WO2005056532A1

WO2005056532A1 - Indazole derivatives which interact with the g-protein coupled receptor family

Info

Publication number: WO2005056532A1
Application number: PCT/GB2004/005169
Authority: WO
Inventors: Emma Barker; Roger Crossley
Original assignee: Biofocus Discovery Limited
Priority date: 2003-12-12
Filing date: 2004-12-10
Publication date: 2005-06-23
Also published as: GB0328796D0

Abstract

Compounds of the general formula: (I) wherein Y, R and R’ are as described in the specification. Further included are pharmaceutical compositions comprising the compounds, processes for their preparation, as well as the use of the compounds for the preparation of a medicament against BRS-3 receptor-related disorders.

Description

INDAZOLE DERIVATIVES WHICH INTERACT WITH THE G-PROTEIN COUPLED RECEPTOR FAMILY

The present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, to processes for their preparation, as well as to the use of the compounds for the preparation of a medicament against BRS-3 receptor-related disorders.

The orphan receptor human bombesin receptor subtype 3 (BRS-3) was assigned to the G-protein coupled bombesin receptor family because of its high sequence homology with neuromedin B receptor (NMB-R) (BB1) and gastrin-releasing peptide receptor (GRP-R) (BB2). Studies of the distribution of this orphan receptor show that the BRS-3 receptor is present in the central nervous system and gastrointestinal tract.

The role of BRS-3 in physiological or pathological processes remains unknown due to the lack of selective ligands or identification of its endogenous ligand. Data obtained from the knock-out mouse model suggest that the BRS-3 receptor may be required for the regulation of glucose metabolism, energy balance and maintenance of blood pressure (Okhi-Hamazaki, H.; Watase, K.; Yamamoto, K.; Ogura, H.; Yamano, M.; Yamada, K.; Maeno, H.; Imaki, J.; Kikuyama, S.; Wada, E.; Wada, K., Nature, 390, 165 (1997); Yamada, K.; Wada, E.; Imaki, J.; Okhi- Hamazaki, H.; Wada, K., Physiol. Behav., 66, 863 (1999)). Mice lacking functional BRS-3 developed mild obesity, diabetes and hypertension.

Bombesin like peptides are involved in the growth regulation of various cancers (Toi-Scott, M.; Jones, C.L.; Kane, M.A., Lung Cancer, 15, 3, 341 (1996)). Expression of BRS-3 in human tumor was found preferentially in the neuroendocrine tumors of the lung (bronchial carcinoids, small-cell lung cancer cell lines and large cell neuroendocrine carcinoma), which may indicate that BRS-3 could serve as a potential therapeutic target for human lung carcinoma (Fathi, Z.; Corjay, M.H.; Shapira, H.; Wada, E.; Benya, R.; Jensen, R.; Viallet, J.; Sausville, E.A.; Battey, J.F., J. Biol. Chem., 268, 8, 5979 (1993); Reubi, J.C.; Wenger, S.; Schmuckli-Maurer, J.; Schaer, J.C.; Gugger, M., Clin. Cancer. Res., 8, 4, 1139 (2002)). BRS-3 antagonists may therefore be useful in the treatment of such cancers.

Recently BRS-3 was connected to the treatment of neurological disorders such as stroke, ischaemia, head injury, Alzheimer's disease, and also learning, memory and attention disorders (Smart, D.; Strijbos, P., Bombesin receptor subtype 3 polynucleotides, polypeptides and ligands for use in treating neurological disorders. PTC Int. Appl. WO 0168120 (2001)).

BRS-3 antagonists may also be useful in the treatment of anxiety and panic disorders and in the oncology area, in particular for the treatment of small cell lung cancer, ovarian cancer and prostate cancer.

However, despite indications discussed above that BRS-3 antagonists may be useful in the treatment of a variety of diseases, no non-peptide BRS-3 antagonists have previously been disclosed. The development of non- peptide BRS-3 antagonists with good activity, selectivity and pharmacokinetic profiles is therefore needed to fully exploit the clinical potential of this target receptor.

Remarkably, the present invention provides a class of compounds which interact with the BRS-3 receptor.

In a first aspect the invention provides a compound of Formula (I)

Formula (I)

wherein: R is aryl-Cι_-6-alkyl optionally independently substituted with one or more of C_1-6-alkoxy, Cι_-6-alkyl, methylenedioxy, aryl, halogen and halo Cι_ e-alkyl; or heteroaryl-Cι_-6-alkyl optionally independently substituted with one or more of Cι_-6-alkoxy, Cι_-6-alkyl, methylenedioxy, aryl, halogen and halo C_1-6-alkyl; or aryloxy-Cι-₆-alkyl optionally independently substituted with one or more of Cι_-6-alkoxy, Cι_-6-alkyl, methylenedioxy, aryl, halogen and halo Cι_-6-alkyl; or heteroaryloxy-Cι-₆-alkyl optionally independently substituted with one or more of Cι_-6-alkoxy, C_1-6-alkyl, methylenedioxy, aryl, halogen and halo Cι_-6-alkyl;

R' is Cι-₆-dialkyl amine, optionally independently substituted with one or more of Cι_-6-alkoxy; or Ci-e-alkyl amine, optionally independently substituted with one or more of Cι_₆-alkoxy; or - C_4-7-cyclic alkyl amine, optionally independently substituted with one or more of Cι-₆-alkoxy; or - C_3-8-cycloalkyl amine, optionally independently substituted with one or more of Cι_-6-alkoxy;

Y is hydrogen, C_1-6-alkyl, Cι_-6-alkoxy or halogen;

and pharmaceutically acceptable salts, hydrates, solvates, geometrical isomers, tautomers, optical isomers, and prodrug forms thereof.

In a preferred embodiment, R is aryl-Cι_-6-alkyl optionally independently substituted with one or more of Cι_-6-alkoxy; or aryloxy-Cι_-6-alkyl optionally independently substituted with one or more of halogen.

More preferably, R is phenoxymethylene or benzo[l,3]dioxol-5-yl- methylene.

In a preferred embodiment R' is C_1-6-dialkyl amine, Cι_-6-alkyl amine or C_4- ₇-cyclic alkyl amine. More preferably, R ' is /V,/V-diethylamine.

Preferred compounds are given in Examples 1-20.

Any known compound having a structural formula identical to any one of the compounds covered by formula (I) is hereby explicitly disclaimed per se.

In a second aspect the present invention provides a pharmaceutical formulation comprising a compound of the present invention and a pharmaceutically acceptable diluent or carrier. In a third aspect the invention provides a process for the preparation of a compound as mentioned above, which process comprises the following steps: a) reaction of a compound of Formula (II) with hydroxylamine, to give an amidine of formula (III);

(II) (HI)

b) reaction of an amidine of formula (III) with diethyl carbonate in sodium methoxide to give an oxadiazolone of formula (IV);

(IV)

c) thermal de-carboxylation of an oxadazolone of formula (IV) to give an indazole of formula (V);

(V) d) synthesis of an alkylating agent of formula (VI) from reaction of 4- (bromomethyl)benzene sulfonyl chloride with an amine R'NH or R'NH₂;

(VI)

e) alkylation of an indazole of formula (V) with the alkylating agent of formula (VI) to give a sulfonamide of formula (VII);

(VII)

f) acylation of a sulfonamide of formula (VII) with an acyl choride RCOCI to give a compound of formula (I)

(I) wherein

Y is hydrogen, Cι_-6-alkyl, Cι_-6-alkoxy or halogen; R' is - Ci-e-dialkyl amine, optionally independently substituted with one or more of Cι_-6-alkoxy; or - Cι-₆-alkyl amine, optionally independently substituted with one or more of Cι_-6-alkoxy; or - C_4-7-cyclic alkyl amine, optionally independently substituted with one or more of Cι_-6-alkoxy; or - C_3-8-cycloalkyl amine, optionally independently substituted with one or more of Cι_-6-alkoxy;

R is - aryl-Cι-₆-alkyl optionally independently substituted with one or more of Ci-e-alkoxy, Cι_-6-alkyl, methylenedioxy, aryl, halogen and halo _.- ₆-alkyl; or - heteroaryl-Cι-₆-alkyl optionally independently substituted with one or more of Cι_-6-alkoxy, Cι_-6-alkyl, methylenedioxy, aryl, halogen and halo Ci-β-alkyI; or - aryloxy-Cι-₆-alkyl optionally independently substituted with one or more of C_1-6-alkoxy, Cι_₆-alkyl, methylenedioxy, aryl, halogen and halo Cι-₆-alkyl; or - heteroaryloxy-C_1-6-alkyl optionally independently substituted with one or more of d_-6-alkoxy, Cι_-6-alkyl, methylenedioxy, aryl, halogen and halo d_-6-alkyl;

In a fourth aspect the invention provides a method for the prophylaxis or treatment of a BRS-3 receptor-related disorder, which comprises administering to a subject in need of such treatment an effective amount of a compound or a pharmaceutical formulation of the invention.

In a fifth aspect the present invention provides a method for modulating BRS-3 receptor activity, which comprises administering to a subject in need of such treatment an effective amount of a compound or a pharmaceutical formulation as mentioned above.

In a sixth aspect the present invention provides a compound as mentioned above for use in therapy, especially for use in the prophylaxis or treatment of a BRS-3 receptor-related disorder.

In a seventh aspect the present invention provides a method for modulating BRS-3 receptor activity, which comprises administering to a subject in need of such treatment an effective amount of a compound as mentioned above.

Another object of the present invention is the use of a compound as mentioned above for the manufacture of a medicament for use in the prophylaxis or treatment of a BRS-3 receptor-related disorder.

The compounds as mentioned above may be agonists, partial agonists or antagonists for the BRS-3 receptor.

Examples of putative BRS-3 receptor-related disorders are obesity, diabetes and hypertension. Expression of BRS-3 in human tumor was found preferentially in the neuroendocrine tumors of the lung (bronchial carcinoids, small-cell lung cancer cell lines and large cell neuroendocrine carcinoma), which may indicate that BRS-3 could serve as a potential therapeutic target for human lung carcinoma. Recently BRS-3 was connected to the treatment of neurological disorders such as stroke, ischaemia, head injury, Alzheimer's disease, and also learning, memory and attention disorders.

Definitions

The following definitions shall apply throughout the specification and the appended claims.

Unless otherwise stated or indicated, the term "Cι_-6-alkyl" denotes a straight or branched alkyl group having from 1 to 6 carbon atoms. ^wCι_-6- alkyl may also be referred to as "lower alkyl". Examples of lower alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec- butyl, t-butyl and straight- and branched-chain pentyl and hexyl. For parts of the range ^,Cι_-6-alkyl" all subgroups thereof are contemplated such as Cι. ₅-alkyl, Cι- -alkyl, Cι_-3-alkyl, Cι_-2-alkyl, C_2-6-alkyl, C_2-5-alkyl, C_2-4-alkyl, C_2-3- alkyl, C_3-6-alkyl, C_4-5-aIkyl, etc. ^uHalo-Cι_-6-alkyl" means a Cι_-6-alkyl group substituted with one or more halogen atoms. Likewise, "aryl-Cι_-6-alkyl" means a Cι_-6-alkyl group substituted with one or more aryl groups.

Unless otherwise stated or indicated, the term "C_3-8-cycloalkyl" denotes a cyclic alkyl group having a ring size from 3 to 8 carbon atoms. Examples of C₃-₈-cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl, and cyclooctyl. For parts of the range "C_3-8-cycloalkyl" all subgroups thereof are contemplated such as C_3- ₇-cycloalkyl, C₃-₆-cycloalkyl, C_3-5-cycloalkyl, C_3-4-cycloalkyl, C_4-8-cycloalkyl, C_4-7-cycloalkyl, C_4-6-cycloaIkyl, C_4-5-cycloalkyl, C_5- -cycloalkyl, C_6-7- cycloalkyl, etc. Unless otherwise stated or indicated, the term "C_1-6-alkoxy" denotes a straight or branched alkoxy group having from 1 to 6 carbon atoms. "C_1-6- alkoxy may also be referred to as "lower alkoxy". Examples of lower alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight- and branched-chain pentoxy and hexoxy. For parts of the range "Cι_-6-alkoxy" all subgroups thereof are contemplated such as Cι-₅-alkoxy, Cι_-4-alkoxy, Cι_-3-alkoxy, Cι. ₂-alkoxy, C_2-6-alkoxy, C_2-5-alkoxy, C_2-4-alkoxy, C_2-3-alkoxy, C_3-6-alkoxy, C_4- ₅-alkoxy, etc.

Unless otherwise stated or indicated, the term "halogen" shall mean fluorine, chlorine, bromine or iodine.

Unless otherwise stated or indicated, the term "aryl" refers to a hydrocarbon ring system having at least one aromatic ring. Examples of aryls are phenyl, pentalenyl, indenyl, indanyl, isoindolinyl, chromanyl, naphthyl, fluorenyl, anthryl, phenanthryl and pyrenyl. The aryl rings may optionally be substituted with Cι-₆-alkyl. Examples of substituted aryl groups are benzyl and 2-methylphenyl. Likewise, aryloxy refers to an aryl group bonded to an oxygen atom.

The term "heteroaryl" refers to a hydrocarbon ring system having at least one aromatic ring which contains at least one heteroatom such as O, N, or S. Examples of heteroaryl groups include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, quinazolinyl, indolyl, pyrazolyl, pyridazinyl, quinolinyl, benzofuranyl, dihydrobenzofuranyl, benzodioxolyl, benzodioxinyl, benzothiazolyl, benzothiadiazolyl, and benzotriazolyl groups. The term "leaving group" refers to a group to be displaced from a molecule during a nucleophilic displacement reaction. Examples of leaving groups are bromide, chloride and methanesulfonate, especially bromide and methanesulfonate.

"Pharmaceutically acceptable" means being useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use.

"Treatment" as used herein includes prophylaxis of the named disorder or condition, or amelioration or elimination of the disorder once it has been established.

"An effective amount" refers to an amount of a compound that confers a therapeutic effect on the treated subject. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect).

The term "prodrug forms" means a pharmacologically acceptable derivative, such as an ester or an amide, which derivative is biotransformed in the body to form the active drug. Reference is made to Goodman and Gilman 's, The Pharmacological basis of Therapeutics, 8^th ed., Mc-Graw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p. 13-15. The following abbreviations have been used: ACINI means acetonitrile, DEA means diethylamine, DEPT means distortion enhancement polarisation transfer, DMSO means dimethyl sulfoxide, ELS means electron light scattering, HPLC means high performance liquid chromatography, Rt means retention time, TFA means trifluoroacetic acid, THF means tetrahydrofuran, TLC means thin layer chromatography.

All diastereomeric forms possible (pure enantiomers, tautomers, racemic mixtures and unequal mixtures of two enantiomers) are within the scope of the invention. Compounds according to the present invention can also occur as cis- or trans-, E- or Z- double bond isomer forms. All isomeric forms are contemplated.

The compounds of formula (I) may be used as such or, where appropriate, as pharmacologically acceptable salts (acid or base addition salts) thereof. The pharmacologically acceptable addition salts mentioned above are meant to comprise the therapeutically active non-toxic acid and base addition salt forms that the compounds are able to form. Compounds that have basic properties can be converted to their pharmaceutically acceptable acid addition salts by treating the base form with an appropriate acid. Exemplary acids include inorganic acids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid; and organic acids such as formic acid, acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid, malic acid, tartaric acid, citric acid, salicylic acid, p-aminosalicylic acid, pamoic acid, benzoic acid, ascorbic acid and the like. Exemplary base addition salt forms are the sodium, potassium, calcium salts, and salts with pharmaceutically acceptable amines such as, for example, ammonia, alkylamines, benzathine, and amino acids, such as, e.g. arginine and lysine. The term addition salt as used herein also comprises solvates which the compounds and salts thereof are able to form, such as, for example, hydrates, alcoholates and the like.

For clinical use, a compound according to the present invention is formulated into a pharmaceutical formulation which is formulated to be compatible with its intended route of administration, for example for oral, rectal, parenteral or other modes of administration. Pharmaceutical formulations are usually prepared by mixing the active substance, or a pharmaceutically acceptable salt thereof, with a conventional pharmaceutically acceptable diluent or carrier. As used herein the language "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Examples of pharmecuetically acceptable diluents or carrier are water, gelatin, gum arabicum, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talcum, colloidal silicon dioxide, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated.

Such formulations may also contain other pharmacologically active agents, and conventional additives, such as stabilizers, wetting agents, emulsifiers, flavouring agents, buffers, and the like.

The formulations can be further prepared by known methods such as granulation, compression, microencapsulation, spray coating, etc. The formulations may be prepared by conventional methods in the dosage form of tablets, capsules, granules, powders, syrups, suspensions, suppositories or injections. Liquid formulations may be prepared by dissolving or suspending the active substance in water or other suitable vehicles. Tablets and granules may be coated in a conventional manner.

Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, 'chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum mono stearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the active compound (e.g., a compound according to an embodiment of the invention) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

The compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery. In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art.

It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.

Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50. Compounds which exhibit large therapeutic indices are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.

The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound used in the method of the invention, the therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography.

The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

In a further aspect the invention relates to methods of making compounds of any of the formulae herein comprising reacting any one or more of the compounds of the formulae delineated herein, including any processes delineated herein. The compounds of formula (I) may be prepared by, or in analogy with, conventional methods. The processes described above may be carried out to give a compound of the invention in the form of a free base or as an acid addition salt. A pharmaceutically acceptable acid addition salt may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Examples of addition salt forming acids are mentioned above.

The compounds of formula (I) may possess one or more chiral carbon atoms, and they may therefore be obtained in the form of optical isomers, e.g. as a pure enantiomer, or as a mixture of enantiomers (racemate) or as a mixture containing diastereomers. The separation of mixtures of optical isomers to obtain pure enantiomers is well known in the art and may, for example, be achieved by fractional crystallization of salts with optically active (chiral) acids or by chromatographic separation on chiral columns.

The necessary starting materials for preparing the compounds of formula (I) are either known or may be prepared in analogy with the preparation of known compounds. The dose level and frequency of dosage of the specific compound will vary depending on a variety of factors including the potency of the specific compound employed, the metabolic stability and length of action of that compound, the patient's age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the condition to be treated, and the patient undergoing therapy. The daily dosage may, for example, range from about 0.001 mg to about 100 mg per kilo of body_weight, administered singly or multiply in doses, e.g. from about 0.01 mg to about 25 mg each. Normally, such a dosage is given orally but parenteral administration may also be chosen.

The invention will now be further illustrated by the following non-limiting Examples.

Within this specification embodiments have been described in a way that enables a clear and concise specification to be written, but it will be appreciated that embodiments may be variously combined or separated without parting from the invention.

EXAMPLES

Experimental methods

All reagents were commercial grade and were used as received without further purification, unless otherwise specified. Commercially available anhydrous solvents were used for reactions conducted under inert atmosphere. Reagent grade solvents were used in all other cases, unless otherwise specified. Column chromatography was performed on Matrex® silica gel 60 (35-70 micron). TLC was carried out using pre-coated silica gel F-254 plates (thickness 0.25 mm). ^XH NMR spectra were recorded on a Bruker Avance250 at 250 MHz. Chemical shifts for H NMR spectra are given in part per million and either tetramethylsilane (0.00 ppm) or residual solvent peaks were used as internal reference. Splitting patterns are designated as follows: s, singlet; d, doublet; t, triplet; q, quartet; p, pentet; m, multiplet; br, broad. Coupling constants are given in Hertz (Hz). Only selected data are reported. The ¹³C NMR spectra were recorded at 62.5 MHz. DEPT experiments were used to help assign ¹³C NMR resonances where necessary. Chemical shifts for ¹³C NMR spectra are expressed in parts per million and residual solvent peaks were used as internal reference. HPLC analyses were performed using a Waters Xterra MS C18 column (100 x 4.6 mm, 5μ) eluting with a gradient of 5% ACN in 95% water to 95% ACN in 5% water (0.2% TFA buffer) over 3.5 mins, then 95% ACN in 5% water (0.2% TFA buffer) for a further 2.5 mins at a flow rate of 3 ml/min on a Waters 600E or Gilson system with monitoring at 254 nm. Reverse phase preparative HPLC was carried out using a Xterra MS C18 column (100 x 19 mm, 5Dm) eluting with a gradient of 5% ACN in 95% water to 95% ACN in 5% water (0.05% DEA) over 12.0 mins, then 95% ACN in 5% water (0.05% DEA) for a further 5.0 mins at a flow rate of 25 ml/min with monitoring at 254 nm. The fractions that contained the desired product were concentrated under reduced pressure and the resultant residue was lyophilised from a mixture of dioxane and water. Electrospray MS spectra were obtained on a Micromass platform LCMS spectrometer. Compounds were named using AutoNom 2000.

EXAMPLE 1 (General Procedure A)

/V-[l-(4-Dϊethylsulfamoyl-benzyl)-lH-ϊndazol-3-yl]-2-phenoxy- acetamide

Step 1; 2-Amino-Λf-hydroxy-benzamidine

Hydroxylamine hydrochloride (23.53g, 338mmol) was added portion-wise to a mixture of sodium hydrogen carbonate (28.44g, 338mmol) in water (80ml). The mixture was stirred for 10 minutes and a solution of anthranilonitrile (20g, 169mmol) in ethanol (250ml) was added drop-wise. The reaction mixture was refluxed for 5 hours and then cooled to room temperature. The solvent was removed under reduced pressure to give an aqueous residue. The aqueous mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo to afford a light brown solid. The solid was washed with diethyl ether to yield 2-amino-/V-hydroxy-benzamidine (20.96g, 82%) as a pink solid.

^XH-NMR (250MHz, DMSO-d₆) δ 5.73 (brs, 2H, NH₂), 6.20 (brs, 2H, NH₂), 6.51 (t, 1H, J 8.1 Hz), 6.64 (d, 1H, J 8.1 Hz), 7.01 (td, 1H, J 1.5 Hz, 8.4 Hz), 7.35 (dd, 1H, J 1.5 Hz, 7.9 Hz), 9.57 (s, 1H, OH); HPLC 100%, Rt = 0.56 min. MS (AP) m/z 152 (M⁺+H).

Step 2; 3-(2-Amino-phenyI)-4H-[l,2,4]oxadiazol-5-one

Sodium methoxide (25wt% in MeOH, 336mmol, 77ml), was added to a stirred solution of 2-amino-/V-hydroxy-benzamidine (16.95g, 112mmol) in ethanol (330ml) at room temperature. The mixture was vigorously stirred and diethyl carbonate (54.4ml, 449mmol) was added. The reaction mixture was refluxed for 2 hours and then allowed to cool to room temperature. The solvent was removed under reduced pressure and the residue was diluted with water (300ml). The basic solution was neutralised to pH7 with IM hydrochloric acid at 0°C. The resulting precipitate was filtered under reduced pressure, washed with water and dissolved in ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and evaporated in vacuo. 3-(2-Amino-phenyl)-4H-[l,2,4]oxadiazol-5-one (17.7g, 89%) was obtained as a green-brown solid.

*H-NMR (250MHz, DMSO-d₆) δ 6.63 (dt, 1H, J 1.1 Hz, 8.1 Hz), 6.84 (dd, 1H, J 1.0 Hz, 8.4 Hz), 7.23 (dt, 1H, J 1.5 Hz, 8.5 Hz), 7.44 (dd, 1H, J 1.4 Hz, 8.0 Hz), 8.33 (brs, 2H); HPLC 100%, Rt = 1.61 min. MS (AP) m/z 178 (M⁺+H).

Step 3; lH-Indazol-3-ylamine

3-(2-Amino-phenyl)-4H-[l,2,4]oxadiazol-5-one (9g, 50.85mmol) was heated at 190°C for 90 minutes. The mixture was cooled to room temperature and dissolved in ethyl acetate. The dark solution was filtered through a pad of celite. The solvent was removed in vacuo and the resulting residue was purified by flash chromatography eluting with ethyl acetate to give lH-indazol-3-ylamine (4.6g, 68%) as a tan solid. *H-NMR (250MHz, DMSO-d₆) δ 5.32 (brs, 2H, NH₂), 6.86 (m, IH), 7.19 (t, 2H, J 2.1 Hz), 7.64 (d, IH, J 8.0 Hz), 11.34 (brs, IH, NH); HPLC 98%, Rt = 1.05 min. MS (AP) m/z 134 (M⁺+H).

Step4; 4-Bromomethyl-/V_/ V-diethylbenzenesulfonamide

A solution of diethylamine (7.42mmol) and Λ/,/V-diisopropylethylamine (l.Olg, 7.79mmol) in dry dichloromethane (15ml) was added drop-wise to a stirred solution of 4-(bromomethyl)benzene sulfonyl chloride (2g, 7.42mmol) in dry dichloromethane (15ml) at 0°C. After the addition, the mixture was stirred at room temperature for 2 hours. The solution was washed with water. The aqueous layer was extracted with dichloromethane. The combined organic phase was dried over magnesium sulfate, filtered and evaporated in vacuo.

Step 5; 4-(3-Amino-indazol-l-ylmethyl)- v,/V-diethyl- benzenesulfonamide

A solution of indazole (0.45g, 3.41mmol) in dry dirnethylformamide (10ml) was added drop-wise to a slurry of sodium hydride (60% in mineral oil, 4.09mmol) in dry dirnethylformamide (5ml) at 0°C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 30 minutes, then cooled to 0°C and a solution of 4-(bromomethyl)benzene sulfonamide (1.04g, 3.41mmol) in dry dirnethylformamide (10ml) was added dropwise. The mixture was stirred at room temperature overnight and then diluted with ethyl acetate. The solution was washed with water (x3), brine, dried over magnesium sulfate and filtered. The solvent was evaporated in vacuo and the resulting residue was purified by flash chromatography eluting with diethyl ether. The product (0.543g, 45%) was isolated as a yellow crystalline solid. Step 6; /V-[l-(4-Diethylsulfamoyl-benzyl)-lH-indazol-3-yl]-2- phenoxy-acetamide

A solution of phenoxyacetyl chloride (70.7mg, 0.41mmol) in dry dichloromethane (2ml) was added to a mixture of 4-(3-amino-indazol-l- ylmethyl)-/V,/V-diethyl-benzenesulfonamide (135mg, 0.38mmol), pyridine (0.1ml) and DMAP (5mg) in dry dichloromethane at room temperature. The mixture was stirred for 1 hour and IM hydrochloric acid was added. The organic layer was separated and washed with sat. sodium bicarbonate and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the product (171.7mg, 93%) as a yellow solid.

Hl-NMR (250MHz, CDCI₃) δ 1.10 (t, 6H, J 7.1 Hz), 3.18 (q, 4H, J 7.1 Hz), 4.73 (s, 2H), 5.55 (s, 2H), 6.99-7.09 (m, 3H), 7.39 (m, 7H), 7.72 (d, 2H, J 8.4 Hz), 8.06 (d, IH, J 8.3 Hz), 8.93 (brs, IH, NH); ¹³C-NMR (62.5MHz, CDCI₃) δ 14.25 (CH₃), 42.12 (CH₂), 51.95 (CH₂), 67.38 (CH₂), 108.82 (CH), 114.74 (CH), 116.99 (C_q), 120.91 (CH), 122.43 (CH), 123.26 (CH), 127.52 (CH), 127.54 (CH), 127.71 (CH), 129.90 (CH), 138.87 (C_q), 139.94 (C_q), 141.06 (C_q), 141.22 (C_q), 156.96 (C_q), 166.41 (C_q); HPLC 99% 3.19 min. MS (AP) m/z 493 (M⁺+H).

EXAMPLE 2

2-Benzo[l_f3]dioxo-5-yl-W-[l-(4-diethylsulfamoyl-benzyl)-lH- indazol-3-yl]-acetamide

A solution of benzo[l,3]dioxol-5-yl-acetyl chloride (O.lg, 0.55mmol) in dry dichloromethane (2ml) was added to a mixture of 4-(3-amino-indazol-l- ylmethyl)-Λ/,Λ/-diethyl-benzenesulfonamide (0.15g, 0.418mmol), pyridine (0.2ml) and DMAP (5mg) in dry dichloromethane (3ml) at room temperature. The mixture was stirred for 1 hour and water was added. The organic phase was dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting residue was purified by flash chromatography eluting with ethyl acetate-hexane 1: 1 v/v to afford the product (127mg, 59%) as an off-white solid.

'H-NMR (250MHz, CDCI₃) δ 1.10 (t, 6H, J 7.1 Hz), 3.18 (q, 4H, J 7.1 Hz), 3.75 (s, 2H), 5.49 (s, 2H), 5.99 (s, 2H), 6.83 (s, IH), 6.85 (d, 2H, J 8.9 Hz), 7.12-7.23 (m, 4H), 7.36 (t, IH, J 7.1 Hz), 7.70 (d, 2H, J 8.3 Hz), 7.76 (s, IH), 7.99 (d, IH, J 8.3 Hz); HPLC 99%, Rt = 2.97 min. MS (AP) m/z 521 (M⁺+H).

General procedure B for examples 3, 4 and 5: (array synthesis):

A solution of acid chloride (0.2M in dry DCM, 1ml) was added to a mixture of 4-(3-amino-indazol-l-ylmethyl)-/V,/V-di-substituted- benzenesulfonamide* (0.2M in dry DCM, 1ml), pyridine (0.15ml) and 4- dimethylaminopyridine (3mg). The reaction mixture was stirred at room temperature for 2 hours, diluted with dichloromethane and washed with IM hydrochloric acid, dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was purified by flash chromatography eluting with diethyl ether. *Was synthesised according to general procedure A, steps 1-5.

Example 3

2,3-Dihydro-benzo[l,4]dioxine-2-carboxylic acid [l-(4- diethylsulfamoyl-benzyl)-lH-indazol-3-yl]-amide

2,3-Dihydro-benzo[l,4]dioxine-2-carboxylic acid [l-(4-diethylsulfamoyl- benzyl)-lH-indazol-3-yl]-amide (89.7mg, 86%) was isolated as an off- white solid. H-NMR (250MHz, CDCI₃) δ 1.10 (t, 6H, J 7.1 Hz), 3.18 (q, 4H, J 7.1 Hz), 4.33 (dd, IH, J 7.6 Hz, 11.4 Hz), 4.67 (dd, IH, J 2.6 Hz, 11.4 Hz), 4.92 (dd, IH, J 2.6 Hz, 7.46 Hz), 5.55 (s, 2H), 6.90-7.05 (m, 4H), 7.15-7.28 (m, 4H), 7.39 (t, IH, J 7.5 Hz), 7.73 (d, 2H, J 8.2 Hz), 8.05 (d, IH, J 8.3 Hz), 8.91 (brs, IH, NH); ¹³C-NMR (62.5MHz, CDCI₃) δ 14.25 (CH₃), 42.12 (CH₂), 51.96 (CH₂), 65.27 (CH₂), 73.34 (CH), 108.84 (CH), 116.77 (C_q), 117.26 (CH), 117.76 (CH), 120.96 (CH), 122.16 (CH), 122.70 (CH), 123.26 (CH), 127.53 (CH), 127.77 (CH), 138.64 (C_q), 139.96 (C_q), 140.99 (C_q), 141.21 (C_q), 141.43 (C_q), 143.21 (C_q), 165.32 (C_q); HPLC 100%, Rt = 3.17 min. MS (AP) m/z 521 (M⁺+H).

Example 4 iV-[l-(4-Diethylsulfamoyl-benzyl)-lH-indazoI-3-yl]-2-(3-methoxy- phenyl)-acetamide

Λ/-[l-(4-Diethylsulfamoyl-benzyl)-lH-indazol-3-yl]-2-(3-methoxy-phenyl)- acetamide (83.5mg, 83%) was isolated as a colourless solid. *H-NMR (250MHz, CDCI₃) δ 1.10 (t, 6H, J 7.1 Hz), 3.17 (q, 4H, J 7.1 Hz), 3.81 (s, 2H), 3.82 (s, 3H), 5.48 (s, 2H), 6.86-6.99 (m, 3H), 7.11-7.39 (m, 6H), 7.69 (d, 2H, J 8.3 Hz), 7.78 (brs, IH, NH), 7.98 (d, IH, J 8.3 Hz); ¹³C-NMR (62.5MHz, CDCI₃) δ 14.23 (CH₃), 42.11 (CH₂), 44.14 (CH₂), 51.83 (CH₂), 55.26 (CH₃), 108.70 (CH), 113.21 (CH), 115.25 (CH), 117.04 (Cq), 120.75 (CH), 121.82 (CH), 123.40 (CH), 127.47 (CH), 127.60 (CH), 130.37 (CH), 135.56 (Cq), 139.65 (Cq), 139.83 (Cq), 141.09 (Cq), 160.19 (Cq), 169.06 (Cq); HPLC 100%, Rt = 3.00 min. MS (AP) m/z 507 (M⁺+H).

Example 5

2-Phenoxy-/V-{l-[4-(pyrrolidine-l-sulfonyl)-benzyl]-lH-indazol-3- yl}propionamϊde

2-Phenoxy-Λ/-{l-[4-(pyrrolidine-l-sulfonyl)-benzyl]-lH-indazol-3- yl}propionamide (69.1mg, 69%) was isolated as an off-white solid. *H-NMR (250MHz, CDCI₃) δ 1.70-176 (m, 7H), 3.16-3.22 (m, 4H), 4.93 (q, IH, J 6.8 Hz), 5.55 (s, 2H), 6.99-7.08 (m, 3H), 7.17 (dt, IH J 0.9 Hz, 8.2 Hz), 7.25-7.42 (m, 6H), 7.75 (d, 2H, J 8.4 Hz), 8.03 (d, IH, J 8.3 Hz), 8.81 (brs, IH, NH); ¹³C-NMR (62.5MHz, CDCI₃) δ 18.67 (CH₃), 25.17 (CH₂), 47.84 (CH₂), 51.90 (CH₂), 75.09 (CH), 108.75 (CH), 115.68 (CH), 116.89 (Cq), 120.83 (CH), 122.43 (CH), 123.24 (CH), 127.54 (CH), 127.69 (CH), 128.00 (CH), 129.91 (CH), 136.55 (Cq), 139.07 (Cq), 141.19 (Cq), 141.40 (Cq), 156.62 (Cq), 170.45 (Cq); HPLC 100%, Rt = 3.05 min. MS (AP) m/z 505 (M⁺+H).

Example 6

2-(4-Chloro-phenoxy-/V-[l-(4-diethylsulfamoyl-benzyl)-lH- indazol-3-yl]-acetamide

2-(4-Chloro-phenoxy-V-[l-(4-diethylsulfamoyl-benzyl)-lH-indazol-3-yl]- acetamide (83.1mg, 79%) was isolated as a colourless solid. ^XH-NMR (250MHz, CDCI₃) δ 1.10 (t, 6H, J 7.1 Hz), 3.19 (q, 4H, J 7.1 Hz), 4.70 (s, 2H), 5.55 (s, 2H), 6.95 (dt, 2H, J 2.7 Hz, 9.5 Hz), 7.16-7.44 (m, 7H), 7.73 (dd, 2H, J 1.8 Hz, 6.62 Hz), 8.07 (d, IH, J 8.3 Hz), 8.86 (brs, IH, NH); ¹³C-NMR (62.5MHz, CDCI₃) δ 14.24 (CH₃), 42.11 (CH₂), 51.97 (CH₂), 67.64 (CH₂), 108.84 (CH), 116.05 (CH), 116.93 (Cq), 120.98 (CH), 123.25 (CH), 127.54 (CH), 127.77 (CH), 129.82 (CH), 138.75 (Cq), 139.98 (Cq), 141.00 (Cq), 141.23 (Cq), 155.51 (Cq), 165.89 (Cq); HPLC 100%, Rt = 3.28 min. MS (AP) m/z 527 (M⁺+H).

Example 7

N-[l-(4-Diethylsulfamoyl-benzyl)-lH-indazol-3-yl]-2-(3,4- dimethoxy-phenyl)-acetamide

Λ -[l-(4-Diethylsulfamoyl-benzyl)-lH-indazol-3-yl]-2-(3,4-dimethoxy- phenyl)-acetamide (92mg, 86%) was isolated as an off-white solid. ^XH-NMR (250MHz, CDCI₃) δ 1.09 (t, 6H, J 7.1 Hz), 3.17 (q, 4H, J 7.1 Hz), 3.78 (s, 2H), 3.88 (s, 3H), 3.90 (s, 3H), 5.47 (s, 2H), 6.86-6.93 (m, 3H), 7.11-7.23 (m, 4H), 7.36 (t, IH, J 7.6 Hz), 7.68 (d, 2H, J 8.3 Hz), 7.86 (brs, IH, NH), 7.99 (d, IH, J 8.2 Hz); ¹³C-NMR (62.5MHz, CDCI₃) δ 14.23 (CH₃), 42.10 (CH₂), 43.65 (CH₂), 51.81 (CH₂), 55.93 (CH₃), 108.72 (CH), 111.69 (CH), 112.48 (CH), 117.00 (C_q), 120.73 (CH), 121.83 (CH), 123.38 (CH), 126.54 (C_q), 127.45 (CH), 127.60 (CH), 139.70 (Cq), 139.83 (C_q), 141.09 (C_q), 148.59 (C_q), 149.42 (C_q), 169.55 (C_q); HPLC 98% 2.82 min. MS (AP) m/z 537 (M⁺+H).

Example 8

W-[l-(4-Dipropylsulfamoyl-benzyl)-lH-indazol-3-yl]-2-phenoxy- acetamide

Λ/-[l-(4-Dipropylsulfamoyl-benzyl)-lH-indazol-3-yl]-2-phenoxy-acetamide (102.4mg, 98%) was isolated as an off-white solid.

^XH-NMR (250MHz, CDCI₃) δ 0.84 (t, 6H, J 7.4 Hz), 1.53 (sext, 4H, J 7.6 Hz), 3.01 (t, 4H, J 7.7 Hz), 4.73 (s, 2H), 5.55 (s, 2H), 6.99-7.09 (m, 3H), 7.15-7.43 (m, 7H), 7.72 (dd, 2H, J 1.7 Hz, 6.6 Hz), 8.07 (d, IH, J 8.3 Hz), 8.93 (brs, IH, NH); ¹³C-NMR (62.5MHz, CDCI₃) δ 11.15 (CH₃), 22.09 (CH₂), 50.12 (CH₂), 51.98 (CH₂), 67.37 (CH₂), 108.84 (CH), 114.74 (CH), 117.00 (C_q), 120.92 (CH), 122.43 (CH), 123.26 (CH), 127.52 (CH), 127.58 (CH),

127.70 (CH), 129.91 (CH), 138.84 (C_q), 139.67 (C_q), 141.03 (C_q), 141.20 (C_q), 156.95 (C_q), 166.42 (C_q); HPLC 100%, Rt = 3.39 min. MS (AP) m/z 521 (M⁺+H).

Example 9 yv-[l-(4-Dipropylsulfamoyl-benzyl)-lH-indazol-3-yl]-2-phenoxy- propionamide

Λ/-[l-(4-Dipropylsulfamoyl-benzyl)-lH-indazol-3-yl]-2-phenoxy- propionamide (96.6mg, 90%) was isolated as an off-white solid. *H-NMR (250MHz, CDCI₃) δ 0.84 (t, 6H, J 7.4 Hz), 1.52 (sext, 4H, J 7.5 Hz), 1.73 (d, 3H, J 6.8 Hz), 3.01 (t, 4H, J 7.7 Hz), 4.93 (q, IH, J 6.8 Hz), 5.53 (s, 2H), 7.00-7.07 (m, 3H), 7.13-7.41 (m, 7H), 7.71 (dd, 2H, J 1.7 Hz), 8.02 (d, IH, J 8.3 Hz), 8.82 (brs, IH, NH); ¹³C-NMR (62.5MHz, CDCI₃) δ 11.15 (CH₃), 18.67 (CH₃), 22.09 (CH₂), 50.11 (CH₂), 51.95 (CH₂), 75.10 (CH), 108.80 (CH), 115.68 (CH), 116.93 (C_q), 120.79 (CH), 122.42 (CH), 123.23 (CH), 127.49 (CH), 127.56 (CH), 127.64 (CH), 129.91 (CH), 139.02 (C_q), 139.62 (C_q), 141.05 (C_q), 141.16 (C_q), 156.63 (C_q), 170.45 (C_q); HPLC 99%, Rt = 3.46 min. MS (AP) m/z 535 (M⁺+H).

Example 10

2,3-Dihydro-benzo[l,4]dioxine-2-carboxylic acid [l-(4- dipropylsulfamoyl-benzyl)lH-indazol-3-yl]-amide

2,3-Dihydro-benzo[l,4]dioxine-2-carboxylic acid [l-(4-dipropylsulfamoyl- benzyl)lH-indazol-3-yl]-amide (94mg, 86%) was isolated as a colourless solid. H-NMR (250MHz, CDCI₃) δ 0.84 (t, 6H, J 7.4 Hz), 1.53 (sext, 4H, J 7.6 Hz), 3.02 (t, 4H, J 7.7 Hz), 4.34 (dd, IH, J 7.6 Hz, 11.4 Hz), 4.68 (dd, IH, J 2.8 Hz, 11.4 Hz), 4.93 (dd, IH, J 2.8 Hz, 7.5 Hz), 5.56 (s, 2H), 6.87-6.98 (m, 3H), 7.03 (m, IH), 7.19 (dt, IH, J 0.9 Hz, 8.2 Hz), 7.28 (d, 3H, J 7.0 Hz), 7.40 (dt, IH, J 1.0 Hz, 8.4 Hz), 7.73 (dd, 2H, J 1.8 Hz, 6.6 Hz), 8.05 (d, IH, J 8.3 Hz), 8.90 (brs, IH, NH); ¹³C-NMR (62.5MHz, CDCI₃) δ 11.15 (CH₃), 22.09 (CH₂), 50.11 (CH₂), 52.01 (CH₂), 65.27 (CH₂), 73.34 (CH), 108.84 (CH), 116.77 (Cq), 117.25 (CH), 117.77 (CH), 120.97 (CH), 122.17 (CH), 122.71 (CH), 123.27 (CH), 127.49 (CH), 127.61 (CH), 127.77 (CH), 138.63 (Cq), 139.74 (Cq), 140.93 (Cq), 141.21 (Cq), 141.42 (Cq), 143.21 (Cq), 165.31 (Cq); HPLC 99%, Rt = 3.47 min. MS (AP) m/z 549 (M⁺+H).

Example 11

2-(4-Chloro-phenoxy)-/V-[l-(4-dipropylsulfamoyl-benzyl)-lH- indazol-3-yl]-acetamide

2-(4-Chloro-phenoxy)-/V-[l-(4-dipropylsulfamoyl-benzyl)-lH-indazol-3-yl]- acetamide (70.6mg, 64%) was isolated as an off-white solid. *H-NMR (250MHz, CDCI₃) δ 0.84 (t, 6H, J 7.4 Hz), 1.53 (sext, 4H, J 7.6 Hz), 3.02 (t, 4H, J 7.7 Hz), 4.70 (s, 2H), 5.56 (s, 2H), 6.94 (dt, 2H, J 2.8 Hz, 9.1 Hz), 7.16-7.44 (m, 7H), 7.72 (dt, 2H, J 1.9 Hz, 8.5 Hz), 8.06 (d, IH, J 8.3 Hz), 8.87 (brs. IH, NH); ¹³C-NMR (62.5MHz, CDCI₃) δ 11.15 (CH₃), 22.09 (CH₂), 50.11 (CH₂), 51.99 (CH₂), 67.64 (CH₂), 108.86 (CH), 116.05 (CH), 116.94 (C_q), 120.97 (CH), 123.24 (CH), 127.51 (CH), 127.59 (CH), 127.75 (CH), 129.82 (CH), 138.74 (C_q), 139.72 (C_q), 140.97 (C_q), 141.22 (C_q), 155.51 (C_q), 165.91 (C_q); HPLC 100%, Rt = 3.55 min. MS (AP) m/z 555 (M⁺+H).

Example 12

2-(3_/4-Dimethoxy-phenyl)-/V-[l-(4-dipropylsuIfamoyl-benzyl)-lH- indazol-3-yl]-acetamide

2-(3,4-Dimethoxy-phenyl)-/V-[l-(4-dipropylsulfamoyl-benzyl)-lH-indazol- 3-yl]-acetamide (77.2mg, 70%) was isolated as a colourless solid. ^XH-NMR (250MHz, CDCI₃) δ 0.84 (t, 6H, J 7.4 Hz), 1.52 (sext, 4H, J 7.6 Hz), 3.01 (t, 4H, J 7.7 Hz), 3.79 (s, 2H), 3.89 (s, 3H), 3.91 (s, 3H), 5.49 (s, 2H), 6.84-6.96 (m, 3H), 7.12-7.24 (m, 4H), 7.36 (t, IH, J 7.2 Hz), 7.70 (d, 3H, J 8.3 Hz, NH), 7.99 (d, IH, J 8.3 Hz); HPLC 100%, Rt = 3.05 min. MS (AP) m/z 556 (M⁺+H).

Example 13

/V-[l-(4-Dipropylsulfamoyl-benzyl)-lH-indazol-3-yl]-2-(4- methoxy-phenyl)-acetamϊde

/V-[l-(4-Dipropylsulfamoyl-benzyl)-lH-indazol-3-yl]-2-(4-methoxy- phenyl)-acetamide (100.7mg, 94%) was isolated as a pale yellow solid. ^XH-NMR (250MHz, CDCI₃) δ 0.84 (t, 6H, J 7.4 Hz), 1.52 (sext, 4H, J 7.6 Hz), 3.00 (t, 4H, J 7.7 Hz), 3.78 (s, 2H), 3.81 (s, 3H), 5.48 (s, 2H), 6.93 (d, 2H, J 8.6 Hz), 7.11-7.39 (m, 7H), 7.68 (d, 2H, J 8.3 Hz), 7.77 (brs, IH, NH), 7.99 (d, IH, J 8.3 Hz); ¹³C-NMR (62.5MHz, CDCI₃) δ 11.14 (CH₃), 22.08 (CH₂), 43.18 (CH₂), 50.09 (CH₂), 51.85 (CH₂), 55.31 (CH₃), 108.70 (CH), 114.70 (CH), 117.03 (Cq), 120.71 (CH), 123.45 (CH), 126.05 (Cq), 127.45 (CH), 127.52 (CH), 130.75 (CH), 139.59 (Cq), 139.71 (Cq), 141.07 (Cq), 159.14 (Cq), 169.64 (Cq); HPLC 99%, Rt = 3.28 min. MS (AP) m/z 535 (M⁺+H).

Example 14

/V-[l-(4-Dϊpropylsulfamoyl-benzyl)-lH-indazol-3-yl]-2-(3- methoxy-phenyl)-acetamideV-[l-(4-Dipropylsulfamoyl-benzyl)-lH-indazol-3-yl]-2-(3-methoxy- phenyl)-acetamide (93.3mg, 87%) was isolated as a pale yellow solid. ^XH-NMR (250MHz, CDCI₃) δ 0.83 (t, 6H, J 1A Hz), 1.51 (sext, 4H, J 7.6 Hz), 2.99 (t, 4H, J 7.7 Hz), 3.80 (s, 2H), 3.81 (s, 3H), 5.47 (s, 2H), 6.84- 6.98 (m, 3H), 7.10-7.38 (m, 6H), 7.67 (d, 2H, J 8.3 Hz), 7.89 (brs, IH, NH), 7.97 (d, IH, J 8.3 Hz); ¹³C-NMR (62.5MHz, CDCI₃) δ 11.14 (CH₃), 22.08 (CH₂), 44.09 (CH₂), 50.10 (CH₂), 51.83 (CH₂), 55.25 (CH₃), 108.72 (CH), 113.17 (CH), 115.24 (CH), 117.06 (C_q), 120.72 (CH), 121.80 (CH), 123.38 (CH), 127.45 (CH), 127.51 (CH), 127.57 (CH), 130.33 (CH), 135.60 (C_q), 139.55 (C_q), 139.66 (C_q), 141.07 (C_q), 160.16 (C_q), 169.11 (C_q); HPLC 99%, Rt = 3.30 min. MS (AP) m/z 535 (M⁺+H).

Example 15

2,3-Dihydro-benzofuran-2-carboxyIic acid [ l-(4-dipropylsulfamoyl- benzyl)-lH-indazol-3-yl]-amide

2,3-Dihydro-benzofuran-2-carboxylic acid [l-(4-dipropylsulfamoyl-benzyl)- lH-indazol-3-yl]-amide (75mg, 70%) was isolated as a pale yellow solid. *H-NMR (250MHz, CDCI₃) δ 0.84 (t, 6H, J 7.4 Hz), 1.52 (sext, 4H, J 7.5 Hz), 3.01 (t, 4H, J 7.7 Hz), 3.55-3.79 (m, 2H), 5.38 (dd, IH, J 6.9 Hz, 10.7 Hz), 5.53 (s, 2H), 6.95 (dt, 2H, J 1.0 Hz, 8.4 Hz), 7.13-7.27 (m, 6H), 7.38 (dt, IH, J 1.1 Hz, 8.5 Hz), 7.71 (dt, 2H, J 1.9 Hz, 8.5 Hz), 8.06 (dt, IH, J 0.9 Hz, 8.3 Hz), 8.96 (brs, IH, NH); ¹³C-NMR (62.5MHz, CDCI₃) δ 11.14 (CH₃), 22.09 (CH₂), 34.10 (CH₂), 50.12 (CH₂), 51.95 (CH₂), 80.39 (CH), 108.79 (CH), 109.92 (CH), 116.79 (C_q), 120.82 (CH), 122.04 (CH), 123.33 (CH), 125.05 (C_q), 125.21 (CH), 127.48 (CH), 127.57 (CH), 127.67 (CH), 128.41 (CH), 138.89 (C_q), 139.65 (C_q), 141.01 (C_q), 141.18 (C_q), 158.07 (C_q), 169.96 (C_q); HPLC 100% 3.44 min. MS (AP) m/z 533 (M⁺+H).

Example 16

2,3-Dihydro-benzo[l,4]dioxine-2-carboxylic acid [l-(4- ethylsulfamoyl-benzyl)-lH-indazol-3-yl]-amide

2,3-Dihydro-benzo[l,4]dioxine-2-carboxylic acid [l-(4-ethylsulfamoyl- benzyl)-lH-indazol-3-yl]-amide (39.1mg, 40%) was isolated as a colourless solid.

^XH-NMR (250MHz, CDCI₃) δ 1.07 (t, 3H, J 7.2 Hz), 2.96 (quin, 2H, J 7.2 Hz), 4.33 (dd, IH, J 7.5 Hz, 11.4 Hz), 4.44 (t, IH, J 6.0 Hz, NH), 4.68 (dd, IH, J 2.8 Hz, 11.44 Hz), 4.92 (dd, IH, J 2.8 Hz, 7.5 Hz), 5.56 (s, 2H), 6.84-6.97 (m, 3H), 7.02 (m, IH), 7.18 (dt, IH, J 0.9 Hz, 8.25 Hz), 7.28 (d, 3H, J 7.6 Hz), 7.40 (dt, IH, J 1.1 Hz, 8.5 Hz), 7.78 (dt, 2H, J 1.6 Hz, 8.4 Hz), 8.05 (d, IH, J 8.3 Hz), 8.92 (brs, IH, NH); ¹³C-NMR (62.5MHz, CDCI₃) δ 15.09 (CH₃), 38.23 (CH₂), 51.95 (CH₂), 65.26 (CH₂), 73.34 (CH), 108.80 (CH), 116.79 (C_q), 117.26 (CH), 117.77 (CH)120.99 (CH), 122.17 (CH), 122.70 (CH), 123.29 (CH), 127.62 (CH), 127.82 (CH), 138.70 (C_q), 139.59 (C_q), 141.22 (C_q), 141.41 (C_q), 143.21 (C_q), 165.36 (C_q); HPLC 98%, Rt = 2.85 min. MS (AP) m/z 493 (M⁺+H).

Example 17

2,3-Dihydro-benzo[l,4]dioxine-2-carboxylic acid [1~(4- dimethylsulfamoyl-benzyl)-lH-indazol-3-yl]-amide

2,3-Dihydro-benzo[l,4]dioxine-2-carboxylic acid [l-(4-dimethylsulfamoyl- benzyl)-lH-indazol-3-yl]-amide was isolated as a colourless solid. ^XH-NMR (250MHz, CDCI₃) δ 2.67 (s, 6H, CH₃), 4.34 (dd, IH, J 7.5 Hz, 11.4 Hz), 4.68 (dd, IH, J 2.8 Hz, 11.4 Hz), 4.93 (dd, IH, J 2.8 Hz, 7.5 Hz), 5.57 (s, 2H), 6.89-6.98 (m, 3H), 7.02 (m, IH), 7.19 (dt, IH J 0.9 Hz, 8.2 Hz), 7.28-7.33 (m, 3H), 7.42 (dt, IH, J 1.0 Hz, 8.5 Hz), 7.70 (dd, 2H, J 1.8 Hz, 6.6 Hz), 8.05 (d, IH, J 8.3 Hz), 8.92 (brs, IH, NH); ¹³C-NMR (62.5MHz, CDCI₃) δ 37.84 (CH₃), 51.90 (CH₂), 65.25 (CH₂), 73.35 (CH), 108.79 (CH), 116.77 (Cq), 117.25 (CH), 117.78 (CH), 121.01 (CH), 122.17 (CH), 122.71 (CH), 123.28 (CH), 127.56 (CH), 127.85 (CH), 128.28 (CH), 135.23 (Cq), 138.25 (Cq), 141.25 (Cq), 141.42 (Cq), 141.51 (Cq), 143.21 (Cq), 165.37 (Cq); HPLC 99%, Rt = 2.94 min. MS (AP) m/z 493 (M⁺+H).

Example 18

2-(3,4-Dimethoxy-phenyl)-W-[l-(4-dimethylsulfamoyl-benzyl)-lH- indazol-3-yl]-acetamide

2-(3,4-Dimethoxy-phenyl)-Λ/-[l-(4-dimethylsulfamoyl-benzyl)-lH-indazol- 3-yl]-acetamide (86.3mg, 85%) was isolated as a colourless solid. ^XH-NMR (250MHz, CDCI₃) δ 2.65 (s, 6H, CH₃), 3.78 (s, 2H), 3.88 (s, 3H), 3.89 (s, 3H), 5.49 (s, 2H), 6.86-6.94 (m, 3H), 7.15 (t, IH, J 7.9 Hz), 7.25 (d, 3H, J 7.5 Hz), 7.37 (t, IH, J 8.0 Hz), 7.65 (d, 2H, J 8.3 Hz), 7.84 (brs, IH, NH), 7.99 (d, IH, J 8.3 Hz); ¹³C-NMR (62.5MHz, CDCI₃) δ 37.83 (CH₃), 43.67 (CH₂), 51.75 (CH₂), 55.93 (CH₃), 108.68 (CH), 111.69 (CH), 112.49 (CH), 117.01 (Cq), 120.77 (CH), 121.84 (CH), 123.40 (CH), 126.52 (Cq), 127.51 (CH), 127.66 (CH), 128.19 (CH), 135.09 (Cq), 139.77 (Cq), 141.16 (Cq), 141.62 (Cq), 148.61 (Cq), 149.44 (Cq), 169.54 (Cq); HPLC 99%, Rt = 2.47 min. MS (AP) m/z 509 (M⁺+H).

Example 19

/V-[l-4-Diethylsulfamoyl-benzyl)-lH-indazol-3-yl]-2-phenoxy- propionamide Λ/-[l-4-Diethylsulfamoyl-benzyl)-lH-indazol-3-yl]-2-phenoxy- propionamide (95.8mg, 94%) was isolated as a colourless solid. HPLC 99%, Rt = 3.17 min. MS (AP) m/z 507 (M⁺+H).

Example 20

2,3-Dihydro-benzofuran-2-carboxylic acid [ l-(4-diethylsulfamoyl- benzyl)-lH-indazol-3-yl]-amide

2,3-Dihydro-benzofuran-2-carboxylic acid [l-(4-diethylsulfamoyl-benzyl)- lH-indazol-3-yl]-amide (74.2mg, 74%) was isolated as a colourless solid. HPLC 100% 3.15 min. MS (AP) m/z 505 (M⁺+H).

PREPARATION OF A PHARMACEUTICAL COMPOSITION

Preparation of tablets Ingredients mg/tablet

1. Active compound of formula (I) 10.0

2. Cellulose, microcrystalline 57.0

3. Calcium hydrogen phosphate 15.0

4. Sodium starch glycolate 5.0

5. Silicon dioxide, colloidal 0.25

6. Magnesium stearate 0.75

The active ingredient 1 is mixed with ingredients 2, 3, 4 and 5 for about 10 minutes. The magnesium stearate is then added, and the resultant mixture is mixed for about 5 minutes and compressed into tablet form with or without film-coating.

BIOLOGICAL METHODS

Experimental methods

Primary screening and IC₅₀ determination

HEK293EBNA cells stably expressing the BRS-3 seeded in 96 well plates are pre-loaded with Fluo-4AM fluorescent dye at a concentration of 4 μM for one hour. Subsequently, test compounds at a final concentration of 5 μM for primary screen are added automatically. Fluorescent intensity is recorded using a Fluorometric imaging plate reader (FLIPR-98, 96-well format, Molecular Devices) and inhibition of the peak response evoked by dY-bombesin (EC₇₀ concentration) is calculated. IC₅₀ determinations are performed utilizing the same functional assay as described for primary screening, applying the compounds in the concentration range of 0.34 nM to 20 μM.

Biological summary

The calculation of the K| values for the inhibitors was performed by use of Activity Base. The Ki value is calculated from IC50 using the Cheng Prushoff equation (with reversible inhibition that follows the Michaelis- Menten equation): K, = IC50 (1+[S]/K_m) [Cheng, Y.C.; Prushoff, W.H. Biochem. Pharmacol. 1973, 22, 3099-3108]. The compounds of Formula (I) exhibit IC50 values for the BRS-3 in the range from 35 nM to 1.5 μM.

BRS-3 antagonist lead compounds were identified in FLIPR-based functional screening of the BRS-3. Two of these compounds were tested in equilibrium displacement binding measurements at the BRS-3. The results show that Example 19 and Example 20 are high affinity ligands for the BRS-3 receptor subtype, with functional Ki values of 73 and 38, respectively.

Table 1

Table 1 shows the affinities of Examples 19 and 20 for the BRS-3 compared to the inhibition constants from functional studies.

Compounds with a similar core structure to compounds of the present invention, but falling outside the scope of the present invention were subjected to primary screening as discussed above. The inhibition of the peak response evoked by dY-bombesin for these compounds, added at a concentration of 5 μM, is shown in Table 2.

Table 2

0.01%

0.07%

It is apparent from the data shown in Table 2 that the test compounds which fall outside the scope of the present invention show very low levels of inhibition. In view of this, experiments to determine K| would be expected to show that these test compounds have a very low affinity for the BRS-3 receptor subtype.

It will be appreciated by those skilled in the art that the foregoing description is exemplary and explanatory in nature, and is intended to illustrate the invention and its preferred embodiments. Through routine experimentation, an artisan will recognise apparent modifications and variations that may be made without departing from the spirit of the invention. Thus, the invention is intended to be defined not by the above description, but by the following claims and their equivalents.

Claims

1. A compound of formula (I)

(I) wherein:

R is aryl-Cι-₆-alkyl, heteroaryl-Cι_₆-alkyl, aryloxy-C_1-6-alkyl or heteroaryloxy-Cι-₆-alkyl; and R is optionally independently substituted with one or more of Cι_-6-alkoxy, C_1-6-alkyl, methylenedioxy, aryl, halogen and halo Cι_-6-alkyl;

R ' is Cι-₆-dialkyl amine, Cι_-6-alkyl amine, C_4-7-cyclic alkyl amine or C_3-8-cycloalkyl amine; and R' is optionally independently substituted with one or more of Cι_-6-alkoxy; and

Y is hydrogen, Cι_-6-alkyl, Cι-₆-alkoxy or halogen; or a pharmaceutically acceptable salt, hydrate, solvate, geometrical isomer, tautomer, optical isomer, or prodrug form thereof.

2. A compound according to claim 1, wherein R is aryl-Cι_-6-alkyl optionally independently substituted with one or more of Cι-₆-a[koxy; or aryloxy-C_1-6-alkyl optionally independently substituted with one or more of halogen.

3. A compound according to claim 1 or 2, wherein R is phenoxymethylene or benzo[l,3]dioxol-5-yl-methylene.

4. A compound according to any preceding claim wherein R ' is Cι_-6- dialkyl amine, Cι_-6-alkyl amine or C_4-7-cyclic alkyl amine.

5. A compound according to any preceding claim, wherein R' is N,N- diethylamine.

6. A compound according to any preceding claim, which is selected from the group consisting of: Λ/-[l-(4-Diethylsulfamoyl-benzyl)-lH-indazol-3-yl]-2-phenoxy- acetamide; 2-Benzo[l,3]dioxo-5-yl-/V-[l-(4-diethylsulfamoyl-benzyl)-lH- indazol-3-yl]-acetamide; 2,3-Dihydro-benzo[l,4]dioxine-2-carboxylic acid [l-(4- diethylsulfamoyl-benzyl)-lH-indazol-3-yl]-amide; Λ/-[l-(4-Diethylsulfamoyl-benzyl)-lH-indazol-3-yl]-2-(3-methoxy- phenyl)-acetamide; 2-Phenoxy-Λ/-{l-[4-(pyrrolidine-l-sulfonyl)-benzyl]-lH-indazol-3- yl}propionamide; 2-(4-Chloro-phenoxy- V-[l-(4-diethylsulfamoyl-benzyl)-lH-indazol- 3-yl]-acetamide; Λ/-[l-(4-Diethylsulfamoyl-benzyl)-lH-indazol-3-yl]-2-(3,4- dimethoxy-phenyl)-acetamide;

Λ/-[l-(4-Dipropylsulfamoyl-benzyl)-lH-indazol-3-yl]-2-phenoxy- acetamide;

Λ/-[l-(4-Dipropylsulfamoyl-benzyl)-lH-indazol-3-yl]-2-phenoxy- propionamide;

2,3-Dihydro-benzo[l,4]dioxine-2-carboxylic acid [l-(4- dipropylsulfamoyl-benzyl)lH-indazol-3-yl]-amide;

2-(4-Chloro-phenoxy)-Λ/-[l-(4-dipropylsulfamoyl-benzyl)-lH- indazol-3-yl]-acetamide;

2-(3,4-Dimethoxy-phenyl)-/V-[l-(4-dipropylsulfamoyl-benzyl)-lH- indazol-3-yl]-acetamide;

Λ/-[l-(4-Dipropylsulfamoyl-benzyl)-lH-indazol-3-yl]-2-(4-methoxy- phenyl)-acetamide;

Λ/-[l-(4-Dipropylsulfamoyl-benzyl)-lH-indazol-3-yl]-2-(3-methoxy- phenyl)-acetamide;

2,3-Dihydro-benzofuran-2-carboxylic acid [l-(4-dipropylsulfamoyl- benzyl)-lH-indazol-3-yl]-amide;

2,3-Dihydro-benzo[l,4]dioxine-2-carboxylic acid [l-(4- ethylsulfamoyl-benzyl)-lH-indazol-3-yl]-amide;

2,3-Dihydro-benzo[l,4]dioxine-2-carboxylic acid [l-(4- dimethylsulfamoyl-benzyl)-lH-indazol-3-yl]-amide;

2-(3,4-Dimethoxy-phenyl)-Λ/-[l-(4-dimethylsulfamoyl-benzyl)-lH- indazol-3-yl]-acetamide;V-[l-4-Diethylsulfamoyl-benzyl)-lH-indazol-3-yl]-2-phenoxy- propionamide; and

2,3-Dihydro-benzofuran-2-carboxylic acid [l-(4-diethylsulfamoyl- benzyl)-lH-indazol-3-yl]-amide.

7. A pharmaceutical composition comprising a compound according to any preceding claim and a pharmaceutically acceptable diluent or carrier.

8. A process for the preparation of a compound according to any one of claims 1 to 6, which process comprises at least one of the steps of: a) reaction of a compound of formula (II) with hydroxylamine, to give an amidine of formula (III);

(H) (III) b) reaction of the amidine of formula (III) with diethyl carbonate in sodium methoxide to give an oxadiazolone of formula (IV);

(IV) c) thermal de-carboxylation of the oxadiazolone of formula (IV) to give an indazole of formula (V);

(V) d) synthesis of an alkylating agent of formula (VI) from reaction of 4-(bromomethyl)benzene sulfonyl chloride with an amine R'NH or R'NH_2;

(VI)

e) alkylation of the indazole of formula (V) with the alkylating agent of formula (VI) to give a sulfonamide of formula (VII);

(VII)

f) acylation of the sulfonamide of formula (VII), with an acyl choride RCOCI, to give a compound of formula (I)

(I) wherein;

Y is hydrogen, Cι_-6 alkyl, Cι_-6-alkoxy or halogen;

R' is Cι-₆-dialkyl amine, Cι-₆-alkyl amine, C_4-7-cyclic alkyl amine, C_3-8- cydoalkyl amine, all optionally independently substituted with one or more Cι_-6-alkoxy; and

R is aryl-C_1-6-alkyl, heteroaryl-Cι_-5-alkyl, aryloxy-Cι_-6-alkyl, or heteroaryloxy-Cι-₆-alkyl; all optionally independently substituted with one or more of Cι-₆-alkoxy, Cι_-6-alkyl, methylenedioxy, aryl, halogen and halo Cι_-6-alkyl.

9. A method according to claim 8 which comprises all of steps a) to f).

10. A method for the prophylaxis, or treatment of a BRS-3 receptor- related disorder, which comprises administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 7.

11. A method according to claim 9 or 10, wherein the BRS-3 receptor- related disorder is obesity, diabetes, hypertension, cancer or a neurological disorder.

12. A method according to claim 11 wherein the cancer is small cell lung cancer, ovarian cancer or prostate cancer.

13. A method according to claim 11 wherein the neurological disorder is stroke, ischaemia, head injury, Alzheimer's disease, a learning disorder, an anxiety disorder, a panic disorder, a memory disorder or an attention disorder.

14. A method for modulating BRS-3 receptor activity, which comprises administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 1 to 6.-

15. A method for modulating BRS-3 receptor activity, which comprises administering to a subject in need of such treatment an effective amount of a pharmaceutical formulation according to claim 7.

16. A compound according to any one of claims 1 to 6 for use in therapy.

17. A compound according to any one of claims 1 to 6 for use in the prophylaxis or treatment of a BRS-3 receptor-related disorder.

18. Use of a compound according to any one of claims 1 to 6 for the manufacture of a medicament for use in the prophylaxis or treatment of a BRS-3 receptor-related disorder.

19. A use according to claim 18, wherein the BRS-3 receptor-related disorder is obesity, diabetes, hypertension, cancer or a neurological disorder.

20. A use according to claim 19 wherein the cancer is small cell lung cancer, ovarian cancer or prostate cancer.

21. A use according to claim 20 wherein the neurological disorder is stroke, ischaemia, head injury, Alzheimer's disease, a learning disorder, an anxiety disorder, a panic disorder, a memory disorder or an attention disorder.

22. A compound, a process for the preparation of a compound, a pharmaceutical formulation, a use or a method of treatment or prophylaxis substantially as described herein.