EP1363638A2 - Utilisation d'antagonistes du recepteur gal3 dans le traitement de la depression et/ou de l'anxiete et composes utiles dans de telles methodes - Google Patents

Utilisation d'antagonistes du recepteur gal3 dans le traitement de la depression et/ou de l'anxiete et composes utiles dans de telles methodes

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Publication number
EP1363638A2
EP1363638A2 EP02714918A EP02714918A EP1363638A2 EP 1363638 A2 EP1363638 A2 EP 1363638A2 EP 02714918 A EP02714918 A EP 02714918A EP 02714918 A EP02714918 A EP 02714918A EP 1363638 A2 EP1363638 A2 EP 1363638A2
Authority
EP
European Patent Office
Prior art keywords
branched
straight chained
alkyl
aryl
heteroaryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP02714918A
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German (de)
English (en)
Other versions
EP1363638A4 (fr
Inventor
Thomas P. Blackburn
Michael Konkel
Lakmal W. Boteju
Ian Jamie Talisman
John M. Wetzel
Mathivanan Packiarajan
Heidi Chen
Hermo Jimenez
Bharat Lagu
Kitae Lim
Stewart Noble
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
H Lundbeck AS
Original Assignee
Synaptic Pharmaceutical Corp
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Publication date
Application filed by Synaptic Pharmaceutical Corp filed Critical Synaptic Pharmaceutical Corp
Priority to EP09010003A priority Critical patent/EP2140864A3/fr
Priority to EP09010004A priority patent/EP2140862A3/fr
Priority claimed from PCT/US2002/004608 external-priority patent/WO2002060392A2/fr
Publication of EP1363638A2 publication Critical patent/EP1363638A2/fr
Publication of EP1363638A4 publication Critical patent/EP1363638A4/fr
Withdrawn legal-status Critical Current

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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Definitions

  • Depression is the most common of mental disorders and yet is often underdiagnosed and undertreated, inflicting substantial morbidity and psychosocial impairment on its sufferers. Depression is mainly characterized by sadness, flatness, loss of feeling, anhedonia (lack of pleasure) , tearfulness, agitation or retardation, thoughts of guilt, and worthlessness; in severe cases, suicide, hallucinations and delusions .
  • Depression can be mainly categorized into bipolar disorders, identifying wide swings of mood; major depressive illness, marked by severe depressive symptoms but without manic swings; and less defined milder forms of bipolar and major depression that fall short of the specific diagnostic criteria e.g. dysthymic disorder (formerly called depressive neurosis) .
  • the symptomatology and diagnostic criteria for depression are set out in the DS IV guidelines (American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders) .
  • DS IV guidelines American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders
  • depressive illness a markedly gloomy mood in which there is a loss of interest in life, and general feelings of hopelessness and worthlessness.
  • Depressive symptoms range in severity from mild mood swings to severe delusions about self-worth, accomplishments, and the future.
  • the "blackness" of the presentation in the depressed patient is most often accompanied by severe motor retardation with profound sleep and appetite disturbance and suicidal ideation. Furthermore, depressive illness can also present in a highly anxious or agitated state.
  • the degree to which the underlying brain mechanisms in anxiety and depression differ or overlap remains unknown. The fact, however, that to some extent the same neurotransmitter systems are involved in depression and anxiety does not mean that the mechanisms are identical. However, the majority of people in an episode of either depression or anxiety also meet criteria for at least one other psychiatric disorder. But by far the strongest comorbidities in both cases are between depression and anxiety disorders. Therefore, it is now becoming common clinical practice to treat both indications with antidepressants such as SSRIs .
  • the key clinical features of anxiety disorders relate to various combinations of psychological and physical manifestations of anxiety, not attributable to real danger and occurring either in attacks (panic disorder - PD) or as a persisting state (generalized anxiety disorder -GAD) . Other neurotic features may be present (obsessional or hysterical symptoms) but do not dominate the clinical picture.
  • TCAs tricylic antidepressants
  • SSRIs selective serotonin re-uptake inhibitors
  • MAOIs monoamine oxidase inhibitors
  • This theory postulates that a certain level of amines and/or receptor sensitivity to catecholamines functions to generate a normal mood.
  • a receptor insensitivity, a depletion of monoamines, or a decrease in their release, synthesis or storage have been postulated to lead to depression.
  • a variety of pharmacological agents have been employed to treat depression based on the catecholamine-indolamine hypothesis of depression.
  • Drugs used to treat depression include MAOIs, atypical antipsychotics, lithium, TCAs, and SSRIs.
  • off-label agents such as antiepileptics are used to treat depression in treatment-resistant patients.
  • Tricyclic antidepressants are about equal to SSRIs in effectiveness against depression thus providing supporting evidence for the catecholamine-indolamine hypothesis of depression.
  • SSRIs have largely displaced TCAs because of side effects associated with TCAs and the need to monitor EKG and plasma drug concentration.
  • Adverse effects on sexual function primarily anorgasmia and delayed ejaculation, have been consistently reported.
  • Other, common side-effects include sleep disorders, yawning, weight changes, suicidal ideation and extrapyramidal-like side-effects such as dystonic reactions.
  • OCD obsessive compulsive disorder
  • GAD generalized anxiety disorder
  • PD panic disorder
  • the rat Forced Swim Test is a behavioral test that is used to screen compounds for antidepressant efficacy (Porsolt et al . , 1977, 1978; Porsolt, 1981). This test is widely used as it is reliable across laboratories, relatively easy to perform and is sensitive to the effects of some of the major classes of antidepressant drugs, including TCAs and MAOIs, and various atypical antidepressants. Furthermore, this test is relatively selective for antidepressant drugs, as few psychoactive drugs produce similar behavioral actions in the FST.
  • animals are placed in a cylinder of water, from which there is no escape, for an extended period of time.
  • animals will display a range of behaviors such as immobility, climbing, swimming, and diving, with immobility being predominant after several minutes of immersion in the water. Consequently, many past studies have only measured or scored immobility after the administration of the test agent .
  • this method does not score any other active behaviors that may be produced by potential antidepressants. Thus, if a particular class of antidepressant were to have very little effect on immobility, yet produce characteristic behaviors during the FST, these behaviors would not be scored and the conclusion would be that the compound in question does not possess antidepressant action.
  • SIT Social Interaction Test
  • rats previously housed singly are placed in a familiar, dimly lit, test arena with weight- matched, novel partners.
  • the principal anxiogenic stimulus under these conditions is the partner novelty, which involves an unconditioned response to a potential threat.
  • the following behaviors are scored as active social interaction: grooming, sniffing, biting, boxing, wrestling, following, crawling over and crawling under.
  • the social interaction test can distinguish anxiolytics from antidepressants, antipsychotics, analeptics and sedative agents (File, 1985; Guy and Gardner, 1985) .
  • This test can detect anxiolytic agents such as the benzodiazepines (File and Hyde, 1978; File and Hyde, 1979; File, 1980), in addition to non-benzodiazepines, including paroxetine and other SSRIs (Lightowler, et al . , 1994).
  • the social interaction test can detect anxiogenic agents, including the inverse benzodiazepine receptor agonists (File, et al., 1982; File and Pellow, 1983; File and Pellow, 1984; File , 1985 ) .
  • the synthesis of novel pyrimidines which bind selectively to the cloned human GAL3 receptor, compared to other cloned human G- protein coupled receptors, as measured in in vi tro assays is disclosed.
  • the synthesis of indolones which bind selectively to the cloned human GAL3 receptor, compared to other cloned human G-protein coupled receptors, as measured in in vi tro assays is disclosed.
  • the in vi tro receptor assays described hereinafter were performed using various cultured cell lines, each transfected with and expressing only a single galanin-type receptor.
  • the present invention provides a method of treating a subject suffering from depression which comprises administering to the subject an amount of compound effective to treat the subject's depression wherein the compound has the structure:
  • W is H, -F, -Cl, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy;
  • X is; NR ⁇ R ⁇ 2 ;
  • Rn is H, straight chained or branched C ⁇ -C 7 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , aryl, or aryl (C ⁇ -C 6 ) alkyl; wherein R 12 is straight chained or branched C ⁇ -C 7 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , or -(CH 2 ) ra -Z;
  • R 13 is a bicyclic alkyl ring system, adamantyl, noradamantyl , C 3 -C ⁇ 0 cycloalkyl, heteroaryl, aryl, aryl(C ⁇ - C 6 ) alkyl, Q_ ⁇ or Q 2 ;
  • aryl may be substituted with one or more C ⁇ -C 10 straight chained or branched alkyl, aryl, heteroaryl, or N(R ⁇ g)-Z;
  • each J is independently O, S, C(R 22 ) 2 or NR 4 wherein R 4 is H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl or aryl;
  • Y is NR ⁇ 4 R ⁇ 5 ;
  • R i4 is H, straight chained or branched C ⁇ -C 3 alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3 , C 3 -C 6 cycloalkyl, or (C (R i9 ) 2 ) m -Z;
  • R 15 is straight chained or branched C 3 -C 6 alkyl
  • R ⁇ S is straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ! -C 7 monofluoroalkyl, straight chained or branched C ⁇ -C polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R i7 is independently H; -0R 2 ⁇ , -OCOR 2 ⁇ , -COR 2 ⁇ , -NCOR21, -N(R 2 ⁇ ) 2 , -CON(R 2 ⁇ ) 2 , -COOR21, straight chained or branched C x -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl , straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 3 -C 7 cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) n -0- (CH 2 ) m -CH 3 ,-
  • R ⁇ 8 is straight chained or branched C ⁇ -C 3 alkyl, - (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R ⁇ 9 is independently H, or straight chained or branched C ⁇ -C 6 alkyl
  • each R 2 o is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl or C 5 -C 7 cycloalkenyl; -F, -CI, -Br, or -I; -N0 2 ; -N 3 ; -CN; -OR 2 ⁇ , -OCOR 21 , -COR 21 , -NCOR 21 , -N(R 2 ⁇ ) a , - CON(R 2 ⁇ ) 2 , or -COOR21; aryl or heteroaryl; or two R 20 groups present on adjacent carbon atoms can join together to form a methylenedioxy group;
  • each R 2 ⁇ is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -
  • each R 22 is independently H, F, CI or C ! -C 4 straight chained or branched alkyl
  • each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive
  • p is an integer from 0 to 2 inclusive
  • q is an integer from 2 to 4 inclusive
  • t is 1 or 2;
  • U is 0, -NR ⁇ 6 , S, C(R 17 ) 2 , or -NS0 2 R 5 ;
  • Z is C 3 -C ⁇ 0 cycloalkyl, C 4 -C 7 cyclic ether, C-C 7 cyclic thioether, aryl, or heteroaryl; or
  • the present invention provides a method of treating a subject suffering from depression which comprises administering to the subject an amount of compound effective to treat the subject's depression wherein the compound has the structure:
  • W is H, -F, -CI, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy;
  • X is NRuR ⁇ 2 ;
  • R u is H, straight chained or branched C x -C 7 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , aryl or aryl (C-.-C 6 ) alkyl;
  • R ⁇ 2 is straight chained or branched C ⁇ -C 7 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , or -(CH 2 ) m -Z;
  • R i3 is a bicyclic alkyl ring system, aryl 'or aryl (Ci-Cs) alkyl;
  • Y is NR ⁇ 4 R 15 ;
  • R i4 is H, straight chained or branched C ⁇ -C 6 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , C 3 -C 6 cycloalkyl , or ( C (R 19 ) 2 ) m -Z ;
  • R ⁇ 5 is straight chained or branched C 3 -C 5 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , C 3 -C e cycloalkyl, or (C (R 19 ) 2 ) ra -Z;
  • U is 0, -NR ⁇ 6/ S, C(R ⁇ 7 ) 2 , or -NS0 2 R ⁇ S ;
  • Z is C 3 -C 10 cycloalkyl, aryl, or heteroaryl
  • R 1S is straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C ⁇ -C polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched 2 - ⁇ alkynyl, C 3 -C ⁇ cycloalkenyl, - (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ; wherein each R x7 is independently H; -OR 2 ⁇ , -OCOR 2 ⁇ , -COR 2 ⁇ , -NCOR 2 ⁇ , -N(R 2 ⁇ ) 2 , -CON(R 21 ) 2 , -COOR 2 ⁇ , straight chained or branched Q L -C 7 alkyl, straight chained or branched C
  • R ⁇ 8 is straight chained or branched C ⁇ -C 6 alkyl, - (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R ⁇ 9 is independently H, or straight chained or branched C ⁇ -C e alkyl
  • each R 20 is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl or C 5 -C 7 cycloalkenyl; -F, -CI, -Br, or -I; -N0 2 ; -N 3 ; -CN; -OR 2 ⁇ , -OCOR 2 ⁇ , -COR 21 , -NCOR 21 , -N (R 2 ⁇ ) 2 , - CON(R 2 ⁇ ) 2 , or -COOR 2 ⁇ ; aryl or heteroaryl; or two R 2 o groups present on adjacent carbon atoms can join together to form a methylenedioxy group;
  • each R 2 ⁇ is independently -H; straight chained or branched C-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, aryl or aryl (Ci- C s ) alkyl;
  • each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive; wherein p is an integer from 0 to 2 inclusive;
  • q is an integer from 2 to 4 inclusive
  • t is 1 or 2;
  • the present invention provides a method of treating a subject suffering from depression which comprises administering to the subject an amount of compound effective to treat the subject's depression wherein the compound has the structure:
  • W is H, -F, -CI, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy;
  • R i3 is an aryl, adamantyl, noradamantyl , C 3 -C ⁇ 0 cycloalkyl, heteroaryl, Q or Q 2 ;
  • aryl may be substituted with one or more C ⁇ -C ⁇ 0 straight chained or branched alkyl, aryl, heteroaryl, or N(R i9 ) -Z;
  • each J is independently O, S, C(R 22 ) 2 or NR 4 ; wherein R 4 is -H; straight chained or branched C ⁇ -C ⁇ alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl or aryl;
  • Y is NR ⁇ 4 R ⁇ S ;
  • R i4 is H, straight chained or branched C ⁇ -C 6 alkyl
  • R ⁇ S is straight chained or branched C 3 -C 6 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , C 3 -C 6 cycloalkyl, or (C (R 19 ) 2 ) m -Z;
  • U is O, -NR 1S , S, C(R 17 ) 2 , or -NS0 2 R ⁇ e ;
  • Z is C 3 -C ⁇ 0 cycloalkyl, aryl, or heteroaryl; wherein R ⁇ 6 is straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl , straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, - (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R i7 is independently H; -OR 2i , -OC0R 2i , -COR 21 , -NCOR21, -N(R 2 ⁇ ) 2 / -C0N(R 21 ) 2 , -COOR21, straight chained or branched C x -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) n -0- (CH 2 ) m -CH 3 ;
  • R ⁇ 8 is straight chained or branched C ⁇ -C 6 alkyl, - (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R 19 is independently H, or straight chained or branched C ⁇ -C 6 alkyl
  • each R 2 o is independently -H; straight chained or branched C x -C alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl or C 5 -C 7 cycloalkenyl; -F, -CI, -Br, or -I; -N0 2 ; -N 3 ; -CN; -OR 2i , -OCOR 2 ⁇ , -COR 21 , -NCOR 2i , -N(R 2 ⁇ ) 2 , - CON(R 2 ⁇ ) 2 , or -COOR21; aryl or heteroaryl; or two R 20 groups present on adjacent carbon atoms can join together to form a methylenedioxy group;
  • each R 21 is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, aryl or aryl(C ⁇ - C 6 ) alkyl;
  • each R 22 is independently H, F, CI or C ⁇ -C 4 straight chained or branched alkyl
  • each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive
  • p is an integer from 0 to 2 inclusive
  • q is an integer from 2 to 4 inclusive
  • t is 1 or 2;
  • the present invention provides a method of treating a subject suffering from depression which comprises administering to the subject an amount of compound effective to treat the subject's depression wherein the compound has the structure:
  • W is H, -F, -CI, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy;
  • R 13 is a bicyclic alkyl ring system, aryl or aryl (Ci-Cs) alkyl;
  • Y is NR 14 R ⁇ 5 ;
  • R 14 is H, straight chained or branched C ⁇ -C 6 alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3 , C 3 -C 6 cycloalkyl, or (C (R 19 ) 2 ) m -Z;
  • R ⁇ 5 is (C (R 19 ) 2 ) m -N(R ⁇ 6 ) 2 ;
  • Z is C 3 -C ⁇ 0 cycloalkyl, aryl, or heteroaryl
  • R 1S is straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R 1 is independently H; -0R 2i , -OC0R 2 ⁇ , -COR 2 ⁇ , -NCOR 21 , -N(R 2 ⁇ ) 2 , -CON(R 2 ⁇ ) 2 , -COOR21, straight chained or branched C 1 -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) n -0- (CH 2 ) m -CH 3 ;
  • each R 19 is independently H, or straight chained or branched C ⁇ -C 6 alkyl
  • each R 21 is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, aryl or aryl (C ⁇ C 6 ) alkyl;
  • each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive
  • q is an integer from 2 to 4 inclusive;
  • the present invention also provides a method of treating a subject suffering from anxiety which comprises administering to the subject an amount of compound effective to treat the subject's anxiety wherein the compound has the structure:
  • W is H, -F, -CI, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy;
  • X is; NRnR ⁇ 2 ;
  • R n is H, straight chained or branched C ⁇ -C 7 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , aryl, or aryl (C ⁇ -C 3 ) alkyl;
  • R i2 is straight chained or branched C ⁇ -C 7 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , or -(CH 2 ) m -Z;
  • R i3 is a bicyclic alkyl ring system, adamantyl, noradamantyl , C 3 -C ⁇ 0 cycloalkyl, heteroaryl, aryl, aryl (C x - C 6 ) alkyl , & or Q 2 ;
  • aryl may be substituted with one or more C ⁇ -C ⁇ 0 straight chained or branched alkyl, aryl, heteroaryl, or N(R 19 )-Z;
  • each J is independently 0, S, C(R 22 ) 2 or NR 4 ;
  • R is H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl or aryl;
  • R 14 is H, straight chained or branched C x -C 6 alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3 , C 3 -C 6 cycloalkyl, or (C (R x9 ) 2 ) m -Z;
  • R iS is straight chained or branched C 3 -C 3 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , C 3 -C 6 cycloalkyl, (C (R 19 ) 2 ) m N (R 16 ) 2 or
  • R ⁇ S is straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C 7 monof luoroalkyl, straight chained or branched C ⁇ -C polyfluoroalkyl, straight chained or branched C 2 -C ⁇ alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, - (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R 17 is independently H; -OR 2 ⁇ , -OCOR 2 ⁇ , -COR 2 ⁇ , -NCOR 21 , -N(R 2i ) 2 , -CON(R 21 ) 2 , -COOR21, straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C 1 -C 7 monofluoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) n -0- (CH 2 ) m -CH 3 ;
  • R ⁇ 8 is straight chained or branched C ⁇ -C 6 alkyl, - (CH 2 ) ra -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R i9 is independently H, or straight chained or branched C ⁇ -C 6 alkyl
  • each R 2 o is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C alkenyl or alkynyl; C 3 - C 7 cycloalkyl or C 5 -C 7 cycloalkenyl; -F, -CI, -Br, or -I; -N0 2 ; -N 3 ; -CN; -OR 2 ⁇ , -OCOR 2 i, -C0R 21 , -NCOR 21 , -N(R 21 ) 2 , - CON(R 2 ⁇ ) 2 , or -COOR21; aryl or heteroaryl; or two R 20 groups present on adjacent carbon atoms can join together to form a methylenedioxy group;
  • each R 21 is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, aryl, or aryl (Cx- C 6 ) alkyl;
  • each R 22 is independently H, F, CI or C ⁇ -C 4 straight chained or branched alkyl
  • each m is an integer from 0 to 4 inclusive; wherein each n is an integer from 1 to 4 inclusive;
  • p is an integer from 0 to 2 inclusive
  • q is an integer from 2 to 4 inclusive
  • t is 1 or 2;
  • U is 0, -NR ⁇ 6 , S, C(R 17 ) 2 , or -NS0 2 R ⁇ e ;
  • Z is C 3 -C ⁇ 0 cycloalkyl, C 4 -C 7 cyclic ether, C 4 -C 7 cyclic thioether, aryl, or heteroaryl; or
  • the invention provides a method of treating a subject suffering from anxiety which comprises administering to the subject an amount of compound effective to treat the subject's anxiety wherein the compound has the structure:
  • W is H, -F, -Cl, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy; wherein X is NRnR ⁇ 2 ;
  • Ru is H, straight chained or branched C x -C 7 alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3 , aryl or aryl (C ⁇ -C 6 ) alkyl;
  • R 12 is straight chained or branched C ⁇ -C 7 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , or -(CH 2 ) m -Z;
  • R 13 is a bicyclic alkyl ring system, aryl or aryl (Ci-Cg) alkyl;
  • Y is NR ⁇ 4 R ⁇ 5 ;
  • R i4 is H, straight chained or branched C ⁇ -C 6 alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3 , C 3 -C 6 cycloalkyl, or (C(R ⁇ 9 ) 2 ) m -Z;
  • R 15 is straight chained or branched C 3 -C 6 alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3 , C 3 -C 6 cycloalkyl, or (C (R 19 ) 2 ) m -Z;
  • U is 0, -NR i6 , S, C(R ⁇ 7 ) 2 , or -NS0 2 R ⁇ g;
  • Z is C 3 -C ⁇ 0 cycloalkyl, aryl, or heteroaryl
  • R 16 is straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ; wherein each R 17 is independently H; -OR 21 , -OCOR 1 , -COR 21 , -NCOR 2 ⁇ , -N(R 2 ⁇ ) 2 / -CON(R 2 ⁇ ) 2 , -COOR 2 ⁇ , straight chained or branched C 1 -C 7 alkyl, straight chained or branched C x -C 7 mono
  • polyfluoroalkyl straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) n -0- (CH 2 ) m -CH 3 ;
  • R ⁇ 8 is straight chained or branched C ⁇ -C 6 alkyl, - (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) ra -CH 3 ;
  • each R i9 is independently H, or straight chained or branched C ⁇ -C 3 alkyl
  • each R 0 is independently -H; straight chained or branched C ⁇ C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl or C 5 -C 7 cycloalkenyl; -F, -CI, -Br, or -I; -N0 2 ; -N 3 ; -CN; -OR 2 ⁇ , -OCOR 21 , -C0R 21 , -NCOR2 1 , -N(R 21 ) 2 , - CON(R 2 ⁇ ) 2 , or -COOR21; aryl or heteroaryl; or two R 20 groups present on adjacent carbon atoms can join together to form a methylenedioxy group;
  • each R 2i is independently -H; straight chained or branched C1-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, aryl or aryl (Ci- C 6 ) alkyl;
  • each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive; wherein p is an integer from 0 to 2 inclusive;
  • q is an integer from 2 to 4 inclusive
  • t is 1 or 2;
  • the invention provides a method of treating a subject suffering from anxiety which comprises administering to the subject an amount of compound effective to treat the subject's anxiety wherein the compound has the structure:
  • W is H, -F, -CI, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy;
  • R ⁇ 3 is an aryl, adamantyl, noradamantyl, C 3 -C ⁇ 0 cycloalkyl, heteroaryl, Qi or Q 2 ;
  • aryl may be substituted with one or more C ⁇ -C ⁇ o straight chained or branched alkyl, aryl, heteroaryl, or N(R ⁇ 9 ) -Z;
  • each J is independently 0, S, C(R 22 ) 2 or NR 4 ;
  • R 4 is -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl or aryl; wherein Y is NR ⁇ 4 R ⁇ 5 ;
  • R 14 is H, straight chained or branched £ ⁇ -ds alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3 , C 3 -C 6 cycloalkyl, or (C (R 19 ) 2 ) m -Z;
  • R 15 is straight chained or branched C 3 -C 6 alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3 , C 3 -C 6 cycloalkyl, or (C (R 19 ) 2 ) m -Z;
  • U is O, -NR ⁇ 6 , S, C(R ⁇ ? ) 2 , or -NS0 2 R ⁇ 5 ;
  • Z is C 3 -C ⁇ 0 cycloalkyl, aryl, or heteroaryl
  • R i5 is straight chained or branched C-C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C1-C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, - (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R i7 is independently H; -OR ⁇ , -OCOR 2 ⁇ , -COR 2 ⁇ , -NCOR 2 ⁇ , -N(R 2i ) 2 , -CON(R 2 ⁇ ) 2 , -COOR 2i , straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) n -0- (CH 2 ) m -CH 3 ;
  • R ⁇ 8 is straight chained or branched C ⁇ -C 6 alkyl, - (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R i9 is independently H, or straight chained or branched C ⁇ -C 6 alkyl
  • each R 20 is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C-C alkenyl or alkynyl; C 3 - C 7 cycloalkyl or C 5 -C 7 cycloalkenyl; -F, -CI, -Br, or -I; -N0 2 ; -N 3 ; -CN; -OR 21 , -OCOR 2 ⁇ , -COR 21f -NCOR 2 ⁇ , -N (R 21 ) 2 , - C0N(R 2 ⁇ ) 2 , or -COOR 21 ; aryl or heteroaryl; or two R 20 groups present on adjacent carbon atoms can join together to form a methylenedioxy group;
  • each R 2 ⁇ is independently -H; straight chained or branched C1-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, aryl or aryl(C ⁇ - C 6 ) alkyl; wherein each R 22 is independently H, F, Cl or C ⁇ -C 4 straight chained or branched alkyl;
  • each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive
  • p is an integer from 0 to 2 inclusive
  • q is an integer from 2 to 4 inclusive
  • t is 1 or 2;
  • the invention provides a method of treating a subject suffering from anxiety which comprises administering to the subject an amount of compound effective to treat the subject's anxiety wherein the compound has the structure:
  • W is H, -F, -Cl, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy;
  • R i3 is a bicyclic alkyl ring system, aryl or aryl (Ci-Cg) alkyl ;
  • Y is NR ⁇ 4 R ⁇ 5 ;
  • R i4 is H, straight chained or branched C ⁇ -C 6 alkyl , (CH 2 ) q -0- (CH 2 ) m -CH 3 , C 3 -C 6 cycloalkyl , or (C (R 19 ) 2 ) m -Z ;
  • R ⁇ 5 is (C (R X9 ) 2 ) m -N (R 16 ) 2 ;
  • Z is C 3 -C ⁇ 0 cycloalkyl, aryl, or heteroaryl
  • R i6 is straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C 1 -C7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R 17 is independently H; -OR 2 ⁇ , -OCOR 2 ⁇ , -COR 2 ⁇ , -NCOR2 1 , -N(R 2i ) 2 , -CON(R 2 ⁇ ) 2 , -COOR 2 , straight chained or branched C1-C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C 1 -C7 polyfluoroalkyl, straight chained or branched C 2 -C alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 3 -C 7 cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) n -0- (CH 2 ) m -CH 3 ; wherein each R 19 is independently H, or straight chained or branched C -C 6 alkyl;
  • each R 2i is independently -H; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C cycloalkyl, C 3 -C 7 cycloalkenyl, aryl or aryl(C ⁇ - C e ) alkyl;
  • each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive
  • q is an integer from 2 to 4 inclusive;
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the structure:
  • W is H, -F, -Cl , -Br, -I , CN, methyl , ethyl , propyl , methoxy or ethoxy; wherein X is ; NR ⁇ R ⁇ 2 ;
  • R u is H, straight chained or branched C 1 -C7 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , aryl, or aryl (C ⁇ -C 3 ) alkyl;
  • R 12 is straight chained or branched C ⁇ -C 7 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , or -(CH 2 ) m -Z;
  • R 13 is a bicyclic alkyl ring system, adamantyl, noradamantyl, C 3 -C ⁇ 0 cycloalkyl, heteroaryl, aryl, aryl(C ⁇ - C 6 ) alkyl, & or Q 2 ;
  • aryl may be substituted with one or more Ci-Cio straight chained or branched alkyl, aryl, heteroaryl, ⁇ or N(R ⁇ 9 )-Z;
  • each J is independently O, S, C(R 22 ) 2 or NR 4 ;
  • R 4 is H; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl or aryl;
  • R i4 is H, straight chained or branched C ! -C 6 alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3 , C 3 -C 6 cycloalkyl, or (C (R 19 ) 2 ) m -Z;
  • R ⁇ 5 is straight chained or branched C 3 -C 3 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , C 3 -C 6 cycloalkyl, (C(R 19 ) 2 ) m N(R ⁇ 6 ) 2 or
  • R i6 is straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R i7 is independently H; -OR 2 ⁇ , -0C0R 2 ⁇ , -COR 2 ⁇ , -NCOR 21 , -N(R 2 ⁇ ) 2 , -CON(R 2 ⁇ ) , -COOR 2 ⁇ , straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 3 -C 7 cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) n -0- (CH 2 ) m -CH 3 ;
  • R ⁇ 8 is straight chained or branched C ⁇ -C 6 alkyl, - (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R 19 is independently H, or straight chained or branched Ci-Cg alkyl
  • each R 20 is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl or C 5 -C 7 cycloalkenyl; -F, -Cl, -Br, or -I; -N0 2 ; -N 3 ; -CN; -OR 21 , -OCOR 21/ -COR 21 , -NCOR 2 ⁇ , -N(R 2i ) 2 , - CON(R 2 ⁇ ) 2 , or -COOR2 1 ; aryl or heteroaryl; or two R 20 groups present on adjacent carbon atoms can join together to form a methylenedioxy group;
  • each R 21 is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, aryl, or aryl (Ci- C 6 ) alkyl;
  • each R 22 is independently H, F, Cl or C ⁇ -C 4 straight chained or branched alkyl
  • each m is an integer from 0 to 4 inclusive; wherein each n is an integer from 1 to 4 inclusive;
  • p is an integer from 0 to 2 inclusive
  • q is an integer from 2 to 4 inclusive
  • t is 1 or 2 ;
  • U is 0, -NR ⁇ 6 S, C(R 17 ) 2 , or -NS0 2 R ⁇ 6 ;
  • Z is C 3 -C ⁇ 0 cycloalkyl, C ⁇ -C-, cyclic ether, C 4 -C 7 cyclic thioether, aryl, or heteroaryl; or
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the structure:
  • W is H, -F, -Cl, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy; wherein X is NRnR 2 ;
  • Rn is H, straight chained or branched C ⁇ -C 7 alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3 , aryl or aryl (C ⁇ -C 6 ) alkyl;
  • R 12 is straight chained or branched C ⁇ -C 7 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , or - ⁇ CH 2 ) m -Z;
  • R X3 is a bicyclic alkyl ring system, aryl or aryl (C ⁇ -C 6 ) alkyl ;
  • Y is NR 4 R 5 ;
  • R i is H, straight chained or branched C ⁇ -C 6 alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3 , C 3 -C 6 cycloalkyl, or (C (R i9 ) 2 ) m -Z;
  • R 15 is straight chained or branched C 3 -C 3 alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3 , C 3 -C 3 cycloalkyl, or (C(R 19 ) 2 ) m -Z;
  • U is O, -NR ⁇ 6 , S, C(R ⁇ 7 ) 2 , or -NS0 2 R ⁇ 6 ;
  • Z is C 3 -C ⁇ 0 cycloalkyl, aryl, or heteroaryl
  • Rig is straight chained or branched C ⁇ -C alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, - (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ; wherein each R i7 is independently H; -OR 2 ⁇ , -OCOR21, -COR 2 ⁇ , -NCOR 21 , -N(R 2 ⁇ ) 2 , -CON(R 2 ⁇ ) 2/ -COOR 2 ⁇ , straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C monofluor
  • R 18 is straight chained or branched C ⁇ -C 6 alkyl, - (CH 2 ) ra -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R i9 is independently H, or straight chained or branched C ⁇ -C 3 alkyl
  • each R 2 o is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl or C 5 -C 7 cycloalkenyl; -F, -Cl, -Br, or -I; -N0 2 ; -N 3 ; -CN; -OR 21 , -OCOR 2 ⁇ , -COR 21 , -NCOR 21 , -N(R 2 ⁇ ) 2 , - CON(R 2 ⁇ ) 2 , or -COOR21; aryl or heteroaryl; or two R 20 groups present on adjacent carbon atoms can join together to form a methylenedioxy group;
  • each R 2i is independently -H; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, aryl or aryl (Ci- C e ) alkyl;
  • each m is an integer from 0 to 4 inclusive; wherein each n is an integer from 1 to 4 inclusive;
  • p is an integer from 0 to 2 inclusive
  • q is an integer from 2 to 4 inclusive
  • t is 1 or 2;
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the structure :
  • W is H, -F, -Cl, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy;
  • R ⁇ 3 is an aryl, adamantyl, noradamantyl, C 3 -C ⁇ 0 cycloalkyl, heteroaryl, Q x or Q 2 ;
  • aryl may be substituted with one or more C ⁇ -C 10 straight chained or branched alkyl, aryl, heteroaryl, or N(R ⁇ 9 )-Z;
  • each J is independently 0, S, C(R 22 ) 2 or NR 4 ; wherein R 4 is -H; straight chained or branched C ⁇ -C 7 alkyl, monof luoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl or aryl;
  • Y is NR ⁇ 4 R ⁇ 5 ;
  • R i4 is H, straight chained or branched C ⁇ -C 6 alkyl
  • R ⁇ 5 is straight chained or branched C 3 -C e alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , C 3 -C e cycloalkyl, or (C (R 19 ) 2 ) m -Z;
  • U is 0, -NR ⁇ S , S, C(R 17 ) 2 , or -NS0 2 R ⁇ 6 ;
  • Z is C 3 -C ⁇ 0 cycloalkyl, aryl, or heteroaryl; wherein R 16 is straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C 1 -C7 monofluoroalkyl, straight chained or branched C 1 -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C-C alkynyl, C 5 -C 7 cycloalkenyl, (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R ⁇ 7 is independently H; -OR 2i , -OCOR 2 ⁇ , -COR 2 ⁇ , -NCOR21, -N(R 2 ⁇ ) 2 , -CON(R 2 ⁇ ) 2 , -COOR21, straight chained or branched C 1 -C 7 alkyl, straight chained or branched C 1 -C 7 monofluoroalkyl, straight chained or branched C 1 -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) n -0- (CH 2 ) m -CH 3 ;
  • R 18 is straight chained or branched C ⁇ -C 6 alkyl, - (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R i9 is independently H, or straight chained or branched C ⁇ -C 6 alkyl
  • each R 20 is independently -H; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl or C 5 -C 7 cycloalkenyl; -F, -Cl, -Br, or -I; -N0 2 ; -N 3 ; -CN; -OR 21 , -OCOR 21 , -COR 2 ⁇ , -NCOR 2 ⁇ , -N(R 2 ⁇ ) 2 , - CON(R 2i ) 2 , or -COOR 21 ; aryl or heteroaryl; or two R 20 groups present on adjacent carbon atoms can join together to form a methylenedioxy group;
  • each R 2i is independently -H; straight chained or branched Q L -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, aryl or aryl (Ci- C 6 ) alkyl;
  • each R 2 is independently H, F, Cl or C ⁇ -C 4 straight chained or branched alkyl ,-
  • each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive
  • p is an integer from 0 to 2 inclusive
  • q is an integer from 2 to 4 inclusive
  • t is 1 or 2;
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the structure:
  • W is H, -F, -Cl, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy;
  • R ⁇ 3 is a bicyclic alkyl ring system, aryl or aryl (Ci-Cg) alkyl;
  • Y is NR 14 R 15 ;
  • R x4 is H, straight chained or branched C ⁇ -C 6 alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3 , C 3 -C 6 cycloalkyl, or (C (R 19 ) 2 ) m -Z;
  • R 15 is (C (R i9 ) 2 ) m -N(R ⁇ ) 2 ;
  • Z is C 3 -C ⁇ 0 cycloalkyl, aryl, or heteroaryl
  • R i6 is straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C ⁇ -C polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, ( CH 2 ) m - Z , or (CH 2 ) q -0- ( CH 2 ) m - CH 3 ;
  • each R 17 is independently H; -OR 2x , -OCOR 2 ⁇ , -C0R 2 ⁇ , -NCOR 21 , -N(R 2i ) 2 , -CON(R 2 ⁇ ) 2 , -COOR21, straight chained or branched C 1 -C 7 alkyl, straight chained or branched C 1 -C 7 monofluoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) n -0- (CH 2 ) m -CH 3 ;
  • each R i9 is independently H, or straight chained or branched C ⁇ -C 6 alkyl
  • each R 2 ⁇ is independently -H; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, aryl or aryl (C ⁇ Cg) alkyl;
  • each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive
  • q is an integer from 2 to 4 inclusive;
  • the invention provides a compound having the structure:
  • W is H, -F, -Cl, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy;
  • R Xi is H, straight chained or branched C ⁇ -C 7 alkyl, (CH 2 ) q -0- (CH 2 ) ra -CH 3 , aryl, or aryl (Ci-Cg) alkyl;
  • R i is straight chained or branched C ⁇ -C 7 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , or -(CH 2 ) m -Z;
  • R i3 is a bicyclic alkyl ring system, adamantyl, noradamantyl, C 3 -C ⁇ 0 cycloalkyl, heteroaryl, aryl, aryl(C ⁇ - Cg) alkyl, Q x or Q 2 ;
  • aryl may be substituted with one or more C ⁇ -C ⁇ 0 straight chained or branched alkyl, aryl, heteroaryl, or N(R 19 )-Z;
  • each J is independently 0, S, C(R 22 ) 2 or NR 4 ;
  • R 4 is H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl or aryl;
  • Y is NR ⁇ 4 R ⁇ 5 ;
  • R 14 is H, straight chained or branched C ⁇ -C 5 alkyl, (CH 2 ) q -0- (CH 2 ) ra -CH 3 , C 3 -C 6 cycloalkyl, or (C(R 19 ) 2 ) m -Z;
  • R 15 is straight chained or branched C 3 -C 6 alkyl, (CH 2 )q-0-(CH 2 ) m -CH 3 , C 3 -C 3 cycloalkyl, (C (R X9 ) 2 ) m N(R 16 ) 2 or
  • R i6 is straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C 7 monof luoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, - (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R 17 is independently H; -OR 2 ⁇ , -OCOR 2 ⁇ , -COR 2 ⁇ , -NCOR21, -N(R 2X ) 2 , -CON(R 2 ⁇ ) 2 , -COOR21, straight chained or branched C 1 -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) n -0- (CH 2 ) m -CH 3 ;
  • R ⁇ 8 is straight chained or branched C ⁇ -C 6 alkyl, - (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R i9 is independently H, or straight chained or branched C ⁇ -C 3 alkyl
  • each R 20 is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl or C 5 -C 7 cycloalkenyl; -F, -Cl, -Br, or -I; -N0 2 ; -N 3 ; -CN; -0R 2 ⁇ , -OCOR 2 ⁇ , -COR 21 , -NCOR 2 ⁇ , -N(R 2 ⁇ ) 2 , - CON(R 21 ) 2 , or -COOR 21 ; aryl or heteroaryl; or two R 20 groups present on adjacent carbon atoms can join together to form a methylenedioxy group;
  • each R 2i is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, aryl, or aryl (C x - C 6 ) alkyl;
  • each R 22 is independently H, F, Cl or C ⁇ -C 4 straight chained or branched alkyl
  • each m is an integer from 0 to 4 inclusive; wherein each n is an integer from 1 to 4 inclusive;
  • p is an integer from 0 to 2 inclusive
  • q is an integer from 2 to 4 inclusive
  • t is 1 or 2 ;
  • U is 0, -NR 16 , S, C(R ⁇ 7 ) 2 , or -NS0 2 R ⁇ 6 ;
  • Z is C 3 -C ⁇ 0 cycloalkyl, C 4 -C 7 cyclic ether, C-C 7 cyclic thioether, aryl, or heteroaryl; or
  • the invention provides a compound having the structure:
  • W is H, -F, -Cl, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy;
  • Rn is H, straight chained or branched C ⁇ -C 7 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , aryl or aryl (C ⁇ -C 6 ) alkyl;
  • R ⁇ 2 is straight chained or branched C-C 7 alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3 , or -(CH 2 ) m -Z;
  • R ⁇ 3 is a bicyclic alkyl ring system, aryl or aryl (C ⁇ -C 6 ) alkyl;
  • Y is NR ⁇ 4 R ⁇ 5 ;
  • R ⁇ 4 is H, straight chained or branched C ⁇ -C 6 alkyl , (CH 2 ) q -0- (CH 2 ) m -CH 3 , C 3 -C 6 cycloalkyl , or (C (R i9 ) 2 ) m -Z ;
  • R ⁇ 5 is straight chained or branched C 3 -C 3 alkyl , (CH 2 ) q -0-(CH 2 ) m -CH 3 , C 3 -C 6 cycloalkyl, or (C (R i9 ) 2 ) m -Z;
  • U is O, -NR ⁇ 6/ S, C(R ⁇ 7 ) 2 , or -NS0 2 R ⁇ S ;
  • Z is C 3 -C ⁇ 0 cycloalkyl, aryl, or heteroaryl
  • Ri is straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, - (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R 17 is independently H; -OR 2 ⁇ , -OCOR 2 ⁇ , -COR 2 ⁇ , -NCOR 2 ⁇ , -N(R 2 ⁇ ) 2 , -C0N(R 2 ⁇ ) 2 , -COOR 2i , straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) n -0- (CH 2 ) m -CH 3 ;
  • R 18 is straight chained or branched Cx-C alkyl, - (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R 19 is independently H, or straight chained or branched C ⁇ -C 5 alkyl
  • each R 20 is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl or C 5 -C 7 cycloalkenyl; -F, -Cl, -Br, or -I; -N0 2 ; -N 3 ; -CN; -OR 21 , -OCOR 2 ⁇ , -COR 2 ⁇ , -NCOR 2i , -N(R 21 ) 2 , - CON(R 2 ⁇ ) 2 , or -COOR 21 ; aryl or heteroaryl; or two R 20 groups present on adjacent carbon atoms can join together to form a methylenedioxy group,-
  • each R 2 ⁇ is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, aryl or aryl (O . - C 6 ) alkyl;
  • each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive
  • p is an integer from 0 to 2 inclusive
  • q is an integer from 2 to 4 inclusive
  • t is 1 or 2;
  • the invention provides a compound having the structure:
  • W is H, -F, -Cl, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy;
  • R 13 is an aryl, adamantyl, noradamantyl, C 3 -C ⁇ 0 cycloalkyl, heteroaryl, Q x or Q 2 ;
  • aryl may be substituted with one or more C ⁇ -C ⁇ 0 straight chained or branched alkyl, aryl, heteroaryl, or N(R ⁇ 9 )-Z;
  • each J is independently 0, S, C(R 22 ) 2 or NR 4 ;
  • R 4 is -H; straight chained or branched C 1 -C 7 alkyl , monof luoroalkyl or polyfluoroalkyl ; straight chained or branched C 2 -C alkenyl or alkynyl ; C 3 -C 7 cycloalkyl , C 5 -C 7 cycloalkenyl or aryl ;
  • Y is NR ⁇ 4 R ⁇ 5 ;
  • R 14 is H, straight chained or branched C ⁇ -C 3 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , C 3 -Cg cycloalkyl, or (C (R i9 ) 2 ) m -Z;
  • R ⁇ 5 is straight chained or branched C 3 -C 6 alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3 , C 3 -C 6 cycloalkyl, or (C (R i9 ) 2 ) m -Z;
  • U is O, -NR X6 , S, C(R ⁇ 7 ) 2 , or -NS0 2 R ⁇ 6 ;
  • Z is C 3 -C ⁇ 0 cycloalkyl, aryl, or heteroaryl
  • R ⁇ 6 is straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl , straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R i7 is independently H; -OR 2 ⁇ , -OCOR 2i , -COR 2 ⁇ , -NCOR21, -N(R 21 ) 2 , -CON(R 2 ⁇ ) 2 , -COOR21, straight chained or branched C 1 -C7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) n -Or (CH 2 ) m -CH 3 ;
  • R ⁇ 8 is straight chained or branched C ⁇ -C 6 alkyl, - (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) ra -CH 3 ;
  • each R i9 is independently H, or straight chained or branched C ⁇ -C 6 alkyl; wherein each R 20 is independently -H; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl or C 5 -C 7 cycloalkenyl; -F, -Cl, -Br, or -I; -N0 2 ; -N 3 ; -CN; -OR 2 ⁇ , -OCOR 21 , -COR 2 ⁇ , -NCOR 2 ⁇ , -N(R 2i ) 2 , - CON(R 2i ) , or -COOR21; aryl or heteroaryl; or two R 20 groups present on adjacent carbon atoms can join together to form a methylenedioxy group
  • each R 21 is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C alkenyl or alkynyl; C 3 - C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, aryl or aryl(C ⁇ - C 6 ) alkyl;
  • each R 22 is independently H, F, Cl or C ⁇ -C 4 straight chained or branched alkyl
  • each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive,-
  • p is an integer from 0 to 2 inclusive
  • q is an integer from 2 to 4 inclusive
  • t is 1 or 2;
  • the invention provides a compound having the structure:
  • W is H, -F, -Cl, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy;
  • R i3 is a bicyclic alkyl ring system, aryl or aryl (C ⁇ -C 6 ) alkyl;
  • Y is NR ⁇ 4 R ⁇ 5 ;
  • R i4 is H, straight chained or branched C ⁇ -C 6 alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3 , C 3 -Cg cycloalkyl, or (C (R 19 ) 2 ) m -Z;
  • R i5 is (C (R 19 ) 2 ) ra -N (R ⁇ 6 ) 2,
  • Z is C 3 -C ⁇ 0 cycloalkyl, aryl, or heteroaryl; wherein R 16 is straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, - (CH 2 ) m -Z, or (CH 2 )q-0-(CH 2 ) m -CH 3 ;
  • each R 17 is independently H; -OR 2 ⁇ , -OCOR 2 ⁇ , -COR 2 ⁇ , -NCOR 2 i, -N(R 2 ⁇ ) 2 -CON(R 2 ⁇ ) 2 , -COOR 2 ⁇ , straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) n -0- (CH 2 ) m -CH 3 ;
  • each R ⁇ 9 is independently H, or straight chained or branched C ⁇ -C 6 alkyl
  • each R 21 is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, aryl or aryl (C x - C 6 ) alkyl;
  • each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive
  • q is an integer from 2 to 4 inclusive;
  • the invention also provides a method of treating a subject suffering from depression which comprises administering to the subject an amount of compound effective to treat the subject's depression wherein the compound has the structure.
  • each of Y l r Y 2 , Y 3 , and Y 4 is independently - H; straight chained or branched C-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, or C 5 -C 7 cycloalkenyl; -F, -Cl, -Br, or - I; -N0 2 ; -N 3 ; -CN; -OR 4 , -SR 4 , -OCOR 4 , -COR 4 , -NC0R 4 , - N(R 4 ) 2 , -CON(R 4 ) 2 , or -COOR ; aryl or heteroaryl; or any two of Y ⁇ , Y 2 , Y 3 and Y 4 present on adjacent carbon atoms can constitute a
  • each R 4 is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, aryl or aryl (C ⁇ -C ⁇ ) alkyl; wherein A is A' , Q 3 , Q 4 , Q 5 , straight chained or branched C ⁇ -C 7 alkyl, aryl, heteroaryl, aryl (C x - C e ) alkyl, heteroaryl (C ⁇ -C 3 ) alkyl, aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl; or (CHR ⁇ 7 ) - (CHR ⁇ 7 ) n -Z;
  • Ri and R 2 are each independently H, straight chained or branched C ⁇ -C 7 alkyl, -F, -Cl, -Br, -I, - N0 2 , or -CN;
  • R 3 is H, straight chained or branched C ⁇ -C 7 alkyl, -F, -Cl, -Br, -I, -N0 2 , -CN, -OR 6 , aryl or heteroaryl;
  • R s is straight chained or branched C ⁇ -C 7 alkyl, -N(R 4 ) 2 , ⁇ OR 6 or aryl; wherein R 6 is straight chained or branched C x -C 7 alkyl or aryl ,-
  • each R i7 is independently H; straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) n -0-
  • each R 20 is independently -H; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl; -F, -Cl, -Br, or -I; -N0 2 ; -N 3 ; -CN; - OR 2 ⁇ , -OCOR 2l7 -COR 2 ⁇ , -NCOR 2 ⁇ , -N(R 2 ⁇ ) 2 , -CON(R 2 ⁇ ) 2 , or -COOR 21 ; aryl or heteroaryl; or two R 2 o groups present on adjacent carbon atoms can join together to form a methylenedioxy group;
  • each R 2i is independently -H; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C alkenyl or alkynyl; C 3 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, aryl or aryl (C ⁇ -C 6 ) alkyl; wherein each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive
  • each p is an integer from 0 to 2 inclusive;
  • U is O, -NR ⁇ 6 , S, C(R ⁇ 7 ) 2 , or -NS0 2 R ⁇ 6 ;
  • Z is C 3 -C ⁇ 0 cycloalkyl , C 4 -C 7 cyclic ether, C 4 -C 7 cyclic thioether, aryl , or heteroaryl ;
  • R ⁇ 6 is straight chained or branched C ⁇ -C 7 alkyl , straight chained or branched C ⁇ -C 7 monof luoroalkyl , straight chained or branched C ⁇ -C 7 polyfluoroalkyl , straight chained or branched C 2 -C 7 alkenyl , straight chained or branched C -C 7 alkynyl , C 5 -C7 cycloalkenyl , - (CH 2 ) m -Z , or (CH 2 ) q -0- (CH 2 ) m -CH 3 ;
  • q is an integer from 2 to 4 inclusive ;
  • B is aryl, heteroaryl, aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl, tricyclic heteroaryl or Q 6 ; 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; wherein a tricyclic heteroaryl is a fused three member aromatic system in which one or more of the rings is heteroaryl; carbazole; or acridine;
  • each R 22 is independently H, F,
  • the invention provides a method of treating a subject suffering from depression which comprises administering to the subject an amount of compound effective to treat the subject's depression wherein the compound has the structure :
  • each of Y lf Y 2 , Y 3 , and Y 4 is independently - H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C cycloalkyl, or C 5 -C 7 cycloalkenyl; -F, -Cl, -Br, or - I; -N0 2 ; -N 3 ; -CN; -OR 4 , -SR 4 , -0C0R 4 , -COR 4 , -NCOR 4 , - N(R 4 ) 2 , -C0N(R 4 ) 2 , or -COOR 4 ; aryl or heteroaryl; or any two of Y 1; Y 2 , Y 3 and Y 4 present on adjacent carbon atoms can constitute
  • each R 4 is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, aryl or aryl (C ⁇ -C 6 ) alkyl;
  • A is A' , straight chained or branched C ⁇ -C 7 alkyl, aryl, heteroaryl, aryl (C ⁇ -C 6 ) alkyl or heteroaryl (C ⁇ -C 6 ) alkyl ;
  • Ri and R 2 are each independently H, straight chained or branched C ⁇ -C 7 alkyl, -F, -Cl, -Br, -I, - N0 2 , or -CN;
  • R 3 is H, straight chained or branched C ⁇ -C 7 alkyl, -F, -Cl, -Br, -I, -N0 2 , -CN, -OR 6 aryl or heteroaryl;
  • R 5 is straight chained or branched C ⁇ -C 7 alkyl, -N(R 4 ) 2 , -OR 6 or aryl;
  • R 6 is straight chained or branched C ⁇ -C 7 alkyl or aryl ;
  • 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, -I, -CN, methyl, ethyl or methoxy;
  • n is an integer from 1 to 4 inclusive;
  • the invention provides a method of treating a subject suffering from depression which comprises administering to the subject an amount of compound effective to treat the subject's depression wherein the compound has the structure:
  • each of Y l t Y 2 , Y 3 , and Y 4 is independently - H; straight chained or branched C ⁇ -C 6 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, or C 5 -C 7 cycloalkenyl; -F, -Cl, -Br, or - I; -N0 2 ; -N 3 ; -CN; -OR 4 , -SR 4 , -OCOR 4 , -COR 4 , -NCOR 4 , - N(R 4 ) 2 , -CON(R 4 ) 2 , or -COOR 4 ; aryl or heteroaryl; or any two of Y 1# Y , Y 3 and Y 4 present on adjacent carbon atoms can constitute a methyl
  • each R 4 is independently -H; straight chained or branched Ci-C 6 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 6 alkenyl or alkynyl; C 3 -C 6 cycloalkyl, C 5 -C 6 cycloalkenyl, aryl or aryl (C ⁇ -C G ) alkyl;
  • A is A' , straight chained or branched C ⁇ -C 6 alkyl, aryl, heteroaryl, aryl (C-C 6 ) alkyl or heteroaryl (C ⁇ -C 6 ) alkyl; wherein A' is
  • B is aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl, tricyclic heteroaryl or Q s ;
  • a tricyclic heteroaryl is a fused three ring aromatic system in which one or more of the rings is heteroaryl; carbazole; or acridine;
  • n is an integer from 1 to 4 inclusive; wherein each R 22 is independently H, F, Cl, or straight chained or branched C ⁇ -C 4 alkyl;
  • the invention provides a method of treating a subject suffering from depression which comprises administering to the subject an amount of compound effective to treat the subject's depression wherein the compound has the structure :
  • each of Y 1# Y 2 , Y 3 , and Y 4 is independently - H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 6 alkenyl or alkynyl; C 3 -C 6 cycloalkyl, or C 5 -C 7 cycloalkenyl; -F, -Cl, -Br, or - I; -N0 2 ; -N 3 ; -CN; -OR 4 , -SR 4 , -OCOR 4 , -COR 4 , -NCOR 4 , - N(R 4 ) 2 , -CON(R 4 ) 2 , or -COOR 4 ; aryl or heteroaryl; or any two of Y ⁇ 7 Y 2 , Y 3 and Y 4 present on adjacent carbon atoms can constitute a methylened
  • A is Q 3 , Q , Q 5 , aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl, or (CHR 17 ) - (CHR 17 ) n -Z;
  • each R ⁇ 7 is independently H; straight chained or branched C ⁇ -C? alkyl, straight chained or branched
  • C ⁇ -C 6 monofluoroalkyl straight chained or branched Cx-C 6 polyfluoroalkyl, straight chained or branched C 2 -C 6 alkenyl, straight chained or branched C 2 -C 6 alkynyl, C 5 -C 6 cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) n -0- (CH 2 ) m -CH 3 ;
  • each R 20 is independently -H; straight chained or branched C ⁇ -C 6 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 6 alkenyl or alkynyl; C 3 -C 7 cycloalkyl or C 5 -C 6 cycloalkenyl; -F, -Cl, -Br, or -I; -N0 2 ; -N 3 ; -CN; - OR 2 ⁇ , -OCOR 2 ⁇ , -C0R 2 ⁇ , -NCOR 2 ⁇ , -N(R 2 ⁇ ) 2 , -C0N(R 2 ⁇ ) 2 , or -COOR 2 ⁇ ; aryl or heteroaryl; or two R 2 o groups present on adjacent carbon atoms can join together to form a methylenedioxy group;
  • each R 2 ⁇ is independently -H; straight chained or branched C ⁇ -C 6 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl or aryl; wherein each R 22 is independently H, F, Cl, or straight chained or branched C ⁇ -C 4 alkyl;
  • each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive
  • each p is an integer from 0 to 2 inclusive;
  • U is O, -NR ⁇ 6 , S, C(R 17 ) 2 , or -NS0 2 R ⁇ e ;
  • Z is C 3 -C 10 cycloalkyl, C 4 -C 6 cyclic ether, C 4 -C 7 cyclic thioether, aryl, or heteroaryl;
  • R 16 is straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C 6 monofluoroalkyl, straight chained or branched C ⁇ -C 6 polyfluoroalkyl, straight chained or branched C 2 -C 6 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C? cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) q -0- (CH 2 ) m -CH 3 ;
  • q is an integer from 2 to 4 inclusive
  • 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, -I, -CN, methyl, ethyl or methoxy;
  • the invention provides a method of treating a subject suffering from anxiety which comprises administering to the subject an amount of compound effective to treat the subject's anxiety wherein the compound has the structure:
  • each of Y X/ Y 2 , Y 3 , and Y 4 is independently - H; straight chained or branched C ⁇ -C 6 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 6 alkenyl or alkynyl; C 3 -C 6 cycloalkyl, or C 5 -C 7 cycloalkenyl; -F, -Cl, -Br, or - I; -N0 2 ; -N 3 ; -CN; -OR 4 , -SR 4 , -OCOR 4 , -COR 4 , -NCOR 4 , - N(R 4 ) 2 , -CON(R 4 ) 2 , or -COOR 4 ; aryl or heteroaryl; or any two of Y l t Y 2 , Y 3 and Y 4 present on adjacent carbon atoms can constitute a
  • each R 4 is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, C 5 -C 6 cycloalkenyl, aryl or aryl (C ⁇ -C 3 ) alkyl;
  • A is A' , Q 3 , Q 4/ Q 5 , straight chained or branched C ⁇ -C 6 alkyl, aryl, heteroaryl, aryl (C ⁇ C 6 ) alkyl, heteroaryl (C ⁇ -C 6 ) alkyl, aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl; or (CHRi ? ) - (CHRi ? ) n -Z;
  • R x and R 2 are each independently H, straight chained or branched Ci-C 6 alkyl, -F, -Cl, -Br, -I, - N0 2 , or -CN;
  • R 3 is H, straight chained or branched C ⁇ -C 7 alkyl, -F, -Cl, -Br, -I, -N0 2 , -CN, -OR 6 , aryl or ⁇ heteroaryl;
  • R 5 is straight chained or branched C ⁇ -C 7 alkyl, -N(R 4 ) 2 , -OR 6 or aryl; wherein R ⁇ is straight chained or branched Ci-C 6 alkyl or aryl ;
  • each R ⁇ 7 is independently H; straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched
  • C ⁇ -C 7 monofluoroalkyl straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 6 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 3 -C 6 cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) n -0- (CH 2 ) m -CH 3 ;
  • each R 0 is independently -H; straight chained or branched C -C 6 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkenyl; -F, -Cl, -Br, or -I; -N0 2 ; -N 3 ; -CN; - OR 2 ⁇ , -OCOR 2 ⁇ , -COR 2 ⁇ , -NCOR 21 , -N(R 2i ) 2 , -CON(R 21 ) 2 , or -COOR 2 i; aryl or heteroaryl; or two R 20 groups present on adjacent carbon atoms can join together to form a methylenedioxy group;
  • each R 2 ⁇ is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 6 cycloalkyl, C 5 -C 6 cycloalkenyl, aryl or aryl (C ⁇ -C 6 ) alkyl ;
  • each m is an integer from 0 to 4 inclusive; wherein each n is an integer from 1 to 4 inclusive;
  • each p is an integer from 0 to 2 inclusive;
  • U is O, -NR 16 , S, C(R ⁇ 7 ) 2 , or -NS0 2 R ⁇ e ;
  • Z is C 3 -C ⁇ 0 cycloalkyl, C 4 -C 6 cyclic ether, C 4 -C 6 cyclic thioether, aryl, or heteroaryl;
  • R ⁇ 6 is straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 6 alkenyl, straight chained or branched C 2 -C 6 alkynyl, C 5 -C 6 cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) q -0- (CH 2 ) m -CH 3 ;
  • q is an integer from 2 to 4 inclusive
  • B is aryl, heteroaryl, aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl, tricyclic heteroaryl or Q 6 ; 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; wherein a tricyclic heteroaryl is a fused three member aromatic system in which one or more of the rings is heteroaryl; carbazole; or acridine;
  • each R 22 is independently H, F,
  • the invention provides a method of treating a subject suffering from anxiety which comprises administering to the subject an amount of compound effective to treat the subject's anxiety wherein the compound has the structure:
  • each of Y 1# Y 2 , Y 3 , and Y 4 is independently - H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, or C-C 6 cycloalkenyl; -F, -Cl, -Br, or - I; -N0 2 ; -N 3 ; -CN; -OR 4 , -SR 4 , -OCOR 4 , -COR, -NCOR 4 , - N(R 4 ) 2 , -CON(R 4 ) 2 , or -C00R 4 ; aryl or heteroaryl; or any two of Yi, Y 2 , Y 3 and Y 4 present on adjacent carbon atoms can constitute a methylenedioxy group;
  • each R 4 is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 6 alkenyl or alkynyl; C 3 -C 6 cycloalkyl, C 5 -C 6 cycloalkenyl, aryl or aryl (C ⁇ -C 6 ) alkyl;
  • A is A' , straight chained or branched Ci-C 6 alkyl, aryl, heteroaryl, aryl (C ⁇ -C 3 ) alkyl or heteroaryl (C ⁇ -C 3 ) alkyl ;
  • R x and R 2 are each independently H, straight chained or branched Ci-C 6 alkyl, -F, -Cl, -Br, -I, - N0 2 , or -CN;
  • R 3 is H, straight chained or branched Ci-C 6 alkyl, -F, -Cl, -Br, -I, -N0 2 , -CN, -OR 6 aryl or heteroaryl;
  • R 5 is straight chained or branched Ci-C 6 alkyl, -N(R 4 ) 2 , -OR 5 or aryl;
  • R s is straight chained or branched Q L -C 6 alkyl or aryl ;
  • 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, -I, -CN, methyl, ethyl or methoxy;
  • n is an integer from 1 to 4 inclusive;
  • the invention provides a method of treating a subject suffering from anxiety which comprises administering to the subject an amount of compound effective to treat the subject's anxiety wherein the compound has the structure:
  • each of Y 1# Y 2 , Y 3 , and Y 4 is independently - H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkenyl; -F, -Cl, -Br, or - I; -N0 2 ; -N 3 ; -CN; -OR 4 , -SR 4 , -OCOR 4 , -COR 4 , -NCOR 4 , - N(R 4 ) 2 , -CON(R 4 ) 2 , or -C00R 4 ; aryl or heteroaryl; or any two of Yi, Y 2 , Y 3 and Y 4 present on adjacent carbon atoms can constitute a methylenedi
  • each R 4 is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 6 alkenyl or alkynyl; C 3 -C 6 cycloalkyl, C 5 -C 6 cycloalkenyl, aryl or aryl (C ⁇ -C 6 ) alkyl;
  • A is A' , straight chained or branched Ci-C 6 alkyl, aryl, heteroaryl, aryl (C ⁇ -C 3 ) alkyl or heteroaryl (C ⁇ -C 3 ) alkyl; wherein A' is
  • B is aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl, tricyclic heteroaryl or Q s ;
  • a tricyclic heteroaryl is a fused three ring aromatic system in which one or more of the rings is heteroaryl; carbazole; or acridine;
  • n is an integer from 1 to 4 inclusive;
  • each R 22 is independently H, F, Cl, or straight chained or branched C ⁇ -C 4 alkyl
  • the invention provides a method of treating a subject suffering from anxiety which comprises administering to the subject an amount of compound effective to treat the subject's anxiety wherein the compound has the structure:
  • each of Y l r Y 2 , Y 3 , and Y 4 is independently - H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, or C 5 -C 7 cycloalkenyl; -F, -Cl, -Br, or - I; -N0 2 ; -N 3 ; -CN; -OR 4 , -SR 4 , -OCOR 4 , -COR 4 , -NCOR ⁇ - N(R 4 ) 2 , -C0N(R 4 ) 2 , or -COOR 4 ; aryl or heteroaryl; or any two of Y x , Y 2 , Y 3 and Y 4 present on adjacent carbon atoms can constitute
  • each R is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C? cycloalkyl, C 5 -C 6 cycloalkenyl, aryl or aryl (C ⁇ -C 6 ) alkyl;
  • A is Q 3 , Q 4 , Q 5 , aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl, or (CHRi?) - (CHRi?) n -Z;
  • each R i7 is independently H; straight chained or branched C ⁇ -C 6 alkyl, straight chained or branched C ⁇ -C 6 monofluoroalkyl , straight chained or branched C ⁇ -C 6 polyfluoroalkyl, straight chained or branched C 2 -C 6 alkenyl, straight chained or branched C 2 -C? alkynyl, C 5 -C 6 cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) n -0-
  • each R 2 o is independently -H; straight chained or branched Ci-C 6 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 6 alkenyl or alkynyl; C 3 -C 6 cycloalkyl or C 5 -C 6 cycloalkenyl; -F, -Cl, -Br, or -I; -N0 2 ; -N 3 ; -CN; - 0R 2 ⁇ , -0C0R 2 ⁇ , -COR 21 , -NCOR 21 , -N(R 21 ) 2 , -C0N(R 2 ⁇ ) 2 , or -CO0R 2 ⁇ ,- aryl or heteroaryl; or two R 20 groups present on adjacent carbon atoms can join together to form a methylenedioxy group;
  • each R 2 ⁇ is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 6 alkenyl or alkynyl; C 3 -C 6 cycloalkyl, C 5 -C 6 cycloalkenyl or aryl;
  • each R 22 is independently H, F, Cl, or straight chained or branched C ⁇ -C alkyl
  • q is an integer from 2 to 4 inclusive
  • each m is an integer from 0 to 4 inclusive;
  • each n is an integer from 1 to 4 inclusive; wherein each p is an integer from 0 to 2 inclusive;
  • U is 0, -NR 16 , S, C(R ⁇ 7 ) 2 , or -NS0 2 R ⁇ S ;
  • Z is C 3 -C ⁇ 0 cycloalkyl, C 4 -C 7 cyclic ether,
  • R ⁇ S is straight chained or branched C ⁇ -C 6 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 6 alkynyl, C 5 -C 7 cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) q -0- (CH 2 ) m -CH 3 ;
  • 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, -I, -CN, methyl, ethyl or methoxy;
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the structure :
  • each of Y 1# Y, Y 3 , and Y 4 is independently - H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, or C 3 -C 7 cycloalkenyl; -F, -Cl, -Br, or - I; -N0 2 ; -N 3 ; -CN; -0R 4 , -SR 4 , -0C0R 4 , -C0R , -NC0R 4 , - N(R 4 ) 2 , -CON(R 4 ) 2 , or -C00R 4/ - aryl or heteroaryl; or any two of Yi, Y 2 , Y 3 and Y 4 present on adjacent carbon atoms can constitute a
  • each R 4 is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 6 alkenyl or alkynyl; C 3 -C? cycloalkyl, C 5 -C 6 cycloalkenyl, aryl or aryl (C ⁇ -C 6 ) alkyl;
  • A is A' , Q 3 , Q 4 , Q 5 , straight chained or branched C ⁇ -C? alkyl, aryl, heteroaryl, aryl (Ci- C 6 ) alkyl, heteroaryl (C ⁇ -C 6 ) alkyl, aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl; or (CHRi ? ) - (CHRi ? ) n -Z; wherein A' is
  • Rx and R 2 are each independently H, straight chained or branched C ⁇ -C 7 alkyl, -F, -Cl, -Br, -I, - N0 2 , or -CN;
  • R 3 is H, straight chained or branched C ⁇ -C 7 alkyl, -F, -Cl, -Br, -I, -N0 2 , -CN, -OR 6 , aryl or heteroaryl ;
  • R 5 is straight chained or branched C ⁇ -C 7 alkyl, -N(R 4 ) 2 , -OR s or aryl; wherein R 6 is straight chained or branched C ⁇ -C 7 alkyl or aryl ;
  • each R i7 is independently H; straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched Ci-C 6 monofluoroalkyl, straight chained or branched Ci-C 6 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 6 cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) n -0-
  • each R 2 o is independently -H; straight chained or branched Ci-C 6 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C? alkenyl or alkynyl; C 3 -C 6 cycloalkyl or C 5 -C 6 cycloalkenyl; -F, -Cl, -Br, or -I; -N0 2 ; -N 3 ; -CN; - OR 2 ⁇ , -OCOR 2 ⁇ , -COR 2 ⁇ , -NC0R 2 ⁇ , -N(R 2i ) 2 , -CON(R 21 ) 2 , or -COOR 2 ⁇ ,- aryl or heteroaryl; or two R 20 groups present on adjacent carbon atoms can join together to form a methylenedioxy group;
  • each R i is independently -H; straight chained or branched Ci-C 6 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 6 cycloalkyl, C 5 -C 6 cycloalkenyl, aryl or aryl (C x -C 6 ) alkyl; wherein each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive,-
  • each p is an integer from 0 to 2 inclusive,-
  • U is O, -NR 16 , S, C(R ⁇ 7 ) 2 , or -NS0 2 R 16 ;
  • Z is C 3 -C ⁇ 0 cycloalkyl, C 4 -C 6 cyclic ether, C 4 -C 6 cyclic thioether, aryl, or heteroaryl;
  • R 16 is straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 6 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 6 cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) q -0- (CH 2 ) m -CH 3 ;
  • q is an integer from 2 to 4 inclusive
  • B is aryl, heteroaryl, aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl, tricyclic heteroaryl or Q s ; 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; wherein a tricyclic heteroaryl is a fused three member aromatic system in which one or more of the rings is heteroaryl; carbazole; or acridine;
  • each R 22 is independently H, F,
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the structure :
  • each of Y ⁇ ; Y, Y 3 , and Y 4 is independently H; straight chained or branched Q L -C 6 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 6 cycloalkyl, or C 5 -C?
  • cycloalkenyl -F, -Cl, -Br, or - I; -N0 2 ; -N 3 ; -CN; -OR 4 , -SR 4 , -OCOR 4 , -C0R 4 , -NCOR 4 , - N(R 4 ) 2 , -CON(R 4 ) 2 , or -COOR 4 ; aryl or heteroaryl; or any two of Yi, Y 2 , Y 3 and Y 4 present on adjacent carbon atoms can constitute a methylenedioxy group;
  • each R 4 is independently -H; straight chained or branched Ci-C 6 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 6 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, aryl or aryl (C;j . -C 6 ) alkyl;
  • A is A' , straight chained or branched Q L -C 6 alkyl, aryl, heteroaryl, aryl (C ⁇ -C 6 ) alkyl or heteroaryl (C ⁇ -C e ) alkyl;
  • Rx and R 2 are each independently H, straight chained or branched Ci-C 6 alkyl, -F, -Cl, -Br, -I, -
  • R 3 is H, straight chained or branched C ⁇ -C 7 alkyl, -F, -Cl, -Br, -I, -N0 2 , -CN, -OR 6 aryl or heteroaryl;
  • R 5 is straight chained or branched Ci-C 6 alkyl, -N(R 4 ) 2 , -OR 6 or aryl;
  • R 6 is straight chained or branched Ci-C 6 alkyl or aryl ,-
  • 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, -I, -CN, methyl, ethyl or methoxy;
  • n is an integer from 1 to 4 inclusive;
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the structure:
  • each of Y l r Y 2 , Y 3 , and Y 4 is independently - H; straight chained or branched Q L -C 6 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 6 alkenyl or alkynyl; C 3 -C 6 cycloalkyl, or C 3 -C 6 cycloalkenyl; -F, -Cl, -Br, or - I; -N0 2 ; -N 3 ; -CN; -OR 4 , -SR 4 , -OCOR 4 , -COR 4 , -NCOR 4 , - N(R 4 ) 2 , -CON(R 4 ) 2 , or -COOR 4 ; aryl or heteroaryl; or any two of Y 1# Y 2 , Y 3 and Y 4 present on adjacent carbon atoms can constitute a
  • each R 4 is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C? cycloalkyl, C 5 -C 6 cycloalkenyl, aryl or aryl (C ⁇ -C 6 ) alkyl;
  • A is A' , straight chained or branched Ci-C 6 alkyl, aryl, heteroaryl, aryl (C ⁇ -C 6 ) alkyl or heteroaryl (C ⁇ -C 6 ) alkyl;
  • B is aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl, tricyclic heteroaryl or Q 6 ;
  • a tricyclic heteroaryl is a fused three ring aromatic system in which one or more of the rings is heteroaryl; carbazole; or acridine;
  • n is an integer from 1 to 4 inclusive;
  • each R 22 is independently H, F, Cl, or straight chained or branched C ⁇ -C 4 alkyl
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the structure :
  • each of Yi, Y 2 , Y 3 , and Y 4 is independently - H; straight chained or branched Ci-C 6 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 6 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, or C 5 -C 7 cycloalkenyl; -F, -Cl, -Br, or - I; -N0 2 ; -N 3 ; -CN; -OR 4 , -SR 4 , -OCOR 4 , -COR 4 , -NCOR 4 , - N(R 4 ) 2 , -CON(R 4 ) 2 , or -COOR 4 ; aryl or heteroaryl; or any two of Y x , Y 2 , Y 3 and Y 4 present on adjacent carbon atoms can constitute a methylenedi
  • each R 4 is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 6 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkenyl, aryl or aryl (C ⁇ -C 6 ) alkyl;
  • A is Q 3 , Q 4 , Q 5 , aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl, or (CHRi ? ) - (CHR 17 ) n -Z;
  • each R x7 is independently H; straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched
  • Ci-C 6 monofluoroalkyl straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 6 alkenyl, straight chained or branched C 2 -C 6 alkynyl, C 5 -C 7 cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) n -0- (CH 2 ) m -CH 3 ;
  • each R 20 is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C-C 6 alkenyl or alkynyl; C 3 -C 6 cycloalkyl or C 5 -C 7 cycloalkenyl; -F, -Cl, -Br, or -I; -N0 2 ; -N 3 ; -CN; - OR 2 ⁇ , -OCOR 2 ⁇ , -COR 2 ⁇ , -NC0R 21 , -N(R 2 ⁇ ) 2 , -CON(R 2 ⁇ ) 2 , or -COOR 2 ⁇ ,- aryl or heteroaryl; or two R 20 groups present on adjacent carbon atoms can join together to form a methylenedioxy group;
  • each R 2 is independently -H; straight chained or branched Ci-C 6 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 6 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, C 5 -C 6 cycloalkenyl or aryl; wherein each R 22 is independently H, F, Cl, or straight chained or branched C ⁇ -C 4 alkyl;
  • q is an integer from 2 to 4 inclusive
  • each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive
  • each p is an integer from 0 to 2 inclusive;
  • U is O, -NR i6 , S, C(R ⁇ 7 ) 2 , or -NS0 2 R ⁇ ⁇ ;
  • Z is C 3 -C ⁇ 0 cycloalkyl, C 4 -C 6 cyclic ether, C 4 -C 6 cyclic thioether, aryl, or heteroaryl;
  • R ⁇ 6 is straight chained or branched Ci-C 6 alkyl, straight chained or branched Cx-C 6 monofluoroalkyl, straight chained or branched C -C 6 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 6 alkynyl, Cs-C 6 cycloalkenyl, -(CH 2 ) ra -Z, or (CH 2 ) q -0- (CH 2 ) m -CH 3 ;
  • 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, -I, -CN, methyl, ethyl or methoxy;
  • each of Y x , Y 2 , Y 3 , and Y 4 is independently - H; straight chained or branched Ci-C 6 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 6 cycloalkyl, or C 5 -C 7 cycloalkenyl; -F, -Cl, -Br, or - I; -N0 2 ; -N 3 ; -CN; -0R 4 , -SR 4 , -0C0R 4 , -C0R 4 , -NC0R 4 , - N(R 4 ) 2 , -CON(R 4 ) 2 , or -C00R 4 ; aryl or heteroaryl; or any two of Y ⁇ # Y 2 , Y 3 and Y 4 present on adjacent carbon atoms
  • each R 4 is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 6 alkenyl or alkynyl; C 3 -C 6 cycloalkyl, C 5 -C 6 cycloalkenyl, aryl or aryl (C ⁇ -C 6 ) alkyl;
  • A is A', Q 3 , Q 4 , Q 5 straight chained or branched C ⁇ -C 7 alkyl, aryl, heteroaryl, aryl (C ⁇ C ⁇ ) alkyl, heteroaryl (C ⁇ -C 6 ) alkyl, aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl; or (CHRi ? ) - (CHRi ? ) n -Z;
  • R x and R 2 are each independently H, straight chained or branched C ⁇ -C 7 alkyl, -F, -Cl, -Br, -I, - N0 2 , or -CN;
  • R 3 is H, straight chained or branched Ci-C 6 alkyl, -F, -Cl, -Br, -I, -N0 2 , -CN, -OR 6 , aryl or heteroaryl; wherein R 5 is straight chained or branched Ci-C 6 alkyl, -N(R) 2 , -OR 6 or aryl;
  • R 6 is straight chained or branched C ⁇ C 7 alkyl or aryl ;
  • each R i7 is independently H; straight chained or branched Ci-C 6 alkyl, straight chained or branched Ci-C 6 monofluoroalkyl, straight chained or branched
  • Ci-C 6 polyfluoroalkyl straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C? cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) n -0- (CH 2 ) m -CH 3 ;
  • each R 20 is independently -H; straight chained or branched Ci-C 6 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl or C 5 -C 6 cycloalkenyl; -F, -Cl, -Br, or -I; -N0 2 ; -N 3 ; -CN; -
  • each R i is independently -H; straight chained or branched Q L -C 6 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 6 alkenyl or alkynyl; C 3 -C 6 cycloalkyl, C 5 -C 6 cycloalkenyl, aryl or aryl (C ⁇ -C ⁇ ) alkyl; wherein each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive
  • each p is an integer from 0 to 2 inclusive;
  • U is 0, -NR ⁇ 6 , S, C(R 17 ) 2 , or -NS0 2 R ⁇ 6 ;
  • Z is C 3 -C ⁇ 0 cycloalkyl, C 4 -C 6 cyclic ether,
  • R 16 is straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 6 alkynyl, C 5 -C 6 cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) q -0- (CH 2 ) m -CH 3 ;
  • q is an integer from 2 to 4 inclusive
  • B is aryl, heteroaryl, aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl, tricyclic heteroaryl or Q 6 ; 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;
  • a tricyclic heteroaryl is a fused three member aromatic system in which one or more of the rings is heteroaryl; carbazole; or acridine,-
  • each R 2 is independently H, F,
  • the invention provides a compound having the structure:
  • each of Yi, Y 2 , Y 3 , and Y 4 is independently - H; straight chained or branched Ci-C 6 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 6 alkenyl or alkynyl; C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkenyl; -F, -Cl, -Br, or - I; -N0 2 ; -N 3 ; -CN; -0R 4 , -SR 4 , -0C0R 4 , -C0R 4 , -NC0R 4 , - N(R 4 ) 2 , -CON(R 4 ) 2 , or -COOR 4 ; aryl or heteroaryl; or any two of Yi, Y / Y 3 and Y present on adjacent carbon atoms can constitute a methylenedioxy
  • each R 4 is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 6 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, aryl or aryl (C ⁇ -C 6 ) alkyl;
  • A is A' , straight chained or branched C ⁇ -C 7 alkyl, aryl, heteroaryl, aryl (C ⁇ -C 6 ) alkyl or heteroaryl (C ⁇ -C 3 ) alkyl;
  • R x and R 2 are each independently H, straight chained or branched C ⁇ -C 7 alkyl, -F, -Cl, -Br, -I, - N0 2 , or -CN;
  • R 3 is H, straight chained or branched C-C 6 alkyl, -F, -Cl, -Br, -I, -N0 2 , -CN, -OR s aryl or heteroaryl;
  • R 5 is straight chained or branched Ci-C 6 alkyl, -N(R 4 ) 2 , -OR s or aryl;
  • R s is straight chained or branched Ci-C 6 alkyl or aryl ,-
  • 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, -I, -CN, methyl, ethyl or methoxy;
  • n is an integer from 1 to 4 inclusive;
  • the invention provides a compound having the structure:
  • each of Y , Y 2 , Y 3 , and Y 4 is independently - H; straight chained or branched Ci-C 6 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 6 alkenyl or alkynyl; C 3 -C 6 cycloalkyl, or C 5 -C 6 cycloalkenyl; -F, -Cl, -Br, or - I; -N0 2 ; -N 3 ; -CN; -0R 4 , -SR 4 , -OCOR 4 , -C0R 4 , -NC0R 4 , - N(R 4 ) 2 , -CON(R 4 ) 2 , or -COOR 4 ; aryl or heteroaryl; or any two of Y , Y 2 , Y 3 and Y 4 present on adjacent carbon atoms can constitute a
  • each R 4 is independently -H; straight chained or branched Ci-C 6 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 6 cycloalkyl, C 5 -C 7 cycloalkenyl, aryl or aryl (C ⁇ -C 6 ) alkyl;
  • A is A' , straight chained or branched C ⁇ -C 7 alkyl, aryl, heteroaryl, aryl (C ⁇ -C 6 ) alkyl or heteroaryl (C ⁇ -C 6 ) alkyl;
  • B is aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl, tricyclic heteroaryl or Q 6 ;
  • a tricyclic heteroaryl is a fused three ring aromatic system in which one or more of the rings is heteroaryl; carbazole; or acridine,-
  • n is an integer from 1 to 4 inclusive; wherein each R 22 is independently H, F, Cl, or straight chained or branched C ⁇ -C 4 alkyl;
  • the invention provides a compound having the structure:
  • each of Y x , Y 2 , Y 3 , and Y 4 is independently - H; straight chained or branched Ci-C 6 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C?
  • alkenyl or alkynyl C 3 -C 7 cycloalkyl, or C 5 -C 6 cycloalkenyl; -F, -Cl, -Br, or - I; -N0 2 ; -N 3 ; -CN; -0R 4 , -SR 4 , -0C0R 4 , -COR 4 , -NCOR 4 , - N(R 4 ) 2 , -CON(R 4 ) 2 , or -COOR 4 ; aryl or heteroaryl; or any two of Y x , Y 2 , Y 3 and Y 4 present on adjacent carbon atoms can constitute a methylenedioxy group;
  • each R 4 is independently -H; straight chained or branched Ci-C? alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 6 alkenyl or alkynyl; C 3 -C 6 cycloalkyl, C 5 -C 6 cycloalkenyl, aryl or aryl (C ⁇ -C 6 ) alkyl;
  • A is Q 3 , Q 4 , Q s , aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl, or (CHRi ? ) - (CHRi ? ) n -Z ;
  • each R 1 is independently H; straight chained or branched Ci-C 6 alkyl, straight chained or branched
  • each R 20 is independently -H; straight chained or branched Ci-C 6 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 6 cycloalkyl or C 5 -C 7 cycloalkenyl; -F, -Cl, -Br, or -I; -N0 2 ; -N 3 ; -CN; - 0R 2 ⁇ , -OCOR21, -C0R 2 ⁇ , -NCOR 2 ⁇ , -N(R 2 ⁇ ) 2 , -CON(R 2 ⁇ ) 2 , or -C00R 2 ⁇ ; aryl or heteroaryl; or two R 2 o groups present on adjacent carbon atoms can join together to form a methylenedioxy group;
  • each R 2 ⁇ is independently -H; straight chained or branched Ci-C? alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 6 cycloalkyl, C 5 -C 6 cycloalkenyl or aryl; wherein each R 22 is independently H, F, Cl, or straight chained or branched C ⁇ -C 4 alkyl;
  • q is an integer from 2 to 4 inclusive
  • each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive
  • each p is an integer from 0 to 2 inclusive;
  • U is 0, -NR ⁇ 6 , S, C(R ⁇ 7 ) 2 , or -NS0 2 R ⁇ 6 ;
  • Z is C 3 -C ⁇ 0 cycloalkyl, C 4 -C 6 cyclic ether, C 4 -C 6 cyclic thioether, aryl, or heteroaryl;
  • R 16 is straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 6 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) q -0- (CH 2 ) m -CH 3 ;
  • 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, -I, -CN, methyl, ethyl or methoxy;
  • the invention provides a method of treating depression in a subject which comprises administering to the subject a composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a GAL3 receptor antagonist, wherein:
  • the GAL3 receptor antagonist binds to the human GAL3 receptor with a binding affinity at least ten-fold higher than the binding affinity with which it binds to the human GALl receptor;
  • the GAL3 receptor antagonist does not inhibit the activity of central monoamine oxidase A greater than 50 percent, at a concentration of 10 ⁇ M;
  • the GAL3 receptor antagonist does not inhibit the activity of central monoamine oxidase B greater than 50 percent, at a concentration of lO ⁇ M;
  • the GAL3 receptor antagonist binds to the human GAL3 receptor with a binding affinity at least tenfold higher than the binding affinity with which it binds to each of the following transporters: serotonin transporter, norepinephrine transporter, and dopamine transporter.
  • the invention provides a method of treating anxiety in a subject which comprises administering to the subject a composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a GAL3 receptor antagonist, wherein:
  • the GAL3 receptor antagonist binds to the human GAL3 receptor with a binding affinity at least ten-fold higher than the binding affinity with which it binds to the human GALl receptor; and (b) the GAL3 receptor antagonist binds to the human GAL3 receptor with a binding affinity at least ten-fold higher than the binding affinity with which it binds to each of the following transporters : serotonin transporter, norepinephrine transporter, and dopamine transporter.
  • rats were examined in a 5 minute forced swim test. For each treatment condition, the number of 5-sec intervals culminating with a display of climbing was derived and plotted as the average +/- S.E.M.
  • Example 92 A significant increase in climbing was observed for rats injected with Example 92 at 10 mg/kg, relative to vehicle injected controls (p ⁇ 0.01, ANOVA and Student-Nerman-Keuls) , but not in rats dosed with Example 92 at 30 mg/kg ip .
  • rats were examined in a 5 minute forced swim test.
  • the number of 5-sec intervals culminating with a display of swimming was derived and plotted as the average +/- S.E.M.
  • a significant increase in swimming was observed for rats injected with fluoxetine at 10 mg/kg ip or with Example 92 at 30 mg/kg, relative to vehicle injected controls (p ⁇ 0.01, ANOVA and Student-Nerman-Keuls).
  • n 5 for each treatment condition
  • unfamiliar rats were examined in a 15 minute social interaction test.
  • the amount of time spent in social interaction was derived and plotted as the average +/- S.E.M.
  • a significant increase in social interaction was observed for rats injected with chlordiazepoxide at 5 mg/kg i.p. or with Example 92 at 10 mg/kg ip (p ⁇ 0.05) as well as 30 mg/kg (p ⁇ 0.01) .
  • Example 92 When the dose of Example 92 was increased to 100 mg/kg, the amount of social interaction time was significantly less than measured after chlordiazepoxide at 5 mg/kg ip or Example 92 at 30 mg/kg ip (p ⁇ 0.01) . Significance in all cases was determined by ANOVA and Student-Nerman-Keuls.
  • the anti- GAL3 antiserum labeled proteins in membranes only from rat GAL3-transfected cells (Lane 2) ; a predominant band was evident with an apparent molecular weight of approximately 56 kDa, (somewhat higher than the amino acid-derived value of ⁇ 40.4 kDa) .
  • the apparently high molecular weight observed for rat GAL3 very likely reflects post-translational processing such as glycosylation; note that rat GAL3 contains multiple N- terminal glycosylation sites (Smith et al . , 1998).
  • Relative to the predominant band additional species of higher molecular weight as well as lower molecular 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.
  • the present invention • provides a method of treating a subject suffering from depression which comprises administering to the subject an amount of compound effective to treat the subject's depression wherein the compound has the structure:
  • W is H, -F, -Cl, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy;
  • X is; NR ⁇ R 12 ;
  • R xx is H, straight chained or branched C ⁇ -C 7 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , aryl, or aryl (C ⁇ -C 6 ) alkyl;
  • R X is straight chained or branched C ⁇ -C 7 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , or -(CH 2 ) m -Z;
  • R i3 is a bicyclic alkyl ring system, adamantyl, noradamantyl, C 3 -C ⁇ 0 cycloalkyl, heteroaryl, aryl, aryl(C ⁇ - C s ) alkyl, Q x or Q 2 ;
  • aryl may be substituted with one or more C ⁇ -C 10 straight chained or branched alkyl, aryl, heteroaryl, or N(R ⁇ 9 ) -Z;
  • each J is independently O, S, C(R 2 ) 2 or NR 4 ; wherein R 4 is H; straight chained or branched Ci-C 6 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 6 alkenyl or alkynyl; C 3 -C 6 cycloalkyl, C 5 -C 7 cycloalkenyl or aryl;
  • Y is NR ⁇ 4 R ⁇ 5 ;
  • R ⁇ 4 is H, straight chained or branched C ⁇ -C e alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3 , C 3 -C 6 cycloalkyl, or (C (R i9 ) 2 ) m -Z;
  • R i5 is straight chained or branched C 3 -C 3 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , C 3 -C ⁇ cycloalkyl, (C (R i9 ) 2 ) m N (R 16 ) 2 or (C (R ⁇ 9 ) 2 ) m ⁇ Z ;
  • R 16 is straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C? alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 6 cycloalkenyl, - (CH 2 ) m -Z, or (CH 2 )q-0-(CH 2 ) m -CH 3 ;
  • each R 17 is independently H; -0R 2 ⁇ , -OCOR 2 ⁇ , -C0R 21 , -NCOR 2i , -N(R 21 ) 2 , -CON(R 21 ) 2 , -COOR 21 , straight chained or branched C-C 7 alkyl, straight chained or branched C-C 6 monofluoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 6 alkenyl, straight chained or branched C 2 -C 6 alkynyl, C 5 -C 6 cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) n -0- (CH 2 ) m -CH 3 ;
  • R i8 is straight chained or branched C ⁇ -C 6 alkyl, - (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R X9 is independently H, or straight chained or branched C ⁇ -C 3 alkyl
  • each R 20 is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 6 alkenyl or alkynyl; C 3 - C ?
  • each R 2 ⁇ is independently -H; straight chained or branched C ⁇ -C 6 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C 7 cycloalkyl, C 5 -C 6 cycloalkenyl, aryl, or aryl (d- C 6 ) alkyl;
  • each R 2 is independently H, F, Cl or C ⁇ -C 4 straight chained or branched alkyl
  • each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive
  • p is an integer from 0 to 2 inclusive
  • q is an integer from 2 to 4 inclusive
  • t is 1 or 2;
  • U is O, -NR ⁇ 6 , S, C(R ⁇ ?) 2 , or -NS0 2 R ⁇ 6 ;
  • Z is C 3 -C ⁇ 0 cycloalkyl, C 4 -C? cyclic ether, C 4 -C 7 cyclic thioether, aryl, or heteroaryl; or
  • the invention provides a method of treating a subject suffering from depression which comprises administering to the subject an amount of compound effective to treat the subject's depression wherein the compound has the structure :
  • W is H, -F, -Cl, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy;
  • R x is H, straight chained or branched C ⁇ -C 7 alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3 , aryl or aryl (C ⁇ -C 6 ) alkyl;
  • R 2 is straight chained or branched C ⁇ -C 7 alkyl, (CH 2 ) g -0-(CH 2 ) m -CH 3 , or -(CH 2 ) m -Z;
  • R 13 is a bicyclic alkyl ring system, aryl or aryl (C ⁇ -C 6 ) alkyl;
  • Y is NR ⁇ 4 R ⁇ 5 ;
  • R i4 is H, straight chained or branched C ⁇ -C 6 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , C 3 -C 3 cycloalkyl, or (C (R i9 ) 2 ) m -Z;
  • R 1 5 is straight chained or branched C 3 -C 6 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , C 3 -C 6 cycloalkyl, or (C (R 19 ) 2 ) m -Z;
  • U is 0, -NR ⁇ S , S, C(R ⁇ 7 ) 2 , or -NS0 2 R 1S ;
  • Z is C 3 -C 10 cycloalkyl, aryl, or heteroaryl
  • R 16 is straight chained or branched C ⁇ -C 6 alkyl, straight chained or branched C-C 7 monofluoroalkyl, straight chained or branched C ⁇ -C? polyfluoroalkyl, straight chained or branched C 2 -C?
  • each R ⁇ 7 is independently H; -OR 2 ⁇ , -OCOR 2 ⁇ , -COR 21 , -NCOR21, -N(R 2 ⁇ ) 2 , -CON(R 2 ⁇ ) 2 , -COOR 21 , straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C -C monofluoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 6 alkenyl, straight chained or branched C 2 -C 6 alkynyl, C 5 -C 7 cycloalkenyl,
  • R X8 is straight chained or branched C ⁇ -C 6 alkyl, - (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R 19 is independently H, or straight chained or branched C ⁇ -C 6 alkyl
  • each R 2 o is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 6 alkenyl or alkynyl; C 3 - C?
  • each R 2 ⁇ is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C? cycloalkyl, C 5 -C 6 cycloalkenyl, aryl or aryl(C ⁇ - C 6 ) alkyl;
  • each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive; wherein p is an integer from 0 to 2 inclusive;
  • q is an integer from 2 to 4 inclusive
  • t is 1 or 2;
  • the invention provides a method of treating a subject suffering from depression which comprises administering to the subject an amount of compound effective to treat the subject's depression wherein the compound has the structure :
  • W is H, -F, -Cl, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy;
  • R i3 is an aryl, adamantyl, noradamantyl, C 3 -C ⁇ 0 cycloalkyl, heteroaryl, Qi or Q 2 ;
  • aryl may be substituted with one or more C-Cio straight chained or branched alkyl, aryl, heteroaryl, or N(R i9 ) -Z;
  • each J is independently 0, S, C(R 22 ) 2 or NR 4 ; wherein R 4 is -H; straight chained or branched C ⁇ -C 7 alkyl, monof luoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 6 cycloalkyl, C 5 -C 6 cycloalkenyl or aryl;
  • Y is NR ⁇ 4 R ⁇ 5 ;
  • R i4 is H, straight chained or branched C ⁇ -C 6 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , C 3 -C 3 cycloalkyl, or (C (R 19 ) 2 ) m -Z;
  • R ⁇ 5 is straight chained or branched C 3 -C 6 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , C 3 -C 3 cycloalkyl, or (C (R 19 ) 2 ) m -Z;
  • U is 0, -NR ⁇ S , S, C(R 17 ) 2 , or -NS0 2 R ⁇ 6 ;
  • Z is C 3 -C ⁇ 0 cycloalkyl, aryl, or heteroaryl; wherein R ls is straight chained or branched C ⁇ -C 6 alkyl, straight chained or branched Ci-C 6 monofluoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 6 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R ⁇ 7 is independently H; -0R 2 ⁇ , -OCOR 21 , -COR 2 ⁇ , -NC0R 2 ⁇ , -N(R 2 ⁇ ) 2 / -C0N(R 2 ⁇ ) 2 , -C00R 2 ⁇ , straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C x -C 7 monofluoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 6 alkenyl, straight chained or branched C 2 -C 6 alkynyl, C 5 -C 6 cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) n -0- (CH 2 ) m -CH 3 ;
  • R 18 is straight chained or branched C ⁇ -C 3 alkyl, - (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R i9 is independently H, or straight chained or branched C x -C 6 alkyl
  • each R 20 is independently -H; straight chained or branched Ci-C 6 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 6 alkenyl or alkynyl; C 3 - C ?
  • each R 21 is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 6 alkenyl or alkynyl; C 3 -
  • each R 22 is independently H, F, Cl or C ⁇ -C 4 straight chained or branched alkyl
  • each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive
  • p is an integer from 0 to 2 inclusive
  • q is an integer from 2 to 4 inclusive
  • t is 1 or 2 ;
  • the invention provides a method of treating a subject suffering from depression which comprises administering to the subject an amount of compound effective to treat the subject's depression wherein the compound has the structure:
  • W is H, -F, -Cl, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy;
  • R ⁇ 3 is a bicyclic alkyl ring system, aryl or aryl (C ⁇ -C 3 ) alkyl;
  • Y is NR 14 R ⁇ 5 ;
  • R 14 is H, straight chained or branched Ci-C 6 alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3 , C 3 -C 3 cycloalkyl, or (C (R 19 ) 2 ) m -Z;
  • R 15 is (C (R 19 ) 2 ) m -N(R ⁇ 6 ) 2 ;
  • Z is C 3 -C ⁇ 0 cycloalkyl, aryl, or heteroaryl
  • R i6 is straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C ⁇ -C? polyfluoroalkyl, straight chained or branched C 2 -C 6 alkenyl, straight chained or branched C 2 -C 6 alkynyl, C 5 -C 6 cycloalkenyl, - (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) ra -CH 3 ;
  • each R 17 is independently H; -OR 2 ⁇ , -0C0R 2i , -C0R 2 ⁇ , -NCOR 2 ⁇ , -N(R 2 ⁇ ) 2 , -C0N(R 2 ⁇ ) 2 , -COOR2 1 , straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C 1 -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 6 alkenyl, straight chained or branched C 2 -C 6 alkynyl, C 5 -C 6 cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) n -0- (CH 2 ) m -CH 3 ;
  • each R ⁇ 9 is independently H, or straight chained or branched C ⁇ -C 6 alkyl
  • each R 2 ⁇ is independently -H; straight chained or branched Ci-C 6 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 6 alkenyl or alkynyl; C 3 - C ? cycloalkyl, C 5 -C 7 cycloalkenyl, aryl or aryl (C x - C 6 ) alkyl;
  • each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive
  • q is an integer from 2 to 4 inclusive;
  • bicyclic alkyl ring systems includes, but is not limited to, bicyclo [2.2.1] heptane, bicyclo [3.1.1] heptane and bicyclo [2.2.2] octane.
  • the bicyclic alkyl ring systems may be substituted with one or more of the following: -F, -N0 2 , -CN, straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 5 -C 7 cycloalkenyl, -N(R 21 ) 2 , -0R 2 ⁇ , -C0R 2i , - C0 2 R 2 ⁇ , -C0N (R 2 ⁇ ) 2 or ( CH 2 ) n -0- ( CH 2 ) m - CH 3 .
  • cycloalkyl includes, C 3 -C 6 cycloalkyl moieties which may be substituted with one or more of the following: -F, -N0 2 , -CN, straight chained or branched Ci-C 6 alkyl, straight chained or branched Ci-C 6 monofluoroalkyl, straight chained or branched C1-C7 polyfluoroalkyl, straight chained or branched C 2 -C 6 alkenyl, straight chained or branched C 2 -C?
  • alkynyl C 3 -C 6 cycloalkyl, C 3 -C 6 monofluorocycloalkyl, C 3 -C 7 polyfluorocycloalkyl, C 5 -C 6 cycloalkenyl, -N(R 4 ) 2 , -0R 4 , -C0R 4 , -NC0R 4 , -C0 2 R 4 , C0N(R 4 ) 2 or (CH 2 ) n -0- (CH 2 ) m -CH 3 .
  • cyclohexyl includes, cyclohexyl groups which may be substituted with one or more of the following: -F, -N0 2 , -CN, straight chained or branched Ci-C? alkyl, straight chained or branched Ci-C?
  • cycloalkenyl includes, C 5 -C 6 cycloalkenyl moieties which may be substituted with one or more of the following: -F, -Cl, -Br, -I, -N0 2 , -CN, straight chained or branched Ci-C 6 alkyl, straight chained or branched Ci-C?
  • Ci-C 6 polyfluoroalkyl straight chained or branched Ci-C 6 polyfluoroalkyl, straight chained or branched C 2 -C 6 alkenyl, straight chained or branched C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 6 monofluorocycloalkyl, C 3 -C 7 polyfluorocycloalkyl, C 5 -C 6 cycloalkenyl, -N(R 4 ) 2 , -0R 4 , -C0R 4 , -NCOR 4 , -C0 2 R 4 , C0N(R 4 ) 2 or (CH 2 ) n -0-(CH 2 ) m -CH3.
  • heteroaryl is used to include five and six membered unsaturated rings that may contain one or more oxygen, sulfur, or nitrogen atoms.
  • 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 .
  • heteroaryl is used to include fused bicyclic ring systems that may contain one or more heteroatoms such as oxygen, sulfur and nitrogen.
  • heteroaryl groups include, but are not limited to, indolizinyl, indolyl, isoindolyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, benzimidazolyl, purinyl, benzoxazolyl, benzisoxazolyl, benzo [b] thiazolyl, imidazo [2 , 1-b] thiazolyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1, 8-naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, phthalimidyl and 2, 1, 3-benzothiazolyl .
  • heteroaryl also includes those chemical moieties recited above which may be substituted with one or more of the following: -F, -Cl, -Br, -I, -N0 2 , -CN, straight chained or branched Ci-C 6 alkyl, straight chained or branched Ci-C?
  • heteroaryl further includes the N-oxides of those chemical moieties recited above which include at least one nitrogen atom.
  • 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, -I, -N0 2 , -CN, straight chained or branched Ci-C 6 alkyl, straight chained or branched Ci-C 6 monofluoroalkyl, straight chained or branched Ci-C 6 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 7 monofluorocycloalkyl, C 3 -C 6 polyfluorocycloalkyl, C 5 -C?
  • the compound is enantiomerically and diasteriomerically pure. In one embodiment, the compound is enantiomerically or diasteriomerically pure.
  • the compound in one embodiment of any of the methods described herein, can be administered orally.
  • X is:
  • X is NRnR ⁇ 2 and R n is H or straight chained or branched C ⁇ -C 7 alkyl.
  • the compound has the structure
  • R ⁇ 3 is a bicyclic alkyl ring system, cyclohexyl or aryl .
  • R 14 is H, straight chained or branched Ci-Cs alkyl or (CH 2 ) q -0- (CH 2 ) m -CH 3 .
  • R ⁇ 4 is H, straight chained or branched C ⁇ -C 6 alkyl or (CH 2 ) q -0- (CH 2 ) m -CH 3 .
  • the compound is selected from the group consisting of:
  • Y is
  • U is NR ⁇ 6 .
  • R 16 is (CH 2 ) m -Z.
  • Z is aryl or heteroaryl.
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • Y is
  • U is NR 16 .
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • X is N(CH 3 ) 2 .
  • Y is
  • R 13 is an aryl substituted with a C ⁇ -C 10 straight chained alkyl .
  • the compound is selected from a group consisting of :
  • the invention provides a method of treating a subject suffering from anxiety which comprises administering to the subject an amount of compound effective to treat the subject's anxiety wherein the compound has the structure:
  • W is H, -F, -Cl, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy;
  • X is; NRnR ⁇ 2 ;
  • Rn is H, straight chained or branched Q L -C 6 alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3 , aryl, or aryl (C ⁇ -C 6 ) alkyl; wherein R x2 is straight chained or branched C ⁇ -C 7 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , or -(CH 2 ) m -Z;
  • R i3 is a bicyclic alkyl ring system, adamantyl, noradamantyl, C 3 -C ⁇ 0 cycloalkyl, heteroaryl, aryl, aryl (Ci- C 6 ) alkyl, Q x or Q 2 ;
  • aryl may be substituted with one or more C ⁇ -C ⁇ 0 straight chained or branched alkyl, aryl, heteroaryl, or N(R ⁇ 9 )-Z;
  • each J is independently 0, S, C(R 22 ) 2 or NR 4 ;
  • R 4 is H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 6 alkenyl or alkynyl; C 3 -C 6 cycloalkyl, C 5 -C 6 cycloalkenyl or aryl;
  • R ⁇ 4 is H, straight chained or branched C ⁇ -C 6 alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3 , C 3 -C 6 cycloalkyl, or (C(R 19 ) 2 ) n -Z;
  • R 1S is straight chained or branched C 3 -C 5 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , C 3 -C 6 cycloalkyl, (C (R 19 ) 2 ) m N (R 16 ) 2 or (C (Rig) 2 ) m ⁇ Z ;
  • R 16 is straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 6 alkynyl, C 5 -C 7 cycloalkenyl, - (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R 17 is independently H; -0R 21 , -OCOR 2 ⁇ , -COR 2 ⁇ , -NCOR21, -N(R 2 ⁇ ) 2 , -C0N(R 2 ⁇ ) 2 , -COOR21, straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl , straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) n -0- (CH 2 ) m -CH 3 ;
  • R 18 is straight chained or branched C ⁇ -C 6 alkyl, - (CH 2 ) ra -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R 19 is independently H, or straight chained or branched C ⁇ -C 6 alkyl
  • each R 20 is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 - C ?
  • each R 2 ⁇ is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C? alkenyl or alkynyl; C 3 - C ? cycloalkyl, C 5 -C 7 cycloalkenyl, aryl, or aryl (C ⁇ C 6 ) alkyl; wherein each R 2 is independently H, F, Cl or C ⁇ -C 4 straight chained or branched alkyl;
  • each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive
  • p is an integer from 0 to 2 inclusive
  • q is an integer from 2 to 4 inclusive
  • t is 1 or 2;
  • U is O, -NR ⁇ 6 , S, C(R ⁇ ? ) 2 , or -NS0 2 R ⁇ 6 ;
  • Z is C 3 -C ⁇ 0 cycloalkyl, C 4 -C 7 cyclic ether, C 4 -C 6 cyclic thioether, aryl, or heteroaryl; or
  • the invention provides a method of treating a subject suffering from anxiety which comprises administering to the subject an amount of compound effective to treat the subject's anxiety wherein the compound has the structure:
  • W is H, -F, -Cl, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy;
  • R u is H, straight chained or branched Ci-C 6 alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3 , aryl or aryl (C-.-C 6 ) alkyl;
  • R i2 is straight chained or branched C ⁇ -C 7 alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3 , or -(CH 2 ) m -Z;
  • R i3 is a bicyclic alkyl ring system, aryl or aryl (C ⁇ -C 6 ) alkyl;
  • Y is NR 1 R 15 ;
  • R i4 is H, straight chained or branched C ⁇ -C 6 alkyl, (CH 2 ) q -0-(CH 2 ) ra -CH 3 , C 3 -C 6 cycloalkyl, or (C(R X$ ) 2 ) m -Z;
  • R ⁇ S is straight chained or branched C 3 -C 6 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , C 3 -C 6 cycloalkyl, or (C(R ⁇ 9 ) 2 ) m -Z;
  • U is O, -NR X6 , S, C(R ⁇ 7 ) 2 , or -NS0 2 R ⁇ 6 ;
  • Z is C 3 -C ⁇ 0 cycloalkyl, aryl, or heteroaryl
  • R ⁇ 6 is straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched Q L -C 6 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 6 alkynyl, C 5 -C 6 cycloalkenyl, - (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ; wherein each R ⁇ 7 is independently H; -OR 2 ⁇ , -OCOR 2 ⁇ , -COR 2 ⁇ , -NCOR 2 ⁇ , -N(R 2 ⁇ ) 2 , -CON(R 2 ⁇ ) 2 , -COOR 2 ⁇ , straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C
  • polyfluoroalkyl straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C-C? alkynyl, C 5 -C? cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) n -0- (CH 2 ) m -CH 3 ;
  • R 18 is straight chained or branched C ⁇ -C 6 alkyl, - (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R ⁇ 9 is independently H, or straight chained or branched C ⁇ -C ⁇ alkyl
  • each R 20 is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C? alkenyl or alkynyl; C 3 - C ?
  • each R 2i is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C? alkenyl or alkynyl; C 3 - C 7 cycloalkyl, C 5 -C 6 cycloalkenyl, aryl or aryl (Ci- C 6 ) alkyl;
  • each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive; wherein p is an integer from 0 to 2 inclusive;

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Abstract

Cette invention concerne des dérivés de pyrimidine et d'indolone lesquels sont des antagonistes sélectifs du récepteur GAL3. L'invention concerne une composition pharmaceutique contenant une dose thérapeutique efficace d'un composé de l'invention et un excipient pharmaceutiquement acceptable. Cette invention concerne également une composition pharmaceutique obtenue par combinaison d'une dose thérapeutique efficace d'un composé de l'invention et d'un excipient pharmaceutiquement acceptable. Cette invention concerne aussi un procédé de production d'une composition pharmaceutique consistant à combiner une dose thérapeutique efficace d'un composé de l'invention et d'un excipient pharmaceutiquement acceptable. De plus, l'invention concerne une méthode de traitement d'un sujet souffrant de dépression et/ou d'anxiété consistant à administrer à ce dernier une dose d'un composé de l'invention efficace pour traiter la dépression et/ou l'anxiété du sujet. En outre, cette invention concerne une méthode de traitement de la dépression et/ou de l'anxiété chez un sujet consistant à lui administrer une composition contenant un excipient pharmaceutiquement acceptable ainsi qu'une dose thérapeutique efficace d'un antagoniste du récepteur GAL3.
EP02714918A 2001-01-31 2002-01-31 Utilisation d'antagonistes du recepteur gal3 dans le traitement de la depression et/ou de l'anxiete et composes utiles dans de telles methodes Withdrawn EP1363638A4 (fr)

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EP09010004A EP2140862A3 (fr) 2001-01-31 2002-01-31 Utilisation d'antagonistes du recepteur GAL3 dans le traitement de la dépression et/ou de l'anxiété et composés utiles dans de telles méthodes

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EP1474401A2 (fr) * 2002-02-05 2004-11-10 Novo Nordisk A/S Nouvelles aryl- et heteroarylpiperazines
CN101973925B (zh) * 2010-10-15 2012-03-28 中国药科大学 具有抗炎活性的2-吲哚酮类化合物、其制备方法及医药用途
CN104903312B (zh) * 2013-10-07 2019-01-29 卡德门企业有限公司 Rho激酶抑制剂
CN110325516A (zh) * 2016-12-29 2019-10-11 米尼奥尔克斯治疗有限公司 杂芳基化合物和它们的用途
BR112020001698A2 (pt) 2017-08-03 2020-07-21 Galectin Sciences, Llc compostos para prevenção e tratamento de distúrbios médicos e usos dos mesmos
WO2020160156A2 (fr) * 2019-01-30 2020-08-06 Immutics, Inc. Anticorps anti-gal3 et leurs utilisations
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