WO2007057742A2 - Novel piperazinone derivatives - Google Patents

Abstract

Compounds, compositions, medicinal compounds, psychotherapeutic agents, and pharmaceutical compositions relating to the formula I, and pharmaceutical salts thereof, wherein R1, R2, R3, Rn, each X, W1, W2, Y1 and Y2 are defined in the specification. Methods of preparing the compounds, compositions, medicinal compounds, psychotherapeutic agents, and pharmaceutical compositions thereof. Methods of treating various disorders and diseases utilizing the compounds, compositions, medicinal compounds, psychotherapeutic agents, and pharmaceutical compositions of the present invention.

Description

NOVEL PIPERAZINONE DERIVATIVES

Field of the Invention

The present invention relates to compounds and related pharmaceutical compositions for medicinal uses thereof. Background Art

The present invention relates to novel piperazinones, intermediates for their preparation, pharmaceutical compositions containing them, and their medicinal use. The compounds of the present invention include selective agonists and antagonists of serotonin 1 (5-HT₁) receptors, specifically, of one or both of the 5-HTi_A and 5-HT_1B (formerly classified 5- HT_{1 D}) receptors. They are useful in treating hypertension, depression and other disorders for which a 5-HT₁ agonist or antagonist is indicated.

European Patent Publication 434,561, published June 26, 1991, refers to 7-alkyl alkoxy, and hydroxy substituted-1-(4-substituted-1-piperazinyl)-naphthalenes. The compounds are referred to as 5-HT₁ agonists and antagonists useful for the treatment of migraine, depression, anxiety, schizophrenia, stress and pain.

European Patent Publication 343,050, published on Nov. 23, 1989, refers to 7- unsubstituted, halogenated, and methoxy substituted-1-(4-substituted-1-piperazinyl)- naphthalenes as useful 5-HT_1A ligand therapeutics.

PCT publication WO 94/21619, published Sep. 29, 1994, refers to naphthalene derivatives as 5-HT₁ agonists and antagonists.

PCT publication WO 96/00720, published Jan. 11, 1996, refers to naphthyl ethers as useful 5-HT₁ agonists and antagonists.

European Patent Publication 701,819, published Mar. 20, 1996, refers to the use of

5-HT₁ agonists and antagonists in combination with a 5-HT re-uptake inhibitor. Glennon et al., refers to 7-methoxy-1-(1-piperazinyl)-naphthalene as a useful 5-HT₁ ligand in the article "5-HT₁₀ Serotonin Receptors", Clinical Drug Res. Dev., 22, 25-36 (1991).

Glennon's article "Serotonin Receptors: Clinical Implications", Neuroscience and

Behavioral Reviews, 14, 35-47 (1990), refers to the pharmacological effects associated with serotonin receptors including appetite suppression, thermoregulation, cardiovascular/hypotensive effects, sleep, psychosis, anxiety, depression, nausea, emesis,

Alzheimer's disease, Parkinson's disease and Huntington's disease.

World Patent Application WO 95/31988, published Nov. 30, 1995, refers to the use of a 5-HT₁ D antagonist in combination with a 5-HT_1A antagonist to treat CNS disorders such as depression, generalized anxiety, panic disorder, agoraphobia, social phobias, obsessive- compulsive disorder, post-traumatic stress disorder, memory disorders, anorexia nervosa and bulimia nervosa, Parkinson's disease, tardive dyskinesias, endocrine disorders such as hyperprolactinaemia, vasospasm (particularly in the cerebral vasculature) and hypertension, disorders of the gastrointestinal tract where changes in motility and secretion are involved, as well as sexual dysfunction.

G. Maura et al., J. Neurochem, 66 (1), 203-209 (1996), have stated that administration of agonists selective for 5-HTIA receptors or for both 5-HT_1A and 5-HTi_D receptors might represent a great improvement in the treatment of human cerebellar ataxias, a multifaceted syndrome for which no established therapy is available.

European Patent Publication 666,261, published Aug. 9, 1995 refers to thiazine and thiomorpholine derivatives, which are claimed to be useful for the treatment of cataracts.

United States Patent Number 6,472,388 to Howard, issued October 29, 2002, discloses aralkyl and aralkylidene heterocyclic lactams and imides for use in pharmaceutical compositions for medicinal purposes.

Accordingly, there is a need for a composition and therapeutics utilized as selective agonists and antagonists of serotonin 1 (5-HTi) receptors in order to be useful in treating migraine, depression and other disorders for which a 5-HT₁ agonist or antagonist is indicated.

SUMMARY OF THE INVENTION

The present invention provides compositions of the formula (hereinafter, "formula I"):

wherein R₁ is G¹, G², G³, G⁴, G⁵, G⁶, or G⁷, wherein

k is one or two; a is zero to eight;

Each Ri₃ is, independently, (Ci-C₄)alkyl, C₃-C₈cycloalkyl, or a (Ci-C₄) methylene bridge from one of the ring carbons of the piperazine or piperidine ring of G¹ or G², respectively, to the same or another ring carbon or a ring nitrogen of the piperazine or piperidine ring of G¹ or G², respectively, having an available bonding site, or to a ring carbon of R⁶ having an available bonding site;

E is oxygen, sulfur, SO, or SO₂; Each X is independently hydrogen, chloro, fluoro, bromo, iodo, cyano, (C₁-C₈)alkyl, hydroxy, trifluoromethyl, (Ci-C₈)alkoxy,

CO₂Ri_O, Or CONR₁₁Ri₂; t is zero, one, or two;

R_n is hydrogen, (CrC₆)alkyl, (C₃-C₆)cycloalkyl, C(O)(Ci-C₃)alkyl, aryl, orSO₂R_s;

R_s is (Ci-C₆)alkyl, (C₃-C₈)cycloalkyl, or phenyl; Yi and Y₂ are independently C-X or N, provided that Y₁ and Y₂ are not simultaneously

N;

R₂ is hydrogen, (Ci-C₄)alkyl, phenyl or naphthyl, wherein said phenyl or naphthyl may optionally be substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, (Ci-C₈)alkyl, (Ci-Cβ)alkoxy, trifluoromethyl, cyano and -SO,(Ci-C₈)alkyl;

R₃ is vinyl, C(=O)R, wherein R is straight chain or branched (Ci-C₈)alkyl, (C₃-C₈)cycloalkyl, trifluoromethyl, or aryl; or,

R₃ is -(CH₂)_gB, wherein B is hydrogen, phenyl, naphthyl or a 5- to 7-membered heteroaryl ring containing from one to four heteroatoms in the ring selected from oxygen, nitrogen and sulfur, provided that said ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms and wherein each of the foregoing phenyl, naphthyl and heteroaryl rings may optionally be substituted with one to three substituents independently selected from fluoro, chloro, bromo, iodo, nitro, trifluoromethyl, cyano, trifluoromethoxy, (C₁-C₈)alkyl, (C₁-C₈)BIkOXy, (Ci-C_fOalkoxyfd-CβJalkyl, hydroxy, COOH,

(C_rC₈)hydroxyalkyl-, (C₃-C₈)cycloalkyl-, (C₃-C₈)hydroxycycloalkyl-, (C_rC₈)aikoxy-(C₃-C₈)cycloalkyl-, heterocycloalkyl, hydroxyheterocycloalkyl, (Ci-C₈)alkoxy-heterocycloalkyl, phenyl, naphthyl or a 5- to 7-membered heteroaryl ring containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur, provided that the heteroaryl ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms, and wherein each independently selected phenyl, naphthyl or heteroaryl substituent may itself be substituted with from 1 to 3 (CrC₈)alkyl, (C₃_C₈)cycloalkyl substituents, or heteroaryl groups including, but not limited to, pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl, dihydraisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridinyl, pyrolopyrimidinyl, and azaindolyl;

When B is a phenyl, naphthyl or heteroaryl ring, each said ring may be optionally substituted with one to three substituents independently selected from (a) a lactone formed from -(CH₂XiOH with an ortho -COOH; (b) -CONR₁₄R₁₅, wherein R₁₄ and R₁₅ are independently selected from (C₁-C₈)alkyl, and benzyl, or R₁₄ and R₁₅ together with the nitrogen to which they are attached form a 4- to 7-membered heteroalkyl ring that may contain from zero to three heteroatoms selected from nitrogen, sulfur and oxygen in addition to the nitrogen of the -CONR₁₄R₁₅ group, wherein when any of said heteroatoms is nitrogen it can be optionally substituted with (C₁-C₈)alkyl or benzyl, provided that said ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms; (c) -(CH₂)VNCOR₁₆R₁/ and COR₁₆ and R₁₇ taken together with the nitrogen to which they are attached form a 4- to 7-membered lactam ring; and, (d) -(C₁-C₈)NR₁₈R_1S where each of R₁₈ and R_1g is selected, independently, from hydrogen and (Ci-C₄)alkyl, or R₁₈ and R<_tg, together with the nitrogen to which they are attached, form a 4- to 7-membered heteroalkyl ring that may contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen; g is zero to three; n is 1 to 3; v is zero to three; W¹ and W² are each independently H or (Ci-C₃)alkyl; R₆ is selected from the group consisting of hydrogen, (C₁-C₈)alkyl, or

(C₃-C₈)cycloalkyl, wherein alkyl or cycloalkyl is optionally substituted with hydroxy, (CrCβ)alkoxy or one to three fluorine atoms, or [(C₁-C₄)alkyl]aryl wherein the aryl moiety is phenyl, naphthyl, or heteroaryl-(CH₂)_q--, wherein the heteroaryl moiety is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl and benzisothiazolyl, and wherein said aryl and heteroaryl moieties can optionally be substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, bromo, iodo, hydroxy, ( -C^alkyl, (d-C^alkoxy, trifluoromethyl, cyano and SOt(C_rC_β)alkyl; q is zero, one, two, three or four;

R₇ is selected from the group consisting of hydrogen, (Ci-C₈)alkyl, (C₃-C₈)cycloalkyl, and, [(Ci-C₄)alkyl]aryl wherein the aryl moiety is phenyl, naphthyl, or heteroaryl-(CH₂)r~, wherein the heteroaryl moiety is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, and benzisothiazolyl and wherein said aryl and heteroaryl moieties may optionally be substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, bromo, iodo, hydroxy, (Ci-C₈)alkyl, (C_rC₈)alkoxy, trifluoromethyl, C(=O)-(Ci-C₈)alkyl, cyano and --SO_t(Ci-C₈)alkyl; or

R₆ or R₇ taken together form a 2 to 4 carbon chain; r is zero, one, two, three or four;

R₈ is hydrogen, (Ci-C₈)alkyl, or (C₃-C₈)cycloalkyl;

R₉ is hydrogen, (Ci-C_B)alkyl, or (C₃-C₈)cycloalkyl; or R₆ and Rg₁ together with the nitrogen atom to which they are attached, form a 5- to 7-membered heteroalkyl ring that can contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen; p is zero, one, two, or three;

Each of R₁₀, Rn and Ri₂ is selected, independently, from the radicals set forth in the definition of R₂; or R₁₁ and Ri₂, together with the nitrogen to which they are attached, form a 5- to 7-membered heteroalkyl ring that can contain from zero to three additional heteroatoms selected from nitrogen, sulfur and oxygen; the broken line indicates optional double bond, provided that when the broken line in G² is a double bond that R₈ is absent; and a pharmaceutically acceptable salt thereof.

An embodiment of the present invention is where Ri is any one of G¹, G², G³, G⁴, G⁵, G⁶, or G⁷. The following are more specific embodiments of groups G¹ and G².

Another embodiment of the present invention is where each X is independently any one of the following: hydrogen, chloro, fluoro, bromo, iodo, cyano, (C₁-CeJaIlCyI, hydroxy, trifluoromethyl, (Ci-C₈)alkoxy, SO_t(C₁-C₈JaIlCyI, CO₂Ri_O, or CONRHRI₂, and preferably each X is independently hydrogen, chloro, fluoro, (d-C₄)alkyl, trifluoromethyl, or (C₁-C₄JaIkOXy.

Another embodiment of the present invention is where Yi and Y₂ are both C-X, where X may have any definition provided herein. Another embodiment is where only one of Y₁ and Y₂ is C-X and the other is N, where X may have any definition provided herein.

Another embodiment of the present invention is where R_n is independently any one of the following: hydrogen, (C_rC₆)alkyl, C(O)(Ci-C₃)alkyl, aryl, or SO₂R₃, preferably, R_n is hydrogen, or (Ci-C₃)alkyl.

Another embodiment of the present invention is where W¹ and W² are independently H or (C₁-C₃JaIkVl₁ preferably independently H or methyl.

Another embodiment of the present invention is where R₂ is any one of the following: hydrogen, (C₁-C₄JaIlCyI, phenyl or naphthyl, wherein said phenyl or naphthyl may optionally be substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, (C₁-C₈)alkyl, (C₁-C₈JaIkOXy, trifluoromethyl, cyano and -SO_f(C₁-C₈JaIlCyI, preferably, R₂ is hydrogen.

Another embodiment of the present invention is where R₃ is -(CH₂)_gB, wherein g is zero, one, two, or three, preferably zero, and wherein B is hydrogen, phenyl, naphthyl or a 5- to 7-membered heteroaryl ring as described in formula I, preferably phenyl or pyridinyl, wherein each of the foregoing phenyl, naphthyl and heteroaryl rings may be unsubstituted or optionally substituted with one to three substituents independently being any one or more or combination of the following: fluoro, chloro, bromo, iodo, nitra, trifluoromethyl, cyano, trifluoramethoxy, (C₁-C₈JaIlCyI. (C₁-C₈JaIkOXy, (C₁-C₈JaIkOXy(C₁-C₈JaIlCyI, hydroxy, COOH, S(O)₁(C₁-C₈JaIlCyI. (C_rC₈)hydraxyalkyl-, (C₁-CaJaIkOXy-(C₁-C₈JaIlCyI-, (C₃-C₈)hydroxycycloalkyl-. (C₁-C₈JaIkOXy- (C₃-C₈)cycloalkyl-, heterocycloalkyl, hydroxyheterocycloalkyl, (d-CβJalkoxy-heterocycloalkyl, phenyl, naphthyl or a 5- to 7-membered heteroaryl ring as described in formula I, and wherein each independently selected phenyl, naphthyl or heteroaryl substituent may itself be substituted with from 1 to 3 (C_rC₈)alkyl, (C₃-C₈)cycloalkyl substituents, or heteroaryl groups as described in formula I. Preferably, the optional substituents on phenyl or pyridinyl of B is one to three substituents independently selected from (d-GOalkyl, (Ci-C₄)alkoxy, trifluoromethoxy, (Ca-CβJhydroxycycloalkyl-, (Ci-C₃)alkoxy-heterocycloalkyl, and heterocycloalkyl. The substituents can be in any combination and all from the same substituent group, e.g., all from (C₁-C₄)alkyli ^or from different substituent groups, e.g., one each from (C₃-C₈)hydraxycycloalkyl-, (CrCβJalkoxy-heterocycloalkyl, and heterocycloalkyl.

Another embodiment of the present invention is where Re is any one of the following: hydrogen, (Cr-C₈)alkyl_> preferably (Ci-C₄)alkyl, (Cr-QOcycloalkyl, or [(C₁-C₄)alkyl]aryl, where the alkyl, cycloalkyl, and aryl are unsubstituted or substituted as allowed by formula I.

Another embodiment of the present invention is where Yi and Y₂ are both C-X and R_n is aryl. Another embodiment of the present invention is where Yi and Y₂ are both C-X and R_n is hydrogen or (CrC₃)alkyl, R₃ is phenyl or pyridinyl (g is zero and B is phenyl or pyridinyl), optionally substituted with (C₃-C₈)hydroxycycloalkyl-, (Ci-C₈)alkoxy-heterocycloalkyl, and heterocycloalkyl. Another embodiment of the present invention is where only one of Y₁ and Y₂ is C-X, and R_n is (Ci-C₆)alkyl, (C₃-C₆)cycloalkyl, C(O)(C₁-C₃)alkyl, aryl, OrSO₂R₈.

The present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula I. The acids that are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1'-methylene-bis- (2-hydroxy-3-naphthoate)]salts.

The invention also relates to base addition salts of formula I. The chemical bases that can be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of formula I that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g. potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.

The compounds of the present invention include all stereoisomers (e.g., cis and trans isomers) and all optical isomers of compounds of the formula I (e.g., R and S enantiomers), as well as racemic, diastereomeric and other mixtures of such isomers. The compounds of the present invention can contain olefin-like double bonds. When such bonds are present, the compounds of the invention exist as cis and trans configurations and as mixtures thereof. Unless otherwise indicated, the term "alkyl", as used herein, includes straight or branched alkyl groups having one to eight carbon atoms.

Unless otherwise indicated the term "cycloalkyl" as used herein includes moieties derived from cyclic hydrocarbons containing from three to eight ring carbon atoms, including cyclic hydrocarbon moieties substituted with straight or branched alkyl moieties.

Unless otherwise indicated the term "heterocycloalkyl" as used herein includes a cyclic hydrocarbon in which one or more of the ring carbon atoms has been replaced with a nitrogen, oxygen or sulfur atom or any combination thereof. Examples of such groups are oxetanyl, tetrahydrofuranyl, tetrahydropyran, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorphlinyl, piperazinyl, and azapinyl.

The term "heteroaryl" is intended to include aromatic heterocyclic groups and includes the non-limiting examples thiophenyl, pyridyl, pyrimidyl, pyridazyl, oxazolyl, isooxazolyl, thiazolyl and isothiazolyl, among others.

Unless otherwise indicated, the term "one or more substituents", as used herein, refers to from one to the maximum number of substituents possible based on the number of available bonding sites.

The term "alkoxy", as used herein, means "alkyl-O-", wherein "alkyl" is defined as above.

Unless otherwise indicated, halogen includes fluorine, chlorine, bromine, and iodine. The present invention also relates to a pharmaceutical composition or a method for treating any one or more or combination of a disorder or condition selected from hypertension, all forms of depression (e.g., depression in cancer patients, depression in Parkinson's patients, postmyocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, pediatric depression, major depressive disorder, single episode depression, recurrent depression, child abuse induced depression, post partum depression, dysthymia; mild, moderate, or severe depressions with or without atypical features, melancholic features, psychotic features, catatonic features; seasonal affective disorder, geriatric depression, chronic depression; adjustment disorder with depressed mood or with anxiety and depressed mood; mixed anxiety and depression; substance induced mood disorder; and mood disorder secondary to a general medical condition), bipolar disorder (including in the depressed phase), generalized anxiety disorder, social anxiety, separation anxiety disorder, phobias (e.g., agoraphobia, social phobia and simple phobias), posttraumatc stress syndrome, avoidant personality disorder, premature ejaculation, eating disorders (e.g., binge eating disorder, anorexia nervosa and bulimia nervosa), obesity, chemical dependencies (e.g., addictions to alcohol, ***e, heroin, phenobarbital, marijuana, nicotine and benzodiazepines), cluster headache, migraine, pain, Alzheimer's disease, obsessive- compulsive disorder; panic disorder with and without agoraphobia; memory disorders (e.g., dementia, amnestic disorders, and age-related cognitive decline (ARCD)), Parkinson's diseases (e.g., dementia in Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesias), endocrine disorders (e.g., hyperprolactinaemia), vasospasm (particularly in the cerebral vasculature), cerebellar ataxia, gastrointestinal tract disorders (involving changes in motility and secretion), negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette's syndrome, trichotillomania, kleptomania, male impotence, cancer (e.g., small cell lung carcinoma), chronic paroxysmal hemicrania, headache (associated with vascular disorders) autism, pervasive developmental disorder NOS, Asperger's disorder, selective mutism, chronic motor or vocal tic disorder, somatization disorder, insomnia, intermittent explosive disorder, pyromania, pathological gambling, impulse-control disorder, premenstrual dysphoric disorder, and attention-deficit hyperactivity disorder (ADHD), in a mammal, preferably a human, including an effective amount of a compound of the formula I or a pharmaceutically acceptable salt thereof effective in treating such disorder or condition and a pharmaceutically acceptable carrier.

The present invention also relates to a pharmaceutical composition or a method for treating a disorder or condition that can be treated by enhancing serotonergic neurotransmission in a mammal, preferably a human, including an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in treating such disorder or condition and a pharmaceutically acceptable carrier. Examples of such disorders and conditions are those enumerated herein, e.g., those enumerated in the immediately preceding paragraph.

The present invention also relates to a pharmaceutical composition or a method for treating any one or more or combination of the following a disorder or condition selected from attention-deficit/hyperactivity disorder (ADHD), bipolar disorder, bipolar disorder-depressed phase; mild, moderate, or severe depression with or without atypical features, melancholic features, psychotic features, catatonic features; seasonal affective disorder, postpartum depression, geriatric depression, chronic depression, dysthymia, adjustment disorder with depressed mood, adjustment disorder with anxiety, depressed mood, mixed anxiety and depression, substance induced mood disorder, mood disorder secondary to a general medical condition, social anxiety, separation anxiety disorder, binge eating disorder, dependencies and addictions to marijuana, panic disorder with agoraphobia; autism, pervasive developmental disorder NOS, Asperger's disorder, selective mutism, chronic motor or vocal tic disorder, somatization disorder, insomnia, intermittent explosive disorder, pyromania, pathological gambling, impulse-control disorder, and premenstrual dysphoric disorder, in a mammal, preferably a human, including an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof effective in treating such disorder or condition and a pharmaceutically acceptable carrier.

The compounds of the present invention are also useful in the treatment of patients afflicted with two or more of the above disorders. It is not uncommon for certain of the above listed disorders, which can be treated using the novel compounds of the invention, to exist in patients afflicted with one or more other such disorders. For example, depression is often comorbid with anxiety and both can be treated using the compounds or pharmaceutical compositions of the present invention. A further particular advantage of the serotonin 1 (5-HT₁) receptor agonist/antagonist compounds of the present invention is that they exhibit pharmacological and therapeutic activity without the delayed onset of action usually associated with selective serotonin reuptake inhibitors.

The present invention further relates to a pharmaceutical composition for treating a condition or disorder that can be treated by enhancing serotonergic neurotransmission in a mammal, preferably a human, including: a) a pharmaceutically acceptable carrier; b) an amount of a compound of formula I or a pharmaceutically acceptable salt thereof; and c) an amount of a serotonin re-uptake inhibitor or a pharmaceutically acceptable salt thereof; wherein the amounts of (b) and (c) are together pharmaceutically effective. The present invention also relates to a method for treating a disorder or condition that can be treated by enhancing serotonergic neurotransmission in a mammal, preferably a human, including administering to a mammal requiring such treatment: a) an amount of a compound of the formula I, as described anywhere herein, or a pharmaceutically acceptable salt thereof; and b) an amount of a 5-HT re-uptake inhibitor, preferably sertraline, or a pharmaceutically acceptable salt thereof; wherein the amounts of (a) and (b) are together effective in treating said disorder or condition.

The present invention also relates to a method for treating a disorder or condition that can be treated by enhancing serotonergic neurotransmission in a mammal, preferably a human, including administering to the mammal requiring such treatment: a) an amount of a 5-HT_1A antagonist or a pharmaceutically acceptable salt thereof; and b) an amount of a 5-HT_{1 B} antagonist of formula I or a pharmaceutically acceptable salt thereof; wherein the amounts of (a) and (b) are together effective in treating said disorder or condition.

The present invention also relates to a pharmaceutical composition for treating a disorder or condition that can be treated by enhancing serotonergic neurotransmission in a mammal, preferably a human, including: a) an amount of a 5-HT_1A antagonist or a pharmaceutically acceptable salt thereof; and b) an amount of a 5-HT_{1 B} antagonist of formula I or a pharmaceutically acceptable salt thereof; wherein the amounts of (a) and (b) are together effective in treating said disorder or condition.

"Treating" refers to, and includes, reversing, alleviating, inhibiting the progress of, or preventing, a disease, disorder or condition, or one or more symptoms thereof; and, "treatment" and "therapeutically" refer to the act of treating, as defined above. "Enhanced serotonergic neurotransmission," as used herein, refers to increasing or improving the neuronal process whereby serotonin is released by a pre-synaptic cell upon excitation and crosses the synapse to stimulate or inhibit the post-synaptic cell.

"Chemical dependency," as used herein, means an abnormal craving or desire for, or an addiction to a drug. Such drugs are generally administered to the affected individual by any of a variety of means of administration, including oral, parenteral, nasal or by inhalation. Examples of chemical dependencies treatable by the methods of the present invention are dependencies on alcohol, nicotine, ***e, heroin, phenobarbital, and benzodiazepines (e.g., Valium (trademark)). "Treating a chemical dependency," as used herein, means reducing or alleviating such dependency. Sertraline, (1S-cis)-4-(3,4-dichlorophenyl)-1 ,2,3,4-tetrahydro-N-methyl-1- naphthalenamine, as used herein has the following structural formula:

and ordinarily used in the form of its hydrochloride salt. The synthesis of sertraline is described in U.S. Pat. No.4,536,518, assigned to Pfizer Inc. Sertraline hydrochloride is useful as an antidepressant and anorectic agent, and is also useful in the treatment of depression, chemical dependencies, anxiety obsessive compulsive disorders, phobias, panic disorder, post traumatic stress disorder, and premature ejaculation. DETAILED DESCRIPTION QF THE INVENTION

Compounds of formula I may be prepared according to the following reaction schemes and discussion. Unless otherwise indicated, R₁, R₃, R₆, R_n, X, Y₁, Y₂, W¹, W², and all other variables of structural formula I in the reaction schemes and discussion that follow are as defined above.

Scheme 1

Step 1 of Scheme 1 is a coupling reaction between an amine and an aromatic ring. A mixture of 2-substituted benzaldehyde (Yi = Y₂ = CH) or pyridylaldehyde 13 (Y₁ = N; Y₂ = CH or Y₁ = CH; Y₂ = N) wherein the substituent at the 2-position, indicated as Z₁ is a functional group that has the ability to undergo nucleophilic displacement or oxidative addition such as, but not limited to, F, Cl, Br, I, and sulfonate, such as 2-fluorobenzaldehyde, and an N- substituted compound of the formula H-G¹, such as 1-methylpiperazine, are treated in a solvent selected from water, 1 ,4-dioxane, n-butanol, W,/V-dimethylfonmamide, dimethyl sulfoxide, acetonitrile or mixtures thereof, preferably water, with a base such as a trialkyl amine or an alkali metal carbonate, preferably potassium carbonate, at a temperature of about 4O⁰C to about 150°C, preferably about 90⁰C to about 120⁰C to yield an aldehyde of the formula 2. Compounds of R₁ = G² can be prepared using standard variations of the methods discussed herein using procedures known to those of ordinary skill in the art.

Alternatively, this coupling can be facilitated by use of a transition metal such as palladium and the preferred method is that of Buchwald as described in Buchwald, et al. J. Org. Chβm., 2000, 65, pp. 1144-1157 and pp. 1158-1174. A mixture of the 2-Z-benzaldehyde 12 and N-substituted compound of the formula G¹, G³, G⁵, G⁶, or G⁷, such as 1- methylpiperazine, are treated in a solvent selected from toluene, benzene, DME wherein toluene is preferred with a base such as sodium or potassium tert-butoxide, sodium or potassium carbonate, potassium phosphonate preferably sodium tert-butoxide with a palladium source such as tetrakis(triphenylphosphine)palladium, palladium acetate, tris(dibenzyideneacetone)dipalladium, transdichloro-bis(triphenylphospine)palladium or optionally added phosphine ligands where added such as BINAP or triphenylphosphine where palladium acetate and BINAP is preferred at a temperature of about 4O⁰C to 15O⁰C, preferably about 9O⁰C to 120⁰C to yield an aldehyde of the formula 2.

Step 2 of Scheme 1 is an aldol condensation. Addition of a solution of 3 and aldehyde 2 in tetrahydrofuran to a solution of a base such as sodium hydride, potassium hydride, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyiamide), or potassium bis(trimethylsilylamide), where sodium bis(trimethylsilyl)amide is preferred, in a solvent such as tetrahydrofuran, at a temperature from about O⁰C to 100⁰C, where 3O⁰C to 8O⁰C is preferred, affords 1b. Step 3 of Scheme 1 is a reduction of a carbon-carbon double bond. Catalytic reduction of the double bond of compound 1b to afford 1a is accomplished in a reaction inert solvent such as a lower alcohol, preferably methanol or ethanol, with a noble metal catalyst, such as platinum or palladium, suspended on a solid support, preferably 10% palladium on carbon, under a hydrogen pressure of about 1 atmosphere to about 5 atmospheres, preferably about 3 atmospheres to about 4 atmospheres, at a temperature of about 10⁰C to about 100⁰C, preferably about 4O⁰C to about 60°C, while shaking the reaction mixture. Alternatively, the double bond can be reduced under transfer hydrogenation conditions where a hydride donor such as cyclohexadiene or ammonium formate is used in place of hydrogen, where ammonium formate is preferred, in a reaction inert solvent such as a lower alcohol, THF, dioxane or ethyl acetate, preferably methanol or ethanol, in the presence of a noble metal catalyst on a solid support such as palladium on carbon (Pd/C), palladium on barium sulfate (Pd/BaSO₄), platinum on carbon (Pt/C), or tris(triphenylphosphine) rhodium chloride (Wilkinson's catalyst), preferably about 10% palladium on carbon, at a temperature of about 2O⁰C to 15O⁰C, preferably 4O⁰C to 8O⁰C. Alternatively, the double bond can be reduced with sodium borohydride or sodium cyanoborohydride, with the optional addition of acetic acid, in a solvent such as methanol, water, ethanol, tetrahydrofuran, or any mixture thereof, at a temperature from 0 to 50⁰C.

Alternatively, the reduction of the carbon-carbon double bond of 1b to produce a compound 1a can be accomplished using alternative procedures known to one skilled in the art; see Larock, R. C. Comprehensive Organic Transformations. VCN Publishers, 1989, for examples.

Step 4 of Scheme 1 is an alkylation, acylation, or sulfonylation of the secondary amine of 1a to afford 1c. The alkylation, acylation, and sulfonylation can be carried out according to methods known to one skilled in the art. Such methods can be found in Larock, R. C. Comprehensive Organic Transformations. VCN Publishers, 1989. The preferred method is the reductive alkylation, wherein 1a (R_n = H)₁ a lower aldehyde or ketone, and an optional acid, such as acetic acid, in a solvent such as 1 ,2-dichloroethane, methanol, ethanol, water or tetrahydrofuran, are treated with a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride, where sodium triacetoxyborohydride is preferred, to afford 1c.

The acylation of 1a can be effected by treating a mixture of 1a, a base such as sodium hydroxide, in a solvent system such as chloroform-water with an acylating agent including, but not limited to, acid chlorides, acid anhydrides, or other activated carboxylic acid derivatives, where acid anhydrides and acid chlorides are preferred, to afford 1c.

The sulfonylation of 1a to can be effected by treating a mixture of 1a, a trialkylamine base, such as triethylamine or diisopropylethylamine, where triethylamine is preferred, in a solvent such as methylene chloride, with an alkylsulfonyl chloride, to afford 1c. Scheme 2 outlines methods for preparing piperazinones of formula 3.

Scheme 2.

Step 1 of Scheme 2 is an acylation reaction. Treatment of a solution of diamine 4 in methylene chloride with an' acylating agent such as O-benzyl-O'-(Λ/-succimidyl) carbonate affords 5 (Adamczyk, M.; Fishpaugh, J. R.; Heuser, K. J. Organic Preparations and Procedures Int. 1998, 30, pp. 339-348). Step 2 of Scheme 2 is an alkylation reaction. Treatment of 5 and a base such as sodium or potassium carbonate, triethylamine, or diisopropylethylamine, where diisopropylethylamine is preferred, in a solvent such as methylene chloride, chloroform, diethyl ether, or tetrahydrofuran, where tetrahydrofuran is preferred, with an ethylbromoacetate or ethylchloroacetate, where ethylbromoacetate is preferred, affords 6. Step 3 of Scheme 2 is an amine deprotection/cyclization. A mixture of 6 and a noble metal catalyst such as palladium or platinum on carbon, where palladium on carbon is preferred, in a lower alcohol solvent, where ethanol is preferred, under a hydrogen atmosphere of about 10-100 psi, where 35 to 60 psi is preferred, at a temperature from about 40 to 100⁰C, where 60 to 75⁰C is preferred, affords 7 (W¹ = W² = CH₃).

Step 4 of Scheme 2 is an acylation of an amine. To a mixture of 7 and a base such as sodium or potassium carbonate, where sodium carbonate is preferred, in a solvent system of 2:1 ethylacetate-water, at a temperature from about O⁰C to 5O⁰C, where about 2O⁰C to 3O⁰C is preferred, is added to an acylating agent such as methyl chloroformate, ethyl chloroformate, BOC-anhydride, benzyl chloroformate, or allyl chloroformate, where benzyl chloroformate is preferred, to afford 8.

Step 5 of Scheme 2 is a transition-metal mediated arylation (R₃ = aryl or heteroaryl). The conversion of 8 to 3, wherein R₃ is an optionally substituted aryl or heteroaryl group as described in the general claims, can be accomplished by treating 8, an aryl or heteroaryl chloride, bromide, iodide, or sulfonate, where the bromide is preferred, a base such as potassium phosphate, potassium carbonate, sodium carbonate, thallium carbonate, cesium carbonate, potassium terf-butoxide, lithium terf-butoxide, or sodium terf-butoxide, where potassium carbonate is preferred, a diamine, such as 1 ,2-ethylenediamine, /V₁AT- dimethylethylenediamine, Λ/,Λ/-dimethylethylenediamine, or cis-1 ,2-diaminocyclohexane, where Λ/,Λf-dimethylethylenediamine is preferred, cuprous chloride, bromide or iodide, where cuprous iodide is preferred, a small amount of water, where about 1 to 4 percent is preferred, in a reaction inert solvent such as 1,2-dimethoxyethane, diglyme, t-butyi methyl ether, tetrahydrofυran, benzene, toluene, where toluene is preferred, from about 40 ⁰C to 150 ⁰C, where about 80⁰C to 12O⁰C is preferred affords 3. Alternatively, the conversion of 8 to 3, wherein R₃ is an optionally substituted aryl or heteroaryl group as described in the general claims, can be accomplished by treating 8 and an aryl or heteroaryl chloride, bromide, iodide, or sulfonate, where the bromide is preferred, with a base such as an alkali metal carbonate, an alkali metal amine base, an alkali metal phosphonate, or an alkali metal alkoxide, where cesium carbonate is preferred, a phosphine ligand, where 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (XANTPHOS™) is preferred, a palladium species, such as palladium (II) acetate or tris(dibenzylideneacetone)dipalladium (0) or the corresponding chloroform adduct, where tris(dibenzylideneacetone)dipalladium (0) is preferred, in an inert solvent such as 1 ,4-dioxane or toluene, where 1 ,4-dioxane is preferred, at a temperature from about 40 to 160⁰C, where 80 to 120⁰C is preferred. For compounds of 7 where W¹ = W² = H, the intermediate is prepared according to

Choi, S. -W et. al J. Med. Chem. 1999, 42, pp. 3647-3656. To a mixture of 7 and a base such as sodium or potassium carbonate, where sodium carbonate is preferred, in a solvent system of 2:1 ethylacetate-water, at a temperature from about 0 to 50⁰C, where about 2O⁰C to 30⁰C is preferred, is added an acylating agent such as methyl chloroformate, ethyl chloroformate, BOC-anhydride, benzyl chloroformate, or allyl chloroformate, where benzyl chloroformate is preferred, to afford 8. Compound 3 is obtained as described for compounds where W¹ = W² = CH₃.

Scheme 3 shows an alternative route to compounds of formula 3.

Scheme 3

3 12

Step 1 of Scheme 3 is a nucleophilic displacement of a carbamate oxygen by an amine nucleophile. Heating a mixture of an aromatic/heteroaromatic amine hydrochloride salt 9 (R₃-NH₂ HCI) and oxazolidinone in a solvent such as 2-(2-methoxyethoxy)ethanol at a temperature about 165⁰C affords diamine 10.

Step 2 of Scheme 3 is a nitrogen acylation reaction. Addition of an acylating reagent such as methyl chloroformate, ethylchloroformate, allylchloroformate, or benzyl chloroformate, where benzylchloroformate is preferred, to a mixture of diamine 10 in 5:1 ethylacetate-20% aqueous sodium hydroxide at a temperature about 0⁰C affords 11.

Step 3 of Scheme 3 is a nitrogen acylation reaction. The reaction mixture from Step 2, containing 11 was treated with bromoacetylbromide to afford 12.

Step 4 of Scheme 3 is an intramolecular nucleophilic substitution reaction. Addition of a base, such as sodium hydride, potassium hydride, sodium bis(trimethylsilylamide), or potassium bis(trimethylsilylamide), to a solution of 12 in tetrahydrofuran at a temperature from about 20 to 30⁰C, followed by warming to a temperature from about 50 to 60⁰C, where 55 ⁰C is preferred, yields compound 3. Scheme 4 shows a route to compounds of formula 1 wherein R₁ = G². Scheme 4

ig 1f

Step 1 of Scheme 4 is a palladium-catalyzed cross-coupling. Aryl/heteroaryl halide or sulfonate 13 (as defined in Scheme 1), wherein Z = OSO₂CF₃ is preferred, is coupled with vinyl stannane 14, wherein A is -OaIIyI, -Oterf-butyl, or Obenzyl, in the presence of a palladium catalyst via the method outlined in Bioorganic and Medicinal Chemistry Letters, 2004, 14, pp. 3747-3751, to afford 15.

Step 2 of Scheme 4 is an aldol condensation. Addition of a solution of 3 and aldehyde 15 in tetrahydrofuran to a solution of a base such as sodium hydride, potassium hydride, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilylamide), or potassium bis(trimethylsilylamide), where sodium bis(trimethylsilyl)amide is preferred, in a solvent such as tetrahydrofuran, at a temperature from about O⁰C to 100⁰C, where 30°C to 80°C is preferred, affords 16. Step 3 of Scheme 4, wherein A = -OBenzyl for 16, is a reduction of two carbon- carbon double bonds and removal of a carboxybenzyl (CBz) protecting group. Reduction/deprotection of 16 to afford 1d is accomplished in a reaction inert solvent such as a lower alcohol, preferably methanol or ethanol, with a noble metal catalyst, such as platinum or palladium, suspended on a solid support, preferably 10% palladium on carbon, under a hydrogen pressure of about 1 atmosphere to about 5 atmospheres, preferably about 3 atmospheres to about 4 atmospheres, at a temperature of about 10°C to about 100⁰C, preferably about 40°C to about 60°C, while shaking the reaction mixture. Alternatively, transfer hydrogenation conditions can be utilized where a hydride donor such as cyclohexadiene or ammonium formate is used in place of hydrogen, where ammonium formate is preferred, in a reaction inert solvent such as a lower alcohol, THF, dioxane or ethyl acetate, preferably methanol or ethanol, in the presence of a noble metal catalyst on a solid support such as palladium on carbon (Pd/C), palladium on barium sulfate (Pd/BaSO₄), platinum on carbon (Pt/C), or tris(triphenylphosphine) rhodium chloride (Wilkinson's catalyst), preferably about 10% palladium on carbon, at a temperature of about 20⁰C to 15O⁰C, preferably 4O⁰C to 80⁰C.

Step 4 of Scheme 4, wherein A = -Oterf-butyl for 16, is a reduction of two carbon- carbon double bonds. The method used to accomplish this is the same as described in Step 3 of Scheme 4, and results in the conversion of 16 to 17.

Step 5 of Scheme 4 is an alkylation, acylation, or sulfonylation of the secondary amine of 17 to afford 18. The alkylation, acylation, and sulfonylation can be carried out according to methods known to one skilled in the art. Such methods can be found in Larock, R. C. Comprehensive Organic Transformations. VCN Publishers, 1989. The preferred method is the reductive alkylation, wherein 17 (R_n = H), a lower aldehyde or ketone, and an optional acid, such as acetic acid, in a solvent such as 1,2-dichloroethane, methanol, ethanol, water or tetrahydrofuran, are treated with a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride, where sodium triacetoxyborohydride is preferred, to afford 18. The acylation of 17 can be effected by treating a mixture of 17, a base such as sodium hydroxide, in a solvent system such as chloroform-water with an acylating agent including, but not limited to, acid chlorides, acid anhydrides, or other activated carboxylic acid derivatives, where acid anhydrides and acid chlorides are preferred, to afford 18. The suifonylation of 17 to can be effected by treating a mixture of 17, a trialkylamine base, such as triethylamine or diisopropylethylamine, where triethylamine is preferred, in a solvent such as methylene chloride, with an alkylsulfonyl chloride, to afford 18.

Step 6 of Scheme 4 is a fe/f-butoxycarbonyl deprotection. Treatment of 18 in a solvent such as dichloromethane or 1 ,4-dioxane with an acid such as trifluoroacetic acid or anhydrous hydrogen chloride at a temperature from about -10⁰C to 50⁰C affords 1 e.

Step 7 of Scheme 4 is a reductive alkylation. Treatment of 1e, a lower aldehyde or ketone, and an optional acid, such as acetic acid, in a solvent such as 1 ,2-dichloroethane, methanol, ethanol, water or tetrahydrofuran, are treated with a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride, where sodium triacetoxyborohydride is preferred, to afford 1f.

Step 8 of Scheme 4 is an acylation. Treatment of 17, wherein A = -Otert-butyl, with benzyl chloroformate in a solvent such as 1:1 dichloromethane/water with a base such as sodium or potassium carbonate affords 19.

Step 9 of Scheme 4 is a terf-butoxycarbonyl deprotection. Treatment of 19 in a solvent such as dichloromethane or 1 ,4-dioxane with an acid such as trifluoroacetic acid or anhydrous hydrogen chloride at a temperature from about -10⁰C to 50⁰C affords 20.

Step 10 of Scheme 4 is a reductive alkylation. Treatment of 20, a lower aldehyde or ketone, and an optional acid, such as acetic acid, in a solvent such as 1 ,2-dichloroethane, methanol, ethanol, water or tetrahydrofuran, are treated with a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride, where sodium triacetoxyborohydride is preferred, affords 21.

Step 11 of Scheme 4 is a carboxybenzyl deprotection. Conversion of 21 to afford 1g is accomplished in a reaction inert solvent such as a lower alcohol, preferably methanol or ethanol, with a noble metal catalyst, such as platinum or palladium, suspended on a solid support, preferably 10% palladium on carbon, under a hydrogen pressure of about 1 atmosphere to about 5 atmospheres, preferably about 3 atmospheres to about 4 atmospheres, at a temperature of about 10⁰C to about 100⁰C, preferably about 4O⁰C to about 60°C, while shaking the reaction mixture. Alternatively, transfer hydrogenation conditions can be utilized where a hydride donor such as cyclohexadiene or ammonium formate is used in place of hydrogen, where ammonium formate is preferred, in a reaction inert solvent such as a lower alcohol, THF, dioxane or ethyl acetate, preferably methanol or ethanol, in the presence of a noble metal catalyst on a solid support such as palladium on carbon (Pd/C), palladium on barium sulfate (Pd/BaSO₄), platinum on carbon (Pt/C), or tris(triphenylphosphine) rhodium chloride (Wilkinson's catalyst), preferably about 10% palladium on carbon, at a temperature of about 20⁰C to 15O⁰C, preferably 40⁰C to 8O⁰C.

General methods for the preparation of aryl halides used in the N-arylation and N- heteroarylation coupling reactions described herein are given in Murugusan, N. US Patent 5,612,359, 1997; Guay, D. et al. Biorganic and Medicinal Chemistry Letters 2002, 12, 1457- 1461; Sail, D. J. et al. Journal of Medicinal Chemistry 2000, 43, 649-663; Olah, G. A.; Porter, R. D. Journal of the American Chemical Society 1971, 93, 6877-6887; Brown, H.C.; Okamoto, Y.; Ham, G. Journal of the American Chemical Society 1957, 79, 1906-1909; Nenitzescu, C; Necsoiu, I. Journal of the American Chemical Society 1950, 72, 3483-3486; Muci, A. R.; Buchwald, S. L. Topics in Current Chemistry, Springer-Verlag: Berlin Heidelberg, 2002; Vol. 219, pp. 131-209; Schefczik, E. DE 19650708, 1968; Howard, H. R.; Sarges, R. EP 104860, 1984; Wang, X et al. Tetrahedron Letters, 2000, 41, pp. 4335-4338, all of which are herein incorporated by reference in their entirety. Those skilled in the art can recognize that, where appropriate, hydroxyl groups on aryl or heteroaryl halides can be etherified by standard methods known in the art such as treatment with an alkali metal hydride or alkali metal hydroxide, such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, or cesium hydroxide, preferably sodium hydride, in a solvent such as tetrahydrofuran, Λ/,Λ/-dimethylformamide, or dimethylsulfoxide, preferably tetrahydrofuran, at a temperature from about -20 to 50 ⁰C, followed by addition of an alkyl halide or tosylate, preferably an alkyl iodide.

Compounds of the formula I and their pharmaceutically acceptable salts (hereinafter also referred to, collectively, as "the active compounds") are useful psychotherapeutics and are potent agonists and/or antagonists of the serotonin 1A (5-HT_1A) and/or serotonin 1B (5- HT₁B) receptors. The active compounds are useful in the treatment of hypertension, depression, generalized anxiety disorder, phobias (e.g., agoraphobia, social phobia and simple phobias), posttraumatic stress syndrome, avoidant personality disorder, sexual dysfunction (e.g., premature ejaculation), eating disorders (e.g., anorexia nervosa and bulimia nervosa), obesity, chemical dependencies (e.g., addictions to alcohol, ***e, heroin, phenolbarbitol, nicotine and benzodiazepines), cluster headache, migraine, pain, Alzheimer's disease, obsessive-compulsive disorder, panic disorder, memory disorders (e.g., dementia, amnestic disorders, and age-related cognitive decline (ARCD)), Parkinson's diseases (e.g., dementia in Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesias), endocrine disorders (e.g., hyperprolactinaemia), vasospasm (particularly in the cerebral vasculature), cerebellar ataxia, gastrointestinal tract disorders (involving changes in motility and secretion), negative symptoms of schizophrenia, premenstrual syndrome, Fibromyalgia Syndrome, stress incontinence, Tourette syndrome, trichotillomania, kleptomania, male impotence, cancer (e.g., small cell lung carcinoma), chronic paroxysmal hemicrania and headache (associated with vascular disorders). Biological Assay

The in vitro activity of the compounds of the present invention at the 5-HTi_B binding site may be determined according to the following procedure. Bovine caudate tissue is homogenized and suspended in 20 volumes of a buffer containing 50 mM TRIS.hydrochloride (tris[hydroxymethyl]aminomethane hydrochloride) at a pH of 7.7. The homogenate is then centrifuged at 45,000 G for 10 minutes. The supernatant is then discarded and the resulting pellet resuspended in approximately 20 volumes of 50 mM TRIS.hydrochloride buffer at pH 7.7. This suspension is then pre-incubated for 15 minutes at 37°C, after which the suspension is centrifuged again at 45,000 G for 10 minutes and the supernatant discarded. The resulting pellet (approximately 1 gram) is resuspended in 150 ml of a buffer of 15 mM TRIS.hydrochloride containing 0.01 percent ascorbic acid with a final pH of 7.7 and also containing 10 μM pargyiine and 4 mM calcium chloride (CaCI₂). The suspension is kept on ice at least 30 minutes prior to use.

The inhibitor, control or vehicle is then incubated according to the following procedure. To 50 μl of a 20 percent dimethylsulfoxide (DMSO)/80 percent distilled water solution is added 200 μl of tritiated 5-hydroxytryptamine (2 nM) in a buffer of 50 mM TRIS.hydrochloride containing 0.01 percent ascorbic acid at pH 7.7 and also containing 10 μM pargyiine and 4 μM calcium chloride, plus 100 nM of 8-hydroxy-DPAT (dipropylaminotetraline) and 100 nM of mesulergine. To this mixture is added 750 μl of bovine caudate tissue, and the resulting suspension is vortexed to ensure a homogenous suspension. The suspension is then incubated in a shaking water bath for 30 minutes at 25°C. After incubation is complete, the suspension is filtered using glass fiber filters (e.g., Whatman GF/B™ filters.). The pellet is then washed three times with 4 ml of a buffer of 50 mM TRIS.hydrochloride at pH 7.7. The pellet is then placed in a scintillation vial with 5 ml of scintillation fluid (Aquasol 2™) and allowed to sit overnight. The percent inhibition can be calculated for each dose of the compound. An IC₅₀ value can then be calculated from the percent inhibition values.

The activity of the compounds of the present invention for 5-HT_1A binding ability can be determined according to the following procedure. Rat brain cortex tissue is homogenized and divided into samples of 1 gram lots and diluted with 10 volumes of 0.32 M sucrose solution. The suspension is then centrifuged at 900G for 10 minutes and the supernate separated and recentrifuged at 70,000 G for 15 minutes. The supemate is discarded and the pellet re-suspended in 10 volumes of 15 mM TRIS.hydrochloride at pH 7.5. The suspension is allowed to incubate for 15 minutes at 37⁰C. After pre-incubation is complete, the suspension is centrifuged at 70,000 G for 15 minutes and the supernate discarded. The resulting tissue pellet is resuspended in a buffer of 50 mM TRIS.hydrochloride at pH 7.7 containing 4 mM of calcium chloride and 0.01 percent ascorbic acid. The tissue is stored at -70° C until ready for an experiment. The tissue can be thawed immediately prior to use, diluted with 10 μm pargyline and kept on ice.

The tissue is then incubated according to the following procedure. Fifty microliters of control, inhibitor, or vehicle (1 percent DMSO final concentration) is prepared at various dosages. To this solution is added 200 μl of tritiated DPAT at a concentration of 1.5 nM in a buffer of 50 mM TRIS.hydrochloride at pH 7.7 containing 4 mM calcium chloride, 0.01 percent ascorbic acid and pargyline. To this solution is then added 750 μl of tissue and the resulting suspension is vortexed to ensure homogeneity. The suspension is then incubated in a shaking water bath for 30 minutes at 37° C. The solution is then filtered, washed twice with 4 ml of 10 mM TRIS.hydrochloride at pH 7.5 containing 154 mM of sodium chloride. The percent inhibition is calculated for each dose of the compound, control or vehicle. IC₅₀ values are calculated from the percent inhibition values.

The agonist and antagonist activities of the compounds of the invention at 5-HT_1A and 5-HT_{1 B} receptors can be determined using a single saturating concentration according to the following procedure. Male Hartley guinea pigs are decapitated and 5-HT_1A receptors are dissected out of the hippocampus, while 5-HT_{1 B} receptors are obtained by slicing at 350 mM on a Mcllwain tissue chopper and dissecting out the substantia nigra from the appropriate slices. The individual tissues are homogenized in 5 mM HEPES buffer containing 1 mM EGTA (pH 7.5) using a hand-held glass-Teflon^® homogenizer and centrifuged at 35,000xg for 10 minutes at 4°C. The pellets are resuspended in 100 mM HEPES buffer containing 1 mM EGTA (pH 7.5) to a final protein concentration of 20 mg (hippocampus) or 5 mg (substantia nigra) of protein per tube. The following agents are added so that the reaction mix in each tube contained 2.0 mM MgCI₂, 0.5 mM ATP, 1.0 mM cAMP, 0.5 mM IBMX, 10 mM phosphocreatine, 0.31 mg/mL creatine phosphokinase, 100 μM GTP and 0.5-1 microcuries of [³²P]-ATP (30 Ci/mmol: NEG-003-New England Nuclear). Incubation is initiated by the addition of tissue to siliconized microfuge tubes (in triplicate) at 30° C. for 15 minutes. Each tube receives 20 μL tissue, 10 μL drug or buffer (at 10x final concentration), 10 μL 32 nM agonist or buffer (at 10x final concentration), 20 μL forskolin (3 μM final concentration) and 40 μL of the preceding reaction mix. Incubation is terminated by the addition of 100 μL 2% SDS, 1.3 mM cAMP, 45 mM ATP solution containing 40,000 dpm [³H]-CAMP (30 Ci/mmol: NET- 275~New England Nuclear) to monitor the recovery of cAMP from the columns. The separation of [³²P]-ATP and [³²P]-CAMP is accomplished using the method of Salomon et al., Analytical Biochemistry, 1974, 58, 541-548. Radioactivity is quantified by liquid scintillation counting. Maximal inhibition is defined by 10 μM (R)-8-OH-DPAT for 5-HT_1A receptors, and 320 nM 5-HT for 5-HT_{1 B} receptors. Percent inhibitions by the test compounds are then calculated in relation to the inhibitory effect of (R)-8-OH-DPAT for 5-HT_1A receptors or 5-HT for 5-HT_1B receptors. The reversal of agonist induced inhibition of forskolin-stimulated adenylate cyclase activity is calculated in relation to the 32 nM agonist effect. The compounds of the invention can be tested for in vivo activity for antagonism of 5- HT_1B agonist-induced hypothermia in guinea pigs according to the following procedure.

Male Hartley guinea pigs from Charles River, weighing 250-275 grams on arrival and 300-600 grams at testing, serve as subjects in the experiment. The guinea pigs are housed under standard laboratory conditions on a 7 a.m. to 7 p.m. lighting schedule for at least seven days prior to experimentation. Food and water are available ad libitum until the time of testing.

The compounds of the invention can be administered as solutions in a volume of 1 ml/kg. The vehicle used is varied depending on compound solubility. Test compounds are typically administered either sixty minutes orally (p.o.) or 0 minutes subcutaneously (s.c.) prior to a 5-HT_1B agonist, such as [3-(1-methylpyrrolidin-2-ylmethyl)-1H-indol-5-yl]-(3-nitropyridin-3- yl)-amine, which can be prepared as described in PCT publication WO93/11106, published Jun. 10, 1993 which is administered at a dose of 5.6 mg/kg, s.c. Before a first temperature reading is taken, each guinea pig is placed in a clear plastic shoe box containing wood chips and a metal grid floor and allowed to acclimate to the surroundings for 30 minutes. Animals are then returned to the same shoe box after each temperature reading. Prior to each temperature measurement each animal is firmly held with one hand for a 30-second period. A digital thermometer with a small animal probe is used for temperature measurements. The probe is made of semi-flexible nylon with an epoxy tip. The temperature probe is inserted 6 cm. into the rectum and held there for 30 seconds or until a stable recording is obtained. Temperatures are then recorded.

In p.o. screening experiments, a "pre-drug" baseline temperature reading is made at - 90 minutes, the test compound is given at -60 minutes and an additional -30 minute reading is taken. The 5-HT_{1 B} agonist is then administered at 0 minutes and temperatures are taken 30, 60, 120 and 240 minutes later. In subcutaneous screening experiments, a pre-drug baseline temperature reading is made at -30 minutes. The test compound and 5-HT_1B agonists are given concurrently and temperatures are taken at 30, 60, 120 and 240 minutes later.

Data are analyzed with two-way analysis of variants with repeated measures in Newman-Keuls post hoc analysis.

The active compounds of the invention can be evaluated as anti-migraine agents by testing the extent to which they mimic sumatriptan in contracting the dog isolated saphenous vein strip (P. Humphrey et al., Br. J. Pharmacol., 94, 1128 (1988)). This effect can be blocked by methiothepin, a known serotonin antagonist. Sumatriptan is known to be useful in the treatment of migraine and produces a selective increase in carotid vascular resistance in the anesthetized dog. The pharmacological basis of sumatriptan efficacy has been discussed in W. Fenwick et al., Br. J. Pharmacol., 96, 83 (1989).

The serotonin 5-HTi agonist activity can be determined by the in vitro receptor binding assays, as described for the 5-HT_1A receptor using rat cortex as the receptor source and [³H]-8-OH-DPAT as the radioligand (D. Hoyer et al., Eur. J. Pharm., 118, 13 (1985)) and as described for the 5-HT_1B receptor using bovine caudate as the receptor source and [^serotonin as the radioligand (R. E. Heuring and S. J. Peroutka, J- Nβurosciβnce, 7, 894 (1987)).

All tested compounds had IC₅₀ values of 1000 nM or less for the 5HT_1B receptor. The activity of the compounds of the present invention with respect to 5HTi_B (formerly 5HT_{1 D}) binding ability can be determined using standard radioligand binding assays as described in the literature. The 5-HT_1A affinity can be measured using the procedure of Hoyer et al. (Brain Res., 376, 85 (1986)). The 5-HT_{1 D} affinity can be measured using the procedure of Heuring and Peroutka {J. Neurosci., 7, 894 (1987)). The compounds of formula I can advantageously be used in conjunction with one or more other therapeutic agents, for instance, different antidepressant agents such as tricyclic antidepressants (e.g., amitriptyline, dothiepin, doxepin, trimipramine, butripyline, clomipramine, desipramine, imipramine, iprindole, lofepramine, nortriptyline or protriptyline), monoamine oxidase inhibitors (e.g., isocarboxazid, phenelzine or tranylcyclopramine) or 5-HT re-uptake inhibitors (e.g., fluvoxamine, sertraline, fluoxetine or paroxetine), and/or with antiparkinsonian agents such as dopaminergic antiparkinsonian agents (e.g., levodopa, preferably in combination with a peripheral decarboxylase inhibitor e.g., benserazide or carbidopa, or with a dopamine agonist e.g., bromocriptine, lysuride or pergolide). It is to be understood that the present invention covers the use of a compound of general formula (I) or a physiologically acceptable salt or solvate thereof alone and, optionally, in combination with one or more other therapeutic agents.

Compounds of the formula I and the pharmaceutically acceptable salts thereof, in combination with a 5-HT re-uptake inhibitor (e.g., fluvoxamine, sertraline, fluoxetine or paroxetine), preferably sertraline, or a pharmaceutically acceptable salt or polymorph thereof (the combination of a compound of formula I with a 5-HT re-uptake inhibitor is referred herein to as "the active combination"), are useful psychotherapeutics and can be used in the treatment or prevention of disorders the treatment or prevention of which is facilitated by enhanced serotonergic neurotransmission (e.g., hypertension, depression, generalized anxiety disorder, phobias, posttraumatic stress syndrome, avoidant personality disorder, sexual dysfunction, eating disorders, obesity, chemical dependencies, cluster headache, migraine, pain, Alzheimer's disease, obsessive-compulsive disorder, panic disorder, memory disorders (e.g., dementia, amnestic disorders, and age-associated memory impairment), Parkinson's diseases e, dementia in Parkinson's disease, neuroleptic-induced Parkinsonism and tardive dyskinesias), endocrine disorders (e.g., hyperprolactinaemia), vasospasm (particularly in the cerebral vasculature), cerebellar ataxia, gastrointestinal tract disorders (involving changes in motility and secretion) chronic paroxysmal hemicrania and headache (associated with vascular disorders). ^^i/wi^(j u e / 0 0 3 2 C 3

-25-

Serotonin (5-HT) re-uptake inhibitors, preferably sertraline, exhibit positive activity against depression; chemical dependencies; anxiety disorders including panic disorder, generalized anxiety disorder, agoraphobia, simple phobias, social phobia, and post-traumatic stress disorder; obsessive-compulsive disorder; avoidant personality disorder and premature ejaculation in mammals, including humans, due in part to their ability to block the synaptosomal uptake of serotonin. U.S. Pat. No. 4,536,518 describes the synthesis, pharmaceutical composition and use of sertraline for depression and is hereby incorporated by reference in its entirety.

The compositions of the present invention can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, Thus, the active compounds of the invention can be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) or rectal administration or in a form suitable for administration by inhalation or insufflation.

For oral administration, the pharmaceutical compositions can take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate). The tablets can be coated by methods well known in the art. Liquid preparations for oral administration can take the form of, for example, solutions, syrups or suspensions, or they can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).

For buccal administration, the composition can take the form of tablets or lozenges formulated in conventional manner. The active compounds of the invention can be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection can be presented in unit dosage form, e.g, in ampules or in multi-dose containers, with an added preservative. The compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulating agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient can be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. The active compounds of the invention can also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit can be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer can contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator can be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch. A proposed dose of the active compounds of the invention for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above (e.g., depression) is 0.1 to 200 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.

Aerosol formulations for treatment of the conditions referred to above (e.g., migraine) in the average adult human are preferably arranged so that each metered dose or "puff¹ of aerosol contains 20 μg to 1000 μg of the compound of the invention. The overall daily dose with an aerosol can be within the range 100 μg to 10 mg. Administration can be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time.

In connection with the use of an active compound of this invention with a 5-HT re- uptake inhibitor, preferably sertraline, for the treatment of subjects possessing any of the above conditions, it is to be noted that these compounds can be administered either alone or in combination with pharmaceutically acceptable carriers by either of the routes previously indicated, and that such administration can be carried out in both single and multiple dosages. More particularly, the active combination can be administered in a wide variety of different dosage forms, i.e., they can be combined with various pharmaceutically-acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous suspension, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, such oral pharmaceutical formulations can be suitably sweetened and/or flavored by means of various agents of the type commonly employed for such purposes. In general, the compounds of formula I are present in such dosage forms at concentration levels ranging from about 0.5% to about 90% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage and a 5-HT re-uptake inhibitor, preferably sertraline, is present in such dosage forms at concentration levels ranging from about 0.5% to about 90% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage.

A proposed daily dose of an active compound of this invention in the combination formulation (a formulation containing an active compound of this invention and a 5-HT reuptake inhibitor) for oral, parenteral, rectal or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.01 mg to about 2000 mg, preferably from about 0.1 mg to about 200 mg of the active ingredient of formula I per unit dose which could be administered, for example, 1 to 4 times per day. A proposed daily dose of a 5-HT re-uptake inhibitor, preferably sertraline, in the combination formulation for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.1 mg to about 2000 mg, preferably from about 1 mg to about 200 mg of the 5-HT re-uptake inhibitor per unit dose which could be administered, for example, 1 to 4 times per day. A preferred dose ratio of sertraline to an active compound of this invention in the combination formulation for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.00005 to about 20,000, preferably from about 0.25 to about 2,000.

Aerosol combination formulations for treatment of the conditions referred to above in the average adult human are preferably arranged so that each metered dose or "puff" of aerosol contains from about 0.01 μg to about 100 mg of the active compound of this invention, preferably from about 1 μg to about 10 mg of such compound. Administration can be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time. Aerosol formulations for treatment of the conditions referred to above in the average adult human are preferably arranged so that each metered dose or "puff of aerosol contains from about 0.01 mg to about 2000 mg of a 5-HT re-uptake inhibitor, preferably sertraline, preferably from about 1 mg to about 200 mg of sertraline. Administration can be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time. As previously indicated, a 5-HT re-uptake inhibitor, preferably sertraline, in combination with compounds of formula I are readily adapted to therapeutic use as antidepressant agents. In general, these antidepressant compositions containing a 5-HT reuptake inhibitor, preferably sertraline, and a compound of formula I are normally administered in dosages ranging from about 0.01 mg to about 100 mg per kg of body weight per day of a 5- HT re-uptake inhibitor, preferably sertraline, preferably from about 0.1 mg. to about 10 mg per kg of body weight per day of sertraline; with from about 0.001 mg. to about 100 mg per kg of body weight per day of a compound of formula I, preferably from about 0.01 mg to about 10 mg per kg of body weight per day of a compound of formula I, although variations can necessarily occur depending upon the conditions of the subject being treated and the particular route of administration chosen.

The compound of the present invention is administered and dosed in accordance with good medical practice, taking into account the clinical condition of the individual patient, the site and method of administration, scheduling of administration, patient age, sex, body weight and other factors known to medical practitioners. The pharmaceutically "effective amount" for purposes herein is thus determined by such considerations as are known in the art. The amount must be effective to achieve improvement including, but not limited to, improved survival rate or more rapid recovery, or improvement or elimination of symptoms and other indicators as are selected as appropriate measures by those skilled in the art.

In the method of the present invention, the compound of the present invention can be administered in various ways. It should be noted that it can be administered as the compound and can be administered alone or as an active ingredient in combination with pharmaceutically acceptable carriers, diluents, adjuvants and vehicles. The compounds can be administered orally, subcutaneously or parenterally including intravenous, intraarterial, intramuscular, intraperitoneally, intratonsillar, and intranasal administration as well as intrathecal and infusion techniques. Implants of the compounds are also useful. The patient being treated is a warm-blooded animal and, in particular, mammals including man. The pharmaceutically acceptable carriers, diluents, adjuvants and vehicles as well as implant carriers generally refer to inert, non-toxic solid or liquid fillers, diluents or encapsulating material not reacting with the active ingredients of the invention.

The doses can be single doses or multiple doses over a period of several days. The treatment generally has a length proportional to the length of the disease process and drug effectiveness and the patient species being treated. When administering the compound of the present invention parenterally, it can generally be formulated in a unit dosage injectable form (solution, suspension, emulsion). The pharmaceutical formulations suitable for injection include sterile aqueous solutions or dispersions and sterile powders for reconstitution into sterile injectable solutions or dispersions. The carrier can be a solvent or dispersing medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.

Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Nonaqueous vehicles such a cottonseed oil, sesame oil, olive oil, soybean oil, corn oil, sunflower oil, or peanut oil and esters, such as isopropyl myristate, can also be used as solvent systems for compound compositions. Additionally, various additives which enhance the stability, sterility, and isotonicity of the compositions, including antimicrobial preservatives, antioxidants, chelating agents, and buffers, can be added. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. In many cases, it can be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin. According to the present invention, however, any vehicle, diluent, or additive used would have to be compatible with the compounds.

Sterile injectable solutions can be prepared by incorporating the compounds utilized in practicing the present invention in the required amount of the appropriate solvent with various of the other ingredients, as desired.

A pharmacological formulation of the present invention can be administered to the patient in an injectable formulation containing any compatible carrier, such as various vehicle, adjuvants, additives, and diluents; or the compounds utilized in the present invention can be administered parenterally to the patient in the form of slow-release subcutaneous implants or targeted delivery systems such as monoclonal antibodies, vectored delivery, iontophoretic, polymer matrices, liposomes, and microspheres. Examples of delivery systems useful in the present invention include: 5,225,182; 5,169,383; 5,167,616; 4,959,217; 4,925,678; 4,487,603; 4,486,194; 4,447,233; 4,447,224; 4,439,196; and 4,475,196. Many other such implants, delivery systems, and modules are well known to those skilled in the art. The above discussion provides a factual basis for the use of the compound and method for prevention of respiratory viral infection. The methods used with a utility of the present invention can be shown by the following non-limiting examples and accompanying figures.

EXAMPLES The following Examples illustrate the preparation of the compounds of the present invention. Melting points are uncorrected. NMR data are reported in parts per million (δ) and are referenced to the deuterium lock signal from the sample solvent (deuteriochloroform unless otherwise specified). Specific rotations were measured at room temperature using the sodium D line (589 nm). Commercial reagents were utilized without further purification. THF refers to tetrahydrofuran. DMF refers to N,N-dimethylformamide. Chromatography refers to column chromatography performed using 32-63 μm silica gel and executed under nitrogen pressure (flash chromatography) conditions. Room or ambient temperature refers to 20-25⁰C. All non-aqueous reactions were run under a nitrogen atmosphere for convenience and to maximize yields. Concentration at reduced pressure means that a rotary evaporator was used. General Procedure For Copper-Mediated Coupling to Afford Compounds of Formula 3

A mixture 5 of 1 equivalent of the aryl bromide corresponding to the aryl group of the

N-arylated product, copper (I) iodide (0.1 equivalent), potassium carbonate (1.5 equivalents), and N-N'-dimethylethylendiamine (0.1 equivalent) in toluene (5 volumes) containing water

(0.05-0.5 volume) were stirred at reflux until HPLC analysis showed disappearance of the starting aryl bromide. The mixture was cooled to room temperature and filtered through a pad of Celite and washed with toluene. The filtrate was washed with water and the organic extracts were washed with brine and concentrated to provide the crude arylated product 3, which was purified by silica gel chromatography.

The following compounds were made via coupling between the appropriate aryl bromide R₃-Br and the piperazinone 8.

Preparation 1. 4-(4-tert-Butyl-phenyl)-3-oxo-piperazine-1-carboxylic acid benzyl ester. MS (AP/CI) 367.4 (M+H)+. Preparation 2. 3-Oxo-4-[4-(tetrahydro-pyran-4-yl)-phenyl]-piperazine-1-carboxylic acid benzyl ester. MS (AP/CI) 395.3 (M+H)+.

Preparation 3. 4-[4-(1 -Hydroxy-cyclobutyl)-phenyl]-3-oxo-piperazine-1 -carboxylic acid benzyl ester. MS (AP/CI) 381.4 (M+H)+.

Preparation 4. 4-[4-(4-Hydroxy-tetrahydro-pyran-4-yl)-phenyl]-3-oxo-piperazine-1 - carboxylic acid benzyl ester. MS (AP/CI) 411.4 (M+H)+.

Preparation 5. 4-(4-tert-Butyl-phenyl)-2,2-dimethyl-5-oxo-piperazine-1 -carboxylic acid benzyl ester MS (AP/CI) 395.3 (M+H)+

Preparation 6. 2,2-Dimethyl-5-oxo-4-[4-(tetrahydro-pyran-4-yl)-phenyl]-piperazine-1 - carboxylic acid benzyl ester. MS (AP/CI) 423.2 (M+H)+ Preparation 7. 4-[4-(1-Hydroxy-cydobutyl)-phenyl]-2,2-dimethyl-5-oxo-piperazine-1- carboxylic acid benzyl ester. MS (AP/CI) 409.3 (M+H)+.

Preparation 8. 4-(6-Ethoxy-pyridin-3-yl)-3-oxo-piperazine-1 -carboxylic acid benzyl ester. MS (AP/CI) 356.3 (M+H)+.

General Aldol Condensation / Hvdroαeπation Procedure for the Synthesis of Piperazinone Analogs 1a:

1 mL of solvent is used to dissolve 1 mmol of compound to be one volume. Aldehyde 2 (1.0 equiv) and piperazinone 3 (1.2 equiv) in tetrahydrofuran (3.4 volumes) were added dropwise to a solution of sodium bis(trimethylsilylamide) (95%, 1.2 equiv) in tetrahydrofuran (11 volumes) quickly. After 10 minutes, the reaction mixture was removed from the heat and was allowed to cool to room temperature. Silica gel was added and the solvent was removed in vacuo. The residue was purified by silica gel chromatography to afford a compound with mass (AP/CI - M+H+) corresponding to the desired aldol product 1b. This residue was dissolved in ethanol (34 volumes), 10% palladium on carbon (0.5 x weight of 1b) was added, and the mixture was placed under 50 psi hydrogen and was heated at 65 ⁰C for 48 hours. After cooling to room temperature, the hydrogen atmosphere was replaced with nitrogen, the mixture was filtered through Celite, and the solvent was removed in vacuo. The residue was purified by silica gel chromatography, to afford 1a. Example 1:

1 -[4-(1 -Hydroxy-cyclobutyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]-piperazin-2- one. ¹³C NMR (100 MHz, CD3OD) d 171.02, 152.03, 146.17, 141.29, 133.61 , 131.43, 127.98, 125.98, 124.76, 120.85, 75.95, 59.70, 55.30, 52.22, 51.73, 44.99, 41.13, 36.67, 33.76, 12.62; MS (AP/CI) 435.5 (M+H)+. Example 2:

1 -[4-(4-Hydroxy-tetrahydro-pyran-4-yl)-phenyl]-3-[2-(4-methyl-piperazin- 1 -yl)-benzyl]- piperazin-2-one. ¹³C NMR (100 MHz, CD3OD) d 171.01, 152.04, 148.21 , 141.26, 133.61, 131.42, 127.98, 126.01, 125.64, 124.76, 120.86, 69.89, 63.76, 59.70, 55.29, 52.26, 51.71, 44.94, 41.14, 38.49, 33.78; MS (AP/CI) 465.5. Example 3:

3-[2-Fluoro-6-(4-methyl-piperazin-1 -yl)-benzyl]-1 -[4-(1 -hydroxy-cyclobutyl)-phenyl]- piperazin-2-one. ¹³C NMR (100 MHz, CDCI3) d 170.26, 163.81, 161.38, 154.17, 145.02, 141.88, 128.54, 128.45, 126.24, 126.20, 121.67, 121.52, 116.89, 116.86, 111.86, 111.63, 59.02, 55.70, 53.07, 52.09, 46.25, 41.49, 37.14, 29.94, 27.19, 13.14; MS (AP/CI) 453.4 (M+H)+.

Example 4:

3-[2-Fluoro-6-(4-methyl-piperazin-1-yl)-benzyl]-1-[4-(tetrahydro-pyran-4-yl)-phenyl]- piperazin-2-one, tosylate salt. Diagnostic ¹³C NMR (100 MHz, CDCI3) d 163.74, 145.47, 141.58, 140.96, 139.36, 129.31, 127.78, 126.23, 126.05, 68.48, 57.69, 53.76, 49.18, 46.75, 43.34, 41.33, 40.81 , 34.01 , 24.68, 21.57; MS (AP/CI) 467.3 (M+H)+.

Example 5:

3-[2-(4-Methyl-piperazin-1-yl)-benzyl]-1-[4-(tetrahydro-pyran-4-yl)-phenyl]-piperazin-2- one. Diagnostic ¹³C NMR (100 MHz, CD3OD) d 170.95, 152.05, 145.35, 140.84, 133.64, 131.42, 127.97, 127.56, 126.36, 124.76, 120.85, 68.12, 59.70, 55.31, 52.31, 51.78, 45.02, 41.12, 33.93; MS (AP/CI) 449.3 (M+H)+.

Example 6:

5,5-Dimethyl-3-[2-(4-methyl-piperazin-1-yl)-benzyl]-1-[4-(tetrahydro-pyran-4-yl)- phenyl]-piperazin-2-one. ¹³C NMR (100 MHz, CDCI3) d 170.16, 152.26, 144.53, 141.35, 133.52, 132.18, 128.12, 127.69, 126.02, 124.77, 120.35, 68.57, 62.40, 57.17, 55.68, 53.13, 48.86, 46.31 , 41.41 , 34.48, 34.10, 28.25, 23.72; MS (AP/CI) 477.4 (M+H)+.

Example 7:

1 -[4-(1 -Hydroxy-cyclobutyl)-phenyl]-5,5-dimethyl-3-[2-(4-methyl-piperazin-1 -yl)- benzyl]-piperazin-2-one. Diagnostic ¹³C NMR (100 MHz, CD3OD) d 170.64, 151.97, 146.14, 141.37, 132.73, 132.03, 128.28, 125.97, 125.63, 124.79, 120.39, 75.92, 61.89, 56.80, 55.16, 44.96, 36.69, 33.88, 26.48, 21.79, 12.63; MS (AP/CI) 463.3 (M+H)+. Example 8:

1-(4-tert-Butyl-phenyl)-5,5-dimethyl-3-[2-(4-methyl-piperazin-1-yl)-benzyl]-piperazin-2- one. ¹³C NMR (100 MHz, CDCI3) d 170.10, 152.15, 149.74, 140.52, 133.58, 132.19, 128.10, 126.28, 125.37, 124.82, 120.38, 62.37, 57.15, 55.62, 53 (brs), 48.87, 46.20, 34.75, 34.55, 31.55, 28.27, 23.74; MS (AP/CI) 449.3 (M+H)+. Example 9:

1 -(4-tert-Butyl-phenyl)-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]-piperazin-2-one. ¹³C NMR (100 MHz, CDCI₃) δ 170.25, 152.34, 149.87, 140.20, 134.08, 131.47, 128.02, 126.34, 125.72, 124.68, 120.88, 60.10, 55.81, 52.95, 52.04, 46.30, 42.12, 34.77, 34.38, 31.57; MS (AP/CI) 421.5 (M+H)+. Example 10:

4-Acetyl-1-(4-tert-butyl-phenyl)-3-[2-(4-methyl-piperazin-1-yl)-benzyl]-piperazin-2-one. A triphasic mixture of (Example 9, 100 mg, 0.24 mmol) in chloroform (2 ml.) and 10% aqueous sodium hydroxide (0.5 mL) at O⁰C was treated with acetic anhydride (22.5 μL, 0.24 mmol). After stirring for thirty minutes, the mixture was warmed to 23⁰C. More acetic anhydride was added (22.5 μL, 0.24 mmol) and the mixture was stirred overnight. The aqueous layer was removed and the organic layer was dried over magnesium sulfate, was filtered, and was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (75:1 chloroform-methanol w/1% ammonium hydroxide) to afford 66% yield

(72.5 mg) of the title compound. ¹³C NMR (100 MHz, CDCI3) d 169.69, 167.64, 152.59,

150.54, 139.39, 132.71, 131.92, 128.88, 126.62, 125.50, 124.97, 121.01, 61. 42, 55.82,

53.19, 50.08, 46.30, 35.62, 34.84, 33.95, 31.54, 20.12; MS (AP/CI) 463.5 (M+H)+. Example 11:

1-(4-tert-Butyl-phenyl)-4-methanesuIfonyl-3-[2-(4-methyl-piperazin-1-yl)-benzyl]- piperazin-2-one. A solution of (Example 9, 100 mg, 0.24 mmol) and triethylamine (40 μL,

0.29 mmol) in methylene chloride (1 mL) cooled in an ice/acetone bath was treated with methanesulfonyl chloride (18.3 μL, 0.24 mmol). The reaction mixture was stirred overnight, slowly warming to room temperature. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (75:1 chloroform-methanol with 1% ammonium hydroxide) to afford 58% yield (69 mg) of the title compound. 13C NMR (100 MHz, CDCI3) d

167.52, 152.76, 150.48, 139.45, 133.31, 132.17, 128.79, 126.57, 125.67, 124.46, 121.21,

58.42, 55.65, 52.77, 51.36, 46.19, 40.33, 39.19, 35.09, 34.83, 31.54; MS (AP/CI) 499.5 (M+H)+.

Example 12:

1-(4-tert-Butyl-phenyl)-3-[2-fluoro-6-(4-methyl-piperazin-1-yl)-benzyl]-piperazin-2-one. ¹³C NMR (100 MHz, CDCI₃) δ 170.21, 163.82, 161.41, 154.27, 149.86, 140.22, 128.49, 128.39, 126.36, 125.74, 121.77, 116.86, 111.82, 111.58, 58.99, 55.73, 53.12, 52.16, 46.29, 41.50, 34.78, 31.57, 27.24; MS (AP/CI) 439.4 (M+H)+.

Example 13:

1 -(6-Ethoxy-pyridin-3-yl)-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]-piperazin-2-one. ¹³C NMR (100 MHz, CD₃OD) δ 171.47, 162.69, 152.05, 144.61, 137.61, 133.63, 133.04, 131.41,

128.00, 124.74, 120.88, 110.99, 62.08, 59.76, 55.31 , 52.29, 51.99, 45.03, 41.15, 33.82, 13.81; MS (AP/CI) 410.3 (M+H)+.

Example 14:

1-(6-Ethoxy-pyridin-3-yl)-3-[2-fluoro-6-(4-methyl-piperazin-1-yl)-benzyl]-piperazin-2- one. ¹³C NMR (100 MHz, CD₃OD) δ 171.37, 163.74, 162.61 , 161.32, 154.18, 154.05, 144.63, 144.58, 137.62, 137.58, 133.17, 128.52, 128.42, 121.69, 121.54, 116.98, 111.74, 111.50, 111.02, 110.99, 62.07, 58.88, 55.28, 52.50, 52.03, 45.03, 40.70, 26.56, 13.90; MS (AP/CI) 428.3 (M+H)+.

Example 15: 1 -(4-lsopropyl-phenyl)-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]-piperazin-2-one.

¹³C NMR (100 MHz, CDCI₃) δ 170.27, 152.38, 147.69, 140.52, 134.07, 131.46,

128.01, 127.42, 126.12, 124.67, 120.87, 60.11, 55.84, 53.01, 52.11, 46.35, 42.15, 34.35, 34.01, 24.2; MS (AP/CI) 407.4 (M+H)+.

Example 16: 1 -(4-tert-Butyl-phenyl)-3-[2-(4-methyl-piperazin-1 -yl)-benzyl]-4-propyl-piperazin-2- one.

Example 9 (100 mg, 0.24 mmol) and propionaldehyde (17.3 uL, 0.24 mmol) in methanol (2 mL) were stirred for 1.5 hours. Sodium cyanoborohydride (18 mg, 0.285 mmol) and acetic acid (50 uL, 0.8 mmol) were added and the reaction mixture was stirred for 2 hours. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (75:1 chloroform-methanol w/ 1% ammonium hydroxide) to afford 72% yield (79 mg) of the title compound. ¹³C NMR (100 MHz, CDCI₃) δ 171.14, 151.84, 149.78, 140.20, 135.41, 131.20, 127.18, 126.32, 125.51, 124.05, 120.27, 65.84, 56.01, 55.92, 52.94, 48.40, 46.37, 45.65, 34.77, 32.43, 31.57, 20.28, 11.72; MS (AP/CI) 463.5 (M+H)+. Examples 17 to 20 were prepared analogously to Example 16 using the appropriate ketone or aldehyde in the reductive amination step. Example 17:

1-(4-tert-Butyl-phenyl)-4-methyl-3-[2-(4-methyl-piperazin-1-yl)-benzyl]-piperazin-2- one. ¹³C NMR (100 MHz, CDCI₃) δ 170.31, 151.92, 149.87, 140.16, 135.26, 130.52, 127.17, 126.35, 125.48, 124.24, 120.48, 68.84, 55.91, 52.94, 50.76, 49.08, 46.41, 43.60, 34.78, 31.57, 30.95; MS (AP/CI) 435.5 (M+H)+. Example 18: 1-(4-tert-Butyl-phenyl)-4-isopropyl-3-[2-(4-methyl-piperazin-1-yl)-benzyl]-piperazin-2- one. ¹³C NMR (100 MHz, CDCI₃) δ 171.41, 151.92, 149.68, 140.29, 135.38, 131.29, 127.13, 126.28, 125.34, 123.98, 120.21, 63.74, 55.94, 53.03, 50.00, 49.65, 46.39, 41.21, 34.75, 32.97, 31.57, 21.46, 16.57; MS (AP/CI) 463.5 (M+H)+. Example 19:

1-(4-tert-Butyl-phenyl)-4-etⁿy^|-3-[2-(4-methyl-piperazin-1-yl)-benzyl]-piperazin-2-one. ¹³C NMR (100 MHz, CDCI₃) δ 170.98, 151.85, 149.80, 140.19, 135.47, 131.10, 127.18, 126.33, 125.49, 124.12, 120.34, 65.82, 55.94, 53.00, 48.66, 48.00, 46.39, 45.55, 34.77, 32.08, 31.67, 12.27; MS (AP/CI) 449.5 (M+H)+. Example 20

1-(4-tert-Butyl-phenyl)-3-[2-(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-piperazin-2- one. Diagnostic 13C NMR peaks (100 MHz, CDCI3) d 168.87, 162.37, 149.91, 146.54, 140.01, 139.55, 126.33, 125.61, 118.88, 77.66, 59.20, 55.58, 51.99, 50.70, 46.38, 42.25, 34.73, 31.54; MS(AP/CI) 422.4 (M+H)+. Example 21

1-(6-Ethoxy-pyridin-3-yl)-3-[2-(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-piperazin- 2-one. 13C NMR (100 MHz, CD3OD) d 171.47, 162.74, 162.07, 145.99, 144.54, 140.19, 137.57, 133.00, 127.41, 119.46, 110.99, 62.08, 58.63, 55.00, 52.04, 50.07, 44.92, 41.14, 33.81, 13.72; MS (AP/CI) 411.3 (M+H)+. Example 22

1 -[4-(1 -Hydroxy-cyclobutyl)-phenyl]-3-[2-(4-methyl-piperazin-1 -yl)-pyridin-3-ylmethyl]- piperazin-2-one. Diagnostic 13C NMR (100 MHz, CD3OD) d 170.93, 162.10, 146.20, 145.98, 141.28, 140.15, 127.44, 125.97, 119.47; 75.94, 58.68, 55.02, 51.80, 50.10, 45.00, 41.21, 36.70, 33.85, 12.65. Example 23

3-[2-(4-Methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-1-[4-(tetrahydro-pyran-4-yl)-phenyi]- piperazin-2-one. Diagnostic 13C NMR (100 MHz, CD3OD) d 170.90, 162.10, 145.97, 145.40, 140.81, 140.16, 127.58, 127.45, 126.34, 119.47, 68.11, 58.65, 55.01, 51.84, 50.10, 44.94, 41.19, 41.12, 33.91; MS (AP/CI) 450.3 (M+H)+. Example 24

1-(4-tert-Butyl-phenyl)-5,5-dimethyl-3-[2-(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]- piperazin-2-one. Diagnostic 13C NMR (100 MHz, CD3OD) d 170.59, 162.18, 150.34, 146.21, 140.59, 140.18, 127.14, 126.14, 125.47, 119.62, 61.97, 55.46, 54.97, 50.21, 45.01, 34.27, 30.53, 26.65, 21.95; MS(AP/CI) 450.3 (M+H)+. Example 25

5,5-Dimethyl-3-[2-(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-1-[4-(tetrahydro-pyran- 4-yl)-phenyl]-piperazin-2-one. Diagnostic 13C NMR peaks (100 MHz, CDCI3) d 146.69, 144.87, 140.98, 127.83, 126.42, 125.96, 119.84, 76.98, 68.52, 62.10, 55.80, 54.11, 48.68, 44.67, 41.37, 34.98, 34.07, 28.33, 23.67; MS (AP/CI) 478.3 (M+H)+. Example 26

1-(4-tert-Butyl-phenyl)-4-methyl-3-[2-(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]- piperazin-2-one. This compound was prepared using Example 20 as starting material and the procedure in Example 16.

¹³C NMR (100 MHz, CDCI3) d 169.69, 161.62, 150.06, 145.96, 139.88, 139.06, 127.29, 126.38, 125.29, 118.90, 68.26, 54.94, 50.82, 49.91, 49.03, 46.00, 45.71, 43.58, 31.54, 31.34; MS (AP/CI) 436.4 (M+H)+ Throughout this application, various publications, including United States patents, are referenced by author and year and patents by number. Full citations for the publications are listed below. The disclosures of these publications and patents in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains. The invention has been described in an illustrative manner, and it is to be understood that the terminology, which has been used is intended to be in the nature of words of description rather than of limitation.

It is thus apparent that many modifications and variations of the present invention are possible in light of the above teachings. It is, therefore, to be understood that within the scope of the appended claims, the invention can be practiced otherwise than as specifically exemplified herein.

Claims

What is claimed is:

1. A compound of formula I :

wherein R₁ is G¹, G², G³, G⁴, G⁵, G⁶, or G⁷, wherein

k is one or two; a is zero to eight;

Each R₁₃ is, independently, (C₁-C₄)alkyl, (C₃-C₈)cycloalkyl, or a (C₁-C₄)methylene bridge from one of the ring carbons of the piperazine or piperidine ring of G¹ or G², respectively, to the same or another ring carbon or a ring nitrogen of the piperazine or piperidine ring of G¹ or G², respectively, having an available bonding site, or to a ring carbon of R⁶ having an available bonding site;

E is oxygen, sulfur, SO, or SO₂; Each X is independently hydrogen, chloro, fluoro, bromo, iodo, cyano, (CM-C₈)alkyl, hydroxy, trifluoromethyl, (C₁-C₈)SIkOXy, SO_t(Ci-C₈)alkyl, CO₂R₁₀. Or CONR₁₁R₁₂; t is zero, one, or two; R_n is hydrogen, (C_rC₆)alkyl, (C₃-C₆)cycloalkyl, C(O)(Ci-C₃)alkyl, aryl, or SO₂R_s; R_s is (Ci-C₆)alkyl, (C₃-C₈)cycloalkyl, or phenyl;

Yi and Y₂ are independently C-X or N₁ provided that Y₁ and Y₂ are not simultaneously N; R₂ is hydrogen, (C₁- C₄)alkyl, phenyl or naphthyi, wherein said phenyl or naphthyl may optionally be substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, (C₁-C₈)SIkYl₁ (C₁-C₈)alkoxy, trifluoromethyl, cyano and -SCMCrCOalkyl;

Ra is -(CH₂)_gB, wherein B is hydrogen, phenyl, naphthyl or a 5- to 7-membered heteroaryl ring containing from one to four heteroatoms in the ring selected from oxygen, nitrogen and sulfur, provided that said ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms and wherein each of the foregoing phenyl, naphthyl and heteroaryl rings may optionally be substituted with one to three substituents independently selected from fluoro, chloro, bromo, iodo, nitro, trifluoromethyl, cyano, trifluoromethoxy, (C₁-C₈)BIkVl. (C₁-C₈JaIkOXy, (d-CaJalkoxytd-CβJalkyl, hydroxy, COOH, SfOMd-CβJalkyl, (CrC₈)hydroxyalkyl-, (C₃-C₈)cycloalkyl-, (C₃-C₈)hydroxycycloalkyl-, (CrCβJalkoxy-fCa-CβJcycloalkyl-, heterocycloalkyl, hydroxyheterocycloalkyl, (CrC₈)alkoxy-heterocycloalkyl, phenyl, naphthyl or a 5- to 7-membered heteroaryl ring containing from one to four heteroatoms selected from oxygen, nitrogen and sulfur, provided that the heteroaryl ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms, and wherein each independently selected phenyl, naphthyl or heteroaryl substituent may itself be substituted with from 1 to 3 (C_rC₈)alkyl, (C₃-C₈)cycloalkyl substituents, or heteroaryl groups, wherein the heteroaryl group is pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridinyl, pyrolopyrimidinyl, and azaindolyl; When B is a phenyl, naphthyl or heteroaryl ring, each said ring may be optionally substituted with one to three substituents independently selected from (a) a lactone formed from -(CH₂J_nOH with an ortho -COOH; (b) -CONR₁₄R_1S, wherein R₁₄ and R₁₅ are independently selected from (CrC₈)alkyl, and benzyl, or R₁₄ and R₁₆ together with the nitrogen to which they are attached form a 4- to 7-membered heteroalkyl ring that may contain from zero to three heteroatoms selected from nitrogen, sulfur and oxygen in addition to the nitrogen of the -CONR₁₄R₁₅ group, wherein when any of said heteroatoms is nitrogen it can be optionally substituted with (C₁-C₈)alkyl or benzyl, provided that said ring cannot contain two adjacent oxygen atoms or two adjacent sulfur atoms; (c) -(CH₂)_VNCOR₁₆R_1T and CORi₆ and Ri₇ taken together with the nitrogen to which they are attached form a 4- to 7- membered lactam ring; and, (d) -(CrC₈)NR₁₈Ri₉ where each of Ri₈ and Ri₉ is selected, independently, from hydrogen and (Ci-C₄)alkyl, or Ri₈ and Ri₉, together with the nitrogen to which they are attached, form a 4- to 7-membered heteroalkyl ring that may contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen; g is zero to three; n is 1 to 3; v is zero to three;

W¹ and W² are each independently H or (Ci-C₃)alkyl; R₈ is selected from the group consisting of hydrogen, (Ci-C₈)alkyl_> or

(C₃-C₈)cycloalkyl, wherein alkyl or cycloalkyl is optionally substituted with hydroxy, (Ci-C₈)alkoxy or one to three fluorine atoms, or [(Ci-C₄)alkyl]aryl wherein the aryl moiety is phenyl, naphthyl, or heteroaryl-(CH₂)_q-, wherein the heteroaryl moiety is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl and benzisothiazolyl, and wherein said aryl and heteroaryl moieties can optionally be substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, bramo, iodo, hydroxy, (d-C₈)alkyl, (Ci-C₈)alkoxy, trifluoromethyl, cyano and SO_t(Ci-C₈)alkyl; q is zero, one, two, three or four; R₇ is selected from the group consisting of hydrogen, (Ci-C₈)alkyl, (C₃-C₈)cycloalkyl, and, [(Ci-C₄)alkyl]aryl wherein the aryl moiety is phenyl, naphthyl, or heteroaryl-(CH₂)_r-, wherein the heteroaryl moiety is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, and benzisothiazolyl and wherein said aryl and heteroaryl moieties may optionally be substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, bromo, iodo, hydroxy, (Ci-C₈)alkyl, (Ci-C₈)alkoxy, trifluoromethyl, C(=O)-(Ci-C₈)alkyl. cyano and ~SO_t(Ci-C₈)alkyl; or R₆ or R₇ taken together form a 2 to 4 carbon chain; r is zero, one, two, three or four; R₈ is hydrogen, (Ci-C₈)alkyl, or (C₃-C₈)cycloalkyl; Rg is hydrogen, (Ci-C₈)alkyl, or (C₃-C₈)cycloalkyl; or R₆ and R₉, together with the nitrogen atom to which they are attached, form a 5- to 7-membered heteroalkyl ring that can contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen; p is zero, one, two, or three; Each of Ri₀, Rn and Ri₂ is selected, independently, from the radicals set forth in the definition of R₂; or Rn and Ri₂, together with the nitrogen to which they are attached, form a 5- to 7-membered heteroalkyl ring that can contain from zero to three additional heteroatoms selected from nitrogen, sulfur and oxygen; the broken line indicates an optional double bond, provided that when the broken line in G² is a double bond that R₈ is absent; and a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein R-, is G¹.

3. The compound of claim 2, wherein R₃ is phenyl, pyridinyl, ~(CH₂)-phenyl, or

-(CH₂)-pyridinyl wherein said phenyl or pyridinyl group is optionally substituted with one to three substituents independently selected from (Ci-C₄)alkyl, (C₁-C₄)BIkOXy₁ trifluoromethoxy, (C₃-C₈)hydroxycycloalkyl-, (C₁-C₈)alkoxy-heterocycloalkyl, hydroxyheterocycloalkyl, and heterocycloalkyl.

4. The compound of claim 3, wherein R₆ is (C₁-C₄)alkyl.

5. The compound of claim 4, wherein W¹ and W² are independently H or CH₃.

6. The compound of claim 5, wherein R_n is H or (C₁-C₃)BIkVl.

7. The compound of claim 6, wherein each X is independently H, chloro fluoro, (Ci-C₄)alkyl, trifluoromethyl, or (C₁-C^aIkOXy.

8. The compound of any one of claims 1 to 7, wherein Y₁ and Y₂ are C-X.

9. The compound of any one of claims 1 to 7, wherein one of Y₁ and Y₂- is C-X and one is N.

10. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1 ^"to 9, a pharmaceutically acceptable carrier, and optionally a serotonin re-uptake inhibitor (SRI) or a pharmaceutically acceptable salt thereof.

11. A method for treating a disorder or condition selected from hypertension, depression, generalized anxiety disorder, phobias, posttraumatic stress syndrome, avoidant personality disorder, premature ejaculation, sexual dysfunction, eating disorders, obesity, chemical dependencies, cluster headache, migraine, pain, Alzheimer's disease, obsessive- compulsive disorder, panic disorder, memory disorders, Parkinson's diseases, endocrine disorders, vasospasm, cerebellar ataxia, gastrointestinal tract disorders, negative symptoms of schizophrenia, premenstrual syndrome, Fibromyalgia Syndrome, stress incontinence, Tourette's syndrome, trichotillomania, kleptomania, male impotence, cancer, chronic paroxysmal hemicrania and headache in a mammal, comprising administering to a mammal in need of such treatment an amount of a compound of formula 1 according to any one of the claims 1 to 9, and optionally an amount of a serotonin re-uptake inhibitor (SRI) or a pharmaceutically acceptable salt thereof, wherein the amounts of the compound of formula 1 and optionally the SRI are pharmaceutically effective.

12. A method for treating a disorder or condition that can be treated or prevented by enhancing serotonergic neurotransmission in a mammal, comprising administering to a mammal in need of such treatment or prevention an amount of a compound of formula 1 of any one of claims 1 to 9 and optionally an amount of a serotonin re-uptake inhibitor (SRI) or a pharmaceutically acceptable salt thereof, wherein the amounts of the compound of formula 1 and optionally the SRI are effective in treating said disorder or condition.

13. A method for treating a disorder or condition that can be treated or prevented by enhancing serotonergic neurotransmission in a mammal, comprising administering to a mammal in need of such treatment a serotonin receptor antagonizing or agonizing effective amount of a compound of any one of claims 1 to 9 and optionally an amount of a serotonin reuptake inhibitor (SRI) or a pharmaceutically acceptable salt thereof, wherein the amounts of the compound of formula 1 and optionally the SRI are effective in treating said disorder or condition.

14. The method of any of claims 11 to 14, wherein the serotonin re-uptake inhibitor is present and is sertraline or a pharmaceutically acceptable salt thereof.