ZA200206103B

ZA200206103B - Substituted arylpyrazines.

Info

Publication number: ZA200206103B
Application number: ZA200206103A
Authority: ZA
Inventors: Taeyoung Yoon; Ping Ge; Raymond F Horvath; Stephane De Lombaert; Kevin J Hodgetts; Dario Doller; Cunyu Zhang
Original assignee: Neurogen Corp
Priority date: 2000-02-16
Filing date: 2002-07-31
Publication date: 2003-08-20
Also published as: UA75586C2

Description

. SUBSTITUTED ARYLPYRAZINES

This application claims the benefit of U.S. Provisional Application Serial ’ No.60/182,934 filed February 16, 2000 and of U.S. Provisional Application Serial

No.60/206,455 filed May 22, 2000, the teachings of which are incorporated herein by reference. :

FIELD OF THE INVENTION

The present invention relates to novel arylpyrazine compounds that have useful pharmacological properties in that they bind to cellular receptors, including

CREF receptors. Certain of these compounds can bind to and modulate the activity of such receptors. Importantly, the compounds of the invention include compounds that bind with high selectivity and/or high affinity to CRF1 receptors (Corticotropin

Releasing Factor type 1 Receptors). This invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds as pharmaceutical agents, e.g., in treatment of psychiatric disorders and neurological diseases, including major depression, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders, as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress. Additionally this invention relates to the use such compounds as probes for the localization of cellular receptors in tissue sections.

BACKGROUND OF THE INVENTION

Corticotropin releasing factor (CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin (POMC) derived peptide secretion from the anterior pituitary gland. In addition to its endocrine role at the pituitary ’ gland, immunohistochemical localization of CRF has demonstrated that the hormone . 30 has abroad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain. There is also evidence that a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors. ‘ Clinical data provide evidence that CRF has a role in psychiatric disorders and . 5 neurological diseases including depression, anxiety-related disorders and feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of

CRF neurons in the central nervous system.

In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals.

Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression. There is also preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain.

CRF has also been implicated in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine / non- benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models. Preliminary studies using the putative CRF receptor antagonist -helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces "anxiolytic-like" effects that are qualitatively similar to the benzodiazepines.

Neurochemical, endocrine and receptor binding studies have all demonstrated interactions } between CRF and benzodiazepine anxiolytics providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the "anxiogenic"

effects of CRF in both the conflict test and in the acoustic startle test in rats. The benzodiazepine receptor antagonist Ro 15-1788, which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent ’ manner, while the benzodiazepine inverse agonist FG 7142 enhanced the actions of CRF. . 5

CREF has also been implicated in the pathogeneisis of certain immunological, cardiovascular or heart-related diseases such as hypertension, tachycardia and congestive heart failure, stroke and osteoporosis, as well as in premature birth, psychosocial dwarfism, stress-induced fever, ulcer, diarrhea, post-operative ileus and colonic hypersensitivity associated with psychopathological disturbance and stress.

The mechanisms and sites of action through which conventional anxiolytics and antidepressants produce their therapeutic effects remain to be fully elucidated. It has been hypothesized however, that they are involved in the suppression of CRF hypersecretion that is observed in these disorders. Of particular interest are that preliminary studies examining the effects of a CRF receptor antagonist peptide (o-helical

CRF, in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces "anxiolytic-like" effects qualitatively similar to the benzodiazepines.

Certain small molecule compounds for the treatment of CRF related disorders have been disclosed in the literature [for a review see J. McCarthy et al. Curr. Pharm.

Des. 5: 289 (1999)]. However, none of these compounds has an arylpyrazine structure.

Cox et al. (WO 98/38174) have disclosed certain aryl pyrazine derivatives for use as sodium channel blockers in the treatment of central nervous system disorders. The

Cox application requires that the arylpyrazine compounds be substituted with two-amino or amido groups. .

SUMMARY OF THE INVENTION

We have now discovered novel arylpyrazine compounds, including arylpyrazines that can bind with high affinity and high selectivity to CRF, receptors, including human

CRF, receptors. The invention thus includes methods for treatment of disorders and . 5 diseases associated with CRF, receptors, including CNS-related disorders and diseases, particularly affective disorders and diseases, and acute and chronic neurological disorders and diseases.

Arylpyrazine compounds of the invention are preferably substituted at the 2-ring position by a carbocyclic aryl group such as phenyl, naphthyl and the like, or a : heteroaromatic group, particularly a heteroaromatic having a nitrogen ring member such as pyridyl, pyrimidinyl and the like. Arylpyrazine compounds of the invention also are preferably substituted at the 5-ring position (para with respect to the aryl substituent) by a non-hydrogen substituent, particularly a non-aromatic group such as alkyl, alkenyl, alkynyl, heteroalkyl and the like, preferably aminoalkyl and alkoxy. Preferably the 3-ring position of pyrazine compounds of the invention is unsubstituted (i.e. hydrogen) or substituted by other than amino (-NH,) or alkylamide (-NHC(=O)alkyl, particularly -

NHC(=0)C, alkyl or -NHC(=0)C, ,cycloalkyl), and/or the 5-ring position of pyrazine compounds of the invention are other than hydrogen, alkyl, aminoalkyl or a nitrogen- containing heteroalicyclic compound.

Typically preferred compounds of the invention include those of the following

Formula I:

BOY

Ri 7 Ar I wherein:

Ar is substituted phenyl, optionally substituted napthyl, or an optionally substituted heterocyclic group having from 1 to 3 rings, and 3 to 8 ring members in each ring and . 1 to about 3 hetero atoms;

R, and R, are each independently hydrogen, halogen, cyano, nitro, amino, optionally ’ 5 substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted mono or dialkylamino, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted alkylsulfinyl, or optionally substituted alkylsulfonyl; and

R, is halogen, cyano, nitro, amino, optionally substituted alkyl, optionally substituted 10 alkenyl, optionally substituted alkynyl, optionally substituted alkylamino, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted alkylsulfinyl, or optionally substituted alkylsulfonyl; with the proviso that if Ar is phenyl substituted with halogen, napthyl, or naphthyl substituted with halogen, then the compounds where R, is hydrogen or amino are 15 excluded.

Preferred compounds of the invention also include those of the following Formula

IA:

TX

Ri NT Ar 20 3

Formula IA or a pharmaceutically acceptable salt thereof, wherein:

R, is selected from H, C,, alkyl, C,, alkenyl, C,, alkynyl, halogen, CN, C, , haloalkyl, trifluoromethyl, trifluoromethoxy, -NH(C,, alkyl), -N(C,, alkyl)(C,, alkyl), - 25 O(C,, alkyl), and S(0),(C,, alkyl);

R, is selected from the group consisting of —XR, and Y, wherein -X, R,, and Y are defined below; and

R, is selected from the group consisting of hydrogen, halogen, C, , alkyl, -O(C,, alkyl), -

NH(C,, alkyl), -N(C,, alkyl)C,, alkyl), and -S(O),(C,, alkyl), haloalkyl, i trifluoromethyl, trifluoromethoxy, -XR, and Y;

R, is absent or an oxygen atom; - 5 Aris phenyl, mono-, di-, or tri-substituted with R, or

Ar is selected from the group consisting of: naphthyl, pyridyl, pyridonyl, pyrimidinyl, and thiophenyl, each of which is unsubstituted or mono-, di-, or tri-substituted with R; with the proviso that if Ar is phenyl substituted with halogen, napthyl, or naphthyl substituted with halogen, then the compounds where R, is hydrogen are excluded;

R, and Rg, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen and straight, branched, or cyclic alkyl groups consisting of 1 to 8 carbon atoms, which may contain one or more double or triple bonds, each of which may be further substituted with one or more substituent(s) selected from oxo, hydroxy, halogen, -O(C, , alkyl), -NH(C, , alkyl), -N(C,,, alkyl)(C,, alkyl), -NHC(OXC,, alkyl), -N(C,, alkyl)C(=O0)(C,., alkyl), -NHS(0),(C, , alkyl), -S(0),(C,., alkyl), -S(0),NH(C, alkyl), -S(0),N(C,., alkyl)(C,_, alkyl), and Z,

R.. is independently selected at each occurrence from the group consisting of halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy, hydroxy, amino, and C4 alkyl optionally substituted with 0-2 R;,, C, ; alkenyl substituted with 0-2 Ry, C,, alkynyl substituted with 0-2 R;,, C,; cycloalkyl substituted with 0-2 R;, (C,, cycloalkyl)C,-, alkyl substituted with 0-2 Rp, -O(C,, alkyl) substituted with 0-2

Rp, -NH(C,, alkyl) substituted with 0-2 R,, -N(C,, alkyl)}C,, alkyl) each independently substituted with 0-2 Ry, -XR,, and Y;

R,, is independently selected at each occurrence the group consisting of halogen, hydroxy, cyano, Cualkyl, -O(C, alkyl), -NH(C, alkyl), -N(C, ,alkyl)(C, alkyl), morpholino, pyrrolidino, piperidino, thiomorpholino, piperazino, 4- hydroxypiperidino, -S(0),(C, alkyl), trifluoromethyl, trifluoromethoxy, CO(C,. salkyl), CONH(C alkyl), CON(C,_alkyl)(C, alkyl), -XR, and Y;

X is independently selected at each occurrence from the group consisting of -CH,-, -

CHRg-, -O-, -C(=0)-, -C(=0)0-, -S(0),-, -NH-, -NR}-, -C(=0)NH-, -C(=O)NR-, -S(0),NH-, -S(0),NR;-, -OC(=S)S-, -NHC(=0)-, -NR;C(=0)-, -NHS(O),-, -

OSiH, (C, alkyl), -, and -NR;S(O),-; and . 5 Y and Z are independently selected at each occurrence from the group consisting of: 3- to 7-membered carbocyclic and heterocyclic groups, which are saturated, unsaturated, or aromatic, which may be substituted with one or more substituents selected from halogen, haloalkyl, oxo, hydroxy, amino, C,, alkyl, -O(C, alkyl), -

NH(C,, alkyl), -N(C,, alkyl)(C,, alkyl), and -S(O),(C,, alkyl), and said 3- to 7-membered heterocyclic groups contain one or more heteroatom(s) selected from N, O, and S, with the point of attachment being either carbon or nitrogen; and n is independently selected at each occurrence from 0, 1, and 2.

Particularly preferred arylpyrazines of the invention include compounds of the following Formula IB:

TX

Ri NZ Ar IB wherein:

Aris selected from the group consisting of phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2-, 4-, or 5-pyrimidinyl, each Ar optionally substituted with 1 to 5 with R, group, with the proviso that at least one of the positions ortho or para to the point of attachment of

Ar to the pyrazine ring system is substituted;

R, is selected from H, C, , alkyl, C,, alkenyl, C,, alkynyl, (C, cycloalkyl)C, , alkyl, halogen, CN, C,_, haloalkyl, -NH(C, , alkyl), -N(C,, alkyl)(C,, alkyl), -O(C,, alkyl), and -S(0),(C,., alkyl), wherein b is 0, 1, or 2; i R, is selected from the group consisting of —XR, and Y, wherein X, R,, and Y are as defined below;

CHR;-, -O-, -S(0),-, -NH-, -NR,-, -C(=O)NH-, -C(=0)NR;-, -S(O),NH-, -S(O),NR;-, -NHC(=0)-, -NR;C(=0)-, -NHS(0),-, and -NR;S(0O),- (where n is 0, 1, or 2); ] 5 Y and Z are independently selected at each occurrence from the group consisting of: 3- to 7-membered heterocycles, saturated or unsaturated, containing one or more heteroatom(s) selected from N, O, and S, with the point of attachment being either carbon or nitrogen (where applicable), and which may be further substituted with one or more substituents selected from halogen, oxo, hydroxy, amino, C,, alkyl, -O(C, , alkyl), -NH(C,, alkyl), -N(C, , alkyl)}(C,_, alkyl), and -S(0),(C, alkyl) (wherein a is 0, 1, or 2);

R, is selected from the group consisting of hydrogen, halogen,

C,. alkyl, -O(C,_, alkyl), -NH(C,, alkyl), -N(C, , alkyl)(C, alkyl), and -S(0).(C,, alkyl) (wherein c is 0, 1, or 2), trifluoromethyl, trifluoromethoxy, —XR,, and Y, where —X, R,, and Y are as defined above.

R, and R;, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen, straight, branched, or cyclic alkyl groups consisting of 1 to 8 carbon atoms, which may contain one or more double or triple bonds, each of which may optionally be further substituted with one or more substituent(s) selected from oxo, hydroxy, -

O(C,, alkyl), -NH(C, , alkyl), -N(C,, alkyl)(C,, alkyl), -NHC(O)(C,_, alkyl), -N(C, , alkyl)C(O)(C,, alkyl), -NHS(0),,(C,,, alkyl), -S(0),.(C, , alkyl), -S(0),,NH(C, , alkyl), -S(0O),N(C,, alkyl)(C,, alkyl), (where m is 0, 1, or 2), and Z, wherein Z is as defined above;

R, is independently selected at each occurrence from halogen, trifluoromethyl, trifluoromethoxy, hydroxy, amino, and C,-C; alkyl (optionally substituted with 0-2 ) R,, C,, alkenyl substituted with 0-2 R,, C,, alkynyl substituted with 0-2 R,, C, cycloalkyl substituted with 0-2 R,, (C, cycloalkyl)C,-, alkyl substituted with 0-2 R,,

O(C,, alkyl) substituted with 0-2 R,, -NH(C,, alkyl) substituted with 0-2 R,, -N(C,_,

alkyl)(C,, alkyl) each independently substituted with 0-2 R,, -XR,, cyano, and Y; and

R, is independently selected at each occurrence the group consisting of halogen, C, , alkyl, -O(C, alkyl), -NH(C,_, alkyl), -N(C, , alkyl)(C,_, alkyl), morpholino, ’ 5 pyrrolidino, piperidino, thiomorpholino, piperazino, 4-hydroxypiperidino, -S(0),(C 4 alkyl), trifluoromethyl, trifluoromethoxy, CO(C, alkyl), CONH(C,_, alkyl), CON(C,, alkyl)(C,, alkyl), -XR, and Y, wherein X, R, and Y are defined as above and pis 0, 1 or 2; and pharmaceutically acceptable salts thereof; and preferably if Ar is phenyl substituted with halogen, naphthyl, or naphthyl substituted with halogen, then the exclusion of compounds where 1) R; being hydrogen, amino (-NH,) or alkylamide particularly -NHC(=0)C alkyl or -

NHC(=0)C,_,cycloalkyl, and/or 2) R, being hydrogen, alkylamide particularly -NHC(=0)C, ,alkyl or -NHC(=0)C, .cycloalkyl, amino substituted by one or two alkyl particularly C,, alkyl, or a nitrogen-containing 6-membered ring.

In the above Formulae I, IA, and IB, as well as below-specified Formulae Ia through Ie, 11, ITa through Ili, III, II1a through le and IV, preferred Ar groups include 2,4- dichlorophenyl, 2,4-dimethoxyphenyl, 4-methoxy-2-methylphenyl, 2,4,6- trimethylphenyl, 4-methoxy-2,6-dimethylphenyl, 4-cyano-2,6-dimethylphenyl, 2- methoxy-4,6-dimethylphenyl, 2-methoxy-4,6-bis(trifluoromethyl)phenyl, 2,6- dichloro-4-methoxyphenyl, 2-(2-(1-morpholino)ethoxy)-4,6-dimethylphenyl, 2- (2-(4-hydroxy-1-piperidino)ethoxy)-4,6-dimethylphenyl, 2-methyl-4- (dimethylamino)-3-pyridyl, and 2-chloro-4-dimethylamino-3-pyridyl, 2-methoxy- 4,6-dimethyl-3-pyridyl. . In the above Formulae I, IA, and IB, as well as below-specified Formulae Ia through Ie, II, IIa through IIi, ITI, IIIa through Ile and IV, preferred R, groups include . methyl, ethyl, chloro, bromo, iodo, trifluoromethyl, methoxy, dimethylamino, and thiomethoxy. :

In the above Formulae I, IA, and IB, as well as below-specified Formulae Ia ] through Ie, II, ITa through Ili, III, Illa through IIIe and IV, preferred R, groups include dipropylamino, bis(2-methoxyethyl)amino, 4-methyl-1-piperazino, 3-pentylamino, 4- heptylamino, 1,3-dimethoxy-2-propylamino, 1-(dimethylamino)-2-pentylamino, 1-(3- pyridyl)-2-butylamino, (2-methoxy-5-pyridine)amino, 3-pentyloxy, 4-heptyloxy, 1- methoxy-2-butyloxy, and 1,3-dimethoxy-2-propyloxy.

In the above Formulae I, IA, and IB, as well as below-specified Formulae Ia through Ie, II, IIa through IIi, III, la through Nle and IV, preferred R, groups include methyl, ethyl, chloro, trifluoromethyl, methoxy, dimethylamino, thiomethoxy, methanesulfonyl, (1-morpholino)methyl, 2-(1-pyrrolidino)ethyl, and (2-methoxy)ethoxy.

Preferred arylpyrazines of the invention exhibit good activity in a standard in vitro CRF receptor binding assays, specifically the assay as specified in Example 96 which follows. Particularly preferred arylpyrazines of the invention have an IC, in such a defined standard in vitro CRF receptor binding assay of about 1.5 micromolar or less, still more preferably an IC, of about 100 nanomolar or less, or even more preferably an

IC, of about 10 nanomolar or less or even 1 nanomolar or less in a such a defined standard in vitro CRF receptor binding assay.

Preferred arylpyrazines of the invention do not show activity in a standard in vitro

Na channel functional assay, specifically the assay as specified in Example 99 which follows. Particularly preferred arylpyrazines of the invention do not show any statistically significant activity in a defined standard in vitro Na channel functional assay 0 at the p < 0.05 level of significance.

The invention further comprises methods of treating patients suffering from or susceptible to (i.e. prophylactic treatment) certain disorders or diseases with an effective amount of a compound of the invention. The patient may be a human or other mammal oo 10 such as other primates. Treatment of humans, domesticated companion animals (pet) or livestock animals suffering from certain with an effective amount of a compound of the invention is encompassed by the invention. ] 5 Additionally this invention relates to the use of the CRF1 compounds of the invention as probes for the localization of receptors in tissue sections.

The compounds of the present invention are useful for the treatment of CNS disorders particularly affective disorders, anxiety disorders, stress-related disorders, eating disorders and substance abuse. Affective disorders include all types of depression, bipolar disorder, cyclothymia, and dysthymia. Anxiety disorders include generalized anxiety disorder, panic, phobias and obsessive-compulsive disorder. Stress-related disorders include post-traumatic stress disorder, hemorrhagic stress, stress-induced psychotic episodes, psychosocial dwarfism, stress headaches, stress-induced immune systems disorders such as stress-induced fever, and stress-related sleep disorders. Eating disorders include anorexia nervosa, bulimia nervosa, and obesity. These conditions are herein after referred to as the primary CRF-related CNS disorders.

Arylpyrazine compounds of the invention (which includes compounds of the

Formulae I, IA, and IB, as well as below-specified Formulae Ia through Ie, II, ITa through

Ili, II0, IIa through Ile and IV,) are also useful in the treatment of a variety of neurological disorders including supranuclear palsy, AIDS related dementias, multiinfarct dementia, neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, head trauma, spinal cord trauma, ischemic neuronal damage, amyotrophic lateral sclerosis, disorders of pain perception such as fibromyalgia and epilepsy. These conditions are hereinafter referred to as the secondary CRF-related CNS disorders.

Arylpyrazine compounds of the invention are useful as modulators of the G- protein coupled receptor function.

Additionally, arylpyrazine compounds of the invention are useful as modulators of the CRF receptor in the treatment of a number of gastrointestestinal, cardiovascular, hormonal, autoimmune and inflammatory conditions. Such conditions include irritable . 5 bowel syndrome, ulcers, Crohn's disease, spastic colon, diarrhea, post operative ilius and colonic hypersensitivity associated with psychopathological disturbances or stress, hypertension, tachycardia, congestive heart failure, infertility, euthyroid sick syndrome, inflammatory conditions effected by rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies. These conditions are referred to hereinafter as the non-CNS CRF- related disorders.

Arylpyrazine compounds of the invention are also useful as modulators of the

CREF, receptor in the treatment of animal conditions associated with aberrant CRF levels.

These conditions include porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation, and dysfunctions induced by confinement in chickens, sheering stress in sheep or human-animal interaction related stress in dogs, psychosocial dwarfism and hypoglycemia. These animal conditions are referred to hereinafter as the CRF- related animal disorders.

According to yet another aspect, the present invention provides pharmaceutical compositions comprising one or more aryl pyrazine compound of the invention of a pharmaceutically acceptable salt thereof, particularly for use in the treatment of any of the primary CNS disorders, secondary CNS disorders, non-CNS CRF-related disorders, or

CRF-related animal disorders.

According to a still further aspect of the invention, arylpyrazine compounds of the invention (and especially labeled compounds of this invention) are useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the CRF : receptor.

Other aspects of the invention are disclosed infra.

DETAILED DESCRIPTION OF THE INVENTION :

The invention provides compounds of Formula I shown above. Preferred } 5 compound of the invention include those of the following Formula Ia:

Ra 1 N 1

Ry NT Ar

L Ia or a pharmaceutically acceptable salt thereof, wherein:

R, is selected from H, C,, alkyl, C,, alkenyl, C,, alkynyl, halogen, CN, C,_, haloalkyl, trifluoromethyl, trifluoromethoxy, -NH(C, , alkyl), -N(C,,, alkyl)(C,, alkyl), -

O(C,, alkyl), and S(0O),(C,, alkyl);

R, is selected from the group consisting of — XR, and Y, wherein —X, R,, and Y are defined below; and

R, is selected from the group consisting of hydrogen, halogen, C, , alkyl, -O(C, , alkyl), -

NH(C,, alkyl), -N(C, , alkyl)(C,,, alkyl), and -S(0),(C,., alkyl), haloalkyl, trifluoromethyl, trifluoromethoxy, —XR, and Y;

R, is absent or an oxygen atom;

Ar is phenyl, mono-, di-, or tri-substituted with R, or

Ar is selected from the group consisting of: naphthyl, pyridyl, pyridonyl, pyrimidinyl, and thiophenyl, each of which is unsubstituted or mono-, di-, or tri-substituted with R.; with the proviso that if Ar is phenyl substituted with halogen, napthyl, or naphthyl substituted with halogen, then the compounds where R, is hydrogen are excluded;

R, and Rp, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen and straight, branched, or cyclic alkyl groups consisting of 1 to 8 carbon atoms, which may contain one or more double or triple bonds, each of which may be further substituted with one or more substituent(s) selected from oxo, hydroxy, halogen, -O(C,, alkyl), -NH(C, ,

alkyl), -N(C,, alkyI)(C, , alkyl), -NHC(O)(C,, alkyl), -N(C, , alkyDC(=0)(C., alkyl), -NHS(0),(C, alkyl), -S(0),(C,, alkyl), -S(0),NH(C, , alkyl), -S(O}.N(C, , alky!)(C,, alkyl), and Z,

R. is independently selected at each occurrence from the group consisting of halogen, : 5 cyano, haloalkyl, trifluoromethyl, trifluoromethoxy, hydroxy, amino, and C4 alkyl optionally substituted with 0-2 R,,, C, 4 alkenyl substituted with 0-2 R,, C,, alkynyl substituted with 0-2 R;,, C, , cycloalkyl substituted with 0-2 R,,, (C,, cycloalkyl)C,-, alkyl substituted with 0-2 R,, -O(C,, alkyl) substituted with 0-2

Ry, -NH(C,, alkyl) substituted with 0-2 Ry, -N(C, , alky])(C, , alkyl) each independently substituted with 0-2 R,, -XR,,, and Y;

R;, is independently selected at each occurrence the group consisting of halogen, hydroxy, cyano, Cl alkyl, -O(C, alkyl), -NH(C, alkyl), -N(C,_,alkyl)(C, alkyl), morpholino, pyrrolidine, piperidino, thiomorpholino, piperazino, 4- hydroxypiperidino, -S(0),(C, alkyl), trifluoromethyl, trifluoromethoxy, CO(C,. salkyl), CONH(C, _jalkyl), CON(C,_alkyl)(C,_ alkyl), -XR, and Y;

CHRj-, -O-, -C(=0)-, -C(=0)0O-, -S(0),-, -NH-, -NR;-, -C(=O)NH-, -C(=O)NR;-, -S(0),NH-, -8(0),NR;-, -OC(=5)S-, -NHC(=0)-, -NR;C(=0)-, -NHS(O),-, -

OSiH,(C, alkyl), ,-, and -NRzS(O),-; and Y and Z are independently selected at each occurrence from the group consisting of: 3-to 7-membered carbocyclic and heterocyclic groups, which are saturated, unsaturated, or aromatic, which may be substituted with one or more substituents selected from halogen, haloalkyl, oxo, hydroxy, amino, C,, alkyl, -O(C, , alkyl), -

NH(C,, alkyl), -N(C,, alkyl)(C,_, alkyl), and -S(O),(C,, alkyl), and said 3- to 7-membered heterocyclic groups contain one or more heteroatom(s) selected from N, O, and S, with the point of attachment being either carbon or nitrogen; and n is independently selected at each occurrence from 0, 1, and 2.

Preferred compounds of general Formula Ia are those where:

R, is absent and Ar is phenyl, mono-, di-, or tri-substituted with R., and R, and R; are independently selected from the group consisting of hydrogen, halogen, methyl, ethyl, ethoxy and methoxy.

Such compounds are referred to herein as compounds of general Formula Ib. : 5

More preferred compounds of the invention are those of general Formula Ia where:

R, is absent and Ar is phenyl, mono-, di-, or tri-substituted with R; and R, and Rg, which may be the same or different, are independently straight, branched, or cyclic alkyl groups having from 1 to 8 carbon atoms, which may contain one or more double or triple bonds.

Such compounds are referred to as compounds of Formula Ic.

Particularly preferred are compounds of general Formula Ia are those where:

R, is absent and Ar is phenyl mono-, di-, or tri-substituted with R; R, and Ry, which may be the same or different, are independently selected at each occurrence from the group consisting of: straight, branched, and cyclic alkyl groups having from 1 to 8 carbon atoms, which may contain one or more double or triple bonds; and

R, and R, are independently selected from the group consisting of hydrogen, halogen, methyl, ethyl, ethoxy, and methoxy.

Such compounds are referred to herein as compounds of general Formula Id.

Particularly preferred are compounds of general Formula Ia are those where: - (A "NS Ry . pee wherein A is NR, or O.

Such compounds are referred to herein as compounds of general Formula Ie.

Even more preferred compounds of the invention are those of general Formula II:

Rx

Ry NZ Ar

Formula wherein

Ry and R, are the same or different and are independently selected straight, branched, or cyclic alkyl groups having from 1 to 8 carbon atoms, which may contain one or more double or triple bonds, each of which may be further substituted with one or more substituent(s) independently selected from hydroxy, halogen, -O(C,, alkyl), -NH(C,, alkyl), -N(C,, alkyl)(C,_, alkyl), and optionally substituted phenyl.

Other preferred compounds of the invention include those of general Formula 11 (above) and pharmaceutically acceptable salts thereof, wherein:

Ar is phenyl, mono-, di-, or tri-substituted with R.; and R, and R, are independently selected from the group consisting of hydrogen, halogen, methyl, ethyl, ethoxy and methoxy.

Such compounds are referred to herein as compounds of general Formula Ila.

Other preferred compounds of the invention include those of general Formula II (above) and pharmaceutically acceptable salts thereof, wherein:

R, and R; are independently chosen from halogen, C,, alkyl, -O(C,, alkyl), -NH(C,,, alkyl), -N(C,, alkyl)}(C,, alkyl), haloalkyl, trifluoromethyl, and trifluoromethoxy; and

Ar is phenyl, which is mono-, di-, or trisubstituted with one or more substituent(s) independently selected from:

halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy, hydroxy, amino, and C4 alkyl, C, alkoxy, C,alkoxy(C, alkoxy), mono- or di(C,,)amino(C,. qsalkoxy), and mono- or di(C,_, alkyl)amino.

Such compounds are referred to herein as compounds of general Formula IIb. : 5

Ry is hydrogen;

Ry is chosen from the group consisting of: straight, branched, or cyclic alkyl groups having from 1 to 8 carbon atoms, which may contain one or more double or triple bonds;

R, and R; are independently chosen from halogen, C,, alkyl, -O(C,, alkyl), -NH(C,, alkyl), -N(C,, alkyl)(C,, alkyl), haloalkyl, trifluoromethyl, and trifluoromethoxy; and

Ar is phenyl, which is mono-, di-, or trisubstituted with substituent(s) independently selected from: halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy, hydroxy, amino, and C,, alkyl, C alkoxy, C alkoxy(C, alkoxy), mono- or di(C, )amino(C,. .alkoxy), and mono- or di(C, , alkyl)amino.

Such compounds are referred to herein as compounds of general Formula Ilc.

Ry is hydrogen;

R, and R; are independently chosen from halogen, C,, alkyl, -O(C,, alkyl), -NH(C,, i alkyl), -N(C,, alkyl)C,, alkyl), haloalkyl, trifluoromethyl, and trifluoromethoxy; and

Ar is a phenyl group of the formula: 0D 6 wherein L indicates a bond to the pyrazine ring in Formula A; and the phenyl group is substituted at one, two or three of positions 2, 4, and 6 with substituent(s) independently selected from: halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy, hydroxy, amino, and C,, alkyl, C, alkoxy, C,_alkoxy(C, alkoxy), mono- or di(C,_)amino(C,. salkoxy), and mono- or di(C, , alkyl)amino.

Such compounds are referred to herein as compounds of general Formula IId.

Ry is hydrogen;

R, is chosen from the group consisting of: straight, branched, or cyclic alkyl groups having from 1 to 8 carbon atoms, which may contain one or more double or triple bonds;

R, and R, are independently chosen from halogen, C,, alkyl, -O(C,, alkyl), -NH(C, alkyl), -N(C,, alkyl)(C,, alkyl), haloalkyl, trifluoromethyl, and trifluoromethoxy; and

Aris a phenyl group of the formula: 2 0 : wherein L indicates a bond to the pyrazine ring in Formula A; and the pheny! group is substituted at positions 2 and 4 with substituents independently selected from:

halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy, hydroxy, amino, and C,, alkyl, C, alkoxy, C,,alkoxy(C,, alkoxy), mono- or di(C,,)amino(C,. 4alkoxy), and mono- or di(C,_, alkyl)amino.

Such compounds are referred to herein as compounds of general Formula Ile. } 5

Ry Ne Ar wherein:

R, and R, are independently chosen at each occurrence from halogen, C,, alkyl, -O(C,, alkyl), -NH(C,, alkyl), -N(C, , alkyD)(C,, alkyl), haloalkyl, trifluoromethyl, and trifluoromethoxy; and

Ar is a phenyl group of the formula: 2 0 \ wherein L indicates a bond to the pyrazine ring in Formula A; and the phenyl group is substituted at one, two or three of positions 2, 4, and 6 with substituent(s) independently selected from: halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy, hydroxy, amino, and C,, alkyl, C, alkoxy, C,,alkoxy(C,_ alkoxy), mono- or di(C,)amino(C,. 20 .alkoxy), and mono- or di(C, , alkyl)amino.

Such compounds are referred to herein as compounds of general Formula IIf.

[TY

N “J : pe )® wo ye

R R wherein

R is independently selected at each occurrence from the oroup consisting of: hydrogen, halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy, hydroxy, amino, C,. salkyl, C, jalkoxy, C,,alkoxy(C, alkoxy), mono- or di(C,,)amino(C, alkoxy), and mono- or di(C, , alkyl)amino; and

R, and R, are independently chosen from halogen, C,, alkyl, -O(C,_, alkyl), -NH(C,, alkyl), -N(C,, alkyl)(C,, alkyl), haloalkyl, trifluoromethyl, and trifluoromethoxy.

Such compounds are referred to herein as compounds of general Formula Ig.

Ar is phenyl, which is mono-, di-, or tri-substituted with R;

Ry and Ry, which may be the same or different, are independently selected at each occurrence from the group consisting of: straight, branched, and cyclic alkyl groups having from 1 to 8 carbon atoms, which may contain one or more double or triple bonds; and

Such compounds are referred to herein as compounds of general Formula ITh.

ih

N N R

I 1 ) =

Ry N Ar . wherein Ry and R, are independently hydrogen or C, ; alkyl; or

NRyRy is:

VEEN

IN a (CHa) whereinzisOor 1.

Such compounds are referred to herein as compounds of general Formula IIi.

Other highly preferred compounds are those of general Formula III:

Rx

N Rs

I T

FZ

Ry N Ar III wherein:

Ry is chosen from the group consisting of: straight, branched, or cyclic alkyl groups, including (cycloalkyl)alkyl groups, having from 1 to 8 carbon atoms, which may contain one or more double or triple bonds, each of which may be further substituted with one or more substituent(s) independently selected from (a) hydroxy, halogen, -O(C,, alkyl), -NH(C,, alkyl), -N(C,, alkyl)(C,,, alkyl), and : 20 (b) 3- to 7-membered carbocyclic and heterocyclic groups, which are saturated, unsaturated, or aromatic, which may be substituted with one or more substituents selected from halogen, haloalkyl, oxo, hydroxy, amino,

C4 alkyl, -O(C, , alkyl), -NH(C,, alkyl), and -N(C, , alkyl)(C,, alkyl)and wherein said 3- to 7-membered heterocyclic groups contain one or more " heteroatom(s) selected from N, O, and S, with the point of attachment being either carbon or nitrogen. - 5

Other preferred compounds of the invention include those of general Formula III (above) and pharmaceutically acceptable salts thereof, wherein:

R, is selected from straight, branched, or cyclic alkyl groups containing of 1 to 8 carbon atoms, which may contain one or more double or triple bonds; and;

Ar is phenyl, which is mono-, di-, or trisubstituted with one or more substituent(s) independently selected from: halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy, hydroxy, amino, and C, alkyl, C alkoxy, C,_,alkoxy(C, alkoxy), mono- or di(C,,)amino(C,. q.alkoxy), and mono- or di(C,, alkyl)amino.

Such compounds are referred to herein as compounds of general Formula Ila.

Ar is a phenyl group of the formula: 2

Or 6 wherein L indicates a bond to the pyrazine ring in Formula III; and the phenyl group is substituted at one, two, or three of positions 2, 4, and 6 with substituent(s)independently selected from:

halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy, hydroxy, amino, and C, alkyl, C, alkoxy, C, alkoxy(C,_ alkoxy), mono- or di(C,_)amino(C,. alkoxy), and mono- or di(C,_, alkyl)amino.

Such compounds are referred to herein as compounds of general Formula IIIb. : 5 .

Ar is a phenyl group of the formula: 2 — wherein L indicates a bond to the pyrazine ring in Formula III; and the phenyl group is substituted at positions 2 and 4 with substitutuents independently selected from halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy, hydroxy, amino, C, alkyl, C, alkoxy, C,_alkoxy(C, alkoxy), mono- or di(C,. »amino(C, alkoxy), and mono- or di(C,, alkyl)amino.

Such compounds are referred to herein as compounds of general Formula IIIc.

Ri WZ Ar IIc

R, and R, are independently chosen from halogen, C,, alkyl, -O(C,, alkyl), -NH(C,, alkyl), -N(C,, alkyl)(C,, alkyl), haloalkyl, trifluoromethyl, and trifluoromethoxy; and

Ar is a phenyl group of the formula:

> wherein L indicates a bond to the pyrazine ring in Formula B; . and the phenyl group is substituted at one, two, or three of positions 2, 4, and 6 with substituent(s)independently selected from: halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy, hydroxy, amino, C,, alkyl, C, alkoxy, C,. [alkoxy(C, alkoxy), mono- or di(C,,)amino(C, alkoxy), and mono- or di(C,, alkyl)amino.

Such compounds are referred to herein as compounds of general Formula IIId.

Other preferred compounds of the invention include those of general Formula HI (above) and pharmaceutically acceptable salts thereof, wherein:

R, and R, are independently selected from the group consisting of hydrogen, halogen, methyl, ethyl, ethoxy and methoxy.

Such compounds are referred to herein as compounds of general Formula Ile.

Another preferred compound of the invention include 2-(2-methoxy-5- triflurormethoxyphenyl)-3-ethyl-6-methylamino-5-(1-ethylpropoxy)-pyrazine. and pharmaceutically acceptable salts thereof, the compound structure is: ne Oscr, ! Oo : DEFINITIONS

The compounds herein described may have one or more asymmetric centers or planes. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms (racemates), by . asymmetric synthesis, or by synthesis from optically active starting materials. Resolution of the racemates can be accomplished, for example, by conventional methods such as : 5 crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable : isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral (enantiomeric and diastereomeric), and racemic forms, as well as all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.

The CRF antagonist compounds provided by this invention and labeled denivatives thereof are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the CRF receptor.

Labeled derivatives the CRF antagonist compounds provided by this invention are also useful as radiotracers for positron emission tomography (PET) imaging or for single photon emission computerized tomography (SPECT).

The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., =0), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers, By way : of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include 'C, *C, and “C.

When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R’, then said group may optionally be substituted with up to two R" groups and R’ at each occurrence is selected independently from the definition of R”. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

As indicated above, various substituents of the various formulae are “optionally substituted”, including Ar, R,, R,, and R, of Formula I, and such substituents as recited in the sub-formulae such as Formulae Ia and the like. When substituted, those substituents (Ar, R,, R,, and R,) may be substituted by other than hydrogen at one or more available positions, typically 1 to 3 or 4 positions, by one or more suitable groups such as those disclosed herein. Suitable groups that may be present on a “substituted” Ar, R,, R,, and

R, group or other substituent include e.g. halogen such as fluoro, chloro, bromo and iodo; cyano; hydroxyl; nitro; azido; alkanoyl such as a C, ; alkanoyl group such as acyl and the like; carboxamido; alkyl groups including those groups having 1 to about 12 carbon atoms, or 1, 2, 3, 4, 5, or 6 carbon atoms; alkenyl and alkynyl groups including groups having one or more unsaturated linkages and from 2 to about 12 carbon, or 2, 3,4, 50r 6 carbon atoms; alkoxy groups having those having one or more oxygen linkages and from 1 to about 12 carbon atoms, or 1, 2, 3, 4, 5 or 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups including those moieties having one or more thioether linkages and from 1 to about 12 carbon atoms, or 1, 2, 3, 4, 5S or 6 carbon atoms; alkylsulfinyl groups including those moieties having one or more sulfinyl linkages and from 1 to about 12 carbon atoms, or 1, 2, 3, 4, 5, or 6 carbon atoms; alkylsulfonyl groups including those moieties having one or more sulfonyl linkages and from 1 to about 12 carbon atoms, or 1, 2,3,4,5, or 6 carbon atoms; aminoalkyl groups such as groups having one or more N atoms and from 1 to about 12 carbon atoms, or 1, 2, 3, 4, 5 or 6 carbon atoms; carbocyclic aryl having 6 or more carbons, particularly phenyl (e.g. an Ar group being a substituted or unsubstituted biphenyl moiety); aralkyl having 1 to 3 separate or fused rings and from 6 to about 18 carbon ring atoms, with benzyl being a preferred group; aralkoxy having 1 to 3 separate or fused rings and from 6 to about 18 carbon ring atoms, with O-benzyl being a preferred group; or a heteroaromatic or heteroalicyclic group having 1 to 3 separate or . 5 fused rings with 3 to about 8 members per ring and one or more N, O or S atoms, e.g. coumarinyl, quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholino and pyrrolidinyl.

As used herein, the substitution position of a substituent on a phenyl ring is dependent on the point of attachment of the substitutent to the phenyl ring relative to the point of attachment of the phenyl group to the remainder of the chemical compound. For example, L indicates the point of attachment of the phenyl ring to the remainder of the chemical compound. The numbers 2, 3, 4, 5 and 6 identify the individual ring atoms to which substituents can be attached. 2 3 6 5

As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups, having the specified number of carbon atoms.

Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n- butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. Alkyl groups typically have 1 to about 16 carbon atoms, more typically 1 to about 12 carbon atoms. Preferred alkyl groups are C,- : C, alkyl groups. Especially preferred alkyl groups are methyl, ethyl, propyl, butyl, 3- pentyl.

As used herein, "cycloalkyl" is intended to include saturated ring groups, having the specified number of carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Cycloalkyl groups typically will have 3 to about 8 ring members. : 5 In the term "(C, 4 cycloalkyl)C,-, alkyl", as defined above, the point of attachment is on the alkyl group. This term encompasses, but is not limited to, cyclopropylmethyl, cyclohexylmethyl, cyclohexylmethyl.

As used here, "alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl.

Alkenyl groups typically will have 2 to about 12 carbon atoms, more typically 2 to about 12 carbon atoms.

As used herein, "alkynyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl. Alkynyl groups typically will have 2 to about 16 carbon atoms, more typically 2 to about 12 carbon atoms.

As used herein, "haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example -C F,, where v=1 to 3 and w =1 to (2v+1). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. Typical haloalkyl groups will have 1 to about 16 carbon atoms, more typically 1 to about 12 carbon atoms. . : As used herein, "alkoxy" represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3- pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy. Alkoxy groups typically have 1 to about 16 carbon atoms, more typically 1 to about 12 carbon atoms.

As used herein, the term “alkylthio” includes those groups having one or more thioether linkages and suitably from 1 to about 16 carbon atoms, more typically 1 to about 12 carbon atoms, still more typically] to about 6 or 8 carbon atoms.

As used herein, the term “alkylsulfinyl” includes those groups having one or more sulfoxide (SO) linkage groups and suitably from 1 to about 16 carbon atoms, more typically 1 to about 12 carbon atoms, still more typically 1 to about 6 or 8 carbon atoms.

As used herein, the term “alkylsulfonyl” includes those groups having one or more sulfonyl (SO,) linkage groups and suitably from 1 to about 16 carbon atoms, more typically 1 to about 12 carbon atoms, still more typically 1 to about 6 or § carbon atoms.

As used herein, the term “alkylamino” includes those groups having one or more primary, secondary and/or tertiary amine groups and suitably from 1 to about 16 carbon atoms, more typically 1 to about 12 carbon atoms, still more typically 1 to about 6 or 8 carbon atoms.

As used herein, "halo" or "halogen" as used herein refers to fluoro, chloro, bromo, and iodo; and "counter-ion" is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.

As used herein, "carbocycle" or "carbocyclic residue” is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7-to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,

cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl,

. naphthyl, indanyl, adamantyl, and tetrahydronaphthy]l.

: 5 As used herein, the term "heterocycle" or " heterocycloalky!" is intended to mean a stable 5-to 7-membered monocyclic or bicyclic or 7-to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.

The nitrogen and sulfur heteroatoms may optionally be oxidized.

The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure.

The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable.

A nitrogen in the heterocycle may optionally be quaternized.

It is preferred that when the total number of S and 0 atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another.

It is preferred that the total number of S and 0 atoms in the heterocycle is not more than 1. As used herein, the term "aromatic heterocyclic system" or similar term such as “heteroaryl” is intended to mean a stable 5-to 7-membered monocyclic or bicyclic or 7-to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S.

It is preferred that the total number of S and O atoms in the aromatic heterocycle. is not more than 1. Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl,

benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,

decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl,

isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl,

naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-0xadiazolyl;- 1,2,50xadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, : 5 pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4- thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, and isatinoyl.

Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

As used herein, the term “carbocyclic aryl” includes groups that contain 1 to 3 separate or fused rings.and from 6 to about 18 ring atoms, without hetero atoms as ring members. Specifically preferred carbocyclic aryl groups include phenyl, and naphthyl including 1-napthyl and 2-naphthyl.

The phrase "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.

Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.

The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.

For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic,

lactic, malic, tartaric, citric, ascorbic, pamoic, malefic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH,)n-COOH where n is 0-4, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.

Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, p. 1418 (1985), the disclosure of which is hereby incorporated by reference.

"Prodrugs" are intended to include any covalently bonded carriers which release the active parent drug according to formula I in vivo when such prodrug is administered to a mammalian subject.

Prodrugs of a compound of formula I are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.

Prodrugs include compounds of formula I wherein a hydroxy, amino, or sulfhydryl group is bonded ) to any group that, when the prodrug or compound of formula I is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group,

respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula

I, and the like. : 5 Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an effective therapeutic agent. The term "therapeutically effective amount" of a compound of this invention means an amount effective to antagonize abnormal level of CRF or treat the symptoms of affective disorder, anxiety or depression in a host.

The compounds of general Formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal 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 [ may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or : 5 sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene } sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredients in a : 5 vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations.

These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

Pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate. The emulsions may also contain sweetening and flavoring agents. . Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. } This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. : 5 The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3- butanediol. Among the acceptable vehicles and solvents that may be employed are water,

Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compounds of general Formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

Compounds of general Formula I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.

Typical subjects to which compounds of the invention may be administered will be mammals, particularly primates, especially humans. For veterinary applications, a wide variety of subjects will be suitable, e.g. livestock such as cattle, sheep, goats, cows, swine and the like; poultry such as chickens, ducks, geese, turkeys, and the like; and domesticated animals particularly pets such as dogs and cats. For diagnostic or research i applications, a wide variety of mammals will be suitable subjects including rodents (e.g. mice, rats, hamsters), rabbits, primates, and swine such as inbred pigs and the like.

Additionally, for in vitro applications, such as in vitro diagnostic and research applications, body fluids and cell samples of the above subjects will be suitable for use such as mammalian, particularly primate such as human, blood, urine or tissue samples, or blood urine or tissue samples of the animals mentioned for veterinary applications. : 5

Dosage levels of the order of from about 0.1 mg to about 140 mg of a compound of the invention per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 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 CNS disorders, a dosage regimen of 4 times daily or less is preferred. For the treatment of stress and depression a dosage regimen of 1 or 2 times daily is particularly preferred.

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 certain 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 bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. Toxicity to cultured hepatocyctes may be used to : 5 predict compound toxicity. Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals given the compound intravenously.

Serum protein binding may be predicted from albumin binding assays. Such assays are described in a review by Oravcova, et al. (Journal of Chromatography B (1996) volume 677, pages 1-27).

Compound half-life is inversely proportional to the frequency of dosage of a compound. In vitro half-lives of compounds may be predicted from assays of microsomal half-life as described by Kuhnz and Gieschen (Drug Metabolism and

Disposition, (1998) volume 26, pages 1120-1127). Alternatively, compound half-life may be predicted from an in vitro microsomal assay such as the assay given in example 9%b.

The present invention also pertains to methods for altering the activity of CRF receptors, said method comprising exposing cells expressing such receptors to an effective amount of a compound of the invention, wherein the compound is present in the solution at a concentration sufficient to specifically alter the signal transduction activity in response to CRF in cells expressing high levels of CRF1 receptors in vitro. This method includes altering the signal transduction activity of CRF receptors in vivo, e.g., in a patient given an amount of a compound of Formula I that would be sufficient to alter the signal transduction activity in response to CRF in cells expressing high levels of

CRF1 in vitro. The amount of a compound that would be sufficient to alter the signal . transduction activity in response to CRF receptors may be determined via an assay of

CREF receptor mediated signal transduction, such as an assay wherein the binding of CRF to a cell surface CRF receptor effects a changes in reporter gene expression.

The present invention also pertains to packaged pharmaceutical compositions for. : 5 treating disorders responsive to C5a receptor modulation, e.g., eating disorders, depression or stress. The packaged pharmaceutical compositions include a container holding a therapeutically effective amount of at least one CRF1 receptor modulator as described supra and instructions for using the treating disorder responsive to CRF1 receptor modulation in the patient.

PREPARATION OF ARYLPYRAZINES

The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below. Each of the references cited below are hereby incorporated herein by reference. Preferred methods for the preparation of compounds of the present invention include, but are not limited to, those described in Scheme I, Scheme

II, and Scheme III. Those who are skilled in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present invention. All references cited herein are hereby incorporated in their entirety herein by reference. The following abbreviations are used herein:

AcOH acetic acid

DMF N,N-dimethylformamide

Et,0 diethyl ether

EtOAc ethyl acetate . EtOH ethanol

NaH sodium hydride

NaHMDS sodium bis(trimethylsilyl)amide

THF tetrahydrofuran

EX# example number

Scheme | (Method A)

A Halogenalti i} rR Base; rR:

Deh Roxn Teboenae Sd AM) SY Rial Le)

RON (cat) RON Hal ®t RNTDAr | X=NH) gS ar vi (X= NH, NR, O, 5) vit i

According to the general method A, wherein R] and R3 are as defined for formula

I and Hal represents a halogen atom, suitably chloride or bromide, the halide in VI can be displaced by an amine or (thio)alkoxide nucleophile. Thus, aminopyrazine can be prepared from VI and an amine in the presence of a suitable transition metal catalyst such as but not limited to palladium(II) acetate or tris(dibenzylideneacetone)dipalladium(0), a ligand such as but not limited to 1,1'-bis(diphenylphosphine)ferrocene, 2,2'- bis(diphenylphosphine)-1,1'-binaphthyl, dicyclohexyl(2-biphenyl)phosphine, tricyclohexylphosphine, or tri-zert-butylphosphine, and a base such as sodium or potassium fert-butoxide in inert solvents such as but not limited to toluene, ethyleneglycol dimethyl ether, diglyme, DMF, or N-methylpyrrolidinone at temperatures ranging from ambient to 100°C. (Thio)alkoxypyrazines can be prepared by treating VI with a sodium or potassium salt of an alcohol or thiol in an inert solvent such as THF,

DMF, N-methylpyrrolidinone, or methyl sulfoxide at ambient temperature or at elevated temperature up to the boiling point of the solvent employed. Halogenation may be accomplished by a variety of methods known in the art, including treatment with N- chlorosuccinimide, bromine, N-bromosuccinimide, pyridinium tribromide, triphenylphosphine dibromide, iodine, and N-iodosuccinimide in solvents such as but not limited to dichloromethane, acetic acid, or methyl sulfoxide. The bromopyrazine can be converted to arylpyrazine VII by a transition metal-catalyzed coupling reaction with a metalloaryl reagent (Ar-[M]). More commonly employed reagent/catalyst pairs include - aryl boronic acid/palladium(0) (Suzuki reaction; N. Miyaura and A. Suzuki, Chemical

Review 1995, 95, 2457), aryl trialkylstannane/palladium(0) (Stille reaction; T. N.

Mitchell, Synthesis 1992, 803), arylzinc/palladium(0) and aryl Grignard/nickel(II).

Palladium(0) represents a catalytic system made of a various combination of metal/ligand pair which includes, but not limited to, tetrakis(triphenylphosphine)palladium(0), palladium(II) acetate/tri(o-tolyl)phosphine, tris(dibenzylideneacetone)dipalladium(0)/tri- ‘ 5 tert-butylphosphine and dichloro[1,1’-bis(diphenylphosphine)ferrocene]palladium(0).

Nickel(II) represents a nickel-containing catalyst such as [1,2- bis(diphenylphosphino)ethane}dichloronickel(Il) and [1,3- bis(diphenylphosphino)propane]dichloronickel(II). The arylpyrazine VII, when X is

NH, may be further transformed to VIII by N-alkylation. The N-H group is deprotonated by a strong base such as but not limited to alkali metal hydride, alkali metal amide, or alkali metal alkoxide in inert solvents such as but not limited to THF, DMF, or methyl sulfoxide. Alkylation may be conducted using alkyl halide, suitably bromide or iodide, at temperatures ranging from 0°C to 100°C.

Scheme Il (Method B)

N Rs AM] NgRs 1)N-oxidation ci _N__Rg RAXH x Nea

A & Hal LL — BOY = A L vi IX (x=NH,NRE,O, 5) vil

In an alternative way, compounds of Formula VII can be prepared as outlined in Scheme

II. Transition metal-catalyzed coupling of the halo pyrazine VI as described in the

Method A can provide the intermediate VIII. Oxidation of sterically less hindered nitrogen can be effected by using a variety of oxidizing agents known in the art, which includes m-chloroperoxybenzoic acid, trifluoroperacetic acid, hydrogen peroxide, and monoperoxyphthalic acid. The N-oxide can undergo rearrangement to give chloropyrazine IX upon the action of phosphorus oxychloride at temperatures ranging from ambient to 100°C. Displacement of the chloride with a nitrogen, oxygen, or sulfur nucleophile as described in the Method A can furnish the compounds of Formula VII.

Claims

WHAT IS CLAIMED IS:

1. A compound of the formula: ) R, Na Rs . = R4 N Ar or a pharmaceutically acceptable salt thereof, wherein: Ar is substituted phenyl, optionally substituted napthyl, or an optionally substituted heterocyclic group having from 1 to 3 rings, and 3 to 8 ring members in each ring and 1 to about 3 hetero atoms; RR, and R, are each independently hydrogen, halogen, cyano, nitro, amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted mono or dialkylamino, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted alkylsulfinyl, or optionally substituted alkylsulfonyl; and R, is halogen, cyano, nitro, amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkylamino, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted alkylsulfinyl, or optionally substituted alkylsulfonyl; with the proviso that if Ar is phenyl substituted with halogen, napthyl, or naphthyl substituted with halogen, then the compounds where R, is hydrogen or amino are excluded. h

2. A compound according to Claim 1, wherein: Ar is substituted phenyl, optionally substituted naphthyl, or an optionally substituted heterocyclic group having at least one nitrogen ring atom or at least one sulfur ring atom.

3. A compound of the formula:

pee Ry NT Ar : or a pharmaceutically acceptable salt thereof, wherein: R, is selected from H, C,, alkyl, C,,, alkenyl, C,, alkynyl, halogen, CN, C,, haloalkyl, trifluoromethyl, trifluoromethoxy, -NH(C,, alkyl), -N(C,, alkyl)(C,, alkyl), - O(C,, alkyl), and S(0),(C,, alkyl); R, is selected from the group consisting of ~XR, and Y, wherein -X, R,, and Y are defined below; and R, is selected from the group consisting of hydrogen, halogen, C,, alkyl, -O(C,,, alkyl), - NH(C,, alkyl), -N(C,, alkyl)(C,, alkyl), and -S(O),(C,, alkyl), haloalkyl, trifluoromethyl, trifluoromethoxy, —XR, and Y; R, is absent or an oxygen atom; Ar is phenyl, mono-, di-, or tri-substituted with Rg, or Ar is selected from the group consisting of: naphthyl, pyridyl, pyridonyl, pyrimidinyl, and thiophenyl, each of which is unsubstituted or mono-, di-, or tri-substituted with Rg; with the proviso that if Ar is phenyl substituted with halogen, napthyl, or naphthyl substituted with halogen, then the compounds where R, is hydrogen are excluded; R, and Rg, which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen and straight, branched, or cyclic alkyl groups consisting of 1 to 8 carbon atoms, which may contain one or more double or triple bonds, each of which may be further substituted with one or more substituent(s) selected from oxo, hydroxy, halogen, -O(C, , alkyl), -NH(C, , alkyl), -N(Cy, alkyl)(C, alkyl), -NHC(O)C,, alkyl), -N(C,, alky)C(=O)(C,, alkyl), -NHS(0),(C, 4 alkyl), -8(0).(C.., alkyl), -S(O),NH(C, alkyl), -S(O),N(C,, alkyl)(C,, alkyl), and Z;

R. is independently selected at each occurrence from the group consisting of halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy, hydroxy, amino, and C,

alkyl optionally substituted with 0-2 R,,, C,¢ alkenyl substituted with 0-2 R;,, C,, alkynyl substituted with 0-2 Rp, C,, cycloalkyl substituted with 0-2 Rp, (C,, cycloalkyl)C,-, alkyl substituted with 0-2 R;, -O(C,, alkyl) substituted with 0-2 Rp, -NH(C,, alkyl) substituted with 0-2 Rp, -N(C,, alkyl)(C,, alkyl) each independently substituted with 0-2 R,, -XR,, and Y; R;, is independently selected at each occurrence the group consisting of halogen, hydroxy, cyano, Cyaalkyl, -O(C alkyl), -NH(C,,alkyl), -N(C,.alkyl)(C, alkyl), morpholino, pyrrolidino, piperidino, thiomorpholino, piperazino, 4- hydroxypiperidino, -S(0),(C, alkyl), trifluoromethyl, trifluoromethoxy, CO(C,. salkyl), CONH(C, alkyl), CON(C, ,alkyl)(C, alkyl), -XR, and Y; X is independently selected at each occurrence from the group consisting of -CH,-, - CHR;-, -O-, -C(=0)-, -C(=0)0-, -S(0),-, -NH-, -NR;-, -C(=0)NH-, -C(=0)NR;-, -S(0),NH-, -S(O),NRg-, -OC(=S)S-, -NHC(=0)-, -NR,C(=0)-, -NHS(O),-, - OSiH,(C alkyl), ,-, and -NRS(O),-; and Y and Z are independently selected at each occurrence from the group consisting of: 3- to 7-membered carbocyclic and heterocyclic groups, which are saturated, unsaturated, or aromatic, which may be substituted with one or more substituents selected from halogen, haloalkyl, oxo, hydroxy, amino, C,, alkyl, -O(C, , alkyl), - NH(C,, alkyl), -N(C,, alkyl)(C,, alkyl), and -S(0),(C,, alkyl), and said 3- to 7-membered heterocyclic groups contain one or more heteroatom(s) selected from N, O, and S, with the point of attachment being either carbon or nitrogen; and n is independently selected at each occurrence from 0, 1, and 2.

4. A compound of according to Claim 1 wherein Ar is substituted phenyl.

5. A compound according to Claim 3, R, is absent and Ar is phenyl, mono-, di-, or tri-substituted with R.

6. A compound according to Claim 3 wherein Ry is absent and Ar is phenyl, mono-, ¢-, or tri-substituted with R, and R; and Ry are independently selected from the group consisting of hydrogen, halogen, methyl, ethyl, ethoxy and methoxy.

7. A compound according to Claim 3 wherein Ry is absent and Ar 1s phenyl, mono-, di, or tri-substituted with R.; and Ry and Rg, which may be the same or different, are independently straight, branched, or cyclic alkyl groups having from | to § carbon atoms, which may contain one or more double or triple bonds.

S. A compound according to Claim 3 wherein Ry is absent and Ar is phenyl mono-, di-, or tri-substituted with R.; Ry and Ry, which may be the same or different, are independently selected at each occurrence trom the group consisting of: straight, branched, and cyche alkyl \ groups having from 1 to § carbon atoms, which may contin one or more double or triple bonds; and R, and Ry are independently selected from the group consisting ot hydrogen, halogen, methyl, cthyl, ethoxy, and methoxy.

Y. A compound of the Formula .

M. N_ fy i. T bl Co ~ Pa Te. ny” ~~ “Ar ) Formula A wheren R, 1s selected from H, Cia alkyl, Cpa alkenyl, Cau alkynyl, halogen, CN, Ci. haloalkyl, trifluoromethyl, trifluoromethoxy, NEH(C a alkyl), -N(Cy. alkyl)(Cy.y alkyl), -O(Ci alkyl), and S(0)(C,.s alkyl); R, is selected from the group consisting of hydrogen, halogen, Cs alkyl, -O(C,.s alkyl), - NH(C,.s alkyl), -N(C 4 alkyl(Cy., alkyl), and —=S(0)n(C.. alkyl), haloalkyl, trifluoromethyl, trifluoromethoxy, -XR, and Y; 169 Amended Sheet — 2003-10-28 ’

R, and R, are the same or different and are independently selected straight, branched, or cyclic alkyl groups having from | to 8 carbon atoms, which may contain one or more double or triple bonds, each of which may be further substituted with one or more substituent(s) independently selected from hydroxy, halogen,-O (C, alkyl),-NH (C, 4 alkyl),-N (C, 4 alkyl) (Cy alkyl), hydrogen and straight, branched, or cyclic alkyl groups consisting of 1 to S carbon atoms, each of which alkyl groups may contain one or more double or triple bonds, and may be further substituted with one or more substituent(s) selected from oxo, hydroxy, halogen, -O(C,. alkyl), -NH(C,, alkyl), -N(C,.; alkyD)(C, 4 alkyl), -NHC(O)(C, 4 alkyl), -N(C, 4 alkyDC(=0)(C, 4 alkyl), -NHS(0),(C. 4 alkyl), -S(O),(C.4 alkyl), -S(O) NH(C, 4 alkyl), -S(0),N(C, 4 alkyl)(C, 4 alkyl), Z, and phenyl, optionally mono-, di- or tri-substituted with substituents independently chosen from Cl-4 alkoxy, Cl-4 alkyl, halogen, CF3, OCF3, OCHF2, OH, and CN; and Ar is phenyl, mono-, di-, or tri-substituted with Re, or Ar is selected from the group consisting of: naphthyl, pyridyl, pynidonyl, pyrimidinyl, and thiophenyl, each of which 1s unsubsututed or mono-, di-, or tri-substituted with Re; with the proviso that if Aris phenyl, phenyl substituted with halogen, napthyl, oc naphthyl substituted with halogen, then the compounds where Riis hydrogen are excluded; R, and Ry, which may be the same or ditterent, are independently selected at cach occurrence from the group consisting ot: hydrogen and straight, branched, or cyclic alkyl groups consisting of 1 to § carbon atoms, which may contain one or more double or triple bonds, cach of which may be further substituted with one or more substituent(s) sciected from oxo, hydroxy, halogen, -O(C.s alkyl), -NH(C, i alkyl), -N(C,s alky)(C,.a alkyl), -NHC(O)(C, 4 alkyl), -N(C,. alkyl)C(=0)(C,., alkyl), -NHS(O),(C,.4 alkyl), -S(0),(C,.. alkyl), -S(0O),NH ) (Cy. alkyl), -S(O).N(Cy 4 alkyl) (C4 alkyl), and Z; Re 1s independently selected at each occurrence trom the group consisting of halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy, hydroxy, amino, and C4 alkyl optionally substituted with 0-2 Rp, Cy alkenyl substituted with 0-2 Ry, C5 alkynyl substituted with 0-2 Rp, Cy; cycloalkyl substituted with 0-2 Rp, (Cy.7 cycloalkyl)Cy.s alkyl substituted with 0-2 Rp, -O(C, 4 alkyl) substituted with 0-2 Rp, -NH(C,.4 alkyl) substituted with 0-2 Rp, -N(C,., alkyl)(C,.s alky!) each independently substituted with 0-2 Rp, -XR 4, and Y; 169A Amended Sheet — 2003-10-28 ’

Rp 15 independently selected at each occurrence the group consisting of haiogen, hydroxy, cyano, Ca alkyl, -O(C. oy atkyl), -NH(C, alkyl), -N(C, 4 alkyv)(C, 4 alkyl), morpholino, ' pyrrolidino, piperidine, thiomorpholing, piperazino, 4-hydroxypiperidino, S10), (Chg alkyl), . trifluoromethyl, trifluoromethoxy, CO(C,. alkyl), CONH(C,.s alkyl), CON(C, 4 atkvI)(C,. alkyl), -XR,, and Y; X is independently selected at each occurrence from the group consisting of ~CH;-, -CHR-, -0-, -C(=0)-, -C(=0)0-, -S(0),-, -NH-, -NRg-, -C(=0)NH-, -C(=O)NRy-, -S(O),NH-, - S(O), NRg-, -OC(=S)S-, -NHC(=0)-, NRyC(=0)-, -NHS(O),-, -OStH,(C, , alkvi),-, and -NRgS(O),-; Y and Z 13 independently selected at each occurrence trom the group consisting of? 3-10 7- membered carbocyclic and heterocyclic groups, which are saturated, unsaturated, or aromatic, which may be substituted with one or more substituents selected from halogen, haloalkyl, oxo, ) hydroxy, amino, C,., alkyl, -O(C,_, alkyl), -NH(C, 4 alkyl), -N(C, 4 alkyl) (C,; alkyl), and -- : S(O),(Cy 4 alkyl), and said 3- to 7-membered heterocyclic groups contain one or more heteroatoms) selected from N, 0, and S, with the pont of attachment being either carbon or nitrogen; and nis independently selected at each occurrence from 0, 1, and 2, ) 169B Amended Sheet - 2003-10-28 ’

10. A compound according to Claim 9, wherein Ar is phenyl, mono-, di-, or tri-substituted with R.; and R, and R, are independently selected from the group consisting of hydrogen, halogen, methyl, ethyl, ethoxy and methoxy. . 5

11. A compound according to Claim 9, wherein: R, and R, are independently chosen from halogen, C,, alkyl, -O(C,, alkyl), -NH(C, alkyl), -N(C,, alkyl)(C,, alkyl), haloalkyl, trifluoromethyl, and trifluoromethoxy; and Ar is phenyl, which is mono-, di-, or trisubstituted with one or more substituent(s) independently selected from: halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy, hydroxy, amino, and C,, alkyl, C, alkoxy, C,,alkoxy(C, alkoxy), mono- or di(C,)amino(C,. salkoxy), and mono- or di(C,_, alkyl)amino.

12. A compound according to Claim 9, wherein: R, is hydrogen; Ry is chosen from the group consisting of: straight, branched, or cyclic alkyl groups having from 1 to 8 carbon atoms, which may contain one or more double or triple bonds; R, and R, are independently chosen from halogen, C,, alkyl, -O(C,, alkyl), -NH(C, alkyl), -N(C,, alkyl}(C,, alkyl), haloalkyl, trifluoromethyl, and trifluoromethoxy; and Ar is phenyl, which is mono-, di-, or trisubstituted with substituent(s) independently selected from: halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy, hydroxy, amino, and C4 alkyl, C alkoxy, C,,alkoxy(C, alkoxy), mono- or di(C,,)amino(C,. ,alkoxy), and mono- or di(C,_, alkyl)amino.

13. A compound according to Claim 9, wherein:

Ry is hydrogen; Ry is chosen from the group consisting of: straight, branched, or cyclic alkyl groups having from 1 to 8 carbon atoms, which may contain one or more double or triple bonds; R, and R, are independently chosen from halogen, C,, alkyl, -O(C, alkyl), -NH(C,., alkyl), -N(C,, alkyl(C,, alkyl), haloalkyl, trifluoromethyl, and trifluoromethoxy; and Ar is a phenyl group of the formula: 2 ESN 6 wherein L indicates a bond to the pyrazine ring in Formula A; and the phenyl group is substituted at one, two or three of positions 2, 4, and 6 with substituent(s) independently selected from: halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy, hydroxy, amino, and C,, alkyl, C, jalkoxy, C, _alkoxy(C, alkoxy), mono- or di(C,_)amino(C, alkoxy), and mono- or di(C,_, alkyl)amino.

14. A compound according to Claim 9, wherein: R is hydrogen; Ry is chosen from the group consisting of: straight, branched, or cyclic alkyl groups having from 1 to 8 carbon atoms, which may contain one or more double or triple bonds; R, and R, are independently chosen from halogen, C,, alkyl, -O(C,, alkyl), -NH(C,_, alkyl), -N(C,, alkyl)(C,, alkyl), haloalkyl, trifluoromethyl, and trifluoromethoxy; and Aris a phenyl group of the formula: 2 —~ wherein L indicates a bond to the pyrazine ring in Formula A;

‘and the phenyl group is substituted at positions 2 and 4 with substituents independently selected from: halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy, hydroxy, amino, and C4 alkyl, C, alkoxy, C _alkoxy(C, alkoxy), mono- or di(C,,)amino(C,. s,alkoxy), and mono- or di(C, , alkyl)amino.

15. A compound according to Claim 9 of the formula: T INQ Rs JL wherein: R, and R, are independently chosen at each occurrence from halogen, C,, alkyl, -O(C,_, alkyl), -NH(C,, alkyl), -N(C, , alkyl)(C,, alkyl), haloalkyl, trifluoromethyl, and trifluoromethoxy; and Ar is a phenyl group of the formula: 2 Or 6 wherein L indicates a bond to the pyrazine ring in Formula A; and the phenyl group is substituted at one, two or three of positions 2, 4, and 6 with substituent(s) independently selected from: halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy, hydroxy, amino, and C4 alkyl, C, alkoxy, C,_alkoxy(C,,alkoxy), mono- or di(C,,)amino(C,. alkoxy), and mono- or di(C,_ alkyl)amino. : 16. A compound according to Claim 9 of the formula:

j {J N Se Bo ye R R wherein R is independently selected at each occurrence from the group consisting of: hydrogen, halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy, hydroxy, amino, C,. alkyl, C, alkoxy, C,,alkoxy(C, alkoxy), mono- or di(C,,)amino(C, alkoxy), and mono- or di(C, , alkyl)amino; and R, and R, are independently chosen from halogen, C,, alkyl, -O(C,, alkyl), -NH(C,,, alkyl), -N(C,, alkyl(C,, alkyl), haloalkyl, trifluoromethyl, and trifluoromethoxy.

17. A compound according to Claim 9 wherein Ar is phenyl, which is mono-, di-, or tri-substituted with R; Ry and Ry, which may be the same or different, are independently selected at each occurrence from the group consisting of: straight, branched, and cyclic alkyl groups having from 1 to 8 carbon atoms, which may contain one or more double or triple bonds; and R, and R; are independently selected from the group consisting of hydrogen, halogen, methyl, ethyl, ethoxy, and methoxy.

18. A compound according to Claim 3 of the formula: Rx 2 0¢ Ry NZ Ar wherein Ry and R, are independently hydrogen or C, 4 alkyl; or

NR(R, 1s: (CHa) ' / "\ Nera ve wherein zis0or |.

19. A compound of the Formula : Rx ] | N Ry ST A 7, nN Al Formula B where Ry is chosen from the group consisting of: strarght, branched, or cyclic alkyl groups, including (cycloalkyl) alkyl groups. having from 1 to S carbon atoms, which groups may contain one or more double or triple bonds, cach of which groups may be further substituted with one or more substituent(s) independently selected trom : oxo, hydroxy, halogen, -O(C, 4 alkyl), -NH(C, , alkyl), -N(C,., alkyl)(C, 4 alkyl), -NHC(O)C,. alkyl), -N(C.s alky)C(=0)(C, 4 alkyl), -NHS(0O),(C,.s alkyl), -S(0)(C, 4 alkyl), -S(O),NH (Cs atkyl), -S(O),N(C, 4 alkv)(C,.s alkyl), Z, and phenyl, optionally mono-. di- or tri- substituted with substituents independently chosen trom C1-4 alkoxy, C1-4 alkyl, halogen, CF3, OCF3, OCHF2, OH, and CN; and R, is selected from H, C4 alkyl, Cy. alkenyl, C4 alkynyl, halogen, CN, Cs haloalkyl, trifluoromethyl, trifluoromethoxy, -NH(C,.s alkyl), -N(C,.4 alkyI}(C,, alkyl), -O(C,_4 alkyl), and 5(0).(C,.. alkyl); 174 Amended Sheet - 2003-10-28

YO 01/60806 PCT/USN/03264 R; 1s selected from the group consisting of hydrogen, halogen, C, 4 alkyl, -O(C,., alkyl), - NH{C,.y alkyl), -N(C,.,; alk D(C, 4 aikvl), and -5(0),(C..; alkyl), hatoalii, tif luoromethyl, trifluoromethoxy, -XR, and Y; Ar is phenyl, mono-, di-, or tri-substituted with Re, or Ar is selected from the group consisting of: naphthyl, pyridyl, pyridonyl, pyrimidinyl, and thiophenyl, each of which is unsubstituted or mono-, di-, or tri-substtuted with Re; with the proviso that if Aris phenyl, phenyl substituted with halogen, napthyl, or naphthyl substituted with halogen, then the compounds where Ry 1s hydrogen are excluded, R, and Ry, which may be the same or different, are independently selected at each occurrence from the group consisting ot: hydrogen and straight, branched, or cyclic alkyl groups consisting of | to § carbon atoms, which may contain one or more double or triple bonds, cach J of which may be further substituted with one or more substituent(s) selected from oxo, hydroxy, halogen, -O(C, 4 alkyl), -NH(C, alkyl), -N(C, 4 alky)(C, 4 alkyl), -NHC{O)C, , alkyl), -N(C, 4 alkyDC(=0)C, 4 alkyl), -NHS(O),(C, 4 alkyl), -S(O)(C, , alkyl), -S(O), NH (Cy alkyl), -S(O)N(C 4 alkyl)C alkyl), and Z; Re: is independently selected at cach occurrence trom the group consisting ot halogen, cyano, haloalkyl, trifluoromethyl, trifluoromcthoxy, hydroxy, amino, and C, 4 alkyl optionally substituted with 0-2 Rp, Cag alkenyl substituted with 0-2 Rp, Cy alkynyl substituted with 0-2 Rp, Cyr cycloalkyl! substituted with 0-2 Ry, (Cy; cycloalky)C, 5 alkyl substituted with 0-2 Ry, -O(C alkyl) substituted with 0-2 Ry, -NH(C, 4 atkyl) substituted with 0-2 Ry, -N(C, 4 alky D(C. alkyl) cach dependently substituted with 0-2 Rp, -XR,, and Y; Rp is independently selected at cach occurrence the group consisting of halogen, hydroxy, cyano, C4 alkyl, -O(C, 4 alkyl), -NH(C,.4 alkyl), -N(C, 4 alkyl)(C, 4 alkyl). morpholino, pyrrolidine, piperidino, thiomorpholino, piperazine, 4-hydroxypiperidino, -5(0),(C, 4 alkyl), trifluoromethyl, trifluoromethoxy, CO(C,.y alkyl), CONH(C, , alkyl), CON(C,., alky[)(C,.4 alkyl), -XR,, and Y; X is independently selected at each occurrence from the group consisting of —-CH,-, -CHRg-, -0-, -C(=0)-, -C(=0)0-, -S(O),-, -NH-, -NRy-, -C(=O)NH-, -C(=0)NRg-, -S(0),NH-, - S(0).NRg-, -OC(=S)S-, -NHC(=0), -NRgC(=0)-, -NHS(O),-, -OSiH,(C,.; alkyl);.,-, and -NRgS(O)u; : 174A Amended Sheet — 2003-10-28

WO £1/69306 PCT USI1/0326- Y and Z is independently selected at each occurrence from the group consising of: 3-to 7- membered carbocyclic and heterocyclic groups, which are saturated, unsaturated, or aromatic, witch may be substituted with one or more substituents selected from halogen, haloalkyl, oxo, hydroxy, amino, C.; alkyl, -O(C,. alkyl), -NH(C, 4 alkyl), -N(C, , alkyl) (C, . alkyl), and -S(O)(Cha alkyh, and said 3- to 7-membered heterocyclic groups contain one or more heteroatoms) selected trom XN, 0, and S, with the point of attachment being either carbon or nitrogen; and n is independently selected at each occurrence from 0, 1, and 2.

! < j

: 174B : Amended Sheet - 2003-10-28 =

20. A compound according to Claim 19, wherein: R, is selected from straight, branched, or cyclic alkyl groups containing of 1 to 8 carbon atoms, which may contain one or more double or triple bonds; and; R; and R; are independently chosen from halogen, C,, alkyl, -O(C,, alkyl), -NH(C,, alkyl), -N(C,, alkkyl)(C,, alkyl), haloalkyl, trifluoromethyl, and trifluoromethoxy; and Ar is phenyl, which is mono-, di-, or trisubstituted with one or more substituent(s) independently selected from: halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy, hydroxy, amino, and C,. ¢ alkyl, C alkoxy, C,_alkoxy(C, alkoxy), mono- or di(C,,)amino(C, ,alkoxy), and mono- or di(C,_, alkyl)amino.

21. A compound according to Claim 20, wherein: Ar is a phenyl group of the formula: 2 —~ 6 wherein L indicates a bond to the pyrazine ring in Formula B; and the phenyl group is substituted at one, two, or three of positions 2, 4, and 6 with substituent(s)independently selected from: halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy, hydroxy, amino, and C,, alkyl, C, alkoxy, C, alkoxy(C,_ alkoxy), mono- or di(C,_ )amino(C,. salkoxy), and mono- or di(C, , alkyl)amino.

22. A compound according to Claim 20, wherein: ’ Ar is a phenyl group of the formula: 2 wherein L indicates a bond to the pyrazine ring in Formula B; and the phenyl group is substituted at positions 2 and 4 with substitutuents independently selected from halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy, hydroxy, amino, C, alkyl, C,_ alkoxy, C,alkoxy(C, alkoxy), mono- or di(C,. Jamino(C, ,alkoxy), and mono- or di(C,, alkyl)amino.

23. A compound according to Claim 19, of the formula: Ri NZ Ar wherein: R, and R; are independently chosen from halogen, C,, alkyl, -O(C,, alkyl), -NH(C, alkyl), -N(C,, alkyl}(C,, alkyl), haloalkyl, trifluoromethyl, and trifluoromethoxy; and Ar is a phenyl group of the formula: 2 > \ wherein L indicates a bond to the pyrazine ring in Formula B; : and the phenyl group is substituted at one, two, or three of positions 2, 4, and 6 with substituent(s)independently selected from: halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy, hydroxy, amino, C,, alkyl, C, alkoxy, C,. 4alkoxy(C, alkoxy), mono- or di(C,,)amino(C, alkoxy), and mono- or di(C,, alkyl)amino.

24. A compound according to Claim 19 wherein R, and R, are independently selected from the group consisting of hydrogen, halogen, methyl, ethyl, ethoxy and methoxy.

A compound according to Claim 3 of the formula: A [5 N _R; f PEN FON, wherein A 1s NR, or O.

26. A compound according to Claim 1 wherein, in a standard in vitro CRF receptor , binding assay the compound exhibits an [Cs value less than or equal to 1 micromolar.

27. A compound according to Claim 1 for use in a method for modulating CRE receptor function, comprising adnunistering to a patient in need of such modulation an effective amount of the compound. 28, A compound according to Claim 1 for use in a micthod tor treating a CNS disorder or disease, comprising administering to a patient in need of such treatment an ettective amount of the compound.

29. The compound of Claim 28 wherein the CNS disorder or disease 1s an anxiety disorder, stress-related disorder, or eating disorder. )

30. A compound according to Claim 1, wherein mn a standard in vitro sodium channel functional assay the compound does not show any statistically significant activity at the p<0.05 level of significance.

31. A compound of Claim 28 wherein the CNS disease or disorder 1s depression or a bipolar disorder. 177 Amended Sheet — 2003-10-28 ’

32. A compound of Claim 28 wherein the CNS disease or disorder is anorexia nervosa, , pulirua nervosa, or obesity.

33. A compound according to Claim 28 wherein in a standard in vitro CRF receptor binding assay the compound exhibits an ICy, value less than or equal to | micromolar. iu y 34 A compound according to Claim 28 wherein in a standard in vitro CRF receptor binding assay the compound exhibits an IC; value less than or equal to 100 nanomolar.

35. A compound according to Claim 28 wherein in a standard in vitro CRF receptor binding assay the compound exhibits an 1Csy value less than or equal to 10 nanomolar. ;

36. A compound according to Clarm 28 wherein the patient 1s a human,

37. A mcthod tor localizing CRE receptors is tissue section samples comprising: contacting with a sample of tissue a deteactably-fabelled compound of Claim | under conditions that permit binding of the compound to CRE receptors within the sample of tissue; washing the tissue sample to remove unbound compound; and detecting remaining bound compound.

33. A cthod of inhibiting the binding of CREF to a CREF1 Receptor which comprises: : 178 Amended Sheet — 2003-10-28 :

contacting a solution comprising CRF and a compound of Claim 3 with cells expressing the receptor, wherein the compound is present in the solution at a concentration sufficient to inhibit CRE binding to IMR32 cells in vitro.

39. A compound according to Claim 3 for use in a method for altering the signal- transducing activity of a CRF receptor, the method comprising contacting cells expressing the receptor with the compound. 40, A compound according to Claim 3 for use in a method of modulating G- protein coupled receptor function, the method comprising exposing cells expressing a G- protein coupled receptor to an effective amount of the compound.

41. A compound according to Claim 40, wherein the G-coupled protein receptor 1s a CRF! receptor,

42. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to Claim 1. 43, A packaged pharmaceutical composition comprising a pharmaceutical composition of claim 42 in a container and instructions for using the composition to treat a patient suffering from an anxiety disorder, a stress-related disorder, or an cating disorder. 44, A compound according to Claim 3, named 5-(2,4-dimethoxyphenyl)-6-ethyl- N-(1-¢thylpropyl}-3-methoxypyrazin-2-amine.

45. A compound according to Claim 3, named 5-[4-bromo-2- (trifluoromethoxy)phenyl]-3,6-dicthyl-N-(1-ethylpropyl)pyrazin-2-amine.

46. A compound according to Claim 3, named 3-cthyl-N-(1-ethylpropyl)-6- 179 Amended Sheet — 2004-05-20 methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl] pyrazin-2-amine.

47. A compound according to Claim 3, named 5-(4-chloro-2-methylphenyl)-6- ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine.

48. A compound according to Claim 3, named 5-[2-chloro-4- (trifluoromethyl)phenyl]-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine.

49. A compound according to Claim 3, named 2-[2,4- bis(trifluoromethyl)phenyl]-3,6-diethyl-5-(1-ethylpropoxy)pyrazine.

50. A compound according to Claim 3, named 3,6-diethyl-N-(1-ethylpropyl)- 5-(2-naphthyl)pyrazin-2-amine.

51. A compound according to Claim 3, named 5-[4-chloro-2- (trifluoromethyl)phenyl]-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine.

52. A compound according to Claim 3, named 3,6-diethyl-N-(1-ethylpropyl)- 5-[2-methoxy-6-(trifluoromethoxy)phenyljpyrazin-2-amine.

53. A compound according to Claim 3, named 5-(2-chloro-4-methoxyphenyl)- 6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine.

54. A compound according to Claim 3, named 5-(2,6-dichloro-4- methoxyphenyl)-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine.

55. A compound according to Claim 3, named 3,6-diethyl-N-(1-ethylpropyl)- 5-(3-methyl-1,1'-biphenyl-4-yl)pyrazin-2-amine.

56. A compound according to Claim 3, named 5-[2,4-

bis(trifluoromethyl)phenyl]-6-ethyl-N-(1 -ethylpropyl)-3-methoxypyrazin-2-amine.

57. A compound according to Claim 3, named 2-(2,4-dichlorophenyl)-3,6- diethyl-5-(1-methylbutoxy)pyrazine.

58. A compound according to Claim 3, named 2,5-diethyl-3~(1-isopropyl-2- methylpropoxy)-6-[4-methoxy-2-(trifluoromethoxy)phenyl]pyrazine.

59. A compound according to Claim 3, named 2,5-diethyl-3-(1-isopropyl-2- methylpropoxy)-6-[2-methyl-4-(trifluoromethoxy)phenyl]pyrazine.

60. A compound according to Claim 3, named 5-[4-chloro-2- (trifluoromethyl)phenyl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine.

61. A compound according to Claim 3, named N-(1-ethylpropyl)-3-methoxy- 5-[2-methoxy-4-(trifluoromethoxy)phenyl]-6-methylpyrazin-2-amine.

62. A compound according to Claim 3, named 5-[4-chloro-2- (trifluoromethyl)phenyl]-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine.

63. A compound according to Claim 3, named 3-ethyl-N-(1-ethylpropyl)-6- methoxy-5-[2-methyl-4-(trifluoromethoxy)phenyl]pyrazin-2-amine.

64. A compound according to Claim 3, named 5-(2,4-dimethylphenyl)-6- ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine.

65. A compound according to Claim 3, named 5-(2-chloro-4-ethoxyphenyl)- N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine.

66. A compound according to Claim 3, named O-(3-chloro-4- {5-[(1-

ethylpropyl)amino]-6-methoxy-3-methylpyrazin-2-yl} phenyl) S-propyl (dithiocarbonate).

67. A compound according to Claim 3, named 2,5-diethyl-3-(1-ethylpropoxy)- 6-[2-methoxy-4,6-bis(trifluoromethyl)phenyl]pyrazine. . 5

68. A compound according to Claim 3, named 3,6-diethyl-N-(1-ethylpropyl)- 5-(4-fluoro-2-methoxyphenyl)pyrazin-2-amine.

69. A compound according to Claim 3, named 5-(2-chloro-4-methylphenyl)- 3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine.

70. A compound according to Claim 3, named 5-(4-chloro-2-methoxyphenyl)- 3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine.

71. A compound according to Claim 3, named O-(3-chloro-4-{3,6-diethyl-5- [(1-ethylpropyl)amino]pyrazin-2-yl} phenyl) S-propyl (dithiocarbonate).

72. A compound according to Claim 3, named 5-(4-chloro-2,6- dimethoxyphenyl)-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine.

73. A compound according to Claim 3, named 2-(2,4-dimethoxyphenyl)-3,6- diethyl-5-(1-ethylbutoxy)pyrazine.

74. A compound according to Claim 3, named 5-[4-(1,3-dioxolan-2-yl)-2,6- dimethoxyphenyl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine.

75. A compound according to Claim 3, named 5-(4-ethoxy-2- methoxyphenyl)-3-ethyl-N-(1-ethylpropyl)-6-methoxypyrazin-2-amine.

76. A compound according to Claim 3, named 6-ethyl-N-(1-ethylpropyl)-3-

methoxy-5-(2-methoxy-6-methylphenyl)pyrazin-2-amine.

77. A compound according to Claim 3, named 2-(2-chloro-4-methoxyphenyl)- 3,6-diethyl-5-(1-isopropyl-2-methylpropoxy)pyrazine. ) 5

78. A compound according to Claim 3, named 2-(4-{5-[(1- ethylpropyl)amino]-6-methoxy-3-methylpyrazin-2-yl}-3,5-dimethoxyphenyl)propan-2-ol.

79. A compound according to Claim 3, named 5-(4-chloro-2-ethoxyphenyl)- N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine.

80. A compound according to Claim 3, named 3-ethyl-5-(2-ethyl-4- methoxyphenyl)-N-(1-ethylpropyl)-6-methoxypyrazin-2-amine.

81. A compound according to Claim 3, named 5-(4-chloro-2-ethoxyphenyl)-3- ethyl-N-(1-ethylpropyl)-6-methoxypyrazin-2-amine.

82. A compound according to Claim 3, named 5-(2-chloro-4- isopropoxyphenyl)-3-ethyl-N-(1-ethylpropyl)-6-methoxypyrazin-2-amine. ~ 83. A compound according to Claim 3, named 5-[2-chloro-4-(1- ethylpropoxy)phenyl]-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine.

84. A compound according to Claim 3, named 5-[2-chloro-4-(1- ethylpropoxy)phenyl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine.

85. A compound according to Claim 3, named 5-(2,4-dichlorophenyl)-N-(1- ethylpropyl)-6-methoxy-3-methylpyrazin-2-amine. ~ 86. A compound according to Claim 3, named 5-[2'-chloro-4',5-

bis(trifluoromethyl)-1,1'-biphenyl-2-y1]-N-(1-ethylpropyl)-6-methoxy-3-methylpyrazin- 2-amine.

87. A compound according to Claim 3, named N-(1-ethylpropyl)-5-(4-fluoro- 2-methoxyphenyl)-6-methoxy-3-methylpyrazin-2-amine.

88. A compound according to Claim 3, named 5-(2,4-dimethylphenyl)-N-(1- ethylpropyl)-6-methoxy-3-methylpyrazin-2-amine.

89. A compound according to Claim 3, named 2,5-diethyl-3-(2-ethyl-4- methoxyphenyl)-6-(1-isopropyl-2-methylpropoxy)pyrazine.

90. A compound according to Claim 3, named 5-(4-ethoxy-2- isopropoxyphenyl)-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine.

15 .

91. A compound according to Claim 3, named 5-[2-chloro-4-(1- ethylpropoxy)phenyl]-3-ethyl-N-(1-ethylpropyl)-6-methoxypyrazin-2-amine.

92. A compound according to Claim 3, named 2-[2-chloro-4- (trifluoromethyl)phenyl]-3,6-diethyl-5-(1-ethylbutoxy)pyrazine.

93. A compound according to Claim 3, named N-(1-ethylpropyl)-5-[4-(1- fluoroethyl)-2,6-dimethoxyphenyl]-3-methoxy-6-methylpyrazin-2-amine.

94. A compound according to Claim 3, named 5-[2-chloro-4-(2- methoxyethoxy)phenyl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine.

9s. A compound according to Claim 3, named 5-[4-(difluoromethoxy)-2- methoxyphenyl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine.

96. A compound according to Claim 3, named 5- {2-[(dimethylamino)methyl]- 4-methoxyphenyl}-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine.

97. A compound according to Claim 3, named (2-{5-[(1-ethylpropyl)amino]- ) 5 6-methoxy-3-methylpyrazin-2-yl}-5-methoxyphenyl)methanol.

98. A compound according to Claim 3, named 5-[4-(difluoromethoxy)-2- methoxyphenyl]-3-ethyl-N-(1-ethylpropyl)-6-methoxypyrazin-2-amine.

99. A compound according to Claim 3, named 2-(2-chloro-4-propoxyphenyl)- 3,6-diethyl-5-(1-ethylpropoxy)pyrazine.

100. A compound according to Claim 3, named 2-[2-chloro-4- (cyclopropylmethoxy)phenyl]-3,6-diethyl-S-(1-ethylpropoxy)pyrazine.

101. A compound according to Claim 3, named 2-[2-chloro-4-(2- fluoroethoxy)phenyl]-3,6-diethyl-5-(1-ethylpropoxy)pyrazine.

102. A compound according to Claim 3, named N-(1-ethylpropyl)-5-(4- isopropoxy-2-methoxyphenyl)-3-methoxy-6-methylpyrazin-2-amine.

103. A compound according to Claim 3, named 2-(4- {[tert- butyl(dimethyl)silylJoxy}-2-isopropoxyphenyl)-3,6-diethyl-5-(1-ethylpropoxy)pyrazine.

104. A compound according to Claim 3, named 2-(4-ethoxy-2- methoxyphenyl!)-3,6-diethyl-5-(1-ethylpropoxy)pyrazine.

105. A compound according to Claim 3, named 2-(2,6-dimethoxyphenyl)-3,6- diethyl-5-(1-ethylbutoxy)pyrazine.

106. A compound according to Claim 3, named 4- {3-ethyl-5-[(1- ethylpropyl)amino]-6-methoxypyrazin-2-yl}-3-methoxyphenol.

107. A compound according to Claim 3, named 6-ethyl-N-(1-ethylpropyl)-5-(4- ) 5 isopropoxy-2-methoxyphenyl)-3-methoxypyrazin-2-amine.

108. A compound according to Claim 3, named 4-[3,6-diethyl-5-(1-isopropyl- 2-methylpropoxy)pyrazin-2-yl}-3-ethylphenol.

109. A compound according to Claim 3, named 3-ethyl-N-(1-ethylpropyl)-5-[4- fluoro-2-(trifluoromethyl)phenyl]-6-methoxypyrazin-2-amine.

110. A compound according to Claim 3, named 2,5-diethyl-3-(1-isopropyl-2- methylpropoxy)-6-mesitylpyrazine.

111. A compound according to Claim 3, named 2,5-diethyl-3-(1-ethylpropoxy)- 6-(4-methoxy-2-methylphenyl)pyrazine.

112. A compound according to Claim 3, named 2,5-diethyl-3-[4-methoxy-2- (trifluoromethoxy)phenyl]-6-(1-propylbutoxy)pyrazine.

113. A compound according to Claim 3, named 6-chloro-5-[2-methoxy-4- (trifluoromethoxy)phenyl]pyrazin-2-amine.

114. A compound according to Claim 3, named 2-(4-butoxy-2-chlorophenyl)- 3,6-diethyl-5-(1-ethylbutoxy)pyrazine.

115. A compound according to Claim 3, named 3-bromo-N-(1-ethylpropyl)-6- methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2-amine.

116. A compound according to Claim 3, named 2-(4-{[tert- butyl(dimethyl)silyl]oxy}-2-ethoxyphenyl)-3,6-diethyl-5-(1-ethylpropoxy)pyrazine.

117. A compound according to Claim 3, named 6-methoxy-5-[2-methoxy-4- } 5 (trifluoromethoxy)phenyl]pyrazin-2-ylformamide.

118. A compound according to Claim 3, named 2,5-diethyl-3-(2-ethylbutyl)-6- [2-methoxy-4-(trifluoromethoxy)phenyl]pyrazine.

119. A compound according to Claim 3, named 2,5-diethyl-3-(1-ethylpropoxy)- 6-(2-isopropoxy-4-propoxyphenyl)pyrazine.

120. A compound according to Claim 3, named 2-(sec-butylthio)-5-(2,4- dimethoxyphenyl)-3,6-diethylpyrazine.

121. A compound according to Claim 3, named 5-(4-chloro-2,6- dimethoxyphenyl)-6-methoxypyrazin-2-amine.

122. A compound according to Claim 3, named 3,6-diethyl-N-(1-ethylpropyl)- 5-(2-methyl-4-chlorophenyl)pyrazin-2-amine.

123. A compound according to Claim 3, named 3,6-diethyl-N-(1-ethylpropyl)- 5-(2-methyl-4-fluorophenyl)pyrazin-2-amine.

124. A compound according to Claim 3, named 3,6-diethyl-N,N-(2- methoxyethyl)-5-(2,4-dichlorophenyl)pyrazin-2-amine.

125. A compound according to Claim 3, named 3,6-diethyl-N-propyl-N- (cyclopropylmethyl)-5-(2,4-dichloropheny!)pyrazin-2-amine.

126. A compound according to Claim 3, named 3,6-diethyl-2-(1- ethylpropoxy)-5-(2-methoxy-4,6-dimethylphenyl)pyrazine.

127. A compound according to Claim 3, named 3,6-dimethyl-2-(1- . 5 ethylpropoxy)-5-(2,4-dichlorophenyl)pyrazine.

128. A compound according to Claim 3, named 3,6-diethyl-2-(1- ethylpropoxy)-5-(2-hydroxy-4,6-dimethylphenyl)pyrazine.

129. A compound according to Claim 3, named 3,6-diethyl-2-(1- ethylpropoxy)-5-(2,4-dichlorophenyl)pyrazine.

130. A compound according to Claim 3, named 3,6-dimethyl-N-(1-methoxy-2- butyl)-5-(2,4-dimethoxyphenyl) pyrazin-2-amine.

131. A compound according to Claim 3, named 2-(2,4-dichlorophenyl)-5-[2- (methoxymethyl)pyrrolidin-1-yl]-3,6-dimethylpyrazine.

132. A compound according to Claim 3, named 2-(2,4-dimethoxyphenyl)-5-[2- (methoxymethyl) pyrrolidin-1-yl]-3,6-dimethylpyrazine.

133. A compound according to Claim 3, named 3,6-dimethyl-N-(1-- ethylpropyl)-5-(2-methyl-4-chlorophenyl)pyrazin-2-amine.

134. A compound according to Claim 3, named 3,6-dimethyl-N-(1- ethylpropyl)-5-(2-trifluoromethyl-4-dimethylaminophenyl)pyrazin-2-amine. ) 135. A compound according to Claim 3, named 3,6-diethyl-N-(1-ethylpropyl)- 5-(2-trifluoromethoxy-4-methoxyphenyl)pyrazin-2-amine.

136. A compound according to Claim 3, named 3,6-diethyl-N-(1-ethylpropyl)- 5-(2-methoxy-4-trifluoromethylphenyl)pyrazin-2-amine.

137. A compound according to Claim 3, named 3,6-diethyl-N-(1-ethylpropyl)- } 5 5-(2-trifluoromethyl-4-methoxyphenyl)pyrazin-2-amine.

138. A compound according to Claim 3, named 3,6-diethyl-N-(1-ethylpropyl)- 5-(2-methoxy-4-methylphenyl)pyrazin-2-amine.

139. A compound according to Claim 3, named 3,6-diethyl-N-(1-methoxy-2- butyl)-5-(2-chloro-4-dimethylaminophenyl)pyrazin-2-amine.

140. A compound according to Claim 3, named 3,6-diethyl-N-(1- methylpropyl)-5-(2-chloro-4-dimethylaminophenyl)pyrazin-2-amine.

141. A compound according to Claim 3, named 3,6-diethyl-N-(2- methylpropyl)-5-(2-chloro-4-dimethylaminophenyl)pyrazin-2-amine.

142. A compound according to Claim 3, named 3,6-diethyl-N-(2-phenylethyl)- 5-(2-chloro-4-dimethylphenyl)pyrazin-2-amine.

143. A compound according to Claim 3, named 3,6-diethyl-N-(1-propylbutyl)- 5-(2-trifluoromethyl-4-dimethylaminophenyl) pyrazin-2-amine.

144. A compound according to Claim 3, named 3,6-diethyl-N-(1-methoxy-2- butyl)-5-(2-trifluoromethyl-4-dimethylaminophenyl) pyrazin-2-amine.

145. A compound according to Claim 3, named 2-(2,6-dimethoxy-4-chloro- ) phenyl)-6-ethyl-5-(1-ethylpropoxy)-3-methoxypyrazine.

148. A compound named 2-(2-methoxy-S-trifivrormethoxyvphenyl)-3 -ethvl-6- meihviamino-3- (I-ethylpropoxy)-pyrazine.

147. A compound according to Claim 3 for use in a method tor treating a CNS disorder or disease, comprising administering to a patient in need of such treatment between 0.1 to 140 mg per kg body weight per day of the compound.

148. The compound of Claim 147 wherein the CNS disorder or disease 1s an anxiety disorder, stress-related disorder, or eating disorder.

149. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to Claim 3.

150. A compound according to Claim 3 wherein, in a standard in vitro CRE receptor binding assay the compound exhibits an ICs; value less than or equal to 1 micromolar.

I5t. A compound according to Clarm 3 for use in a method for modulating CRI receptor function, comprising administering to a patient in need of such modulation an effective amount of the compound.

152. A compound according to Clatm 3 for use in a method for treating a CNS disorder or disease, comprising administering to a patient in need of such treatment an eftective amount of the compound.

. 153. The compound of Claim 152 wherein the CNS disorder or disease is an anxiety disorder, stress-related disorder, or eating disorder. : 190 Amended Sheet — 2003-10-28 ’

{54 A compound according to Claim 3, wherein in a standard in vitro sodium channel functional assay the compound does not show any statistically sigrificant activity 2° the p<0.03 level of significance.

135. A compound of Claim 152 wherein the CNS disease or disorder 1s depression or a bipolar disorder.

136. A compound of Claim 152 wherein the CNS disease or disorder is anorexia nervosa, bulimia nervosa, or obesity. 1357. A compound according to Claim 132 wherein in a standard in vitro CRF receptor binding assay the compound exhibits an ICs value less than or equal to 1 micromolar. /

158. A compound according to Claim 152 wherein in a standard in vitro CRF receptor binding assay the compound exhibits an [Cy value less than or equal to 100 nanomolar.

139. A compound according to Clam 152 wherein tn a standard in vitro CRI receptor binding assay the compound exhibits an Cy value less than or equal to 10 nanomolar.

160. A compound according to Claim 132 wherein the patient is a human.

161. A method for localizing CRI receptors is tissue section samples comprising: contacting with a sample of tissue a deteactably-labelled compound of Claim 3 under conditions that permit binding of the compound to CRE receptors within the sample of tissue; washing the tissue sample to remove unbound compound; and 191 Amended Sheet —- 2003-10-23 detecting remaining bound compound.

162. A packaged pharmaceutical composition comprising a pharmaceutical composition of claim 149 in a container and instructions for using the composition to treat a patient suffering from an anxiety disorder, a stress-related disorder, or an eating disorder.

163. Use of a compound according to Claim 1 in the manufacture of a medicament, for use in a method for modulating the CRF receptor function, comprising administering to a patient in need of such modulation an effective amount of the compound.

164. Use of a compound according to Claim 1 in the manufacture of a medicament, for use in a method for treating a CNS disorder or disease, comprising administering to a patient in need of such treatment an effective amount of the compound.

165. Use of a compound according to Claim 3 in the manufacture of a medicament, for use in a method for treating a CNS disorder or disease, comprising administering to a patient in need of such treatment between 0.1 to 140 mg per kg body weight per day of the compound.

166. Use of a compound according to Claim 3 in the manufacture of a medicament, for use in a method for modulating CRF receptor function, comprising administering to a patient in need of such modulation an effective amount of the compound.

167. Use of a compound according to Claim 3 in the manufacture of a medicament, for use in a method for treating a CNS disorder or disease, comprising administering lo a patient in need of such treatment an effective amount of the compound.

168. Use of a compound according to Claim 3 in the manufacture of a medicament, for use in a method for altering the signal-transducing activity of a CRF1 receptor, the method comprising contacting cells expressing the receptor with the compound.

169. Use of a compound according to Claim 3 in the manufacture of a medicament, for use in a method of modulating G-protein coupled receptor function, the method comprising exposing cells expressing a G-protein coupled receptor to an effective amount of the compound. 192 Amended Sheet — 2004-05-20

170. A compound according to Claim 1 as specifically described herein.

171. © A compound according to Claim 3, other than the compounds of Claims 44 to 146, as specifically described herein.

172. A compound according to Claim 9 as specifically described herein.

173. A compound according to Claim 19 as specifically described herein. 192A Amended Sheet — 2004-05-20