ZA200200811B - Aminoalkoxy carbazoles for the treatment of CNS diseases. - Google Patents

Description

AMINOALKOXY CARBAZOLES FOR Co

THE TREATMENT OF CNS DISEASES Lo

FIELD OF THE INVENTION

The present invention provides aminoalkoxy carbazole derivatives, and more specifically, provides compounds of formula (I) described herein below. These compounds are 5-HT ligands, and are useful for treating diseases wherein modulation of 5-HT activity is desired.

BACKGROUND OF THE INVENTION

Many diseases of the central nervous system are influenced by the adrenergic, the dopaminergic, and the serotonergic neurotransmitter systems. For example, serotonin has been implicated in a number of diseases and conditions which originate in the central nervous system. These include diseases and conditions related to sleeping, eating, perceiving pain, controlling body temperature, controlling blood pressure, depression, anxiety, - schizophrenia, and other bodily states. R. W. Fuller, Biology of Serotonergic Transmission, 221 (1982); D. J. Boullin, Serotonin in Mcntal Abnormalities 1:316 (1978); J. Barchas, et - al., Serotonin and Behavior, (1973). Serotonin also plays an important role in peripheral systems, such as the gastrointestinal system, where it has been found to mediate a variety of contractile, secretory, and electrophysiologic effects.

As a result of the broad distribution of serotonin within the body, there is a tremendous interest in drugs that affect serotonergic systems. In particular, receptor- specific agonists and antagonists are of interest for the treatment of a wide range of disorders, including anxiety, depression, hypertension, migraine, obesity, compulsive disorders, schizophrenia, autism, neurodegenerative disorders (e.g. Alzheimer’s disease,

Parkinsonism, and Huntingtons chorea), and chemotherapy-induced vomiting. M. D.

Gershon, et al., The Peripheral Actions of 5-Hydroxytryptamine, 246 (1989); P.R. Saxena, et al., Journal of Cardiovascular Pharmacology, 15:Supplement 7 (1990).

The major classes of serotonin receptors (5-HT,;) contain fourteen to eighteen separate receptors that have been formally classified. See Glennon, et al., Neuroscience and

Behavioral Reviews, 1990, 14, 35, and D. Hoyer, et al. Pharmacol. Rev. 1994, 46, 157-203,

Recently discovered information regarding subtype identity, distribution, structure, and

. ) function suggests that it is possible to identify novel, subtype specific agents, having : improved therapeutic profiles (e.g. fewer side effects).

For example, The 5-HT6 receptor was identified in 1993 (Monsma et al. Mol. . Pharmacol. 1993, 43, 320-327 and Ruat, M. et al. Biochem. Biophys. Res. Com. 1993, 193,269-276). Several antidepressants and atypical antipsychotics bind to the 5-HT6 receptor with high affinity and this binding may be a factor in their profile of activities (Roth etal. J. Pharm. Exp. Therapeut. 1994, 268, 1403-1410; Sleight et al. Exp. Opin. Ther.

Patents 1998, 8, 1217-1224; Bourson et al. Brit. J. Pharm. 1998, 125, 1562-1566; Boess ct al. Mol. Pharmacol. 1998, 54, 577-583; Sleight et al. Brit. J. Pharmacol. 1998, 124, 556- 562). In addition, the 5S-HT6 receptor has been linked to generalized stress and anxiety states (Yoshioka et al. Life Sciences 1998, 17/18, 1473-1477). Together these studies and observations suggest that compounds that antagonize the 5S-HT receptor will be useful in treating disorders of the central nervous system.

Compounds of the present invention are 5-HT ligands (e.g. receptor-spedific agonists or antagonists). Thus they are useful for treating diseases wherein modulation of 5- - HT activity is desired. Specifically, the compounds of this invention are uscful in the : treatment of psychosis, paraphrenia, psychotic depression, mania, schizophrenia, i schizophreniform disorders, schizoaffective disorder, delusional disorder, panic disorder, a phobia, obsessive compulsive disorder, post-traumatic-stress syndrome, immune System depression, a stress induced problem with the urinary, a stress related disease such as anxiety, migraine headache, drug addiction, convulsive disorders, personality disorders, post-traumatic stress syndrome, alcoholism, panic attacks, obsessive-compulsive disorders, sleep disorders, gastrointestinal or cardiovascular system (e.g., stress incontinence), neurodegenerative disorders, autism, chemotherapy-induced vomiting, hypertension, cluster headaches, sexual dysfunction in a mammal (e.g. a human), addictive disorder and withdrawal syndrome, an adjustment disorder, an age-associated learning and mental disorder, anorexia nervosa, apathy, an attention-deficit disorder due to general medical conditions, attention-deficit hyperactivity disorder, behavioral disturbance (including agitation in conditions associated with diminished cognition (e.g., dementia, mental retardation or delirium)), bipolar disorder, bulimia nervosa, chronic fatigue syndrome, conduct disorder, cyclothymic disorder, dysthymic disorder, hbromyalgia and cther somatoform disorders, an inhalation disorder, an intoxication disorder, movement disorder (e.g., Huntington’s disease or Tardive Dyskinesia), oppositional defiant disorder, peripheral neuropathy, post-traumatic stress disorder, premenstrual dysphoric disorder, a psychotic disorder (brief and long duration disorders, psychotic disorder due to medical condition, psychotic disorder NOS), mood disorder (major depressive or bipolar disorder with psychotic features) seasonal affective disorder, a specific developmental disorder, agitation disorder, selective serotonin reuptake inhibition (SSRI) "poop out" syndrome or a Tic disorder (e.g., Tourette’s syndrome). More specifically, the compounds of this invention are useful to treat psychotic, affective, vegetative, and psychomotor symptoms of schizophrenia and the extrapyramidal motor side effects of other antipsychotic drugs. This last action will allow higher doses of antipsychotics to be used and thus greater antipsychotic efficacy to be obtained as a result of a reduction in side effects. The compounds of this invention are also useful in the modulation of eating behavior and thus are useful in treating excess weight and associated morbidity and mortality.

INFORMATION DISCLOSURE

International Publication No. W095/03296 discloses carbazole and dibenzofuran hapten com pounds.

Abstract of International Publication No. WO/9747601 discloses new heterocyclic ] compounds useful for treating schizophrenia.

European Patent Application EP 839806 discloses tricyclic compounds useful for : inhibiting SPLA2 mediated rclcasc of fatty acids for conditions such as septic shock.

US Patent No. 5,668,167 discloses carbazole derivatives useful for treating microbial infections.

US Patent No. 4,503 067 discloses carbazolyl-(4)-oxypropanolamine compounds useful for treating cardiac diseases. p

US Patent No. 3,932,424 discloses carbazoles usctul as antiviral agents.

US Patent No. 3,896,145 discloses carbazoles useful as antiinflammatory, analgesic, and anti-rheumatic agents.

US Patent No. 3,759,948 discloses tricyclic carboxylic acid and ester derivatives useful as anti-inflammatory, anti-pyretic and analgesic agents.

DE 4330175 discloses beta carbolines useful for treating Parkinson’s disease,

Alzheimer's disease, senile dementia, epilepsy, schizophrenia, migraine etc.

Abstract of Japanese Patent No. 06228095 discloses carbazole derivatives useful for treating ischaemic encephalopathy.

Abstract of French Patent No. 2516512 discloses pyrido-indole derivatives useful for : treating cardiac rhythm diseases. : SUMMARY OF THE INVENTION

The present invention provides a compound of formula I

Ra A, § A (Ry) "

R ey), 1 wherein

R, is (a) H, (b) halo, or (©) Cs alkyl;

Rs is (@ H, b) halo, ©) -OH, (d CN, (e) -CF;, 6) -O(Cre)alkyl, (8) Cigsakyl, (h) Cy ¢ cycloalkyl, (i) -NR;sRs, 6) -CONRG;Re, (k) -SO;NRsRe,

Mm -COORy, (m) -OCF;, or (n) phenyl, optionally substituted with haio, OH, O(C,.4) alkyl, or Cy alkyl; each Rj is independently (@ H _4-

(b) Ci. alkyl, or {c) Cs. cycloalkyl;

Ry is (a) aryl, or (b) heteroaryl;

Rs and Rg are independently (@ H (b) Cis alkyl, or ©) C6 cycloalkyl;

Rjis a H, (by) Cisalkyl or (©) (Cs alkyl)-phenyl wherein phenyl may be substituted with Ri;

Rj; and Ry are independently @ HH, b) Ci. alkyl, optionally substituted with aryl, hetroaryl, or Cs. cycloalkyl, . (c) Cysalkene, } (d) Cs cycloalkyl, ~ (e) Cag alkyl substituted with Ryo, - ® -CHO, provided that only one of the Rs and Ry is CHO, the other one is H, {gy amy, (h) heterocyclic, which is bonded via carbon atom to the nitrogen to which it is gitacncd, OF 0) Rs and Ry taken together with the nitrogen to which they are attached form a heterocyclic ring wherein the heterocyclic ring may have one to two additional heteroatoms selected from the group consisting of oxygen, sulfur and N(Y) and wherein the carbon atoms of the heterocyclic ring is optionally substituted with one or two Rs;

Ryo is (@ -OH, b) -O(C,4 alkyl), optionally alkyl is substituted with OH,

TTT © SO(Ca alkyD-NRyRye (d) heterocyclic, or (&) -COsRs, : ss.

Ri; and Ry; are independently, ) (a) H, or () Cigakyh : aryl is phenyl or naphthyl, optionally substituted with one or more Rys; heteroaryl is a radical of a five- or six-membered monocyclic aromatic ring having one or two heteroatoms each selected from the group consisting of oxygen, sulfur, and N(X), or a radical of a nine- or ten-membered ortho-fused bicyclic aromatic ring having one, two or three heteroatoms each selected from the group consisting of oxygen, sulfur, and N(X); wherein carbon atoms of heteroaryl may be substituted with Rus; heterocyclic is a radical of a five-, six-, or seven-membered partially-saturated or unsaturated heterocyclic ring having one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and N(Y) wherein the carbon atoms of the heterocyclic ring may be substituted with Ra;

X is absent, H or C,4 alkyl;

Ys - (@ HH (b) Cs alkyl, optionally substituted with aryl or hetroaryl, ’ (c) Css cycloalkyl, or (d) C,.¢ alkyl substituted with -OH, -O(C,4 alkyl), -O(C, 4 alkyl)-NRy Riz, -CO;,R5, or NHCHO, or (e) -OH;

Ry; is (a) halo, (b -OH, © CN, (@d CF, (e) -O(Ciglalkyl, (HD Cisalkyl, (2) Css cycloalkyl, (h) -NRsRs, ey; -CONRG;Re,

G -SO,NR;sRs, k) -COOR;, _6-

()] -OCF;, or (m) phenyl, optionally substituted with halo, OH, O(C,.) alkyl, or C, alkyl;

Ris is (@) Cis alkyl, (b) Cs.ecycloalkyl, ©) C,.6 alkyl substituted with -OH, -O(C, alkyl), -O(C,4 alkyl)-NR,;R,, or -CO,Rs, d -OH,or ) oxo (=0); misl, 2, 30rd; nis 1,2,3,o0r4;

Cs. cycloalkyl in each of the above definitions, may be each and independently substituted with -OH, C, 4 alkyl, or oxo (=0), and with the following provisos: (a) when R, is 4-fluorophenyl, n is 1, mis 1, each Rs is independently hydrogen, Rg and

Ry is independently -CH,CHs, then R; cannot be fluoro or chloro at the C-6 position of formula I; (b) when nis 1, mis 1, Ry, Rs, Rs or Ry is hydrogen, Ry is 4-thiazolyl, then said 4- thiazolyl cannot be substituted with 4-chlorophenyl; {c) whennis 1, mis 1, Ry, Rs, Rs or Rg is hydrogen, then R, is not 4-pyridyl; (d) when nis 1, mis 1, Ra, Rs, Rg or Rg is hydrogen, then Ry is not 2-bromophenyl or 4-

UTOINO phSiiyl.

In another aspect, the present invention also provides: a pharmaceutical Coinposition Compiising a compound ul Umi 3, U1 a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient (the composition preferably comprises a therapeutically effective amount of the compound or salt), a method for treating a disease or condition in a mammal (e.g. a human) wherein a 5-HT receptor is implicated and modulation of a 5-HT function is desired comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof to the mammal,

TT method for treating or preventing anxiety, obesity, depression, schizophrenia, a stress related disease (e.g. general anxiety disorder), panic disorder, a phobia, obsessive compulsive disorder, post-traumatic-stress syndrome, immune system depression, a stress

] induced problem with the gastrointestinal or cardiovascular system, eating disorders or . sexual dysfunction in a mammal (e.g. a human) comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof \ to the mammal,

a method of treating or preventing diseases or disorders of the central nervous system such as: psychosis, paraphrenia, psychotic depression, mania, schizophrenia, schizophreniform disorders, schizoaffective disorder, delusional disorder, panic disorder, a phobia, obsessive compulsive disorder, post-traumatic-stress syndrome, immune system depression, a stress induced problem with the urinary, a stress related disease such as anxiety, migraine headache, drug addiction, convulsive disorders, personality disorders, post-traumatic stress syndrome, alcoholism, panic attacks, obsessive-compulsive disorders, sleep disorders, gastrointestinal or cardiovascular system (e.g., stress incontinence), neurodegenerative disorders, autism, chemotherapy-induced vomiting, hypertension, cluster headaches, sexual dysfunction in a mammal (e.g. a human), addictive disorder and withdrawal syndrome, an adjustment disorder, an age-associated learning and mental

- disorder, anorexia nervosa, apathy, an attention-deficit disorder due to general medical conditions, attention-deficit hyperactivity disorder, behavioral disturbance (including } agitation in conditions associated with diminished cognition (e.g., dementia, mental retardation or delirium)), bipolar disorder, bulimia nervosa, chronic fatigue syndrome,

conduct disorder, cyclothymic disorder, dysthymic disorder, fibromyalgia and other somatoform disorders, an inhalation disorder, an intoxication disorder, movement disorder (e.g., Huntington's disease or Tardive Dyskinesia), oppositional defiant disorder, peripheral neuropathy, post-traumatic stress disorder, premenstrual dysphoric disorder, a psychotic disorder (brief and long duration disorders, psychotic disorder due to medical condition,

psychotic disorder NOS), mood disorder (major depressive or bipolar disorder with psychotic features) seasonal affective disorder, a specific developmental disorder, agitation disorder, selective serotonin reuptake inhibition (SSRI) "poop out" syndrome or a Tic disorder (e.g., Tourettes syndrome), comprising administering to a mammal (e.g. a human) in need of such treatment, a therapeutically effective amount of a compound of formula (T)

or a pharmaceutically acceptable salt thereof,

a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in medical diagnosis or therapy (e.g. the treatment or prevention of 5-HT related central nervous system diseases or disorders,

the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof to ’ prepare a medicament for treating or preventing S-HT related central nervous system ] diseases or disorders such as anxiety, obesity, depression, schizophrenia, a stress related disease (e.g. general anxiety disorder), panic disorder, a phobia, obsessive compulsive ] disorder, post-traumatic-stress syndrome, immune system depression, a stress induced problem with the gastrointestinal or cardiovascular system, or sexual dysfunction in a mammal (e.g. a human), and a method for modulating 5-HT (e.g. 5-HTg) receptor function, comprising contacting (in vitro or in vivo) the receptor with an effective inhibitory amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.

The invention also provides novel intermediates and processes disclosed herein that are useful for preparing compounds of formula I.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention are generally named according to the

IUPAC or CAS nomenclature system. Abbreviations which are well known to one of N ordinary skill in the art may be uscd (c.g. “Ph” for phenyl, ‘Me” for methyl, “Et” for ethyl, } “h” for hour or hours and “rt” for room temperature). -

The carbon atom content of various hydrocarbon-containing moieties is indicated by - a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix C |, indicates a moiety of the Liteger I” 10 the icger “7 vatbou divs, ciusive.

Thus, for example, Ci»alkyl refers to alkyl of one to seven carbon atoms, inclusive.

Specific and preformed valucs lisied below 107 radicals, SubSituciiis, ang ranges, ac for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents.

The following definitions are used, unless otherwise described.

Halo is fluoro, chloro, bromo, or iodo.

Alkyl denotes both straight and branched groups; but reference to an individual radical such as “propyl” embraces only the straight chain radical, a branched chain isomer such as “isopropyl” being specifically referred to. Specifically, Cy.7 alkyl can be methyl, ~~ gihyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl.

Alkene denotes both straight and branched groups have at least one double bond.

Cs. cycloalkyl denotes a cycloalkyl having three to six carbon atoms. Specifically,

Cs. cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

Aryl denotes a phenyl or a naphthyl radical. Optionally, aryl is substituted with one or more halo, OH, CN, CFs, O(C,.¢)alkyl, C;.s alkyl, Cs cycloalkyl, NRsRg, CONRsRe,

SO,NRsR¢, COORy, OCF, or phenyl which in turn may be substituted with halo, OH,

O(Ci4) alkyl, or Cy alkyl. Rs and Re are the same as summarized above.

Heteroaryl denotes a radical of a five- or six-membered monocyclic aromatic ring having one or two heteroatoms each selected from the group consisting of oxygen, sulfur, and N(X), or a radical of a nine- or ten-membered ortho-fused bicyclic aromatic ring having one, two or three heteroatoms each selected from the group consisting of oxygen, sulfur, and N(X); wherein X is absent, H or C,. alkyl; wherein carbon atoms of heteroaryl may be substituted with one or more halo, OH, CN, CF;, O(C,.s)alkyl, Ci alkyl, Cs. cycloalkyl,

NR;sRs, CONR;sRs, SO;NRsRg, COOR;, OCF;, or phenyl which in turn may be substituted with halo, OH, O(C,4) alkyl, or C,s alkyl. Rs, Re and Rare the same as summarized above.

Examples of heteroaryl are pyridyl, thiophene, benzothiophene, benzoturan, benzimidazole, imidazole or thiazole.

Heterocyclic is a radical of a five-, six-, or seven-membered partially-saturated or unsaturated heterocyclic ring having one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and N(Y) wherein the carbon atoms of the heterocyclic ring ts optionally substituted with Ris. Y and Ry4 are the same as summarized above. Examples of heterocyclic is azetidyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-benzyl-piperidinyl, 1-methyl-piperidinyl, dioxolane, imidazolidine, oxazolidinyl, oxathiolane, 4-hydroxyl-1-piperidinyl, 4-ethanol-1-piperazinyl-, 4-cthylformamidc-1- piperazinyl-, or 4-methyl-1-piperazinyl.

Pharmaceutically acceptable salts denotes acid addition salts useful for administering the compounds of this invention and include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, mesylate, maleate, malate, succinate, tartrate, citric acid, 2-hydroxyethyl sulfonate, fumarate, methanesulfonic acid salt and etc.

Specifically, pharmaceutically acceptable salts can be maleate, methanesulfonic acid salt and etc.

Mammal denotes human and animals.

A specific value for R, is H, halo, or C, alkyl.

A specific value for R, is H.

A specific value for Rs is H, halo, -OH, -CN, -CF;, -O(C,s)alkyl, Ci alkyl,

Cs. cycloalkyl, -NRsRg, -CONR;R;, -SO,NRRg, -COOR5, or phenyl which may be substituted with halo, -OH, -O(C,.) alkyl, or C,.¢ alkyl; wherein Rs and Re is H, C,.s alkyl, or Cs cycloalkyl; wherein Ry is C,.¢ alkyl, or (C;.3 alkyl)-phenyl wherein phenyl may be substituted with Rj.

A specific value for R; is H, halo, or C,.¢ alkyl.

A specific value for R; is H, chloro, fluoro, or methyl.

A specific value for R; is H.

A speifici value for R; is fluoro or methyl.

A specific value for each R; is independently H, C,_¢ alkyl, or Cs.¢ cycloalkyl.

A specific value for each R; is independently H.

A specific value is wherein Rg and Ry are independently H, C, alkyl (optionally substituted with aryl, heteroaryl or Cs.¢ cycloalkyl), Cz.¢ alkene, Cis cycloalkyl, Cy. alkyl substituted with R,o, -CHO (provided that only one of the Rs and Rs is -CHO, the other one is hydrogen), aryl, heterocyclic wherein heterocyclic is bonded via carbon atom to the nitrogen to which it is attached, or Rs and Ry taken together with the nitrogen to which they are attached form a heterocyclic ring wherein the heterocyclic ring may have one to two additional heteroatoms selected from the group consisting of oxygen, sulfur and N(Y) and wherein the carbon atoms of the heterocyclic ring is optionally substituted with one or two

R;3; wherein Rip, and Y are as defined above, wherein each Cs; cycloalkyl is optionally substituted with -OH, C,4 alkyl, or oxo.

A specific value is wheres Rg is H, and Rg Is H, Cre aikyi, Coq aikene, Cig aikyi * substituted with phenyl, wherein phenyl is optionally substituted with fluoro or chloro.

A SPECITIC Value is WIEIEul Ra i> ki, aud Re 15 Crag alinyl subsiliuicy wiii

Cs. cycloalkyl, wherein cycloalkyl is optionally substituted with —-OH, C4 alkyl or oxo.

A specific value is wherein Rs is H, and Ry is Cz. alkyl substituted with -OH, -O(C,4 alkyl), -O(C,4 alkyl-OH) or -CO,C, 4 alkyl.

A specific value is wherein Rg is H, and Ry is cyclopropyl, cyclobutyl, cyclopently, or cyclohexyl, all of which may be substituted with -OH, C4 alkyl, oxo, or -CHO.

A specific value is wherein Rg is H, and Ry is Cy.¢ alkyl substituted with phenyl, pyridyl, thiophene, benzothiophene, benzofuran, benzimidazole, imidazole or thiazole.

TTT TA specific value is wherein Rs is H, and Rj is heterocyclic wherein heterocyclicis bonded via carbon atom Lo the nitrogen to which it is attached.

A specific value is wherein Rg is H, and Ry is pyridyl methyl, benzimidazole methyl, : or 1-benzyl-piperidinyl.

A specific value is wherein Rg is H; and Ry is C, alkyl substituted with . azetidyl, pyrrolidinyi, piperidinyl, piperazinyl, morpholinyi, thiomorpholinyl, 5S 1-benzyl-piperidinyl, 1-methyl-piperidinyl, dioxolane, imidazolidine, oxazclidinyl, oxathiolane, 4-hydroxyl-1-piperidinyl, 4-ethanol-1-piperazinyl-, 4-ethylformamide-1- piperazinyl-, or 4-methyl-1-piperazinyl.

A specific value is wherein Rs and Ry taken together with the nitrogen to which they are attached form a heterocyclic ring wherein the heterocyclic ring may have one to two additional heteroatoms selected from the group consisting of oxygen, sultur and N(Y), wherein Y is the same as defined in claim 1.

A specific value is wherein Rg and Rs taken together with the nitrogen to which they are attached form 4-morpholinyl, 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-hydroxyl- 1-piperidinyl, 4-ethanol-1-piperazinyl-, 4-ethylformamide- 1-piperazinyl-, or 4- mcthyl-1-piperazinyl. - A specific value for Rg and Ry are independently H, methyl, ethyl, propyl, 1-propanol, 2-propen, 1-pentanol, 2-methyl-1-propanol, 2-butanol, 1-ethanol, ethoxyl-1- ’ ethanol, -CH,CH,CO»ethyl, 2-methoxyethyl, 4-chlorophenethyl, or 4-fluorophenethyl.

A specific value is wherein Rg and Ry are both hydrogen atoms.

A specific value is wherein Rs is H; and Ry is methyl.

A specific value is wherein Rs and R, taken together with the nitrogen to which they are attached form 4-methyl-1-piperazinyl

A spectic value for Ry, is aryl, or heteroaryl; wherein aryl or heteroaryl are as defined as herein above.

A specific value for Ry 1s phenyl.

A specific value for Ry is pyridyl, thiophene, benzothiophene, benzofuran, benzimidazole, imidazole, thiazole pyridyl, thiophene, benzothiophene, benzofuran, benzimidazole, imidazole or thiazole.

A specific value for Ry is 2-methyl-1,3-thiazol-4-yl, or 5-chloro-1-benzothiophn-3-yl.

A specific value for m is one.

Examples of the present invention includes: a) N-{2-[(9-benzyl-9H-carbazol-4-yl)oxylethyl }-N,N-diethylamine, b) N-{2-[(9-benzyl-8-chloro-9H-carbazol-4-yl)oxylethyl }-N,N-diethylamine,

C) N-(2-{[8-chloro-9-(4-fluorobenzyl)-9H-carbazol-4-yi]oxy} ethyl)-N ,N-diethylamine, d) N-{2-[(9-benzyl-8-methyl-9H-carbazol-4-yl)oxylethyl}-N,N-diethylamine, . e) N,N-diethyl-N-(2-{ [9-(4-fluorobenzyl)-8-methyl-9H-carbazol-4-ylJoxy} ethyl)amine, f) N-{2-[(9-benzyl-9H-carbazol-4-yl)oxylethyl}-N-(2-pyridinylmethyl)amine, 8 N-{2-[(9-benzyl-8-fluoro-9H-carbazol-4-yl)oxylethyl }-N,N-diethylamine, h) 9-benzyl-4-[2-(4-morpholinyl)ethoxy]-9H-carbazole, 1) 2-(4-(2-[(9-benzyl-9H-carbazol-4-yl)oxylethyl} -1-piperazinyl)- 1-ethanol,

D) 3-({2-[(9-benzyl-9H-carbazol-4-yl)oxy]ethyl }amino)- 1-propanol, k) N-{2-[(9-benzyl-9H-carbazol-4-yl)oxy]ethyl }-2-propen-1-amine 1) N- (2-[(9-benzyl-9H-carbazol-4-yl)oxylethyl) -3-(4-morpholinyl)- 1-propanamine, m) 5-({2-[(9-benzyl-9H-carbazol-4-yl)oxy]ethyl }amino)- 1-pentanol, n N-{2-[(9-benzyl-9H-carbazol-4-yl)oxy]cthyl}-1-propanamine, 0) N-{2-[(9-benzyl-9H-carbazol-4-yl)oxyJethyl}-N-propyl-1-propanamine,

P) 1-benzyl-N-{2-[(9-benzyl-9H-carbazol-4-yl)oxy] ethyl}-4-piperidinamine, qQ 2-({2-[(9-benzyl-9H-carbazol-4-yl)oxy]ethyl }amino)-2-methyl-1-propanol, r) 2-[(9-benzyl-9H-carbazol-4-yljoxy]-N-(4-chlorophenethyl)- 1-ethanamine, } s) 2-[(9-benzyl-9H-carbazol-4-yl)oxyl-N-(cyclohexylmethyl)- 1 -ethanamine, 18] 2-[(9-benzyl-9H-carbazol-4-yl)oxy]}-N-[2-(4-morpholinyl)ethyl}- 1-ethanamine, - u) 1-({2-[(9-benzyl-9H-carbazol-4-yl)oxy]ethyl }amino)-2-butanol, -

Vv) 2-[(9-benzyl-9H-carbazol-4-yl)oxy)-N-(4-fluorophenethyl)- 1 -ethanamine,

W) 2-[2-{{2-({5-beneyi-SH-Carvacoi-4-yhuayjciliyl jawinu)eibuayj-i-cihani,

X) (1S,25)-2-({2-[(9-benzyl-9H-carbazol-4-yl)oxylethyl }amino)cyclohexanol, ) ily 3-({2-[{5-benzyi-31i I-Carbazol-4- 1) ORY] thy | ainind pi U panoaic, 7) N-{2-[(9-benzyl-9H-carbazol-4-yl)oxy]ethyl }cyclobutanamine, aa) 2-(4-{2-[(9-benzyl-9H-carbazol-4-yl)oxylethyl }- 1-piperazinyl) ethylformamide, bb) N-(1H-benzimidazol-2-ylmethyl)-2-[(9-benzyl-9H-carbazol-4-yl)oxy]-1-ethanamine, cc) 1-{2-{(9-benzyl-9H-carbazol-4-yl)oxy]ethyl }-4-piperidinol, dd) 9-benzyl-4-[2-(4-methyl-1-piperazinyl)ethoxy]-9H-carbazole, ee) N-{2-[(9-benzyl-9H-carbazol-4-yl)oxy]ethyl}-N-cyclopropylamine, ff) N-{2-[(9-benzyl-9H-carbazol-4-yl)oxy]ethyl}-N,N-dimethylamine, gg) N-{2-[(9-benzyl-9H-carbazol-4-yl)oxylethyl} formamide, ~~ hh) N-{2-[(9-benzyl-9H-carbazol-4-yl)oxy]ethyl }-N-methylamine,or its maleic acid salt, 1) 2-[(9-benzyl-9H-carbazol-4-yDoxy]ethylamine,

) in N-{2-[(9-benzyl-9H-carbazol-4-yl)oxy]Jethyl }-N-(2-methoxyethyl)amine, } kk) N-ethyl-N-{[(1-phenyl-1,2-dihydro[1,4}oxazino[2,3,4-jk]carbazol-7-yl) oxyJethyl}amine, or its maleic acid salt, } 1) S-benzyl-4-[2-(1-pyrrolidinyl)ethoxy}-9H-carbazole, mm) 9-benzyl-4-[2-(1-piperidinyl)ethoxy]-9H-carbazole,

nn) 9-benzyl-4-[2-(1-piperazinyl)ethoxy]-9H-carbazole, 00) 2-[(9-benzyl-8-fluoro-9H-carbazol-4-yl)oxy]lethylamine, pp) N,N-diethyl-N-(2-{[8-flucro-9-(4-fluorobenzyl)-9H-carbazol-4-ylloxy }ethyl)amine, qq) N-{2-[(9-benzyl-6-chloro-9H-carbazol-4-yl)oxylethyl}-N,N-diethylamine,

11) N-{2-[(9-benzyl-6-fluoro-9H-carbazol-4-yl)oxylethyl}-N,N-diethylamine, 5S) N-{2-[(9-benzyl-6-methyl-9H-carbazol-4-yl)oxy]ethyl} -N,N-diethylamine, tt) 2-[(9-benzyl-6-methyl-9H-carbazol-4-yl)oxyJethylamine, uu) N-{2-[(9-benzyl-6-methyl-9H-carbazol-4-yl)oxy]Jethyl }-N-methylamine, vv) N,N-diethyl-N-(2-{[9-(4-fluorobenzyl)-6-methyl-9H-carbazol-4-ylJoxy }ethyl)amine,

ww) 2-({2-[(9-benzyl-9H-carbazol-4-yl)oxyJethyl}amino)-1-ethanol or its maleic acid

. salt, } XX) 2-({9-1(5-Chloro-1-benzothiophen-3-yl)methyl}-9H-carbazol-4-yl } oxy)ethylamine or ‘ its methane sulfonate salt,

vy) 2-({9-[(2-Methyi-1,3-thiazol-4-ylymethylj-9H-carbazol-4-yl joxyjeihylamine or iis methane sulfonate salt, 77) 2-[(9-benzyl-3-chloro-9H-carbazol-4-yl)oxy]ethylamine, methanesullonate salt, aaa) 2-{[9-(3-bromobenzyl)-9H-carbazol-4-yljoxy}ethylamine, maleic acid salt, bbb) 2-{[9-(3-fluorobenzyl)-9H-carbazol-4-ylJoxy}ethylamine, maleic acid salt, ccc) 2-{[9-(4-methylbenzyl)-9H-carbazol-4-yljoxy }ethylamine, maleic acid salt,

ddd) 2-{[9-(2-Ffuorobenzyl)-9H-carbazol-4-ylJoxy}ethylamine, maleic acid salt, eee) 2-{[9-(3-methoxybenzyl)-9H-carbazol-4-ylloxy }ethylamine, maleic acid salt, fff) 2-{19-(3,5-dimethoxybenzyl)-9H-carbazol-4-yl]oxy }ethylamine, maleic acid salt, ggg) 2-{[9-(3-methylbenzyl)-9H-carbazol-4-yl]oxy }ethylamine, maleic acid salt, hhh) 2-{[9-(2-methylbenzyl)-9H-carbazol-4-ylJoxy }ethylamine, maleic acid salt,

iii) 2-[(9-benzyl-6-methoxy-9H-carbazol-4-yl)oxyjethylamine, or ih 2-[(9-benzyl-7-methoxy-9H-carbazol-4-yl)oxyJethylamine.

It will be appreciated by those skilled in the art that compounds of the invention may contain a chiral center, therefore, they may be isolated in optically active or racemic forms. .

Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically active, polymorphic, tautomeric, or ] stereoisomeric form, or mixture thereof, of a compound of the invention, which possesses the useful properties described herein. It is well known in the art to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation (using a chiral stationary phase, for example) and to determine 5-HTs activity using the standard tests described herein, or using other similar tests which are well known in the art.

The following Schemes describe the preparation of compounds of the present invention. All of the starting materials are commercially available or prepared by procedures described in these schemes or by procedures that would be well known to one of ordinary skill in organic chemistry. The variables used in the Schemes are as defined above or as in the claims. .

As shown in Chart A, hydrazines 3 can be prepared from commercially available anilines 1. Aniline 1 is stirred in an acidic medium such as TFA, acetic acid, or aq. sulfuric » acid. A nitrite such as sodium nitrite, iscamylnitrite, or n-butylnitrite is added. to give - nitroso aniline 2. Nitroso aniline 2 is reduced with lithium aluminum hydride in ether or

THF 10 give hydrazine 3. For a discussion of additonal methods of preparing 3, see Sandler,

S.R.; Karo, W. Organic Functional Group Preparations; Academic Press: New York, 1983; Vol. 1, znd Ed., pp. 434-465. rydrazone 4 is preparcd from hydrazine 3 and cyclohexane-1,3-dione in solvents such as water, alcohols, or dichloromethane. Hydrazone 4 is then treated under the conditions of the Fischer indole synthesis using an acid and a solvent such as acetic acid, toluene, ethanol, or others, to give tetrahydrocarbazole 5.

Alternatively, hydrazine 3 and cyclohexane-1,3-dione may be reacted under Fischer indole conditions to directly give tetrahydrocarbazole 5. Many additional methods for the Fischer indole synthesis are given in Sundberg, R.J.; /ndoles, Academic Press: London; 1996, and in

Hughes, D.L. Progress in the Fischer Indole Reaction: A Review. Org. Prep. Proceed. Int. ©1993, 25,609-632. The nitrogen of tetrahydrocarbazole § is alkylated by methods well known to those versed in the art. For example, treatment of tetrahydrocarbazole 5 with a -

] base such as sodium hydride, followed by an alkyl halide such as benzyl chloride or benzyl : bromide, gives benzyl tetrahydrocarbazole 6.

Treatment of compound 6 in a single step using Raney nickel on Pd/carbon in . solvents such as cumene, mesitylene, 1,2,3-trimethylbenzene, 1,2,4-trimethylbenzene, dccalin, carbitol, or diphenyl ether at temperatures between 130-270 °C provides phenol 9 directly. Alternatively, benzyl tetrahydrocarbazole 6 is first treated with a copper (II) halide, preferably CuCl, or CuBr, in solvents such as DMF, acetonitrile, EtOAc, chloroform, acetic acid, or acetic acid/water at temperatures between 50 and 120 °C to give halo tetrahydrocarbazoles 7 and 8. For a reference to this reaction, see Matsumoto, M.; Ishida,

Y.; Watanabe, N. Heterocycles 1985, 23, 165-170. A third useful method is treatment of benzyl tetrahydrocarbazole 6 with pyridinium bromide perbromide or phenyltrimethylammonium tribromide in solvents such as DMF, acetonitrile, or THF to give halo tetrahydrocarbazoles 7 and 8. Halo tetrahydrocarbazoles 7 and 8 may be separated and carried on individually in the next steps, or they may be carried forward as a mixture to phenols 9 and 10 and separated at that time. Halo tetrahydrocarbazoles 7 and 8 (separately - or together) are then treated with lithium chloride or lithium bromide (anhydrous LiCl or : LiBr is preferred, but hydrated forms also may be used) in the presence of lithium carbonate ) in a solvent such as DMF at 110-130 °C to give phenols 9 and 10.

Charts B and D disclose some of the ways phenols 9 and 10 may be alkylated with various alkylating agents; and Chart C discloses further transformations of carbazole amine 13 to give alkyl amines 15, 16, and 17 directly or after several steps. Which method is used will depend on the type of amine that is desired and on the availability of alkylating agents.

For clarity, only 13 is depicted in Chart C, but the reaction scheme applies equally well to 14. In chart D, only phenol 9 is depicted, but the reaction scheme applies equally well to phenol 10.

In Chart B, X refers to a halogen atom. Phenols 9 and 10 are alkylated with chloro or bromoethyl amine in the presence of bases such as sodium hydride, potassium carbonate, cesium carbonate, or sodium carbonate in solvents such as DMF, acetonitrile, or acetone at room temperature to 120 °C to give carbazole amines 13 and 14 directly. Alternatively, phenols 9 and 10 are alkylated with chloro or bromoacetonitrile in the presence of bases such as sodium hydride, potassium carbonate, cesium carbonate, or sodium carbonate in solvents such as DMF, acetonitrile, or acetone at room temperature to 120 °C to give nitriles 11 and 12. Reduction of nitriles 11 and 12 with borane in THF or borane-methyl

S16 -

sulfide complex in THF at room temperature to 80 °C gives carbazole amines 13 and 14 (R8 ) and R9 are hydrogen atoms) Other methods for the reduction of the nitrile group to an A amine may be found in March, J. Advanced Organic Chemistry, 3rd ed., John Wiley and

Sons: New York: 1985.

Chart C discloses further functionalization of carbazole amine 14 by several methods.

In Chart C, Q refers to hydrogen, alkyl, or aryl. Z refers to hydrogen or alkyl. One method is acylation with acylating agents such as ethyl formate, acetic anhydride, and the like to give acyl carbazole 15. The carbonyl function of acyl carbazole 15 is reduced to an alkyl group using reagents such as borane in THF or borane-methyl sulfide complex in THF at room temperature to 80 °C to give monoalkylamino carbazole 16; or using lithium aluminum hydride in ethereal solvents to effect the reduction to monoalkylamino carbazole 16. A second method is reductive amination of 14 with an equivalent amount of an aldehyde or ketone in the presence of reducing agents such as sodium cyanoborohydride or sodium triacetoxyborohydride in solvents such as dichloromethane, dichloroethane, and THF at 0 to 80 °C, or Pd/C under a hydrogen atmosphere in solvents such as methanol, ethanol, or cthyl acetate to give monoalkylamino carbazole 16. A third method is alkylation of carbazole - amine 14 with alkyl halides or mesylates or tosylates in the presence of base in solvents such . as THF, acetonitrile, dichloromethane, DMF and the like using methods well known to those i versed in the art to give monoalkylamino carbazole 16.

When dialkylamino carbazole 17 is desired, a second equivalent of the same or a different aldehyde, ketone, or alkylating agent, depending on the method used, is added to monoalkylamino carbazole 16 using the conditons described above. Alternatively, dialkylaminocarbazole 17 may be prepared directly from 14 using two equivalents of the aldehyde, ketone, or alkylating agent. :

Chart D describes another method of preparing mono or dialkylamino carbazole 21, wherein phenol 9 is alkylated by methods well-known to those versed in the art to give carbazole halide 18 or carbazole alcohol 19. In Chart D, L refers to a leaving group such as halo atom or a sulfonate group. The alcohol group of carbazole alcohol 19 is converted to a leaving group with methane sulfonyl halide or toluene sulfonyl halide to give carbazole _ sulfonate 20. The mesyl or tosyl group of carbazole sulfonate 20 or carbazole halide 18is then displaced by amines to give amino carbazole 21.

S17 -

Claims (61)

R WO 01/17963 ~ PCT/US00/20809 CLAIMS What is claimed is

1. A compound of formula I oan Fc oO Ry No R R CH, 1 or a pharmaceutically acceptable salt, racemate, solvate, tautomer, optical isomer or prodrug derivative thereof; wherein _ Ris @ H, 0) halo, or © Ci. alkyl; ’ each R; is independently (a H (b) halo, (©) -OH, (d) -CN, (e) -CF;, ® -O(Ci¢)alkyl, (8) Cisalkyl (h) Cs. cycloalkyl, i) -NRsR, 0) -CONRsRs, (k) -SO,NR;Rg, 0) -COORy, : (m) -OCFs, or (n) phenyl, optionally substituted with halo, OF, O(C, 4) alkyl, or C6 alkyl; each Rj is independently (a) H. 0) Cis alkyl, or

(©) Ci. cycloalkyl; : i Riis (a) aryl, or (b) heteroaryl, Rs and R¢ are independently (@ H, (b) Ciealkyl, or (©) C,.6 cycloalkyl, Ry is (a) H, (b) Cisalkyl, or ©) (Ci.3 akkyl)-phenyl wherein phenyl may be substituted with Rs; Rs and Ry are independently @ H, (b) Cc alkyl, optionally substituted with aryl, hetroaryl, or Cs cycloalkyl, ©) C,.¢ alkene, . (d) Cs. cycloalkyl, - (e) Ca. alkyl substituted with Ro, “ H -CHO, provided that only one of the Rg and Ry is CHO, the other one is H, (8) and, (h) heterocyclic, wherein heterocyclic is bonded via carbon atom to the nitrogen to which it is attached, or (1) Rg and Ry taken together with the nitrogen to which they are attached form a heterocyclic ring wherein the heterocyclic ring may have one to two additional heteroatoms selected from the group consisting of oxygen, sultur and N(Y) and wherein the carbon atoms of the heterocyclic ring is optionally substituted with one or two Ry; Riis (a) -OH, (b) -O(C,4 alkyl), optionally alkyl is substituted with OH, © -O(Ci4 alkyD-NRyiRy5, SS ~@ hewerocyclic,or (e) -CO:Rs, Ry; and R; are independently,

(a) H, or (b) Cisalkyl aryl is phenyl or naphthyl, optionally substituted with one or more Rs; heteroaryl is a radical of a tive- or six-membered monocyclic aromatic ring having one OT two heteroatoms each selected from the group consisting of oxygen, sulfur, and N(X), cra radical of a nine- or ten-membered ortho-fused bicyclic aromatic ring having one, two or three heteroatoms each selected from the group consisting of oxygen, sulfur, and N(X); wherein carbon atoms of heteroaryl may be substituted with Rs; heterocyclic is a radical of a five-, six-, or seven-membered partially-saturated or unsaturated heterocyclic ring having one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and N(Y) wherein the carbon atoms of the heterocyclic ring may be substituted with Ry; X is absent, H or C,4 alkyl; Y is (a) H, . (b) C,.¢ alkyl, optionally substituted with aryl or heteroaryl, ‘ (©) Cs. cycloalkyl, or g (d) Cs alkyl substituted with -OH, -O(C, 4 alkyl), -O(C,4 alkyl)-NR;R 2, -COzRs, or NHCHO, or (e -OH; Ry; is (a) halo, (b) -OH, (c) -CN, (d) -CF;, (@ -O(C alkyl, ® Cis alkyl, (8) Ci.s cycloalkyl, (h) -NRsR,, 1) -CONRsRg, @ -SO;NRsRe, k) -COORs, ® -OCF;, or

(m) phenyl, optionally substituted with halo, OH, O(C,) alkyl, or C, alkyl; - ) Ris is (@ Cisalkyl, (b) Cs. cycloalkyl, ©) Cy.¢ alkyl substituted with -OH, -O(C, 4 alkyl), -O(C, 4 alkyl)-NR, ,R,,, or -COqRs, : (d) -OH, or (e) oxo (=0); mis 1, 2,3 ord, nisl, 2,3, 0r4,; C6 cycloalkyl in each of the above definitions, may be each and independently substituted with -OH, C4 alkyl, or oxo (=O), and with the following provisos: (a) when Ry is 4-fluorophenyl, nis 1, mis 1, each R; is independently hydrogen, Rs and Ry is independently -CH,CHs, then R; cannot be fluoro or chloro at the C-6 position of formula; (b) whennis 1, mis 1, Ry, Rs, Rg or Ry is hydrogen, Ry is 4-thiazolyl, then said 4- R thiazolyl cannot be substituted with 4-chlorophenyl; o (c) ~ whennis 1, mis 1, Ry, Rs, Rs or Ry is hydrogen, then Ry is not 4-pyridyl; “ (d) whennis 1, mis 1, Ry, Rs, Rg or Ry is hydrogen, then Ry is not 2-bromophenyl or 4- bromophenyl.

2. A compound of claim 1 wherein R; is H, CH;, fluoro or chloro.

3. A compound of claim 1 wherein R; is H.

4. A compound of claim 1, 2 or 3 wherein R, is H, halo, -OH, -CN, -CF;, -O(Ci.e)alkyl, Cy alkyl, Cs.6 cycloalkyl, -NRsRs, -CONRsRg, -SO,NRsRg, -COOR;, or phenyl, optionally substituted with halo, OH, O(C,.) alkyl, or C,.¢ alkyl, wherein Rs, Rg and Rj are the same as defined in claim 1.

5 Acompoundofclim 1,2 or 3 wherein R, is halo, or Crsalkyl. ~~.

6. A compound of claim 1, 2 or 3 wherein R; is H.

-

7. A compound of claim 1, 2 or 3 wherein R; chloro or fluoro.

8. A compound of claim 1, 2 or 3 wherein R; is methyl.

9. A compound of claim 5 or 6 wherein m is 1.

10. A compound of claim 4 wherein R, is heteroaryl.

11. A compound of claim 4 wherein Ry is phenyl, optionally substituted with fluoro or chloro.

12. A compound of claim 10 wherein Ry is pyridyl, thiophene, benzothiophene, benzofuran, benzimidazole, imidazole or thiazole.

. 13. A compound of claim 10 wherein Ry is 2-methyl-1,3-thiazol-4-yl or 5-chloro-1- : benzothiophn-3-yl.

14. A compound ot claim 4 wherein each R; 1s independently H, C,.6 alkyl, or Css cycloalkyl.

15. A compound of claim 4 wherein each R; is independently H.

16. A compound of claim 4 wherein Rg and Ry are independently (a) H, 0) C..¢ alkyl, optionally substituted with aryl, hetroaryl, or Cs. cycloalkyl, (c) C,¢ alkene, (d) Ci. cycloalkyl, (e) Cs alkyl substituted with Ry, 43) -CHO, (8) aryl, (h) heterocyclic, wherein heterocyclic is bonded via carbon atom to the nitrogen to which it is attached, or

@) Rg and Rs taken together with the nitrogen to which they are attached form a heterocyclic ring wherein the heterocyclic ring may have one to two additional heteroatoms selected from the group consisting of oxygen, sulfur and N(Y) and wherein the carbon atoms of the heterocyclic ring is optionally substituted with one or two Ry; wherein R,, and Y are the same as defined in claim 1.

17. A compound of claim 16 wherein Rs is H, Ry is H.

18. A compound of claim 16 wherein Rs is H, Ry is C,s alkyl, C,4 alkene, or ~CHO.

19, A compound of claim 16 wherein Rg is H, Ry is methyl.

20. A compound of claim 16 wherein Rs is H, Ry is C¢ alkyl substituted with Cs. _ cycloalkyl, wherein cycloalkyl is optionally substituted with ~OH, C4 alkyl or oxo.

21. Acompound of claim 16 wherein cycloalkyl is cyclopropyl, cyclobutyl, cyclopently, . or cyclohexyl. -

22. A compound of claim 16 wherein Rg is H, Ry is C,. alkyl substituted with -OH, -O(C\4 alkyl), -O(C, 4 alkyl-OH), or -CO,C, 4 alkyl,

23. A compound of claim 16 wherein Rg is H, Ry is is cyclopropyl, cyclobutyl, : cyclopently, or cyclohexyl, optionally substituted with —OH, C, alkyl or oxo.

24. A compound of claim 16 wherein Rg is H, Ry is C,.¢ alkyl substituted with (a) phenyl, optionally substituted with fluoro or chloro, (b) pyridyl, thiophene, benzothiophene, benzofuran, benzimidazole, imidazole or thiazole, or (©) heterocyclic, which is bonded via carbon atom to the nitrogen to which it is attached.

25. A compound of clairn 16 wherein Rg is H, Ro is C4 alkyl substituted with fluorophenyl, chlorophenyl, pyridyl, benzimidazole, or 1-benzyl-piperidinyl.

Pp wv

26. A compound of claim 16 wherein Ry is H, Ry is C;.¢ alkyl substituted with azetidyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-benzyl-piperidinyl, 1-methyl-piperidinyl, dioxolane, imidazolidine, oxazolidinyl, S oxathiolane, 4-hydroxyl-1-piperidinyl, 4-ethancl-1-piperazinyl-, 4-ethylformamide-1- piperazinyl-, or 4-methyl- 1-piperazinyl.

27. A compound of claim 16 wherein Rg and Rs taken together with the nitrogen to which they are attached form a heterocyclic ring wherein the heterocyclic ring may have one to two additional heteroatoms selected from the group consisting of oxygen, sulfur and N(Y), wherein Y is the same as defined in claim 1.

28. A compound of claim 27 wherein Rs and Ry taken together with the nitrogen to which they are attached form 4-morpholinyl, 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-hydroxyl- 1-piperidinyl, 4-ethanol-1-piperazinyl-, 4-ethylformamide- 1-piperazinyl-, or 4- . methyl-1-piperazinyl. }

29. A compound of claim 16 wherein Rg and Rs are independently H, methyl, ethyl, propyl, 1-propanol, 2-propen, 1-pentanol, 2-methyl-1-propanol, 2-butanol, 1-ethanol, ethoxyl-1-ethanol, -CH,CH,CO,ethyl, 2-methoxyethyl, 4-chlorophenethyl, or 4-fluorophenethyl. :

30. A compound of claim 16 wherein Rg and Re taken together with the nitrogen to which they are attached form 4-methyl-1-piperazinyl.

31. A compound of claim 1 which is a) N-{2-[(9-benzyl-9H-carbazol-4-yl)oxy]ethyl }-N,N-dicthylamine, b) N-{2-[(9-benzyl-8-chloro-9H-carbazol-4-yl)oxy]ethyl }-N,N-diethylamine, c) N-(2-{[8-chloro-9-(4-fluorobenzyl)-9H-carbazol-4-ylJoxy}ethyl)-N,N-diethylamine, d) N-{2-[(9-benzyl-8-methyl-9H-carbazol-4-yl)oxy]ethyl }-N,N-diethylamine, e) N,N-diethyl-N-(2-{[9-(4-fluorobenzyl)-8-methyl-9H-carbazol-4-ylJoxy} ethyl)amine, f) N-{2-[(9-benzyl-9H-carbazol-4-yl)oxy]ethyl }-N-(2-pyridinylmethyl)amine, 2) N-{2-[(9-benzyl-8-fluoro-9H-carbazol-4-yl)oxylethyl }-N,N-diethylamine, _92

N h) 9-benzyl-4-[2-(4-morpholinyl)ethoxy]-9H-carbazole, i 1) 2-(4-{2-[(9-benzyl-9H-carbazol-4-yl)oxylethyl}- 1-piperazinyl)- 1 -ethanol, i) 3-({2-[(9-benzyl-9H-carbazol-4-yl)oxylethyl }amino)-1-propanol, k) N-{2-[(9-benzyl-9H-carbazol-4-yl)oxy]ethyl}-2-propen-1-amine 5D N-{2-[(9-benzyl-9H-carbazol-4-yl)oxylethyl)-3-(4-morpholinyl)- 1-propanamine, m) 5-({2-[(9-benzyl-9H-carbazol-4-yl)oxy]ethyl }amino)-1-pentanol, n) N-{2-[(9-benzyl-9H-carbazol-4-yl)oxy]ethyl}-1-propanamine, 0) N-{2-[(9-benzyl-9H-carbazol-4-yl)oxy]ethyl}-N-propyl-1-propanamine, P) 1-benzyl-N-{2-[(9-benzyl-9H-carbazol-4-yl)oxy]ethyl } -4-piperidinamine, q 2-({2-[(9-benzyl-9H-carbazol-4-yl)oxyJethyl }amino)-2-methyl- 1-propanol, 9) 2-[(9-benzyl-9H-carbazol-4-yDoxy]-N-(4-chlorophenethyl)- 1 -ethanamine, Ss) 2-[(9-benzyl-9H-carbazol-4-yl)oxy]-N-(cyclohexylmethyl)- 1 -ethanamine,

[9] 2-[(9-benzyl-9H-carbazol-4-yl)oxy}-N-[2-(4-morpholinyl)ethyl]- 1 -ethanamine, u) 1-({2-[(9-benzyl-9H-carbazol-4-yl)oxylethyl}amino)-2-butanol, Vv) 2-[(9-benzyl-9H-carbazol-4-yl)oxy]-N-(4-fluorophenethyl)- 1-ethanamine, w) 2-[2-({2-[(9-benzyl-9H-carbazol-4-yl)oxylethyl}amino)ethoxy]-1-ethanol, . X) (1S,2S)-2-({2-[(9-benzyl-9H-carbazol-4-yhoxy]ethyl ) amino)cyclohexanol, : Y) ethyl 3-({2-[(9-benzyl-9H-carbazol-4-yl)oxylethyl }amino)propanoate, - z) N-{2-[(9-benzyl-9H-carbazol-4-yl)oxy]ethyl}cyclobutanamine, aa) 2-(4-{2-[(9-bcnzyl-9H-carbazol-4-yl)oxy]ethyl}-1-piperazinyl) ethylformamide, bb) N-(1H-benzimidazol-2-ylmethyl)-2-{(9-benzyl-9H-carbazol-4-yl)oxyj-1-ethanamine, cc) 1-{2-[(9-benzyl-9H-carbazol-4-yl)oxy)ethyl }-4-piperidinol, dd) 9-benzyl-4-[2-(4-methyl-1-piperazinyl)ethoxy}-9H-carbazole, ee) N-{2-[(9-benzyl-9H-carbazol-4-yl)oxy]ethyl}-N-cyclopropylamine, fb N-{2-[(9-benzyl-9H-carbazol-4-yl)oxy]ethyl}-N,N-dimethylamine, gp) N-{2-[(9-benzyl-9H-carbazol-4-yl)oxy]ethyl formamide, hh) N-{2-[(9-benzyl-9H-carbazol-4-ylyoxy]ethyl}-N-methylamine,or its maleic acid salt, ii) 2-[(9-benzyl-9H-carbazol-4-yl)oxylethylamine, i) N-{2-[(9-benzyl-9H-carbazol-4-yl)oxylethyl }-N-(2-methoxyethyl)amine, kk) N-ethyl-N-([(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl) TT TTT oxylemylamine, or its maleic acid sat, 1) 9-benzyl-4-[2-(1-pyrrolidinyl)ethoxy]-9H-carbazole, mm) 9-benzyl-4-[2-(1-piperidinyl)ethoxy]-9H-carbazole,

> nn) 9-benzyl-4-[2-(1-piperazinyl)ethoxy]-9H-carbazole, 00) 2-[(9-benzyl-8-fluoro-9H-carbazol-4-yl)oxy]ethylamine, pp) N,N-diethyl-N-(2-{[8-fluoro-9-(4-fluorobenzyl)-9H-carbazol-4-yl]oxy }ethyl)amine, . qq) N-{2-[(9-benzyl-6-chloro-9H-carbazol-4-yl)oxy]jethyl }-N,N-diethylamine, 1m) N-{2-{(9-benzyl-6-fluoro-9H-carbazol-4-yl)oxylethyl }-N,N-diethylamine, 8s) N-{2-[(9-benzyl-6-methyl-9H-carbazol-4-yl)oxy]ethyl}-N,N-diethylamine, tt) 2-[(9-benzyl-6-methyl-9H-carbazol-4-yl)oxy]ethylamine, uu) N-{2-[(9-benzyl-6-methyl-9H-carbazol-4-y))oxy]ethyl}-N-methylamine, vv) N,N-diethyl-N-(2-{[9-(4-fluorobenzyl)-6-methyl-9H-carbazol-4-yljoxy }ethyl)amine, ww) 2-({2-[(9-benzyl-9H-carbazol-4-yl)oxylethyl }amino)- I -cthanol or its maleic acid salt, XX) 2-({9-[(5-chloro-1-benzothiophen-3-yl)methyl]-9H-carbazol-4-yl}oxy)ethylamine or its methane sulfonate salt, yy) 2-({9-[(2-methyl-1,3-thiazol-4-yl)methyl}-9H-carbazol-4-yl }oxy)ethylamine or its methane sulfonate salt, , zz) 2-[(9-benzyl-3-chloro-9H-carbazol-4-yl)oxy]ethylamine, methanesulfonate salt, - aaa) 2-{[9-(3-bromobenzyl)-9H-carbazol-4-ylJoxy}ethylamine, maleic acid salt, v bbb) 2-{[9-(3-fluorobenzyl)-9H-carbazol-4-ylJoxy}ethylamine, maleic acid salt, ccc) 2-{[9-(4-methyibenzyl)-9H-carbazol-4-yljoxy }ethylamine, maleic acid salt, ddd) 2-{[9-(2-Ffuorobenzyl)-9H-carbazol-4-yljoxy }ethylamine, maleic acid salt, eee) 2-{[9-(3-methoxybenzyl)-9H-carbazol-4-ylloxy}ethylamine, maleic acid salt, fff) 2-{[9-(3,5-dimethoxybenzyl)-9H-carbazol-4-ylJoxy }ethylamine, maleic acid salt, ggg) 2-{[9-(3-methylbenzyl)-9H-carbazol-4-yl]Joxy }ethylamine, maleic acid salt, hhh) 2-{[9-(2-methylbenzyl)-9H-carbazol-4-ylJoxy}ethylamine, maleic acid sal, iii) 2-[(9-benzyl-6-methoxy-9H-carbazol-4-yl)oxylethylamine, or AIL) 2-[(9-benzyl-7-methoxy-9H-carbazol-4-yl)oxylethylamine.

32. A compound of claim 1 which is a) 2-[(9-benzyl-8-fluoro-9H-carbazol-4-yl)oxy]ethylamine, or b) 2-[(9-benzyl-8-tluoro-9H-carbazol-4-yl)oxy]ethylamine.

33. A compound of claim 1 which is a) N-{2-[(9-benzyl-9H-carbazol-4-yhoxy]ethyl}-N-methylamine or its maleic acid salt, b) 9-benzyl-4-[2-(4-methyl- L-piperazing) ethoxyl-SH-cartazole, or

’ PCT/US00/20809 c) N-{2-[(9-benzyl-6-methyl-9H-carbazol-4-yl)oxy]ethyl} -N-methylamine.

34. A method for preventing psychosis, paraphrenia, psychotic depression, mania, schizophrenia, schizophreniform disorders, schizoaffective disorder, delusional disorder, panic disorder, a phobia, obsessive compulsive disorder, post-traumatic-stress syndrome, immune system depression, a stress induced problem with the urinary, a stress related disease such as anxiety, migraine headache, drug addiction, convulsive disorders, personality disorders, post-traumatic stress syndrome, alcoholism, panic attacks, obsessive- compulsive disorders, sleep disorders, gastrointestinal or cardiovascular system (e.g., stress incontinence) neurodegenerative disorders, autism, chemotherapy-induced vomiting, hypertension, cluster headaches, sexual dysfunction in a mammal (e.g. a human), addictive disorder and withdrawal syndrome. an adjustment disorder. an age-associated learning and mental disorder, anorexia nervosa, apathy, an attention-deficit disorder due to general medical conditions, attention-deficit hyperactivity disorder, behavioural disturbance (including agitation in conditions associated with diminished cognition (e.g. dementia, mental retardation or delirium), bipolar disorder, bulimia nervosa, chronic fatigue syndrome, conduct disorder, cyclothymic disorder, dysthymic disorder, fibromyalgia and other somatoform disorders, an inhalation disorder, an intoxication disorder, movement disorder (e.g., Huntington's disease or Tardive Dyskinesia), oppositional defiant disorder, peripheral neuropathy, post-traumatic stress disorder, premenstrual dysphoric disorder, a psychotic disorder (brief and long duration disorders, psychotic disorder due to medical condition, psychotic disorder NOS), mood disorder (major depressive or bipolar disorder with psychotic features) seasonal affective disorder, a specific developmental disorder, agitation disorder, selective serotonin reuptake inhibition (SSRI) "poop out" syndrome or a Tic disorder (e.g., Tourette's syndrome), comprising administering to a mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

35. Use of a compound of any one of claims 1 - 33, in the manufacture of a preparation for treating a disease or condition in a mammal wherein the 5-HT receptor is implicated and modulation of 5-HT function is desired.

95. AMENDED SHEET

PCT/US00/19532

36. Use of claim 35 wherein the receptor is a 5-HT, receptor.

37. The method of claim 34 wherein the disease or condition is anxiety, depression, schizophrenia, a stress related disease, panic disorder, a phobia, obsessive compulsive disorder, post-traumatic-stress syndrome, immune system depression, psychosis, paraphrenia, mania, convulsive disorders, personality disorders, migraine headache, drug addiction, alcoholism, obesity, eating disorders, or sleep disorders.

38. The method of claim 34 wherein the disease or condition is psychotic, affective, vegetative, and psychomotor symptoms of schizophrenia and the extrapyramidal motor side effects of other antipsychotic drugs.

39. The method of claim 34 wherein the disease is anxiety, obesity, depression, or a stress related disease.

40. A method for modulating 5-HT receptor function, comprising contacting the receptor with an effective inhibitory amount of a compound of claim 1.

41. The method of claim 40 wherein the receptor is a 5-HT, receptor.

42. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a preparation for treating or preventing psychosis, paraphrenia, psychotic depression, mania, schizophrenia, schizophreniform disorders, schizoaffective disorder, delusional disorder, panic disorder, a phobia, obsessive compulsive disorder, post- traumatic-stress syndrome, immune system depression, a stress induced problem with the urinary, a stress related disease such as anxiety, migraine headache, drug addiction, convulsive disorders, personality disorders, post-traumatic stress syndrome, alcoholism, panic attacks, obsessive-compulsive disorders, sleep disorders, gastrointestinal or cardipvascular system (e g ; stress incontinence) neurodegenerative disorders, autism, chemotherapy-induced vomiting, hypertension, cluster headaches, sexual dysfunction in a mammal (e.g. a human), addictive disorder and withdrawal syndrome, an adjustment disorder, an age-associated learning and mental disorder, anorexia nervosa, apathy, an -96- AMENDED SHEET

PCT/US00/19532 attention-deficit disorder due to general medical conditions, attention-deficit hyperactivity disorder, behavioural disturbance (including agitation in conditions associated with diminished cognition (e.g. dementia, mental retardation or delirium), bipolar disorder, bulimia nervosa, chronic fatigue syndrome, conduct disorder, cyclothymic disorder, dysthymic disorder, fibromyalgia and other somatoform disorders, an inhalation disorder, an intoxication disorder, movement disorder (e.g., Huntington's disease or Tardive Dyskinesia), oppositional defiant disorder, peripheral neuropathy, post-traumatic stress disorder, premenstrual dysphoric disorder, a psychotic disorder (brief and long duration disorders, psychotic disorder due to medical condition, psychotic disorder NOS), mood disorder (major depressive or bipolar disorder with psychotic features) seasonal affective disorder, a specific developmental disorder, agitation disorder, selective serotonin reuptake inhibition (SSRI) "poop out" syndrome or a Tic disorder (e.g., Tourette's syndrome).

43. Use of claim 42 wherein the disease or condition is anxiety, depression, schizophrenia, a stress related disease, panic disorder, a phobia, obsessive compulsive disorder, post-traumatic-stress syndrome, immune system depression, psychosis, paraphrenia, mania, convulsive disorders, personality disorders, migraine headache, drug addiction, alcoholism, obesity, eating disorders, or sleep disorders.

44. Use of claim 42 wherein the disease or condition is psychotic, affective, vegetative, and psychomotor symptoms of schizophrenia and the extrapyramidal motor side effects of other antipsychotic drugs.

45. Use of claim 42 wherein the disease is anxiety, obesity, depression, or a stress related disease.

46. Use of a compound of claim 1 in the manufacture of a preparation for modulating 5-HT receptor function.

47. Use of claim 46 wherein the receptor is a 5-HT, receptor.

48. A substance or composition for use in a method for treating or preventing 97- AMENDED SHEET

. PCT/US00/19532 psychosis, paraphrenia, psychotic depression, mania, schizophrenia, schizophreniform disorders, schizoaffective disorder, delusional disorder, panic disorder, a phobia, obsessive compulsive disorder, post-traumatic-stress syndrome, immune system depression, a stress induced problem with the urinary, a stress related disease such as anxiety, migraine headache, drug addiction, convulsive disorders, personality disorders, post-traumatic stress syndrome, alcoholism, panic attacks, obsessive-compulsive disorders, sleep disorders, gastrointestinal or cardiovascular system (e.g., stress incontinence) neurodegenerative disorders, autism, chemotherapy-induced vomiting, hypertension, cluster headaches, sexual dysfunction in a mammal (e.g. a human), addictive disorder and withdrawal syndrome, an adjustment disorder, an age-associated learning and mental disorder, anorexia nervosa, apathy, an attention-deficit disorder due to general medical conditions, attention-deficit hyperactivity disorder. behavioural disturbance (including agitation in conditions associated with diminished cognition (e.g. dementia, mental retardation or delirium), bipolar disorder, bulimia nervosa, chronic fatigue syndrome, conduct disorder, cyclothymic disorder, dysthymic disorder, fibromyalgia and other somatoform disorders, an inhalation disorder, an intoxication disorder, movement disorder (e.g., Huntington's disease or Tardive Dyskinesia), oppositional defiant disorder, peripheral neuropathy, post-traumatic stress disorder, premenstrual dysphoric disorder, a psychotic disorder (brief and long duration disorders, psychotic disorder due to medical condition, psychotic disorder NOS), mood disorder (major depressive or bipolar disorder with psychotic features) seasonal affective disorder, a specific developmental disorder, agitation disorder, selective serotonin reuptake inhibition (SSRI) "poop out" syndrome or a Tic disorder (e.g., Tourette's syndrome), said substance or composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and said method comprising administering to a mammal in need of such treatment, a therapeutically effective amount of said substance or composition.

49. A substance or composition for use in a method of treating a disease or condition in a mammal wherein the 5-HT receptor is implicated and modulation of 3-HT function is desired, said substance or composition comprising a compound of any one of claims 1 - 33, and said method comprising administering a therapeutically effective amount of said _08- AMENDED SHEET

—y PCT/US00/19532 substance or composition to the mammal.

50. A substance or composition for use in a method of treatment of claim 49 wherein the receptor is a 5-HT, receptor.

51. A substance or composition for use in a method of treatment of claim 48 wherein the disease or condition is anxiety, depression, schizophrenia, a stress related disease, panic disorder, a phobia, obsessive compulsive disorder, post-traumatic-stress syndrome, immune system depression, psychosis, paraphrenia, mania, convulsive disorders, personality disorders, migraine headache, drug addiction, alcoholism, obesity, eating disorders, or sleep disorders.

52. A substance or composition for use in a method of treatment of claim 48 wherein the disease or condition is psychotic, affective, vegetative, and psychomotor symptoms of schizophrenia and the extrapyramidal motor side effects of other antipsychotic drugs.

53. A substance or composition for use in a method of treatment of claim 48 wherein the disease is anxiety, obesity, depression, or a stress related disease.

54. A substance or composition for use in a method for modulating 5-HT receptor function, said substance or composition comprising a compound of claim 1, and said method comprising contacting the receptor with an effective inhibitory amount of said substance or composition.

SS. A substance or composition for use in a method of treatment of claim 54 wherein the receptor 1s a 5-HT, receptor.

56. A compound as claimed in claim 1, substantially as herein described and illustrated.

57. A method as claimed in claim 34, substantially as herein described and illustrated.

99. AMENDED SHEET

€ PCT/US00/19532

58. Use as claimed in claim 35 or claim 42 or claim 46, substantially as herein described and illustrated.

59. A method as claimed in claim 40, substantially as herein described and illustrated.

60. A substance or composition for use in a method of treatment or prevention as claimed in claim 48 or claim 49 or claim 54, substantially as herein described and illustrated.

61. A new compound, a new non-therapeutic method of treatment, a new use of a compound of formula (I) or of a pharmaceutically acceptable salt thereof, a new use of a compound as claimed in any one of claims 1 to 33, or a substance or composition tor a new use in a method of treatment or prevention, substantially as herein described. -100- AMENDED SHEET