WO2003016311A1 - Tricyclic pyridin-2-one analogues as ligands for gaba-a receptors - Google Patents

Abstract

A class of selectively substituted fused tricyclic compounds based on a substituted pyridinone moiety are potent and functionally selective ligands for the α2/α3 subunit of the human GABA-A receptor and are thereby effective in the treatment of anxiety. The present invention provides a compound of formula (I), or a salt or N-oxide thereof: wherein E represents -(CH2)n-; n is 1, 2 or 3; R1 represents aryl, C¿3-7? heterocycloalkyl, C3-7 heterocycloalkenyl or heteroaryl, any of which groups may be optionally substituted; or halogen, -NHCOR?3, -COR3¿ or CO¿2R?3; R2 represents aryl or heteroaryl, either of which groups may be optionally substituted; and R3 represents C¿3-6? alkyl, hydroxy(C1-6)alkyl, C2-6 alkenyl, C3-7 cycloalkyl, aryl, aryl(C1-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted; said optional substitutents on R?1, R2 and R3¿ being independently selected from C¿1-6? alkyl, halo(C1-6)alkyl, C3-7 cycloalkyl, halogen, formyl and C2-6 alkylcarbonyl; excluding compounds in which R?1¿ represents methylthiazolyl or hydroxymethylthiazolyl.

Description

TRICYCLIC PYRIDIN-2-ONE ANALOGUES AS LIGANDS FOR

GABA-A RECEPTORS

The present invention relates to a class of fused tricyclic compounds based on a substituted pyridone ring, and to their use in therapy. More particularly, this invention is concerned with tricyclic pyridin-2-one analogues which are ligands for GABAA receptors and are therefore useful in the therapy of deleterious mental states.

Receptors for the major inhibitory neurotransmitter, gamma- aminobutyric acid (GABA), are divided into two main classes: (1) GABAA receptors, which are members of the ligand-gated ion channel superfamily; and (2) GABAB receptors, which may be members of the G-protein linked receptor superfamily. Since the first cDNAs encoding individual GABAA receptor subunits were cloned the number of known members of the mammalian family has grown to include at least six α subunits, four β subunits, three γ subunits, one δ subunit, one ε subunit and two p subunits.

Although knowledge of the diversity of the GABAA receptor gene family represents a huge step forward in our understanding of this ligand- gated ion channel, insight into the extent of subtype diversity is still at an early stage.

However, the results of various studies (summarised, for example, in WO 98/50384) indicate that GABAA receptor agonists which interact more favourably with the α2 and/or α3 subunit than with l will be effective in the treatment.of anxiety with a reduced propensity to cause sedation. Also, agents which are antagonists or inverse agonists at αl might be employed to reverse sedation or hypnosis caused by αl agonists. The compounds of the present invention, being selective ligands for GABAA receptors, are therefore of use in the treatment and/or prevention of a variety of disorders of the central nervous system. Such disorders include anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, animal and other phobias including social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic and acute stress disorder, and generalized or substance-induced anxiety disorder; neuroses; convulsions; migraine; depressive or bipolar disorders, for example single -episode or recurrent major depressive disorder, dysthymic disorder, bipolar I and bipolar II manic disorders, and cyclothymic disorder; psychotic disorders including schizophrenia; neurode eneration arising from cerebral ischemia; attention deficit hyperactivity disorder; speech disorders, including stuttering; and disorders of circadian rhythm, e.g. in subjects suffering from the effects of jet lag or shift work.

Further disorders for which selective ligands for GABAA receptors may be of benefit include pain and nociception; emesis, including acute, delayed and anticipatory emesis, in particular emesis induced by chemotherapy or radiation, as well as motion sickness, and post-operative nausea and vomiting; eating disorders, including anorexia nervosa and bulimia nervosa; premenstrual syndrome; muscle spasm or spasticity, e.g. in paraplegic patients; hearing disorders, including tinnitus and age- related hearing impairment; urinary incontinence; and the effects of substance abuse and dependency, including alcohol withdrawal. Selective ligands for GABAA receptors may also be effective as pre-medication prior to anaesthesia or minor procedures such as endoscopy, including gastric endoscopy.

In addition, the compounds in accordance with the present invention may be useful as radioligands in assays for detecting compounds capable of binding to the human GABAA receptor.

EP-A-0183994 relates to bi- and tricyclic pyridone derivatives which are stated to have muscle relaxant, sedative-hypnotic, anxiolytic and/or anticonvulsant activity. There is no disclosure nor any suggestion therein, however, of compounds possessing a pyridinyl moiety attached via its 3- position to the 6-position of the pyridin-2-one ring. WO 98/50384 describes a class of tricyclic pyridin-2-one analogues, substituted at the 3-position of the pyridone ring by an ester or thiazole moiety, which are stated to be selective ligands for GABA_A receptors beneficial in the treatment and/or prevention of neurological disorders, including anxiety and convulsions.

The present invention provides a class of tricyclic pyridin-2-one analogues which possess desirable binding properties at various GABA_A receptor subtypes. The compounds in accordance with the present invention have good affinity as ligands for the α2 and/or α3 subunit of the human GABAA receptor. The compounds of this invention may interact more favourably with the α2 and/or α3 subunit than with the αl subunit. Desirably, the compounds of the invention will exhibit functional selectivity in terms of a selective efficacy for the α2 and/or α3 subunit relative to the αl subunit. The compounds of the present invention are GABAA receptor subtype ligands having a binding affinity (Ki) for the α2 and/or α3 subunit, as measured in the assay described hereinbelow, of 100 nM or less, typically of 50 nM or less, and ideally of 10 nM or less. The compounds in accordance with this invention may possess at least a 2-fold, suitably at least a 5-fold, and advantageously at least a 10-fold, selective affinity for the α2 and/or α3 subunit relative to the αl subunit. However, compounds which are not selective in terms of their binding affinity for the α2 and/or α3 subunit relative to the αl subunit are also encompassed within the scope of the present invention; such compounds will desirably exhibit functional selectivity in terms of a selective efficacy for the α2 and/or α3 subunit relative to the αl subunit.

The present invention provides a compound of formula (I), or a salt or N-oxide thereof:

(I)

wherein

E represents -(CH2)n-; n is 1, 2 or 3;

R¹ represents aryl, C3-7 heterocycloalkyl, C3-7 heterocycloalkenyl or heteroaryl, any of which groups may be optionally substituted; or halogen, -NHCOR³, -COR³ or -CO2R³;

R² represents aryl or heteroaryl, either of which groups may be optionally substituted; and

R³ represents C3-6 alkyl, hydroxy(Cι-6) alkyl, C2-6 alkenyl, C3-7 cycloalkyl, aryl, aryl(Cι-6) alkyl, heteroaryl or he teroaryl(Cι-6) alkyl, any of which groups may be optionally substituted; excluding compounds in which R¹ represents methylthiazolyl or hydroxy methylthiazolyl.

The groups R¹, R² and R³ as defined above may be unsubstituted, or substituted by one or more substituents. Typically, the groups R¹, R² and/or R³ will be unsubstituted, or substituted by one or two substituents. Suitably, the groups R¹, R² and/or R³ will be unsubstituted or monosubstituted. Examples of suitable substituents on the groups R¹, R² and R³ include Ci-β alkyl, halo (Ci-β) alkyl, C3-7 cycloalkyl, halogen, formyl and C2-6 alkylcarbonyl.

For use in medicine, the salts of the compounds of formula I will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically" acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.

Suitable alkyl groups include straight-chained and branched alkyl groups containing from 1 to 6 carbon atoms. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl, isobutyl, tert-butyl and 2,2-dimethylpropyl. Derived expressions such as "halo(Ci.₆)al r, "hydroxy(Cι-₆)alkyr, "C_1-6 alkoxy" and "Cι-₆ alkylthio" are to be construed accordingly.

Suitable C2-6 alkenyl groups include vinyl, allyl and dimethylallyl groups.

Suitable C3-7 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Particular aryl groups include phenyl and naphthyl, especially phenyl. Particular aryl(C₁-e) alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl, especially benzyl.

Suitable heterocycloalkyl groups include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl groups.

A particular C3-7 heterocycloalkenyl group is thiazolinyl. Suitable heteroaryl groups include pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, fu yl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl groups.

The expression "heteroaryl(C_1-6)alkyl" as used herein includes furylmethyl, furylethyl, thienylmethyl, thienylethyl, oxazolylmethyl, oxazolylethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl, imidazolylethyl, oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl, thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl and isoquinolinylmethyl.

The term "halogen" as used herein includes fluorine, chlorine, bromine and iodine, especially fluorine or chlorine.

Where the compounds according to the invention have at least one asymmetric centre, they may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centres, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.

In the compounds of formula (I), n is preferably 2 or 3 and most preferably 3.

Suitable values for the substituent R¹ include phenyl, pyrrolidinyl, thiazolinyl, pyridinyl, thienyl, pyrrolyl, isoxazolyl, thiazolyl, oxadiazolyl or thiadiazolyl, any of which groups may be optionally substituted; or iodo, -NHCOR³, -COR³ or -CO₂R³ in which R³ is as defined above. Examples of typical substituents on the group R¹ include CI-_G alkyl, halo (Ci-e) alkyl, C3-7 cycloalkyl, halogen and formyl. Examples of specific substituents on R¹ include methyl (except on a thiazolyl ring when the other substituent is hydrogen), ethyl, fluoromethyl, cyclopropyl, chloro and formyl. Suitable values of R³ include isopropyl, teri-butyl, hydroxyethyl, allyl, cyclop entyl, benzyl, thiazolyl or thiazolylmethyl, any of which groups may be optionally substituted.

Examples of typical substituents on the group R³ include Ci-β alkyl, especially methyl.

Specific values of R³ include isopropyl, tert-butyl, hydroxyethyl, allyl, cyclopentyl, benzyl, methylthiazolyl or methyl-thiazolylmethyl.

Representative values of R¹ include phenyl, methylphenyl, pyrrolidinyl, thiazolinyl, pyridinyl, thienyl, methylthienyl, chlorothienyl, pyrrolyl, chloro-isoxazolyl, thiazolyl, dimethylthiazolyl, ethylthiazolyl, fluoromethyl-thiazolyl, cyclopropyl-thiazolyl, chlorothiazolyl, formylthiazolyl, methyloxadiazolyl, methylthiadiazoyl, iodo, tert- butylcarbonylamino, methylthiazolylcarbonyl, isopropyloxycarbonyl, tert- butyloxycarbonyl, hydroxyethoxycarbonyl, allyloxycarbonyl, cyclopentyloxycarbonyl, benzyloxycarbonyl and methylthiazolyl- methoxycarbonyl.

Suitable values for the substituent R² include phenyl, pyridinyl, benzofuryl and thienyl, any of which groups may be optionally substituted by one or more substituents. Illustrative values of R² include phenyl and pyridinyl, either of which groups may be optionally substituted by one or more substituents.

Typically, the group R² may be unsubstituted, or substituted by one or two substituents. Examples of typical substituents on the group R² include halogen, hydroxy(Cι-6) alkyl, Ci-e alkoxy, Cι-3 alkylenedioxy, formyl and Ci-e alkylthio.

Particular values of R² include phenyl, fluorophenyl, chlorophenyl, dichlorophenyl, hydroxymethyl-phenyl, methoxyphenyl, dimethoxyphenyl, (fluoro) (methoxy)phenyl, (chloro) (fluoro)phenyl, (chloro) (methoxy)phenyl, methylenedioxyphenyl, formylphenyl, methylthio-phenyl, pyridinyl, benzofuryl and thienyl.

Specific values of R² include phenyl and pyridinyl. A particular sub-class of compounds according to the invention is represented by the compounds of formula (LA), and pharmaceutically acceptable salts and N-oxides thereof:

(IA)

wherein

R¹¹ represents phenyl, pyrrolidinyl, thiazolinyl, pyridinyl, thienyl, pyrrolyl, isoxazolyl, oxadiazolyl or thiadiazolyl, any of which groups may be optionally substituted; or iodo, -NHCOR³, -COR³ or -C0₂R³; W represents -N- or -CH-;

R⁴ represents hydrogen, halogen or Ci-e alkoxy; and R³ is as defined above.

Examples of typical substituents on the group R¹¹ include Ci-β alkyl and halogen. Examples of specific substituents on R¹¹ include methyl and chloro.

Particular values of R¹¹ include phenyl, methylphenyl, pyrrolidinyl, thiazolinyl, pyridinyl, thienyl, methylthienyl, chlorothienyl, pyrrolyl, chloro-isoxazolyl, methyloxadiazolyl, methylthiadiazolyl, iodo, tert- butylcarbonylammo, methylthiazolylcarbonyl, isopropyloxycarbonyl, tert- butyloxycarbonyl, hydroxyethoxy carbonyl, allyloxycarbonyl, cyclop entyloxycarbonyl, benzyloxycarbonyl and methylthiazolyl- methoxycarbonyl.

In one embodiment, W is -N-. In another embodiment, W is -CH-. Typical values of R⁴ include hydrogen, fluoro, chloro and methoxy, especially hydrogen.

Another sub-class of compounds according to the invention is represented by the compounds of formula (IB), and pharmaceutically acceptable salts and N-oxides thereof:

(IB)

wherein R⁵ represents hydrogen, C2-6 alkyl,

C3-7 cycloalkyl, halogen, formyl or C2-6 alkylcarbonyl; and

W and R⁴ are as defined above.

In one embodiment, R⁵ suitably represents hydrogen, halo (Ci-e) alkyl, C3-7 cycloalkyl, halogen or formyl. Specific values of R⁵ include hydrogen, ethyl, fluoromethyl, cyclopropyl, chloro and formyl.

Particular values of R⁵ include hydrogen, fluoromethyl, cyclopropyl, chloro and formyl.

In an individual embodiment, R⁵ represents hydrogen. In another embodiment, R⁵ represents cyclopropyl. In a further embodiment, R⁵ represents fluoromethyl.

Specific compounds within the scope of the present invention include: 1 l-phenyl-9-(thien-2-yl)-6, -dihydro-5H-2, 7a-diaza- dibenzo[α,c]cyclohepten-8-one; ll-phenyl-9-(thien-3-yl)-6,7-dihydro-5H-2,7a-diaza- dibenzo[α,e]cyclohepten-8-one; 9,ll-diphenyl-6,7-dihydro-5H-2,7a-diazadibenzo[α,c]cyclohepten-8-one; 9-(5-methylthien-2-yl)-ll-phenyl-6,7-dihydro-5H-2,7a-diaza- dibenzo [a,c] cyclohepten-8-one; ll-phenyl-9-(m^,-tolyl)-6,7-dihydro-5H-2,7a-diazadibenzo[α,c]cyclohepten-8- one; ll-phenyl-9-(lH-pyrrol-2-yl)-6,7-dihydro-5H-2,7a-diaza- dibenzo [a, c] cyclohep ten-8-one ;

9-(5-chlorothien-2-yl)-ll-phenyl-6,7-dihydro-5H-2,7a-diaza- dibenzo [a, c] cyclohep ten-8-one; ll-phenyl-9-(pyrrolidin-l-yl)-6,7-dihydro-5H-2,7a-diaza- dibenzo [a, c]cyclohepten-8-one ;

8-oxo-ll-phenyl-5,6,7,8-tetrahydro-2,7a-diazadibenzo[ ,c]cycloheptene-9- carboxylic acid tert-butyl ester;

8-oxo-ll-phenyl-5,6,7,8-tetrahydro-2,7a-diazadibenzo[α,c]cycloheptene-9- carboxylic acid allyl ester; 8-oxo-ll-phenyl-5,6,7,8-tetrahydro-2,7a-diazadibenzo[α,c]cycloheptene-9- carboxylic acid 2-hydroxyethyl ester;

8-oxo-ll-phenyl-5,6,7,8-tetfahydro-2,7a-diazadibenzo[ ,c]cycloheptene-9- carboxylic acid cyclopentyl ester;

8-oxo-ll-phenyl-5,6,7,8-tetrahydro-2,7a-diazadibenzo[ ,c]cycloheptene-9- carboxylic acid 4-methylthiazol-2-ylmethyl ester;

8-oxo-ll-phenyl-5,6,7,8-tetrahydro-2,7a-diazadibenzo[ ,c]cycloheptene-9- carboxylic acid benzyl ester;

8-oxo-ll-phenyl-5,6,7,8-tetrahydro-2,7a-diazadibenzo[α,c]cycloheptene-9- carboxylic acid isopropyl ester; 9-(4-methylthiazol-2-ylcarbonyl)- 1 l-phenyl-6, 7-dihydro-5H-2, 7a-diaza- dibenzo[α,c]cyclohepten-8-one; 2,2-dimethyl-iV-(8-oxo-ll-phenyl-5,6,7,8-tetrahydro-2,7a-diaza- dibenzo[ ,c]cyclohepten-9-yl)propionamide; 9-(4,5-dihydrothiazol-2-yl)-ll-phenyl-6,7-dihydro-5H-2,7a-diaza- dibenzo [a, c] cyclohep ten-8-one ; 9-(5-chloroisoxazol-3-yl)-ll-phenyl-6,7-dihydro-5H-2,7a-diaza- dibenzo [a, c] cyclohep ten-8-one;

9-(5-methyl-[l,2,4]oxadiazol-3-yl)-ll-phenyl-6,7-dihydro-5H-2,7a-diaza- dibenzo [a, c] cyclohep ten-8-one ;

9-(3-methyl-[l,2,4]oxadiazol-5-yl)-ll-phenyl-6,7-dihydro-5H-2,7a-diaza- dibenzo[α,c]cyclohepten-8-one;

9-(3-methyl-[l,2,4]thiadiazol-5-yl)-ll-phenyl-6,7-dihydro-5H-2,7a-diaza- dibenzo[α,c]cyclohepten-8-one;

9-(4-chlorothiazol-2-yl)-ll-phenyl-6,7-dihydro-5H-2,7a-diaza- dibenzo[ ,c]cyclohepten-8-one; 9-(4-cyclopropylthiazol-2-yl)-ll-phenyl-6,7-dihydro-5H-2,7a-diaza- dibenzo[α,c]cyclohepten-8-one;

9-(4-cyclopropylthiazol-2-yl)-ll-(pyridin-4-yl)-6,7-dihydiO-5H-2,7a-diaza- dibenzo[α,c]cyclohepten-8-one; ll-phenyl-9-(thiazol-2-yl)-6,7-dihydro-5H-2,7a-diaza- dibenzo[α,c]cyclohepten-8-one; ll-(pyridin-4-yl)-9-(thiazol-2-yl)-6,7-dihydro-5H-2,7a-diaza- dibenzo[ ,c]cyclohepten-8-one;

9-(4,5-dimethylthiazol-2-yl)-ll-phenyl-6,7-dihydro-5H-2,7a-diaza- dibenzo [a, c] cyclohepten-8-one; 2-[8-oxo-ll-(pyridin-4-yl)-5,6,7,8-tetrahydro-2,7a-diaza- dibenzo [a, c] cyclohep ten-9-yl]thiazole-4-carbaldehyde ;

9-(4-methylthien-2-yl)-ll-phenyl-6,7-dihydro-5H-2,7a-diaza- dibenzo[α,c]cyclohepten-8-one;

9-(4-ethylthiazol-2-yl)-ll-phenyl-6,7-dihydro-5H-2,7a-diaza- dibenzo[ ,c]cyclohepten-8-one; 9-(4-fluoromethylthiazol-2-yl)-ll-phenyl-6,7-dihydro-5H-2,7a-diaza- dibenzo[α,c]cyclohepten-8-one; ll-phenyl-9-(pyridin-2-yl)-6,7-dihydro-5H-2,7a-diaza- dibenzo [a, c] cyclohepten-8-one; and salts and iV-oxides thereof.

Also provided by the present invention is a method for the treatment and/or prevention of anxiety which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof. Further provided by the present invention is a method for the treatment and/or prevention of convulsions (e.g. in a patient suffering from epilepsy or a related disorder) which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof. The binding affinity (Ki) of the compounds according to the present invention for the α3 subunit of the human GABAA receptor is conveniently as measured in the assay described hereinbelow. The α3 subunit binding affinity (Ki) of the compounds of the invention is ideally 10 nM or less, preferably 2 nM or less, and more preferably 1 nM or less. The compounds according to the present invention will ideally elicit at least a 40%, preferably at least a 50%, and more preferably at least a 60%, potentiation of the GABA EC20 response in stably transfected recombinant cell lines expressing the α3 subunit of the human GABAA receptor. Moreover, the compounds of the invention will ideally elicit at most a 30%, preferably at most a 20%, and more preferably at most a 10%, potentiation of the GABA EC20 response in stably transfected recombinant cell lines expressing the αl subunit of the human GABAA receptor.

The potentiation of the GABA EC20 response in stably transfected cell lines expressing the α3 and αl subunits of the human GABAA receptor can conveniently be measured by procedures analogous to the protocol described in Wafford et al, Mol. Pharmacol, 1996, 50, 670-678. The procedure will suitably be carried out utilising cultures of stably transfected eukaryotic cells, typically of stably transfected mouse Ltk- fibroblast cells.

The compounds according to the present invention exhibit anxiolytic activity, as may be demonstrated by a positive response in the elevated plus maze and conditioned suppression of drinking tests (cf. Dawson et al, Psychopharmacology, 1995, 121, 109-117). Moreover, the compounds of the invention are substantially non-sedating, as may be confirmed by an appropriate result obtained from the response sensitivity (chain-pulling) test (cf. Bayley et al, J. PsychopharmacoL, 1996, 10, 206- 213).

The compounds according to the present invention may also exhibit anticonvulsant activity. This can be demonstrated by the ability to block pentylenetetrazole-induced seizures in rats and mice, following a protocol analogous to that described by Bristow et al. in J. Pharmacol. Exp. Ther., 1996, 279, 492-501.

In order to elicit their behavioural effects, the compounds of the invention will ideally be brain-penetrant; in other words, these compounds will be capable of crossing the so-called "blood-brain barrier". Preferably, the compounds of the invention will be capable of exerting their beneficial therapeutic action following administration by the oral route.

The invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a sohd preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. Typical unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate. The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.

In the treatment of anxiety, a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day.

The compounds in accordance with the present invention may be prepared by a process which comprises cyclising a compound of formula (II):

(ID

wherein E, R¹ and R² are as defined above, and L¹ represents a readily displaceable group. The readily displaceable group L¹ is suitably a halogen atom, e.g. bromo, in which case the cyclisation is conveniently carried out by treating the compound of formula (II) with tributyltin hydride in the presence of a radical initiator such as l,l'-azobisisobutyronitrile (AIBN), typically in an inert solvent such as benzene. In an alternative procedure, the compounds in accordance with the present invention may be prepared by a process which comprises cyclising a compound of formula (III):

(in)

wherein E, R¹ and R² are as defined above, and L² represents a readily displaceable group.

The readily displaceable group L² may suitably be a halogen atom, e.g. bromo, in which case the cyclisation of compound (III) is conveniently effected by treatment with sodium hydride in the presence of lithium bromide, in a solvent system which may typically be a mixture of 1,2- dimethoxyethane and iV,N-dimethylformamide. Alternatively, the readily displaceable group L² may be hydroxy, in which case the cyclisation of compound (III) is conveniently effected by treatment with triphenylphosphine in the presence of diethyl azodicarboxylate (DEAD), typically in an inert solvent such as tetrahydrofuran or dichloromethane.

The intermediates of formula (II) above may suitably be prepared by reacting a compound of formula (IN) with a compound of formula (V):

(IV) (V)

wherein E, R¹, R², L¹ and L² are as defined above; under conditions analogous to those described above for the cyclisation of compound (III). In another procedure, the compounds according to the present invention may be prepared by a process which comprises reacting a compound of formula (VI) with a compound of formula (VII):

(VI) (VII)

wherein E, R¹ and R² are as defined above, M represents -B(OH)2 or -Sn(Alk)3 in which Alk represents a Ci-β alkyl group, typically ?ι-butyl, and L³ represents a suitable leaving group; in the presence of a transition metal catalyst.

The leaving group L³ is suitably a halogen atom, e.g. iodo or bromo; or a sulfonyloxy moiety, e.g. trifluoromethanesulfonyloxy (triflyloxy) ox p- toluenesulfonyloxy (tosyloxy). Favourably, L³ is iodo or triflyloxy.

A suitable transition metal catalyst of use in the reaction between compounds (VI) and (VII) comprises diehlorobis(triphenylphosphine)- palladium(II) or tetrakis(triphenylphosphine)palladium (0).

The reaction between compounds (VI) and (VII) is conveniently effected in an inert solvent such as N,N-dimethylformamide, typically in the presence of potassium phosphate at an elevated temperature. The intermediates of formula (VI) above wherein L³ represents triflyloxy may be prepared by methods analogous to those described in WO 98/50384.

In an additional procedure, the compounds according to the present invention wherein R¹ represents an optionally substituted aryl or heteroaryl moiety may be prepared by a process which comprises reacting a compound of formula (VIII) with a compound of formula (IX):

(VIII) (IX)

wherein E, R², M and L³ are as defined above, and R^la represents aryl or heteroaryl, either of which groups may be optionally substituted; in the presence of a transition metal catalyst; under conditions analogous to those described above for the reaction between compounds (VI) and (VII).

In a similar procedure, the compounds according to the present invention wherein R¹ represents an optionally substituted aryl or heteroaryl moiety may be prepared by reacting a compound of formula (X) with a compound of formula (XI):

(X) (XI)

wherein E, R², M, L³ and R^la are as described above; in the presence of a transition metal catalyst; under conditions analogous to those described above for the reaction between compounds (VI) and (VII).

In a typical procedure, the intermediates of formula (X) wherein M represents -Sn(Alk)3 may be prepared from the corresponding compound of formula (VIII) wherein L³ is iodo by treatment with [Sn(Alk)3J2 in the presence of a transition metal catalyst such as tetrakis(triphenylphosphine)palladium (0).

In a further procedure, the compounds according to the present invention wherein R¹ represents an optionally substituted thiazolyl or thiazolinyl moiety may be prepared by reacting a compound of formula (XII):

(XII)

wherein E and R² are as defined above; with the appropriate α- bromoketone or 1,2-dibromoalkane derivative respectively.

In a still further procedure, the compounds according to the present invention wherein R¹ represents an optionally substituted 1,2,4-oxadiazol- 3-yl moiety may be prepared by reacting a compound of formula (XIII):

(XIII)

wherein E and R² are as defined above; with the appropriate acid anhydride derivative. In a yet further procedure, the compounds according to the present invention wherein R¹ represents an optionally substituted 1,2,4-oxadiazol- 5-yl moiety may be prepared by reacting a compound of formula (XIV):

(XIV)

wherein E and R² are as defined above, and Alk¹ represents methyl or ethyl, typically methyl; with the appropriate amide oxime derivative.

The intermediates of formula (XIV) may be prepared by methods analogous to those described in WO 98/50384.

The compounds according to the present invention wherein R¹ represents 5-chloroisoxazol-3-yl may be prepared by a process which comprises reacting a compound of formula (XIII) as defined above with sodium nitrite at 0°C in aqueous mineral acid, e.g. dilute hydrochloric acid; then treating the product thereby obtained with vinylidene chloride, advantageously in the presence of triethylamine.

The compounds according to the present invention wherein R¹ represents -NHCOR³ may be prepared by a process which comprises reacting a compound of formula (XV) with a compound of formula (XVI):

(XV) (XVI) wherein E, R² and R³ are as defined above, and Hal represents halogen, typically chloro; typically in the presence of 4-dimethylaminopyridine (DMAP) and pyridine.

The compounds of formula (VIII) above wherein L³ represents halogen may be prepared by diazotising the corresponding compound of formula (XV) by treatment with sodium nitrite, followed by treatment with the appropriate copper(I) halide, or with potassium halide in the presence of metallic copper, under acidic conditions. As will be appreciated, where L³ in the compounds of formula (VIII) above represents halogen, the resulting compounds of formula (VIII) are compounds according to the invention in their own right, and may consequently be prepared by any other appropriate method as described herein for the preparation of compounds in accordance with the invention.

The compounds according to the present invention wherein R¹ represents -COR³ may be prepared by a process which comprises reacting a compound of formula (XVII) with an anion of formula (XVTII):

(XVII) (XVIII)

wherein E, R² and R³ are as defined above.

The anion (XVIir), as appropriate, may be in the form of a Grignard reagent R³-MgBr; or it may be generated from a starting compound R³-H by treatment with 7i-butyllithium. The compounds according to the present invention wherein R¹ represents -CO2R³ may be prepared by a process which comprises reacting a compound of formula (XIX) with a compound of formula (XX):

(XIX) (XX)

wherein E, R², R³ and Hal are as defined above; typically in the presence of DMAP and pyridine.

Additionally, the compounds according to the present invention wherein R¹ represents -CO2R³ and R³ represents ieri-butyl may be prepared by reacting a compound of formula (XXI) with the compound of formula (XXII):

(XXI) (XXII)

wherein E and R² are as defined above; typically in toluene at reflux. The intermediates of formula (XVII) above may be prepared by reacting a compound of formula (XIX) with dimethylhydroxylamine hydrochloride, typically in the presence of DMAP and pyridine. The intermediates of formula (XIX) wherein Hal is chloro may be prepared by treating the corresponding compound of formula (XXI) with oxalyl chloride.

The intermediates of formula (XV) may be prepared by treating the corresponding compound of formula (XXI) with PI12PON3 and ierf-butanol, typically in the presence of triethylamine at reflux, followed by hydrolysis of the resulting terέ-butyloxycarbonylamino derivative thereby obtained by treatment with trifluoroacetic acid.

The intermediates of formula (XII), (XIII) and (XXI) above may be prepared from the corresponding compound of formula (I) wherein R¹ is cyano by treatment with gaseous hydrogen sulfide or with hydroxylamine hydrochloride or with refluxing hydrochloric acid respectively.

Where they are not commercially available, the starting materials of formula (III), (IV), (V), (VII), (IX), (XI), (XVI), (XX) and (XXII) may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art.

It will be understood that any compound of formula (I) initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula (I) by techniques known from the art. For example, a compound of formula (I) initially obtained wherein R¹ represents iodo may be converted into the corresponding compound wherein R¹ represents pyrrolidin-1-yl by treatment with pyrrolidine, typically in the presence of a transition metal catalyst such as tris(dibenzyhdeneacetone)dipalladium(0). A compound of formula (I) initially obtained wherein the R¹ moiety is substituted by carboxy may be converted into the corresponding compound wherein the R¹ moiety is substituted by hydroxymethyl by treatment with a reducing agent, e.g. lithium aluminium hydride. Alternatively, a compound of formula (I) initially obtained wherein the R¹ moiety is substituted by carboxy may be converted into the corresponding compound wherein the R¹ moiety is substituted by -CON(CH₃)OCH₃ by treatment with N,0- dimethylhydroxylamine hydrochloride, typically in the presence of bis(2- oxo-3-oxazoHdinyl)phosphinic chloride (BOP-C1) and triethylamine; and the resulting product may in turn be converted into the corresponding compound wherein the R¹ moiety is substituted by formyl by treatment with a reducing agent such as diisobutylaluminium hydride (DIBAL-H). Where the above-described processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The novel compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific or enantioselective synthesis or by resolution. The novel compounds may, for example, be resolved into their component enantiomers by standard techniques such as preparative HPLC, or the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l- tartaric acid, followed by fractional crystallization and regeneration of the free base. The novel compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

The following Examples illustrate the preparation of compounds according to the invention. The compounds in accordance with this invention potently inhibit the binding of [³H]-flumazenil to the benzodiazepine binding site of human GABAA receptors containing the α2 or α3 subunit stably expressed in Ltk- cells.

Reagents • Phosphate buffered saline (PBS).

• Assay buffer: 10 mM KH2PO4, 100 mM KC1, pH 7.4 at room temperature.

• [³H]-Flumazenil (18 nM for αlβ3γ2 cells; 18 nM for α2β3γ2 cells; 10 nM for α3β3γ2 cells) in assay buffer. • Flunitrazepam 100 μM in assay buffer.

• Cells resuspended in assay buffer (1 tray to 10 ml).

Harvesting Cells

Supernatant is removed from cells. PBS (approximately 20 ml) is added. The cells are scraped and placed in a 50 ml centrifuge tube. The procedure is repeated with a further 10 ml of PBS to ensure that most of the cells are removed. The cells are pelleted by centrifuging for 20 min at 3000 rpm in a benchtop centrifuge, and then frozen if desired. The pellets are resuspended in 10 ml of buffer per tray (25 cm x 25 cm) of cells.

Assay

Can be carried out in deep 96-well plates or in tubes. Each tube contains:

• 300 μl of assay buffer. • 50 μl of [³H]-flumazenil (final concentration for αlβ3γ2: 1.8 nM; for α2β3γ2: 1.8 nM; for α3β3γ2: 1.0 nM).

• 50 μl of buffer or solvent carrier (e.g. 10% DMSO) if compounds are dissolved in 10% DMSO (total); test compound or flunitrazepam (to determine non-specific binding), 10 μM final concentration. • 100 μl of cells. Assays are incubated for 1 hour at 40°C, then filtered using either a Tomtec or Brandel cell harvester onto GF/B filters followed by 3 x 3 ml washes with ice cold assay buffer. Filters are dried and counted by liquid scintillation counting. Expected values for total binding are 3000-4000 dpm for total counts and less than 200 dpm for non-specific binding if using liquid scintillation counting, or 1500-2000 dpm for total counts and less than 200 dpm for non-specific binding if counting with meltilex solid scintillant. Binding parameters are determined by non-linear least squares regression analysis, from which the inhibition constant Ki can be calculated for each test compound.

The compounds of the accompanying Examples were tested in the above assay, and all were found to possess a Ki value for displacement of [³H]-flumazenil from the α2 and/or α3 subunit of the human GABA_A receptor of 100 nM or less.

INTERMEDIATE 1

1 - (4- [3 - (ter £-Butyldimethylsilanyloxy)pr op yll p yridin- 3 -yl }- 3- dimethylamino-2-phenylpropenone

a) 3-Bromo-4-(3-hydroχvpropyDpyridine

7i-Butyllithium solution (445 ml, 2.5 M in hexanes, 1.125 mol) was added over 30 min to a cooled solution of diisopropylamine (157 ml, 1.11 mol) in tetrahydrofuran (1.5 1) with mechanical stirring, keeping the temperature below 10°C. The reaction was stirred at 5°C for 5 min then 3-bromo-4-methylpyridine (175 g, 1.02 mol) was added and the reaction heated to 50°C for 45 min. The reaction was cooled to -20°C and a cold (-78°C) solution of ethylene oxide (69 g, 1.5 mol, condensed into cold tetrahydrofuran) in tetrahydrofuran (500 ml) was added. The reaction temperature was maintained below 0°C. After 30 minutes the reaction was quenched by the addition of water (750 ml). The layers were separated and the aqueous extracted with ethyl acetate. The combined organics were dried over Na₂SO4 and the solvent was removed in vacuo before purification on a pad of silica to afford the title compound as an oil (172 g, 78%). ⁱH NMR (400 MHz, CDC1₃) δ 1.87-1.94 (2H, m), 2.84 (2H, dd, J 10, 8), 3.72 (2H, t, J 6), 7.19 (IH, d, J 5), 8.40 (IH, d, J 5), 8.65 (IH, s). mlz (ES⁺) 215, 217 (M⁺+H).

b) 3-Bromo-4- \ 3-(fer -butyldimethylsilanyloxy)propyllpyridine

Imidazole (19.4 g, 285.9 mmol) was added to a solution of 3-bromo- 4-(3-hydroxypropyl)pyridine (47.5 g, 219.9 mmol) in dry dichloromethane (250 ml) followed by teri-butyldimethylsilyl chloride (34.8 g, 230.9 mmol) and the reaction mixture stirred at room temperature for 17 h. The reaction mixture was washed with water (3 x 200 ml), dried (MgS0₄) and concentrated in vacuo to a colourless oil (72.5 g, 100%). *H NMR (400 MHz, CDCI3) δ 0.07 (6H, s), 0.84 (9H, s), 1.75-1.78 (2H, m), 2.71-2.75 (2H, m), 3.60 (2H, t, 6), 7.10 (IH, d, 5), 8.32 (IH, d, =75), 8.57 (IH, s). mlz (ES⁺) 330, 332 (M⁺+H).

c) 4-[3-(ter-:-Butyldimethylsilanyloxy)propyllnicotinic acid methyl ester A solution of 3-bromo-4-[3-(ter^butyldimethylsilanyloxy)propyl]- pyridine (20.0 g, 60.6 mmol) in dry methanol (250 ml) and N,N- dimethylformamide (250 ml) was degassed with nitrogen for 20 min. Diisopropylethylamine (31.7 ml, 181.8 mmol) and 1,3- bis(diphenylphosphino)propane (2.5 g, 6.0 mmol) was added and the solution degassed for a further 5 min. Palladium(II) acetate (1.3 g, 6.0 mmol) was added, and carbon monoxide bubbled through for 20 min at room temperature. The flow rate was reduced and the mixture heated at 95°C for 20 h. The reaction mixture was poured into water (1 1) and extracted with ethyl acetate (3 x 400 ml), dried (MgS0₄) and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate/isohexanes (30/70) to yield the title compound as a brown oil (33.5 g, 88%). NMR (400 MHz, CDCls) δ 0.07 (6H, s), 0.85 (9H, s), 1.75- 1.79 (2H, m), 2.96-3.00 (2H, m), 3.60 (2H, t, =76), 3.86 (3H, s), 7.14 (IH, d, e/ 5), 8.52 (IH, d, =75), 8.98 (IH, s). mlz (ES⁺) 310 (M⁺+H).

d) 4-[3-(t:ert:-Butyldimethylsilanyloxy)propyllnicotinic acid

To a suspension of potassium trimethylsilanolate (9.4 g, 72.8 mmol) in dry diethyl ether (250 ml) was added 4-[S-(tert- butyldimethylsilanyloxy)propyl]nicotinic acid methyl ester (15.0 g, 48.5 mmol) and the mixture stirred at room temperature for 48 h. The resulting white solid was filtered, taken into water (300 ml) and the pH adjusted with citric acid (10% w/v) to pH 5. The aqueous was extracted with ethyl acetate (2 x 300 ml), dried (MgSO₄) and evaporated to give the title compound (12.8 g, 89%) as a white solid, mp 84-86°C (from ethyl acetate). Η NMR (400 MHz, d₆-DMSO) δ 0.07 (6H, s), 0.84 (9H, s), 1.71- 1.78 (2H, m), 2.93-2.97 (2H, m), 3.60 (2H, t, =76), 7.31 (IH, d, J 5), 8.55 (IH, d, = 5), 8.96 (IH, s), 13.25 (IH, br s). mlz (ES⁺) 296 (M⁺+H).

e) 3-{4-f3-(tert:-Butyldimethylsilanyloxy)propynpyridin-3-yl}-3-oxo-2- phenylpropionic acid methyl ester ljl'-Carbonyldiimidazole (19.6 g, 120.8 mmol) was added to a solution of 4-[3-(ter^butyldimethylsilanyloxy)propyl]nicotinic acid (34 g, 115 mmol) in dry N-N-dimethylformamide (1 1). The mixture was heated at 50°C for 90 min before cooling to -10°C and methyl phenylacetate (17.4 ml, 120.8 mmol) added followed by sodium hydride (60% in mineral oil) (16.1 g, 402 mmol) in portions over 20 min. The reaction was stirred at

-10°C for 15 min and allowed to warm to room temperature. After 3 h the reaction was quenched by slowly pouring into ammonium chloride solution (1 1, sat. aq.). The aqueous was extracted with ethyl acetate (3 x 400 ml). The combined organics were washed with H2O (3 x 200 ml), brine (2 x 200 ml), dried (MgSO₄) and evaporated. The crude product was purified by chromatography (30% ethyl acetate/hexanes) to afford the product (49.2 g, 98%) as a colourless oil. mlz (ES⁺) 428 (M⁺+H).

f) l-{4- T3-(t:6rt:-Butyldimethylsilanyloxy)propynpyridin-3-yl)-2- phenylethanone

Sodium chloride (7.36 g, 126 mmol) and water (3 ml, 172 mmol) were added to a solution of 3-{4-[S-(tert- butyldimethylsilanyloxy)propyl]pyridin-3-yl}-3-oxo-2-phenylpropionic acid methyl ester (49.0 g, 114 mmol) in DMSO (800 ml) and the solution heated at 150°C. After 2 hours the reaction was allowed to cool and poured into water (2 1). The aqueous was extracted with 1:1 ethyl acetate/Et₂O (5 x 800 ml). The combined organic extracts were washed with water (4 x 800 ml) and brine (2 x 800 ml) and dried (Na2SO₄). After evaporation the crude product was purified by flash chromatography (30% ethyl acetate/hexanes) to afford the product as an oil (29.6 g, 70%). *H NMR

(400 MHz, CDCls) δ 0.01 (6H, s), 0.86 (9H, s), 1.85-1.69 (2H, m), 2.77-2.81 (2H, m), 4.19 (2H, s), 7.16-7.28 (6H, m), 8.50 (IH, d, =75), 8.90 (IH, s). mlz (ES⁺) 370 (M⁺+H).

g) l-{4-|^"3-(tert;-Butyldimethylsilanyloxy)propynpyridin-3-yl}-3- dimethylamino-2-phenylpropenone l-{4-[3-(teri-Butyldimethylsilanyloxy)propyl]pyridin-3-yl}-2- phenylethanone (29.2 g, 79 mmol) was dissolved in N,N- dimethylformamide dimethyl acetal (400 ml) and stirred for 18 hours at room temperature under nitrogen. The iV,N-dimethylformamide dimethyl acetal was evaporated and azeotroped with toluene (2 x 200 ml). The oil thus produced was used without purification in subsequent reactions (33.55 g, 100%). mlz (ES⁺) 425 (M⁺+H). INTERMEDIATE 2

!-{4-r3-(tert:-Butyldimethylsilanyloxy)propynpyridin-3-yl}-3- dimethylamino-2-(pyridin-4-yl)propenone

a) Benzyl 4-pyridylacetate

Ethyl 4-pyridylacetate (100 g, 0.61 mol) was dissolved in benzyl alcohol (300 ml, 3.01 mol) and a catalytic amount of potassium carbonate was added. The reaction was heated to 120°C and nitrogen bubbled through to evaporate ethanol as it was released. After 6 h the reaction was allowed to cool and was partitioned between 2N HC1 (750 ml) and ether (500 ml). The aqueous was washed with ether (3 x 500 ml) and then neutralised with NaOH at which point turbidity appeared. The aqueous was extracted with ethyl acetate (3 x 500 ml) and the combined ethyl acetate extracts were washed with brine (250 ml), dried (Na2SO₄) and evaporated to afford the title compound as a waxy solid (103 g, 75%). ¹H NMR (360 MHz, CDC1₃) δ 3.66 (2H, s), 5.15 (2H, s), 7.20 (2H, d, =74), 7.26- 7.38 (5H, m), 8.54 (2H, d, =74). mlz (ES⁺) 318 (M⁺+H).

b) 3 -{4- [3 - (fert Butyldimethylsilanyloxy)prop vDp yridin- 3 -yl) - 3 -oxo-2- (pyridin-4-yDpropionic acid benzyl ester

To a solution of 4-[3-(teri-butyldimethylsilanyloxy)propyl]nicotinic acid (24.2 g, 81.9 mmol) in dry N,N-dimethylformamide (600 ml) was added l,l'-carbonyldiimidazole (13.95 g, 86 mmol) and the reaction heated to 45°C for 90 min. The reaction was cooled to -10°C and benzyl 4- pyridylacetate (19.55 g, 86 mmol) was added followed by sodium hydride (11.47 g, 60% dispersion in oil, 287 mmol) in portions over 20 min. The reaction was allowed to warm to room temperature and stirred for 2 h before the reaction was quenched by pouring onto ice/water and the pH adjusted to neutral with citric acid. The aqueous was extracted with ethyl acetate (4 x 500 ml) and the combined organic extracts were washed with water (4 x 250 ml), brine (2 x 250 ml), dried (Na₂SO₄) and the solvent removed in vacuo. The crude product was purified by flash chromatography (ethyl acetate) to afford the title compound as an oil (33.5 g, 81%). ⁱH NMR (400 MHz, CDC1₃, as mixture of ketone and enol tautomers) δ 0.07 (6H, s), 0.05 (6H, s), 0.83 (2 x 9H, s), 1.60-1.70 (2H, m), 1.70-1.80 (2H, m), 2.62-2.66 (2H, m), 2.76-2.80 (2H, m), 3.52 (2H, t, =76), 3.60 (2H, t, =76), 5.12 (2H, s), 5.22 (2H, s), 5.45 (IH, s), 6.85 (2H, d, =75), 7.03 (IH, d, J 5), 7.19-7.29 (2 x 7H, m), 8.12 (IH, s), 8.28-8.33 (2 x 2H, m), 8.81 (IH, s), 13.47 (IH, s). mlz (ES⁺) 506 (M⁺+H).

c) l-{4-[3-(t:er-:-Butyldimethylsilanyloxy)propyllpyridin-3-yl}-2-(pyridin-4- vDethanone

3-{4-[3-(terέ-Butyldimethylsilanyloxy)propyl]pyridin-3-yl}-3-oxo-2- (pyridin-4-yl)propionic acid benzyl ester (32.5 g, 64.4 mmol) was dissolved in ethanol (600 ml) in a three-neck flask and the system flushed with nitrogen. Palladium on carbon catalyst (3.25 g, 10% Pd) was added as a slurry in water (10 ml) (to reduce risk of fire) followed by ammonium formate (20.3 g, 322 mmol). The flask was fitted with a condenser and heated to 60°C for 30 min. The reaction was allowed to cool and then filtered through celite and the filtrate was evaporated in vacuo and the residue partitioned between water (500 ml) and ethyl acetate (500 ml). The organic layer was washed with brine, dried (Na2SO₄) and evaporated to afford the product as a colourless oil (21.6 g, 91%) which was used without further purification. Η NMR (400 MHz, CDCI3) δ 0.01 (6H, s), 0.86 (9H, s), 1.85-1.69 (2H, m), 2.77-2.81 (2H, m), 3.57 (2H, t, =76), 4.19 (2H, s), 7.16-7.28 (6H, m), 8.50 (IH, d, =75), 8.90 (IH, s). mlz (ES⁺) 370 (M⁺+H). d) l-{4- 3-(-:grt:-Butyldimethylsilanyloxy)propynpyridin-3-yl}-3- dimethylamino-2-(pyridin-4-yl)propenone l-{4-[3-(tert^:-Butyldimethylsilanyloxy)propyl]pyridin-3-yl}-2- (pyridin-4-yl)ethanone (43.2 g, 117 mmol) was dissolved in N,N- dimethylformamide dimethyl acetal (750 ml) and stirred for 60 h. The solvent was removed in vacuo and the resulting oil was purified by flash chromatography (ethyl acetate - 10% methanol/ethyl acetate) to afford the title compound as an oil (43.2 g, 87%). *H NMR (400 MHz, CDCls) δ 0.01 (6H, s), 0.85 (9H, s), 1.65-1.80 (2H, m), 2.65-2.69 (2H, ), 2.70 (6H, br s), 3.58 (2H, t, =76), 7.07-7.13 (4H, m), 8.35 (IH, s), 8.41 (IH, d, =75), 8.48 (IH, d, =75). mlz (ES⁺) 426 (M⁺+H).

EXAMPLE 1

ll-Phenyl-9-(thien-2-yl)-6.7-dihvdro-5H-2.7a-diaza- dibenzo|^~α,c^'|cvclohepten-8-one

a) 2-(Thien-2-yl)acetamide

Formamide (1.55 ml, 39 mmol) was added to a solution of 2- thiopheneacetic acid (1.95 ml, 13 mmol) in iV,N-dimethylformamide (10 ml) and the reaction was heated to 100°C. Sodium methoxide (25 wt % in methanol) (1.3 ml, 6.5 mmol) was added and the reaction heated at 100°C for 1 h. The reaction was allowed to cool and then was filtered. The filtrate was poured into water (50 ml) and extracted with ethyl acetate (4 x 50 ml). The combined extracts were washed with water (3 x 50 ml), brine (2 x 50 ml) and evaporated to 10 ml volume. A white solid was collected by filtration and washed with ether to afford the title compound (0.66 g, 36%). ⁱΗ NMR (400 MHz, de-DMSO) δ 3.59 (2H, s), 6.88-6.95 (3H, m), 7.34 (IH, d, J 5), 7.48 (IH, br s). b) 1 l-Phenyl-9-(thien-2-yl)-6.7-dihvdro-5H-2.7a-diaza- dibenzorα.clcyclohepten-8-one: Standard Procedure A

Lithium hexamethyldisilazide (IM in tetrahydrofuran) (0.94 ml, 0.94 mmol) was added to a cold (-78°C) solution of l-{4-[3-(tert- butyldimethylsilanyloxy)propyl]pyridin-3-yl}-3-dimethylamino-2- phenylpropenone (0.1 g, 0.235 mmol) and 2-(thien-2-yl)acetamide (37 mg, 0.26 mmol) in dry tetrahydrofuran (20 ml). The reaction was allowed to warm to room temperature and stirred for 1 h before quenching by the addition of NΗ₄C1 solution (20 ml, sat. aqueous). The reaction was poured into ethyl acetate (10 ml) and the layers separated. The aqueous was extracted with ethyl acetate (3 x 10 ml). The combined organic extracts were washed with water (10 ml) and brine (20 ml), dried (Na2SO₄) and evaporated. The reaction was partly purified through a plug of silica (ethyl acetate). The product was dissolved in N,N- dime thy lformamide (2 ml) and IN HCl added (2 ml). The reaction was allowed to stand for 5 min and then neutralised with NaHCθ3 (sat. aqueous) and the aqueous was extracted with ethyl acetate (4 x 10 ml). The combined organic extracts were washed with water (2 x 10 ml), brine (10 ml), dried (Na2SO₄) and evaporated to afford an oil (35 mg, 38%). mlz (ES⁺) 389. The oil was dissolved in tetrahydrofuran (25 ml) and triphenylphosphine (31 mg, 0.12 mmol) added, followed by diethyl azodicarboxylate (0.018 ml, 0.11 mmol), and the reaction stirred for 10 min. The reaction was quenched by the addition of water (10 ml) and then poured into ethyl acetate (10 ml). The layers were separated and the aqueous layer extracted with ethyl acetate (10 ml). The combined organic extracts were washed with water (10 ml), brine (10 ml), dried (Na₂SO4) and evaporated. The residue was purified on SCX ion exchange cartridges. Crystallisation from methanol afforded the product as yellow crystals (29 mg, 87%). Η NMR (360 MHz, CDCI3) δ 1.96-2.06 (IH, m), 2.54-2.63 (IH, m), 2.76-2.90 (2H, m), 3.08 (IH, td, =7 13, 5), 6.97-7.00 (2H, m), 7.13 (IH, dd, =75, 4), 7.13 (IH, dd, =75, 4), 7.22-7.25 (4H, m), 7.43 (IH, dd, =75, 1), 7.71-7.73 (IH, m), 7.98 (IH, d, =74), 7.99 (IH, s), 8.46 (IH, d, =74). mlz (ES⁺) 371 (M⁺+H).

EXAMPLE 2

ll-Phenyl-9-(thien-3-yl)-6.7-dihvdro-5H-2.7a-diaza- dibenzo [α, c] cyclohep ten-8-one

a) 2-(Thien-3-yl)acetamide Formamide (0.77 ml, 19.5 mmol) was added to a solution of 3- thiopheneacetic acid (0.88 ml, 6.5 mmol) in N,N-dimethylformamide (10 ml) and the reaction was heated to 100°C. Sodium methoxide (25 wt % in methanol) (0.65 ml, 3.24 mmol) was added and the reaction heated at 100°C for 1 h. The reaction was poured into water (50 ml) and extracted with ethyl acetate (4 x 50 ml). The combined extracts were washed with water (3 x 50 ml), brine (2 x 50 ml) and evaporated to 10 ml volume. A white solid was collected by filtration and washed with ether to afford the title compound (0.72 g, 34%). Η NMR (360 MHz, de-DMSO) δ 3.38 (2H, s), 6.85 (IH, br s), 7.02 (IH, dd, =75, 1), 7.22-7.24 (IH, m), 7.40 (IH, br s), 7.44 (IH, dd, =75, 3).

b) ll-Phenyl-(9-thien-3-yl)-6.7-dihvdro-5H-2.7a-diaza- dibenzo \a, c] cyclohep ten-8-one

Prepared by standard procedure A using 2-(thien-3-yl)acetamide: ^XΗ NMR (360 MHz, CDC1₃) δ 1.90-2.03 (IH, m), 2.25-2.35 (IH, m), 2.70-2.81 (IH, m), 2.88-2.97 (2H, m), 7.05-7.07 (2H, m), 7.21-7.26 (3H, m), 7.41 (IH, d, =75), 7.56-7.58 (IH, m), 7.80 (IH, d, =75), 7.85 (IH, s), 7.99 (IH, s), 8.42 (IH, d, =75), 8.45 (IH, d, =72). mlz (ES⁺) 371 (M⁺+H). EXAMPLE 3

9.11-Di^phen^yl-6,7-dih^ydro-5H-2.7a-diazadibenzorα.clcvclohepten-8-one

Prepared by standard procedure A using phenylacetamide: ^XΗ NMR (360 MHz, CDCls) δ 1.94-2.06 (IH, m), 2.50-2.61 (IH, m), 2.84-2.89 (2H, m), 3.05 (IH, td, =713, 5), 6.95-6.99 (2H, m), 7.17-7.24 (4H, m), 7.33-7.45 (3H, m), 7.68 (IH, s), 7.78 (2H, d, =78), 7.99 (IH, s), 8.46 (IH, d, =75). mlz (ES⁺) 365 (M⁺+H).

EXAMPLE 4

9-(5-Methylthien-2-yl)-ll-phenyl-6.7-dihvdro-5H-2.7a-diaza- dibenzo[α,c1cvclohepten-8-one

a) 4'-(3-Ηvdroxypropyl)-6-oxo-3-phenyl-1.6-dihydro-r2,3^,1bipyridinyl-5- carbonitrile

Intermediate 1 (6.2 g, 15 mmol) was suspended in N,N- dimethylformamide (150 ml) and 2-cyanoacetamide (1.84 g, 22 mmol) was added. Sodium hydride (60% dispersion in oil) (2.22 g, 56 mmol) was added and the reaction heated at 50°C for 1.5 h. Water was added and the aqueous was extracted with ethyl acetate (x 4) and the combined organic extracts were washed with water (x 2), brine (x 2), dried (MgSO4) and solvent removed in vacuo. The yellow solid was dissolved in methanol/dichloromethane (2:1) (150 ml) and pαrα-toluenesulphonic acid added (3.5 g, 18 mmol). Solvent was removed in vacuo and water was added. Solid sodium bicarbonate was added until pH 5 was obtained and a yellow sohd precipitated out. The title compound was obtained after drying as a pale yellow solid (2.50 g, 44%). Η NMR (400 MHz, de-DMSO) δ 1.30-1.70 (2H, m), 2.20-2.40 (2H, m), 3.27-3.31 (2H, m), 4.50 (IH, br s), 7.02-7.05 (2H, m), 7.17-7.23 (4H, m), 8.32 (IH, s), 8.41 (IH, s), 8.44 (IH, d, =75), 12.90 (IH, br s). b) 8-Oxo-ll-phenyl-5.6.7.8-tetrahvdro-2.7a-diazadibenzorα.clcvcloheptene- 9-carbonitrile

The alcohol (3.1 g, 9.3 mmol) was suspended in dry tetrahydrofuran (250 ml) and triphenylphosphine (3.07 g, 11.7 mmol) added. Diethyl azodicarboxylate (1.85 ml, 11.7 mmol) was added and the reaction stirred for 1 h during which time complete dissolution occurred. The reaction was quenched by pouring into water and extracting with ethyl acetate (x 3). The combined organics were washed with brine, dried M SO4) and evaporated. The crude product was purified by chromatography with methanol/ethyl acetate (1:9). The title compound was obtained as a yellow solid (1.8 g, 62%). Η NMR (360MHz, CDC1₃) δ 2.01-2.09 (IH, m), 2.50-2.59 (IH, m), 2.71-2.80 (IH, m), 2.84-2.88 (IH, m), 2.94-3.06 (IH, m), 5.12-5.17 (IH, dd, =713, 5), 6.87-6.90 (2H, m), 7.22-7.27 (4H, m), 7.96 (2H, m), 8.50 (IH, d, =75). mlz (ES⁺) 315 (M⁺+H).

c) 8-Oxo-ll-phenyl-5,6.7,8-tetrahvdro-2.7a-diazadibenzorα.c1cycloheptene- 9-carboxylic acid

8-Oxo-ll-phenyl-5,6,7,8-tetrahydro-2,7a-diaza- dibenzoføGjcycloheptene-9-carbonitrile (160 mg, 0.51 mmol) was suspended in 8N HCl (50 ml). The reaction was heated at 95°C for 2 days before allowing to cool. The solution was neutralised with solid NaHCθ3 and re-acidified with citric acid solution (10% aq.). The solution was extracted with ethyl acetate (3 x 15 ml) and the organics washed with brine (2 ml), dried (Na₂SO4) and evaporated to afford a pale solid. The solid was triturated with ether to afford the title product (130 mg, 77%). iH NMR (400 MHz, de-DMSO) δ 2.05-2.09 (IH, m), 2.29-2.39 (IH, m), 2.83-2.92 (2H, m), 3.12 (IH, td, =714, 4.9), 7.03-7.05 (2H, m), 7.26-7.28 (3H, m), 7.46 (IH, d, =75), 7.89 (IH, s), 8.36 (IH, s), 8.48 (IH, d, =75), 14.5 (IH, br s). mlz (ES⁺) 333 (M⁺+H). d) (^'8-Oxo-ll-phenyl-5.6.7,8-tetrahydro-2.7a-diazadibenzorα.c1cvclohepterι- 9-yl)carbamic acid £βrt butyl ester

Diphenylphosphonic azide (2.1 ml, 9.6 mmol) and triethylamine (1.7 ml, 12.0 mmol) were added to a solution of 8-oxo-ll-phenyl-5,6,7,8- tetrahydro-2,7a-diazadibenzo[α,c]cycloheptene-9-carboxylic acid (2 g, 6.0 mmol) in tert- uOΗ. (100 ml). The reaction was heated at reflux for 36 h. The reaction was cooled and the solvent removed in vacuo to afford a solid. The solid was triturated with hot ethyl acetate (25 ml), allowed to cool and then collected by filtration and washed with ether to afford the product as a pale solid (1.9 g, 78%). V . NMR (360 MHz, CDC1₃) δ 1.52 (9H, s), 1.88- 2.01 (IH, m), 2.48-2.52 (IH, m), 2.68-2.80 (2H, m), 5.12 (IH, dd, J 14, 6), 6.93-6.96 (2H, m), 7.15-7.19 (3H, m), 7.79 (IH, s), 7.94 (IH, s), 8.19 (IH, s), 8.42 (IH, d, =75). mlz (ES⁺) 404 (M⁺+H).

e) 9-Amino-ll-phenyl-6,7-dihydro-5H-2.7a-diazadibenzofq.c1cvclohepten-8- one

Trifluoroacetic acid (5 ml) was added to a solution of (8-oxo-ll- phenyl-5,6,7,8-tetrahydro-2,7a-diazadibenzo[α,c]cyclohepten-9-yl)carbamic acid feri-butyl ester (0.7 g, 1.73 mmol) in dichloromethane (50 ml). The reaction was stirred for 2 h and then evaporated to dryness. A solid crystallised upon addition of Et2θ. The solid was collected by filtration and dried under vacuum to afford the product as the trifluoroacetate salt (0.65 g, 90%), mp 142-147°C. Η NMR (400 MHz, c2₆-DMSO) δ 1.88-1.98 (IH, m), 2.18-2.30 (IH, m), 2.65-2.80 (IH, m), 2.89-2.97 (2H, m), 6.58 (IH, s), 6.95 (2H, dd, =78, 2), 7.19-7.24 (3H, m), 7.54 (IH, d, =75), 7.79 (IH, s), 8.44 (IH, d, =75). mlz (ES⁺) 304 (M⁺+H).

f) 9-Iodo-ll-phenyl-6.7-dihydro-5H-2.7a-diazadibenzo g.c1cyclohepten-8- one A cold (0°C) solution of sodium nitrite (59 mg, 0.86 mmol) in water

(2 ml) was slowly added to a cold (-5°C) suspension of 9-amino-ll-phenyl- 6,7-dihydro-5H-2,7a-diazadibenzo[α,c]cyclohepten-8-one (350 mg, 0.84 mmol) in 50% Η2SO4 (10 ml). The reaction was stirred at -5°C for 30 min and a cold (-5°C) solution of potassium iodide (170 mg, 1.01 mmol) in IN H2SO4 (5 ml) was added. After 5 min a catalytic amount of copper was added and the reaction stirred for 30 min. The reaction was quenched by pouring into NaOH solution and extracting with ethyl acetate (3 x 75 ml). The combined organic extracts were washed with water and brine, and dried (Na2SU4). Solvent was removed in vacuo and the residue purified by chromatography (ethyl acetate) to afford the product (140 mg, 40%). H NMR (360 MHz, CDCI3) δ 1.92-2.02 (IH, m), 2.47-2.58 (IH, m), 2.72-2.89 (2H, m), 3.07 (IH, td, =7 13, 5), 6.82-6.90 (2H, m), 7.19-7.22 (3H, m), 7.95 (IH, s), 8.17 (IH, s), 8.46 (IH, d, =76). mlz (ES⁺) 415 (M⁺+H).

g) ll-Phenyl-9-tributylstannanyl-6,7-dihydro-5H-2,7a-diaza- dibenzo \a, c] cyclohep ten-8-one

Ηexabutylditin (0.073 ml, 0.14 mmol) was added to a solution of 9- iodo-ll-phenyl-6,7-dihydro-5H-2,7a-diazadibenzo[α,c]cyclohepten-8-one (40 mg, 0.097 mmol) in toluene (2 ml) followed by a catalytic amount of Pd(PPli3)4. The reaction was heated at 70°C for 72 h. The reaction was allowed to cool, aq. KF added (0.5 ml, 10%) and the reaction stirred for 3 h. The reaction was partitioned between water and ethyl acetate and the layers separated. The aqueous was extracted with ethyl acetate and the organics dried and evaporated. The residue was purified by flash chromatography (30% hexanes in ethyl acetate) to afford the stannane (38 mg, 68%) as a pale oil. Η NMR (360 MHz, CDCI3) δ 0.88-0.94 (9H, m),

1.10-1.14 (2H, m), 1.25-1.40 (6H, m), 1.54-1.68 (4H, m), 2.42-2.53 (IH, m), 2.79-2.83 (2H, m), 2.96 (IH, td, =7 14, 5), 5.03 (IH, dd, =7 14, 5), 6.92 (2H, dd, =79, 2), 7.17-7.21 (4H, m), 7.57 (IH, s), 8.42 (IH, d, =77). mlz (ES⁺) 579 (M⁺+H). h) 9-(5-Methylthien-2-vI)- 1 l-phenyl-6.7-dihvdro-5H-2.7a-diaza- dibenzo \a, c] cyclohep ten-8-one

1 l-Phenyl-9-tributylstannanyl-6, 7-dihydro-5H-2, 7a-diaza- dibenzo[α,c] cyclohep ten-8-one (40 mg, 0.069 mmol), 2-iodo-5- methylthiophene (0.021 ml, 0.17 mmol) and lithium chloride (18 mg, 0.42 mmol) were dissolved in N,iV-dimethylformamide and degassed with N₂ at 40°C for 20 min. Copper(I) iodide (1.3 mg, 0.007 mmol) was added followed by Pd(PPh.3)4 (14 mg, 0.007 mmol) and the reaction heated at 100°C for 24 h. The reaction was allowed to cool and poured into water (100 ml). The aqueous was extracted with ethyl acetate (3 x 50 ml) and the combined organic extracts were washed with water (3 x 50 ml), brine (2 x 50 ml), dried (Na2SO ) and evaporated. The residue was purified by prep tic and crystallised from ether to afford the title compound (4.6 mg, 17%). Ή NMR (360 MHz, CDC1₃) δ 1.96-2.03 (IH, m), 2.52-2.59 (IH, m), 2.53 (3H, s), 2.78-2.89 (2H, m), 5.26 (IH, dd, =713, 6), 6.78 (IH, d, =73), 6.96-6.99 (2H, m), 7.21-7.25 (3H, m), 7.53 (IH, d, =73), 7.89 (IH, s), 7.96 (IH, br s), 8.45 (IH, br s). mlz (ES⁺) 385 (M⁺+H).

EXAMPLE 5

ll-Phenyl-9-(m.-tolyl)-6.7-dihydro-5H-2.7a-diazadibenzorα.c]cvclohepten-8- one: Standard Procedure B

9-Iodo-ll-phenyl-6,7-dihydro-5H-2,7a-diaza- dibenzo[α,c]cyclohepten-8-one (40 mg, 0.097 mmol) was dissolved in dry Λ iV-dimethylformamide (1 ml) and /ra-tolylboronic acid (20 mg, 0.14 mmol) added followed by potassium phosphate (51 mg, 0.24 mmol) and a catalytic amount of Pd(PPh3)4 (5 mg). The reaction was heated to 100°C for 16 h. The reaction was allowed to cool and then partitioned between water (5 ml) and ethyl acetate (5 ml). The layers were separated and the aqueous extracted with ethyl acetate (5 ml). The combined organic extracts were washed with water (2 x 1 ml), brine (1 ml) and evaporated. The product was purified using an SCX ion exchange cartridge and prep tic (ethyl acetate), mp 208-212°C. Η NMR (360 MHz, CDC1₃) δ 1.96-2.04 (IH, m), 2.40 (3H, s), 2.49-2.57 (IH, m), 2.83-2.88 (2H, ), 5.22 (IH, dd, =7 13, 5), 6.95-6.98 (2H, m), 7.16-7.26 (5H, m), 7.32 (IH, t, =78), 7.56 (IH, d, =7 8), 7.62 (IH, s), 7.67 (IH, s), 7.99 (IH, s), 8.46 (IH, d, =75). mlz (ES+) 379 (M⁺+H).

EXAMPLE 6

ll-Phenyl-9-(lH-pyrrol-2-yl -6.7-dihvdro-5H-2.7a-diaza- dibenzofα.c] cyclohep ten-8-one

Prepared according to procedure B: Η NMR (400 MHz, CDCI3) δ

1.96-2.06 (IH, m), 2.46-2.56 (IH, m), 2.74-2.89 (2H, m), 3.07 (IH, td, =7 13,

5), 6.29-6.31 (IH, m), 6.66-6.68 (IH, m), 6.91-6.93 (IH, m), 6.96-6.98 (2H, m), 7.20-7.26 (4H, m), 7.85 (IH, s), 7.96 (IH, s), 8.44 (IH, d, =75), 11.47

(IH, br s). mlz (ES⁺) 354 (M⁺+H).

EXAMPLE 7

9-(5-Chlorothien-2-yl)-ll-phenyl-6.7-dihvdro-5H-2.7a-diaza- dibenzof .cl cyclohep ten-8-one

Prepared according to procedure B: *Η NMR (400 MHz, CDCI3) δ 1.98-2.07 (IH, m), 2.53-2.61 (IH, m), 2.75-2.89 (2H, m), 3.08 (IH, td, =7 13, 5), 6.94 (IH, d, =74), 6.96-6.99 (2H, m), 7.20-7.26 (4H, m), 7.42 (IH, d, =75), 7.93 (IH, s), 7.97 (IH, s), 8.46 (IH, d, J 5). mlz (ES⁺) 404 (M⁺+H).

EXAMPLE 8

ll-Phenyl-9-(pyrrolidin-l-yl)-6,7-dihydro-5H-2,7a-diaza- dibenzofα,c^"|cvclohepten-8-one 9-Iodo-ll-phenyl-6,7-dihydro-5H-2,7a-diaza- dibenzo[α-c]cyclohepten-8-one (30 mg, 0.072 mmol), sodium teri-butoxide (10 mg, 0.10 mmol), crown ether 18-crown-6 (20 mg, 0.072 mmol), BINAP (4 mg, 0.005 mmol), Pd dba3 (2 mg, 0.002 mmol) and pyrrolidine (0.01 ml, 0.087 mmol) were weighed into a round-bottomed flask and flushed with nitrogen. Tetrahydrofuran (2 ml) was added and the reaction stirred at room temperature. The reaction was stirred for 5 days. The reaction was partitioned between water (5 ml) and ethyl acetate (5 ml). The layers were separated and the aqueous extracted with ethyl acetate (2 5 ml). The combined organic extracts were washed with ammonium chloride (5 ml, sat. aq.) and brine (5 ml), dried (Na2Sθ4) and evaporated. The residue was purified by prep tic (ethyl acetate). *Η NMR (360 MHz, CDCI3) δ 1.20- 1.25 (IH, m), 2.00-2.07 (4H, m), 2.38-2.53 (IH, m), 2.73-2.81 (2H, m), 3.47- 3.50 (2H, m), 3.65-3.73 (2H, m), 5.08 (IH, dd, =713, 6), 6.37 (IH, s), 6.94- 6.96 (2H, m), 7.13-7.18 (4H, m), 7.87 (IH, s), 8.42 (IH, d, =75). mlz (ES+) 358 (M⁺+H).

EXAMPLE 9

8-Oxo-ll-phenyl-5.6.7.8-tetrahydro-2.7a-diazadibenzorα.c1cvcloheptene-9- carboxylic acid tert-butyl ester

ΛT.iV-Dimethylfbrmamide di-teri-butyl acetal (0.144 ml, 0.60 mmol) was added over 5 minutes to a suspension of 8-oxo-ll-phenyl-5,6,7,8- tetrahydro-2,7a-diazadibenzo[α.c]cycloheptene-9-carboxylic acid (50 mg, 0.15 mmol) in hot toluene (90°C). The reaction was maintained at 90°C for 45 min. The solvent was removed in vacuo. The solid was dissolved in ethyl acetate (75 ml) and the solution washed with NaHCO3 (3 x 50 ml, sat. aq.) and brine (50 ml), dried and evaporated to give a white solid which was triturated with Et2θ to afford the title compound as a pale solid (22 mg, 38%). Η NMR (360 MHz, CDCI3) δ 1.98-2.09 (IH, m), 2.55-2.65 (IH, m), 2.79-2.93 (2H, m), 3.13 (IH, td, =713, 5), 5.08 (IH, dd,^'=7 l3, 6), 6.96-7.02 (2H, m), 7.21-7.25 (2H, m), 7.50 (IH, d, =73), 7.96 (IH, d, =73), 8.03 (IH, s), 8.49 (IH, d, =75), 8.79 (IH, s). mlz (ES⁺) 372 (M⁺+H).

EXAMPLE 10

8-Oxo-ll-phenyl-5.6.7,8-tetrahydro-2,7a-diazadibenzo|^" .clcvcloheptene-9- carboxylic acid allyl ester: Standard Procedure C

8-Oxo-ll-phenyl-5,6,7,8-tetrahydro-2,7a-diaza- dibenzo[α,c]cycloheptene-9-carboxylic acid (0.35 g, 1.05 mmol) was dissolved in oxalyl chloride (4 ml) and AT,iV-dimethylformamide (1 drop) added. The reaction was stirred for 20 min before concentrating in vacuo and azeotroping with toluene (2 x 10 ml). The residue was dissolved in Λ^N-dimethylformamide (7 ml), to afford a stock solution of the acid chloride in N,Λ -dimethylformamide of 0.15 M, and used in subsequent reactions without purification. A solution of the acid chloride (1 ml, 0.15 M in N,N-dimethylformamide, 0.15 mmol) was added to a solution of allyl alcohol (0.45 mmol) in pyridine/N,N-dimethylformamide (1:1). The reaction was mixed by vortex and allowed to stand for 1 h. The reaction was quenched by the addition of water (2 ml). The reaction was partitioned between water (25 ml) and ethyl acetate (25 ml). The layers were separated and the aqueous extracted with ethyl acetate (20 ml). The combined organic extracts were washed with NaHCO3 (2 x 10 ml, sat. aq.), water (2 x 10 ml), brine (10 ml), dried (Na2SO ) and evaporated to afford crude product. The product was crystallised from diethyl ether. ^XH NMR (400 MHz, CDCls) δ 1.95-2.05 (IH, m), 2.48-2.61 (IH, m), 2.70-2.79 (IH, m), 2.87 (IH, dd, =713, 7), 4.84-4.87 (2H, m), 5.22 (IH, dd, =713, 5), 5.29 (IH, d, =710), 5.46 (IH, d, J 17), 6.00-6.10 (IH, m), 6.91-6.93 (2H, m), 7.19- 7.26 (4H, ), 7.99 (IH, s), 8.30 (IH, s), 8.48 (IH, d, =75). mlz (ES⁺) 373 (M++H). EXAMPLE 11

8-Oxo-ll-phen^yl-5,6.7,8-tetrah^ydro-2.7a-diazadibenzo[α,c1cycloheptene-9- carboxylic acid 2-hydroxyethyl ester

Prepared according to procedure C: Η NMR (400 MHz, CDC1₃) δ 1.99-2.07 (IH, m), 2.50-2.59 (IH, m), 2.71-2.79 (IH, m), 2.88 (IH, dd, =7 13, 7), 3.93 (2H, t, =75), 4.46-4.55 (2H, m), 5.19 (IH, dd, =7 13, 5), 6.91-6.94 (2H, m), 7.20-7.25 (4H, m), 7.99 (IH, s), 8.24 (IH, s), 8.49 (IH, d, =75). mlz (ES⁺) 377 (M++H).

EXAMPLE 12

8-Oxo-ll-phenyl-5,6.7,8-tetrahydro-2.7a-diazadibenzor .c1cycloheptene-9- carboxylic acid cyclopentyl ester Prepared according to procedure C: Η NMR (400 MHz, CDCI3) δ

1.57-1.66 (3H, m), 1.77-1.90 (4H, m), 1.96-2.04 (2H, m), 2.51-2.58 (IH, m), 2.90 (IH, dd, J 13, 7), 3.00 (IH, td, =713, 5), 5.20 (IH, dd, =713, 5), 5.40- 5.44 (IH, m), 6.89-6.93 (2H, m), 7.21-7.26 (4H, m), 7.99 (IH, s), 8.19 (IH, s), 8.47 (IH, d, =75). mlz (ES⁺) 401 (M⁺+H).

EXAMPLE 13

8-Oxo-ll-phenyl-5,6.7_<8-tetrahydro-2.7a-diazadibenzo|^"α.c1cycloheptene-9- carboxylic acid 4-methylthiazol-2-ylmethyl ester Prepared according to procedure C: VEL NMR (400 MHz, CDCI3) δ

1.99-2.04 (IH, m), 2.46 (3H, s), 2.52-2.61 (IH, m), 2.71-2.79 (IH, m), 2.98 (IH, td, =713, 5), 5.23 (IH, dd, =713, 5), 5.57-5.64 (2H, m), 6.89-6.92 (3H, m), 7.21-7.26 (4H, m), 7.99 (IH, s), 8.34 (IH, s), 8.49 (IH, d, =75). mlz (ES⁺) 444 (M⁺+H). EXAMPLE 14

8-Oxo-ll-phenyl-5.6,7,8-tetrahydro-2.7a-diazadibenzorα.c1cvcloheptene-9- carboxyiic acid benzyl ester

Prepared according to procedure C: Η NMR (400 MHz, CDC1₃) δ 1.97-2.08 (IH, m), 2.51-2.58 (IH, m), 2.70-2.78 (IH, m), 2.87 (IH, dd, =713, 7), 5.23 (IH, dd, =713, 5), 5.36-5.44 (2H, m), 6.89-6.92 (2H, m), 7.19-7.39 (7H, m), 7.48 (2H, dd, =78, 2), 7.97 (IH, br s), 8.28 (IH, s), 8.48 (IH, br s). mlz (ES⁺) 423 (M⁺+H).

EXAMPLE 15

8-Oxo-ll-phenyl-5.6.7.8-tetrahvdro-2,7a-diazadibenzorα.clcycloheptene-9- carboxylic acid isopropyl ester Prepared according to procedure C: Η NMR (400 MHz, CDCI3) δ

1.37 (3H, d, =76), 1.39 (3H, d, =76), 1.96-2.05 (IH, m), 2.49-2.61 (IH, m), 2.86 (IH, dd, =713, 7), 2.97 (IH, td, =713, 5), 5.21 (IH, dd, J 13, 5), 5.27- 5.32 (IH, m), 6.91-6.93 (2H, m), 7.21-7.25 (4H, m), 7.95 (IH, s), 8.21 (IH, s), 8.48 (IH, d, = 5). mlz (ES⁺) 375 (M⁺+H).

EXAMPLE 16

9-(4-Methylthiazol-2-ylcarbonyl)-ll-phenyl-6.7-dihydro-5H-2.7a-diaza- dibenzo \a, c\ cyclohep ten-8-one A solution of the acid chloride (5.2 ml, 0.15 M in N,N- dimethylformamide, 0.78 mmol) was added to a solution of N,0- dimethylhydroxylamine HCl salt (0.153 g, 1.57 mmol) in pyridine/iV,A^- dimethylformamide (1:1). The reaction was mixed by vortex and allowed to stand for 1 h. The reaction was quenched by the addition of water (2 ml). The reaction was partitioned between water (25 ml) and ethyl acetate (25 ml). The layers were separated and the aqueous extracted with ethyl acetate (20 ml). The combined organic extracts were washed with NaHC0₃ (2 x 10 ml, sat. aq.), water (2 x 10 ml), brine (10 ml), dried (Na2S0₄) and evaporated to afford crude Weinreb amide. 4- Methylthiazole (0.03 ml, 0.3 mmol) was added dropwise over 5 min to a stirred solution of n.-BuLi (0.19 ml, 1.6 M in hexanes, 0.31 mmol) in Et₂θ (5 ml) at -78°C under nitrogen. The resulting mixture was stirred at -78°C for 90 min and then a solution of Weinreb amide (75 mg, 0.2 mmol) in tetrahydrofuran (5 ml) was added over 15 min. The reaction was allowed to warm to room temperature overnight. The reaction was quenched with water and then extracted with ethyl acetate. The product was purified by preparative tic to afford the title compound (30 mg, 36%). H NMR (360 MHz, CDCI3) δ 1.99-2.04 (IH, m), 2.49-2.58 (IH, m), 2.55 (3H, s), 2.82-2.89 (2H, m), 5.17 (IH, dd, =713, 5), 6.94-6.96 (2H, m), 7.19-7.29 (5H, m), 8.01 (IH, br s), 8.23 (IH, s), 8.49 (IH, br s). mlz (ES⁺) 414 (M⁺+H).

EXAMPLE 17

2.2-Dimethyl-A^r-(8-oxo-ll-phenyl-5.6.7,8-tetrahydro-2.7a-diaza- dibenzo[α,c]cvclohepten-9-yl)propionamide Pivaloyl chloride (0.018 ml, 0.15 mmol) was added to a solution of 9- amino-ll-phenyl-6,7-dihydro-5H-2,7a-diazadibenzo[α,c]cyclohepten-8-one (50 mg, 0.12 mmol) and 4-dimethylaminopyridine (catalytic amount) in pyridine (1.5 ml). The reaction was vortexed for 30 seconds and the reaction allowed to stand for 4 h. The reaction was quenched by partitioning between water (50 ml) and ethyl acetate (25 ml). The layers were separated and the aqueous was extracted with ethyl acetate. The organic extracts were washed with brine and dried (Na2S0₄). The residue was purified by preparative tic (ethyl acetate) to afford the desired compound (20 mg, 43%). *Η NMR (400 MHz, de-DMSO) δ 1.25 (9H, s), 1.88-2.01 (IH, m), 2.20-2.33 (IH, m), 2.68-2.78 (IH, m), 3.00 (IH, td, =7 13, 4), 4.90 (IH, dd, =713, 5), 6.98-7.00 (2H, m), 7.21-7.25 (3H, m),^'7.39 (IH, d, =75), 8.82 (IH, s), 8.38 (IH, s), 8.40 (IH, d, =75), 8.80 (IH, s). mlz (ES+) 388 (M⁺+H).

EXAMPLE 18

9-(4.5-Dihvdrothiazol-2-yl -ll-phenyl-6.7-dihvdro-5H-2.7a-diaza- dibenzo[α,c]cyclohepten-8-one

a) 8-Oxo-ll-phenyl-5,6.7.8-tetrahydro-2.7a-diazadibenzorα.c1cvcloheptene- 9-carbothioic acid amide

8-Oxo-ll-phenyl-5,6,7,8-tetrahydro-2,7a-diaza- dibenzo[ ,c]cyclohepte e-9-carbonitrile (1.3 g, 4.1 mmol) was dissolved in pyridine (45 ml) and triethylamine (0.6 ml, 4.1 mmol) added. Hydrogen sulphide was bubbled through the reaction for 3 h. Solvent was removed in vacuo and azeotroped with toluene (x 2). The yellow solid was dissolved in water and extracted into dichloromethane (x 3); organics were combined, dried (Na2SO₄) and solvent removed in vacuo to give the title compound as a yellow solid (1.44 g, 100%). Η NMR (360 MHz, CDC1₃) δ 2.01-2.11 (IH, m), 2.46-2.58 (IH, m), 2.71-2.80 (IH, m), 2.88-2.94 (IH, m), 3.04-3.12 (IH, m), 5.17-5.22 (IH, dd, =713, 5), 6.95 (2H, m), 7.22-7.26 (4H, m), 7.96-8.04 (2H, m), 8.50 (IH, d, =74), 9.31 (IH, s), 11.59 (IH, s). mlz (ES⁺) 348 (M⁺H).

b) 9-(^'4.5-Dihvdrothiazol-2-yl)-ll-phenyl-6.7-dihydro-5H-2,7a-diaza- dibenzo \a. clcvclohepten-8-one

8-Oxo-ll-phenyl-5,6,7,8-tetrahydro-2,7a-diaza- dibenzo[α,c]cycloheptene-9-carbothioic acid amide (75 mg, 0.21 mmol) was dissolved in N,iV-dimethylformamide (2 ml) and 1,2-dibromoethane (0.02 ml, 0.23 mmol) added. The reaction was heated at 75°C for 24 h. Ethyl acetate was added and the yellow solid obtained was dissolved in methanol/dichloromethane (1:9) and purified using preparative tic (10% ethyl acetate/hexanes) to give the title compound (3 mg, 5%). Η VT 353K NMR (500 MHz, de-DMSO) δ 1.98-2.04 (IH, m), 2.31-2.34 (IH, m), 2.78- 2.81 (IH, m), 2.89-3.02 (2H, m), 3.21-3.25 (2H, ), 4.17-4.25 (2H, m), 4.96- 4.99 (IH, dd, =713, 5), 7.00-7.02 (2H, m), 7.22-7.26 (3H, m), 7.39 (IH, d, =7 5), 7.91 (IH, s), 8.21 (IH, s), 8.44 (IH, d, =75). mlz (ES⁺) 374 (M++H).

EXAMPLE 19

9-(5-Chloroisoxazol-3-yl)-ll-phenyl-6,7-dihydro-5H-2.7a-diaza- dibenzo \a, c]cyclohepten-8-one

a) N-Ηvdroxy-8-oxo-ll-phenyl-5,6,7.8-tetrahydro-2,7a-diaza- dibenzo .c] cyclohep tene-9-carboxamidine

Sodium hydroxide (38 mg, 0.96 mmol) was dissolved in water (2 ml) and added to a warmed solution of hydroxylamine hydrochloride (67 mg, 0.96 mmol) in ethanol (7 ml). 8-Oxo-ll-phenyl-5,6,7,8-tetrahydro-2,7a- diazadibenzo[α,c]cycloheptene-9-carbonitrile (300 mg, 0.96 mmol) was dissolved in ethanol (3 ml) and added to the reaction and heated at reflux for 16 h. Solvent was removed in vacuo to one-third original and 5N hydrochloric acid (5 ml) added. The reaction was heated to reflux for 0.5 h, cooled and filtered. The filtrate was extracted with dichloromethane (x 2) and the aqueous layer basified to pH 8 with ammonia solution. The aqueous was concentrated to one-third original volume and cooled in an ice/water bath. The solid was filtered off and dried to give the title compound (265 mg, 80%). Η NMR (360 MHz, MeOD) δ 1.99-2.08 (IH, m), 2.39-2.51 (IH, m), 2.76-2.86 (IH, m), 2.94-2.99 (IH, m), 3.05-3.14 (IH, m), 5.03-5.08 (IH, dd, =713, 5), 7.00-7.02 (2H, m), 7.22-7.29 (3H, m), 7.42 (IH, d, =75), 7.88 (IH, s), 8.06 (IH, s), 8.35 (IH, s), 8.38 (IH, d, =75), 8.97 (IH, s). b) 9-(5-Chloroisoxazol-3-yl)-ll-phenyl-6.7-dihydro-5H-2,7a-diaza- dibenzo[α,c|cyclohepten-8-one

N-Ηydroxy-8-oxo-ll-phenyl-5,6,7,8-tetrahydro-2,7a-diaza- dibenzo[α,c]cycloheptene-9-carboxamidine (0.265 g, 0.78 mmol) was dissolved in water (8 ml) and concentrated hydrochloric acid (3 ml). The reaction was cooled to 0°C and sodium nitrite (66 mg, 0.96 mmol) in water (2 ml) was added. Solvent was removed in vacuo and azeotroped with toluene (x 3). The chloro-oxime (54 mg, 0.15 mmol) was suspended in vinylidene chloride (10 ml) and triethylamine (0.028 ml, 0.15 mmol) added via syringe pump over 4 h. Solvent was removed in vacuo, dissolved in dichloromethane and washed with water (x 3). Organics were dried (MgS0₄), solvent removed in vacuo and the residue purified on silica gel chromatography eluting with methanol/ethyl acetate (1:9). Preparative tic eluting with methanoi/dichloromethane (1:9) afforded the title compound (2 mg, 4%). iH NMR (400 MHz, CDCI3) δ 2.04 (IH, m), 2.50 (IH, ), 2.80- 2.88 (2H, m), 3.02-3.06 (IH, m), 5.17-5.22 (IH, dd, =713, 5), 6.93-6.96 (2H, m), 7.17-7.26 (5H, m), 8.00 (IH, s), 8.33 (IH, s), 8.49 (IH, d, =75). mlz (ES⁺) 390 (M⁺+H).

EXAMPLE 20

9-(5-Methyl-ri.2.41oxadiazol-3-yl -ll-phenyl-6.7-dihvdro-5H-2.7a-diaza- dibenzof .clcyclohepten-8-one

N-Ηydroxy-8-oxo-ll-phenyl-5,6,7,8-tetrahydro-2,7a-diaza- dibenzo[α-c]cycloheptene-9-carboxamidine (50 mg, 0.14 mmol) was dissolved in acetic anhydride (8 ml) and heated at 140°C for 18 h. Solvent was removed in vacuo and the residue basified to pH 7 with sodium bicarbonate, the aqueous was extracted with ethyl acetate (x 3), dried (MgSO ) and solvent removed in vacuo. The crude product was purified on silica gel chromatography eluting with ethyl acetate. The oil was purified on preparative tic eluting with ethyl acetate to give the title compound as an orange/brown solid (4 mg, 8%). Η NMR (400 MHz, CDCI3) δ 1.99-2.06 (IH, m), 2.54-2.62 (IH, m), 2.78 (3H, s), 2.73-2.82 (IH, m), 2.85-2.90 (IH, m), 2.91-3.08 (IH, m), 5.27-5.32 (IH, dd, =713, 5), 6.95-6.97 (2H, m), 7.20- 7.26 (4H, m), 8.01 (IH, s), 8.38 (IH, s), 8.48 (IH, d, = 4). mlz (ES+) 371 (M++H).

EXAMPLE 21

9-(3-Methyl-n.2.41oxadiazol-5-yl)-ll-phenyl-6.7-dihvdro-5H-2.7a-diaza- dibenzofα.c^'lcyclohepten-δ-one

Methylcarboxamidine (6 mg, 0.09 mmol) was dissolved in tetrahydrofuran (3 ml). Sodium hydride (60% dispersion in oil) (3 mg, 0.09 mmol) was added followed by 8-oxo-ll-phenyl-5,6,7,8-tetrahydro- 2,7a-diazadibenzo[α,c]cycloheptene-9-carboxylic acid methyl ester (prepared according to procedure C; 30 mg, 0.09 mmol) in tetrahydrofuran (3 ml) and the reaction heated to reflux for 1 h. Solvent was removed in vacuo and the residue purified on preparative tic eluting with methanol/ethyl acetate (1:9). The title compound was obtained as a yellow sohd (10 mg, 33%). *Η NMR (360 MHz, CDCI3) δ 2.01-2.09 (IH, m), 2.50 (3H, s), 2.54-2.61 (IH, m), 2.73-2.80 (IH, m), 2.87-2.93 (IH, m), 3.01-3.10 (IH, m), 5.26-5.31 (IH, dd, =715, 7), 6.94-6.96 (2H, m), 7.22-7.26 (4H, m), 8.02 (IH, s), 8.46 (IH, s), 8.50 (IH, d, J 4). mlz (ES⁺) 371 (M⁺+H).

EXAMPLE 22

9-(3-Methyl-n.2.41thiadiazol-5-yl -ll-phenyl-6.7-dihvdro-5H-2.7a-diaza- dibenzofα.clcyclohepten-8-one

a) 5-Chloro-3-methyl-ri,2.4^"lthiadiazole Acetamidine hydrochloride (12 g, 128 mmol) was suspended in dichloromethane (150 ml) and perchlorometbyl mercaptan (23.48 g, 128 mmol) added. The mixture was cooled to -20°C and a cooled 10°C solution of sodium hydroxide (24 g, 601 mmol) in water (60 ml) added dropwise, keeping the internal temperature below -5°C. Upon complete addition the reaction was warmed to room temperature and stirred for 16 h. The organic layer was drained off and the aqueous extracted with dichloromethane (x 2). Organics were washed with water (x 2), dried (MgSO₄) and solvent removed in vacuo. The orange oil was distilled at 3°C at 10 mmHg to give the title compound as a colourless oil (7.7 g, 45%). ⁱH NMR (360 MHz, CDC1₃) δ 2.64 (3H, s).

b) 2-(3-Methyl-4H-[l,2,4^'|thiadiazol-5-vhdene)malonic acid diethyl ester

Diethyl malonate (18.4 g, 115 mmol) was dissolved in tetrahydrofuran (150 ml) and sodium hydride (60% dispersion in oil) (4.6 g, 115 mmol) added over a 20 min period. The reaction was stirred at room temperature for 0.5 h before the addition of 5-chloro-3-methyl-

[l,2,4]thiadiazole (7.7 g, 57 mmol). The reaction was heated at reflux for 16 h. Solvent was removed in vacuo and the residue partitioned between water and ethyl acetate. The aqueous was neutralised to pΗ 7 with 5N hydrochloric acid and a white precipitate was generated; the solid was dissolved in ethyl acetate and washed with water (x 2) and brine (x 2). Organics dried (MgSO₄) and solvent removed in vacuo to give the title compound as a white solid (6.7 g, 45%). Η NMR (400 MHz, CDCI3) δ 1.34- 1.39 (6H, m), 2.48 (3H, s), 4.26-4.33 (4H, m), 13.00 (IH, br s).

c) (3-Methyl-[l,2,4^"lthiadiazol-5-yl)acetic acid ethyl ester

2-(3-Methyl-4H-[l,2,4]thiadiazol-5-ylidene)malonic acid diethyl ester (3.07 g, 19 mmol) was dissolved in acetic acid (300 ml) and concentrated hydrochloric acid (9 ml) and heated at reflux for 5 h. Solvent was removed in vacuo and the residue taken up into water and extracted with diethyl ether (x 3). Organics were washed with sodium bicarbonate solution (x 2), brine (x 2), dried (M SO4) and solvent removed in vacuo to give the title compound as a yellow waxy solid (1.53 g, 70%). ^XH NMR (360 MHz, CDCls) δ 1.31-1.35 (3H, t, =77), 2.65 (3H, s), 4.16 (2H, s), 4.26-4.32 (2H, q, =77).

d) 2-(^'3-Methyl-ri.2.41thiadiazol-5-yl)acetamide

(3-Methyl-[l,2,4]thiadiazol-5-yl)acetic acid ethyl ester (1.53 g, 8.2 mmol) was dissolved in concentrated ammonia solution (10 ml) and stirred for 6 h at room temperature. Solvent was removed in vacuo and azeotroped with ethanol (x 3). The crude product was purified on silica gel chromatography eluting with methanol/ethyl acetate (1:9) to obtain the title compound as a white solid (0.55 g, 43%). Η NMR (400 MHz, de- DMSO) δ 2.52 (3H, s), 4.09 (2H, s), 7.39 (IH, bs), 7.82 (IH, br s).

e) 9-(3-Methyl-π.2.41thiadiazol-5-yl)-ll-phenyl-6.7-dihvdro-5H-2.7a-diaza- dibenzo|^~α,c^"lcvclohepten-8-one: Standard Procedure D l-{4-[3-(ter-:-Butyldimethylsilanyloxy)propyl]pyridin-3-yl}-3- dimethylamino-2-phenylpropenone (0.25 g, 0.59 mmol) in N,N- dimethylformamide was added to 2-(3-methyl-[l,2,4]thiadiazol-5- yl)acetamide (0.139 g, 0.89 mmol) and sodium hydride (60% dispersion in oil) (0.09 g, 2.2 mmol). The reaction was left to stir at room temperature for 0.25 h and methanol (1.0 eq) added, then the reaction was heated at 50°C for 1.5 h. Water was added and the aqueous was extracted with ethyl acetate (x 3); organics were combined, washed with water (x 2) and brine (x 2), dried (M SO4) and solvent removed in vacuo. The residue was dissolved in N,AT-dimethylformamide (15 ml) and 2N hydrochloric acid (5 ml) added. The reaction was stirred for 0.25 h at room temperature and neutralised with aqueous sodium bicarbonate solution. The aqueous was extracted with ethyl acetate (x 3); organics were combined and washed with water (x 2), brine (x 2), dried (MgSO₄) and solvent removed in vacuo. The solid (30 mg, 0.074 mmol) was dissolved in tetrahydrofuran (20 ml) and triphenylphosphine (24 mg, 0.093 mmol) added followed by diethyl azodicarboxylate (0.016 ml, 0.093 mmol) and the reaction stirred for 0.25 h. The reaction was quenched by the addition of water (10 ml) and then poured into ethyl acetate (10 ml). The layers were separated and the aqueous layer extracted with ethyl acetate (x 2). The combined organics were washed with water (x 2), brine (x 2), dried (MgSO4) and solvent removed in vacuo. The residue was purified on SCX ion exchange cartridges. Crystallisation from ethyl acetate EfeO afforded the product as a yellow solid (12 mg, 43%). Η NMR (400 MHz, CDCls) δ 2.08-2.11 (IH, m), 2.59-2.62 (IH, m), 2.72 (3H, s), 2.76-2.84 (IH, m), 2.89-2.94 (IH, m), 3.12-3.20 (IH, m), 5.30-5.35 (IH, dd, =713, 5), 6.99-7.01 (2H, m), 7.23-7.27 (4H, m), 8.03 (IH, s), 8.50 (IH, d, =75), 8.75 (IH, s). mlz (ES+) 387 (M⁺+H).

EXAMPLE 23

9-(4-Chlorothiazol-2-yl)-ll-phenyl-6.7-dihvdro-5H-2.7a-diaza- dibenzo α.c] cyclohep ten-8-one

Prepared by standard procedure D: Η NMR (400 MHz, CDCI3) δ 2.03-2.10 (IH, m), 2.54-2.62 (IH, m), 2.74-2.92 (2H, m), 3.08-3.16 (IH, m), 5.27-5.32 (IH, dd, =715, 6), 6.99-7.00 (2H, m), 7.21-7.25 (5H, m), 8.02 (IH, s), 8.48 (IH, d, =75), 8.75 (IH, s). mlz (ES⁺) 406/408 (M⁺+H).

EXAMPLE 24

9-(4-Cyclopropylthiazol-2-yl)-ll-phenyl-6,7-dihydro-5H-2.7a-diaza- dibenzo \a. c\ cyclohep ten-8-one

Produced by standard procedure D: Η NMR (400 MHz, CDCI3) δ 0.86-0.98 (4H, m), 2.00-2.15 (2H, m), 2.54-2.61 (IH, m), 2.73-2.90 (2H, m), 3.06-3.14 (IH, m), 5.29-5.33 (IH, dd, =714, 5), 6.99-7.02 (3H, m), 7.20-7.26 (4H, m), 8.00 (IH, s), 8.47 (IH, d, =75), 8.69 (IH, s). mlz (ES⁺) 412 (M⁺+H). EXAMPLE 25

9-(^'4-Cvclopro^pylthiazol-2-yl⁾-ll-^(pyridin-4-yl⁾-6.7-dihvdro-5H-2.7a-diaza- dibenzofα.c]cvclohepten-8-one Produced by standard procedure D using Intermediate 2: *Η NMR

(400 MHz, CDC 3) δ 0.87-0.98 (4H, m), 2.01-2.16 (2H, m), 2.53-2.62 (IH, m), 2.73-2.83 (IH, m), 2.88-2.94 (IH, m), 3.08-3.15 (IH, m), 5.28-5.34 (IH, dd, =715, 6), 6.92 (IH, d, =72), 6.93 (IH, d, =72), 7.01 (IH, s), 7.28 (IH, m), 7.54 (IH, s), 8.48 (IH, d, =71), 8.49 (IH, d, =71), 8.54 (IH, d, =75), 8.65 (IH, s). mlz (ES+) 413 (M⁺+H).

EXAMPLE 26

ll-Phenyl-9-(thiazol-2-yl)-6.7-dihvdro-5H-2.7a-diaza- dibenzof .c]cyclohepten-8-one

Produced by standard procedure D: mp 220-222°C. Η NMR (400 MHz, CDCI3) δ 2.04-2.09 (IH, m), 2.56-2.63 (IH, m), 2.79-2.93 (2H, m), 3.13 (IH, td, = 13, 5), 6.96-7.02 (2H, m), 7.21-7.24 (4H, m), 7.50 (IH, d, =7 3), 7.96 (IH, d, =73), 8.03 (IH, s), 8.49 (IH, d, =75), 8.78 (IH, s). mlz (ES⁺) 372 (M⁺+H).

EXAMPLE 27

1 l-(Pyridin-4-yl)-9-(thiazol-2-yl)-6.7-dihvdro-5H-2.7a-diaza- dibenzo [α. c] cyclohep ten-8-one

Produced by standard procedure D using l-{4-[3-(tert:-butyl- dimethylsilanyloxy)propyl]pyridinyl}-3-dimethylamino-2-(pyridin-4- yl)propenone. Η NMR (360 MHz, CDCI3) δ 2.05-2.15 (IH, m), 2.55-2.65 (IH, m), 2.77-2.86 (IH, m), 2.93 (IH, dd, =7 13, 7), 5.33 (IH, dd, =713, 6), 6.93 (2H, d, =75), 7.30 (IH, d, =75), 7.52 (IH, d, =73), 7.97 (IH, d, =73), 8.04 (1H, s), 8.48 (2H, d, =75), 8.57 (IH, d, =75), 8.74 (IH, s). mlz (ES+) 373 (M⁺+H).

EXAMPLE 28

9-(4.5-Dimethylthiazol-2-yl)-ll-phenyl-6.7-dihvdro-5H-2.7a-diaza- dibenzo \a, c]cyclohepten-8-one

8-Oxo-ll-phenyl-5,6,7,8-tetrahydro-2,7a-diaza- dibenzo[ ,c]cycloheptene-9-carbothioic acid amide (0.1 g, 0.29 mmol) was dissolved in teri-butanol (4 ml) at 45°C and 3-bromo-2-butanone (0.03 ml, 0.32 mmol) added. The reaction was heated for 16 h. Water was added and the aqueous was extracted with dichloromethane (x 3); organics were combined, dried (MgSO₄) and solvent removed in vacuo. The crude product was purified on silica gel chromatography eluting with ethyl acetate to methanol/ethyl acetate (3:97). After recrystallisation from acetonitrile the title compound was obtained as a yellow solid (34 mg, 30%). Ή NMR (400 MHz, CDC1₃) δ 2.00-2.05 (IH, m), 2.39 (3H, s), 2.43 (3H, s), 2.54-2.61 (IH, m), 2.74-2.89 (2H, m), 3.05-3.13 (IH, m), 5.27-5.32 (IH, dd, =7 14, 5), 6.98-7.01 (2H, m), 7.19-7.26 (4H, m), 8.00 (IH, s), 8.45 (IH, d, =75), 8.65 (IH, s). mlz (ES⁺) 400 (M⁺+H).

EXAMPLE 29

2-r8-Oxo-ll-(pyridin-4-yl)-5.6.7.8-tetrahvdro-2.7a-diaza- dibenzo α₁c]cyclohepten-9-yl1thiazole-4-carbaldehvde

a) 2-r8-Oxo-ll-(pyridin-4-yl)-5.6.7.8-tetrahvdro-2.7a-diaza- dibenzo[α.c]cvclohepten-9-yllthiazole-4-carboxylic acid

8-Oxo-ll-(pyridin-4-yι)-5,6,7,8-tetrahydro-2,7a-diaza- dibenzo[α,c]cycloheptene-9-carbothioie acid amide (0.1 g, 0.29 mmol) was dissolved in teri-butanol (6 ml) and bromopyruvic acid (0.05 g, 0.03 mmol) added. The reaction was heated for 1 h. Solvent was removed in vacuo and the crude product purified on silica gel chromatography eluting with methanol/dichloromethane (30:70) followed by dichloromethane/methanol/ acetic acid (70:29:1). The product was obtained as the acetate salt as a yellow solid (40 mg, 33%). Η NMR (400 MHz, de-DMSO) δ 2.00 (IH, m), 2.35 (IH, m), 2.85-3.00 (2H, m), 3.02-3.10 (IH, m), 5.05 (IH, m), 7.11 (2H, m), 7.47 (IH, d, =75), 7.91 (IH, s), 7.96 (IH, s), 8.42 (2H, m), 8.51 (IH, d, =7 5), 8.67 (IH, s). mlz (ES⁺) 417 (M⁺+H).

b) 2-r8-Oxo-ll-(pyridin-4-yl)-5.6.7.8-tetrahvdro-2.7a-diaza- dibenzorα.clcyclohepten-9-yl1thiazole-4-carboxylic acid N-methoxy-JV- methylamide

2-[8-Oxo-ll-(pyridin-4-yl)-5,6,7,8-tetrahydro-2,7a-diaza- dibenzo[α,c]cyclohepten-9-yl]thiazole-4-carboxylic acid (0.1 g, 0.24 mmol) and N,0-dimethylhydroxylamine hydrochloride (0.048 g, 0.48 mmol) were suspended in dichloromethane (10 ml) and triethylamine (0.07 ml, 0.48 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.064 mg, 0.025 mmol) added. The reaction was stirred at room temperature for 0.25 h, water was added and extracted with dichloromethane (x 3). Organics were combined, washed with citric acid solution (x 2), sodium bicarbonate solution (x 1), brine (x 1), dried (MgSO4) and solvent removed in vacuo. The crude product was purified on silica gel chromatography eluting with methanol/dichloromethane (6:94). The title compound was obtained as a yellow solid (25 mg, 20%). Η NMR (400 MHz, CDC1₃) δ 2.00 (IH, m), 2.60 (IH, m), 2.80 (IH, m), 2.95 (IH, m), 3.10 (IH, m), 3.50 (3H, s), 3.78 (3H, s), 5.31 (IH, m), 6.92 (2H, m), 7.29 (IH, d, =73), 8.03 (IH, s), 8.14 (IH, s), 8.48 (2H, m), 8.56 (IH, d, =75), 8.80 (IH, s). c 2-r8-Oxo-ll-(pyridin-4-yl)-5.6.7.8-tetrahvdro-2.7a-diaza- dibenzo[α,clcyclohepten-9-yl]thiazole-4-carbaldehvde

2-[8-Oxo-ll-(pyridin-4-yl)-5,6,7,8-tetrahydro-2,7a-diaza- dibenzo[ ,c]cyclohepten-9-yl]thiazole-4-carboxylic acid iV-methoxy-N- methylamide (25 mg, 0.054 mmol) was dissolved in tetrahydrofuran (3 ml) and cooled to -78°C. Diisobutylaluminium hydride (1.0 M in tetrahydrofuran) (0.06 ml, 0.06 mmol) was added and the reaction stirred for 2 h before warming to room temperature and leaving for a further 3 h. The reaction was cooled to -78°C and quenched by the addition of water (0.5 ml), 4N sodium hydroxide (0.5 ml) and methanol (0.2 ml). The reaction was filtered through hyflo and washed with dichloromethane. Solvent was removed in vacuo and the residue purified on silica gel chromatography eluting with methanol/dichloromethane (2:98) to give the product as a white solid (1.4 mg, 6%). Η NMR (400 MHz, CDC1₃) δ 2.10 (IH, m), 2.60 (IH, m), 2.80 (IH, m), 2.95 (IH, m), 3.20 (IH, m), 5.29 (IH, m), 6.94-6.95 (2H, m), 7.30 (IH, d, =74), 8.04 (IH, s), 8.31 (IH, s), 8.50-8.51 (2H, m), 8.57 (IH, d, =74), 8.90 (IH, s), 10.11 (IH, s). mlz (ES⁺) 401 (M⁺+H).

EXAMPLE 30

9-(4-Methylthien-2-yl)-ll-phenyl-6.7-dihvdro-5H-2.7a-diaza- dibenzofα,clcyclohepten-8-one

Prepared from Intermediate 1 and 4-methyl-3-thiopheneacetic acid ethyl ester following the procedure described for Example 2. Η NMR (360 MHz, CDCI3) δ 2.01 (IH, m), 2.30 (3H, s), 2.55 (IH, m), 2.75-2.89 (2H, m), 3.06 (IH, m), 5.27 (IH, m), 6.97-7.00 (3H, m), 7.21-7.25 (4H, m), 7.57 (IH, d, =71), 7.94 (IH, s), 7.98 (IH, s), 8.45 (IH, d, =75). mlz (ES⁺) 385 (M⁺+H). EXAMPLE 31

9-(4-Ethylthiazol-2-yl)-ll-phenyl-6.7-dihvdro-5H-2.7a-diaza- dibenzo \a. c] cyclohepten-8-one Prepared from l-bromobutan-2-one and 8-oxo-ll-phenyl-5, 6,7,8- tetrahydro-2,7a-diazadibenzo[α,c]cycloheptene-9-carbothioic acid amide following the procedure described for Example 28. *Η NMR (360 MHz, CDCI3) δ 1.99-2.10 (IH, m), 2.53-2.64 (IH, m), 2.74-2.94 (4H, m), 3.11 (IH, td, =713, 5), 5.32 (IH, dd, =713, 5), 7.00-7.06 (3H, m), 7.22-7.24 (6H, m), 8.02 (IH, s), 8.47 (IH, d, =75), 8.74 (IH, s). mlz (ES⁺) 349 (M++H).

EXAMPLE 32

9-(4-Fluoromethylthiazol-2-yl)-ll-phenyl-6.7-dihvdro-5H-2,7a-diaza- dibenzo \a, c) cyclohep ten-8-one

a) l-Chloro-3-fluoropropanone

3A Molecular sieves and N-methylmorpholine-AT-oxide (6.24 g, 53 mmol) were added to a solution of l-chloiO-3-fluoropropan-2-ol (2 g, 17.8 mmol) in dichloromethane (100 ml). The mixture was stirred for 15 minutes at room temperature and then tetra-71-propylammonium perruthenate (0.31 g, 0.89 mmol) was added. The mixture was stirred at room temperature for 3 hours and then passed through a small column of silica gel using dichloromethane as eluent to give the title-product:. ⁱΗ NMR (360 MHz, CDCI3) δ 4.34 (2H, d, =72), 5.13 (2H, d, =747).

b) (4-Fluoromethylthiazol-2-yl)acetic acid ethyl ester l-Chloro-3-fluoropropanone (250 mg, 2.27 mmol) and thiocarbamoylacetic acid ethyl ester (250 mg, 1.68 mmol) were stirred together at room temperature for 10 h. The mixture was diluted with dichloromethane and purified by column chromatography on silica gel, using dichloromethane/methanol as eluent, to give the title-product. Η NMR (360 MHz, CDC1₃) δ 1.30 (3H, t, =77), 4.07 (2H, s), 4.24 (2H, q, =71), 5.45 (2H, dd, =747, 1), 7.35 (IH, d, =73). mlz (ES⁺) 204 (M⁺+H).

c) 2-(4-Fluoromethylthiazol-2-yl)acetamide

(4-Fluoromethylthiazol-2-yT)acetic acid ethyl ester (200 mg, 0.98 mmol) was stirred in ammonia (4 ml) overnight at room temperature. The mixture was diluted with water and dichloromethane. The aqueous was extracted with dichloromethane (x 10). The combined organics were dried (sodium sulfate) and the solvent removed to give the title-product. ¹H

NMR (CDCI3) δ 3.87 (2H, s), 5.59 (2H, d, =747), 7.16 (IH, br s), 7.69 (IH, br s), 7.73 (IH, d, =74). mlz (ES⁺) 175 (M⁺+H).

d) 9-(4-Fluoromethylthiazol-2-yl)-ll-phenyl-6,7-dihydro-5H-2.7a-diaza- dibenzo \a, c) cyclohepten-8-one

Prepared by standard procedure D. Η NMR (360 MHz, CDCI3) δ 1.09 (3H, t, J l), 2.02-2.10 (IH, m), 2.31-2.43 (IH, m), 2.77-2.87 (IH, ), 2.89-2.96 (IH, m), 3.08 (IH, td, J l, 3), 3.38 (2H, d, J l), 5.07 (IH, dd, J l, 3), 5.52 (2H, d, =7_H-F 48), 7.08-7.09 (2H, m), 7.22-7.31 (3H, m), 7.44 (IH, d, =75), 7.91 (IH, d, =73), 8.46 (IH, d, J 5), 8.54 (IH, s). mlz (ES⁺) 404 (M++H).

EXAMPLE 33

ll-Phenyl-9-(pyridin-2-yl)-6.7-dihvdro-5H-2.7a-diaza- dibenzo \a, c\ cyclohepten-8-one

Prepared by standard procedure A using 2-pyridylacetamide. ¹Η NMR (360 MHz, CDCI3) δ 1.98-2.09 (IH, m), 2.51-2.59 (IH, m), 2.78-2.92 (2H, m), 3.06 (IH, td, =713, 5), 5.27 (IH, dd, J 13, 5), 6.97-7.02 (2H, ), 7.17-7.28 (4H, ), 7.77-7.83 (IH, m), 8.03 (IH, s), 8.47 (IH, d, J 5), 8.62- 8.67 (2H, m). mlz (ES⁺) 366 (M⁺+H).

Claims

CLAIMS:

A compound of formula (I), or a salt or iV-oxide thereof:

wherein

E represents -(CH2)n-; n is 1, 2 or 3; R¹ represents aryl, C3-7 heterocycloalkyl, C3-7 heterocycloalkenyl or heteroaryl, any of which groups may be optionally substituted; or halogen, -NHCOR³, -COR³ or -CO2R³;

R² represents aryl or heteroaryl, either of which groups may be optionally substituted; and R³ represents C3-6 alkyl, hydroxy(Cι-6)alkyl, C2-6 alkenyl, C3-7 cycloalkyl, aryl, aryl(Cι-6)alkyl, heteroaryl or heteroaryl(Cι-6)alkyl, any of which groups may be optionally substituted; said optional substituents on R¹, R² and R³ being independently selected from Ci-β alkyl, halo(Cι.e)alkyl, C3-7 cycloalkyl, halogen, formyl and C2-6 alkylcarbonyl; excluding compounds in which R¹ represents methylthiazolyl or hydroxymethylthiazolyl.

2. A compound according to claim 1 of formula (IA) or a salt or N-oxide threof:

(IA)

wherein

R¹¹ represents phenyl, pyrrolidinyl, thiazolinyl, pyridinyl, thienyl, pyrrolyl, isoxazolyl, oxadiazolyl or thiadiazolyl, any of which groups may be optionally substituted; or iodo, -NHCOR³, -COR³ or -CO₂R³;

W represents -N- or -CH-;

R⁴ represents hydrogen, halogen or Ci-e alkoxy; and

R³ is as defined in claim 1.

3. A compound according to claim 1 of formula (IB) or a salt or N-oxide thereof:

(IB)

wherein

R⁵ represents hydrogen, C2-6 alkyl, halo (Ci-e) alkyl, C₃-7 cycloalkyl, halogen, formyl or C2-6 alkylcarbonyl; and W and R⁴ are as defined in claim 2.

4. A compound according to claim 1 selected from ll-phenyl-9-(thien-2-yl)-6,7-dihydro-5H-2,7a-diaza- dibenzo[α,c]cyclohepten-8-one; ll-phenyl-9-(thien-3-yl)-6,7-dihydro-5H-2,7a-diaza- dibenzo [a, c] cyclohep ten-8-one;

9,ll-diphenyl-6,7-dihydro-5H-2,7a-diazadibenzo[ ,c]cyclohepten-8-one; 9-(5-methylthien-2-yl> ll-phenyl-6, 7-dihydro-5H-2, 7a-diaza- dibenzo[α,c]cyclohepten-8-one; ll-phenyl-9-(7?ι-tolyl)-6,7-dihydro-5H-2,7a-diazadibenzo[α,c]cyclohepten-8- one; ll-phenyl-9-(lH-pyrrol-2-yl)-6,7-dihydro-5H-2,7a-diaza- dibenzo[α,c]cyclohepten-8-one; 9-(5-chlorothien-2-yl)-ll-phenyl-6,7-dihydro-5H-2,7a-diaza- dibenzo [a, c] cyclohep ten-8-one ; ll-phenyl-9-(pyrrolidin-l-yl)-6,7-dihydro-5H-2,7a-diaza- dibenzo [a, c] cyclohep ten-8-one ;

8-oxo-ll-phenyl-5,6,7,8-tetrahydro-2,7a-diazadibenzo[ ,c]cycloheptene-9- carboxylic acid ter -butyl ester;

8-oxo-ll-phenyl-5,6,7,8-tetrahydro-2,7a-diazadibenzo[ ,c]cycloheptene-9- carboxylic acid allyl ester;

8-oxo-ll-phenyl-5,6,7,8-tetrahydro-2,7a-diazadibenzo[α,c]cycloheptene-9- carboxylic acid 2-hydroxyethyl ester; 8-oxo-ll-phenyl-5,6,7,8-tetrahydro-2,7a-diazadibenzo[ ₃c]cycloheptene-9- carboxylic acid cyclopentyl ester;

8-oxo-ll-phenyl-5,6,7,8-tetrahydro-2,7a-diazadibenzo[α,c]cycloheptene-9- carboxylic acid 4-methylthiazol-2-ylmethyl ester;

8-oxo-ll-phenyl-5,6,7,8-tetrahydro-2,7a-diazadibenzo[ ,c]cycloheptene-9- carboxylic acid benzyl ester; 8-oxo-ll-phenyl-5,6,7,8-tetrahydro-2,7a-diazadibenzo[ ,c]cycloheptene-9- carboxylic acid isopropyl ester;

9-(4-methylthiazol-2-ylcarbonyl)-ll-phenyl-6,7-dihydro-5H-2,7a-diaza- dibenzo[α,c]cyclohepten-8-one; 2,2-dimethyl-iV-(8-oxo-ll-phenyl-5,6,7,8-tetrahydro-2,7a-diaza- dibenzo [a, c] cyclohepten-9-yl)propionamide; 9-(4,5-dihydrothiazol-2-yl)-ll-phenyl-6,7-dihydro-5H-2,7a-diaza- dibenzo [a, c] cyclohep ten-8-one;

9-(5-chloroisoxazol-3-yl)-ll-phenyl-6,7-dihydro-5H-2,7a-diaza- dibenzo[α,c]cyclohepten-8-one;

9-(5-methyl-[l,2,4]oxadiazol-3-yl)-ll-phenyl-6,7-dihydro-5H-2,7a-diaza- dibenzo[α,c]cyclohepten-8-one;

9-(3-methyl-[l,2,4]oxadiazol-5-yl)-ll-phenyl-6,7-dihydro-5H-2,7a-diaza- dibenzo[α,c]cyclohepten-8-one; 9-(3-methyl-[l,2,4]thiadiazol-5-yl)-ll-phenyl-6,7-dihydro-5H-2,7a-diaza- dibenzo [a, c] cyclohepten-8-one;

9-(4-chlorothiazol-2-yl)-ll-phenyl-6,7-dihydro-5H-2,7a-diaza- dibenzo[ ,c]cyclohepten-8-one;

9-(4-cyclopropylthiazol-2-yl)-ll-phenyl-6,7-dihydro-5H-2,7a-diaza- dibenzo [a, c] cyclohep ten-8-one;

9-(4-cyclopropylthiazol-2-yl)- 1 l-(pyridin-4-yl)-6, 7-dihydro-5H-2, 7a-diaza- dibenzo [a, c] cyclohep ten-8-one; ll-phenyl-9-(thiazol-2-yl)-6,7-dihydro-5H-2,7a-diaza- dibenzo[α,c]cyclohepten-8-one; ll-(pyridin-4-yl)-9-(thiazol-2-yl)-6,7-dihydro-5H-2,7a-diaza- dibenzo [a, c] cyclohepten-8-one;

9-(4,5-dimethylthiazol-2-yl)-ll-phenyl-6,7-dihydro-5H-2,7a-diaza- dibenzo[α,c]cyclohepten-8-one;

2-[8-oxo-ll-(pyridin-4-yl)-5,6,7,8-tetrahydro-2,7a-diaza- dibenzo[α,c]cyclohepten-9-yl]thiazole-4-carbaldehyde; 9-(4-methylthien-2-yl)-ll-phenyl-6,7-dihydro-5H-2,7a-diaza- dibenzo [a, c] cyclohep ten-8-one;

9-(4-ethylthiazol-2-yl)- 1 l-phenyl-6, 7-dihydro-5H-2, 7a-diaza- dibenzo[α.c]cyclohepten-8-one;

9-(4-fluoromethylthiazol-2-yl)- 1 l-phenyl-6, 7-dihydro-5H-2, 7a-diaza- dibenzo [a, c] cyclohep ten-8-one; ll-phenyl-9-(pyridin-2-yl)-6,7-dihydro-5H-2,7a-diaza- dibenzo[ ,c]cyclohepten-8-one; and salts, and N-oxides thereof.

5. A pharmaceutical composition comprising a compound according to any previous claim in association with a pharmaceutically acceptable carrier.

6. A compound according to any of claims 1-4 for use in therapy of the human body.

7. The use of a compound according to any of claims 1-4 in the manufacture of a medicament for treatment or prevention of anxiety.

8. The use of a compound according to any of claims 1-4 in the manufacture of a medicament for treatment or prevention of convulsions.

9. A method for the treatment or prevention of anxiety which comprises administering to a patient in need of such treatment an effective amount of a compound according to any of claims 1-4.

10. A method for the treatment or prevention of convulsions which comprises administering to a patient in need of such treatment an effective amount of a compound according to any of claims 1-4.

11. A process for the preparation of a compound according to claim 1 which comprises cyclising a compound of formula (III):

Oil)

wherein E, R¹ and R² are as defined in claim 1, and L² represents a readily displaceable group.