(12) Patent Application Publication (10) Pub. No.: US 2003/0078271 A1 Blackburn Et Al

US 2003OO78271A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0078271 A1 Blackburn et al. (43) Pub. Date: Apr. 24, 2003

(54) USE OF GAL3 RECEPTOR ANTAGONISTS Publication Classification FOR THE TREATMENT OF DEPRESSION AND/OR ANXIETY AND COMPOUNDS (51) Int. Cl." ...... A61K 31/513; A61K 31/505; USEFUL IN SUCH METHODS A61K 31/506 (52) U.S. Cl...... 514/252.14; 514/256; 514/275; 514/269 (76) Inventors: Thomas P. Blackburn, Hoboken, NJ (57) ABSTRACT (US); Michael J. Konkel, Garfield, NJ (US); Lakmal W. Boteju, Cedar, NJ This invention is directed to pyrimidine and indolone deriva (US); Ian Jamie Talisman, New York, tives which are Selective antagonists for the GAL3 receptor. NY (US); John M. Wetzel, Fairlawn, The invention provides a pharmaceutical composition com NJ (US); Mathivanan Packiarajan, prising a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. This Saddle Brook, NJ (US); Heidi Chen, invention also provides a pharmaceutical composition made Wyckoff, NJ (US); Hermo Jimenez, by combining a therapeutically effective amount of a com Hackensack, NJ (US) pound of the invention and a pharmaceutically acceptable Correspondence Address: carrier. This invention further provides a process for making Cooper & Dunham LLP a pharmaceutical composition comprising combining a 1185 Avenue of the Americas therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. This New York, NY 10036 (US) invention also provides a method of treating a Subject (21) Appl. No.: 10/066,175 Suffering from depression and/or anxiety which comprises administering to the Subject an amount of a compound of the (22) Filed: Jan. 31, 2002 invention effective to treat the Subject's depression and/or anxiety. This invention also provides a method of treating Related U.S. Application Data depression and/or anxiety in a Subject which comprises administering to the Subject a composition comprising a (60) Provisional application No. 60/265,586, filed on Jan. pharmaceutically acceptable carrier and a therapeutically 31, 2001. effective amount of a GAL3 receptor antagonist. Patent Application Publication Apr. 24, 2003 Sheet 1 of 5 US 2003/0078271 A1

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USE OF GAL3 RECEPTOR ANTAGONSTS FOR 0008. The key clinical features of anxiety disorders relate THE TREATMENT OF DEPRESSION AND/OR to various combinations of psychological and physical mani ANXETY AND COMPOUNDS USEFUL IN SUCH festations of anxiety, not attributable to real danger and METHODS occurring either in attacks (panic disorder -PD) or as a persisting State (generalized anxiety disorder-GAD). Other BACKGROUND OF THE INVENTION neurotic features may be present (obsessional or hysterical Symptoms) but do not dominate the clinical picture. 0001) This application claims the benefit of U.S. Provi sional Application No. 60/265,586, filed Jan. 31, 2001, the 0009. The Pathophysiology of Depression contents of which is incorporated by reference into the 0010. Theories underlying the pathophysiology of Subject application. depression have developed from Several lines of evidence 0002 Throughout this application, various publications including: 1) changes in neurotransmitter monoamine lev are referenced in parentheses by author and year. Full els; 2)endocrine imbalance; and 3) electrophysiological citations for these references may be found at the end of the Studies on Sleep functions. Specification immediately preceding the claims. The disclo 0011 Evidence implicating the role of neurotransmitters Sures of these publications in their entireties are hereby in depression, in particular the monoamines Serotonin, nora incorporated by reference into this application to describe drenaline and dopamine, include the Success of pharmaco more fully the art to which this invention pertains. logical agents in treating depressive disorders. Many of the tricylic antidepressants (TCAS), Selective Serotonin re-up 0003) Depression is the most common of mental disor take inhibitors (SSRIs) and monoamine oxidase inhibitors derS and yet is often underdiagnosed and undertreated, (MAOIs) effective in the treatment of depression increase inflicting Substantial morbidity and psychoSocial impair the availability of the catecholamines (noradrenaline and ment on its Sufferers. Depression is mainly characterized by dopamine) and indolamines (serotonin) in the central ner sadness, flatness, loss of feeling, anhedonia (lack of plea vous system (CNS). The clinical efficacy of these agents has Sure), tearfulness, agitation or retardation, thoughts of guilt, given rise to the catecholamine-indolamine hypothesis of and worthlessness, in Severe cases, Suicide, hallucinations depression. This theory postulates that a certain level of and delusions. amines and/or receptor Sensitivity to catecholamines func 0004 Depression can be mainly categorized into bipolar tions to generate a normal mood. A receptor insensitivity, a disorders, identifying wide Swings of mood; major depres depletion of monoamines, or a decrease in their release, Sive illness, marked by Severe depressive symptoms but Synthesis or storage have been postulated to lead to depres without manic Swings, and less defined milder forms of SO. bipolar and major depression that fall short of the Specific diagnostic criteria e.g. dysthymic disorder (formerly called 0012 Current Treatments for Depression depressive neurosis). The Symptomatology and diagnostic 0013) A variety of pharmacological agents have been criteria for depression are set out in the DSMIV guidelines employed to treat depression based on the catecholamine (American Psychiatric Association (1994) Diagnostic and indolamine hypothesis of depression. Drugs used to treat Statistical Manual of Mental Disorders). Although many depression include MAOIs, atypical antipsychotics, lithium, patients have Single episodes of major depressive illness, the TCAS, and SSRIs. In addition, a number of off-label agents condition also can be repetitive, and this recurrent condition Such as antiepileptics are used to treat depression in treat is frequently called unipolar depressive illness. ment-resistant patients. 0005 The key features of depressive illness are a mark 0014 Tricyclic antidepressants are about equal to SSRIs edly gloomy mood in which there is a loSS of interest in life, in effectiveness against depression thus providing Support and general feelings of hopelessness and worthlessness. ing evidence for the catecholamine-indolamine hypothesis Depressive Symptoms range in Severity from mild mood of depression. However, SSRIs have largely displacedTCAS Swings to Severe delusions about Self-worth, accomplish because of side effects associated with TCAS and the need ments, and the future. to monitor EKG and plasma drug concentration. Although the SSRIs are viewed as an improvement over other anti 0006. The “blackness” of the presentation in the depressants, they are not without their clinical problems. depressed patient is most often accompanied by Severe Adverse effects on Sexual function, primarily anorgasmia motor retardation with profound sleep and appetite distur and delayed ejaculation, have been consistently reported. bance and Suicidal ideation. Furthermore, depressive illness Other, common Side-effects include sleep disorders, yawn can also present in a highly anxious or agitated State. ing, weight changes, Suicidal ideation and extrapyramidal like Side-effects Such as dystonic reactions. Thus, there 0007. The degree to which the underlying brain mecha clearly remains a medical need for new treatments of depres nisms in anxiety and depression differ or overlap remains Sion, without the adverse side-effect profile of existing unknown. The fact, however, that to Some extent the same agents and with improved efficacy. neurotransmitter Systems are involved in depression and anxiety does not mean that the mechanisms are identical. 0.015 Current Treatments for Anxiety However, the majority of people in an episode of either depression or anxiety also meet criteria for at least one other 0016. There is now considerable direct evidence for the psychiatric disorder. But by far the Strongest comorbidities efficacy of the SSRIs both in depression and in anxiety in both cases are between depression and anxiety disorders. disorders. Therefore, it is now becoming common clinical practice to 0017. Of the current SSRIs approved for marketing in the treat both indications with antidepressants such as SSRIs. USA all have shown sufficient efficacy to be further US 2003/0078271 A1 Apr. 24, 2003

approved for the treatment of at least one anxiety disorder, behaviors would not be scored and the conclusion would be for example; obsessive compulsive disorder (OCD) and that the compound in question does not possess antidepres generalized anxiety disorder (GAD). Compounds Such as Sant action. paroxetine and Sertraline are also indicated for the treatment 0025 Recently, however, a sampling technique was of panic disorder (PD). developed to score active behaviors in the FST, such as 0.018. However, it is clear from the issues raised earlier Swimming, climbing and diving, in addition to immobility relating to the efficacy and side-effect profile of SSRIs and (Detke, et al., 1995; Lucki, 1997; Page, et al., 1999; Reneric for that matter the more widely prescribed benzodiazapines, and Lucki, 1998). This modified sampling technique has there Still exists a real medical need for novel approaches for indicated that SSRIs, Such as fluoxetine, paroxetine and the treatment of anxiety and depression. Sertraline, Significantly decrease immobility and increase Swimming time (Detke, et al., 1995; Page, et al., 1999). In 0019 Discovery of GAL3 Receptor Subtype and its Role contrast, Selective reuptake inhibitors of norepinephrine in Depression and Anxiety (NE) increase climbing behavior but do not alter swimming 0020. The investigations leading to the present invention time (Detke, et al., 1995; Page, et al., 1999). arose from the discovery that mRNA for the GAL3 receptor is localized to areas of the rat brain associated with mood 0026 Rat Social Interaction Test (SIT) and emotion (see PCT International Publication No. WO 0027. There are a number of paradigms that have been 98/15570, published Apr. 16, 1998), thus supporting the used to determine whether a compound possesses anxiolytic expression of GAL3 in those regions. Protein for the GAL3 action. A number of these tests involve food or water receptor is also shown to localize to areas of the rat brain deprivation, punishment or measurement of consummatory associated with mood and emotion (see Table 11 and dis behavior (see File, et al., 1980; File, 1985; Rodgers, et al., cussion herein). 1997; and Treit, 1985, for review). In addition, in these models, prior conditioning reduces the uncertainty or anxi 0021. This discovery led to the hypothesis that the GAL3 ety. In general, these tests lack ethological validity. receptor may play a role in controlling the activity of catecholamine and indolamine neurons in the CNS. Galanin 0028. One model that is based upon an unconditioned is known to hyperpolarize neurons, including monoaminer response that does not involve punishment or deprivation is gic neurons (Seutin, et al., 1989) and to have inhibitory the Social Interaction Test (SIT) (File and Hyde, 1978, effects on 5-HT neurons (Xu, et al., 1998), and dopamine 1979). In this model, rats previously housed singly are neurons (Gopalan, et al., 1993; De Weille, et al., 1989; placed in a familiar, dimly lit, test arena with weight Jansson, et al., 1989; Nordstrom, et al., 1987; Weiss, et al., matched, novel partners. The principal anxiogenic Stimulus 1998). In light of these reports, a series of in vivo behavioral under these conditions is the partner novelty, which involves experiments were carried out to evaluate the antidepressant an unconditioned response to a potential threat. After phar properties of a Selective GAL3 receptor antagonist. The rat macological treatments, the following behaviors are Scored Forced Swim Test and the rat Social Interaction Test were as active Social interaction: grooming, Sniffing, biting, box employed to evaluate the use of Selective GAL3 receptor ing, wrestling, following, crawling over and crawling under. antagonists to treat depression and anxiety. These models are A wide range of psychoactive drugs have been examined in considered by experts in the field to reflect the potential of this paradigm and it has been shown that the Social inter agents to treat depression and anxiety. action test can distinguish anxiolytics from antidepressants, antipsychotics, analeptics and Sedative agents (File, 1985; 0022 Rat Forced Swim Test (FST) Guy and Gardner, 1985). This test can detect anxiolytic 0023 The rat Forced Swim Test (FST) is a behavioral test agents such as the benzodiazepines (File and Hyde, 1978; that is used to Screen compounds for antidepressant efficacy File and Hyde, 1979; File, 1980), in addition to non (Porsolt et al., 1977, 1978; Porsolt, 1981). This test is widely benzodiazepines, including paroxetine and other SSRIS used as it is reliable acroSS laboratories, relatively easy to (Lightowler, et al., 1994). Finally, the social interaction test perform and is Sensitive to the effects of Some of the major can detect anxiogenic agents, including the inverse benzo classes of antidepressant drugs, including TCAS and diazepine receptor agonists (File, et al., 1982, File and MAOIs, and various atypical antidepressants. Furthermore, Pellow, 1983; File and Pellow, 1984; File, 1985). this test is relatively Selective for antidepressant drugs, as 0029. In an embodiment of the present invention the few psychoactive drugs produce Similar behavioral actions synthesis of novel pyrimidines which bind selectively to the in the FST. cloned human GAL3 receptor, compared to other cloned human G-protein coupled receptors, as measured in in Vitro 0024. In the rat FST, animals are placed in a cylinder of assays, is disclosed. In a further embodiment of the present water, from which there is no escape, for an extended period invention the synthesis of indolones which bind selectively of time. Typically, animals will display a range of behaviors to the cloned human GAL3 receptor, compared to other Such as immobility, climbing, Swimming, and diving, with cloned human G-protein coupled receptors, as measured in immobility being predominant after Several minutes of in Vitro assays, is disclosed. The in Vitro receptor assays immersion in the water. Consequently, many past Studies described hereinafter were performed using various cultured have only measured or Scored immobility after the admin cell lines, each transfected with and expressing only a single istration of the test agent. Unfortunately, this method does galanin-type receptor. not Score any other active behaviors that may be produced by potential antidepressants. Thus, if a particular class of 0030. From the binding information described hereinaf antidepressant were to have very little effect on immobility, ter, it has unexpectedly been discovered that compounds yet produce characteristic behaviors during the FST, these which are specific for the human GAL3 receptor with a US 2003/0078271 A1 Apr. 24, 2003 binding affinity greater than ten-fold higher than the binding 0038 wherein Q is affinity with which the compounds bind to a human GAL1 receptor are effective in animal models of depression and anxiety which are predictive of efficacy in humans. Thus, we demonstrate that the GAL3 receptor antagonists, which may be classified as neutral antagonists, inverse agonists or allosteric modulators, provide a novel method to treat depressive disorders and/or anxiety. 0039 wherein Q is SUMMARY OF THE INVENTION 0031. The present invention provides a method of treat R22 R22 ing a Subject Suffering from depression which comprises R22 administering to the Subject an amount of compound effec R22 tive to treat the Subject's depression wherein the compound R22 has the Structure: p N R22 J-Rs AQex1. X R20 R20 N21 W 0040 wherein each J is independently O, S, C(R) or NR; Y ls N R13 0041 wherein R is H; straight chained or branched H C-C, alkyl, monofluoroalkyl or polyfluoroalkyl; Straight chained or branched C-C, alkenyl or alkynyl, C-C-7 cycloalkyl, Cs-C7 cycloalkenyl or aryl; 0032 wherein W is H, -F, -Cl, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy; 0042 wherein Y is NRRs; 0033 wherein X is; NRR;

-Nx )-R ; -N/ Y=0. O \ v R,

0043 wherein R is H, straight chained or branched C-C alkyl, (CH), O-(CH2)-CH3, Cs-Co 0034 wherein R is H, straight chained or branched cycloalkyl, or (COR))-Z, C-C, alkyl, (CH)-O-(CH), CH, aryl, or aryl (C-C)alkyl, 0044) wherein Rs is straight chained or branched C-C alkyl, (CH2). -O-(CH2)-CH3, C5-C1s 0035 wherein R is straight chained or branched cycloalkyl, (C(Rio)2)N(R) or (C(Rio)), Z, C-C, alkyl, (CH2)-O-(CH2), —CHs, or 0045 wherein R is straight chained or branched C-C, alkyl, straight chained or branched C-C, monof luoroalkyl, Straight chained or branched C-C, poly 0036 wherein R is a bicyclic alkyl ring system, fluoroalkyl, Straight chained or branched C-C, alk adamantyl, noradamantyl, C-C cycloalkyl, het enyl, straight chained or branched C-C, alkynyl, C-C, eroaryl, aryl, aryl(C-C)alkyl, Q or Q2; cycloalkenyl, -(CH2), Z, or (CH2)-O-(CH2)- 0037 wherein aryl may be substituted with one or CH; more C-Co straight chained or branched alkyl, aryl, 0046 wherein each R, is independently H; -OR, heteroaryl, or -OCOR, -COR, -NCOR1, -N(R), US 2003/0078271 A1 Apr. 24, 2003

-CON(R), -COOR, straight chained or 0061 wherein W is H, -F, -Cl, -Br, -I, CN, branched C-C, alkyl, Straight chained or branched methyl, ethyl, propyl, methoxy or ethoxy, C-C, monofluoroalkyl, straight chained or branched C-C, polyfluoroalkyl, straight chained or branched 0062 wherein X is NRR; C-C, alkenyl, straight chained or branched C-C, alkynyl, C-C, cycloalkenyl, -(CH-)-Z, or (CH), O-(CH), CH; R17 R17 0047 wherein Rs is straight chained or branched x -R /\ C-C alkyl, -(CH2), Z, or (CH-)-O-(CH-)- -N ) ; or -N N-Rs: CH; 0048 wherein each Ro is independently H, or straight chained or branched C-C alkyl, 0063 wherein R is H, straight chained or branched 0049 wherein each Ro is independently -H; straight C-C, alkyl, (CH2)-O-(CH2)-CHs, aryl or chained or branched C-C, alkyl, monofluoroalkyl or aryl(C-C)alkyl, polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C-7 cycloalkyl or Cs-C7 cycloalk 0064 wherein R is straight chained or branched enyl; -F, -Cl, -Br, or -I; -NO; -N, -CN; C-C, alkyl, (CH-)-O-(CH), CH, or -OR-, -OCOR, -COR, -NCOR, -N(R), -CON(R), or -COOR, aryl or het 0065 wherein R is a bicyclic alkyl ring system, aryl eroaryl; or two Rao groups present on adjacent carbon or aryl (C-C) alkyl, atoms can join together to form a methylenedioxy grOup, 0066 wherein Y is NRRs; 0050 wherein each R is independently -H; straight chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C-7 cycloalkyl, Cs-C, cycloalk enyl, aryl, or aryl(C-C) alkyl, 0051 wherein each R is independently H, F, CI or C-C straight chained or branched alkyl; 0052 wherein each m is an integer from 0 to 4 inclu Sive, 0053 wherein each n is an integer from 1 to 4 inclu Sive, 0054 wherein p is an integer from 0 to 2 inclusive; 0055 wherein q is an integer from 2 to 4 inclusive; 0056 wherein t is 1 or 2; 0067 wherein R is H, straight chained or branched C-C alkyl, (CH), O-(CH), CH, C-C, 0057 wherein U is O, -NR, S, C(R-), or cycloalkyl, or (COR))-Z, -NSOR; 0068 wherein R is straight chained or branched 0.058 wherein Z is C-C cycloalkyl, C-C, cyclic C-C alkyl, (CH), O-(CH2)-CH3, Cs-Co ether, C-C-7 cyclic thioether, aryl, or heteroaryl; or cycloalkyl, or (COR))-Z, 0059 a pharmaceutically acceptable salt thereof. 0069 wherein U is O, -NR, S, C(R), or 0060. The present invention provides a method of treat -NSOR; ing a Subject Suffering from depression which comprises 0070 wherein Z is C-Clocycloalkyl, aryl, or het administering to the Subject an amount of compound effec eroaryl; tive to treat the Subject's depression wherein the compound 0071 wherein R is straight chained or branched has the Structure: C-C, alkyl, straight chained or branched C-C, monof luoroalkyl, Straight chained or branched C-C, poly fluoroalkyl, Straight chained or branched C-C, alk X enyl, straight chained or branched C-C, alkynyl, C-C, W cycloalkenyl, -(CH2), Z, or (CH), O N21 (CH-)-CH, ls R13 0072 wherein each R, is independently H; -OR, Y N -OCOR1, -COR, -NCOR1, -N(R), H -CON(R), -COOR, straight chained or branched C-C, alkyl, Straight chained or branched C-C, monofluoroalkyl, straight chained or branched US 2003/0078271 A1 Apr. 24, 2003

C-C, polyfluoroalkyl, Straight chained or branched 0086 wherein X is N(CH) or C-C, alkenyl, straight chained or branched C-C, alkynyl, C-C, cycloalkenyl, -(CH-)-Z, or (CH), O-(CH), CH; R17 0073 wherein Rs is straight chained or branched C-C alkyl, -(CH2), Z, or (CH-)-O-(CH-)- CH; 0087 wherein R is an aryl, adamantyl, noradaman 0074 wherein each Ro is independently H, or straight tyl, C-Cocycloalkyl, heteroaryl, Q or Q, chained or branched C-C alkyl, 0088 wherein aryl may be substituted with one or 0075 wherein each Ro is independently -H; straight more C-Co Straight chained or branched alkyl, aryl, chained or branched C-C, alkyl, monofluoroalkyl or heteroaryl, or N(R)-Z, polyfluoroalkyl, 0089 wherein Q is 0076 straight chained or branched C-C, alkenyl or alkynyl, C-C-7 cycloalkyl or Cs-C7 cycloalkenyl, -F, Cl, -Br, or -I; -NO; -N; -CN; -OR, -OCOR1, -COR, -NCOR1, -N(R), -CON(R), or -COOR, aryl or heteroaryl; or two Rao groups present on adjacent carbon atoms can join

together to form a methylenedioxy group; 0077 wherein each R is independently -H; straight chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C-7 cycloalkyl, Cs-C, cycloalk enyl, aryl or aryl(C-C6) alkyl; 0078 wherein each m is an integer from 0 to 4 inclu Sive, 0079 wherein each n is an integer from 1 to 4 inclu Sive, 0080 wherein p is an integer from 0 to 2 inclusive; 0091 wherein each J is independently O, S, C(R) or 0081 wherein q is an integer from 2 to 4 inclusive; NR; 0092 wherein R is -H; straight chained or branched 0082 wherein t is 1 or 2; or C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, 0083) a pharmaceutically acceptable salt thereof. C-C-7 cycloalkyl, Cs-C7 cycloalkenyl or aryl; 0084. The present invention provides a method of treat 0093 wherein Y is NRRs; ing a Subject Suffering from depression which comprises administering to the Subject an amount of compound effec tive to treat the Subject's depression wherein the compound has the Structure:

X N21 W ls R13 Y N / XR H -N s

M 0085 wherein W is H, -F, -Cl, -Br, -I, CN, \ 5. methyl, ethyl, propyl, methoxy or ethoxy, US 2003/0078271 A1 Apr. 24, 2003

(0094) wherein R is H, straight chained or branched 0111. The present invention provides a method of treating C-C alkyl, (CH-)-O-(CH-)-CH, C-C, a Subject Suffering from depression which comprises admin cycloalkyl, or (C(R))-Z, istering to the Subject an amount of compound effective to 0095 wherein Rs is straight chained or branched treat the Subject's depression wherein the compound has the C-C alkyl, (CH), O-(CH2)-CH3, Cs-Co Structure: cycloalkyl, or (C(R)), Z; 0096 wherein U is O, -NR, S, C(R), or X -NSOR; W 0097 wherein Z is C-C cycloalkyl, aryl, or het N21 eroaryl; ls R13 0098 wherein R is straight chained or branched Y N C-C, alkyl, straight chained or branched C-C, monof H luoroalkyl, Straight chained or branched C-C, poly fluoroalkyl, Straight chained or branched C-C, alk enyl, straight chained or branched C-C, alkynyl, C-C, 0112 wherein W is H, -F, -Cl, -Br, -I, CN, cycloalkenyl, -(CH), Z, or (CH), O methyl, ethyl, propyl, methoxy or ethoxy, 0113 wherein X is N(CH) or 0099 wherein each R, is independently H; -OR, -OCOR, -COR, -NCOR, -N(R), -CON(R), -COOR, straight chained or R17 branched C-C, alkyl, Straight chained or branched C-C, monofluoroalkyl, straight chained or branched C-C, polyfluoroalkyl, straight chained or branched C-C, alkenyl, straight chained or branched C-C, alkynyl, C-C, cycloalkenyl, -(CH-)-Z, or (CH), O-(CH), CH; 0114 wherein R is a bicyclic alkyl ring System, aryl 0100 wherein Rs is straight chained or branched or aryl (C-C)alkyl; C-C alkyl, -(CH), Z, or (CH-)-O-(CH),- CH; 0115 wherein Y is NRRs; 0101 wherein each Ro is independently H, or straight 0116 wherein R is H, straight chained or branched C-C alkyl, (CH), O-(CH2), CH5, C-C, chained or branched C-C alkyl, cycloalkyl, or (COR))-Z, 0102 wherein each Ro is independently -H; straight chained or branched C-C, alkyl, monofluoroalkyl or 0117 wherein Rs is (C(Ro))-N(R), polyfluoroalkyl, Straight chained or branched C-C, 0118 wherein Z is C-Cocycloalkyl, aryl, or het alkenyl or alkynyl, C-C-7 cycloalkyl or Cs-C7 cycloalk eroaryl; enyl; -F, -Cl, -Br, or -I; -NO; -N; -CN; -OR-, -OCOR, -COR, -NCOR, 0119 wherein R is straight chained or branched -N(R), -CON(R), or -COOR, aryl or het C-C, alkyl, straight chained or branched C-C, monof eroaryl; or two Rao groups present on adjacent carbon luoroalkyl, Straight chained or branched C-C, poly atoms can join together to form a methylenedioxy fluoroalkyl, Straight chained or branched C-C, alk grOup, enyl, straight chained or branched C-C, alkynyl, C-C, cycloalkenyl, -(CH2), Z, or (CH), O 0.103 wherein each R is independently -H; straight chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, 0120 wherein each R, is independently H; -OR, alkenyl or alkynyl, C-C, cycloalkyl, Cs-C, cycloalk -OCOR, -COR, -NCOR1, -N(R), enyl, aryl or aryl(C-C) alkyl, -CON(R), -COOR, straight chained or branched C-C, alkyl, Straight chained or branched 0104 wherein each R is independently H, F, CI or C-C, monofluoroalkyl, straight chained or branched C-C straight chained or branched alkyl; C-C, polyfluoroalkyl, straight chained or branched C-C, alkenyl, straight chained or branched C-C, 0105 wherein each m is an integer from 0 to 4 inclu alkynyl, C-C, cycloalkenyl, -(CH-)-Z, or Sive, (CH), O-(CH), CH; 0106 wherein each n is an integer from 1 to 4 inclu 0121 wherein each Rio is independently H, or straight Sive, chained or branched C-C alkyl, 0107 wherein p is an integer from 0 to 2 inclusive; 0122 wherein each R is independently-H; straight 0108) wherein q is an integer from 2 to 4 inclusive; chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, 01.09) wherein t is 1 or 2; or alkenyl or alkynyl, C-C-7 cycloalkyl, Cs-C7 cycloalk 0110) a pharmaceutically acceptable Salt thereof. enyl, aryl or aryl(C-C) alkyl, US 2003/0078271 A1 Apr. 24, 2003

0123 wherein each m is an integer from 0 to 4 inclu- 0135) wherein Q is Sive,

0.124 wherein each n is an integer from 1 to 4 inclu Sive, 0.125 wherein q is an integer from 2 to 4 inclusive; or 0.126 a pharmaceutically acceptable salt thereof. 0127. The present invention also provides a method of treating a Subject Suffering from anxiety which comprises administering to the Subject an amount of compound effec tive to treat the Subjects anxiety wherein the compound has the Structure: 0136 wherein each J is independently O, S, C(R) or NR; X 0.137 wherein R is H; straight chained or branched W C-C, alkyl, monofluoroalkyl or polyfluoroalkyl; N21 Straight chained or branched C-C, alkenyl or alkynyl, ls C-C-7 cycloalkyl, Cs-C7 cycloalkenyl or aryl; Y s - Ris 0138 wherein Y is NRRs; h R R17 S4 20 0128 wherein W is H, -F, -Cl, -Br, -I, CN, / \ R20 N. S methyl,y1, elnyl,ethyl, propypropyl, methoxyy or ethoxy,y -N ŽSRU 21 or 0129 wherein X is; NRR; p s Rio N-- N N s

R17 R17 / yW R20 X y Rii / -N XEK : -N Q -N SC O; or \ VR, \ R. \ X f MNR20 -N N-Ris 0.139 wherein R is H, straight chained or branched \ R. C-C alkyl, (CH), O-(CH2)-CH3, Cs-Co cycloalkyl, or (COR))-Z, 0140 wherein R is straight chained or branched 0130 wherein R is H, straight chained or branched C-C3 alkyl, (CH), O-(CH2),il CH,s C-C, . (CH-)-O-(CH-)-CH, aryl, or aryl cycloalkyl, (C(R))N(R) or (C(R)-Z, (C-C)alkyl, 0141 wherein R is straight chained or branched 0131 wherein R is straight chained or branched C-C, alkyl, straight chained or branched C-C, monof C-C, alkyl, (CH-)-(CH2)-CH3, or -(CH2), Z; luoroalkyl, Straight chained or branched C-C, poly - 0 fluoroalkyl, Straight chained or branched C-C, alk 0132 wherein R is a bicyclic alkyl ring system, enyl, straight chained or branched C-C, alkynyl, C-C, adamantyl, noradamantyl, C-C cycloalkyl, het- cycloalkenyl, -(CH2), Z, or (CH), O eroaryl, aryl, aryl(C-C)alkyl, Q or Q2; (CH), CH, 0.133 wherein aryl may be substituted with one or 0142 wherein each R, is independently H; -OR, more C-Co Straight chained or branched alkyl, aryl, -OCOR, -COR, -NCOR1, N(Ra). heteroaryl, or N(Ro)-Z, -CON(R), -COOR, straight chained or branched C-C, alkyl, Straight chained or branched 0134) wherein Q is C-C, monofluoroalkyl, straight chained or branched C-C, polyfluoroalkyl, straight chained or branched C-C, alkenyl, straight chained or branched C-C, N-J R22 alkynyl, C-C, cycloalkenyl, -(CH-)-Z, or -H X. (CH), O-(CH), CH; 21N R22 0.143 wherein Rs is straight chained or branched i. alkyl, -(CH2), Z, or (CH-)-O-(CH2)- 3. US 2003/0078271 A1 Apr. 24, 2003

0144 wherein each Ro is independently H, or straight 0159) wherein X is NRR; chained or branched C-C alkyl, 0145 wherein each Rao is independently -H; straight chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, 0146 straight chained or branched C-C, alkenyl or alkynyl, C-C-7 cycloalkyl or Cs-C7 cycloalkenyl, -F, Cl, -Br, or -I; -NO; -N; -CN; -OR, -OCOR1, -COR, -NCOR1, -N(R), 0160 wherein R is H, straight chained or branched -CON(R), or -COOR, aryl or heteroaryl; or two C-C, alkyl, (CH), O-(CH-)-CH, aryl or Rao groups present on adjacent carbon atoms can join aryl(C-C)alkyl, together to form a methylenedioxy group; 0.161 wherein R is straight chained or branched 0147 wherein each R is independently -H; straight C-C, alkyl, (CH-)-O-(CH), CH, or chained or branched C-C, alkyl, monofluoroalkyl or 0162 wherein R is a bicyclic alkyl ring System, aryl polyfluoroalkyl, Straight chained or branched C-C, or aryl(C-C)alkyl, alkenyl or alkynyl, C-C-7 cycloalkyl, Cs-C, cycloalk enyl, aryl, or aryl(C-C) alkyl, 0163 wherein Y is NRRs;

0148 wherein each R is independently H, F, CI or R20 C-C straight chained or branched alkyl; R17 1á 0149 wherein each m is an integer from 0 to 4 inclu /-V Sive, -N U 0150 wherein each n is an integer from 1 to 4 inclu Sive, 0151 wherein p is an integer from 0 to 2 inclusive; 0152 wherein q is an integer from 2 to 4 inclusive; / 2. 0153 wherein t is 1 or 2; -N o A. 0154 wherein U is O, -NR, S, C(R), or \ ŽSR. -NSOR; O155 wherein Z is C-C cycloalkyl, C-C, cyclic ether, C-C-7 cyclic thioether, aryl, or heteroaryl; or 0164 wherein R is H, straight chained or branched C-C alkyl, (CH), O-(CH2)-CH3, Cs-Co 0156 a pharmaceutically acceptable salt thereof. cycloalkyl, or (COR))-Z, O157 The invention provides a method of treating a 0.165 wherein Rs is straight chained or branched Subject Suffering from anxiety which comprises administer C-C alkyl, (CH), O-(CH2), CH5, C-C, ing to the Subject an amount of compound effective to treat cycloalkyl, or (COR))-Z, the Subject's anxiety wherein the compound has the Struc 0166 wherein U is O, -NR, S, C(R), or ture: -NSOR; 0.167 wherein Z is C-Clocycloalkyl, aryl, or het eroaryl; X 0168 wherein R is straight chained or branched W C-C, alkyl, straight chained or branched C-C, monof N21 luoroalkyl, Straight chained or branched C-C, poly fluoroalkyl, Straight chained or branched C-C, alk Y S. R13 enyl, straight chained or branched C-C, alkynyl, C-C, cycloalkenyl, -(CH2), Z, or (CH), O H (CH-)-CH, 0169 wherein each R, is independently H; -OR, -OCOR, -COR, -NCOR1, -N(R), -CON(R), -COOR, straight chained or 0158 wherein W is H, -F, -Cl, -Br, -I, CN, methyl, branched C-C, alkyl, Straight chained or branched ethyl, propyl, methoxy or ethoxy, C-C, monofluoroalkyl, straight chained or branched US 2003/0078271 A1 Apr. 24, 2003

C-C, polyfluoroalkyl, Straight chained or branched 0182 wherein X is N(CH) or C-C, alkenyl, straight chained or branched C-C, alkynyl, C-C, cycloalkenyl, -(CH-)-Z, or (CH), O-(CH), CH; R17 0170 wherein Rs is straight chained or branched - Y C-C alkyl, -(CH2), Z, or (CH-)-O-(CH-)- \ R. CH; 0183 wherein R is an aryl, adamantyl, noradaman 0171 wherein each Ro is independently H, or straight tyl, C-Co cycloalkyl, heteroaryl, Q or Q, chained or branched C-C alkyl, 0.184 wherein aryl may be substituted with one or more C-Co Straight chained or branched alkyl, aryl, 0172 wherein each Ro is independently -H; straight heteroaryl, or N(R)-Z, chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, 0185 wherein Q is alkenyl or alkynyl, C-C-7 cycloalkyl or Cs-C7 cycloalk enyl; -F, -Cl, -Br, or -I; -NO; -N; -CN; -OR. --OCOR, -COR, -NCOR, -N(R), -CON(R), or -COOR, aryl or het eroaryl; or two Rao groups present on adjacent carbon J R22: atoms can join together to form a methylenedioxy grOup, 0186 wherein Q is 0173 wherein each R is independently -H; straight chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, R22 R22 alkenyl or alkynyl, C-C-7 cycloalkyl, Cs-C, cycloalk R22 enyl, aryl or aryl(C-C) alkyl; R22 R 0.174 wherein each m is an integer from 0 to 4 inclu 22 p N Sive, R22 J-Rs AleX1. 0.175 wherein each n is an integer from 1 to 4 inclu R20 R20 Sive, 0176 wherein p is an integer from 0 to 2 inclusive; 0187 wherein each J is independently O, S, C(R) or 0177 wherein q is an integer from 2 to 4 inclusive; NR; 0188 wherein R is -H; straight chained or branched 0178 wherein t is 1 or 2; or C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, 0179 a pharmaceutically acceptable salt thereof. C-C-7 cycloalkyl, Cs-C7 cycloalkenyl or aryl; 0180. The invention provides a method of treating a 0189 wherein Y is NRRs; Subject Suffering from anxiety which comprises administer ing to the Subject an amount of compound effective to treat the Subject's anxiety wherein the compound has the Struc R20 ture: /-VR17 1á -N U X N21 W Y S R13 / x: H -N o

M 0181 wherein W is H, -F, -Cl, -Br, -I, CN, \ ŽSR. methyl, ethyl, propyl, methoxy or ethoxy, US 2003/0078271 A1 Apr. 24, 2003 10

(0190) wherein R is H, straight chained or branched 0207. The invention provides a method of treating a C-C alkyl, (CH-)-O-(CH-)-CH, C-C, Subject Suffering from anxiety which comprises administer cycloalkyl, or (C(R)), Z; ing to the Subject an amount of compound effective to treat 0191 wherein Rs is straight chained or branched the Subject's anxiety wherein the compound has the Struc C-C alkyl, (CH), O-(CH2)-CH3, Cs-Co ture: cycloalkyl, or (C(R)), Z; 0192 wherein U is O, -NR, S, C(R), or X -NSOR; W 0193 wherein Z is C-C cycloalkyl, aryl, or het N 21 eroaryl; R13 0194 wherein R is straight chained or branched Y N C-C, alkyl, straight chained or branched C-C, monof H luoroalkyl, Straight chained or branched C-C, poly fluoroalkyl, Straight chained or branched C-C, alk enyl, straight chained or branched C-C, alkynyl, C-C, 0208 wherein W is H, -F, -Cl, -Br, -I, CN, cycloalkenyl, -(CH), Z, or (CH), O methyl, ethyl, propyl, methoxy or ethoxy, 0209 wherein X is N(CH) or 0195 wherein each R, is independently H; -OR, -OCOR, -COR, -NCOR, -N(R), -CON(R), -COOR, straight chained or R17 branched C-C, alkyl, Straight chained or branched C-C, monofluoroalkyl, straight chained or branched C-C, polyfluoroalkyl, straight chained or branched - YSC C-C, alkenyl, straight chained or branched C-C, alkynyl, C-C, cycloalkenyl, -(CH-)-Z, or (CH), O-(CH), CH; 0210 wherein R is a bicyclic alkyl ring system, aryl 0196) wherein Rs is straight chained or branched or aryl(C-C)alkyl, C-C alkyl, -(CH), Z, or (CH-)-O-(CH),- CH; 0211 wherein Y is NRRs; 0.197 wherein each Ro is independently H, or straight 0212 wherein R is H, straight chained or branched C-C alkyl, (CH2), O-(CH2)-CH3, Cs-Co chained or branched C-C alkyl, cycloalkyl, or (COR))-Z, 0198 wherein each Ro is independently -H; straight chained or branched C-C, alkyl, monofluoroalkyl or 0213 wherein Rs is (C(Ro))-N(R); polyfluoroalkyl, Straight chained or branched C-C, 0214) wherein Z is C-C cycloalkyl, aryl, or het alkenyl or alkynyl, C-C-7 cycloalkyl or Cs-C7 cycloalk eroaryl; enyl; -F, -Cl, -Br, or -I; -NO; -N; -CN; -OR-, -OCOR, -COR, -NCOR, 0215 wherein R is straight chained or branched -N(R), -CON(R), or -COOR, aryl or het C-C, alkyl, straight chained or branched C-C, monof eroaryl; or two Rao groups present on adjacent carbon luoroalkyl, Straight chained or branched C-C, poly atoms can join together to form a methylenedioxy fluoroalkyl, Straight chained or branched C-C, alk grOup, enyl, Straight chained or branched CC, alkynyl, C-C, cycloalkenyl, -(CH2), Z, or (CH), O 0199 wherein each R is independently -H; straight chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, 0216 wherein each R, is independently H; -OR, alkenyl or alkynyl, C-C, cycloalkyl, Cs-C, cycloalk -OCOR, -COR, -NCOR1, -N(R), enyl, aryl or aryl(C-C) alkyl, -CON(R), -COOR, straight chained or branched C-C, alkyl, Straight chained or branched 0200 wherein each R is independently H, F, CI or C-C, monofluoroalkyl, straight chained or branched C-C straight chained or branched alkyl; C-C, polyfluoroalkyl, straight chained or branched C-C, alkenyl, straight chained or branched C-C, 0201 wherein each m is an integer from 0 to 4 inclu alkynyl, C-C, cycloalkenyl, -(CH-)-Z, or SIVe; (CH), O-(CH), CH; (0202) wherein each n is an integer from 1 to 4 inclu 0217 wherein each Rio is independently H, or straight SIVe; chained or branched C-C alkyl, 0203 wherein p is an integer from 0 to 2 inclusive; 0218 wherein each R is independently-H; straight 0204 wherein q is an integer from 2 to 4 inclusive; chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, 0205 wherein t is 1 or 2; or alkenyl or alkynyl, C-C-7 cycloalkyl, Cs-C7 cycloalk 0206 a pharmaceutically acceptable salt thereof. enyl, aryl or aryl(C-C) alkyl, US 2003/0078271 A1 Apr. 24, 2003

0219 wherein each m is an integer from 0 to 4 inclu 0231 wherein Q is Sive, 0220 wherein each n is an integer from 1 to 4 inclu R22 R22 Sive, 0221 wherein q is an integer from 2 to 4 inclusive; or 0222 a pharmaceutically acceptable Salt thereof. 0223) The invention also provides a pharmaceutical com position comprising a pharmaceutically acceptable carrier R20 R20 and a compound having the Structure: 0232 wherein each J is independently O, S, C(R) or X NR; W 0233 wherein R is H; straight chained or branched Na C-C, alkyl, monofluoroalkyl or polyfluoroalkyl; Straight chained or branched C-C, alkenyl or alkynyl, Y ls N R13 C-C, cycloalkyl, Cs-C, cycloalkenyl or aryl;

H 0234 wherein Y is NRRs;

0224 wherein W is H, -F, -Cl, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy, 0225 wherein X is; NRR;

0235 wherein R is H, straight chained or branched C-C alkyl, (CH), O-(CH2)-CH3, Cs-Co cycloalkyl, or (COR))-Z, 0226 wherein R is H, straight chained or branched C-C, alkyl, (CH2)-O-(CH2), —CHs, aryl, or aryl 0236 wherein R is straight chained or branched (C-C)alkyl, C-C alkyl, (CH), O-(CH2), CH5, C-C, cycloalkyl, (C(Rio)2)N(R) or (C(R)2), Z; 0227 wherein R is straight chained or branched 0237 wherein R is straight chained or branched C-C, alkyl, (CH2)-O-(CH2), —CHs, or C-C, alkyl, straight chained or branched C-C, monof luoroalkyl, Straight chained or branched C-C, poly fluoroalkyl, Straight chained or branched C-C, alk 0228 wherein R is a bicyclic alkyl ring system, enyl, straight chained or branched C-C, alkynyl, C-C, adamantyl, noradamantyl, C-C cycloalkyl, het cycloalkenyl, -(CH2), Z, or (CH), O eroaryl, aryl, aryl(C-C)alkyl, Q or Q2; (CH), CH, 0229 wherein aryl may be substituted with one or 0238 wherein each R, is independently H; -OR, more C-Co Straight chained or branched alkyl, aryl, -OCOR1, -COR, -NCOR1, -N(R), heteroaryl, or N(R)-Z, -CON(R), -COOR, straight chained or branched C-C, alkyl, Straight chained or branched 0230 wherein Q is C-C, monofluoroalkyl, straight chained or branched C-C, polyfluoroalkyl, straight chained or branched C-C, alkenyl, straight chained or branched C-C, N J. R22 alkynyl, C-C, cycloalkenyl, -(CH-)-Z, or (CH), O-(CH), CH; - 21IX J R22: 0239 wherein Rs is straight chained or branched i. alkyl, -(CH2), Z, or (CH-)-O-(CH2)- 3. US 2003/0078271 A1 Apr. 24, 2003

0240 wherein each Ro is independently H, or straight 0255 wherein R is H, straight chained or branched chained or branched C-C alkyl, C-C, alkyl, (CH), O-(CH-)-CH, aryl or aryl(C-C)alkyl, 0241 wherein each Ro is independently -H; straight chained or branched C-C, alkyl, monofluoroalkyl or 0256 wherein R is straight chained or branched polyfluoroalkyl, Straight chained or branched C-C, C-C, alkyl, (CH2)-O-(CH2)-CH3, or alkenyl or alkynyl, C-C, cycloalkyl or C-C, cycloalk enyl; -F, -Cl, -Br, or -I; -NO; -N, -CN; 0257 wherein R is a bicyclic alkyl ring system, aryl -OR-, -OCOR, -COR, -NCOR, or aryl(C-C)alkyl, -N(R), -CON(R), or -COOR, aryl or het eroaryl; or two Rao groups present on adjacent carbon 0258 wherein Y is NRRs; atoms can join together to form a methylenedioxy grOup, 0242 wherein each R is independently -H; straight chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C-7 cycloalkyl, Cs-C, cycloalk enyl, aryl, or aryl(C-C) alkyl, 0243 wherein each R is independently H, F, CI or C-C straight chained or branched alkyl; 0244 wherein each m is an integer from 0 to 4 inclu Sive, 0245 wherein each n is an integer from 1 to 4 inclu Sive, 0246 wherein p is an integer from 0 to 2 inclusive; 0259 wherein R is H, straight chained or branched 0247 wherein q is an integer from 2 to 4 inclusive; C-C alkyl, (CH), O-(CH2)-CH3, Cs-Co 0248 wherein t is 1 or 2; cycloalkyl, or (C(R)), Z. 0249 wherein U is O, -NR, S, C(R), or 0260 wherein Rs is straight chained or branched -NSOR; C-C alkyl, (CH), O-(CH), CH, C-C, cycloalkyl, or (COR))-Z, 0250 wherein Z is C-Clocycloalkyl, C-C, cyclic ether, C-C-7 cyclic thioether, aryl, or heteroaryl; or 0261 wherein U is O, -NR, S, C(R), or -NSOR; 0251 a pharmaceutically acceptable salt thereof. 0262 wherein Z is C-Clocycloalkyl, aryl, or het 0252) The invention provides a pharmaceutical compo eroaryl; Sition comprising a pharmaceutically acceptable carrier and 0263 wherein R is straight chained or branched a compound having the Structure: C-C, alkyl, straight chained or branched C-C, monof luoroalkyl, Straight chained or branched C-C, poly fluoroalkyl, Straight chained or branched C-C, alk X enyl, straight chained or branched C-C, alkynyl, C-C, W cycloalkenyl, -(CH2), Z, or (CH), O N21 (CH-)-CH, ls R13 0264 wherein each R, is independently H; -OR, Y N -OCOR, -COR, -NCOR1, -N(R), H -CON(R), -COOR, straight chained or branched C-C, alkyl, Straight chained or branched C-C, monofluoroalkyl, straight chained or branched 0253) wherein W is H, -F, -Cl, -Br, -I, CN, C-C, polyfluoroalkyl, straight chained or branched methyl, ethyl, propyl, methoxy or ethoxy, C-C, alkenyl, straight chained or branched C-C, alkynyl, Cs-C7 cycloalkenyl, -(CH2)-Z, or 0254 wherein X is NRR; (CH), O-(CH), CH; 0265 wherein Rs is straight chained or branched i. alkyl, -(CH2), Z, or (CH-)-O-(CH), 39 0266 wherein each Rio is independently H, or straight chained or branched C-C alkyl, 0267 wherein each Rao is independently -H; straight chained or branched C-C, alkyl, monofluoroalkyl or US 2003/0078271 A1 Apr. 24, 2003 13

polyfluoroalkyl, Straight chained or branched C-C, 0280 wherein Q is alkenyl or alkynyl, C-C, cycloalkyl or C-C, cycloalk enyl; -F, -Cl, -Br, or -I; -NO; -N, -CN; -OR2, -R, COR2, -NCOR1, -N(R), -CON(R), or -COOR, aryl or heteroaryl; or two Rao groups present on adjacent carbon atoms can join together to form a methylenedioxy group; 0268 wherein each R is independently -H; straight chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C-7 cycloalkyl, Cs-C, cycloalk enyl, aryl or aryl(C-C) alkyl, 0269 wherein each m is an integer from 0 to 4 inclu Sive, 0270 wherein each n is an integer from 1 to 4 inclu SIVe; 0271 wherein p is an integer from 0 to 2 inclusive; 0272 wherein q is an integer from 2 to 4 inclusive; 0273 wherein t is 1 or 2; or 0282) wherein each J is independently O, S, C(R) or NR; 0274 a pharmaceutically acceptable salt thereof. 0283 wherein R is -H; straight chained or branched 0275. The invention provides a pharmaceutical compo C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Sition comprising a pharmaceutically acceptable carrier and Straight chained or branched C-C, alkenyl or alkynyl, a compound having the Structure: C-C, cycloalkyl, Cs-C, cycloalkenyl or aryl; 0284 wherein Y is NRRs;

X N21 W -NV X.U 4\, ls R13 Y R17; Rio - ; or Y N N H / V-R20X 0276 wherein W is H, -F, -Cl, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy, -N o s A. 0277 wherein X is N(CH) or \ 7 s.

R17 0285 wherein R is H, straight chained or branched - )=0 C-C alkyl, (CH), O-(CH2), CH5, C-C, \ v R, cycloalkyl, or (COR))-Z, 0286 wherein Rs is straight chained or branched C-C alkyl, (CH), O-(CH), CH, C-C, cycloalkyl, or (COR))-Z, 0278 wherein R is an aryl, adamantyl, noradaman 0287 wherein U is O, -NR, S, C(R), or tyl, C-Cocycloalkyl, heteroaryl, Q or Q, -NSOR; 0288 wherein Z is C-C cycloalkyl, aryl, or het 0279 wherein aryl may be substituted with one or eroaryl; more C-Co Straight chained or branched alkyl, aryl, 0289 wherein R is straight chained or branched heteroaryl, or N(Ro)-Z, C-C, alkyl, straight chained or branched C-C, monof US 2003/0078271 A1 Apr. 24, 2003 14

luoroalkyl, Straight chained or branched C-C, poly 0304 wherein X is N(CH) or fluoroalkyl, Straight chained or branched C-C, alk enyl, straight chained or branched C-C, alkynyl, C-C, cycloalkenyl, -(CH), Z, or (CH), O 0290 wherein each R, is independently H; -OR, R17 -OCOR, -COR, -NCOR, -N(R), -CON(R), -COOR, straight chained or branched C-C, alkyl, Straight chained or branched - Y C-C, monofluoroalkyl, straight chained or branched C-C, polyfluoroalkyl, straight chained or branched C-C, alkenyl, straight chained or branched C-C, alkynyl, C-C, cycloalkenyl, -(CH-)-Z, or (CH), O-(CH), CH; 0291 wherein Rs is straight chained or branched 0305 wherein R is a bicyclic alkyl ring system, aryl C-C alkyl, -(CH2), Z, or (CH2)-O-(CH2)- or aryl (C-C) alkyl, CH; 0306 wherein Y is NRRs; 0292 wherein each Ro is independently H, or straight chained or branched C-C alkyl, 0307 wherein R is H, straight chained or branched 0293 wherein each Ro is independently -H; straight C-C alkyl, (CH), O-(CH), CH, C-C, chained or branched C-C, alkyl, monofluoroalkyl or cycloalkyl, or (COR))-Z, polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C, cycloalkyl or C-C, cycloalk 0308 wherein Rs is (C(R).), N(R); enyl; -F, -Cl, -Br, or -I; -NO; -N, -CN; 0309 wherein Z is C-C cycloalkyl, aryl, or het -OR-, -OCOR, -COR, -NCOR, eroaryl; -N(R), -CON(R), or -COOR, aryl or het eroaryl; or two Rao groups present on adjacent carbon 0310 wherein R is straight chained or branched atoms can join together to form a methylenedioxy C-C, alkyl, straight chained or branched C-C, monof grOup, luoroalkyl, Straight chained or branched C-C, poly 0294 wherein each R is independently -H; straight fluoroalkyl, Straight chained or branched C-C, alk chained or branched C-C, alkyl, monofluoroalkyl or enyl, straight chained or branched C-C, alkynyl, C-C, polyfluoroalkyl, Straight chained or branched C-C, cycloalkenyl, -(CH2), Z, or (CH), O alkenyl or alkynyl, C-C-7 cycloalkyl, Cs-C, cycloalk enyl, aryl or aryl(C-C) alkyl, 0295 wherein each R is independently H, F, Cl or 0311 wherein each R, is independently H; -OR, -OCOR, -COR, -NCOR1, -N(R), C-C straight chained or branched alkyl; -CON(R), -COOR, straight chained or 0296 wherein each m is an integer from 0 to 4 inclu branched C-C, alkyl, Straight chained or branched SIVe; C-C, monofluoroalkyl, straight chained or branched (0297) wherein each n is an integer from 1 to 4 inclu C-C, polyfluoroalkyl, straight chained or branched SIVe; C-C, alkenyl, straight chained or branched C-C, 0298 wherein p is an integer from 0 to 2 inclusive; alkynyl, Cs-C7 cycloalkenyl, -(CH2)-Z, or 0299 wherein q is an integer from 2 to 4 inclusive; (CH), (CH), CH, 0300 wherein t is 1 or 2; or 0312 wherein each Ro is independently H, or straight chained or branched C-C alkyl, 0301 a pharmaceutically acceptable salt thereof. 0302) The invention provides a pharmaceutical compo 0313 wherein each R is independently -H; straight Sition comprising a pharmaceutically acceptable carrier and chained or branched C-C, alkyl, monofluoroalkyl or a compound having the Structure: polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C-7 cycloalkyl, Cs-C7 cycloalk X enyl, aryl or aryl(C-C)alkyl, N21 W 0314 wherein each m is an integer from 0 to 4 inclu ls R13 Sive, Y N 0315) wherein each n is an integer from 1 to 4 inclu H Sive, 0316 wherein q is an integer from 2 to 4 inclusive; or 0303 wherein W is H, -F, -Cl, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy, 0317 a pharmaceutically acceptable salt thereof. US 2003/0078271 A1 Apr. 24, 2003 15

0318. The invention provides a compound having the 0326 wherein Q is Structure:

X N21 W

Y ls N R13

0319 wherein W is H, -F, -Cl, -Br, -I, CN, 0327 wherein each J is independently O, S, C(R) or methyl, ethyl, propyl, methoxy or ethoxy, NR; 0328 wherein R is H; straight chained or branched 0320 wherein X is; NRR; C-C, alkyl, monofluoroalkyl or polyfluoroalkyl; Straight chained or branched C-C, alkenyl or alkynyl, C-C-7 cycloalkyl, Cs-C7 cycloalkenyl or aryl; 0329 wherein Y is NRRs;

HN\ , S:U , 4N Y R17; Rio - ; or N

/ V-R20X 0321 wherein R is H, straight chained or branched -N o s C-C, alkyl, (CH2)-O-(CH2), —CHs, aryl, or aryl A. (C-C)alkyl, \ Žs. 0322 wherein R is straight chained or branched C-C, alkyl, (CH-)-O-(CH2)-CH3, or 0330 wherein R is H, straight chained or branched C-C alkyl, (CH), O-(CH2), CH5, C-C, cycloalkyl, or (COR))-Z, 0323 wherein R is a bicyclic alkyl ring system, adamantyl, noradamantyl, C-Clocycloalkyl, het 0331 wherein R is straight chained or branched eroaryl, aryl, aryl(C-C)alkyl, Q or Q2; C-C alkyl, (CH), O-(CH2), CH5, C-C, cycloalkyl, (C(Rio)2)N(R) or (C(Rio)), Z, 0324 wherein aryl may be substituted with one or 0332 wherein R is straight chained or branched more C-Co Straight chained or branched alkyl, aryl, C-C, alkyl, straight chained or branched C-C, monof heteroaryl, or N(R)-Z, luoroalkyl, Straight chained or branched C-C, poly fluoroalkyl, Straight chained or branched C-C, alk 0325 wherein Q is enyl, straight chained or branched C-C, alkynyl, C-C, cycloalkenyl, (CH2), Z, or (CH), O-(CH2)- CH; 0333 wherein each R, is independently H; -OR, -OCOR1, -COR, -NCOR1, -N(R), -CON(R), -COOR, straight chained or branched C-C, alkyl, Straight chained or branched US 2003/0078271 A1 Apr. 24, 2003 16

C-C monofluoroalkyl, Straight chained or branched 0349 wherein X is NRR; C-C, polyfluoroalkyl, straight chained or branched C-C, alkenyl, straight chained or branched C-C, alkynyl, Cs-C7 cycloalkenyl, -(CH2)-Z, or R17 R17 (CH), O-(CH), CH; /\ y Rit /|\ 0334 wherein Rs is straight chained or branched -N ) ; or -N N-Rs: C-C alkyl, -(CH2), Z, or (CH2)-O-(CH2)- JSR, u v R, CH; 0335 wherein each Ro is independently H, or straight 0350 wherein R is H, straight chained or branched C-C, alkyl, (CH2)-O-(CH2)-CHs, aryl or chained or branched C-C alkyl, aryl(C-C)alkyl, 0336 wherein each Rao is independently -H; straight chained or branched C-C, alkyl, monofluoroalkyl or 0351 wherein R is straight chained or branched polyfluoroalkyl, Straight chained or branched C-C, C-C, alkyl, (CH-)-O-(CH), CH, or alkenyl or alkynyl, C-C, cycloalkyl or C-C, cycloalk enyl; -F, -Cl, -Br, or -I; -NO; -N, -CN; 0352 wherein R is a bicyclic alkyl ring system, aryl -OR2, -OR-, -COR2, -NCOR1, -N(R), or aryl(C-C)alkyl, -CON(R), or -COOR, aryl or heteroaryl; or two Rao groups present on adjacent carbon atoms can join 0353 wherein Y is NRRs; together to form a methylenedioxy group; 0337 wherein each R is independently -H; straight chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C, cycloalkyl, Cs-C, cycloalk S. 2 N- 7 R17 Rio - enyl, aryl, or aryl(C-C) alkyl, p N 0338 wherein each R is independently H, F, Cl or N- N C-C, straight chained or branched alkyl; / x. 0339 wherein each m is an integer from 0 to 4 inclu Sive, -N o A. 0340 wherein each n is an integer from 1 to 4 inclu \ ŽSR. Sive, 0341 wherein p is an integer from 0 to 2 inclusive; 0354) wherein R is H, straight chained or branched 0342 wherein q is an integer from 2 to 4 inclusive; C-C alkyl, (CH), O-(CH2)-CH3, Cs-Co cycloalkyl, or (COR))-Z, 0343 wherein t is 1 or 2; 0355 wherein Rs is straight chained or branched 0344) wherein U is O, -NR, S, C(R), or C-C alkyl, (CH), O-(CH), CH, C-C, -NSOR; cycloalkyl, or (COR))-Z, 0345 wherein Z is C-Cocycloalkyl, C-C, cyclic 0356 wherein U is O, -NR, S, C(R), or ether, C-C-7 cyclic thioether, aryl, or heteroaryl; or -NSOR; 0346 a pharmaceutically acceptable salt thereof. 0357 wherein Z is C-C cycloalkyl, aryl, or het eroaryl; 0347 The invention provides a compound having the Structure: 0358 wherein R is straight chained or branched C-C, alkyl, straight chained or branched C-C, monof luoroalkyl, Straight chained or branched C-C, poly X fluoroalkyl, Straight chained or branched C-C, alk enyl, straight chained or branched C-C, alkynyl, C-C, W cycloalkenyl, -(CH2), Z, or (CH), O N21 (CH-)-CH, ls R13 0359 wherein each R, is independently H; -OR, Y N -OCOR, -COR, -NCOR1, -N(R), H -CON(R), -COOR, straight chained or branched C-C, alkyl, Straight chained or branched C-C, monofluoroalkyl, straight chained or branched 0348 wherein W is H, -F, -Cl, -Br, -I, CN, C-C, polyfluoroalkyl, straight chained or branched methyl, ethyl, propyl, methoxy or ethoxy, C-C, alkenyl, straight chained or branched C-C, US 2003/0078271 A1 Apr. 24, 2003

alkynyl, Cs-C7 cycloalkenyl, -(CH2)-Z, or 0374 wherein aryl may be substituted with one or (CH), O-(CH), CH; more C-Co Straight chained or branched alkyl, aryl, 0360 wherein Rs is straight chained or branched heteroaryl, or N(Ro)-Z, C-C alkyl, -(CH), Z or (CH-)-O-(CH), 0375 wherein Q is CH; 0361 wherein each R is independently H, or straight chained or branched C-C alkyl, 0362 wherein each Rao is independently -H; straight chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C-7 cycloalkyl or Cs-C7 cycloalk enyl; -F, -Cl, -Br, or -I; -NO; -N, -CN; -OR. --OCOR, -COR, -NCOR, -N(R)-CONCR), or -COOR, aryl or het R22 R22 eroaryl; or two Ro groups present on adjacent carbon R22 atoms can join together to form a methylenedioxy R22 grOup, t 0363 wherein each R is independently -H; straight R22 p N chained or branched C-C, alkyl, monofluoroalkyl or R22 J R20; polyfluoroalkyl, Straight chained or branched C-C, A.Qex1. alkenyl or alkynyl, C-C-7 cycloalkyl, Cs-C, cycloalk R20 R20 enyl, aryl or aryl(C-C) alkyl, 0364 wherein each m is an integer from 0 to 4 inclu 0377 wherein each J is independently O, S, C(R) or Sive, NR; 0365 wherein each n is an integer from 1 to 4 inclu 0378 wherein R is -H; straight chained or branched Sive, C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, 0366 wherein p is an integer from 0 to 2 inclusive; C-C, cycloalkyl, Cs-C, cycloalkenyl or aryl; 0367 wherein q is an integer from 2 to 4 inclusive; 0379 wherein Y is NRRs; 0368 wherein t is 1 or 2; or 0369 a pharmaceutically acceptable salt thereof. 0370. The invention provides a compound having the Structure: S. 2 N- 7 R17 Rio - X p N- N N N21 W / XR

-N o Y lsN R13 A. H \ Q R20;

0371 wherein W is H, -F, -Cl, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy, 0380 wherein R is H, straight chained or branched C-C alkyl, (CH), O-(CH2), CH5, C-C, 0372 wherein X is N(CH), or cycloalkyl, or (COR))-Z, 0381 wherein Rs is straight chained or branched C-C alkyl, (CH), O-(CH), CH, C-C, R17 cycloalkyl, or (COR))-Z, 0382 wherein U is O, -NR, S, C(R), or -NSOR; 0383 wherein Z is C-C cycloalkyl, aryl, or het eroaryl; 0373 wherein R is an aryl, adamantyl, noradaman 0384 wherein R is straight chained or branched tyl, C-Co cycloalkyl, heteroaryl, Q or Q, C-C, alkyl, straight chained or branched C-C, monof US 2003/0078271 A1 Apr. 24, 2003 18

Luoroalkyl, Straight chained or branched C-C, poly 0398 wherein W is H, -F, -Cl, -Br, -I, CN, fluoroalkyl, Straight chained or branched C-C, alk methyl, ethyl, propyl, methoxy or ethoxy, enyl, straight chained or branched C-C, alkynyl, C-C, cycloalkenyl, -(CH), Z, or (CH), O 0399 wherein X is N(CH) or (CH2)CH, 0385 wherein each R, is independently H; -OR, R17 -OCOR1, -COR, -NCOR1, -N(R), -CON(R), -COOR, straight chained or branched C-C, alkyl, Straight chained or branched - Y C-C, monofluoroalkyl, straight chained or branched \ R. C-C, polyfluoroalkyl, straight chained or branched C-C, alkenyl, straight chained or branched C-C, alkynyl, C-C, cycloalkenyl, -(CH-)-Z, or 0400 wherein R is a bicyclic alkyl ring system, aryl (CH), O-(CH), CH; or aryl (C-C) alkyl, 0386 wherein Rs is straight chained or branched 0401 wherein Y is NRRs; C-C alkyl, -(CH2), Z, or (CH2)-O-(CH2)- CH; 0402 wherein R is H, straight chained or branched C-C alkyl, (CH), O-(CH2), CH5, C-C, 0387 wherein each Ro is independently H, or straight cycloalkyl, or (COR))-Z, chained or branched C-C alkyl, 0388 wherein each Ro is independently -H; straight 0403 wherein R is (C(R).), N(R); chained or branched C-C, alkyl, monofluoroalkyl or 0404 wherein Z is C-C cycloalkyl, aryl, or het polyfluoroalkyl, Straight chained or branched C-C, eroaryl; alkenyl or alkynyl, C-C-7 cycloalkyl or Cs-C7 cycloalk enyl; -F, -Cl, -Br, or -I; -NO; -N; -CN; 0405 wherein R is straight chained or branched -OR-, -OCOR, -COR, -NCOR, C-C, alkyl, straight chained or branched C-C, monof -N(R), -CON(R), or -COOR, aryl or het luoroalkyl, Straight chained or branched C-C, poly eroaryl; or two Rao groups present on adjacent carbon fluoroalkyl, Straight chained or branched C-C, alk atoms can join together to form a methylenedioxy enyl, straight chained or branched C-C, alkynyl, C-C, grOup, cycloalkenyl, -(CH2), Z, or (CH), O (CH-)-CH, 0389 wherein each R is independently -H; straight chained or branched C-C, alkyl, monofluoroalkyl or 0406 wherein each R, is independently H; -OR, polyfluoroalkyl, Straight chained or branched C-C, -OCOR1, -COR, -NCOR1, -N(R), alkenyl or alkynyl, C-C, cycloalkyl, Cs-C, cycloalk -CON(R), -COOR, straight chained or enyl, aryl or aryl(C-C) alkyl, branched C-C, alkyl, Straight chained or branched C-C, monofluoroalkyl, straight chained or branched 0390 wherein each R is independently H, F, CI or C-C, polyfluoroalkyl, straight chained or branched C-C straight chained or branched alkyl; C-C, alkenyl, straight chained or branched C-C, 0391 wherein each m is an integer from 0 to 4 inclu alkynyl, Cs-C, cycloalkenyl, -(CH), Z or Sive, (CH), O-(CH), CH; 0392 wherein each n is an integer from 1 to 4 inclu 0407 wherein each Ro is independently H, or straight Sive, chained or branched C-C alkyl, 0393 wherein p is an integer from 0 to 2 inclusive; 0408 wherein each R is independently -H; straight chained or branched C-C, alkyl, monofluoroalkyl or 0394 wherein q is an integer from 2 to 4 inclusive; polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C-7 cycloalkyl, Cs-C7 cycloalk 0395 wherein t is 1 or 2; or enyl, aryl or aryl(C-C) alkyl, 0396 a pharmaceutically acceptable salt thereof. 04.09 wherein each m is an integer from 0 to 4 inclu 0397) The invention provides a compound having the Sive, Structure: 0410 wherein each n is an integer from 1 to 4 inclu Sive, X 0411 wherein q is an integer from 2 to 4 inclusive; or W N21 0412 a pharmaceutically acceptable salt thereof. ls R13 0413. The invention also provides a method of treating a Y N Subject Suffering from depression which comprises admin istering to the Subject an amount of compound effective to H treat the Subject's depression wherein the compound has the Structure: US 2003/0078271 A1 Apr. 24, 2003

0419 wherein Q is

0414) wherein each of Y, Y, Y, and Y, is inde pendently -H, Straight chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C, cycloalkyl, or Cs-C7 cycloalkenyl, -F, -Cl, -Br, O I; NO; N; CN; OR, SR, -OCOR, -COR. -NCOR1, -N(R), -CONCR), or -COOR, aryl or heteroaryl; or any two of Y1, Y, Y- and Y present on adjacent carbon atoms can constitute a methylenedioxy grOup, 0421 wherein R and R are each independently H, Straight chained or branched C-C, alkyl, -F, -Cl, 0415 wherein each R is independently -H; -Br, -, -NO, or -CN; Straight chained or branched C-C, alkyl, monofluo 0422 wherein R is H, straight chained or branched roalkyl or polyfluoroalkyl, Straight chained or C-C, alkyl, -F, -Cl, -Br, -, -NO, -CN, branched C-C, alkenyl or alkynyl, C-C, -OR, aryl or heteroaryl; cycloalkyl, Cs-C, cycloalkenyl, aryl or aryl(C- 0423 wherein Rs is straight chained or branched C.)alkyl, C-C, alkyl, -N(R), —OR or aryl; 0416 wherein A is A, Q, Q, Qs, straight chained 0424 wherein R is straight chained or branched or branched C-C, alkyl, aryl, heteroaryl, aryl(C- C-C, alkyl or aryl; C.)alkyl, heteroaryl(C-C)alkyl, aryl Substituted 0425 wherein each R, is independently H; straight with an aryl or heteroaryl, heteroaryl Substituted with chained or branched C-C, alkyl, Straight chained or an aryl or heteroaryl; or (CHR)-(CHR), Z; branched C-C-7 monofluoroalkyl, Straight chained or branched C-C, polyfluoroalkyl, Straight chained or 0417 wherein A' is branched C-C, alkenyl, Straight chained or branched C-C, alkynyl, Cs-C7 cycloalkenyl, -(CH2)-Z, or ((H)-O-(CH2)-CH, O O 0426 wherein each Ro is independently -H; Straight chained or branched C-C, alkyl, monofluo roalkyl or polyfluoroalkyl, Straight chained or N- Rs: -). branched C-C, alkenyl or alkynyl, C-C, cycloalkyl or Cs-C7 cycloalkenyl, -F, -Cl, -Br, or -I; R1 -NO; -N; -CN; -OR-, -OCOR, -COR, -NCOR1, -N(R), -CONCR)/or N-S. ; or -(CH2) E -Ra: -COOR, aryl or heteroaryl; or two Rao groups present on adjacent carbon atoms can join together to form a methylenedioxy group; 0418 wherein Q is 0427 wherein each R is independently -H; Straight chained or branched C-C, alkyl, monofluo roalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C, cycloalkyl, Cs-C, cycloalkenyl, aryl or aryl(C- C.)alkyl, 0428 wherein each m is an integer from 0 to 4 inclusive; 0429 wherein each n is an integer from 1 to 4 inclusive; US 2003/0078271 A1 Apr. 24, 2003 20

0430 wherein each p is an integer from 0 to 2 any two of Y1, Y, Y- and Y present on adjacent carbon inclusive; atoms can constitute a methylenedioxy group; 0431 wherein U is O, -NR, S, C(R), or 0442 wherein each R is independently -H; -NSOR; Straight chained or branched C-C, alkyl, monofluo roalkyl or polyfluoroalkyl, Straight chained or 0432 wherein Z is C-C cycloalkyl, C-C, cyclic branched C-C, alkenyl or alkynyl, C-C, ether, C-C-7 cyclic thioether, aryl, or heteroaryl; cycloalkyl, Cs-C7 cycloalkenyl, aryl or aryl(C- 0433 wherein R is straight chained or branched C.)alkyl, C-C, alkyl, straight chained or branched C-C, 0443 wherein A is A", straight chained or branched monofluoroalkyl, Straight chained or branched C-C, C-C, alkyl, aryl, heteroaryl, aryl(C-C)alkyl or polyfluoroalkyl, Straight chained or branched C-C, heteroaryl (C-C) alkyl, alkenyl, Straight chained or branched C-C, alkynyl, Cs-C, cycloalkenyl, (CH), Z, or (CH), O— (CH-)-CH, O O 0434 wherein q is an integer from 2 to 4 inclusive; 0435 wherein B is aryl, heteroaryl, aryl Substituted N. -). with an aryl or heteroaryl, heteroaryl Substituted with an aryl or heteroaryl, tricyclic heteroaryl or Q, provided however, if B is aryl or heteroaryl the 0444 wherein A' is carbon atom or carbon atoms ortho to the nitrogen atom of the imine bond may only be substituted with one or more of the following -F, -Cl, -Br, -I, R1 -CN, methyl, ethyl or methoxy; 0436 wherein a tricyclic heteroaryl is a fused three N.'s, ; or - (CH), member aromatic System in which one or more of the rings is heteroaryl; carbazole; or acridine, 04:45 wherein R and Rare each independently H, 0437 wherein Q is Straight chained or branched C-C, alkyl, -F, -Cl, -Br, -, -NO, or -CN; 0446 wherein R is H, straight chained or branched C-C, alkyl, -F, -Cl, -Br, -, -NO, -CN, - N x R22 -OR, aryl or heteroaryl; 2 O R22; 0447 wherein Rs is straight chained or branched C-C, alkyl, -N(R) 2, -OR or aryl; 0438 wherein each R is independently H, F, Cl, or 0448 wherein R is straight chained or branched Straight chained or branched C-C alkyl, C-C, alkyl or aryl; 0439 or a pharmaceutically acceptable salt thereof. 0449 wherein B is aryl, or heteroaryl; provided however, if B is aryl or heteroaryl the carbon atom or 0440 The invention provides a method of treating a carbon atoms ortho to the nitrogen atom of the imine Subject Suffering from depression which comprises admin bond may only be substituted with one or more of the istering to the Subject an amount of compound effective to following-F, -Cl, -Br, -, -CN, methyl, ethyl treat the Subject's depression wherein the compound has the or methoxy, Structure: 0450 wherein n is an integer from 1 to 4 inclusive; 04.51 or a pharmaceutically acceptable salt thereof. 0452. The invention provides a method of treating a Subject Suffering from depression which comprises admin istering to the Subject an amount of compound effective to treat the Subject's depression wherein the compound has the Structure:

0441 wherein each of Yi, Y, Y, and Y is indepen dently -H, Straight chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C-7 cycloalkyl, or C-C, cycloalkenyl;-F, -Cl, -Br, or -I;-NO; -Ns; -CN; -OR, -SR, -OCOR, -COR, -NCOR, -N(R), -CON(R), or -COOR, aryl or heteroaryl; or US 2003/0078271 A1 Apr. 24, 2003

0453 wherein each of Yi, Y, Y, and Y is inde pendently -H, Straight chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C, cycloalkyl, or Cs-C7 cycloalkenyl, -F, -Cl, -Br, O I; NO; N; CN; OR, SR, -OCOR, -COR. -NCOR1, -N(R), -CONCR), or -COOR, aryl or heteroaryl; or any two of Y1, Y, Y- and Y present on adjacent carbon atoms can constitute a methylenedioxy grOup, 0454 wherein each R is independently -H; Straight chained or branched C-C, alkyl, monofluo roalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C, cycloalkyl, Cs-C7 cycloalkenyl, aryl or aryl (C-C) alkyl, 0464 wherein each of Yi, Y, Y, and Y is inde pendently-H; Straight chained or branched C-C, 0455 wherein A is A", straight chained or branched alkyl, monofluoroalkyl or polyfluoroalkyl, Straight C-C, alkyl, aryl, heteroaryl, aryl(C-C)alkyl or chained or branched C-C, alkenyl or alkynyl, C-C, heteroaryl (C-C) alkyl, cycloalkyl, or C-C, cycloalkenyl, -F, -Cl, -Br, 0456 wherein A' is O I; NO; N; CN; OR, SR, -OCOR, -COR. -NCOR1, -N(R), -CONCR), or -COOR, aryl or heteroaryl; or O R1 any two of Y1, Y, Y- and Y present on adjacent carbon atoms can constitute a methylenedioxy Ns. grOup, 0465 wherein each R is independently -H; straight chained or branched C-C, alkyl, monofluo roalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C, cycloalkyl, Cs-C, cycloalkenyl, aryl or aryl(C- C.)alkyl, 0457 wherein B is aryl Substituted with an aryl or 0466 wherein A is Q, Q, Qs, aryl Substituted with heteroaryl, heteroaryl Substituted with an aryl or an aryl or heteroaryl, heteroaryl Substituted with an heteroaryl, tricyclic heteroaryl or Q, aryl or heteroaryl, or (CHR)-(CHR), Z; 0458 wherein a tricyclic heteroaryl is a fused three ring aromatic System in which one or more of the 0467 wherein Q is rings is heteroaryl; carbazole; or acridine, 0459 wherein Q is R17 R17

N R17 us R17; 1s X: R17 U 21 No R22;

0468 wherein Q is 0460 wherein n is an integer from 1 to 4 inclusive;

0461 wherein each R is independently H, F, Cl, or Straight chained or branched C-C alkyl, 0462 or a pharmaceutically acceptable salt thereof. 0463 The invention provides a method of treating a Subject Suffering from depression which comprises admin istering to the Subject an amount of compound effective to treat the Subject's depression wherein the compound has the Structure: US 2003/0078271 A1 Apr. 24, 2003 22

0469 wherein Q is 0483 The invention provides a method of treating a Subject Suffering from anxiety which comprises administer ing to the Subject an amount of compound effective to treat the Subject's anxiety wherein the compound has the Struc ture:

0470 wherein each R, is independently H; straight chained or branched C-C, alkyl, Straight chained or branched C-C-7 monofluoroalkyl, Straight chained or branched C-C, polyfluoroalkyl, Straight chained or branched C-C, alkenyl, Straight chained or branched C-C, alkynyl, Cs-C7 cycloalkenyl, -(CH2)-Z, or (CH2)-O-(CH2), CH, 0471 wherein each Ro is independently -H; 0484 wherein each of Yi, Y, Y, and Y is inde Straight chained or branched C-C, alkyl, monofluo pendently -H, Straight chained or branched C-C, roalkyl or polyfluoroalkyl, Straight chained or alkyl, monofluoroalkyl or polyfluoroalkyl, Straight branched C-C, alkenyl or alkynyl, C-C7 cycloalkyl chained or branched C-C, alkenyl or alkyn.yl; or Cs-C7 cycloalkenyl, -F, -Cl, -Br, or -I; C-C, cycloalkyl, or Cs-C, cycloalkenyl; -F, -Cl, NO; N; CN; OR, OCOR, Br, or -I; -NO; -N; -CN; -OR. -SR, -COR, -NCOR1, -N(R), -CONCR), or -OCOR, -COR. -NCOR1, -N(R), -COOR, aryl or heteroaryl; or two Ro groups -CONCR), or -COOR, aryl or heteroaryl; or present on adjacent carbon atoms can join together to any two of Y1, Y, Y- and Y present on adjacent form a methylenedioxy group; carbon atoms can constitute a methylenedioxy 0472 wherein each R is independently -H; grOup, Straight chained or branched C-C, alkyl, monofluo 0485 wherein each R is independently -H; roalkyl or polyfluoroalkyl, Straight chained or Straight chained or branched C-C, alkyl, monofluo branched C-C, alkenyl or alkynyl, C-C, roalkyl or polyfluoroalkyl, Straight chained or cycloalkyl, Cs-C7 cycloalkenyl or aryl; branched C-C, alkenyl or alkynyl, C-C, 0473 wherein each R is independently H, F, Cl, or cycloalkyl, Cs-C, cycloalkenyl, aryl or aryl(C- Straight chained or branched C-C alkyl, C.)alkyl, 0474 wherein each m is an integer from 0 to 4 0486 wherein A is A, Q, Q, Qs, straight chained inclusive; or branched C-C, alkyl, aryl, heteroaryl, aryl(C- C) alkyl, heteroaryl (C-C) alkyl, aryl Substituted 0475 wherein each n is an integer from 1 to 4 with an aryl or heteroaryl, heteroaryl Substituted with inclusive; an aryl or heteroaryl; or (CHR)-(CHR), Z; 0476 wherein each p is an integer from 0 to 2 inclusive; 0487 wherein A' is 0477 wherein U is O, -NR, S, C(R), or -NSOR; O R 0478 wherein Z is C-C cycloalkyl, C-C, cyclic ether, C-C-7 cyclic thioether, aryl, or heteroaryl; 0479 wherein R is straight chained or branched R5; 1sy CR2R3; or C-C, alkyl, straight chained or branched C-C, monofluoroalkyl, Straight chained or branched C-C, -(CH) =E-R: - polyfluoroalkyl, Straight chained or branched C-C, alkenyl, Straight chained or branched C-C, alkynyl, Cs-C, cycloalkenyl, -(CH2)-Z, or (CH-)-O- (CH-)-CH, 0488 wherein Q is 0480 wherein q is an integer from 2 to 4 inclusive; R17 R 0481 wherein B is aryl, or heteroaryl; provided 17 however, if B is aryl or heteroaryl the carbon atom or carbon atoms ortho to the nitrogen atom of the imine N bond may only be substituted with one or more of the following-F, -Cl, -Br, -, -CN, methyl, ethyl R17 us R17; or methoxy, R17 U 0482 or a pharmaceutically acceptable salt thereof. US 2003/0078271 A1 Apr. 24, 2003

0489 wherein Q is 0500 wherein each p is an integer from 0 to 2 inclusive;

0501 wherein U is O, -NR, S, C(R) or -NSOR; 0502 wherein Z is C-Cocycloalkyl, C-C, cyclic ether, C-C-7 cyclic thioether, aryl, or heteroaryl; 0503 wherein R is straight chained or branched. C-C, alkyl, straight chained or branched C-C, monofluoroalkyl, Straight chained or branched C-C, polyfluoroalkyl, Straight chained or branched C-C, alkenyl, Straight chained or branched C-C, alkynyl, Cs-C, cycloalkenyl, -(CH2), Z, or (CH), O— (CH-)-CH, 0504 wherein q is an integer from 2 to 4 inclusive; 0505 wherein B is aryl, heteroaryl, aryl Substituted with an aryl or heteroaryl, heteroaryl Substituted with an aryl or heteroaryl, tricyclic heteroaryl or Q, provided however, if B is aryl or heteroaryl the carbon atom or carbon atoms ortho to the nitrogen atom of the imine bond may only be substituted with one or more of the following -F, -Cl, -Br, -I, 0491 wherein R and R are each independently H, -CN, methyl, ethyl or methoxy; Straight chained or branched C-C, alkyl, -F, -Cl, 0506 wherein a tricyclic heteroaryl is a fused three -Br, -I, -NO, or -CN; member aromatic System in which one or more of the 0492 wherein R is H, straight chained or branched rings is heteroaryl; carbazole; or acridine, C-C, alkyl, -F, -Cl, -Br, -I, -NO, -CN, -OR, aryl or heteroaryl; 0507 wherein Q is 0493 wherein R is straight chained or branched C-C, alkyl, -N(R), —OR or aryl; 0494 wherein R is straight chained or branched - I N x R22 C-C, alkyl or aryl; 21 No R22; 0495 wherein each R, is independently H; straight chained or branched C-C, alkyl, Straight chained or branched C-C, monofluoroalkyl, Straight chained or 0508 wherein each R is independently H, F, Cl, or branched C-C, polyfluoroalkyl, Straight chained or Straight chained or branched C-C alkyl, branched C-C, alkenyl, Straight chained or 0509 or a pharmaceutically acceptable salt thereof. branched. C-C, alkynyl, Cs-C7 cycloalkenyl, -(CH2)-Z, or (CH2)-O-(CH2), CH, 0510) The invention provides a method of treating a Subject Suffering from anxiety which comprises administer 0496 wherein each Ro is independently -H; ing to the Subject an amount of compound effective to treat Straight chained or branched C-C, alkyl, monofluo roalkyl or polyfluoroalkyl, Straight chained or the Subject's anxiety wherein the compound has the Struc branched C-C, alkenyl or alkynyl, C-C7 cycloalkyl ture: or C-C, cycloalkenyl, -F, -Cl, -Br, or -I; NO; N; CN; OR, OCOR, -COR, -NCOR1, -N(R), -CONCR), or -COOR, aryl or heteroaryl; or two Ro groups present on adjacent carbon atoms can join together to form a methylenedioxy group; 0497 wherein each R is independently -H; Straight chained or branched C-C, alkyl, monofluo roalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C, cycloalkyl, Cs-C7 cycloalkenyl, aryl or aryl(C- C.)alkyl, 0511 wherein each of Yi, Y, Y, and Y is inde pendently -H, Straight chained or branched C-C, 0498 wherein each m is an integer from 0 to 4 alkyl, monofluoroalkyl or polyfluoroalkyl, Straight inclusive; chained or branched C-C, alkenyl or alkynyl, C-C, 0499 wherein each n is an integer from 1 to 4 cycloalkyl, or Cs-C7 cycloalkenyl, -F, -Cl, -Br, inclusive; O I; NO; N; CN; OR, SR, US 2003/0078271 A1 Apr. 24, 2003 24

-OCOR, -COR. -NCOR1, -N(R), 0523 wherein each of Yi, Y, Y, and Y is inde -CONCR), or -COOR, aryl or heteroaryl; or pendently -H, Straight chained or branched C-C, any two of Y1, Y, Y- and Y present on adjacent alkyl, monofluoroalkyl or polyfluoroalkyl, Straight carbon atoms can constitute a methylenedioxy chained or branched C-C, alkenyl or alkynyl, C-C, grOup, cycloalkyl, or C-C, cycloalkenyl, -F, -Cl, -Br, 0512 wherein each R is independently -H; O I; NO; N; CN; OR, SR, Straight chained or branched C-C, alkyl, monofluo -OCOR, -COR. -NCOR1, -N(R), roalkyl or polyfluoroalkyl, Straight chained or -CONCR), or -COOR, aryl or heteroaryl; or branched C-C, alkenyl or alkynyl, C-C, any two of Y1, Y, Y- and Y present on adjacent cycloalkyl, Cs-C7 cycloalkenyl, aryl or aryl(C- carbon atoms can constitute a methylenedioxy C.)alkyl, grOup, 0513 wherein A is A", straight chained or branched 0524 wherein each R is independently -H; C-C, alkyl, aryl, heteroaryl, aryl(C-C)alkyl or Straight chained or branched C-C, alkyl, monofluo heteroaryl (C-C) alkyl, roalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C, 0514 wherein A' is cycloalkyl, Cs-C, cycloalkenyl, aryl or aryl(C- C.)alkyl, O O 0525 wherein A is A", straight chained or branched C-C, alkyl, aryl, heteroaryl, aryl(C-C)alkyl or N-s, 1sy. heteroaryl (C-C) alkyl, 0526 wherein A' is N- ; or -(CH2) E -Ra: CRR, O O 0515 wherein R and R are each independently H, N-. 1sy. Straight chained or branched C-C, alkyl, -F, -Cl, -Br, -, -NO, or -CN; R1 0516 wherein R is H, straight chained or branched C-C, alkyl, -F, -Cl, -Br, -, -NO, -CN, S-S. ; or -(CH) = -R: -OE6 aryl or heteroaryl; 0517 wherein Rs is straight chained or branched C-C, alkyl, -N(R), —OR or aryl; 0527 wherein B is aryl Substituted with an aryl or heteroaryl, heteroaryl Substituted with an aryl or 0518 wherein R is straight chained or branched C-C, alkyl or aryl; heteroaryl, tricyclic heteroaryl or Q, 0519 wherein B is aryl, or heteroaryl; provided 0528 wherein a tricyclic heteroaryl is a fused three however, if B is aryl or heteroaryl the carbon atom or ring aromatic System in which one or more of the carbon atoms ortho to the nitrogen atom of the imine rings is heteroaryl; carbazole; or acridine, bond may only be substituted with one or more of the following-F, -Cl, -Br, -, -CN, methyl, ethyl 0529) wherein Q is or methoxy, 0520 wherein n is an integer from 1 to 4 inclusive; O 0521 or a pharmaceutically acceptable salt thereof. N X 21 No "R22: 0522 The invention provides a method of treating a Subject Suffering from anxiety which comprises administer ing to the Subject an amount of compound effective to treat the Subject's anxiety wherein the compound has the Struc 0530 wherein n is an integer from 1 to 4 inclusive; ture: 0531 wherein each R is independently H, F, Cl, or Straight chained or branched C-C alkyl, 0532 or a pharmaceutically acceptable salt thereof. 0533. The invention provides a method of treating a Subject Suffering from anxiety which comprises administer ing to the Subject an amount of compound effective to treat the Subject's anxiety wherein the compound has the Struc ture: US 2003/0078271 A1 Apr. 24, 2003

0539 wherein Q is

0540 wherein each R, is independently H; straight chained 0534 wherein each of Yi, Y, Y, and Y is inde 0541 or branched C-C, alkyl, straight chained or pendently -H, Straight chained or branched C-C, branched C-C-7 monofluoroalkyl, Straight chained or alkyl, monofluoroalkyl or polyfluoroalkyl, Straight branched C-C, polyfluoroalkyl, Straight chained or branched C-C, alkenyl, Straight chained or chained or branched C-C, alkenyl or alkynyl, C-C, branched C-C, alkynyl, Cs-C7 cycloalkenyl, cycloalkyl, or C-C, cycloalkenyl, -F, -Cl, -Br, -(CH2)-Z, or (CH)-O-(CH2)-CH, O I; NO; N; CN; OR, SR, -OCOR, -COR. -NCOR1, -N(R), 0542 wherein each Ro is independently -H; Straight chained or branched C-C, alkyl, monofluo -CONCR), or -COOR, aryl or heteroaryl; or roalkyl or polyfluoroalkyl, Straight chained or any two of Y1, Y, Y- and Y present on adjacent branched C-C, alkenyl or alkynyl, C-C7 cycloalkyl carbon atoms can constitute a methylenedioxy or Cs, cycloalkenyl, -F, -Cl, -Br, or -I; grOup, -NO; -N, -CN; -OR-, -OCOR, -COR, -NCOR1, -N(R), -CONCR), or 0535 wherein each R is independently -H; -COOR, aryl or heteroaryl; or two Ro groups Straight chained or branched C-C, alkyl, monofluo present on adjacent carbon atoms can join together to roalkyl or polyfluoroalkyl, Straight chained or form a methylenedioxy group, branched C-C, alkenyl or alkynyl, C-C, cycloalkyl, Cs-C7 cycloalkenyl, aryl or aryl(C- 0543 wherein each R is independently -H, C.)alkyl, Straight chained or branched C-C, alkyl, monofluo roalkyl or polyfluoroalkyl, Straight chained or 0536 wherein A is Q, Q, Qs, aryl Substituted with branched C-C, alkenyl or alkynyl, C-C, an aryl or heteroaryl, heteroaryl Substituted with an cycloalkyl, Cs-C, cycloalkenyl or aryl; aryl or heteroaryl, or (CHR)-(CHR), Z; 0544 wherein each R is independently H, F, Cl, or 0537) wherein Q is Straight chained or branched C-C alkyl, 0545 wherein q is an integer from 2 to 4 inclusive; 0546 wherein each m is an integer from 0 to 4 inclusive; 0547 wherein each n is an integer from 1 to 4 inclusive; 0548 wherein each p is an integer from 0 to 2 inclusive; 0549 wherein U is O, -NR, S, C(R), or -NSOR; 0538 wherein Q is 0550 wherein Z is C-C cycloalkyl, C-C, cyclic ether, C-C-7 cyclic thioether, aryl, or heteroaryl; 0551 wherein R is straight chained or branched C-C, alkyl, straight chained or branched C-C, monofluoroalkyl, Straight chained or branched C-C, polyfluoroalkyl, Straight chained or branched C-C, alkenyl, Straight chained or branched C-C, alkynyl, Cs-C, cycloalkenyl, -(CH2)-Z, or (CH-)-O- (CH -CH, 0552 wherein B is aryl, or heteroaryl; provided however, if B is aryl or heteroaryl the carbon atom or US 2003/0078271 A1 Apr. 24, 2003 26

carbon atoms ortho to the nitrogen atom of the imine 0559) wherein Q is bond may only be substituted with one or more of the following-F, -Cl, -Br, -, -CN, methyl, ethyl or methoxy, R17 R17

0553 or a pharmaceutically acceptable salt thereof. N 0554. The invention provides a pharmaceutical compo R17 us R17; Sition comprising a pharmaceutically acceptable carrier and R17 U a compound having the Structure: 0560 wherein Q is

0555 wherein each of Yi, Y, Y, and Y is inde 0561 wherein Q is pendently -H, Straight chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkyilyl, C-C, cycloalkyl, or C-C, cycloalkenyl, -F, -Cl, -Br, or -, -NO, -N, -CN, -OR, -SR, -OCOR, -COR. -NCOR1, -N(R), -CONCR), or -COOR, aryl or heteroaryl; or any two of Y1, Y, Y- and Y present on adjacent carbon atoms can constitute a methylenedicXy grOup, 0562 wherein R and R are each independently H, Straight chained or branched C-C, alkyl, -F, -Cl, 0556 wherein each R is independently -H; -Br, -, -NO, or -CN; Straight chained or branched C-C, alkyl, monofluo roalkyl or polyfluoroalkyl, Straight chained or 0563 wherein R is H, straight chained or branched branched C-C, alkenyl or alkynyl, C-C, C-C, alkyl, -F, -Cl, -Br, -, -NO, -CN, cycloalkyl, Cs-C7 cycloalkenyl, aryl or aryl(C- -OR, aryl or heteroaryl; C.)alkyl, 0564 wherein Rs is straight chained or branched 0557 wherein A is A, Q, Q, Qs, straight chained C-C, alkyl, -N(R), -R or aryl; or branched C-C, alkyl, aryl, heteroaryl, aryl(C- 0565 wherein R is straight chained or branched C.)alkyl, heteroaryl(C-C)alkyl, aryl Substituted C-C, alkyl or aryl; with an aryl or heteroaryl, heteroaryl Substituted with 0566 wherein each R, is independently H; straight an aryl or heteroaryl; or (CHR)-(CHR), Z; chained or branched C-C, alkyl, Straight chained or 0558 wherein A' is branched C-C-7 monofluoroalkyl, Straight chained or branched C-C, polyfluoroalkyl, Straight chained or branched C-C, alkenyl, Straight chained or O R1 branched C-C, alkynyl, Cs-C7 cycloalkenyl, -(CH-)-Z, or (CH), O-(CH), CH, N. 0567 wherein each Ro is independently -H; Straight chained or branched C-C, alkyl, monofluo roalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C7 cycloalkyl or Cs-C7 cycloalkenyl, -F, -Cl, -Br, or -I; -NO; -N; -CN; -OR-, -OCOR, -COR, -NCOR1, -N(R), -CONCR), or -COOR, aryl or heteroaryl; or two Rao groups US 2003/0078271 A1 Apr. 24, 2003 27

present on adjacent carbon atoms can join together to 0581. The invention provides a pharmaceutical compo form a methylenedioxy group; Sition comprising a pharmaceutically acceptable carrier and a compound having the Structure: 0568 wherein each R is independently -H; Straight chained or branched C-C, alkyl, monofluo roalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C, cycloalkyl, Cs-C7 cycloalkenyl, aryl or aryl(C- C.)alkyl, 0569 wherein each m is an integer from 0 to 4 inclusive; 0570 wherein each n is an integer from 1 to 4 inclusive; 0582 wherein each of Yi, Y, Y, and Y is inde 0571 wherein each p is an integer from 0 to 2 pendently -H, Straight chained or branched C-C, inclusive; alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C, 0572 wherein U is O, -NR, S, C(R), or cycloalkyl, or Cs-C7 cycloalkenyl, -F, -Cl, -Br, -NSOR; O I; NO; N; CN; OR, SR, -OCOR, -COR. -NCOR1, -N(R), 0573 wherein Z is C-C cycloalkyl, C-C, cyclic -CONCR), or -COOR, aryl or heteroaryl; or ether, C-C-7 cyclic thioether, aryl, or heteroaryl; any two of Y1, Y, Y- and Y present on adjacent 0574 wherein R is straight chained or branched carbon atoms can constitute a methylenedioxy C-C, alkyl, straight chained or branched C-C, grOup, monofluoroalkyl, Straight chained or branched C-C, 0583 wherein each R is independently -H; polyfluoroalkyl, Straight chained or branched C-C, Straight chained or branched C-C, alkyl, monofluo alkenyl, Straight chained or branched C-C, alkynyl, roalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl; C-C, Cs-C, cycloalkenyl, -(CH2)-Z, or (CH-)-O- cycloalkyl, Cs-C7 cycloalkenyl, aryl or aryl(C- (CH-)-CH, C.)alkyl, 0575 wherein q is an integer from 2 to 4 inclusive; 0584 wherein A is A", straight chained or branched 0576 wherein B is aryl, heteroaryl, aryl Substituted C-C, alkyl, aryl, heteroaryl, aryl(C-C)alkyl or with an aryl or heteroaryl, heteroaryl Substituted with heteroaryl (C-C) alkyl, an aryl or heteroaryl, tricyclic heteroaryl or Q, 0585 wherein A' is provided however, if B is aryl or heteroaryl the carbon atom or carbon atoms ortho to the nitrogen atom of the imine bond may only be substituted with one or more of the following -F, -Cl, -Br, -I, O O s -CN, methyl, ethyl or methoxy; Ns. l, CR2R3; or 0577 wherein a tricyclic heteroaryl is a fused three member aromatic System in which one or more of the -(CH) = -R: rings is heteroaryl; carbazole; or acridine, 0578 wherein Q is 0586 wherein R and R are each independently H, Straight chained or branched C-C, alkyl, -F, -Cl, -Br, -, -NO, or -CN; 0587 wherein R is H, straight chained or branched C-C, alkyl, -F, -Cl, -Br, -, -NO, -CN, -OR, aryl or heteroaryl; 0588 wherein R is straight chained or branched C-C, alkyl, -N(R) 2, -OR or aryl; 0589 wherein R is straight chained or branched C-C, alkyl or aryl; 0579 wherein each R is independently H, F, Cl, or Straight chained or branched C-C alkyl, 0590 wherein B is aryl, or heteroaryl; provided however, if B is aryl or heteroaryl the carbon atom or 0580 or a pharmaceutically acceptable salt thereof. carbon atoms ortho to the nitrogen atom of the imine US 2003/0078271 A1 Apr. 24, 2003 28

bond may only be substituted with one or more of the 0600 wherein Q is following-F, -Cl, -Br, -, -CN, methyl, ethyl or methoxy, O 0591 wherein n is an integer from 1 to 4 inclusive; N X 0592 or a pharmaceutically acceptable salt thereof. 21 No R22. 0593. The invention provides a pharmaceutical compo Sition comprising a pharmaceutically acceptable carrier and a compound having the Structure: 0601 wherein n is an integer from 1 to 4 inclusive; 0602 wherein each R is independently H, F, Cl, or Straight chained or branched C-C alkyl, 0603 or a pharmaceutically acceptable salt thereof. 0604. The invention provides a pharmaceutical compo Sition comprising a pharmaceutically acceptable carrier and a compound having the Structure:

0594 wherein each of Yi, Y, Y, and Y is inde pendently -H, Straight chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C, cycloalkyl, or Cs-C7 cycloalkenyl, -F, -Cl, -Br, O I; NO; N; CN; OR, SR, -OCOR, -COR. -NCOR. -N(R), -CONCR), or -COOR, aryl or heteroaryl; or 0605 wherein each of Yi, Y, Y, and Y is inde any two of Y1, Y, Y- and Y present on adjacent pendently -H, Straight chained or branched C-C, carbon atoms can constitute a methylenedioxy alkyl, monofluoroalkyl or polyfluoroalkyl, Straight grOup, chained or branched C-C, alkenyl or alkynyl, C-C, 0595 wherein each R is independently -H; cycloalkyl, or C-C, cycloalkenyl, -F, -Cl, -Br, Straight chained or branched C-C, alkyl, monofluo O I; NO; N; CN; OR, SR, roalkyl or polyfluoroalkyl, Straight chained or -OCOR, -CCOR, -NCOR1, -N(R), branched C-C, alkenyl or alkynyl, C-C, -CONCR), or -COOR, aryl or heteroaryl; or cycloalkyl, Cs-C, cycloalkenyl, aryl or aryl(C- any two of Y1, Y, Y- and Y present on adjacent C.)alkyl, carbon atoms can constitute a methylenedioxy grOup, 0596 wherein A is A", straight chained or branched C-C, alkyl, aryl, heteroaryl, aryl(C-C)alkyl or 0606 wherein each R is independently -H; heteroaryl (C-C) alkyl, Straight chained or branched C-C, alkyl, monofluo roalkyl or polyfluoroalkyl, Straight chained or 0597 wherein A' is branched C-C, alkenyl or alkynyl, C-C, cycloalkyl, Cs-C7 cycloalkenyl, aryl or aryl(C- C.)alkyl, O R1 0607 wherein A is Q, Q, Qs, aryl Substituted with N- Rs: O N CR2R3; or an aryl or heteroaryl, heteroaryl Substituted with an aryl or heteroaryl, or (CHR)-(CHR), Z; 0608 wherein Q is

R17 R17 0598 wherein B is aryl substituted with an aryl or heteroaryl, heteroaryl Substituted with an aryl or N R17; heteroaryl, tricyclic heteroaryl or Q, R17 y-d 0599 wherein a tricyclic heteroaryl is a fused three R17 ring aromatic System in which one or more of the rings is heteroaryl; carbazole; or acridine, US 2003/0078271 A1 Apr. 24, 2003 29

0609 wherein Q is 0621 wherein R is straight chained or branched C-C, alkyl, straight chained or branched C-C, monofluoroalkyl, Straight chained or branched C-C, polyfluoroalkyl, Straight chained or branched C-C, alkenyl, Straight chained or branched C-C, alkynyl, Cs-C, cycloalkenyl, -(CH2), Z, or (CH), O— (CH-)-CH, 0622 wherein B is aryl, or heteroaryl; provided however, if B is aryl or heteroaryl the carbon atom or carbon atoms ortho to the nitrogen atom of the imine bond may only be substituted with one or more of the following-F, -Cl, -Br, -, -CN, methyl, ethyl 0610 wherein Q is or methoxy, 0623 or a pharmaceutically acceptable salt thereof. 0624. The invention provides a compound having the Structure:

0611 wherein each R, is independently H; straight chained or branched C-C, alkyl, Straight chained or branched C-C-7 monofluoroalkyl, Straight chained or branched C-C, polyfluoroalkyl, Straight chained or branched C-C, alkenyl, Straight chained or branched C-C, alkynyl, C-C, cycloalkenyl, -(CH), Z, or (CH), O-(CH), CH, 0625 wherein each of Yi, Y, Y, and Y is inde 0612 wherein each Ro is independently -H; pendently -H, Straight chained or branched C-C, Straight chained or branched C-C, alkyl, monofluo alkyl, monofluoroalkyl or polyfluoroalkyl, Straight roalkyl or polyfluoroalkyl, Straight chained or chained or branched C-C, alkenyl or alkynyl, C-C, branched C-C, alkenyl or alkynyl, C-C, cycloalkyl cycloalkyl, or Cs-C7 cycloalkenyl, -F, -Cl, -Br, or Cs-C7 cycloalkenyl, -F, -Cl, -Br, or -I; O I; NO; N; CN; OR, SR, NO; N; CN; OR, OCOR, -OCOR, -COR. -NCOR1, -N(R), -COR, -NCOR1, -N(R), -CONCR), or -CONCR), or -COOR, aryl or heteroaryl; or -COOR, aryl or heteroaryl; or two Ro groups any two of Y1, Y, Y- and Y present on adjacent present on adjacent carbon atoms can join together to carbon atoms can constitute a methylenedioxy form a methylenedioxy group; grOup, 0626 wherein each R is independently -H; 0613 wherein each R is independently -H; Straight chained or branched C-C, alkyl, monofluo Straight chained or branched C-C, alkyl, monofluo roalkyl or polyfluoroalkyl, Straight chained or roalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C, branched C-C, alkenyl or alkynyl, C-C, cycloalkyl, Cs-C7 cycloalkenyl, aryl or aryl (C-C) cycloalkyl, Cs-C7 cycloalkenyl or aryl; alkyl, 0614 wherein each R is independently H, F, Cl, or 0627 wherein A is A, Q, Q, Qs, straight chained Straight chained or branched C-C alkyl, or branched C-C, alkyl, aryl, heteroaryl, aryl(C- 0.615 wherein q is an integer from 2 to 4 inclusive; C.)alkyl, heteroaryl(C-C)alkyl, aryl Substituted with an aryl or heteroaryl, heteroaryl Substituted with 0616 wherein each m is an integer from 0 to 4 an aryl or heteroaryl; or (CHR)-(CHR), Z; inclusive; 0628 wherein A' is 0.617 wherein each n is an integer from 1 to 4 inclusive; 0618 wherein each p is an integer from 0 to 2 inclusive; 0619 wherein U is O, -NR, S, C(R), or -NSOR; 0620 wherein Z is C-Cocycloalkyl, C-C, cyclic ether, C-C, cyclic thioether, aryl, or heteroaryl; US 2003/0078271 A1 Apr. 24, 2003 30

0629 wherein Q is present on adjacent carbon atoms can join together to form a methylenedioxy group; R17 R17 0638 wherein each R is independently -H; Straight chained or branched C-C, alkyl, monofluo N R17; roalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C, l, y-d cycloalkyl, Cs-C7 cycloalkenyl, aryl or aryl(C- R17 C.)alkyl, 0639 wherein each m is an integer from 0 to 4 inclusive; 0640 wherein each n is an integer from 1 to 4

R17 R17 inclusive; 0641 wherein each p is an integer from 0 to 2 inclusive; 0642 wherein U is O, -NR, S, C(R), or -NSOR; 0643 wherein Z is C-C cycloalkyl, C-C, cyclic ether, C-C-7 cyclic thioether, aryl, or heteroaryl; 0631 wherein Q is 0644 wherein R is straight chained or branched C-C, alkyl, straight chained or branched C-C, monofluoroalkyl, Straight chained or branched C-C, polyfluoroalkyl, Straight chained or branched C-C, alkenyl, Straight chained or branched C-C, alkynyl, Cs-C, cycloalkenyl, -(CH2), Z, or (CH-)-O- (CH-)-CH, 0.645 wherein q is an integer from 2 to 4 inclusive; 0646 wherein B is aryl, heteroaryl, aryl Substituted with an aryl or heteroaryl, heteroaryl Substituted with 0632 wherein R and R are each independently H, an aryl or heteroaryl, tricyclic heteroaryl or Q, Straight chained or branched C-C, alkyl, -F, -Cl, provided however, if B is aryl or heteroaryl the -Br, -, -NO, or -CN; carbon atom or carbon atoms ortho to the nitrogen 0633 wherein R is H, straight chained or branched atom of the imine bond may only be substituted with C-C, alkyl, -F, -Cl, -Br, -, -NO, -CN, one or more of the following -F, -Cl, -Br, -I, -OR, aryl or heteroaryl; -CN, methyl, ethyl or methoxy; 0634 wherein Rs is straight chained or branched 0647 wherein a tricyclic heteroaryl is a fused three C-C, alkyl, -N(R), —OR or aryl; member aromatic System in which one or more of the 0635 wherein R is straight chained or branched rings is heteroaryl; carbazole; or acridine, C-C, alkyl or aryl; 0636 wherein each R, is independently H; straight 0648 wherein Q is chained or branched C-C, alkyl, Straight chained or branched C-C-7 monofluoroalkyl, Straight chained or branched C-C, polyfluoroalkyl, Straight chained or branched C-C, alkenyl, Straight chained or branched C-C, alkynyl, Cs-C7 cycloalkenyl, -(CH-)-Z, or (CH)-O-(CH), CH, 0637 wherein each Ro is independently -H; Straight chained or branched C-C, alkyl, monofluo roalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C7 cycloalkyl or Cs-C7 cycloalkenyl, -F, -Cl, -Br, or -I; 0649 wherein each R is independently H, F, Cl, or NO; N; CN; OR, OCOR, Straight chained or branched C-C alkyl, -COR, -NCOR1, -N(R), -CONCR), or -COOR, aryl or heteroaryl; or two Ro groups 0650 or a pharmaceutically acceptable salt thereof. US 2003/0078271 A1 Apr. 24, 2003

0651. The invention provides a compound having the 0661 wherein n is an integer from 1 to 4 inclusive; Structure: 0662 or a pharmaceutically acceptable salt thereof. 0663 The invention provides a compound having the Structure:

0652 wherein each of Yi, Y, Y, and Y is inde pendently -H, Straight chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C, 0664 wherein each of Yi, Y, Y, and Y is inde cycloalkyl, or Cs-C7 cycloalkenyl, -F, -Cl, -Br, pendently -H, Straight chained or branched C-C, O I; NO; N; CN; OR, SR, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight -OCOR, -COR. -NCOR1, -N(R), chained or branched C-C, alkenyl or alky: nyl, -CONCR), or -COOR, aryl or heteroaryl; or C-C, cycloalkyl, or Cs-C, cycloalkenyl; -F, -Cl, any two of Y1, Y, Y- and Y present on adjacent Br, or -I; -NO; -N, -CN; -OR, -SR, carbon atoms can constitute a methylenedioxy -OCOR, -COR. -NCOR. -N(R), grOup, -CONCR), or -COOR, aryl or heteroaryl; or any two of Y1, Y, Y- and Y present on adjacent 0653 wherein each R is independently -H; carbon atoms can constitute a methylenedioxy Straight chained or branched C-C, alkyl, monofluo roalkyl or polyfluoroalkyl, Straight chained or grOup, branched C-C, alkenyl or alkynyl, C-C, 0665 wherein each R is independently -H; cycloalkyl, Cs-C7 cycloalkenyl, aryl or aryl(C- straight chained or branched C-C, alkyl, monofluo C.)alkyl, roalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C, 0654 wherein A is A", straight chained or branched cycloalkyl, Cs-C7 cycloalkenyl, aryl or aryl(C- C-C, alkyl, aryl, heteroaryl, aryl(C-C)alkyl or C.)alkyl, heteroaryl (C-C) alkyl, 0.666 wherein A is A", straight chained or branched 0655 wherein A' is C-C, alkyl, aryl, heteroaryl, aryl(C-C)alkyl or heteroaryl (C-C) alkyl,

O O R1 0667 wherein A' is S-S. O

-(CH) = -R:

-(CH) = -R: 0656 wherein R and R are each independently H, Straight chained or branched C-C, alkyl, -F, -Cl, -Br, -I, -NO, or -CN; 0668 wherein B is aryl Substituted with an aryl or 0657 wherein R is H, straight chained or branched heteroaryl, heteroaryl Substituted with an aryl or C-C, alkyl, -F, -Cl, -Br, -I, -NO, -CN, heteroaryl, tricyclic heteroaryl or Q, -OR, aryl or heteroaryl; 0669 wherein a tricyclic heteroaryl is a fused three 0658 wherein Rs is straight chained or branched ring aromatic System in which one or more of the C-C, alkyl, -N(R) 2, -OR or aryl; rings is heteroaryl; carbazole; or acridine, 0659 wherein R is straight chained or branched 0670) wherein Q is C-C, alkyl or aryl; 0660 wherein B is aryl, or heteroaryl; provided however, if B is aryl or heteroaryl the carbon atom or carbon atoms ortho to the nitrogen atom of the imine bond may only be substituted with one or more of the following-F, -Cl, -Br, -, -CN, methyl, ethyl or methoxy, US 2003/0078271 A1 Apr. 24, 2003 32

0671 wherein n is an integer from 1 to 4 inclusive; 0680 wherein Q is 0672 wherein each R is independently H, F, Cl, or Straight chained or branched C-C alkyl, 0673 or a pharmaceutically acceptable salt thereof. 0674) The invention provides a compound having the Structure:

0681 wherein each R, is independently H; straight chained or branched C-C, alkyl, Straight chained or branched C-C-7 monofluoroalkyl, Straight chained or branched C-C, polyfluoroalkyl, Straight chained or branched C-C, alkenyl, Straight chained or branched C-C, alkynyl, Cs-C7 cycloalkenyl, -(CH2)-Z, or (CH), O-(CH2), CH, 0682 wherein each Ro is independently -H; Straight chained or branched C-C, alkyl, monofluo roalkyl or polyfluoroalkyl, Straight chained or 0675 wherein each of Yi, Y, Y, and Y is inde branched C-C, alkenyl or alkynyl, C-C, pendently -H, Straight chained or branched C-C, cycloalkyl. or Cs-C7 cycloalkenyl, -F, -Cl, -Br, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight or -I; -NO; -N; -CN; -OR-, -OCOR, chained or branched C-C, alkenyl or alkynyl, C-C, -COR, -NCOR1, -N(R), -CONCR), or cycloalkyl, or Cs-C7 cycloalkenyl, -F, -C:L, -Br, -COOR, aryl or heteroaryl; or two Ro groups O I; NO; N; CN; OR, SR, present on adjacent carbon atoms can join together to -OCOR, -COR. -NCOR1, -N(R), form a methylenedioxy group; -CONCR), or -COOR, aryl or heteroaryl; or 0683 wherein each R is independently -H; any two of Y1, Y, Y- and Y present on adjacent Straight chained or branched C-C, alkyl, monofluo carbon atoms can constitute a methylenedioxy roalkyl or polyfluoroalkyl, Straight chained or grOup, branched C-C, alkenyl or alkynyl, C-C, 0676 wherein each R is independently -H; cycloalkyl, Cs-C7 cycloalkenyl or aryl; Straight chained or branched C-C, alkyl, monofluo 0684 wherein each R is independently H, F, Cl, or roalkyl or polyfluoroalkyl, Straight chained or Straight chained or branched C-C alkyl, branched C-C, alkenyl or alkynyl, C-C, 0685 wherein q is an integer from 2 to 4 inclusive; cycloalkyl, Cs-C7 cycloalkenyl, aryl or aryl(C- C.)alkyl, 0686 wherein each m is an integer from 0 to 4 inclusive; 0677 wherein A is Q, Q, Qs, aryl Substituted with 0687 wherein each n is an integer from 1 to 4 an aryl or heteroaryl, heteroaryl Substituted with an inclusive; aryl or heteroaryl, or (CHR)-(CHR), Z; 0688 wherein each p is an integer from 0 to 2 0678 wherein Q is inclusive; 0689 wherein U is O, -NR, S, C(R), or -NSOR; R17 R17 0690 wherein Z is C-C cycloalkyl, C-C, cyclic N ether, C-C-7 cyclic thioether, aryl, or heteroaryl; 0691 wherein R is straight chained or branched R17 1s U R17; C-C, alkyl, straight chained or branched C-C, R17 monofluoroalkyl, Straight chained or branched C-C, polyfluoroalkyl, Straight chained or branched C-C, 0679 wherein Q is alkenyl, Straight chained or branched C-C, alkynyl,

Cs-C, cycloalkenyl, -(CH2)-Z, or (CH-)-O- (CH-)-CH, 0692 wherein B is aryl, or heteroaryl; provided however, if B is aryl or heteroaryl the carbon atom or carbon atoms ortho to the nitrogen atom of the imine bond may only be substituted with one or more of the following-F, -Cl, -Br, -, -CN, methyl, ethyl or methoxy, 0693 or a pharmaceutically acceptable salt thereof. US 2003/0078271 A1 Apr. 24, 2003

0694. The invention provides a method of treating tonal administration (n=5 for each treatment condition). One depression in a Subject which comprises administering to the hour later, rats were examined in a 5 minute forced Swim Subject a composition comprising a pharmaceutically test. For each treatment condition, the number of 5-Sec acceptable carrier and a therapeutically effective amount of intervals culminating with a display of climbing was derived a GAL3 receptor antagonist, wherein: and plotted as the average +/-S.E.M. A significant increase 0695) (a) the GAL3 receptor antagonist binds to the in climbing was observed for rats injected with Example 92 human GAL3 receptor with a binding affinity at least at 10 mg/kg, relative to vehicle injected controls (p<0.01, ten-fold higher than the binding affinity with which it ANOVA and Student-Nerman-Keuls), but not in rats dosed binds to the human GALL receptor; with Example 92 at 30 mg/kg ip. 0696 (b)(1) the GAL3 receptor antagonist does not 0706 FIG.3: Rat Forced Swim Test Results (Swimming: inhibit the activity of central monoamine oxidase A Normal Rats) greater than 50 percent, at a concentration of 10 uM; and 0707 Vehicle (V) and test compounds (FIO =fluoxetine 0697) (2) the GAL3 receptor antagonist does not at 10 mg/kg ip; C1, C3, C10 or C30=Example 92 at 1, 3, 10 inhibit the activity of central monoamine oxidase B or 30 mg/kg ip) were injected into normal rats by intraperi greater than 50 percent, at a concentration of 10 uM; tonal administration (n=5 for each treatment condition). One and hour later, rats were examined in a 5 minute forced Swim test. For each treatment condition, the number of 5-Sec 0698 (c) the GAL3 receptor antagonist binds to the intervals culminating with a display of Swimming was human GAL3 receptor with a binding affinity at least derived and plotted as the average +/-S.E.M. A significant ten-fold higher than the binding affinity with which increase in Swimming was observed for rats injected with it binds to each of the following transporters: Sero tonin transporter, norepinephrine transporter, and fluoxetine at 10 mg/kg ip or with Example 92 at 30 mg/kg, dopamine transporter. relative to vehicle injected controls (p<0.01, ANOVA and Student-Nerman-Keuls). 0699 The invention provides a method of treating anxi ety in a Subject which comprises administering to the Subject 0708 FIG. 4: Social Interaction Test Results (Social a composition comprising a pharmaceutically acceptable Interaction: Unfamiliar Rats) carrier and a therapeutically effective amount of a GAL3 0709 Vehicle (V) and test compounds (CLD 5=chlor receptor antagonist, wherein: diazepoxide at 5 mg/kg ip; C10, C30 or C100-Example 92 0700 (a) the GAL3 receptor antagonist binds to the at 10, 30 or 100 mg/kg ip) were injected into normal rats by human GAL3 receptor with a binding affinity at least intraperitonal administration (n=5 for each treatment condi ten-fold higher than the binding affinity with which it tion). One hour later, unfamiliar rats were examined in a 15 binds to the human GALL receptor, and minute Social interaction test. For each treatment condition, 0701 (b) the GAL3 receptor antagonist binds to the the amount of time spent in Social interaction was derived human GAL3 receptor with a binding affinity at least and plotted as the average +/-S.E.M. A significant increase ten-fold higher than the binding affinity with which in Social interaction was observed for rats injected with it binds to each of the following transporters: Sero chlordiazepoxide at 5 mg/kg i.p. or with Example 92 at 10 tonin transporter, norepinephrine transporter, and mg/kg ip (p<0.05) as well as 30 mg/kg (p<0.01). When the dopamine transporter. dose of Example 92 was increased to 100 mg/kg, the amount of Social interaction time was significantly less than mea BRIEF DESCRIPTION OF THE FIGURES Sured after chlordiazepoxide at 5 mg/kg ip or Example 92 at 0702 FIG. 1: Rat Forced Swim Test Results (Immobil 30 mg/kg ip (p<0.01). Significance in all cases was deter ity: Normal Rats) mined by ANOVA and Student-Nerman-Keuls. 0703) Vehicle (V) and test compounds (F10=fluoxetine at 0710) FIG. 5: Western Blot Results 10 mg/kg ip; C1, C3, C10 or C30=Example 92 at 1, 3, 10 or 30 mg/kg ip) were injected into normal rats by intraperitonal 0711. In order to establish the specificity of the anti administration (n=5 for each treatment condition). One hour GAL3 antiserum, membranes prepared from COS-7 cells later, rats were examined in a 5 minute forced Swim test. For transiently transfected with the rat recombinant GAL3 each treatment condition, the number of 5-Sec intervals (Borowsky et al., 1999) (Lane 2) or mock-transfected (vec culminating with a display of immobility was derived and tor only) (Lane 3) were applied to an SDS-PAGE gel and plotted as the average +/-S.E.M. A significant decrease in blotted using the GAL3 receptor polyclonal antibody. Lane immobility was observed for rats injected with fluoxetine at 1 corresponds to molecular weight marker. The anti-GAL3 10 mg/kg, or with Example 92 at 3 and 10 mg/kg, relative antiserum labeled proteins in membranes only from rat to vehicle injected controls (p<0.01, ANOVA and Student GAL3-transfected cells (Lane 2); a predominant band was Nerman-Keuls). evident with an apparent molecular weight of approximately 56 kDa, (somewhat higher than the amino acid-derived 0704 FIG. 2: Rat Forced Swim Test Results (Climbing: value of 40.4 kDa). The apparently high molecular weight Normal Rats) observed for rat GAL3 very likely reflects post-translational 0705 Vehicle (V) and test compounds (F10=fluoxetine at processing Such as glycosylation; note that rat GAL3 con 10 mg/kg ip; Cl, C3, C10 or C30 =Example 92 at 1, 3, 10 tains multiple N-terminal glycosylation sites (Smith et al., or 30 mg/kg ip) were injected into normal rats by intraperi 1998). Relative to the predominant band, additional species US 2003/0078271 A1 Apr. 24, 2003 34 of higher molecular weight as well as lower molecular 0720 wherein Q is weight were labeled by the GAL3 antiserum. These are interpreted as protein aggregates of C-terminal fragments, as they are absent in mock-transfected cells.

DETAILED DESCRIPTION OF THE INVENTION 0712. The present invention provides a method of treat ing a Subject Suffering from depression which comprises R22 --R administering to the Subject an amount of compound effec tive to treat the Subject's depression wherein the compound R20A-x has the Structure: 0721 wherein each J is independently O, S, C(R) or X NR; 0722 wherein R is H; straight chained or branched W C-C, alkyl, monofluoroalkyl or polyfluoroalkyl; N21 Straight chained or branched C-C, alkenyl or alkynyl, ls R13 C-C, cycloalkyl, Cs-C, cycloalkenyl or aryl; Y N 0723 wherein Y is NRRs; H

sas 0713 wherein W is H, -F, -Cl, -Br, -I, CN, f %sa methyl, ethyl, propyl, methoxy or ethoxy, -(). ? ; or 0714 wherein X is; NRR; N R17 2 lp Rio N-lin- R17 / x.R

*\ s R. - Y- O -N o s ŽSR, \ R. R17 \ 5.A. N-Rs: 0724 wherein R is H, straight chained or branched C-C alkyl, (CH), O-(CH2)-CH3, Cs-Co cycloalkyl, or (COR))-Z, 0715 wherein R is H, straight chained or branched 0725 wherein Rs is straight chained or branched C-C, alkyl, (CH)-O-(CH), CH, aryl, or aryl C-C alkyl, (CH), O-(CH2), CH5, C-C, (C-C)alkyl, cycloalkyl, (C(Rio)2)N(R) or (C(Rio)), Z, 0716 wherein R is straight chained or branched 0726 wherein R is straight chained or branched C-C, alkyl, (CH), O-(CH-)-CH, or C-C, alkyl, straight chained or branched C-C, monof luoroalkyl, Straight chained or branched C-C, poly fluoroalkyl, Straight chained or branched C-C, alk 0717 wherein R is a bicyclic alkyl ring system, enyl, straight chained or branched C-C, alkynyl, C-C, adamantyl, noradamantyl, C-Clocycloalkyl, het cycloalkenyl, -(CH2), Z, or (CH), O eroaryl, aryl, aryl(C-C)alkyl, Q or Q2; (CH), CH, 0718 wherein aryl may be substituted with one or 0727 wherein each R, is independently H; -OR, more C-Co Straight chained or branched alkyl, aryl, -OCOR1, -COR, -NCOR1, -N(R), heteroaryl, or N(R)-Z, -CON(R), -COOR, straight chained or branched C-C, alkyl, Straight chained or branched 0719 wherein Q is C-C, monofluoroalkyl, straight chained or branched C-C, polyfluoroalkyl, straight chained or branched C-C, alkenyl, straight chained or branched C-C, alkynyl, C-C, cycloalkenyl, -(CH-)-Z, or (CH), O-(CH), CH; 0728 wherein Rs is straight chained or branched C-C alkyl, -(CH2), Z, or (CH2)-O-(CH2)- CH; US 2003/0078271 A1 Apr. 24, 2003 35

0729 wherein each Ro is independently H, or straight 0744 wherein R is H, straight chained or branched chained or branched C-C alkyl, C-C, alkyl, (CH), O-(CH-)-CH, aryl or aryl 0730 wherein each Ro is independently -H; straight (C-C) alkyl, chained or branched C-C, alkyl, monofluoroalkyl or 0745 wherein R is straight chained or branched polyfluoroalkyl, Straight chained or branched C-C, C-C, alkyl, (CH2)-O-(CH2)-CH3, or alkenyl or alkynyl, C-C, cycloalkyl or C-C, cycloalk -(CH), Z; enyl; -F, -Cl, -Br, or -I; -NO; -N, -CN; -OR-, -OCOR, -COR, -NCOR, 0746 wherein R is a bicyclic alkyl ring system, aryl -N(R), -CON(R), or -COOR, aryl or het or aryl (C-C) alkyl, eroaryl; or two Rao groups present on adjacent carbon atoms can join together to form a methylenedioxy 0747 wherein Y is NRRs; grOup, 0731 wherein each R is independently -H; straight ^S chained or branched C-C, alkyl, monofluoroalkyl or f %aS polyfluoroalkyl, Straight chained or branched C-C, -(). -1 ; or alkenyl or alkynyl, C-C, cycloalkyl, Cs-C, cycloalk \, Rii 11N, enyl, aryl, or aryl(C-C)alkyl, Rio - 0732 wherein each R is independently H, F, CI or N-lin C-C straight chained or branched alkyl; V-R20 0733 wherein each m is an integer from 0 to 4 inclu / X Sive,

0734 wherein each n is an integer from 1 to 4 inclu A. Sive, \ 5. 0735 wherein p is an integer from 0 to 2 inclusive; 0736 wherein q is an integer from 2 to 4 inclusive; 0748 wherein R is H, straight chained or branched C-C alkyl, (CH), O-(CH), CH, C-C, 0737 wherein t is 1 or 2; cycloalkyl, or (COR))-Z, 0738 wherein U is O, -NR, S, C(R), or 0749 wherein Rs is straight chained or branched -NSOR; C-C alkyl, (CH), O-(CH2), CH5, C-C, 0739 wherein Z is C-C cycloalkyl, C-C, cyclic cycloalkyl, or (COR))-Z, ether, C-C-7 cyclic thioether, aryl, or heteroaryl; or 0750 wherein U is O, -NR, S, C(R), or 0740 a pharmaceutically acceptable salt thereof. -NSOR; 0741. The invention provides a method of treating a O751 Whereherein in ZZ. isIS C-Clocycloalkyl,C-C cycloalkyl, arylaryl, or hhet Subject Suffering from depression which comprises admin eroaryl; istering to the Subject an amount of compound effective to 0752 wherein R is straight chained or branched treat the Subject's depression wherein the compound has the C-C, alkyl, straight chained or branched C-C, monof Structure: luoroalkyl, Straight chained or branched C-C, poly X fluoroalkyl, Straight chained or branched C-C, alk enyl, straight chained or branched C-C, alkynyl, C-C, N21 W cycloalkenyl, -(CH2), Z, or (CH2)-O-(CH2)- CH;

Y ls N R13 0753 wherein each R, is independently H; -OR, -OCOR1, -COR, -NCOR1, -N(R), H -CON(R), -COOR, straight chained or branched C-C, alkyl, Straight chained or branched 0742 wherein W is H, -F, -Cl, -Br, -I, CN, C-C, monofluoroalkyl, straight chained or branched methyl, ethyl, propyl, methoxy or ethoxy, C-C, polyfluoroalkyl, straight chained or branched C-C, alkenyl, straight chained or branched C-C, 0743 wherein X is NRR; alkynyl, Cs-C7 cycloalkenyl, -(CH2)-Z, or (CH), O-(CH), CH; R17 0754) wherein Rs is straight chained or branched i. alkyl, -(CH2), Z, or (CH-)-O-(CH2)- -N ) ; or 3. \ R. \ 7 R. 0755 wherein each Ro is independently H, or straight chained or branched C-C alkyl, US 2003/0078271 A1 Apr. 24, 2003 36

0756 wherein each Ro is independently -H; straight 0769 wherein Q is chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C-7 cycloalkyl or Cs-C7 cycloalk enyl; -F, -Cl, -Br, or -I; -NO; -N; -CN; -OR-, -OCOR, -COR, -NCOR, -N(R), -CON(R), or -COOR, aryl or het eroaryl; or two Rao groups present on adjacent carbon atoms can join together to form a methylenedioxy 0770 wherein Q is grOup,

0757 wherein each R is independently -H; straight R22 R22 chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C, cycloalkyl, Cs-C, cycloalk enyl, aryl or aryl(C-C) alkyl, 0758 wherein each m is an integer from 0 to 4 inclu Sive, 0759 wherein each n is an integer from 1 to 4 inclu SIVe; 0771 wherein each J is independently O, S, C(R) or 0760 wherein p is an integer from 0 to 2 inclusive; NR; 0761 wherein q is an integer from 2 to 4 inclusive; 0772 wherein R is -H; straight chained or branched C-C, alkyl, monofluoroalkyl or polyfluo 0762 wherein t is 1 or 2; or roalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C-7 cycloalkyl, Cs-C7 cycloalkenyl or 0763 a pharmaceutically acceptable salt thereof. aryl; 0764. The invention provides a method of treating a 0773) wherein Y is NRRs: Subject Suffering from depression which comprises admin istering to the Subject an amount of compound effective to treat the Subject's depression wherein the compound has the R17 R20 Structure: -N/ |\S. R1a ; or X \, f R: 11N, Rio - N21 W N-lin / X R20 Y ls N R13

-N o H \ Žs.M 0765 wherein W is H, -F, -Cl, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy, 0774 wherein R is H, straight chained or branched 0766 wherein X is N(CH) or C-C alkyl, (CH), O-(CH2), CH5, C-C, cycloalkyl, or (COR))-Z, R17 0775 wherein Rs is straight chained or branched C-C alkyl, (CH), O-(CH2)-CH3, Cs-Co cycloalkyl, or (COR))-Z, - Y 0776 wherein U is O, -NR, S, C(R), or -NSOR; 0777 wherein Z is C-C cycloalkyl, aryl, or het 0767 wherein R is an aryl, adamantyl, noradaman eroaryl; tyl, C-Co cycloalkyl, heteroaryl, Q or Q, 0778 wherein R is straight chained or branched 0768 wherein aryl may be substituted with one or C-C, alkyl, straight chained or branched C-C, monof more C-Co Straight chained or branched alkyl, aryl, luoroalkyl, Straight chained or branched C-C, poly heteroaryl, or N(Ro)-Z, fluoroalkyl, Straight chained or branched C-C, alk US 2003/0078271 A1 Apr. 24, 2003 37

enyl, straight chained or branched C-C, alkynyl, C-C, 0792 wherein W is H, –F–Cl, -Br, -I, CN, cycloalkenyl, -(CH2), Z, or (CH), O methyl, ethyl, propyl, methoxy or ethoxy, 0793 wherein X is N(CH) or 0779 wherein each R, is independently H; -OR, -OCOR, -COR, -NCOR, -N(R), -CON(R), -COOR, straight chained or R17 branched C-C, alkyl, Straight chained or branched C-C, monofluoroalkyl, straight chained or branched C-C, polyfluoroalkyl, straight chained or branched - Y C-C, alkenyl, straight chained or branched C-C, \ R. alkynyl, Cs-C7 cycloalkenyl, -(CH2)-Z, or (CH), O-(CH), CH; 0794 wherein R is a bicyclic alkyl ring system, aryl 0780 wherein Rs is straight chained or branched or aryl (C-C) alkyl, C-C alkyl, -(CH2), Z, or (CH2)-O-(CH2)- CH; 0795 wherein Y is NRRs; 0781 wherein each Ro is independently H, or straight 0796 wherein R is H, straight chained or branched chained or branched C-C alkyl, C-C alkyl, (CH), O-(CH), CH, C-C, cycloalkyl, or (COR))-Z, 0782 wherein each Ro is independently -H; straight chained or branched C-C, alkyl, monofluoroalkyl or 0797 wherein R is (C(R).), N(R); polyfluoroalkyl, Straight chained or branched C-C, 0798 wherein Z is C-C cycloalkyl, aryl, or het alkenyl or alkynyl, C-C, cycloalkyl or C-C, cycloalk eroaryl; enyl; -F, -Cl, -Br, or -I; -NO; -N, -CN; -OR. --OCOR, -COR, -NCOR, 0799 wherein R is straight chained or branched -N(R), -CON(R) or -COOR, aryl or het C-C, alkyl, straight chained or branched C-C, monof eroaryl; or two Rao groups present on adjacent carbon luoroalkyl, Straight chained or branched C-C, poly atoms can join together to form a methylenedioxy fluoroalkyl, Straight chained or branched C-C, alk grOup, enyl, straight chained or branched C-C, alkynyl, C-C, 0783 wherein each R is independently -H; straight cycloalkenyl, -(CH2), Z, or (CH2)-O-(CH2) chained or branched C-C, alkyl, monofluoroalkyl or mCH; polyfluoroalkyl, Straight chained or branched C-C, 0800 wherein each R, is independently H; -OR, alkenyl or alkynyl, C-C-7 cycloalkyl, Cs-C, cycloalk -OCOR, -COR, -NCOR1, -N(R), enyl, aryl or aryl(C-C) alkyl, -CON(R), -COOR, straight chained or branched C-C, alkyl, Straight chained or branched 0784 wherein each R is independently H, F, Cl or C-C, monofluoroalkyl, straight chained or branched C-C straight chained or branched alkyl; C-C, polyfluoroalkyl, straight chained or branched 0785 wherein each m is an integer from 0 to 4 inclu C-C, alkenyl, straight chained or branched C-C, Sive, alkynyl, Cs-C7 cycloalkenyl, -(CH2).Z, or (CH2)- 0786 wherein each n is an integer from 1 to 4 inclu O-(CH), CH, Sive, 0801 wherein each Ro is independently H, or straight 0787 wherein p is an integer from 0 to 2 inclusive; chained or branched C-C alkyl, 0802 wherein each R is independently -H; straight 0788 wherein q is an integer from 2 to 4 inclusive; chained or branched C-C, alkyl, monofluoroalkyl or 0789 wherein t is 1 or 2; or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C, cycloalkyl, Cs-C, cycloalk 0790 a pharmaceutically acceptable salt thereof. enyl, aryl or aryl(C-C) alkyl, 0791. The invention provides a method of treating a Subject Suffering from depression which comprises admin 0803 wherein each m is an integer from 0 to 4 inclu istering to the Subject an amount of compound effective to Sive, treat the Subject's depression wherein the compound has the 0804 wherein each n is an integer from 1 to 4 inclu Structure: Sive, 0805 wherein q is an integer from 2 to 4 inclusive; or X 0806 a pharmaceutically acceptable salt thereof. N21 W 0807 AS used in the present invention, the term “bicyclic alkyl ring Systems' includes, but is not limited to, bicyclo ls R13 2.2.1]heptane, bicyclo3.1.1 heptane and bicyclo2.2.2]oc Y N tane. In addition, the bicyclic alkyl ring Systems may be H substituted with one or more of the following: -F, -NO, -CN, Straight chained or branched C-C, alkyl, Straight chained or branched C-C-7 monofluoroalkyl, Straight US 2003/0078271 A1 Apr. 24, 2003 38 chained or branched C-C, polyfluoroalkyl, Straight chained branched C-C, polyfluoroalkyl, Straight chained or or branched C-C, alkenyl, Straight chained or branched branched C-C, alkenyl, Straight chained or branched C-C, C-C, alkynyl, C-C, cycloalkyl, Cs-C, cycloalkenyl, alkynyl, C-C7 cycloalkyl, C-C monofluorocycloalkyl, -N(R), -OR-, -COR, -COR,-CONCR) or C-C, polyfluorocycloalkyl, Cs-C, cycloalkenyl, -N(R), (CH -O-(CH2)-CH. --OR, -COR, -NCOR1, -COR, -CONCR) or 0808 AS used in the present invention, the term (CH), O-(CH), CHs. “cycloalkyl includes, C-C-7 cycloalkyl moieties which may 0814) The term “heteroaryl” further includes the N-ox be substituted with one or more of the following: -F, ides of those chemical moieties recited above which include -NO, -CN, straight chained or branched C-C, alkyl, at least one nitrogen atom. Straight chained or branched C-C-7 monofluoroalkyl, Straight chained or branched C-C, polyfluoroalkyl, Straight 0815. In the present invention the term “aryl' is phenyl or chained or branched C-C, alkenyl, Straight chained or naphthyl. The term “aryl also includes phenyl and naphthyl branched C-C, alkynyl, C-C, cycloalkyl, C-C, monof which may be substituted with one or more of the following: luorocycloalkyl, C-C, polyfluorocycloalkyl, Cs-C, F, -Cl, -Br, -, -NO, -CN, straight chained or cycloalkenyl, -N(R) 2, -OR, -COR, -NCOR, branched C-C, alkyl, Straight chained or branched C-C, -COR, -CONCR) or (CH), O(CH), CHs. monofluoroalkyl, Straight chained or branched C-C, poly fluoroalkyl, Straight chained or branched C-C, alkenyl, 0809. As used in the present invention, the term “cyclo Straight chained or branched C-C, alkynyl, C-C, hexyl” includes, cyclohexyl groups which may be Substi cycloalkyl, C-C monofluorocycloalkyl, C-C, polyfluoro tuted with one or more of the following: -F, -NO,-CN, cycloalkyl, Cs-C, cycloalkenyl, -N(R), -OR, -SR, Straight chained or branched C-C, alkyl, Straight chained or branched C-C monofluoroalkyl, Straight chained or -OCOR,-COR,-NCOR1, -COR,-CONCR) or branched C-C, polyfluoroalkyl, Straight chained or (CH), O-(CH), CHs. branched C-C, alkenyl, Straight chained or branched C-C, 0816. In one embodiment of any of the methods alkynyl, C-C7 cycloalkyl, C-C monofluorocycloalkyl, described herein, the compound is enantiomerically and C-C, polyfluorocycloalkyl, Cs-C, cycloalkenyl, -N(R), diasteriomerically pure. In one embodiment, the compound --OR, -COR, -NCOR1, -COR, -CONCR) or is enantiomerically or diasteriomerically pure. (CH), O-(CH), CH 0817. In one embodiment of any of the methods 0810. As used in the present invention, the term described herein, the compound can be administered orally. “cycloalkenyl' includes, Cs-C, cycloalkenyl moieties which may be substituted with one or more of the following: -F, 0818) In one embodiment, X is: -Cl, -Br, -, -NO,-CN, straight chained or branched C-C, alkyl, Straight chained or branched C-C, monofluo roalkyl, Straight chained or branched C-C, polyfluoroalkyl, Straight chained or branched C-C, alkenyl, Straight chained or branched C-C, alkynyl, C-C-7 cycloalkyl, C-C monof luorocycloalkyl, C-C, polyfluorocycloalkyl, Cs-C, cycloalkenyl, -N(R), -OR, -COR, -NCOR, -COR, -CONCR) or (CH), O-(CH), CH. 0811. In the present invention, the term "heteroaryl” is 0819. In one embodiment, X is NRR and R is H or used to include five and Six membered unsaturated rings that Straight chained or branched C-C, alkyl. may contain one or more oxygen, Sulfur, or nitrogen atoms. Examples of heteroaryl groups include, but are not limited 0820) In one embodiment, the compound has the Struc to, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, ture: pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, N-R12 and triazinyl. N 0812. In addition the term "heteroaryl' is used to include fused bicyclic ring Systems that may contain one or more N21 W heteroatoms Such as oxygen, Sulfur and nitrogen. Examples of Such heteroaryl groups include, but are not limited to, ls R13 indolizinyl, indolyl, isoindolyl, benzobfuranyl, benzob Y N thiophenyl, indazolyl, benzimidazolyl, purinyl, benzox H azolyl, benzisoxazolyl, benzobthiazolyl, imidazo2,1-b thiazolyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1.8- naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, 0821. In one embodiment, R is a bicyclic alkyl ring phthalimidyl and 2,1,3-benzothiazolyl. System, cyclohexyl or aryl. 0813 The term "heteroaryl' also includes those chemical 0822. In one embodiment, R is H, straight chained or moieties recited above which may be substituted with one or more of the following: -F, -Cl, -Br, -, -NO,-CN, branched C-C alkyl or (CH), O-(CH), CHs. Straight chained or branched C-C, alkyl, Straight chained or 0823. In one embodiment, R is H, straight chained or branched C-C monofluoroalkyl, Straight chained or branched C-C alkyl or (CH), O-(CH2), CHs. US 2003/0078271 A1 Apr. 24, 2003 39

0824. In one embodiment, the compound is selected from the group consisting of: -continued oloO co-cC ocO -->O or -N- O - ou) O colo O 9 ou) O a luo, CO - O O cluoloN F N le r --- O? -O US 2003/0078271 A1 Apr. 24, 2003 40

-continued -continued O alo C C, C O

0825. In one embodiment, Y is f N\ R17 ON N1 N l 2 0826. In one embodiment, U is NRs. F F r N N 0827. In one embodiment, R is (CH), Z. F Nu 0828. In one embodiment, Z is aryl or heteroaryl. 0829. In one embodiment, the compound is selected from the group consisting of:

N ; and N US 2003/0078271 A1 Apr. 24, 2003 41

-continued -continued C S S --- F o, At 7 le uo. O F F r N N - N1

N C. 2 N N N le 2 N N C 0830. In one embodiment, the compound is selected from the group consisting of: 0831. In one embodiment, Y is N1 R17 C

-N U . SC Cl DO --- N O? C\ R17

NN 1. Cl 0832. In one embodiment, U is NRs. 0833. In one embodiment, the compound is N1N Cl; l 2 N1 N N N N N1 N

- - ; or N N N Cup: OCO Oud-O ! CC r Cr US 2003/0078271 A1 Apr. 24, 2003 42

0834. In one embodiment, the compound is -continued O C -

N Nu tools occoN1 C l r rom0835. the groupIn one consisting embodiment, of the compound is selected f Clu Nure N N1 N1 No N1 N s N Cl

N N N N-~~ reOur N N1 C N Nu l; N N C 2N l 2 N1 Clu r N N N1 N

r N N N N Nu

N21 ls 0836. In one embodiment, the compound is selected from N N N the group consisting of:

l- N N 1 N1 Cl N N1 N re N 2 Null US 2003/0078271 A1 Apr. 24, 2003 43

-continued -continued

21 N 2N N-N N1 21 Cl CF: 0837. In one embodiment, X is N(CH). N ls 0838. In one embodiment, Y is N r N N 21 Nu N-N /\,Y& n1 \ } / R 17 N

N21 s 0839. In one embodiment, R is an aryl Substituted with

r N ls N N a C-Co Straight chained alkyl. Nu 0840. In one embodiment, the compound is selected from 21 a group consisting of N n1 N nN.1

N1 Sal-N n1 N1N N

r - N - N r lssh ... and US 2003/0078271 A1 Apr. 24, 2003 44

0848 wherein Q is -continued

N J R22 - I 21 x.in R22

0849 wherein Q is

R22 R22 0841. The invention provides a method of treating a Subject Suffering from anxiety which comprises administer ing to the Subject an amount of compound effective to treat the Subject's anxiety wherein the compound has the Struc ture:

W 0850 wherein each J is independently O, S, C(R) or Na NR; ls R13 0851 wherein R is H; straight chained or branched Y N C-C, alkyl, monofluoroalkyl or polyfluoroalkyl; Straight chained or branched C-C, alkenyl or alkynyl, H C-C-7 cycloalkyl, Cs-C7 cycloalkenyl or aryl; 0852 wherein Y is NRRs; 0842) wherein W is H, -F, -C1, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy,

0843 wherein X is; NRR; ^S i. %aS -(). R. ; or R17 N R17 2 lp Rio - or , R17 ; H ()- ; or N-lin SR \ R. / x R

R17 -N o s A. N-Rs: \ Žs. \ v R, 0853 wherein R is H, straight chained or branched C-C alkyl, (CH), O-(CH), CH, C-C, 0844 wherein RR is H, straight chained or cycloalkyl, or (COR))-Z, branched C-C, alkyl, (CH2)-O-(CH2)-CH3, aryl, or aryl (C-C)alkyl, 0854 wherein R is straight chained or branched C-C alkyl, (CH2), O-(CH2)-CH3, Cs-Co 0845 wherein R is straight chained or branched cycloalkyl, (C(Ro))N(R) or (C(R)-)-Z, C-C, alkyl, (CH-)-O-(CH-)-CH, or 0855 wherein R is straight chained or branched C-C, alkyl, straight chained or branched C-C, monof 0846 wherein R is a bicyclic alkyl ring system, luoroalkyl, Straight chained or branched C-C, poly fluoroalkyl, Straight chained or branched C-C, alk adamantyl, noradamantyl, C-Clocycloalkyl, het enyl, straight chained or branched C-C, alkynyl, C-C, eroaryl, aryl, aryl(C-C)alkyl, Q or Q, cycloalkenyl, -(CH2), Z, or (CH), O 0847 wherein aryl may be substituted with one or (CH), CH, more C-Co Straight chained or branched alkyl, aryl, 0856 wherein each R, is independently H; -OR, heteroaryl, or N(Ro)-Z, -OCOR, -COR, -NCOR1, -N(R), US 2003/0078271 A1 Apr. 24, 2003 45

-CON(R), -COOR, straight chained or 0871 wherein W is H, -F, -Cl, -Br, -I, CN, branched C-C, alkyl, Straight chained or branched methyl, ethyl, propyl, methoxy or ethoxy, C-C, monofluoroalkyl, straight chained or branched C-C, polyfluoroalkyl, Straight chained or branched 0872 wherein X is NRR; C-C,1. alkenyl, straight chained or branched C-C, alkynyl, C-C, cycloalkenyl, -(CH-)-Z, or (CH), O-(CH), CH; 0857 wherein Rs is straight chained or branched C-C alkyl, -(CH.) il-Z, or (CH2)-O-(CH2)- CH; 0858 wherein each Ro is independently H, or straight chained or branched C-C alkyl, 0859 wherein each Ro is independently -H; straight 0873 wherein R is H, straight chained or branched chained or branched C-C, alkyl, monofluoroalkyl or C-C, alkyl, (CH), O-(CH), CH, aryl or polyfluoroalkyl, Straight chained or branched C-C, aryl(C-C)alkyl, alkenyl or alkynyl, C-C-7 cycloalkyl or Cs-C7 cycloalk enyl; -F, -Cl, -Br, or -I; -NO; -N, -CN; 0874 wherein R is straight chained or branched -OR-, -OCOR, -COR, -NCOR, C-C, alkyl, (CH2)-O-(CH2)-CH3, or -N(R), -CON(R), or -COOR, aryl or het eroaryl; or two Rao groups present on adjacent carbon atoms can join together to form a methylenedioxy 0875 wherein R is a bicyclic alkyl ring system, aryl grOup, or aryl (C-C) alkyl, 0860 wherein each R is independently -H; straight 0876 wherein Y is NRRs; chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C, cycloalkyl, Cs-C, cycloalk R20 enyl, aryl, or aryl(C-C)alkyl, R17 1, nS 0861 wherein each R is independently H, F, CI or s C-C straight chained or branched alkyl; - \ 21 0862 wherein each m is an integer from 0 to 4 inclu Sive, 0863 wherein each n is an integer from 1 to 4 inclu Sive, 0864 wherein p is an integer from 0 to 2 inclusive; 0865 wherein q is an integer from 2 to 4 inclusive; 0866 wherein t is 1 or 2; 0867 wherein U is O, -NR, S, C(R), or -NSOR; 0877 wherein R is H, straight chained or branched 0868 wherein Z is C-Clocycloalkyl, C-C, cyclic C-C alkyl, (CH2), O-(CH2)-CH3, Cs-Co ether, C-C-7 cyclic thioether, aryl, or heteroaryl; or cycloalkyl, or (COR))-Z, 0869) a pharmaceutically acceptable Salt thereof. 0878 wherein R is straight chained or branched 0870. The invention provides a method of treating a C-C alkyl, (CH), O-(CH2), CH5, C-C, Subject Suffering from anxiety which comprises administer cycloalkyl, or (COR))-Z, ing to the Subject an amount of compound effective to treat the Subject's anxiety wherein the compound has the Struc 0879 wherein U is O, -NR, S, C(R-), or ture: -NSOR; 0880 wherein Z is C-C cycloalkyl, aryl, or het X eroaryl; W 0881 wherein R is straight chained or branched N21 C-C, alkyl, straight chained or branched C-C, monof ls R13 luoroalkyl, Straight chained or branched C-C, poly Y N fluoroalkyl, Straight chained or branched C-C, alk enyl, straight chained or branched C-C, alkynyl, C-C, H cycloalkenyl, -(CH2), Z, or (CH), O (CH-)-CH, US 2003/0078271 A1 Apr. 24, 2003 46

0882 wherein each R, is independently H; -OR, 0895 wherein X is N(CH) or -OCOR, -COR, -NCOR1, -N(R), -CON(R), -COOR, straight chained or branched C-C, alkyl, Straight chained or branched R17 C-C, monofluoroalkyl, straight chained or branched / C-C, polyfluoroalkyl, straight chained or branched C-C, alkenyl, straight chained or branched C-C, alkynyl, Cs-C7 cycloalkenyl, -(CH2)-Z, or (CH), O-(CH), CH; 0883 wherein Rs is straight chained or branched 0896 wherein R is an aryl, adamantyl, noradaman C-C alkyl, -(CH), Z, or (CH-)-O-(CH), tyl, Cs-Cocycloalkyl, heteroaryl, Q or Q, CH; 0897 wherein aryl may be substituted with one or 0884 wherein each Ro is independently H, or straight more C-Co Straight chained or branched alkyl, aryl, chained or branched C-C alkyl, heteroaryl, or N(Ro)-Z, 0885 wherein each Ro is independently -H; straight 0898 wherein Q is chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C-7 cycloalkyl or Cs-C7 cycloalk enyl; -F, -Cl, -Br, or -I; -NO; -N, -CN; -OR. --OCOR, -COR, -NCOR, -N(R), -CON(R), or -COOR, aryl or het eroaryl; or two Rao groups present on adjacent carbon atoms can join together to form a methylenedioxy grOup, 0886 wherein each R is independently -H; straight chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C-7 cycloalkyl, Cs-C, cycloalk enyl, aryl or aryl(C-C) alkyl, 0887 wherein each m is an integer from 0 to 4 inclu Sive, 0888 wherein each n is an integer from 1 to 4 inclu Sive, 0900 wherein each J is independently O, S, C(R) or 0889 wherein p is an integer from 0 to 2 inclusive; NR; 0890 wherein q is an integer from 2 to 4 inclusive; 0901 wherein R is -H; straight chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, 0891 wherein t is 1 or 2; or Straight chained or branched C-C, alkenyl or alkynyl, 0892 a pharmaceutically acceptable salt thereof. C-C, cycloalkyl, Cs-C, cycloalkenyl or aryl; 0893. The invention provides a method of treating a 0902 wherein Y is NRRs; Subject Suffering from anxiety which comprises administer ing to the Subject an amount of compound effective to treat the Subject's anxiety wherein the compound has the Struc R20 ture: R17 1, nS -y \ R2NgN4 X N21 W

Y lsN R13

0894 wherein W is H, -F, -Cl, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy, US 2003/0078271 A1 Apr. 24, 2003 47

(0903) wherein R is H, straight chained or branched 0920. The invention provides a method of treating a C-C alkyl, (CH-)-O-(CH-)-CH, C-C, Subject Suffering from anxiety which comprises administer cycloalkyl, or (C(R)), Z; ing to the Subject an amount of compound effective to treat 0904 wherein Rs is straight chained or branched the Subject's anxiety wherein the compound has the Struc C-C alkyl, (CH), O-(CH2)-CH3, Cs-Co ture: cycloalkyl, or (C(R)), Z; 0905 wherein U is O, -NR, S, C(R-), or X -NSOR; W 0906 wherein Z is C-Clocycloalkyl, aryl, or het N21 eroaryl; ls R13 0907 wherein R is straight chained or branched Y N C-C, alkyl, straight chained or branched C-C, monof H luoroalkyl, Straight chained or branched C-C, poly fluoroalkyl, Straight chained or branched C-C, alk enyl, straight chained or branched C-C, alkynyl, C-C, 0921 wherein W is H, -F, -Cl, -Br, -I, CN, cycloalkenyl, -(CH), Z, or (CH), O methyl, ethyl, propyl, methoxy or ethoxy, 0922 wherein X is N(CH) or 0908 wherein each R, is independently H; -OR, -OCOR, -COR, -NCOR, -N(R), -CON(R), -COOR, straight chained or R17 branched C-C, alkyl, Straight chained or branched C-C, monofluoroalkyl, straight chained or branched / C-C, polyfluoroalkyl, straight chained or branched C-C, alkenyl, straight chained or branched C-C, alkynyl, C-C, cycloalkenyl, -(CH-)-Z, or (CH), O-(CH), CH; 0923 wherein R is a bicyclic alkyl ring system, aryl 0909 wherein Rs is straight chained or branched or aryl (C-C) alkyl; C-C alkyl, -(CH), Z, or (CH-)-O-(CH),- CH; 0924 wherein Y is NRRs; 0910 wherein each Ro is independently H, or straight 0.925 wherein R is H, straight chained or branched C-C alkyl, (CH), O-(CH2)-CH3, Cs-Co chained or branched C-C alkyl, cycloalkyl, or (COR))-Z, 0911 wherein each Rao is independently -H; straight chained or branched C-C, alkyl, monofluoroalkyl or 0926 wherein Rs is (C(R).), N(R); polyfluoroalkyl, Straight chained or branched C-C, 0927 wherein Z is C-Clocycloalkyl, aryl, or het alkenyl or alkynyl, C-C-7 cycloalkyl or Cs-C7 cycloalk eroaryl; enyl; -F, -Cl, -Br, or -I; -NO; -N; -CN; -OR-, -OCOR, -COR, -NCOR, 0928 wherein R is straight chained or branched -N(R), -CON(R), or -COOR, aryl or het C-C, alkyl, straight chained or branched C-C, monof eroaryl; or two Rao groups present on adjacent carbon luoroalkyl, Straight chained or branched C-C, poly atoms can join together to form a methylenedioxy fluoroalkyl, Straight chained or branched C-C, alk grOup, enyl, straight chained or branched C-C, alkynyl, C-C, cycloalkenyl, -(CH2), Z, or (CH), O 0912 wherein each R is independently -H; straight chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, 0929 wherein each R, is independently H; -OR, alkenyl or alkynyl, C-C, cycloalkyl, Cs-C, cycloalk -OCOR, -COR, -NCOR1, -N(R), enyl, aryl or aryl(C-C)alkyl, -CON(R), -COOR, straight chained or branched C-C, alkyl, Straight chained or branched 0913 wherein each R is independently H, F, CI or C-C, monofluoroalkyl, straight chained or branched C-C straight chained or branched alkyl; C-C, polyfluoroalkyl, straight chained or branched C-C, alkenyl, straight chained or branched C-C, 0.914 wherein each m is an integer from 0 to 4 inclu alkynyl, Cs-C7 cycloalkenyl, -(CH2)-Z, or SIVe; (CH), O-(CH), CH; (0915) wherein each n is an integer from 1 to 4 inclu 0930 wherein each Ro is independently H, or straight SIVe; chained or branched C-C alkyl, 0916 wherein p is an integer from 0 to 2 inclusive; 0931 wherein each R is independently -H; straight 0917 wherein q is an integer from 2 to 4 inclusive; chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, 0918 wherein t is 1 or 2; or alkenyl or alkynyl, C-C-7 cycloalkyl, Cs-C7 cycloalk 0919 a pharmaceutically acceptable salt thereof. enyl, aryl or aryl(C-C) alkyl, US 2003/0078271 A1 Apr. 24, 2003 48

0932 wherein each m is an integer from 0 to 4 inclu 0941. In addition the term "heteroaryl' is used to include Sive, fused bicyclic ring Systems that may contain one or more heteroatoms Such as oxygen, Sulfur and nitrogen. Examples 0933 wherein each n is an integer from 1 to 4 inclu of Such heteroaryl groups include, but are not limited to, Sive, indolizinyl, indolyl, isoindolyl, benzobfuranyl, benzob 0934 wherein q is an integer from 2 to 4 inclusive; or thiophenyl, indazolyl, benzimidazolyl, purinyl, benzox azolyl, benzisoxazolyl, benzobthiazolyl, imidazo2,1-b 0935 a pharmaceutically acceptable salt thereof. thiazolyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1.8- 0936 AS used in the present invention, the term “bicyclic naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, alkyl ring Systems' includes, but is not limited to, bicyclo phthalimidyl and 2,1,3-benzothiazolyl. 2.2.1]heptane, bicyclo3.1.1 heptane and bicyclo2.2.2]oc tane. In addition, the bicyclic alkyl ring Systems may be 0942. The term "heteroaryl' also includes those chemical substituted with one or more of the following: -F, -NO, moieties recited above which may be substituted. with one -CN, Straight chained or branched C-C, alkyl, Straight or more of the following: -F, -Cl, -Br, -, -NO, chained or branched C-C-7 monofluoroalkyl, Straight -CN, Straight chained or branched C-C, alkyl, Straight chained or branched C-C, polyfluoroalkyl, Straight chained chained or branched C-C-7 monofluoroalkyl, Straight or branched C-C, alkenyl, Straight chained or branched chained or branched C-C, polyfluoroalkyl, Straight chained C-C, alkynyl, C-C, cycloalkyl, Cs-C, cycloalkenyl, or branched C-C, alkenyl, Straight chained or branched -N(R), -OR-, -COR, -COR,-CONCR) or C-C, alkynyl, Ca-C, cycloalkyl, Ca-C, monofluorocy (CH), O-(CH), CHs. cloalkyl, C-C, polyfluorocycloalkyl, Cs-C7 cycloalkenyl, 0937 AS used in the present invention, the term -N(R), -OR, -COR, -NCOR1, -COR, “cycloalkyl includes, C-C-7 cycloalkyl moieties which may be substituted with one or more of the following: -F, -CONCR), or (CH), O-(CH-)-CHs. -NO, -CN, straight chained or branched C-C, alkyl, 0943) The term “heteroaryl” further includes the N-ox Straight chained or branched C-C-7 monofluoroalkyl, ides of those chemical moieties recited above which include Straight chained or branched C-C, polyfluoroalkyl, Straight at least one nitrogen atom. chained or branched C-C, alkenyl, Straight chained or branched C-C, alkynyl, C-C, cycloalkyl, C-C, monof 0944. In the present invention the term “aryl' is phenyl or luorocycloalkyl, C-C, polyfluorocycloalkyl, C-C, naphthyl. The term “aryl also includes phenyl and naphthyl cycloalkenyl, -N(R) 2-OR, -COR, -NCOR, which may be substituted with one or more of the following: -COR, CONCR) or (CH), O-(CH), CH. F, -Cl, -Br, -, -NO, -CN, straight chained or 0938 AS used in the present invention, the term “cyclo branched C-C, alkyl, Straight chained or branched C-C, hexyl” includes, cyclohexyl groups which may be Substi monofluoroalkyl, Straight chained or branched C-C, poly tuted with one or more of the following: -F, -NO,-CN, fluoroalkyl, Straight chained or branched C-C, alkenyl, Straight chained or branched C-C, alkyl, Straight chained or Straight chained or branched C-C, alkynyl, C-C, branched C-C monofluoroalkyl, Straight chained or cycloalkyl, C-C, monofluorocycloalkyl, C-C, polyfluoro branched C-C, polyfluoroalkyl, Straight chained or cycloalkyl, Cs-C7 cycloalkenyl, -N(R), -OR, -SR, branched C-C, alkenyl, Straight chained or branched C-C, alkynyl, C-C7 cycloalkyl, C-C monofluorocycloalkyl, -OCOR,-COR,-NCOR1, -COR,-CONCR) or C-C, polyfluorocycloalkyl, Cs-C, cycloalkenyl, -N(R), (CH), O-(CH), CHs. --OR, -COR, -NCOR1, -COR, -CONCR) or 0945. In one embodiment of any of the methods (CH), O-(CH), CHs. described herein, the compound is enantiomerically and 0939. As used in the present invention, the term diasteriomerically pure. In one embodiment, the compound “cycloalkenyl' includes, Cs-C7 cycloalkenyl moieties which is enantiomerically or diasteriomerically pure. may be substituted with one or more of the following: -F, 0946. In one embodiment, the compound can be admin -Cl, -Br, -, -NO,-CN, straight chained or branched istered orally. C-C, alkyl, Straight chained or branched C-C-7 monofluo roalkyl, Straight chained or branched C-C, polyfluoroalkyl, 0947) In one embodiment, X is: Straight chained or branched C-C, alkenyl, Straight chained or branched C-C, alkynyl, C-C, cycloalkyl, C-C, monof luorocycloalkyl, C-C, polyfluorocycloalkyl, Cs-C, cycloalkenyl, -N(R), -OR, -COR, -NCOR, -COR, -CONCR) or (CH), O-(CH), CH. 0940. In the present invention, the term “heteroaryl' Is used to include five and Six membered unsaturated rings that may contain one or more oxygen, Sulfur, or nitrogen atoms. Examples of heteroaryl groups include, but are not limited to, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 0948. In one embodiment, X is NRR and R is H or and triazinyl. Straight chained or branched C-C, alkyl. US 2003/0078271 A1 Apr. 24, 2003 49

0949) In one embodiment, the compound has the Struc ture: -continuedO O 0950 In one embodiment, R is a bicyclic alkyl ring System, cyclohexyl or aryl. 0951. In one embodiment, R is H, straight chained or cluolo branched C-C alkyl or (CH), O-(CH2)-CHs. 0952. In one embodiment, the compound is selected from the group consisting of: O O cular Oud-O O cuou? O Oud-O O - -O SSC) O O ou) O \- CO US 2003/0078271 A1 Apr. 24, 2003 50

0957. In one embodiment, the compound is selected from -continued the group consisting of: O O cluo C r) or

1. O O

O O O-O-,CO ClO?

0953. In one embodiment, Y is

().N. SR, ON N1 N s l 2 F r N N 0954. In one embodiment, U is NRs. F Nu F 0955. In one embodiment, R is (CH), Z. 0956. In one embodiment, Z is aryl or heteroaryl. US 2003/0078271 A1 Apr. 24, 2003 51

-continued -continued O ... --

r -O so N1 ; and

N le us 2 IC O N N

st rlost N1 N N N C. - N

l- CuON N CC C

0958. In one embodiment, the compound is selected from 0959. In one embodiment, Y is the group consisting of:

R17 N1 o U V A C N1N s IV PSR

C N N N 0960. In one embodiment, U is NRs. N1 Cl 0961. In one embodiment, the compound is

N1 N Cl; N 1 l 2 N N N N

N1 N1 N - - N N US 2003/0078271 A1 Apr. 24, 2003 52

-continued -continued N1 N1 N F F F l 2 N1 r N N N O N Nu N21 2N r ls N N N Nu 2N 0962. In one embodiment, the compound is

N1 C O N1N N l 2 N1 N r N N

F F F l 2 N r N N N N- N1 2N N1 N Cl; l 2 r N N N 0963. In one embodiment, the compound is selected from Clu Nu the group consisting of:

N1 C N1 N1 N

l 2 Nu D. rulo N N Ouo Nu N1 Cl

N N Cl; and US 2003/0078271 A1 Apr. 24, 2003 53

-continued -continued

JC CO IlN CrO rCN Cr 2 N1

0964. In one embodiment, the compound is selected from the group consisting of: occo Soo loco N O Cr 2N P, r -, -o-C occo Cuo- Cl

21 N acrooro S 0965) In one embodiment, X is N(CH). N1 0966. In one embodiment, Y is

Cl CF: lsN21 3 /|\R17 r N N -N > 21 su p R17. N- 0967. In one embodiment, R is an aryl Substituted- with a C-Co Straight chained alkyl. US 2003/0078271 A1 Apr. 24, 2003 54

0968. In one embodiment, the compound is selected from 0.972 wherein R is H, straight chained or branched a group consisting of C-C, alkyl, (CH-)-O-(CH2), CH, aryl, or aryl (C-C) alkyl, 0973 wherein R is straight chained or branched NN1 C-C, alkyl, (CH2)-O-(CH2)-CH3, or a l s 0974 wherein R is a bicyclic alkyl ring system, N1SN1SN adamantyl, noradamantyl, C-Clocycloalkyl, het ar N- eroaryl, aryl, aryl(C-C)alkyl, Q or Q2; 0975 wherein aryl may be substituted with one or n-N more C-Co Straight chained or branched alkyl, aryl, n 1 heteroaryl, or N(R) -Z, N 0976 wherein Q is r 1sth ; and

N 0977 wherein Q is

1s N. shN. N. Cr

0969. The invention provides a pharmaceutical compo Sition comprising a pharmaceutically acceptable carrier and a compound having the Structure: 0978 wherein each J is independently O, S, C(R) or X NR; 0979 wherein R is H; straight chained or branched N21 W C-C, alkyl, monofluoroalkyl or polyfluoroalkyl; Straight chained or branched C-C, alkenyl or alkynyl, ls -R13 C-C-7 cycloalkyl, Cs-C7 cycloalkenyl or aryl; Y N 0980 wherein Y is NRRs; H

R20 0970) wherein W is H, -F, -Cl, -Br, -I, CN, R20 17 nS methyl, ethyl, propyl, methoxy or ethoxy, /IV 2 -N U 0971 wherein X is;is NRR,11 Y12 \\ ŽSR.\ Rio - lp or N- N R17 R20

/-R \ jš.M -N N-Rs: \ ^ R17 0981 wherein R is H, straight chained or branched C-C alkyl, (CH), O-(CH2), CH5, C-C, cycloalkyl, or (COR))-Z, US 2003/0078271 A1 Apr. 24, 2003 55

0982) wherein R, is straight chained or branched C-C, alkyl, (CH2)-O-(CH2)-CH3, C-C cycloalkyl, (C(R).)N(R16) or (C(R)), Z; X 0983 wherein R is straight chained or branched 21 W C-C, alkyl, straight chained or branched C-C, monof- N luoroalkyl, Straight chained or branched C-C, poly- ls R13 fluoroalkyl, Straight chained or branched C-C, alk- Y N N1 enyl, straight chained or branched C-C, alkynyl, C-C, cycloalkenyl, -(CH2), Z, or (CH), O- H

0984 wherein each R, is independently H; -OR, 0999 wherein W is H, -F, -Cl, -Br, -I, CN, -OCOR, -COR, -NCOR1, -N(R), methyl, ethyl, propyl, methoxy or ethoxy, -CON(R), -COOR, straight chained or branched C-C, alkyl, Straight chained or branched 1000 wherein X is NRR; C-C, monofluoroalkyl, straight chained or branched C-C, polyfluoroalkyl, straight chained or branched C-C, alkenyl, straight chained or branched C-C, R17 R17 alkynyl, Cs-C7 cycloalkenyl, -(CH2)-Z, or X y-R17 /-\ ( 2)n ( 2)n 33 N 2 ; or -N N-Rs 0985 wherein Rs is straight chained or branched v-/ R. \ SR i. alkyl, -(CH2), Z, or (CH), O-(CH), 3. 0986 wherein each R is independently H, or straight 1001 wherein R is H, straight chained or branched chained or branched C-C alkyl, C-C, alkyl, (CH), O-(CH), CH, aryl or aryl(C-C)alkyl, 0987 wherein each Rao is independently -H; straight chained or branched C-C, alkyl, monofluoroalkyl or 1002 wherein R is straight chained or branched polyfluoroalkyl, Straight chained or branched C-C, C-C, alkyl, (CH-)-O-(CH), CH, or alkenyl or alkynyl, C-C7 cycloalkyl or Cs-C7 cycloalk -(CH), Z; enyl; -F, -Cl, -Br, or -I; -NO; -N, -CN; -OR. --OCOR, -COR, -NCOR, 1003 wherein R is a bicyclic alkyl ring system, aryl -N(R), -CON(R), or -COOR, aryl or het or aryl (C-C) alkyl, eroaryl; or two Ro groups present on adjacent carbon atoms can join together to form a methylenedioxy 1004 wherein Y is NRRs; grOup, 0988 wherein each R is independently -H; straight sa R20 chained or branched C-C, alkyl, monofluoroalkyl or R20 1,Ás polyfluoroalkyl, Straight chained or branched C-C, R17 alkenyl or alkynyl, C-C-7 cycloalkyl, Cs-C, cycloalk- 2 enyl, aryl, or aryl(C-C) alkyl, -y \ Rio - p O989) wherein each R is independently H, F, Cl or \ SQ R17; N-N ; or

C-C straight chained or branched alkyl; V-R20;20 0990 wherein each m is an integer from 0 to 4 inclu- / X

Sive, -N o

0991. . . wherein each n is an integer from 1 to 4 inclu M SIVe; \ SS R20 0992 wherein p is an integer from 0 to 2 inclusive; 0993 wherein q is an integer from 2 to 4 inclusive; 1005 wherein R is H, straight chained or branched 0994) wherein t is 1 or 2; C-C alkyl, (CH), O-(CH2)-CH3, Cs-Co 0995 wherein U is O, -NR, S, C(R-), or cycloalkyl, or (COR))-Z, -NSOR; 1006 wherein Rs is straight chained or branched 0.996 wherein Z is C-Clocycloalkyl, C-C, cyclic C-C alkyl, (CH), O-(CH), CH, C-C, ether, C-C-7 cyclic thioether, aryl, or heteroaryl; or cycloalkyl, or (COR))-Z, 0997 a pharmaceutically acceptable salt thereof. 1007 wherein U is O, -NR, S, C(R), or 0998. The invention provides a pharmaceutical compo -NSOR; Sition comprising a pharmaceutically acceptable carrier and 1008 wherein Z is C-C cycloalkyl, aryl, or het a compound having the Structure: eroaryl; US 2003/0078271 A1 Apr. 24, 2003 56

1009 wherein R is straight chained or branched 1022 wherein W is H, -F, -Cl, -Br, -I, CN, C-C, alkyl, straight chained or branched C-C, monof methyl, ethyl, propyl, methoxy or ethoxy, luoroalkyl, Straight chained or branched C-C, poly fluoroalkyl, Straight chained or branched C-C, alk 1023 wherein X is N(CH) or enyl, straight chained or branched C-C, alkynyl, C-C, cycloalkenyl, -(CH2), Z, or (CH), O-(CH2), CH; R17 1010 wherein each R, is independently H; -OR, -OCOR, -COR, -NCOR, -N(R), /- -CON(R), -COOR, straight chained or S -().R17 branched C-C, alkyl, Straight chained or branched C-C, monofluoroalkyl, straight chained or branched C-C, polyfluoroalkyl, straight chained or branched C-C, alkenyl, straight chained or branched C-C, 1024 wherein R is an aryl, adamantyl, noradaman alkynyl, C-C, cycloalkenyl, -(CH-)-Z, or tyl, C-Co cycloalkyl, heteroaryl, Q or Q, (CH), O-(CH), CH; 1025 wherein aryl may be substituted with one or 1011 wherein Rs is straight chained or branched C-C alkyl, -(CH2), Z, or (CH2)-O-(CH2)- more C-Co Straight chained or branched alkyl, aryl, CH; heteroaryl, or N(Ro)-Z, 1012 wherein each Ro is independently H, or straight 1026 wherein Q is chained or branched C-C alkyl, 1013 wherein each Ro is independently -H; straight chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C-7 cycloalkyl or Cs-C7 cycloalk enyl; -F, -Cl, -Br, or -I; -NO; -N, -CN; -OR-, -OCOR, -COR, -NCOR, -N(R), -CON(R), or -COOR, aryl or het eroaryl; or two Ro groups present on adjacent carbon atoms can join together to form a methylenedioxy grOup, 1014 wherein each R is independently -H; straight chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C-7 cycloalkyl, Cs-C, cycloalk enyl, aryl or aryl(C-C) alkyl, 1015 wherein each m is an integer from 0 to 4 inclu Sive, 1016 wherein each n is an integer from 1 to 4 inclu Sive, 1017 wherein p is an integer from 0 to 2 inclusive; 1028 wherein each J is independently O, S, C(R) or 1018 wherein q is an integer from 2 to 4 inclusive; NR; 1019 wherein t is 1 or 2; or 1029 wherein R is -H; straight chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, 1020 a pharmaceutically acceptable salt thereof. Straight chained or branched C-C, alkenyl or alkynyl, 1021. The invention provides a pharmaceutical compo C-C, cycloalkyl, Cs-C, cycloalkenyl or aryl; Sition comprising a pharmaceutically acceptable carrier and a compound having the Structure: 1030 wherein Y is NRRs;

X R20 W Na R17 1ás ls R13 /-\ 4.Y. Y N -N U Rio - H N R. N-N ; or US 2003/0078271 A1 Apr. 24, 2003 57

1042 wherein each m is an integer from 0 to 4 inclu -continued Sive, / y R20;20 1043 wherein each n is an integer from 1 to 4 inclu Sive, -N o 1044 wherein p is an integer from 0 to 2 inclusive;

\ x R20 1045 wherein q is an integer from 2 to 4 inclusive; 1046 wherein t is 1 or 2; or 1031 wherein R is H, straight chained or branched 1047 a pharmaceutically acceptable salt thereof. C-C alkyl, (CH-)-O-(CH2)-CH3, Cs-Co 1048. The invention provides a pharmaceutical compo cycloalkyl, or (C(R)), Z; Sition comprising a pharmaceutically acceptable carrier and a compound having the Structure: 1032 wherein Rs is straight chained or branched C-C alkyl, (CH), O-(CH2)-CH3, Cs-Co cycloalkyl, or (C(R)), Z; X

1033 wherein U is O, -NR, S, C(R), or W -NSOR; Na 1034 wherein Z is C-C cycloalkyl, aryl, or het ls R13 eroaryl; Y N 1035 wherein R is straight chained or branched H C-C, alkyl, straight chained or branched C-C, monof luoroalkyl, Straight chained or branched C-C, poly fluoroalkyl, Straight chained or branched C-C, alk 1049 wherein W is H, -F, -Cl, -Br, -I, CN, enyl, straight chained or branched C-C, alkynyl, C-C, methyl, ethyl, propyl, methoxy or ethoxy, cycloalkenyl, -(CH2), Z, or (CH), O (CH), CH, 1050 wherein X is N(CH) or 1036 wherein each R, is independently H; -OR, -OCOR, -COR, -NCOR1, -N(R), R17 -CON(R), -COOR, straight chained or branched C-C, alkyl, Straight chained or branched /- C-C, monofluoroalkyl, straight chained or branched C-C, polyfluoroalkyl, straight chained or branched -("YoR17 C-C, alkenyl, straight chained or branched C-C, alkynyl, Cs-C7 cycloalkenyl, -(CH2)-Z, or 1051 wherein R is a bicyclic alkyl ring system, aryl (CH), O-(CH), CH; or aryl (C-C)alkyl, 1037 wherein Rs is straight chained or branched i. alkyl, -(CH2), Z, or (CH2)-O-(CH2)- 1052 wherein Y is NRRs; 3. 1053 wherein R is H, straight chained or branched 1038 wherein each Ro is independently H, or straight C-C alkyl, (CH), O-(CH), CH, C-C, chained or branched C-C alkyl, cycloalkyl, or (COR))-Z, 1039 wherein each Ro is independently -H; straight 1054 wherein Rs is (C(R))-N(R); chained or branched C-C, alkyl, monofluoroalkyl or 1055 wherein Z is C-C cycloalkyl, aryl, or het polyfluoroalkyl, Straight chained or branched C-C, eroaryl; alkenyl or alkynyl, C-C-7 cycloalkyl or Cs-C7 cycloalk enyl; -F, -Cl, -Br, or -I; -NO; -N; -CN; 1056 wherein R is straight chained or branched -OR-, -OCOR, -COR, -NCOR, C-C, alkyl, straight chained or branched C-C, monof -N(R), -CON(R), or -COOR, aryl or het luoroalkyl, Straight chained or branched C-C, poly eroaryl; or two Rao groups present on adjacent carbon fluoroalkyl, Straight chained or branched C-C, alk atoms can join together to form a methylenedioxy enyl, straight chained or branched C-C, alkynyl, C-C, grOup, cycloalkenyl, -(CH2), Z, or (CH), O (CH), CH, 1040 wherein each R is independently -H; straight chained or branched C-C, alkyl, monofluoroalkyl or 1057 wherein each R, is independently H; -OR, polyfluoroalkyl, Straight chained or branched C-C, -OCOR, -COR, -NCOR1, -N(R), alkenyl or alkynyl, C-C, cycloalkyl, Cs-C, cycloalk -CON(R), -COOR, straight chained or enyl, aryl or aryl(C-C) alkyl, branched C-C, alkyl, Straight chained or branched C-C, monofluoroalkyl, straight chained or branched 1041 wherein each R is independently H, F, Cl or C-C, polyfluoroalkyl, straight chained or branched C-C straight chained or branched alkyl; C-C, alkenyl, straight chained or branched C-C, US 2003/0078271 A1 Apr. 24, 2003 58

alkynyl, Cs-C7 cycloalkenyl, -(CH2)-Z, or Straight chained or branched C-C, alkenyl, Straight chained (CH), O-(CH), CH; or branched C-C, alkynyl, C-C, cycloalkyl, C-C, monof luorocycloalkyl, C-C, polyfluorocycloalkyl, Cs-C, 1058 wherein each Ro is independently H, or straight cycloalkenyl, -N(R), -OR, -COR, -NCOR, chained or branched C-C alkyl, -COR, -CONCR) or (CH), O-(CH), CH 1059 wherein each R is independently -H; straight 1068. In the present invention, the term "heteroaryl” is chained or branched C-C, alkyl, monofluoroalkyl or used to include five and Six membered unsaturated rings that polyfluoroalkyl, Straight chained or branched C-C, may contain one or more oxygen, Sulfur, or nitrogen atoms. alkenyl or alkynyl, C-C, cycloalkyl, Cs-C, cycloalk Examples of heteroaryl groups include, but are not limited enyl, aryl or aryl(C-C)alkyl, to, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, 1060 wherein each m is an integer from 0 to 4 inclu thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, Sive, and triazinyl. 1061 wherein each n is an integer from 1 to 4 inclu Sive, 1069. In addition the term "heteroaryl' is used to include fused bicyclic ring Systems that may contain one or more 1062 wherein q is an integer from 2 to 4 inclusive; or heteroatoms Such as oxygen, Sulfur and nitrogen. Examples of Such heteroaryl groups include, but are not limited to, 1063) a pharmaceutically acceptable salt thereof. indolizinyl, indolyl, isoindolyl, benzobfuranyl, benzob 1064. As used in the present invention, the term “bicyclic thiophenyl, indazolyl, benzimidazolyl, purinyl, benzox alkyl ring Systems' includes, but is not limited to, bicyclo azolyl, benzisoxazolyl, benzobthiazolyl, imidazo2,1-b 2.2.1]heptane, bicyclo3.1.1 heptane and bicyclo2.2.2]oc thiazolyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1.8- tane. In addition, the bicyclic alkyl ring Systems may be naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, substituted with one or more of the following: -F, -NO, phthalimidyl and 2,1,3-benzothiazolyl. -CN, Straight chained or branched C-C, alkyl, Straight 1070 The term "heteroaryl' also includes those chemical chained or branched C-C-7 monofluoroalkyl, Straight moieties recited above which may be substituted with one or chained or branched C-C, polyfluoroalkyl, Straight chained more of the following:-F, -Cl, -Br, -, -NO,-CN, or branched C-C, alkenyl, Straight chained or branched Straight chained or branched C-C, alkyl, Straight chained or C-C, alkynyl, Ca-C, cycloalkyl, Cs-C, cycloalkenyl, branched C-C monofluoroalkyl, Straight chained or -N(R), -OR-, -COR2, -COR2, -CONCR) or branched C-C, polyfluoroalkyl, Straight chained or (CH), O-(CH), CH branched C-C, alkenyl, Straight chained or branched C-C, 1065. As used in the present invention, the term alkynyl, C-C7 cycloalkyl, C-C monofluorocycloalkyl, “cycloalkyl includes, C-C-7 cycloalkyl moieties which may C-C, polyfluorocycloalkyl, Cs-C, cycloalkenyl, -N(R), be substituted with one or more of the following: -F, -OR, -COR, -NCOR1, -COR, -CONCR) or -NO, -CN, straight chained or branched C-C, alkyl, (CH), O-(CH), CH Straight chained or branched C-C-7 monofluoroalkyl, 1071) The term “heteroaryl” further includes the N-ox Straight chained or branched C-C, polyfluoroalkyl, Straight ides of those chemical moieties recited above which include chained or branched C-C, alkenyl, Straight chained or at least one nitrogen atom. branched C-C, alkynyl, C-C-7 cycloalkyl, C-C monof luorocycloalkyl, C-C, polyfluorocycloalkyl, C-C, 1072. In the present invention the term “aryl' is phenyl or cycloalkenyl, -N(R), -OR, -COR, -NCOR, naphthyl. The term “aryl also includes phenyl and naphthyl -COR, -CONCR) or (CH), O-(CH), CH. which may be substituted with one or more of the following: F, -Cl, -Br, -, -NO, -CN, straight chained or 1066. As used in the present invention, the term “cyclo branched C-C, alkyl, Straight chained or branched C-C, hexyl” includes, cyclohexyl groups which may be Substi monofluoroalkyl, Straight chained or branched C-C, poly tuted with one or more of the following: -F, -NO,-CN, fluoroalkyl, Straight chained or branched C-C, alkenyl, Straight chained or branched C-C, alkyl, Straight chained or Straight chained or branched C-C, alkynyl, C-C, branched C-C monofluoroalkyl, Straight chained or cycloalkyl, C-C monofluorocycloalkyl, C-C, polyfluoro branched C-C, polyfluoroalkyl, Straight chained or cycloalkyl, Cs-C7 cycloalkenyl, -N(R), -OR, -SR, branched C-C, alkenyl, Straight chained or branched C-C, alkynyl, C-C7 cycloalkyl, C-C monofluorocycloalkyl, -OCOR,-COR,-NCOR1, -COR,-CONCR) or C-C, polyfluorocycloalkyl, Cs-C, cycloalkenyl, -N(R), (CH), O-(CH), CH -OR, -COR, -NCOR, -COR, -CONCR) or 1073. In one embodiment of any of the pharmaceutical (CH), O-(CH), CHs. compositions described herein, the compound is enantio merically and diasteriomerically pure. In one embodiment 1067 As used in the present invention, the term the compound is enantiomerically or diasteriomerically “cycloalkenyl' includes, Cs-C, cycloalkenyl moieties which pure. may be substituted with one or more of the following: -F, -Cl, -Br, -, -NO,-CN, straight chained or branched 1074. In one embodiment of any of the pharmaceutical C-C, alkyl, Straight chained or branched C-C-7 monofluo compositions described herein, the compound can be admin roalkyl, Straight chained or branched C-C, polyfluoroalkyl, istered orally. US 2003/0078271 A1 Apr. 24, 2003 59

1075. In one embodiment, X is: 1085. In one embodiment, U is NRs. 1086. In one embodiment, the compound is selected from the group consisting of:

1076. In one embodiment, X is NRR and R is H or Straight chained or branched C-C, alkyl. 1077. In one embodiment, the compound has the struc ture:

R NY 12 N21 W

Y ls N R 13

1078. In one embodiment, R is a bicyclic alkyl ring System, cyclohexyl or aryl. 1079. In one embodiment, R is H, straight chained or branched C-C alkyl or (CH), O-(CH2)-CHs. C c. O 1080. In one embodiment, Y is

N R17. co O 1081. In one embodiment, U is NRs. 1082 In one embodiment, R is (CH), Z. 1083. In one embodiment, Z is aryl or heteroaryl. 1084) In one embodiment, Y is

-NN. UR. US 2003/0078271 A1 Apr. 24, 2003 60

-continued -continued N N1 C N1

N Cl; and 21 Cl CF: N N r 4. N r’s, DON N Nu 21 su CC loc

N rs a 1

1087.2N In one embodiment, compound is selected from the Q -CO group consisting of: r so C so

N US 2003/0078271 A1 Apr. 24, 2003 61

1088. In one embodiment, X is N(CH). 1092 The invention provides a compound having the Structure: 1089. In one embodiment, Y is

R17 /-V 4N -N U ls N. R. Y N N -R13

H 1090. In one embodiment, R is an aryl Substituted with a C-Co Straight chained alkyl. 1091. In one embodiment, the compound is selected from 1093 wherein W is H, -F, -Cl, -Br, -I, CN, a group consisting of methyl, ethyl, propyl, methoxy or ethoxy,

N 21 ls r N N N

N-N

N N1

N 21 ; and ls r N N N

N-N

N1 N21 ls r N N 21 N - US 2003/0078271 A1 Apr. 24, 2003 62

1094) wherein X is; NRR; 1103 wherein Y is NRRs; 1ásR20 -N ) -N.(Y O; or R17 \ v R, \ R. /-v Sry, -N U 19 -

R17 N. SR N-N. O / y Ro: N-Rs: -N o \ ŽSR.M 1095 wherein R is H, straight chained or branched C-C, alkyl, (CH)-O-(CH), CH, aryl, or aryl 1104 wherein R is H, straight chained or branched (C-C)alkyl, C-C alkyl, (CH2), O-(CH2)-CH3, Cs-Co cycloalkyl, or (COR))-Z, 1096 wherein R is straight chained or branched C-C, alkyl, (CH2)-O-(CH2), —CHs, or 1105 wherein R is straight chained or branched -(CH), Z; C-C alkyl, (CH2), O-(CH2)-CH3, Cs-Co cycloalkyl, (C(Ro))N(R) or (C(R)-)-Z, 1097 wherein R is a bicyclic alkyl ring system, adamantyl, noradamantyl, C-Clocycloalkyl, het 1106 wherein R is straight chained or branched eroaryl, aryl, aryl(C-C) alkyl, Q or Q2; C-C, alkyl, straight chained or branched C-C, monof luoroalkyl, Straight chained or branched C-C, poly 1098 wherein aryl may be substituted with one or fluoroalkyl, Straight chained or branched C-C, alk more C-Co straight chained or branched alkyl, aryl, enyl, straight chained or branched C-C, alkynyl, C-C, heteroaryl, or N(Ro)-Z, cycloalkenyl, -(CH2), Z, or (CH), O 1099 wherein Q is 1107 wherein each R, is independently H; -OR, -OCOR, -COR, -NCOR1, -N(R), -CON(R), -COOR, straight chained or branched C-C, alkyl, Straight chained or branched C-C, monofluoroalkyl, straight chained or branched C-C, polyfluoroalkyl, straight chained or branched C-C, alkenyl, straight chained or branched C-C, alkynyl, C-C, cycloalkenyl, -(CH-)-Z, or

(CH), O-(CH), CH; 1108 wherein Rs is straight chained or branched C-C alkyl, -(CH), Z, or (CH-)-O-(CH), CH; 1109 wherein each Ro is independently H, or straight chained or branched C-C alkyl, 1110 wherein each Ro is independently -H; straight chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C, cycloalkyl or C-C, cycloalk enyl; -F, -Cl, -Br, or -I; -NO, -N, -CN; -OR-, -OCOR, -COR, -NCOR, -N(R), -CON(R), or -COOR, aryl or het 1101 wherein each J is independently O, S, C(R) or eroaryl; or two Ro groups present on adjacent carbon NR; atoms can join together to form a methylenedioxy 1102 wherein R is H; straight chained or branched grOup, C-C, alkyl, monofluoroalkyl or polyfluoroalkyl; 1111 wherein each R is independently -H; straight Straight chained or branched C-C, alkenyl or alkynyl, chained or branched C-C, alkyl, monofluoroalkyl or C-C-7 cycloalkyl, Cs-C7 cycloalkenyl or aryl; polyfluoroalkyl, Straight chained or branched C-C, US 2003/0078271 A1 Apr. 24, 2003

alkenyl or alkynyl, C-C-7 cycloalkyl, Cs-C, cycloalk 1127 wherein Y is NRRs; enyl, aryl, or aryl(C-C) alkyl, 1112 wherein each R is independently H, F, Cl or C-C straight chained or branched alkyl; 1113 wherein each m is an integer from 0 to 4 inclu Sive, 1114 wherein each n is an integer from 1 to 4 inclu Sive, 1115 wherein p is an integer from 0 to 2 inclusive; 1116 wherein q is an integer from 2 to 4 inclusive; 1117 wherein t is 1 or 2; 1118 wherein U is O, -NR, S, C(R), or -NSOR; 1128 wherein R is H, straight chained or branched 1119 wherein Z is C-C cycloalkyl, C-C, cyclic C-C alkyl, (CH2), O-(CH2)-CH3, Cs-Co ether, C-C-7 cyclic thioether, aryl, or heteroaryl; or cycloalkyl, or (COR))-Z, 1120) a pharmaceutically acceptable salt thereof. 1129 wherein Rs is straight chained or branched C-C alkyl, (CH-)-O-(CH2), CH5, C-C, 1121. The invention provides a compound having the cycloalkyl, or (COR))-Z, Structure: 1130 wherein U is O, -NR, S, C(R), or -NSOR;

X 1131 Whereinherein Z.Z isIS C-Clocycloalkyl,C-Clocycloalkyl aryl,1 or heth eroaryl; W N21 1132 wherein R is straight chained or branched ls R13 C-C, alkyl, straight chained or branched C-C, monof Y N luoroalkyl, Straight chained or branched C-C, poly fluoroalkyl, Straight chained or branched C-C, alk H enyl, straight chained or branched C-C, alkynyl, C-C, cycloalkenyl, -(CH2), Z, or (CH), O (CH-)-CH, 1122 wherein W is H, -F, -Cl, -Br, -I, CN, 1133 wherein each R, is independently H; -OR, methyl, ethyl, propyl, methoxy or ethoxy, -OCOR1, -COR, -NCOR1, -N(R), -CON(R), -COOR, straight chained or 1123 wherein X is NRR, branched C-C, alkyl, Straight chained or branched C-C, monofluoroalkyl, straight chained or branched C-C, polyfluoroalkyl, straight chained or branched C-C, alkenyl, straight chained or branched C-C, alkynyl, Cs-C7 cycloalkenyl, -(CH2)-Z, or (CH), O-(CH), CH; 1134) wherein Rs is straight chained or branched C-C alkyl, -(CH2), Z, or (CH-)-O-(CH-)- CH; 1124 wherein R is H, straight chained or branched 1135 wherein each Ro is independently H, or straight C-C, alkyl, (CH-)-O-(CH), CH, aryl or chained or branched C-C alkyl, aryl(C-C)alkyl, 1136 wherein each Rao is independently -H; straight 1125 wherein R is straight chained or branched chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, C-C, alkyl, (CH-)-O-(CH-)-CH, or alkenyl or alkynyl, C-C-7 cycloalkyl or Cs-C7 cycloalk enyl; -F, -Cl, -Br, or -I; -NO; -N; -CN; 1126 wherein R is a bicyclic alkyl ring System, aryl -OR-, -OCOR, -COR, -NCOR, or aryl (C-C) alkyl, -N(R), -CON(R), or -COOR, aryl or het US 2003/0078271 A1 Apr. 24, 2003 64

eroaryl; or two Rao groups present on adjacent carbon 1150 wherein Q is atoms can join together to form a methylenedioxy grOup, 1137 wherein each R is independently -H; straight chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C-7 cycloalkyl, Cs-C, cycloalk enyl, aryl or aryl(C-C) alkyl, 1138 wherein each m is an integer from 0 to 4 inclu Sive, 1139 wherein each n is an integer from 1 to 4 inclu 1151 wherein each J is independently O, S, C(R) or Sive, NR; 1140 wherein p is an integer from 0 to 2 inclusive; 1152 wherein R is -H; straight chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, 1141 wherein q is an integer from 2 to 4 inclusive; Straight chained or branched C-C, alkenyl or alkynyl, C-C-7 cycloalkyl, Cs-C7 cycloalkenyl or aryl; 1142 wherein t is 1 or 2; or 1153 wherein Y is NRRs; 1143) a pharmaceutically acceptable salt thereof. 1144. The invention provides a compound having the Structure:

X N21 W

Y lsN R13

1145 wherein W is H, -F, -Cl, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy, 1154 wherein R is H, straight chained or branched 1146 wherein X is N(CH) or C-C alkyl, (CH), O-(CH2), CH5, C-C, cycloalkyl, or (COR))-Z, R17 1155 wherein Rs is straight chained or branched C-C alkyl, (CH), O-(CH2)-CH3, C5-C1s cycloalkyl, or (COR))-Z, S. R17 1156 wherein U is O, -NR, S, C(R), or -NSOR; 1157 wherein Z is C-C cycloalkyl, aryl, or het 1147 wherein R is an aryl, adamantyl, noradaman eroaryl; tyl, C-Co cycloalkyl, heteroaryl, Q or Q, 1158 wherein R is straight chained or branched 1148 wherein aryl may be substituted with one or C-C, alkyl, straight chained or branched C-C, monof more C-Co straight chained or branched alkyl, aryl, luoroalkyl, Straight chained or branched C-C, poly heteroaryl, or N(Ro)-Z, fluoroalkyl, Straight chained or branched C-C, alk enyl, straight chained or branched C-C, alkynyl, C-C, 1149 wherein Q is cycloalkenyl, -(CH2), Z, or (CH), O (CH-)-CH, 1159 wherein each R, is independently H; -OR, -OCOR1, -COR, -NCOR1, -N(R), -CON(R), -COOR, straight chained or branched C-C, alkyl, Straight chained or branched C-C, monofluoroalkyl, straight chained or branched C-C, polyfluoroalkyl, straight chained or branched US 2003/0078271 A1 Apr. 24, 2003 65

C-C, alkenyl, Straight chained or branched C-C, 1174) wherein R, is a bicyclic alkyl ring system, arylor alkynyl, Cs-C, cycloalkenyl, -(CH2) -Z, or aryl (C-C)alkyl, (CH), O-(CH), CH; 1175 wherein Y is NRRs; 1160 wherein R is straight chained or branched 1176 wherein R is H, straight chained or branched C-C alkyl, -(CH2), Z, or (CH2)-O-(CH2)- C-C alkyl, (CH), O-(CH2)-CH3, Cs-Co CH; cycloalkyl, or (COR))-Z, 1161 wherein each Ro is independently H, or straight chained or branched C-C, alkyl, 1177 wherein Rs is (C(Ro))-N(R), 1162 wherein each Rao is independently -H, Straight 1178 wherein Z is C-C cycloalkyl, aryl, or het chained or branched C-C, alkyl, monofluoroalkyl or eroaryl; polyfluoroalkyl, Straight chained or branched C-C, 1179 wherein R is straight chained or branched alkenyl or alkynyl, C-C, cycloalkyl or C-C, cycloalk C-C, alkyl, straight chained or branched C-C, monof enyl; -F, -Cl, -Br, or -I; -NO; -N, -CN; luoroalkyl, Straight chained or branched C-C, poly -OR. --OCOR, -COR, -NCOR, fluoroalkyl, Straight chained or branched C-C, alk -N(R), -CON(R), or -COOR, aryl or het enyl, straight chained or branched C-C, alkynyl, C-C, eroaryl; or two Rao groups present on adjacent carbon cycloalkenyl, -(CH2), Z, or (CH), O atoms can join together to form a methylenedioxy (CH), CH, grOup, 1180 wherein each R, is independently H; -OR, 1163 wherein each R is independently -H; straight -OCOR, -COR, -NCOR1, -N(R), chained or branched C-C, alkyl, monofluoroalkyl or -CON(R), -COOR, straight chained or polyfluoroalkyl, Straight chained or branched C-C, branched C-C, alkyl, Straight chained or branched alkenyl or alkynyl, C-C-7 cycloalkyl, Cs-C, cycloalk C-C, monofluoroalkyl, straight chained or branched enyl, aryl or aryl(C-C) alkyl, C-C, polyfluoroalkyl, straight chained or branched 1164 wherein each R is independently H, F, Cl or C-C, alkenyl, straight chained or branched C-C, C-C straight chained or branched alkyl; alkynyl, Cs-C7 cycloalkenyl, -(CH2)-Z, or (CH), O-(CH), CH; 1165 wherein each m is an integer from 0 to 4 inclu Sive, 1181 wherein each Ro is independently H, or straight chained or branched C-C alkyl, 1166 wherein each n is an integer from 1 to 4 inclu Sive, 1182 wherein each R is independently -H; straight chained or branched C-C, alkyl, monofluoroalkyl or 1167 wherein p is an integer from 0 to 2 inclusive; polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C-7 cycloalkyl, Cs-C7 cycloalk 1168 wherein q is an integer from 2 to 4 inclusive; enyl, aryl or aryl(C-C) alkyl, 1169 wherein t is 1 or 2; or 1183 wherein each m is an integer from 0 to 4 inclu 1170 a pharmaceutically acceptable salt thereof. Sive, 1171. The invention provides a compound having the 1184 wherein each n is an integer from 1 to 4 inclu Structure: Sive, 1185 wherein q is an integer from 2 to 4 inclusive; or X 1186 a pharmaceutically acceptable salt thereof. W 1187. As used in the present invention, the term “bicyclic N21 alkyl ring Systems' includes, but is not limited to, bicyclo ls R13 2.2.1]heptane, bicyclo3.1.1 heptane and bicyclo2.2.2]oc Y N tane. In addition, the bicyclic alkyl ring Systems may be substituted with one or more of the following: -F, -NO, H -CN, Straight chained or branched C-C, alkyl, Straight chained or branched C-C-7 monofluoroalkyl, Straight chained or branched C-C, polyfluoroalkyl, Straight chained 1172 wherein W is H, -F, -Cl, -Br, -I, CN, or branched C-C, alkenyl, Straight chained or branched methyl, ethyl, propyl, methoxy or ethoxy, C-C, alkynyl, Cs-C, cycloalkyl, Cs-C, cycloalkenyl, 1173 wherein X is N(CH) or N(R), -OR-, -COR, -COR, -CONCR) or (CH), O-(CH), CHs. 1188) As used in the present invention, the term R17 “cycloalkyl” includes, C-C-7 cycloalkyl moieties which may be substituted with one or more of the following: -F, - Y -NO, -CN, straight chained or branched C-C, alkyl, \ VR: Straight chained or branched C-C-7 monofluoroalkyl, Straight chained or branched C-C, polyfluoroalkyl, Straight chained or branched C-C, alkenyl, Straight chained or US 2003/0078271 A1 Apr. 24, 2003

branched C-C, alkynyl, C-C-7 cycloalkyl, C-C monof F, -Cl, -Br, -, -NO, -CN, straight chained or luorocycloalkyl, C-C, polyfluorocycloalkyl, Cs-C, branched C-C, alkyl, Straight chained or branched C-C, cycloalkenyl, -N(R), -OR, -COR, -NCOR, monofluoroalkyl, Straight chained or branched C-C, poly -COR, -CONCR) or (CH), O-(CH), CH fluoroalkyl, Straight chained or branched C-C, alkenyl, 1189 AS used in the present invention, the term “cyclo Straight chained or branched C-C, alkynyl, C-C, hexyl” includes, cyclohexyl groups which may be Substi cycloalkyl, C-C, monofluorocycloalkyl, C-C, polyfluoro tuted with one or more of the following: -F, -NO,-CN, cycloalkyl, Cs-C7 cycloalkenyl, -N(R), -OR, -SR, Straight chained or branched C-C, alkyl, Straight chained or -OCOR,-COR,-NCOR1, -COR,-CONCR) or branched C-C monofluoroalkyl, Straight chained or branched C-C, polyfluoroalkyl, Straight chained or (CH), O-(CH), CH branched C-C, alkenyl, Straight chained or branched C-C, 1196. In one embodiment of any of the compounds alkynyl, C-C7 cycloalkyl, C-C monofluorocycloalkyl, described herein, the compound is enantiomerically or dias C-C, polyfluorocycloalkyl, Cs-C, cycloalkenyl, -N(R), teriomerically pure. In one embodiment of any of the --OR, -COR, -NCOR1, -COR, -CONCR) or compounds described herein, the compound is enantiomeri (CH), O-(CH), CH cally and diasteriomerically pure. 1190 AS used in the present invention, the term “cycloalkenyl' includes, Cs-C, cycloalkenyl moieties which 1197. In one embodiment, X is: may be substituted with one or more of the following: -F, -Cl, -Br, -, -NO,-CN, straight chained or branched C-C, alkyl, Straight chained or branched C-C-7 monofluo R17 roalkyl, Straight chained or branched C-C, polyfluoroalkyl, Straight chained or branched C-C, alkenyl, Straight chained R17SC x R17 /-\ or branched C-C, alkynyl, C-C-7 cycloalkyl, C-C monof -N Q ; or N N-Ris s luorocycloalkyl, C-C, polyfluorocycloalkyl, C-C, \ / R 17 \ VR, cycloalkenyl, -N(R), -OR, -COR, -NCOR, -COR, -CONCR) or (CH), O-(CH), CH. 1191. In the present invention, the term "heteroaryl” is 1198. In one embodiment, X is NRR and R is H or used to include five and Six membered unsaturated rings that Straight chained or branched C-C, alkyl. may contain one or more oxygen, Sulfur, or nitrogen atoms. Examples of heteroaryl groups include, but are not limited 1199. In one embodiment, the compound has the struc to, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, ture: pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. NY R12

1192. In addition the term "heteroaryl' is used to include W fused bicyclic ring Systems that may contain one or more Na heteroatoms Such as oxygen, Sulfur and nitrogen. Examples of Such heteroaryl groups include, but are not limited to, ls R13 indolizinyl, indolyl, isoindolyl, benzobfuranyl, benzob Y N thiophenyl, indazolyl, benzimidazolyl, purinyl, benzox H azolyl, benzisoxazolyl, benzobthiazolyl, imidazo2,1-b thiazolyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1.8- naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, 1200. In one embodiment, R is a bicyclic alkyl ring phthalimidyl and 2,1,3-benzothiazolyl. System, cyclohexyl or aryl. 1193) The term "heteroaryl also includes those chemical moieties recited above which may be substituted with one or 1201. In one embodiment, R is H, straight chained or more of the following: -F, -Cl, -Br, -, -NO,-CN, branched C-C alkyl or (CH), O-(CH), CHs. Straight chained or branched C-C, alkyl, Straight chained or branched C-C monofluoroalkyl, Straight chained or 1202. In one embodiment, Y is branched C-C, polyfluoroalkyl, Straight chained or branched C-C, alkenyl, Straight chained or branched C-C, alkynyl, C-C7 cycloalkyl, C-C monofluorocycloalkyl, R17 C-C, polyfluorocycloalkyl, Cs-C, cycloalkenyl, -N(R), --OR, -COR, -NCOR1, -COR, -CONCR) or U (CH), O-(CH), CHs. \ R. 1194 The term “heteroaryl” further includes the N-ox ides of those chemical moieties recited above which include at least one nitrogen atom. 1203. In one embodiment, U is NRs. 1195. In the present invention the term “aryl' is phenyl or 1204. In one embodiment, R is (CH), Z. naphthyl. The term “aryl' also includes phenyl and naphthyl which may be substituted with one or more of the following: 1205. In one embodiment Z is aryl or heteroaryl. US 2003/0078271 A1 Apr. 24, 2003 67

1206. In one embodiment, Y is -continued N1 R17 - \ c -Cl: \ Y& R17 Clu O --- N 1207. In one embodiment, U is NRs. 1208. In one embodiment, the compound is selected from the group consisting of: N C

SCO N N N OC co 2N

ls 1209. In one embodiment, the compound is selected from r the group consisting of: N Nu 2N N1 N1 Cl N

2 O re- N US 2003/0078271 A1 Apr. 24, 2003 68

-continued -continued C-C O

N-NY Nu O ro

2- Cl CF: l DO 1210. In one embodiment, X is N(CH). N 1211) In one embodiment, Y is

R17 N-N /-V n1 N N \ R17

N 2 ls 1212) In one embodiment, R is an aryl Substituted with - N N a C-C Straight chained alkyl. N 21 1213. In one embodiment, the compound is selected from N-N a group consisting of

n1 N nN.1 N1 n r N l N a N -Cl O lssh n- N. N. N. N a Nu

Sa ... and US 2003/0078271 A1 Apr. 24, 2003 69

-OCOR, -COR. -NCOR1, -N(R), -continued -CONCR), or -COOR, aryl or heteroaryl; or any two of Y1, Y, Y- and Y present on adjacent carbon atoms can constitute a methylenedioxy grOup, 1222 wherein each R is independently -H; Straight chained or branched C-C, alkyl, monofluo roalkyl or polyfluoroalkyl, Straight chained or Y a cr branched C-C, alkenyl or alkynyl, C-C, N-N cycloalkyl, Cs-C, cycloalkenyl, aryl or aryl(C- C.)alkyl, 1223 wherein A is A, Q, Q, Q Straight chained or 1214) The invention provides a pharmaceutical compo branched C-C, alkyl, aryl, heteroaryl, aryl(C-C) Sition comprising a therapeutically effective amount of any alkyl, heteroaryl (C-C) alkyl, aryl Substituted with of the compounds described herein and a pharmaceutically an aryl or heteroaryl, heteroaryl Substituted with an acceptable carrier. aryl or heteroaryl; or (CHR)-(CHR), Z; 1215. The invention provides a pharmaceutical compo 1224 wherein A' is Sition made by combining a therapeutically effective amount of any of the compounds described herein and a pharma ceutically acceptable carrier. O O R1 1216) The invention provides a process for making a pharmaceutical composition comprising combining a thera N-in R5 ln N-in CR2R3 ; or peutically effective amount of any of the compounds described herein and a pharmaceutically acceptable carrier. -(CH2) E R4; 1217. The invention provides a method of treating a Subject Suffering from depression which comprises admin istering to the Subject an amount of any of the compounds 1225 wherein Q is described herein effective to treat the Subject's depression.

1218. The invention provides a method of treating a R17 R Subject Suffering from anxiety which comprises administer 17 ing to the Subject an amount of any of the compounds described herein effective to treat the subjects anxiety. N R17 1s R17; 1219. The invention provides a method of treating a R17 U Subject Suffering from depression and anxiety which com prises administering to the Subject an amount of any of the compounds described herein effective to treat the Subject's 1226 wherein Q is depression and anxiety.

1220. The invention provides a method of treating a Subject Suffering from depression which comprises admin istering to the Subject an amount of compound effective to treat the Subject's depression wherein the compound has the Structure:

1227 wherein Qs is R17ev ( |/U; 1221 wherein each of Yi, Y, Y, and Y is inde R17 pendently -H, Straight chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C, 1228 wherein R and R are each independently H, cycloalkyl, or C-C, cycloalkenyl, -F, -Cl, -Br, Straight chained or branched C-C, alkyl, -F, -Cl, O I; NO; N; CN; OR, SR, -Br, -, -NO, or -CN; US 2003/0078271 A1 Apr. 24, 2003 70

1229 wherein R is H, straight chained or branched 1243 wherein a tricyclic heteroaryl is a fused three C-C, alkyl, -F, -Cl, -Br, -, -NO, -CN, member aromatic System in which one or more of the -OR, aryl or heteroaryl; rings is heteroaryl; carbazole; or acridine, (1230) wherein Rs is straight chained or branched C-C, 1244 wherein Q is alkyl, -N(R), -OR or aryl; 1231 wherein R is straight chained or branched C-C, alkyl or aryl; 1232 wherein each R, is independently H; straight O XR22 chained or branched C-C, alkyl, Straight chained or 21 No R22 branched C-C-7 monofluoroalkyl, Straight chained or branched C-C, polyfluoroalkyl, Straight chained or branched C-C, alkenyl, Straight chained or 1245 wherein each R is independently H, F, Cl, or branched C-C, alkynyl, Cs-C7 cycloalkenyl, Straight chained or branched C-C alkyl, -(CH2)-Z, or (CH2)-O-(CH2), CH, 1246 or a pharmaceutically acceptable Salt thereof. 1233 wherein each Ro is independently -H; Straight chained or branched C-C, alkyl, monofluo 1247 The invention provides a method of treating a roalkyl or polyfluoroalkyl, Straight chained or Subject Suffering from depression which comprises admin branched C-C, alkenyl or alkynyl, C-C, cycloalkyl istering to the Subject an amount of compound effective to or Cs-C7 cycloalkenyl, -F, -Cl, -Br, or -I; treat the Subject's depression wherein the compound has the NO; N; CN; OR, OCOR, Structure: -COR, -NCOR1, -N(R)-CONCR), or

-COOR, aryl or heteroaryl; or two Ro groups present on adjacent carbon atoms can join together to form a methylenedioxy group; 1234 wherein each R is independently -H; Straight chained or branched C-C, alkyl, monofluo roalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C, cycloalkyl, Cs-C7 cycloalkenyl, aryl or aryl(C- C.)alkyl, 1235 wherein each m is an integer from 0 to 4 inclusive; 1248 wherein each of Yi, Y, Y, and Y is inde pendently -H, Straight chained or branched C-C, 1236 wherein each n is an integer from 1 to 4 alkyl, monofluoroalkyl or polyfluoroalkyl, Straight inclusive; chained or branched C-C, alkenyl or alkynyl, C-C, cycloalkyl, or Cs-C7 cycloalkenyl, -F, -Cl, -Br, 1237 wherein each p is an integer from 0 to 2 O I; NO; N; CN; OR, SR, inclusive; -OCOR, -COR. -NCOR1, -N(R), 1238 wherein U is O, -NR, S, C(R) or -CONCR), or -COOR, aryl or heteroaryl; or -NSOR; any two of Y1, Y, Y- and Y present on adjacent carbon atoms can constitute a methylenedioxy 1239 wherein Z is C-C cycloalkyl, C-C, cyclic grOup, ether, C-C, cyclic thioether, aryl, or heteroaryl; 1249 wherein each R is independently -H; 1240 wherein R is straight chained or branched Straight chained or branched C-C, alkyl, monofluo C-C, alkyl, straight chained or branched C-C, roalkyl or polyfluoroalkyl, Straight chained or monofluoroalkyl, Straight chained or branched C-C, branched C-C, alkenyl or alkynyl, C-C, polyfluoroalkyl, Straight chained or branched C-C, cycloalkyl, Cs-C7 cycloalkenyl, aryl or aryl(C- alkenyl, Straight chained or branched C-C, alkynyl, C.)alkyl, Cs-C, cycloalkenyl, -(CH2)-Z, or (CH-)-O- (CH-)-CH,il 1250 wherein A is A", straight chained or branched C-C, alkyl, aryl, heteroaryl, aryl(C-C)alkyl or 1241 wherein q is an integer from 2 to 4 inclusive; heteroaryl (C-C) alkyl, 1242 wherein B is aryl, heteroaryl, aryl Substituted with an aryl or heteroaryl, heteroaryl Substituted with an aryl or heteroaryl, tricyclic heteroaryl or Q, provided however, if B is aryl or heteroaryl the carbon atom or carbon atoms ortho to the nitrogen atom of the imine bond may only be substituted with one or more of the following -F, -Cl, -Br, -I, -CN, methyl, ethyl or methoxy; US 2003/0078271 A1 Apr. 24, 2003

1251 wherein A' is 1262 wherein A is A", straight chained or branched C-C, alkyl, aryl, heteroaryl, aryl(C-C)alkyl or heteroaryl (C-C) alkyl, R1 1263 wherein A' is

1252 wherein R and R are each independently H, Straight chained or branched C-C, alkyl, -F, -Cl, -Br, -, -NO, or -CN; 1253 wherein R is H, straight chained or branched C-C, alkyl, -F, -Cl, -Br, -, -NO, -CN, -OR, aryl or heteroaryl; 1264 wherein B is aryl Substituted with an aryl or 1254 wherein Rs is straight chained or branched heteroaryl, heteroaryl Substituted with an aryl or C-C, alkyl, -N(R), —OR or aryl; heteroaryl, tricyclic heteroaryl or Q, 1255 wherein R is straight chained or branched 1265 wherein a tricyclic heteroaryl is a fused three C-C, alkyl or aryl; ring aromatic System in which one or more of the 1256 wherein B is aryl, or heteroaryl; provided rings is heteroaryl; carbazole; or acridine, however, if B is aryl or heteroaryl the carbon atom or carbon atoms ortho to the nitrogen atom of the imine 1266 wherein Q is bond may only be substituted with one or more of the following-F, -Cl, -Br, -, -CN, methyl, ethyl or methoxy, 1257 wherein n is an integer from 1 to 4 inclusive; O XR22 1258 or a pharmaceutically acceptable salt thereof. 21 No R22 1259. The invention provides a method of treating a Subject Suffering from depression which comprises admin 1267 wherein n is an integer from 1 to 4 inclusive; istering to the Subject an amount of compound effective to treat the Subject's depression wherein the compound has the 1268 wherein each R is independently H, F, Cl, or Structure: Straight chained or branched C-C alkyl, 1269 or a pharmaceutically acceptable salt thereof.

1270. The invention provides a method of treating a Subject Suffering from depression which comprises admin istering to the Subject an amount of compound effective to treat the Subject's depression wherein the compound has the Structure:

1260 wherein each of Yi, Y, Y, and Y is inde pendently -H, Straight chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C, cycloalkyl, or Cs-C7 cycloalkenyl, -F, -Cl, -Br, O I; NO; N; CN; OR, SR, -OCOR, -COR. -NCOR1, -N(R), -CONCR), or -COOR, aryl or heteroaryl; or 1271 wherein each of Yi, Y, Y, and Y is indepen any two of Y1, Y, Y- and Y present on adjacent dently -H, Straight chained or branched C-C, alkyl, carbon atoms can constitute a methylenedioxy monofluoroalkyl or polyfluoroalkyl, Straight chained or grOup, branched C-C, alkenyl or alkynyl, C-C-7 cycloalkyl, 1261 wherein each R is independently -H; or C-C, cycloalkenyl;-F, -Cl,-Br, or-I;-NO; Straight chained or branched C-C, alkyl, monofluo N; -CN; -OR, -SR, -OCOR, -COR, roalkyl or polyfluoroalkyl, Straight chained or -NCOR1, -N(R), -CON(R), or -COOR, aryl branched C-C, alkenyl or alkynyl, C-C, or heteroaryl; or any two of Y1, Y, Y- and Y present cycloalkyl, Cs-C7 cycloalkenyl, aryl or aryl(C- on adjacent carbon atoms can constitute a methylene C.)alkyl, dioxy group; US 2003/0078271 A1 Apr. 24, 2003 72

1272 wherein each R is independently -H; straight polyfluoroalkyl; straight chained or branched C-C, chained or branched C-C, alkyl, monofluoroalkyl or alkenyl or alkynyl, C-C-7 cycloalkyl, Cs-C7 cycloalk polyfluoroalkyl, Straight chained or branched C-C, enyl or aryl; t".lkenvl o lkvnvl:Si. C-Cd aii.loalkvl, Oal Kyl, C-CCs-C7 cycloaloalk 1280 wherein each R is independently H, F, Cl, or s 1 - 6 s Straight chained or branched C-C alkyl, 1273 wherein A is Q, Q, Qs, aryl substituted with an v . aryl or heteroaryl, heteroaryl Substituted with an aryl or 1281 wherein q is an integer from 2 to 4 inclusive; heteroaryl, or (CHR)-(CHR), Z; 1282 wherein each m is an integer from 0 to 4 inclu 1274 wherein Q is SIVe; 1283 wherein each n is an integer from 1 to 4 inclu Sive, R17 R 17 1284 wherein each p is an integer from 0 to 2 inclu N Sive, R 3- 1285 wherein U is O, -NR, S, C(R), or 17 R17 U -NSOR; 1286 wherein Z is C-C cycloalkyl, C-C, cyclic ether, C-C-7 cyclic thioether, aryl, or heteroaryl; 1275 wherein Q is 1287 wherein R is straight chained or branched C-C, alkyl, straight chained or branched C-C, monof luoroalkyl, Straight chained or branched C-C, poly fluoroalkyl, Straight chained or branched C-C, alk enyl, straight chained or branched C-C, alkynyl, C-C, cycloalkenyl, -(CH2), Z, or (CH), O (CH-)-CH, 1288 wherein B is aryl, or heteroaryl; provided how ever, if B is aryl or heteroaryl the carbon atom or carbon atoms ortho to the nitrogen atom of the imine bond may only be substituted with one or more of the following-F, -Cl, -Br, -, -CN, methyl, ethyl or methoxy, 1289 or a pharmaceutically acceptable salt thereof. 1290. As used in the present invention, the term tv “cycloalkyl” includes C-C7 cycloalkyl moieties which may U; be substituted with one or more of the following: -F, / -NO, -CN, straight chained or branched C-C, alkyl, Straight chained or branched C-C-7 monofluoroalkyl, Straight chained or branched C-C, polyfluoroalkyl, Straight chained or branched C-C, alkenyl, Straight chained or branched C-C, alkynyl, C-C, cycloalkyl, C-C, monof (1277) wherein each R, is independently H; straight luorocycloalkyl, C-C, polyfluorocycloalkyl, Cs-C, chained or branched C-C, alkyl, Straight chained or cycloalkenyl, -N(R), -OR, -COR. -NCOR, branched C-C-7 monofluoroalkyl, Straight chained or -COR, -CONCR) or (CH), O-(CH), CH. branched C-C, polyfluoroalkyl, Straight chained or 2Y-49 42 2n 2m 3. branched C-C, alkenyl, Straight chained or branched 1291. As used in the present invention, the term C-C, alkynyl, Cs-C, cycloalkenyl, -(CH), Z, or “cycloalkenyl' includes Cs-C7 cycloalkenyl moieties which (CH), O-(CH), CH; may be substituted with one or more of the following: -F, -Cl, -Br, -, -NO,-CN, straight chained or branched 1278 wherein each Ro is independently -H; straight C-C, alkyl, Straight chained or branched C-C monofluo chained or branched C-C, alkyl, monofluoroalkyl or roalkyl, Straight chained or branched C-C, polyfluoroalkyl, polyfluoroalkyl, Straight chained or branched C-C, Straight chained or branched C-C, alkenyl, Straight chained alkenyl or alkynyl, C-C, cycloalkyl or C-C, cycloalk- or branched C-C, alkynyl, C-C, cycloalkyl, C-C, monof enyl; -F, -Cl, -Br, or -I; -NO; -N, -CN; luorocycloalkyl, C-C, polyfluorocycloalkyl, Cs-C, OR21, OCOR21, COR21, NCOR21, cycloalkenyl, -N(R), -OR. -COR. -NCOR, -N(R2)2, -CONCR2)2 or -COOR21, aryl or het- - -COR, CONCR), or (CH), (CH), -CH eroaryl; or two Rao groups present on adjacent carbon atoms can join together to form a methylenedioxy 1292. In the present invention, the term "heteroaryl” is grOup, used to include five and Six membered unsaturated rings that may contain one or more oxygen, Sulfur, or nitrogen atoms. 1279 wherein each R is independently -H; straight Examples of heteroaryl groups include, but are not limited chained or branched C-C, alkyl, monofluoroalkyl or to, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, US 2003/0078271 A1 Apr. 24, 2003 pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, 1299 wherein Rs is methyl, ethyl, allyl, phenyl and thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, the phenyl is optionally substituted with a F, Cl, Br, and triazinyl. CF, NO. 1293. In addition the term "heteroaryl' is used to include 1300. In one embodiment of any one of the methods fused bicyclic ring Systems that may contain one or more described herein, the compound is enantiomerically or dias heteroatoms Such as oxygen, Sulfur and nitrogen. Examples tereomerically pure. In one embodiment of any of the of Such heteroaryl groups include, but are not limited to, indolizinyl, indolyl, isoindolyl, benzobfuranyl, benzob methods described herein, the compound is enantiomerically thiophenyl, indazolyl, benzimidazolyl, purinyl, benzox and diastereomerically pure. azolyl, benzisoxazolyl, benzobthiazolyl, imidazo2,1-b 1301. In one embodiment, the compound is a pure z thiazolyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1.8- imine isomer or a pure Zalkene isomer. In one embodiment, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, the compound is a pure E imine isomer or a pure E alkene phthalimidyl and 2,1,3-benzothiazolyl. isomer. 1294 The term "heteroaryl' also includes those chemical 1302. In one embodiment, the compound is administered moieties recited above which may be substituted with one or orally. more of the following:-F, -Cl, -Br, -, -NO,-CN, Straight chained or branched C-C, alkyl, Straight chained or 1303. In one embodiment, the compound has the struc branched C-C monofluoroalkyl, Straight chained or ture: branched C-C, polyfluoroalkyl, Straight chained or branched C-C, alkenyl, Straight chained or branched C-C, alkynyl, C-C7 cycloalkyl, C-C monofluorocycloalkyl, C-C, polyfluorocycloalkyl, Cs-C, cycloalkenyl, -N(R), --OR, -COR, -NCOR, -COR, -CONCR) or (CH), O-(CH), CHs. 1295. The term “heteroaryl” further includes the N-ox ides of those chemical moieties recited above which include at least one nitrogen atom. 1296. In the present invention the term “aryl” is phenyl or naphthyl. The term “aryl' also includes phenyl and naphthyl which may be substituted with one or more of the following: F, -Cl, -Br, -, -NO, -CN, straight chained or 1304 wherein each of Yi, Y, Y, and Y is inde branched C-C, alkyl, Straight chained or branched C-C, pendently -H, Straight chained or branched C-C, monofluoroalkyl, Straight chained or branched C-C, poly alkyl, CF, F, Cl, Br, I, OR, fluoroalkyl, Straight chained or branched C-C, alkenyl, -N(R), or -CONCR); Straight chained or branched C-C, alkynyl, C-C, 1305 wherein each R is independently -H; cycloalkyl, C-C monofluorocycloalkyl, C-C, polyfluoro Straight chained or branched C-C, alkyl, -CF, or cycloalkyl, Cs-C, cycloalkenyl, -N(R), -OR, -SR, phenyl; -OCOR,-COR, -NCOR1, -COR, -CONCR) or (CH), O-(CH), CHs. 1306 wherein A is A", straight chained or branched C-C, alkyl, aryl, heteroaryl, aryl(C-C)alkyl or 1297. The present invention also provides a method of treating a Subject Suffering from depression which compro heteroaryl(C-C)alkyl, and mises administering to the Subject an amount of compound 1307 wherein A' is effective to treat the Subject's depression, wherein the com pound has the Structure: R1 R24 S-S. S-X W R24; 1308. In one embodiment, B is heteroaryl. In one O embodiment, B is aryl. N 1309. In one embodiment, B is phenyl and the phenyl is V optionally substituted with one or more of the following: R25 -F, -Cl, -Br, -CF, straight chained or branched C-C, alkyl, -N(R), -OR,-COR, -NCOR1, -COR, or 1298 wherein each R is independently one or -CON(R). more of the following: H, F, Cl, Br, I, CF, OCH or 1310. In one embodiment, A is aryl. In one embodiment, NO; A is heteroaryl. US 2003/0078271 A1 Apr. 24, 2003 74

1311. In one embodiment, the compound is selected from the group consisting of: -continued

ON O Br: 7 s

1312. In one embodiment, the compound is selected from the group consisting of: OCC OC US 2003/0078271 A1 Apr. 24, 2003 75

1318. In one embodiment, the compound is: -continued C. N O F

/ N X F / O

N O C N O

1313. In one embodiment, A is A and A' is 1319. In one embodiment, B is aryl. R1 1320 In one embodiment, A is (CHR)-(CHR), Z. N- 1321. In one embodiment, the compound is: CR2R3. C

1314. In one embodiment, the compound is: C. N Cl; or W N O / N

N O C s \ 2 N Cl 1322 The invention provides a method of treating a N Subject Suffering from anxiety which comprises administer / ing to the Subject an amount of compound effective to treat C. the Subject's anxiety wherein the compound has the Struc ture: N O

1315) In one embodiment, B is Q. 1316. In one embodiment, A is aryl. 1317. In one embodiment, the compound has the struc ture:

O R22 1323 wherein each of Yi, Y, Y, and Y is inde y y< pendently -H, Straight chained or branched C-C, O alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C, cycloalkyl, or Cs-C7 cycloalkenyl, -F, -Cl, -Br, O I; NO; N; CN; OR, SR, -OCOR, -COR. -NCOR1, -N(R), -CONCR), or -COOR, aryl or heteroaryl; or any two of Y1, Y, Y- and Y present on adjacent carbon atoms can constitute a methylenedioxy grOup, US 2003/0078271 A1 Apr. 24, 2003 76

1324 wherein each R is independently -H; 1332 wherein Rs is straight chained or branched Straight chained or branched C-C, alkyl, monofluo C-C, alkyl, -N(R), —OR or aryl; roalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C, 1333 wherein R is straight chained or branched cycloalkyl, Cs-C7 cycloalkenyl, aryl or aryl(C- C-C, alkyl or aryl; C.)alkyl, 1334 wherein each R, is independently H; straight 1325 wherein A is A, Q, Q, Qs, straight chained chained or branched C-C, alkyl, Straight chained or or branched C-C, alkyl, aryl, heteroaryl, aryl(C- branched C-C-7 monofluoroalkyl, Straight chained or C.)alkyl, heteroaryl (C-C) alkyl, aryl Substituted branched C-C, polyfluoroalkyl, Straight chained or with an aryl or heteroaryl, heteroaryl Substituted with branched C-C, alkenyl, Straight chained or an aryl or heteroaryl; or (CHR)-(CHR), Z; branched C-C, alkynyl, Cs-C7 cycloalkenyl, -(CH-)-Z, or (CH), O-(CH), CH, 1326 wherein A' is 1335 wherein each Ro is independently -H; Straight chained or branched C-C, alkyl, monofluo O O R1 roalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C7 cycloalkyl or C-C, cycloalkenyl, -F, -Cl, -Br, or -I; N-. 1sy. S-S. O -NO; -N, -CN; -OR-, -OCOR, -COR, -NCOR1, -N(R), -CONCR), or -(CH) =E-R: - -COOR, aryl or heteroaryl; or two Rao groups present on adjacent carbon atoms can join together to form a methylenedioxy group; 1327 wherein Q is 1336 wherein each R is independently -H; Straight chained or branched C-C, alkyl, monofluo roalkyl or polyfluoroalkyl, Straight chained or R17 R17 branched C-C, alkenyl or alkynyl, C-C, cycloalkyl, Cs-C7 cycloalkenyl, aryl or aryl(C- y C.)alkyl, R17 p-d 1337 wherein each m is an integer from 0 to 4 R17 inclusive; 1338 wherein each n is an integer from 1 to 4 1328 wherein Q is inclusive; 1339 wherein each p is an integer from 0 to 2

inclusive; 1340 wherein U is O, -NR, S, C(R) or -NSOR; 1341 wherein Z is C-Co cycloalkyl, C-C, cyclic ether, C-C, cyclic thioether, aryl, or heteroaryl; 1342 wherein R is straight chained or branched C-C, alkyl, straight chained or branched C-C, monofluoroalkyl, Straight chained or branched C-C, polyfluoroalkyl, Straight chained or branched C-C, 1329 wherein Q is alkenyl, Straight chained or branched C-C, alkynyl, Cs-C, cycloalkenyl, -(CH2)-Z, or (CH-)-O- (CH-)-CH, 1343 wherein q is an integer from 2 to 4 inclusive; 1344 wherein B is aryl, heteroaryl, aryl Substituted with an aryl or heteroaryl, heteroaryl Substituted with an aryl or heteroaryl, tricyclic heteroaryl or Q, provided however, if B is aryl or heteroaryl the carbon atom or carbon atoms ortho to the nitrogen 1330 wherein R and R are each independently H, atom of the imine bond may only be substituted with Straight chained or branched C-C, alkyl, -F, -Cl, one or more of the following -F, -Cl, -Br, -I, -Br, -, -NO, or -CN; -CN, methyl, ethyl or methoxy; 1331 wherein R is H, straight chained or branched 1345 wherein a tricyclic heteroaryl is a fused three C-C, alkyl, -F, -Cl, -Br, -, -NO, -CN, member aromatic System in which one or more of the -OR, aryl or heteroaryl; rings is heteroaryl; carbazole; or acridine, US 2003/0078271 A1 Apr. 24, 2003 77

1346 wherein Q is 1354 wherein R and R are each independently H, Straight chained or branched C-C, alkyl, -F, -Cl, -Br, -, -NO, or -CN; 1355 wherein R is H, straight chained or branched -Ox2 O R22 C-C, alkyl, -F, -Cl, -Br, -, -NO, -CN, -OR, aryl or heteroaryl; 1347 wherein each R is independently H, F, Cl, or 1356 wherein R is straight chained or branched Straight chained or branched C-C alkyl, C-C, alkyl, -N(R), —OR or aryl; 1348 or a pharmaceutically acceptable salt thereof. 1357 wherein R is straight chained or branched 1349 The invention provides a method of treating a C-C, alkyl or aryl; Subject Suffering from anxiety which comprises administer 1358 wherein B is aryl, or heteroaryl; provided ing to the Subject an amount of compound effective to treat however, if B is aryl or heteroaryl the carbon atom or the Subject's anxiety wherein the compound has the Struc carbon atoms ortho to the nitrogen atom of the imine ture: bond may only be substituted with one or more of the following-F, -Cl, -Br, -, -CN, methyl, ethyl or methoxy, 1359 wherein n is an integer from 1 to 4 inclusive; 1360 or a pharmaceutically acceptable salt thereof. 1361 The invention provides a method of treating a Subject Suffering from anxiety which comprises administer ing to the Subject an amount of compound effective to treat the Subject's anxiety wherein the compound has the Struc ture: 1350 wherein each of Y1, Y, Y, and Y is inde

pendently -H, Straight chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C, cycloalkyl, or Cs-C7 cycloalkenyl, -F, -Cl, -Br, O I; NO; N; CN; OR, SR, -OCOR, -COR. -NCOR1, -N(R), -CONCR), or -COOR, aryl or heteroaryl; or any two of Y1, Y, Y- and Y present on adjacent carbon atoms can constitute a methylenedioxy grOup, 1351 wherein each R is independently -H; Straight chained or branched C-C, alkyl, monofluo 1362 wherein each of Yi, Y, Y, and Y is inde roalkyl or polyfluoroalkyl, Straight chained or pendently -H, Straight chained or branched C-C, branched C-C, alkenyl or alkynyl, C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight cycloalkyl, Cs-C7 cycloalkenyl, aryl or aryl(C- chained or branched C-C, alkenyl or alkynyl, C-C, C.)alkyl, cycloalkyl, or C-C, cycloalkenyl, -F, -Cl, -Br, O I; NO; N; CN; OR, SR, 1352 wherein A is A", straight chained or branched -OCOR, -COR. -NCOR1, -N(R), C-C, alkyl, aryl, heteroaryl, aryl(C-C)alkyl or -CONCR), or -COOR, aryl or heteroaryl; or heteroaryl (C-C) alkyl, any two of Y1, Y, Y- and Y present on adjacent 1353 wherein A' is carbon atoms can constitute a methylenedioxy grOup,

O O 1363 wherein each R is independently -H; Straight chained or branched C-C, alkyl, monofluo roalkyl or polyfluoroalkyl, Straight chained or N-s, -y branched C-C, alkenyl or alkynyl, C-C, cycloalkyl, Cs-C7 cycloalkenyl, aryl or aryl(C- C.)alkyl, 1364 wherein A is A", straight chained or branched C-C, alkyl, aryl, heteroaryl, aryl(C-C)alkyl or heteroaryl (C-C) alkyl, US 2003/0078271 A1 Apr. 24, 2003 78

1365 wherein A' is branched C-C, alkenyl or alkynyl, C-C, cycloalkyl, Cs-C7 cycloalkenyl, aryl or aryl(C- C.)alkyl, O O R1 1375 wherein A is Q, Q, Qs, aryl Substituted with an aryl or heteroaryl, heteroaryl Substituted with an N-. ln: S-S. O aryl or heteroaryl, or (CHR)-(CHR), Z;

- (CH), R4; 1376 wherein Q is

R17 R 1366 wherein B is aryl Substituted with an aryl or 17 heteroaryl, heteroaryl Substituted with an aryl or N heteroaryl, tricyclic heteroaryl or Q, R17 1367 wherein a tricyclic heteroaryl is a fused three R17 U ring aromatic System in which one or more of the rings is heteroaryl; carbazole; or acridine, 1368 wherein Q is 1377 wherein Q is

N-O

o 2 O R22

1369 wherein n is an integer from 1 to 4 inclusive; 1370 wherein each R is independently H, F, Cl, or Straight chained or branched C-C alkyl, 1371 or a pharmaceutically acceptable salt thereof. 1378 wherein Q is 1372 The invention provides a method of treating a Subject Suffering from anxiety which comprises administer ing to the Subject an amount of compound effective to treat the Subject's anxiety wherein the compound has the Struc ture:

1379 wherein each R, is independently H; straight chained or branched C-C, alkyl, Straight chained or branched C-C-7 monofluoroalkyl, Straight chained or branched C-C, polyfluoroalkyl, Straight chained or branched C-C, alkenyl, Straight chained or branched C-C, alkynyl, Cs-C7 cycloalkenyl, -(CH-)-Z, or (CH), O-(CH), CH, 1380 wherein each Ro is independently -H; 1373 wherein each of Yi, Y, Y, and Y is inde Straight chained or branched C-C, alkyl, monofluo pendently -H, Straight chained or branched C-C, roalkyl or polyfluoroalkyl, Straight chained or alkyl, monofluoroalkyl or polyfluoroalkyl, Straight branched C-C, alkenyl or alkynyl, C-C, cycloalkyl chained or branched C-C, alkenyl or alkynyl, C-C, or Cs-C7 cycloalkenyl, -F, -Cl, -Br, or -I; cycloalkyl, or Cs-C7 cycloalkenyl, -F, -Cl, -Br, -NO; -N, -CN; -OR-, -OCOR, O I; NO; N; CN; OR, SR, -COR, -NCOR1, -N(R), -CONCR), or -OCOR, -COR. -NCOR1, -N(R), -COOR, aryl or heteroaryl; or two Rao groups -CONCR), or -COOR, aryl or heteroaryl; or present on adjacent carbon atoms can join together to any two of Y1, Y, Y- and Y present on adjacent form a methylenedioxy group; carbon atoms can constitute a methylenedioxy 1381 wherein each R is independently -H; grOup, Straight chained or branched C-C, alkyl, monofluo 1374 wherein each R is independently -H; roalkyl or polyfluoroalkyl, Straight chained or Straight chained or branched C-C, alkyl, monofluo branched C-C, alkenyl or alkynyl, C-C, roalkyl or polyfluoroalkyl, Straight chained or cycloalkyl, Cs-C7 cycloalkenyl or aryl; US 2003/0078271 A1 Apr. 24, 2003 79

1382 wherein each R is independently H, F, Cl, or 1395. In addition the term "heteroaryl' is used to include Straight chained or branched C-C alkyl, fused bicyclic ring Systems that may contain one or more heteroatoms Such as oxygen, Sulfur and nitrogen. Examples 1383 wherein q is an integer from 2 to 4 inclusive; of Such heteroaryl groups include, but are not limited to, indolizinyl, indolyl, isoindolyl, benzobfuranyl, benzob 1384 wherein each m is an integer from 0 to 4 thiophenyl, indazolyl, benzimidazolyl, purinyl, benzox inclusive; azolyl, benzisoxazolyl, benzobthiazolyl, imidazo2,1-b 1385 wherein each n is an integer from 1 to 4 thiazolyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1.8- inclusive; naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, phthalimidyl and 2,1,3-benzothiazolyl. 1386 wherein each p is an integer from 0 to 2 inclusive; 1396 The term "heteroaryl' also includes those chemical moieties recited above which may be substituted with one or 1387 wherein U is O, -NR, S, C(R), or more of the following:-F, -Cl, -Br, -, -NO,-CN, -NSOR; Straight chained or branched C-C, alkyl, Straight chained or 1388 wherein Z is C-C cycloalkyl, C-C, cyclic branched C-C monofluoroalkyl, Straight chained or ether, C-C-7 cyclic thioether, aryl, or heteroaryl; branched C-C, polyfluoroalkyl, Straight chained or branched C-C, alkenyl, Straight chained or branched C-C, 1389 wherein R is straight chained or branched alkynyl, C-C, cycloalkyl, C-C, monofluorocycloalkyl, C-C, alkyl, straight chained or branched C-C, C-C, polyfluorocycloalkyl, Cs-C, cycloalkenyl, -N(R), monofluoroalkyl, Straight chained or branched C-C, --OR, -COR, -NCOR, -COR, -CONCR) or polyfluoroalkyl, Straight chained or branched C-C, (CH), O-(CH), CHs. alkenyl, Straight chained or branched C-C, alkynyl, 1397) The term “heteroaryl” further includes the N-ox Cs-C, cycloalkenyl, -(CH2)-Z, or (CH-)-O- ides of those chemical moieties recited above which include (CH2). CH; at least one nitrogen atom. 1390 wherein B is aryl, or heteroaryl; provided however, if B is aryl or heteroaryl the carbon atom or 1398. In the present invention the term “aryl' is phenyl or carbon atoms ortho to the nitrogen atom of the imine naphthyl. The term “aryl also includes phenyl and naphthyl bond may only be substituted with one or more of the which may be substituted with one or more of the following: following-F, -Cl, -Br, -, -CN, methyl, ethyl F, -Cl, -Br, -, -NO, -CN, straight chained or or methoxy, branched C-C, alkyl, straight chained or branched C-C, monofluoroalkyl, Straight chained or branched C-C, poly 1391 or a pharmaceutically acceptable salt thereof. fluoroalkyl, Straight chained or branched C-C, alkenyl, Straight chained or branched C-C, alkynyl, C-C, 1392. As used in the present invention, the term cycloalkyl, C-C monofluorocycloalkyl, C-C, polyfluoro “cycloalkyl includes C-C7 cycloalkyl moieties which may cycloalkyl, Cs-C7 cycloalkenyl, -N(R), -OR, -SR, be substituted with one or more of the following: -F, -OCOR,-COR,-NCOR1, -COR,-CONCR) or -NO, -CN, straight chained or branched C-C, alkyl, Straight chained or branched C-C-7 monofluoroalkyl, (CH), O-(CH), CHs. Straight chained or branched C-C, polyfluoroalkyl, Straight 1399. The present invention also provides a method of chained or branched C-C, alkenyl, Straight chained or treating a Subject Suffering from anxiety which compromises branched C-C, alkynyl, C-C-7 cycloalkyl, C-C monof administering to the Subject an amount of compound effec luorocycloalkyl, C-C, polyfluorocycloalkyl, Cs-C, tive to treat the Subjects anxiety where in the compound has cycloalkenyl, -N(R), -OR, -COR, -NCOR, the Structure: -COR, -CONCR) or (CH), O-(CH), CH 1393 As used in the present invention, the term “cycloalkenyl' includes C-C, cycloalkenyl moieties which R24 may be substituted with one or more of the following: -F, -Cl,-Br, -, -NO,-CN, straight chained or branched C-C, alkyl, Straight chained or branched C-C-7 monofluo IC) roalkyl, Straight chained or branched C-C, polyfluoroalkyl, /N N X. Straight chained or branched C-C, alkenyl, Straight chained or branched C-C, alkynyl, C-C-7 cycloalkyl, C-C monof O luorocycloalkyl, C-C, polyfluorocycloalkyl, C-C, N cycloalkenyl, -N(R), -OR, -COR, -NCOR, \ -COR, -CONCR) or (CH), O-(CH), CH R25 1394. In the present invention, the term “heteroaryl” is used to include five and Six membered unsaturated rings that 1400 wherein each R is independently one or may contain one or more oxygen, Sulfur, or nitrogen atoms. more of the following: H, F, Cl, Br, I, CF, OCH or Examples of heteroaryl groups include, but are not limited to, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, NO; pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, 1401 wherein Rs is methyl, ethyl, allyl, phenyl and thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, the phenyl is optionally substituted with a F, Cl, Br, and triazinyl. CF, NO. US 2003/0078271 A1 Apr. 24, 2003 80

1402. In one embodiment of any of the methods 1412. In one embodiment, the compound is selected from described herein, the compound is enantiomerically and the group consisting of: diastereomerically pure. In one embodiment of any of the methods described herein, the compound is enantiomerically or diastereomerically pure. 1403. In one embodiment of any of the methods described herein, the compound is a pure Zimine isomer or N a pure Zalkene isomer. In one embodiment, the compound / is a pure E imine isomer or a pure E alkene isomer. O 1404. In one embodiment, the compound has the struc- N ture:

Cl; and

N W

N 1405 wherein each of Yi, Y, Y, and Y is inde pendently -H, straight chained or branched C-C, / \ alkyl, -CF, -F, -Cl, -Br, -, -OR, -N(R), or -CON(R); S 1406 wherein each R is independently -H; Straight chained or branched C-C, alkyl, -CF, or phenyl; C. 1407 wherein A is A", straight chained or branched N C-C, alkyl, aryl, heteroaryl, aryl (C-C) alkyl or W heteroaryl (C-C) alkyl, and O 1408 wherein A' is N

S R1 N- 1413. In one embodiment, the compound is selected from CR2R3. the group consisting of:

F 1409. In one embodiment, B is heteroaryl. In one embodiment, B is aryl. F; N F 1410. In one embodiment, B is phenyl and the phenyl is / optionally substituted with one or more of the following: -F, -Cl, -Br, -CF, straight chained or branched C-C, N O alkyl, -N(R), -OR,-COR. -NCOR1, -COR, or -CON(R). 1411. In one embodiment, A is aryl. In one embodiment, A is heteroaryl. US 2003/0078271 A1 Apr. 24, 2003 81

-continued -continued C. /

1414) In one embodiment, A is A and A is S-S.R1 1415) In one embodiment, the compound is:

Cl N %

O ; Or N Cl

C N Z C.

N O

1416) In one embodiment, B is Q. 1417 In one embodiment, A is aryl. 1418) In one embodiment, the compound has the Struc ture:

; and US 2003/0078271 A1 Apr. 24, 2003 82

1419. In one embodiment, the compound is: 1425 wherein each R is independently -H; Straight chained or branched C-C, alkyl, monofluo roalkyl or polyfluoroalkyl, Straight chained or O F branched C-C, alkenyl or alkynyl, C-C, N Y- cycloalkyl, Cs-C7 cycloalkenyl, aryl or aryl(C- C.)alkyl, 1426 wherein A is A, Q, Q, Qs, straight chained O or branched C-C, alkyl, aryl, heteroaryl, aryl(C- C) alkyl, heteroaryl (C-C) alkyl, aryl Substituted with an aryl or heteroaryl, heteroaryl Substituted with an aryl or heteroaryl; or (CHR)-(CHR), Z; 1427 wherein A' is

O O 1420. In one embodiment, B is aryl. N 1421. In one embodiment, A is (CHR)-(CHR), Z. Rs: ln 1422. In one embodiment, the compound is: R 1. Cl S-S. or - (CH), E -R:

C. 1428 wherein Q is

R17 O R17

N N

R17 s R17 l/U \ 2 N 1429 wherein Q is

1423. The invention provides a pharmaceutical compo Sition comprising a pharmaceutically acceptable carrier and a compound having the Structure:

1424 wherein each of Yi, Y, Y, and Y is inde- /y pendently -H, Straight chained or branched C-C, alkyl, monofluoroalkyl or polytluoroalkyl, Straight R17 chained or branched C-C, alkenyl or alkynyl, C-C, cycloalkyl, or Cs-C7 cycloalkenyl, -F, -Cl, -Br, or -I; -NO; -N; -CN; -OR, -SR, 1431 wherein R and R are each independently H, -OCOR, -COR. -NCOR1, -N(R), Straight chained or branched C-C, alkyl, -F, -Cl, -CONCR), or -COOR, aryl or heteroaryl; or -Br, -, -NO, or -CN; any two of Y1, Y, Y- and Y present on adjacent 1432 wherein R is H, straight chained or branched carbon atoms can constitute a methylenedioxy C-C, alkyl, -F, -Cl, -Br, -, -NO, -CN, grOup, -OR, aryl or heteroaryl; US 2003/0078271 A1 Apr. 24, 2003

1433 wherein Rs is straight chained or branched 1447 wherein Q is C-C, alkyl, -N(R), —OR or aryl; 1434 wherein R is straight chained or branched C-C, alkyl or aryl; - N X R22; 1435 wherein each R, is independently H; straight chained or branched C-C, alkyl, Straight chained or branched C-C-7 monofluoroalkyl, Straight chained or branched C-C, polyfluoroalkyl, Straight chained or 1448 wherein each R is independently H, F, Cl, or branched C-C, alkenyl, Straight chained or Straight chained or branched C-C alkyl, branched C-C, alkynyl, Cs-C7 cycloalkenyl, -(CH-)-Z, or (CH)-O-(CH), CH, 1449 or a pharmaceutically acceptable salt thereof. 1450. The invention provides a pharmaceutical compo 1436 wherein each Ro is independently -H; Sition comprising a pharmaceutically acceptable carrier and Straight chained or branched C-C, alkyl, monofluo roalkyl or polyfluoroalkyl, Straight chained or a compound having the Structure: branched C-C, alkenyl or alkynyl, C-C7 cycloalkyl or C-C, cycloalkenyl, -F, -Cl, -Br, or -I; NO; N; CN; OR, OCOR, -COR, -NCOR1, -N(R), -CONCR), or -COOR, aryl or heteroaryl; or two Ro groups present on adjacent carbon atoms can join together to form a methylenedioxy group; 1437 wherein each R is independently -H; Straight chained or branched C-C, alkyl, monofluo roalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C, cycloalkyl, Cs-C7 cycloalkenyl, aryl or aryl(C- 1451 wherein each of Yi, Y, Y, and Y is inde C.)alkyl, pendently -H, Straight chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight 1438 wherein each m is an integer from 0 to 4 chained or branched C-C, alkenyl or alkynyl, C-C, inclusive; cycloalkyl, or C-C, cycloalkenyl, -F, -Cl, -Br, 1439 wherein each n is an integer from 1 to 4 O I; NO; N; CN; OR, SR, -OCOR, -COR. -NCOR. -N(R), inclusive; -CONCR), or -COOR, aryl or heteroaryl; or 1440 wherein each p is an integer from 0 to 2 any two of Y1, Y, Y- and Y present on adjacent inclusive; carbon atoms can constitute a methylenedioxy grOup, 1441 wherein U is O, -NR, S, C(R), or -NSOR; 1452 wherein each R is independently -H; Straight chained or branched C-C, alkyl, monofluo 1442 wherein Z is C-Co cycloalkyl, C-C, cyclic roalkyl or polyfluoroalkyl, Straight chained or ether, C-C, cyclic thioether, aryl, or heteroaryl; branched C-C, alkenyl or alkynyl, C-C, cycloalkyl, Cs-C7 cycloalkenyl, aryl or aryl(C- 1443 wherein R is straight chained or branched C.)alkyl, C-C, alkyl, straight chained or branched C-C, monofluoroalkyl, Straight chained or branched C-C, 1453 wherein A is A", straight chained or branched polyfluoroalkyl, Straight chained or branched C-C, C-C, alkyl, aryl, heteroaryl, aryl(C-C)alkyl or alkenyl, Straight chained or branched C-C, alkynyl, heteroaryl (C-C) alkyl, Cs-C, cycloalkenyl, -(CH2)-Z, or (CH-)-O- 1454 wherein A' is (CH-)-CH,

1444 wherein q is an integer from 2 to 4 inclusive; O O 1445 wherein B is aryl, heteroaryl, aryl Substituted with an aryl or heteroaryl, heteroaryl Substituted with N-. ln an aryl or heteroaryl, tricyclic heteroaryl or Q, provided however, if B is aryl or heteroaryl the carbon atom or carbon atoms ortho to the nitrogen R1 atom of the imine bond may only be substituted with one or more of the following -F, -Cl, -Br, -I, S-S. O -(CH) = -R: -CN, methyl, ethyl or methoxy; 1446 wherein a tricyclic heteroaryl is a fused three 1455) wherein R and Rare each independently H, member aromatic System in which one or more of the Straight chained or branched C-C, alkyl, -F, -Cl, rings is heteroaryl; carbazole; or acridine, -Br, -I, -NO, or -CN; US 2003/0078271 A1 Apr. 24, 2003

1456 wherein R is H, straight chained or branched C-C, alkyl, -F, -Cl, -Br, -, -NO, -CN, -continued -OR, aryl or heteroaryl; R1 1457 wherein R is straight chained or branched C-C, alkyl, -N(R) 2, -OR or aryl; S-S. O -(CH2) E-Ra: 1458 wherein R is straight chained or branched C-C, alkyl or aryl; 1467 wherein B is aryl Substituted with an aryl or 1459 wherein B is aryl, or heteroaryl; provided heteroaryl, heteroaryl Substituted with an aryl or however, if B is aryl or heteroaryl the carbon atom or heteroaryl, tricyclic heteroaryl or Q, carbon atoms ortho to the nitrogen atom of the imine 1468 wherein a tricyclic heteroaryl is a fused three bond may only be substituted with one or more of the ring aromatic System in which one or more of the following-F, -Cl, -Br, -, -CN, methyl, ethyl rings is heteroaryl; carbazole; or acridine, or methoxy, 1469 wherein Q is 1460 wherein n is an integer from 1 to 4 inclusive; 1461 or a pharmaceutically acceptable Salt thereof. N O R22; 1462. The invention provides a pharmaceutical compo Sition comprising a pharmaceutically acceptable carrier and 2N/ "R22 a compound having the Structure:

1470 wherein n is an integer from 1 to 4 inclusive; 1471 wherein each R is independently H, F, Cl, or Straight chained or branched C-C alkyl, 1472 or a pharmaceutically acceptable salt thereof. 1473. The invention provides a pharmaceutical compo Sition comprising a pharmaceutically acceptable carrier and a compound having the Structure:

1463 wherein each of Yi, Y, Y, and Y is inde pendently -H, Straight chained or branched C-C, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C, cycloalkyl, or Cs-C7 cycloalkenyl, -F, -Cl, -Br, O I; NO; N; CN; OR, SR, -OCOR, -COR. -NCOR1, -N(R), -CONCR), or -COOR, aryl or heteroaryl; or any two of Y1, Y, Y- and Y present on adjacent carbon atoms can constitute a methylenedioxy 1474 wherein each of Yi, Y, Y, and Y is inde grOup, pendently -H, Straight chained or branched C-C, 1464 wherein each R is independently -H; alkyl, monofluoroalkyl or polyfluoroalkyl, Straight Straight chained or branched C-C, alkyl, monofluo chained or branched C-C, alkenyl or alkynyl, C-C, roalkyl or polyfluoroalkyl, Straight chained or cycloalkyl, or Cs-C7 cycloalkenyl, -F, -Cl, -Br, branched C-C, alkenyl or alkynyl, C-C, O I; NO; N; CN; OR, SR, cycloalkyl, Cs-C, cycloalkenyl, aryl or aryl (C-C) -OCOR, -COR. -NCOR1, -N(R), alkyl, -CONCR), or -COOR, aryl or heteroaryl; or any two of Y1, Y, Y- and Y present on adjacent 1465 wherein A is A", straight chained or branched C-C, alkyl, aryl, heteroaryl, aryl(C-C)alkyl or carbon atoms can constitute a methylenedioxy heteroaryl (C-C) alkyl, grOup, 1475 wherein each R is independently -H; 1466 wherein A' is Straight chained or branched C-C, alkyl, monofluo roalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C, cycloalkyl, Cs-C7 cycloalkenyl, aryl or aryl(C- C.)alkyl, 1476 wherein A is Q, Q, Qs, aryl Substituted with an aryl or heteroaryl, heteroaryl Substituted with an aryl or heteroaryl, or (CHR)-(CHR), Z; US 2003/0078271 A1 Apr. 24, 2003 85

1477) wherein Q, is 1486 wherein each n is an integer from 1 to 4 inclusive;

R17 R 1487 wherein each p is an integer from 0 to 2 17 inclusive; N 1488 wherein U is O, -NR, S, C(R), or -NSOR; R17 us R17; R17 U 1489 wherein Z is C-Cocycloalkyl, C-C, cyclic ether, C-C, cyclic thioether, aryl, or heteroaryl; 1490 wherein R is straight chained or branched 1478 wherein Q is C-C, alkyl, straight chained or branched C-C, monofluoroalkyl, Straight chained or branched C-C, polyfluoroalkyl, Straight chained or branched C-C, alkenyl, Straight chained or branched C-C, alkynyl, Cs-C, cycloalkenyl, (CH2), Z, or (CH-)-O- (CH-)-CH,il 1491 wherein B is aryl, or heteroaryl; provided however, if B is aryl or heteroaryl the carbon atom or carbon atoms ortho to the nitrogen atom of the imine bond may only be substituted with one or more of the following-F, -Cl, -Br, -, -CN, methyl, ethyl or methoxy, 1492 or a pharmaceutically acceptable salt thereof. 1493 As used in the present invention, the term “cycloalkyl” includes C-C, cycloalkyl moieties which may be substituted with one or more of the following: -F, -NO, -CN, straight chained or branched C-C, alkyl, Straight chained or branched C-C7 monofluoroalkyl, Straight chained or branched C-C, polyfluoroalkyl, Straight chained or branched C-C, alkenyl, Straight chained or branched C-C, alkynyl, C-C-7 cycloalkyl, C-C monof 1480 wherein each R, is independently H; straight luorocycloalkyl, C-C, polyfluorocycloalkyl, C-C, chained or branched C-C, alkyl, Straight chained or cycloalkenyl, -N(R), -OR, -COR, -NCOR, branched C-C-7 monofluoroalkyl, Straight chained or -COR, -CONCR) or (CH), O-(CH), CH branched C-C, polyfluoroalkyl, Straight chained or 1494 AS used in the present invention, the term branched C-C, alkenyl, Straight chained or “cycloalkenyl' includes C-C, cycloalkenyl moieties which branched C-C, alkynyl, Cs-C7 cycloalkenyl, may be substituted with one or more of the following: -F, -(CH-)-Z, or (CH)-O-(CH), CH, -Cl, -Br, -, -NO,-CN, straight chained or branched 1481 wherein each Ro is independently -H; C-C, alkyl, Straight chained or branched C-C monofluo Straight chained or branched C-C, alkyl, monofluo roalkyl, Straight chained or branched C-C, polyfluoroalkyl, roalkyl or polyfluoroalkyl, Straight chained or Straight chained or branched C-C, alkenyl, Straight chained branched C-C, alkenyl or alkynyl, C-C7 cycloalkyl or branched C-C, alkynyl, C-C-7 cycloalkyl, C-C monof or Cs-C7 cycloalkenyl, -F, -Cl, -Br, or -I; luorocycloalkyl, C-C, polyfluorocycloalkyl, C-C, NO; N; CN; OR, OCOR, cycloalkenyl, -N(R), -OR, -COR, -NCOR, -COR, -NCOR1, -N(R), -CONCR), or -COR, -CONCR) or (CH), O-(CH), CH. -COOR, aryl or heteroaryl; or two Ro groups 1495. In the present invention, the term "heteroaryl” is present on adjacent carbon atoms can join together to used to include five and Six membered unsaturated rings that form a methylenedioxy group; may contain one or more oxygen, Sulfur, or nitrogen atoms. Examples of heteroaryl groups include, but are not limited 1482 wherein each R is independently -H; to, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, Straight chained or branched C-C, alkyl, monofluo pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, roalkyl or polyfluoroalkyl, Straight chained or thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, branched C-C, alkenyl or alkynyl, C-C, cycloalkyl, Cs-C7 cycloalkenyl or aryl; and triazinyl. 1496. In addition the term "heteroaryl' is used to include 1483 wherein each R is independently H, F, Cl, or fused bicyclic ring Systems that may contain one or more Straight chained or branched C-C alkyl, heteroatoms Such as oxygen, Sulfur and nitrogen. Examples of Such heteroaryl groups include, but are not limited to, 1484 wherein q is an integer from 2 to 4 inclusive; indolizinyl, indolyl, isoindolyl, benzobfuranyl, benzob 1485 wherein each m is an integer from 0 to 4 thiophenyl, indazolyl, benzimidazolyl, purinyl, benzox inclusive; azolyl, benzisoxazolyl, benzobthiazolyl, imidazo2,1-b US 2003/0078271 A1 Apr. 24, 2003 thiazolyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1.8- 1507 wherein A is A", straight chained or branched naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, C-C, alkyl, aryl, heteroaryl, aryl(C-C)alkyl or phthalimidyl and 2,1,3-benzothiazolyl. heteroaryl(C-C)alkyl, and 1497. The term "heteroaryl' also includes those chemical moieties recited above which may be substituted with one or 1508 wherein A' is more of the following: -F, -Cl, -Br, -, -NO,-CN, Straight chained or branched C-C, alkyl, Straight chained or branched C-C monofluoroalkyl, Straight chained or branched C-C, polyfluoroalkyl, Straight chained or branched C-C, alkenyl, Straight chained or branched C-C, alkynyl, C-C7 cycloalkyl, C-C monofluorocycloalkyl, R1 C-C, polyfluorocycloalkyl, Cs-C, cycloalkenyl, -N(R), --OR, -COR, -NCOR, -COR, -CONCR) or S-S. (CH), O-(CH), CHs. 1498. The term “heteroaryl” further includes the N-ox ides of those chemical moieties recited above which include at least one nitrogen atom. 1499. In the present invention the term “aryl' is phenyl or 1509. In one embodiment, B is heteroaryl. naphthyl. The term “aryl' also includes phenyl and naphthyl 1510) In one embodiment, B is aryl. which may be substituted with one or more of the following: F, -Cl, -Br, -, -NO, -CN, straight chained or 1511. In one embodiment, B is phenyl and the phenyl is branched C-C, alkyl, Straight chained or branched C-C, optionally substituted with one or more of the following: monofluoroalkyl, Straight chained or branched C-C, poly -F, -Cl, -Br, -CF, straight chained or branched C-C, fluoroalkyl, Straight chained or branched C-C, alkenyl, Straight chained or branched C-C, alkynyl, C-C, alkyl, -N(R), -OR,-COR, -NCOR1, -COR, or cycloalkyl, C-C monofluorocycloalkyl, C-C, polyfluoro -CON(R). cycloalkyl, Cs-C7 cycloalkenyl, -N(R), -OR, -SR, 1512. In one embodiment, A is aryl. In one embodiment, -OCOR,-COR. -NCOR, -COR, -CONCR) or A is heteroaryl. (CH -O-(CH2)-CHs. 1500. In one embodiment of any of the pharmaceutical 1513. In one embodiment, the compound is selected from compositions described herein, the compound is enantio the group consisting of: merically and diastereomerically pure. In one embodiment, the compound is enantiomerically or diastereomerically pure. 1501. In one embodiment, the compound is a pure Z imine isomer or a pure Z alkene isomer. 1502. In one embodiment, the compound is a pure E N imine isomer or a pure E alkene isomer. / 1503. In one embodiment, the composition can be admin istered orally. O N 1504. In one embodiment of the pharmaceutical compo Sition, the compound has the Structure:

Cl; and

N W 1505 wherein each of Yi, Y, Y, and Y is inde pendently -H, Straight chained or branched C-C, N alkyl, CF, -F, Cl, -Br, -I, OR, -N(R), or -CON(R); 1506 wherein each R is independently -H; Straight chained or branched C-C, alkyl, -CF, or phenyl; US 2003/0078271 A1 Apr. 24, 2003 87

1521. The invention provides a compound having the -continued Structure: C.

S 1514. In one embodiment, B is Q. 1522 wherein each of Yi, Y, Y, and Y is inde 1515. In one embodiment, A is aryl. pendently H, Straight chained or branched C-C, 1516. In one embodiment, the compound has the struc alkyl, monofluoroalkyl or polyfluoroalkyl, Straight ture: chained or branched C-C, alkenyl or alkynyl, C-C, cycloalkyl, or C-C, cycloalkenyl, -F, -Cl, -Br, O I; NO; N; CN; OR, SR, -OCOR, -COR. -NCOR1, -N(R), -CONCR), or -COOR, aryl or heteroaryl; or any two of Y1, Y, Y- and Y present on adjacent carbon atoms can constitute a methylenedioxy grOup, 1523 wherein each R is independently -H; Straight chained or branched C-C, alkyl, monofluo roalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C, 1517. In one embodiment, the compound is: cycloalkyl, Cs-C7 cycloalkenyl, aryl or aryl(C- C.)alkyl, 1524 wherein A is A, Q, Q, Qs, straight chained or branched C-C, alkyl, aryl, heteroaryl, aryl(C- C) alkyl, heteroaryl (C-C) alkyl, aryl Substituted with an aryl or heteroaryl, heteroaryl Substituted with an aryl or heteroaryl; or (CHR)-(CHR), Z; 1525 wherein A' is

O O 1518. In one embodiment, B is aryl. 1519 In one embodiment, A is (CHR)-(CHR), Z. 1520. In one embodiment, the compound is: Cl N- ; or -(CH) = -R: CR2R3 C. C C US 2003/0078271 A1 Apr. 24, 2003

1527 wherein Q is 1538 wherein each p is an integer from 0 to 2 inclusive; 1539 wherein U is O, -NR, S, C(R-) 2, or -NSOR; 1540 wherein Z is C-Cocycloalkyl, C-C, cyclic ether, C-C, cyclic thioether, aryl, or heteroaryl; 1541 wherein R is straight chained or branched C-C, alkyl, straight chained or branched C-C, monofluoroalkyl, Straight chained or branched C-C, polyfluoroalkyl, Straight chained or branched C-C, alkenyl, Straight chained or branched C-C, alkynyl, 1528 wherein Q is Cs-C, cycloalkenyl, -(CH2)-Z, or (CH-)-O- (CH-)-CH, 1542 wherein q is an integer from 2 to 4 inclusive; 1543 wherein B is aryl, heteroaryl, aryl Substituted with an aryl or heteroaryl, heteroaryl Substituted with an aryl or heteroaryl, tricyclic heteroaryl or Q, provided however, if B is aryl or heteroaryl the carbon atom or carbon atoms ortho to the nitrogen atom of the imine bond may only be substituted with 1529 wherein R and R are each independently H, one or more of the following -F, -Cl, -Br, -I, Straight chained or branched C-C, alkyl, -F, -Cl, -CN, methyl, ethyl or methoxy; -Br, -I, -NO, or -CN; 1544 wherein a tricyclic heteroaryl is a fused three 1530 wherein R is H, straight chained or branched member aromatic System in which one or more of the C-C, alkyl, -F, -Cl, -Br, -I, -NO, -CN, rings is heteroaryl; carbazole; or acridine, -OR, aryl or heteroaryl; 1545 wherein Q is 1531 wherein R is straight chained or branched C-C, alkyl, -N(R), —OR or aryl; 1532 wherein R is straight chained or branched - I N X R22; C-C, alkyl or aryl; 1533 wherein each R, is independently H; straight chained or branched C-C, alkyl, Straight chained or branched C-C, monofluoroalkyl, Straight chained or branched C-C, polyfluoroalkyl, Straight chained or 1546 wherein each R is independently H, F, Cl, or branched C-C, alkenyl, Straight chained or Straight chained or branched C-C alkyl, branched C-C, alkynyl, Cs-C7 cycloalkenyl, 1547 or a pharmaceutically acceptable salt thereof. -(CH) mZ, or (CH) n-(CH2),il CH, 1548. The invention provides a compound having the 1534 wherein each Ro is independently -H; Structure: Straight chained or branched C-C, alkyl, monofluo roalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C7 cycloalkyl or C-C, cycloalkenyl, -F, -Cl, -Br, or -I; NO; N; CN; OR, OCOR, -COR, -NCOR1, -N(R), -CONCR), or -COOR, aryl or heteroaryl; or two Ro groups present on adjacent carbon atoms can join together to form a methylenedioxy group; 1535 wherein each R is independently -H; Straight chained or branched C-C, alkyl, monofluo roalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C, 1549 wherein each of Yi, Y, Y, and Y is inde cycloalkyl, Cs-C7 cycloalkenyl, aryl or aryl(C- pendently -H, Straight chained or branched C-C, C.)alkyl, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight 1536 wherein each m is an integer from 0 to 4 chained or branched C-C, alkenyl or alkynyl, C-C, inclusive; cycloalkyl, or Cs-C7 cycloalkenyl, -F, -Cl, -Br, O I; NO; N; CN; OR, SR, 1537 wherein each n is an integer from 1 to 4 -OCOR, -COR. -NCOR1, -N(R), inclusive; -CONCR), or -COOR, aryl or heteroaryl; or US 2003/0078271 A1 Apr. 24, 2003

any two of Y1, Y, Y- and Y present on adjacent 1561 wherein each of Yi, Y, Y, and Y is inde carbon atoms can constitute a methylenedioxy pendently -H, Straight chained or branched C-C, grOup, alkyl, monofluoroalkyl or polyfluoroalkyl, Straight 1550 wherein each R is independently -H; chained or branched C-C, alkenyl or alkynyl, C-C, Straight chained or branched C-C, alkyl, monofluo cycloalkyl, or Cs-C7 cycloalkenyl, -F, -Cl, -Br, roalkyl or polyfluoroalkyl, Straight chained or O I; NO; N; CN; OR, SR, branched C-C, alkenyl or alkynyl, C-C, -OCOR, -COR. -NCOR1, -N(R), cycloalkyl, Cs-C, cycloalkenyl, aryl or aryl(C- -CONCR), or -COOR, aryl or heteroaryl; or C.)alkyl, any two of Y1, Y, Y- and Y present on adjacent carbon atoms can constitute a methylenedioxy 1551 wherein A is A", straight chained or branched grOup, C-C, alkyl, aryl, heteroaryl, aryl(CL-C)alkyl or heteroaryl (C-C) alkyl, 1562 wherein each R is independently -H; Straight chained or branched C-C, alkyl, monofluo 1552 wherein A' is roalkyl or polyfluoroalkyl, Straight chained or branched C-C, alkenyl or alkynyl, C-C, cycloalkyl, Cs-C7 cycloalkenyl, aryl or aryl(C- O O C.)alkyl, N-. ln; 1563 wherein A is A", straight chained or branched C-C, alkyl, aryl, heteroaryl, aryl(C-C)alkyl or heteroaryl (C-C) alkyl, S-S. O -(CH) = -R: 1564 wherein A' is 1553 wherein R and R are each independently H, Straight chained or branched C-C, alkyl, -F, -Cl, -Br, -I, -NO, or -CN; 1554 wherein R is H, straight chained or branched C-C, alkyl, -F, -Cl, -Br, -, -NO, -CN, -OR, aryl or heteroaryl; 1555 wherein Rs is straight chained or branched C-C, alkyl, -N(R), —OR or aryl; 1556 wherein R is straight chained or branched C-C, alkyl or aryl; 1557 wherein B is aryl, or heteroaryl; provided however, if B is aryl or heteroaryl the carbon atom or 1565 wherein B is aryl Substituted with an aryl or carbon atoms ortho to the nitrogen atom of the imine heteroaryl, heteroaryl Substituted with an aryl or bond may only be substituted with one or more of the heteroaryl, tricyclic heteroaryl or Q, following-F, -Cl, -Br, -, -CN, methyl, ethyl or methoxy, 1566 wherein a tricyclic heteroaryl is a fused three ring aromatic System in which one or more of the 1558 wherein n is an integer from 1 to 4 inclusive; rings is heteroaryl; carbazole; or acridine, 1559 or a pharmaceutically acceptable salt thereof. 1567 wherein Q is 1560. The invention provides a compound having the Structure: N x N4 / "R.

1568 wherein n is an integer from 1 to 4 inclusive; 1569 wherein each R is independently H, F, Cl, or Straight chained or branched C-C alkyl, 1570 or a pharmaceutically acceptable salt thereof. US 2003/0078271 A1 Apr. 24, 2003 90

1571. The invention provides a compound having the 1577 wherein Q is Structure:

1578 wherein each R, is independently H; straight chained or branched C-C, alkyl, Straight chained or branched C-C, monofluoroalkyl, Straight chained or branched C-C, polyfluoroalkyl, Straight chained or branched C-C, alkenyl, Straight chained or 1572 wherein each of Yi, Y, Y, and Y is inde branched C-C, alkynyl, C-C, cycloalkenyl, pendently -H, Straight chained or branched C-C, -(CH) MZ, or (CH), O-(CH), CH; alkyl, monofluoroalkyl or polyfluoroalkyl, Straight 1579 wherein each Ro is independently -H; chained or branched C-C, alkenyl or alkynyl, C-C, Straight chained or branched C-C, alkyl, monofluo cycloalkyl, or Cs-C7 cycloalkenyl, -F, -Cl, -Br, roalkyl or polyfluoroalkyl, Straight chained or O I; NO; N; CN; OR, SR, branched C-C, alkenyl or alkynyl, C-C7 cycloalkyl -OCOR, -COR. -NCOR. -N(R), or C-C, cycloalkenyl, -F, -Cl, -Br, or -I; -CONCR), or -COOR, aryl or heteroaryl; or -NO; -N, -CN; -OR-, -OCOR, any two of Y1, Y, Y- and Y present on adjacent -COR, -NCOR1, -N(R), -CONCR), or carbon atoms can constitute a methylenedioxy -COOR, aryl or heteroaryl; or two Ro groups grOup, present on adjacent carbon atoms can join together to 1573 wherein each R is independently -H; form a methylenedioxy group; Straight chained or branched C-C, alkyl, monofluo 1580 wherein each R is independently -H; roalkyl or polyfluoroalkyl, Straight chained or Straight chained or branched C-C, alkyl, monofluo branched C-C, alkenyl or alkynyl, C-C, roalkyl or polyfluoroalkyl, Straight chained or cycloalkyl, Cs-C7 cycloalkenyl, aryl or aryl(C- branched C-C, alkenyl or alkynyl, C-C, C.)alkyl, cycloalkyl, Cs-C7 cycloalkenyl or aryl; 1574 wherein A is Q, Q, Qs, aryl Substituted with 1581 wherein each R is independently H, F, Cl, or an aryl or heteroaryl, heteroaryl Substituted with an Straight chained or branched C-C alkyl, aryl or heteroaryl, or (CHR)-(CHR), Z; 1582 wherein q is an integer from 2 to 4 inclusive; 1575 wherein Q is 1583 wherein each m is an integer from 0 to 4 inclusive; 1584 wherein each n is an integer from 1 to 4 R17 R 17 inclusive;

N 1585 wherein each p is an integer from 0 to 2 inclusive; R17 1s R17; R17 U 1586 wherein U is O, -NR, S, C(R), or -NSOR; 1587 wherein Z is C-Cocycloalkyl, C-C, cyclic 1576 wherein Q is ether, C-C-7 cyclic thioether, aryl, or heteroaryl; 1588 wherein R is straight chained or branched C-C, alkyl, straight chained or branched C-C, monofluoroalkyl, Straight chained or branched C-C, polyfluoroalkyl, Straight chained or branched C-C, alkenyl, Straight chained or branched C-C, alkynyl, Cs-C, cycloalkenyl, -(CH2)-Z, or (CH-)-O- (CH-)-CH, 1589 wherein B is aryl, or heteroaryl; provided however, if B is aryl or heteroaryl the carbon atom or carbon atoms ortho to the nitrogen atom of the imine US 2003/0078271 A1 Apr. 24, 2003 91

bond may only be substituted with one or more of the which may be substituted with one or more of the following: following-F, -Cl, -Br, -, -CN, methyl, ethyl F, -Cl, -Br, -, -NO, -CN, straight chained or or methoxy, branched C-C, alkyl, Straight chained or branched C-C, monofluoroalkyl, Straight chained or branched C-C, poly 1590 or a pharmaceutically acceptable salt thereof. fluoroalkyl, Straight chained or branched C-C, alkenyl, 1591 AS used in the present invention, the term Straight chained or branched C-C, alkynyl, C-C, “cycloalkyl includes C-C7 cycloalkyl moieties which may cycloalkyl, C-C monofluorocycloalkyl, C-C, polyfluoro be substituted with one or more of the following: -F, cycloalkyl, Cs-C7 cycloalkenyl, -N(R), -OR, -SR, -NO, -CN, straight chained or branched C-C, alkyl, -OCOR,-COR,-NCOR, -COR,-CONCR) or Straight chained or branched C-C, monofluoroalkyl, (CH), O-(CH), CHs. Straight chained or branched C-C, polyfluoroalkyl, Straight 1598. In one embodiment of any of the compounds chained or branched C-C, alkenyl, Straight chained or described herein, the compound is enantiomerically and branched C-C, alkynyl, C-C-7 cycloalkyl, C-C monof diastereomerically pure. In one embodiment, the compound luorocycloalkyl, C-C, polyfluorocycloalkyl, Cs-C, is enantiomerically or diastereomerically pure. cycloalkenyl, -N(R), -OR, -COR, -NCOR, 1599. In one embodiment, the compound is a pure Z -COR, -CONCR) or (CH), O-(CH), CH. imine isomer or a pure Z alkene isomer. 1592. As used in the present invention, the term “cycloalkenyl' includes Cs-C7 cycloalkenyl moieties which 1600. In one embodiment, the compound is a pure E may be substituted with one or more of the following: -F, imine isomer or a pure E alkene isomer. -Cl, -Br, -, -NO,-CN, straight chained or branched 1601. In one embodiment, the compound can be admin C-C, alkyl, Straight chained or branched C-C-7 monofluo istered orally. roalkyl, Straight chained or branched C-C, polyfluoroalkyl, Straight chained or branched C-C, alkenyl, Straight chained 1602) In one embodiment, the compound has the Struc or branched C-C, alkynyl, C-C, cycloalkyl, C-C, monof ture: luorocycloalkyl, C-C, polyfluorocycloalkyl, Cs-C, cycloalkenyl, -N(R), -OR, -COR, -NCOR, -COR, -CONCR) or (CH), O-(CH), CH. 1593. In the present invention, the term “heteroaryl” is used to include five and six membered unsaturated rings that may contain one or more oxygen, Sulfur, or nitrogen atoms. Examples of heteroaryl groups include, but are not limited to, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. 1594. In addition the term "heteroaryl' is used to include 1603 wherein each of Yi, Y, Y, and Y is inde fused bicyclic ring Systems that may contain one or more pendently -H, Straight chained or branched C-C, heteroatoms Such as oxygen, Sulfur and nitrogen. Examples alkyl, CF, F, Cl, Br, I, OR, of Such heteroaryl groups include, but are not limited to, -N(R), or -CONCR); indolizinyl, indolyl, isoindolyl, benzobfuranyl, benzob 1604 wherein each R is independently -H; thiophenyl, indazolyl, benzimidazolyl, purinyl, benzox straight chained or branched C-C, alkyl, -CF3, or azolyl, benzisoxazolyl, benzobthiazolyl, imidazo2,1-b phenyl; thiazolyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1.8- naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, 1605 wherein A is A", straight chained or branched phthalimidyl and 2,1,3-benzothiazolyl. C-C, alkyl, aryl, heteroaryl, aryl(C-C)alkyl or heteroaryl(C-C)alkyl, and 1595. The term "heteroaryl' also includes those chemical moieties recited above which may be substituted with one or 1606 wherein A' is more of the following: -F, -Cl, -Br, -, -NO,-CN, Straight chained or branched C-C, alkyl, Straight chained or branched C-C monofluoroalkyl, Straight chained or R1 branched C-C, polyfluoroalkyl, Straight chained or branched C-C, alkenyl, Straight chained or branched C-C, alkynyl, C-C, cycloalkyl, C-C, monofluorocycloalkyl, S-S. C-C, polyfluorocycloalkyl, Cs-C, cycloalkenyl, -N(R), --OR, -COR, -NCOR1, -COR, -CONCR) or 1607. In one embodiment, B is heteroaryl. (CH), O-(CH), CHs. 1608. In one embodiment, B is aryl. 1596) The term “heteroaryl” further includes the N-ox 1609. In one embodiment, B is phenyl and the phenyl is ides of those chemical moieties recited above which include optionally substituted with one or more of the following: at least one nitrogen atom. -F, -Cl, -Br, -CF, straight chained or branched C-C, 1597. In the present invention the term “aryl' is phenyl or alkyl, -N(R), -OR,-COR, -NCOR1, -COR, or naphthyl. The term “aryl' also includes phenyl and naphthyl -CON(R) US 2003/0078271 A1 Apr. 24, 2003 92

1610. In one embodiment, A is aryl. 1616) In one embodiment, the compound is: 1611. In one embodiment, A is heteroaryl. 1612. In one embodiment, the compound is selected from the group consisting of:

F F O X- S. O-C, 1 NO Ry 1617. In one embodiment, B is aryl. Cl 1618) In one embodiment, A is (CHR)-(CHR), Z. 1619. In one embodiment, the compound is: -O- C ; and C C N W O S N

...Or s \ 4 C N 1620. In one embodiment, the compound is a pure Z imine isomer. S 1621. In one embodiment, the compound is a pure E imine isomer. 1622. The invention provides a pharmaceutical compo 1613) In one embodiment, B is Q. Sition comprising a therapeutically effective amount of any 1614. In one embodiment, A is aryl. of the compounds described herein and a pharmaceutically 1615. In one embodiment, the compound has the struc acceptable carrier. ture: 1623 The invention provides a pharmaceutical compo Sition made by combining a therapeutically effective amount R22 O of any of the compounds described herein and a pharma (-, ceutically acceptable carrier. Nvvvy O 1624. The invention provides a process for making a Z pharmaceutical composition comprising combining a thera peutically effective amount of any of the compounds O N described herein and a pharmaceutically acceptable carrier. 1625. The invention provides a method of treating a Subject Suffering from depression which comprises admin istering to the Subject an amount of any of the compounds described herein effective to treat the Subject's depression. US 2003/0078271 A1 Apr. 24, 2003

1626 The invention provides a method of treating a 1633. The present invention further includes metabolites Subject Suffering from anxiety which comprises administer of the compounds of the present invention. Metabolites ing to the Subject an amount of any of the compounds include active Species produced upon introduction of com described herein effective to treat the subjects anxiety. pounds of this invention into the biological milieu. 1627 The invention provides a method of treating a 1634 Throughout the invention, the term “binding affin Subject Suffering from depression and anxiety which com ity’ describes the concentration of a compound required to prises administering to the Subject an amount of any of the occupy one-half of the binding Sites in a receptor population, compounds described herein effective to treat the Subject's as detectable by radioligand binding. Binding affinity con depression and anxiety. centration can be represented as K. inhibition constant, or KD, dissociation constant. 1628. The invention provides for each pure stereoisomer of any of the compounds described herein. Such Stereoiso 1635. The term “selectivity of binding affinity” refers to merS may include enantiomers, diastereomers, or E or Z the ability of a chemical compound to discriminate one alkene or imine isomers. The invention also provides for receptor from another. For example, a compound showing Stereoisomeric mixtures, including racemic mixtures, dias selectivity for receptor A versus receptor B will bind recep tereomeric mixtures, or E/Z isomeric mixtures. Stereoiso tor A at lower concentrations than those required to bind mers can be synthesized in pure form (N6gradi, M.; Stereo receptor B. selective Synthesis, (1987) VCH Editor Ebel, H. and 1636. Therefore, the statements of the form “binds to the Asymmetric Synthesis, Volumes 3-5, (1983) Academic GAL3 receptor with a binding affinity at least ten-fold higher Press, Editor Morrison, J.) or they can be resolved by a than a named receptor, indicates that the binding affinity at variety of methods Such as crystallization and chromato the GAL3 receptor is at least ten-fold greater than that for a graphic techniques (Jaques, J.; Collet, A.; Wilen, S.; Enan named receptor, and binding affinity measurements (i.e. K tiomer, Racemates, and Resolutions, 1981, John Wiley and or K) for the compound are at least ten-fold lower in Sons and Asymmetric Synthesis, Vol. 2, 1983, Academic numerical value. Press, Editor Morrison, J). 1637. The present invention provides a method of treat 1629. In addition the compounds of the present invention ing depression in a Subject which comprises administering to may be present as enantiomers, diasteriomers, isomers or the Subject a composition comprising a pharmaceutically two or more of the compounds may be present to form a acceptable carrier and a therapeutically effective amount of racemic or diastereomeric mixture. a GAL3 receptor antagonist, wherein: 1630. The compounds of the present invention are pref 1638 (a) the GAL3 receptor antagonist binds to the erably 80% pure, more preferably 90% pure, and most human GAL3 receptor with a binding affinity at least preferably 95% pure. ten-fold higher than the binding affinity with which 1631. Included in this invention are pharmaceutically it binds to the human GAL1 receptor; acceptable Salts and complexes of all of the compounds 1639 (b)(1) the GAL3 receptor antagonist does not described herein. The acids and bases from which these salts inhibit the activity of central monoamine oxidase A are prepared include but are not limited to the acids and greater than 50 percent, at a concentration of 10 uM; bases listed herein. The acids include, but are not limited to, and the following inorganic acids: hydrochloric acid, hydrobro mic acid, hydroiodic acid, Sulfuric acid and boric acid. The 1640 (2) the GAL3 receptor antagonist does not acids include, but are not limited to, the following organic inhibit the activity of central monoamine oxidase acids: acetic acid, malonic acid, Succinic acid, fumaric acid, B greater than 50 percent, at a concentration of 10 tartaric acid, maleic acid, citric acid, methaneSulfonic acid, tM; and benzoic acid, glycolic acid, lactic acid and mandelic acid. The bases include, but are not limited to ammonia, methy 1641 (c) the GAL3 receptor antagonist binds to the lamine, ethylamine, propylamine, dimethylamine, diethy human GAL3 receptor with a binding affinity at least lamine, trimethylamine, triethylamine, ethylenediamine, ten-fold higher than the binding affinity with which hydroxyethylamine, morpholine, piperazine and guanidine. it binds to each of the following transporters: Sero This invention further provides for the hydrates and poly tonin transporter, norepinephrine transporter, and morphs of all of the compounds described herein. dopamine transporter. 1632. The present invention includes within its scope 1642. The present invention provides a method of treat prodrugs of the compounds of the invention. In general, Such ing anxiety in a Subject which comprises administering to prodrugs will be functional derivatives of the compounds of the Subject a composition comprising a pharmaceutically the invention which are readily convertible in vivo into the acceptable carrier and a therapeutically effective amount of required compound. Thus, in the present invention, the term a GAL3 receptor antagonist, wherein: “administering” shall encompass the treatment of the Vari 1643 (a) the GAL3 receptor antagonist binds to the ous conditions described with the compound Specifically human GAL3 receptor with a binding affinity at least disclosed or with a compound which may not be specifically ten-fold higher than the binding affinity with which disclosed, but which converts to the Specified compound in it binds to the human GALL receptor; and Vivo after administration to the patient. Conventional pro cedures for the Selection and preparation of Suitable prodrug 1644 (b) the GAL3 receptor antagonist binds to the derivatives are described, for example, in Design of Pro human GAL3 receptor with a binding affinity at least drugs, ed. H. Bundgaard, Elsevier, 1985. ten-fold higher than the binding affinity with which US 2003/0078271 A1 Apr. 24, 2003

it binds to each of the following transporters: Sero 1996). Indeed, there is now evidence from studies with tonin transporter, norepinephrine transporter, and known pharmacological agents to Support the existence of dopamine transporter. inverse agonists for numerous receptors, including hista 1645. In some embodiments of this invention, the GAL3 mine, 5HT1A, 5HT, cannabinoid, dopamine, calcitonin receptor antagonist binds to the human GAL3 receptor with and human formyl peptide receptors, among others (de Ligt, a binding affinity at least 30-fold higher than the binding et al., 2000; Herrick-Davis, et al., 2000; Bakker, et al., 2000). affinity with which it binds to the human GALL receptor. In the case of the 5HT2 receptor, clinically effective atypi cal antipsychotics drugs. Such as Sertindole, clozapine, olan 1646. In further embodiments of the invention, the GAL3 Zapine, Ziprasidone, risperidone, Zotepine, tioSpirone, flu receptor antagonist binds to the human GAL3 receptor with perlapine and tenilapine displayed potent inverse activity a binding affinity at least 50-fold higher than the binding whereas typical antipsychotic drugs Such as chlorpromazine, affinity with which it binds to the human GAL1 receptor. thioridazine, Spiperone and thiothixene were classified as 1647. In other embodiments of the invention, the GAL3 neutral antagonists (Herrick-Davis et al., 2000). In the case receptor antagonist binds to the human GAL3 receptor with of the histamine H receptor, the therapeutically used anti a binding affinity at least 100-fold higher than the binding allergicScetirizine, loratadine and epinastine were found to affinity with which it binds to the human GALL receptor. be inverse agonists. These findings further extend the idea that many compounds previously thought of as neutral 1648. In still other embodiments of the invention, the GAL3 receptor antagonist binds to the human GAL3 recep antagonists will be reclassified as inverse agonists when tor with a binding affinity at least 200-fold higher than the tested in a constitutively active receptor System (de Ligt et binding affinity with which it binds to the human GAL1 al, 2000). receptor. 1652 For the purpose of the claimed invention, a GAL3 antagonist useful in the treatment of depression is one which 1649 For the purposes of this invention the term “phar a) selectively binds to the GAL3 receptor, and b) displays maceutically acceptable carrier' has been defined herein. antidepressant activity in the rat Forced Swim Test. Further 1650. The term “antagonist” refers to a compound which more, a GAL3 antagonist useful in the treatment of anxiety binds to, and decreases the activity of, a receptor in the is one which a) selectively binds to the GAL3 receptor, and presence of an agonist. In the case of a G-protein coupled b) displays anxiolytic activity in the rat Social Interaction. receptor, activation may be measured using an appropriate Also for the purpose in the present invention, a GAL3 Second messenger System which is coupled to the receptor in antagonist useful in the treatment of depression and anxiety, a cell or tissue in which the receptor is expressed. Some is one which a) selectively binds to the GAL3 receptor, b) Specific but by no means limiting examples of well-known displays antidepressant activity in the rat Forced Swim Test, Second messenger Systems are adenylate cyclase, intracel and c) displays anxiolytic activity in the rat Social Interac lular calcium mobilization, ion channel activation, guanylate tion Test. cyclase, inositol phospholipid hydrolysis, and MAP kinase activation. Conversely, the term "agonist” refers to a com 1653. In order to test compounds for selective binding to pound which binds to, and increases the activity of, a the human GAL3 receptor the cloned cDNAs encoding both receptor as compared with the activity of the receptor in the the human and rat GAL1 and GAL2 receptors have been absence of any agonist. Methods to perform Second mes used. The cloning and assay methods for the human and rat senger assays are described in PCT International Publication GAL1 receptors may be found in PCT International Publi No. 97/46250 and in PCT International Publication No. cation No. WO95/22608, the contents of which are hereby 98/15570, the contents of which are hereby incorporated by incorporated by reference. The cloning and assay methods reference. for the human and rat GAL2 receptors may be found in PCT International Publication No. WO 97/26853, the contents of 1651. In the case that a receptor has activity in the which are hereby incorporated by reference. absence of an agonist (constitutive receptor activity) the antagonist may act as an inverse agonist or an allosteric 1654. The present invention provides for a method of modulator, as opposed to a neutral antagonist, and SuppreSS determining the binding affinity of a GAL3 antagonist, receptor signaling independent of the agonist (Lutz and wherein the GAL3 antagonist is dissolved in a “suitable Kenakin, 1999). The categories of “antagonist compounds” solvent'. A “suitable solvent’ means one which permits the are therefore seen to include 1) neutral antagonists (which measurement of binding affinity of the GAL3 antagonist to block agonist actions but do not affect constitutive activity); the human GAL3 receptor at concentrations less than 1 uM, 2) inverse agonists (which block agonist actions as well as preferably less than 100 nM. Examples of solvents include, constitutive activity by Stabilizing an inactive receptor con but are not limited to, DMSO, ethanol, N,N-dimethylaceta formation); 3) and allosteric modulators (which block ago mide, or water. For indolones, the preferred solvent is 3% nist actions to a limited extent and which may also block DMSO (final concentration in the assay). For pyrimidines, constitutive activity through allosteric regulation). The prob the preferred solvent is 1% ethanol/0.09% polypuronic acid ability that an antagonist is neutral and therefore of “Zero F-127 (final concentration in the assay). For any other type efficacy’ is relatively low, given that this would require of compounds, the preferred solvent is the solvent which identical affinities for different tertiary conformations of the permits the measurement of binding affinity of a GAL3 receptor. Thus, Kenakin proposed in 1996 that, “with the antagonist at the lowest concentration. Once a Suitable development of Sensitive test Systems for the detection of Solvent is ascertained for the binding assay of the human inverse agonism will come a reclassification of many drugs. GAL3 receptor, the same Solvent is used in assays to It might be observed that numerous previously classified determine the binding affinity at the GALL receptor, the neutral antagonists may be inverse agonists' (Kenakin, Serotonin transporter, the norepinephrine transporter, and the