6,7-tetrahydro-1H-indole-3-carboxamide N-(2-ethoxy-4-methylpyrid-5-yl)-4-oxo-4,5,6,7-tetrahydro-1H- indole-3-carboxamide 4-0x0-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid {4- [2- (thiophene-2-sulfonylamino) -ethoxy] -phenyl}-amide; 4-0x0-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (4- f1,2,4])-triazol-1-yl-phenyl) -amide; 4-0x0-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid {4- (3-(1-methyl-1H-imidazole-4-sulfonylamino) -propoxy] -phenyl}- : 15 amide; 4-0x0-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid imidazo[1l,2-a)pyridin-S5-ylamide; or 4-0xo0-3a,4,5,6,7,7a-hexahydro-~1H-indole-3-carboxylic acid [6- (3-propyl-[1,2,4)thidazol-5-ylamino) -pyridin-2-yllamide.

62. A compound according to Claim 1, of the formula: Ry 0 0 at, , Shad N Hn Rs TN Re n ~N H or the pharmaceutically acceptable non-toxic salts thereof wherein: Q is phenyl or 3-pyridyl, each of which may be mono or disubstituted with hydroxy or halogen; 5S W is oxygen or nitrogen; Z is hydrogen, hydroxy, C3;-C; cycloalkyl(C;-C¢ alkoxy), amino, mono- or di(C.-Cs¢ alkyl;)amino, or CC3;-C; azacycloalkyl, -{(C1-C¢ alkyli), -8(0)-2(C1-Cs alkyl), -C(=0) {(C,-Cs alkyl,), -0C(=0) (C1-C¢ alkyl,), -0OC(=0)H, -C(=0)0(C,-Cs alkyl,), -C{(=O)OH, -C(=0)NH(C.-Cs alkyl;), -C(=0)N(C;-C¢ alkyl;)s, -C(=0)NH,, -NHC (=0) (C;-C¢ alkyl;), -NHC(=0)H, -N(C,~Cg alkyl,)C(=0) (C1-Cs alkyl,), -NHS (0) 4-2 (C1-Cs alkyl;), -N(Ci1-C¢ alkyl;)S(0)s-2(C;-Cs alkyl,), -S(0)o- 2NH (C1-Cs alkyl,;), or -S{0);.2(C1-C¢ alkyl )N(C;-Cs alkyl,), wherein C;-Cs alkyl; is independently chosen at each occurrence and is straight, branched, or cyclic, may contain one or two double and/or triple bonds, and is unsubstituted or substituted with one or more substituents selected from: hydroxy, oxo, halogen, —20- - amino, cyano, nitro, and alkoxy, or Z is phenyl or phenyl (C;-Cglalkyl where the phenyl portion is optionally substituted with C;-C¢ alkyl, hydroxy.

Ci-Cg alkoxy, trifluoromethyl, trifluoromethoxy, halogen, amino, or mono- or diC;-C¢ alkylamino, or Z is 2-, 3-, or 4-pyridyl, 1- or 2-imidazolyl, 1-, 2-, or 3- pyrrolyl, or adamantane-2-yl; each of which may be

: substituted on a tertiary carbon or a secondary nitrogen with C;-Cgalkyl, or Z is NR9CORj1p where Rg and Rjg are the same or different and represent hydrogen or C;-C¢ alkyl or C;-C; cycloalkyl, or 2 is connected, optionally through W, to Q to from a 1-6 membered ring; or Z represents a group of the formula: R 2, 3N4, where p is 1, 2, or 3; D and D’ independently represent oxygen, NR, or CHR, provided that only one of D and D’ may be NR, where each R, is hydrogen or C;-C¢ alkyl; or and . R; is hydrogen or C,-Cs alkyl, or 'Z represents a group of the formula: 9); N—R, 24 a where p is 1, 2, or 3; g is 0, 1, or 2; and R; is hydrogen or C;-Cs alkyl; or 2 is a group of the formula: yl Re Oo where s is 0, 1, 2 or 3, and the sum of s and m 1s not less than

Ro is hydroxy, C,-Csalkoxy, amino, mono - or diC;- C¢alkylamino where each alkyl 1s independently optionally substituted with amino, mono- or diG- Csalkylamino, or Ro is a group of the formula io D' 3, where p, D, D’, and R, are as defined above; AN and Ada independently represent a carbon chain optionally substituted with halogen, oxo, cyano, nitro, amino, mono or di(C;-Cg)alkylamino, straight or branched chain C;-C¢ alkyl, C;-C¢ alkenyl, C;-Cq : alkynyl, trifluoromethyl, trifluoromethoxy, or cycloC;-Cs alkyl; wherein k is 0, 1, 2, or 3; ) mis 0, 1, 2, or 3; and A represents a carbon chain optionally substituted with Rg and Rg and n is 0, 1, 2, or 3; R3, Ra, Rs, and Rg are the same or different and are independently selected at each occurrence from hydrogen, C,-Ce¢ alkyl, -COR3j or -CO3Rj3 where Ryj is C:-Céalkyl or C;-C, cycloalkyl; or -CONR]12R13 where R12 and R13 are selected independently from hydrogen, C,-Cs alkyl, Cz-Cy cycloalkyl, phenyl, 2-, 3-, or 4-pyridyl, or NRj3Ri3 forms a heterocyclic group which is worpholinyl, piperidinyl, pyrrolidinyl, or N-alkyl piperazinyl; or R3 and Rg together with the carbon atom to which they are attached form a cyclic moiety having 3-7 carbon atoms; or Rs and Rg together with the carbon atom to which they are attached form a cyclic moiety having 3-7 carbon atoms; and where each alkyl group forming an R3, Rg, Rg, or Rg substituent or portion thereof may be substituted independently with hydroxy or mono- . or dialkylamino where each alkyl is independently C;3-C; alkyl or cycloalkyl having 3- 7 carbon atows.

63. A compound of formula A or formula B: Rs Pp 1 _G Ry © i 6 Rs | \ R | \ Rs N 6 N H H A B or a pharmaceutically acceptable salt thereof wherein R3, R4, Rg, and Rg are the same or different and are selected from hydrogen, alkyl , -CORj11 or -CO2Ri11 where R311 1s alkyl or cycloalkyl having 3-7 carbon atoms; or -CONRj2R13 where R12 and R13 are selected independently from hydrogen, alkyl, cycloalkyl having "3-7 carbon atoms, phenyl, 2-, 3-, or 4-pyridyl, or NR12Ri13 forms a heterocyclic group which is morpholinyl, piperidinyl, pyrrolidinyl, or N-alkyl piperazinyl; or R3 and Rg together with the carbon atom to which they are attached form a cyclic moiety having 3-7 carbon atoms; or Rg and Rg together with the carbon atom to which they are attached form a cyclic moiety having 3-7 carbon atoms; and where each alkyl group forming an R3, R4, Rg, or Rg substituent or portion thereof may be substituted independently with hydroxy or mono- or dialkylamino R 20 where each alkyl is independently alkyl or cycloalkyl having 3-7 carbon atoms.; and G represents R, R, 5 Iga -$ 0 © where

Rn is hydrogen, halogen, C1-Csalkyl, Ci- Cgsalkoxy, or trifluoromethyl; s is 0, 1, 2 or 3, and the sum of s and m is not less than 1; Ro, 1s hydroxy, C;-Cgalkoxy, amino, mono- or diC,-Csalkylamino where each alkyl is independently opticnally substituted with amino, mono- or diC;-Cgalkylamino, or Ro, is a group of the formula LLY 2 p is 1, 2, or 3; D and D’ independently represent oxygen, NRy or CHR, provided that only one of D and D’ may be NR, where each R, is hydrogen or C;-C¢ alkyl; and R; is hydrogen or C,-C¢ alkyl.

64. A compound according to claim 63, wherein R, is hydrogen or halogen, and R, is a group of the formula: Ris Ris JN N—~( Ry7 ™ Rie where Ris is hydrogen or C,-Cgalkyl;

Ris is hydrogen or C;-Ce¢alkyl; Rig is hydrogen, ethyl, or methyl; R;7 1s C;-Cgalkyl; and Jd is a C;-C4 alkylene group. S

65. A compound according to claim 63, wherein s is 1 and Res 1s ethoxy, hydroxy, ethylamino, diethylamino, morpholinyl, piperazinyl, 4-methylpiperazinyl, NN — I Ae — I NM 4N NL N NH \ { SN 4 teh AAAS or H .

66. A compound 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, receptor.

67. A pharmaceutical composition comprising a compound according to Claim 1 combined with at least one pharmaceutically acceptable carrier or excipient.

. !

68. Use of a compound according to claim 1, in the treatment of a disease or disorder associated with pathogenic agonism, inverse agonism or antagonism of the GABA, receptor.

69. Use according to Claim 68 wherein the disease or disorder associated with pathogenic agonism, inverse agonism or antagonism of the GABA, receptor is anxiety, depression, a * sleep disorder, or cognitive impairment.

70. The use of a compound 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, receptor.

71. The use of a compound according to Claim 1 for the ’ manufacture of a medicament for the treatment of anxiety, depression, sleep disorders, cognitive impairment, Alzheimer’s dementia. _20 72. A method for localizing GABA, receptors in a tissue sample comprising contacting with the sample a detectablylabeled compound of claim 1 under conditions that permit binding of the compound to GABA, receptors, washing the sample to remove unbound compound, and detecting the bound compound. ane AMENDED SHEET

73. A method of inhibiting the binding of a benzodiazepine compound to a GABA, receptor, said method comprising contacting a compound of claim 1 with cells expressing such a receptor in S the presence of the benzodiazepine, wherein the compound is present at a concentration sufficient to inhibit the binding a benzodiazepine compound to a GABA, receptor in vitro.

74. A method for altering the signal-transducing activity of GABA. receptors, said method comprising exposing cells expressing such receptors to a compound according to claim 1 at a concentration sufficient to inhibit RO15-1788 binding to cells expressing a cloned human GABA, receptor in vitro. 1s 75. A packaged pharmaceutical composition comprising the pharmaceutical composition of Claim 66 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, receptor. To 76.. The packaged pharmaceutical composition of claim 75, wherein said patient is suffering from anxiety, depression, a sleep disorder, cognitive impairment, or Alzheimer’s dementia. -178- AMENDED SHEET

WO e1/16103 PCT/US06/23862

77. A compound according to claim 1 wherein in a assay of GABA, receptor binding the compound exhibits a K; of 1 micromolar or less. ’ S 78. A compound according to claim 1 wherein in a assay of GABA, receptor binding the compound exhibits an XK; of 100 nanomolar or less.

79. A compound according to claim 1 wherein in a assay of GABA, receptor binding the compound exhibits an Ki of 10 nanomolar or less.

80. A compound of the formula: RR O O 6 Ry Nit Re ; N

[] . X or a Pharmaceutically acceptable salt theract wherein: n is 1 or 2; X is hydrogen, or alkyl; oo R3, Re, Rs, and R¢ are the same or different and are independently selected at each occurrence from hydrogen or alkyl; and -179~ AMENDED SHEET

' G represents phenyl or Pyridyl, each of which ig substituted vith a group $5 KWMZ and optionally with halogen, alkyl, alkoxy, hydroxy, amino, or mono- or dialkylamino; where s K and M independently represent a bond or C,-C alkylene; W represents -0-, -NH-, -NR,- where R7 represents hydrogen or alkyl, or C;-G, alkylene; and Z is hydrogen, hydroxy, cycloalkyl (alkoxy), amino, mono- or di(alkyl;)amino, or azacycloalkyl, “Olalkyls), -8(0)e.a(alkyly), -C(=0) (alkyl), ~OC(=0) (alkyl,), -0C(=0)R, -C(=0)0(alkyl,), ~C(=0)OH, -C(=0)NH(alkyl,), -C(=0)N(alkyl,),, ~C(=0)NH,, -NHC (=0) (alkyl,), -NHC (=O) H, 1s ~N(alkyl;) C(=0) (alkyl,), -NHS (0) o-2 (alkyl,), -N (alkyl) 8 (0),-2 (alkyl;), -8(0) o.2NH (alkyl,), =8(0) ¢-2 (alkyl,) N(alkyl,), wherein each alkyl, ia independently straight, branched, or cyclic, may contain One or two double and/or triple bonds, and is unsubstituted or substituted with one ox more substituents independently selected from hydroxy, oxo, halogen, amino, cyano, nitro, and alkoxy, or Z is -N(Ry)38(0)o-2(Rs) whers -180- AMENDED SHEET each Ry is independently hydrogen or alkyl where . ‘the alkyl is straight, branched, or cyclic, may contain one or two double and/or triple bonds, and is unsubstituted or substituted with one or more substituents independently selected from hydroxy, oxo, halogen, amino, ‘cyano, nitro, and alkoxy, and Re is hydroxy, alkoxy, alkyl where the alkyl is optionally substituted with hydroxy, alkoxy, triflouromethyl, halogen, amino, mono- or di- alkylamino, or Rs is hetercaryl unsubstituted or substituted with alkyl, hydroxy, alkoxy, triflouromethyl, halogen, amino, or mono- or 1s dialkylamino; Z is phenyl or phenylalkyl where the phenyl portion is opticnally substituted with alkyl, hydroxy, alkoxy, triflouromethyl, halogen, amino, or

. mono- or di- alkylamino, or 2 is 2-, 3-, or 4-pyridyl, 1- or 2-imidazolyl, 1-, 2-, or 3-pyrrolyl, azeditinyl, norborn-2-yi, or adamantan-2-yl; each of which may be substituted on a textiary carbon or a secondary nitrogen with C;-Cealkyl, or 28 Z represents a group of the formula: -181- : AMENDED SHEET

: : R, 5 B dk where pis 1, 2, or 3; D and D’ independently represent oxygen, NR, or CHR, provided that only one of D and D’ may be NRy where each R, is hydrogen or alkyl; : and Re is hydrogen or alkyl, or Z represents a group of the formula: La where Pis 1, 2, or 3; and q is 0, 1, or 2; or . Z reprasents a group of the formula: Hyer © where 18 8 i880, 1, 20r 3, and the sum of s and m is not less than 1; Ro is hydroxy, Ci-Cealkoxy, amino, mono- or di- alkylamino where each alkyl is independently optionally substituted with amino, mono- or dialkylamino, or Ro is a group of the formula -182- AMENDED SHEET wf where p, D, D’, and R, are as defined above.

81. A compound according to claim 80, where X ig hydrogen.

82. A compound according to claim 871, where K is a bond and W is oxygen.

83. A compound according to claim 82, wherein M is C; or C; alkylene.

84. A compound according to claim 83, wherein G is phenyl.

85. A compound according to claim 84, wherein 2 is amino, mono- or di(alkyl)amino, or azacycloalkyl, -O(alkyl), ~8(0) o-2 (alkyl), -C(=0) (alkyl), -0C (=Q) (alkyl), -OC(=0)H, -C (=0)O (alkyl) ’ -C(=0)0R, -C(=0) NH (alkyl) PF -C(=0) N(C-C¢ : alkyl,),, -C(=0) NH3, -NHC (=0) (alkyl), -NHC (=Q) RH, -N(alkyl)C(=0) (alkyl), ~NHS (0) 0-3 (adky1) , -183- AMENDED SHEET

WO e1/16163 PCT/USN/23862 ~N(alkyl) 8(0),.5 (alkyl), -8(0)o-;NH (alkyl), + ~8{0)o.2(alkyl)N (alkyl), or 2 is -N(Ry)150; (Rs) where each Ry is independently hydrogen or alkyl, and Rs is hydroxy, alkoxy, or alkyl where the alkyl is optionally substituted with hydroxy, alkoxy, triflouromethyl, halogen, amino, or mono- or di- alkylamino, or Re is phenyl, imidazolyl, pyridyl, pyrimidinyl, Pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl, each of which is optionally substituted with alkyl, hydroxy, alkoxy, triflouromethyl, halogen, amino, or mono~ or dialkylamino. 1s

88. A compound according to claim 81, where K is a bond and W is a bond or methylene.

87. A compound according to claim 86, wherein Mis C; or Cj; alkylens.

88. A compound according to claim 87, wherein G is phenyl.

89. A compound according to claim 88, wherein -184- AMENDED SHEET

Zz is amino, mono- or di(alkyl)amino, or - azacycloalkyl, -O(alkyl), -8(0)o-3 (alkyl), -C(=0) (alkyl), -OC(=0) (alkyl), -0C(=0)H, ~C(=0)O(alkyl), -c(=0)oH, -C(=0)NH (alkyl), ~C(=0)N(C,~C¢ alkyl,),, -C (=O) NH,, -NHC (=0) (alkyl), -NHC(=0)H, -N(alkyl)C(=0) (alkyl), “NHS (0) o.2 (alkyl), -N(alkyl)8(0),-2 (alkyl), -8(0),-aNH (alkyl), -5(0) o-3 (alkyl)N (alkyl), or Z is -N(Ry)280; (Rs) where each Ry is independently hydrogen or alkyl, and Rs is hydrexy, alkoxy, or alkyl where the alkyl is optionally substituted with hydroxy, alkoxy, triflouromethyl, halogen, amino, or mono- or di- alkylamino, or Ry, is phenyl, imidazolyi, Pyridyl, Pyrimidinyl, pyrrolyl, Pyrazolyl, oxazolyl, isoxazolyl, © thiazolyl, or isothiazolyl, each of which is Optionally substituted with alkyl, hydroxy, alkoxy, triflouromethyl, halogen, amino, or mono- or dialkylamino.

90. A compound according to claim 83, wherein G is pyridyl.

81. A compound according to claim 9p, wherein } -185- AMENDED SHEET

Z is amino, mono- or di(alkyl)amino, or . azacycloalkyl, -O(alkyl), -8(0)¢-3(alkyl), -C(=0) (alkyl), -0C(=0) (alkyl), -0C (=O) H, -C(=0)0 (alkyl), -C(=0) OH, -C(=0O)NH(alkyl),

5 . -C(=0)N{C;-C¢ alkyli)s, -C(=0) NH;, -NHC (=0) (alkyl), -NHC(=0)H, -N(alkyl)C(=0) (alkyl), -NHS (0) 0-2 (alkyl), -N (alkyl) 8 (0),-2(alkyl), -8(0)o-aMH (alkyl), -8(0)o.2(alkyl)N(alkyl), or : Z is -N(Ry)380;(Rg) where each Ry is independently hydrogen or alkyl, and Rg is hydroxy, alkoxy, or alkyl where the alkyl is optionally substituted with hydroxy, alkoxy, triflouromethyl, halogen, amino, or mono- or di- alkylamino, or 1s Rs is phenyl, imidazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl, each of which is © optionally substituted with alkyl, hydroxy, alkoxy, triflouromethyl, halogen, amino, or mono- or dialkylamino.

92. A compound according to claim 87, wherein G is pyridyl.

93. A compound according to claim 92, wherein . -186- AMENDED SHEET

4 is amino, mono- or di(alkyl)amino, or

: . azacycloalkyl, -O(alkyl), -8(0)¢-2 (alkyl), -C(=0) (alkyl), -0C (=0) (alkyl), -0C(=0) H, -(=0) 0 (alkyl), -C(=0) OH, -C(=0) NH (alkyl), -C(=0)N(C1-Cs alkyl,),, -C(=0) NH,, -NHC (=0) (alkyl), -NHC (=O) H, -(alkyl)C(=0) (alkyl), -NHS (0) o.3 (alkyl), -N(alkyl)8(0)q.3 (alkyl), ~8(0)o-2NH (alkyl), -8(0),-a (alkyl) N (alkyl), or Z is -N(Ry)3180,(Rs) whare

10 . each Ry is independently hydrogen or alkyl, and Bs is hydroxy, alkoxy, or alkyl where the alkyl is optionally substituted with hydroxy, alkoxy, triflouromethyl, halogen, amino, or mono- or di- alkylamino, or 18 ‘Ris phenyl, imidazolyl, pyridyl, pyrimidinyl, pyrrolyl, Pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, ox isothiazolyl, each of which is optionally substituted with alkyl, hydroxy, alkoxy, triflouromethyl, halogen, amino, or | mono- or dialkylamino.

94. A compound according to any one of claims 1,2,63 or 80 substantially as herein described and exemplified, and described with reference to the accompanying figures.

95. Use according to either one of claims 68,70 or 71 substantially as herein described and exemplified, and/or described with reference to the accompanying figures. ~187- AMENDED SHEET

96. A method according to any one of claims 72,73,74 or 75 substantially as herein described and exemplified, and/or described with reference to the accompanying figures.

97. A packaged pharmaceutical compound according to claim 76 substantially as herein described and exemplified, and/or described with reference to the accompanying figures.

98. A pharmaceutical composition according to claim 67 substantially as herein described and exemplified, and/or described with reference to the accompanying figures. -188- AMENDED SHEET