WO2008120000A1 - Therapeutic agents - Google Patents

Abstract

Certain 4, 5, 6, 7 -tetrahydropyrrolo[3,2-c]pyridin-4-one and 4, 5 -dihydropyrrolo[3,2-c]pyridin-4-one compounds of formula (I), processes for preparing such compounds, their use in the treatment of obesity, psychiatric and neurological disorders, methods for their therapeutic use and pharmaceutical compositions containing them are described.

Description

THERAPEUTIC AGENTS

Field of invention

The present invention relates to certain 4, 5, 6, 7 -tetrahydropyrrolo[3,2-c]pyridin- 4-one and 4, 5 -dihydropyrrolo[3,2-c]pyridin-4-one compounds of formula I, to processes for preparing such compounds, to their use in the treatment of obesity, psychiatric and neurological disorders, to methods for their therapeutic use and to pharmaceutical compositions containing them. Background of the invention

It is known that certain CBi modulators (known as antagonists or inverse agonists) are useful in the treatment of obesity, psychiatric and neurological disorders (WOO 1/70700 and EP 656354).

Co-pending application PCT/GB2006/003695 (WO2007/039740) discloses that compounds of formula A

" wherein R¹ represents a C3.₇alkyl group substituted by one or more fluoro or R¹ represents a

group substituted by one or more fluoro;

R² represents cyano, or a

group optionally substituted by hydroxy or by a group

NR^aR^b in which R^a and R^b independently represent H or a Ci^alkyl group; R³ represents piperidin-1-yl or cyclohexyl each of which is optionally substituted by one or more groups selected from hydroxy, fluoro or a group NR^cR^d in which R^c and R^d independently represent H or a

group; and is an optional additional bond between positions 6 and 7;

R represents chloro, fluoro, cyano or methyl; n is 1, 2 or 3 and each R⁴ is independently selected when n > 1; and pharmaceutically acceptable salts thereof, are CBi modulators

WO03/0271 14 discloses the use of 1 , 5, 6, 7 -tetrahydropyrrolo[3,2-c]ρyridine and 1, 5, 6, 7 - tetrahydropyrrolo[3,2-c]pyridin-4-one derivatives of formula B

B in which

R¹ is phenyl optionally substituted with inter alia one or more halogen;

R² is H, halogen, optionally substituted (d-C₉)alkyl, phenyl optionally substituted with one or more halogen, (Cj-C₆)alkyl, (C₂-Cg)alkenyl, (C₂-C8)alkynyl, (C|-C6)alkoxy, (Ci-

C₆)alkylthio, trifluoromethyl or trifluoromethoxy; or a 5- to 10 membered aromatic monocyclic or bicyclic heterocyclic radical which is optionally substituted;

R³ is H, (C|-C₆)alkyl or benzyl;

X is -(C=O) or CH₂; provided that when X is -(C=O) then R⁴ is H; (Ci-C₉)alkyl optionally substituted with one or more hydroxy, benzyloxy, (Ci-C₆)alkoxy, trifluoromethyl, cyano or fluoro; optionally substituted benzyl or phenyl; piperidin-4-yl, piperidin-3-yl or pyrrolidin-3-yl each of which is optionally substituted; or -NR⁵R⁶ in which R⁵ and R⁶ together with the nitrogen atom to which they are attached , form a 5- to 10-membered saturated or unsaturated heterocyclic radical which is optionally substituted; for the treatment of obesity.

The inventors of WO03/027114 have disclosed the structure activity relationships of this group of compounds in Bioorg and Med Chem Letters 17 (2007) 673-678 in terms of binding affinities at the human CB-I receptor. In this paper it is disclosed that when R² is phenyl in structure B above then 4-substiruents should be kept relatively small, for example 4-F, Cl, CH₃, CH₃O and CF₃, since bulky substituents, for example 4-CH₃S, result in substantial loss of potency.

In contrast we have found that certain bulkier groups in the 4-position have acceptable potency and also appear to have improved physicochemical properties and/or DMPK (Drug Metabolism and Pharmacokinetic) properties and/or pharmacodynamic properties.

Description of the invention

The present invention provides a compound of formula I

in which R represents a C₃.₇ alkyl group or a C₃.₇ alkylsulfonyl group, and additionally when R² represents a C

^alkyl group substituted by hydroxy or by a group then R¹ represents a C₃.₇ alkyl group substituted by one or more fluoro, or a C₃.₇ alkylsulfonyl group substituted by one or more fluoro; R² represents a C

^alkyl group optionally substituted by hydroxy or a group; is an optional additional bond between positions 6 and 7 but only when R² represents a C^alkyl group substituted by hydroxy or by a C^alkoxy group; and

R³ represents fluoro or chloro; or a pharmaceutically acceptable salt thereof.

A particular group of compounds of formula I is represented by formula IA

- A -

IA in which R¹ represents a C₃.₇ alkyl group or a C₃.7 alkylsulfonyl group, and additionally when R^" represents a Ci^alkyl group substituted by hydroxy or a Ci^alkoxy group then R represents a C₃.₇ alkyl group substituted by one or more fluoro, or a C₃.₇ alkylsulfonyl group substituted by one or more fluoro;

R² represents a C

^alkyl group optionally substituted by hydroxy or a group; and

R³ represents fluoro or chloro; or a pharmaceutically acceptable salt thereof.

A further particular group of compounds of formula I is represented by formula IB

IB in which in which R¹ represents a C3.7 alkyl group, a C3.7 alkyl group substituted by one or more fluoro, a C₃.7 alkylsulfonyl group or a C₃.7 alkylsulfonyl group substituted by one or more fluoro; R^2a represents a C|.₃alkyl group; is an optional additional bond between positions 6 and 7; and

R³ represents fluoro or chloro; or a pharmaceutically acceptable salt thereof.

A still further particular group of compounds of formula I is represented by formula IC

IC in which R¹ represents a C₃.7 alkylsulfonyl group; R² represents a Ci^alkyl group optionally substituted by hydroxy or a Ci^alkoxy group; is an optional additional bond between positions 6 and 7; and

R³ represents fluoro or chloro; or a pharmaceutically acceptable salt thereof.

Further values of R¹, R² and R³ in compounds of formula I, formula IA, IB and IC now follow. It will be understood that such values may be used where appropriate with any of the definitions, claims or embodiments defined hereinbefore or hereinafter.

In particular R¹ represents 3,3,3-trifluoropropyl-l-sulfonyl, propyl- 1-sulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl or 4-butyl. Particularly R¹ represents 3,3,3- trifluoropropyl- 1-sulfonyl. Particularly R¹ represents propyl- 1-sulfonyl. Particularly R¹ represents butyl. Particularly R² represents methyl or hydroxymethyl or methoxymethyl. In particular R² represents methyl. In particular R² represents hydroxymethyl. In particular R² represents methoxymethyl. In particular R³ represents chloro. In particular R³ represents fluoro. In particular — is an additional bond between positions 6 and 7. In particular — is absent. Specific compounds of the invention include one or more of the following: 4-[ 1 -(2,4-dichlorophenyl)-3-methyl-4-oxo-5-piperidin- 1 -yl-4,5,6,7-tetrahydro- IH- pyrrolo[3,2-c]pyridin-2-yl]phenyl propane- 1 -sulfonate; 2-(4-butoxyphenyl)- 1 -(2,4-dichlorophenyl)-3-methyl-5-piperidin- 1 -yl- 1 ,5,6,7-tetrahydro- 4H-pyrrolo[3,2-c]pyridin-4-one;

4-[ 1 -(2,4-dichlorophenyl)-3-(methoxymethyl)-4-oxo-5-piperidin- 1 -yl-4,5,6,7-tetrahydro- lH-pyrrolo[3,2-c]pyridin-2-yl]phenyl 3,3,3-trifluoropropane-l -sulfonate; 4-[ l-(2-chloro-4-fluorophenyl)-3-(hydroxymethyl)-4-oxo-5-piperidin-l-y 1-4,5, 6,7- tetrahydro-lH-pyrrolo[3,2-c]pyridin-2-yl]phenyl 3,3,3-trifluoropropane-l -sulfonate; or a pharmaceutically acceptable salt thereof.

The compound 4-[ 1 -(2,4-dichlorophenyl)-3-rnethyl-4-oxo-5-piperidin- 1 -yl-4,5,6,7- tetrahydro-lH-pyrrolo[3,2-c]pyridin-2-yl]phenyl propane- 1 -sulfonate or a pharmaceutically acceptable salt thereof. The compound 2-(4-butoxyphenyl)- 1 -(2,4-dichlorophenyl)-3-methyl-5-piperidin- 1 -yl- l,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one or a pharmaceutically acceptable salt thereof.

The compound 4-[ 1 -(2,4-dichlorophenyl)-3-(methoxymethyl)-4-oxo-5-piperidin- 1 -yl- 4,5,6,7-tetrahydro-lH-pyrrolo[3,2-c]pyridin-2-yl]phenyl 3,3,3-trifluoropropane-l -sulfonate or a pharmaceutically acceptable salt thereof. The compound 4-[l-(2-chloro-4-fluorophenyl)-3-(hydroxymethyl)-4-oxo-5-piperidin-l -yl- 4,5,6,7-tetrahydro-lH-pyrrolo[3,2-c]pyridin-2-yl]phenyl 3,3,3-trifluoropropane-l -sulfonate or a pharmaceutically acceptable salt thereof.

"Pharmaceutically acceptable salt", where such salts are possible, includes both pharmaceutically acceptable acid and base addition salts. A suitable pharmaceutically acceptable salt of a compound of formula I is, for example, an acid-addition salt of a compound of formula I which is sufficiently basic, for example an acid-addition salt with an inorganic or organic acid for example a hydrochloride salt, a hydrosulphate salt , a sulphate salt, a methanesulphonate salt, a phenylsulphonate salt or a 1 ,5-naphthalene- disulphonate salt, or for example a salt of a compound of formula I which is sufficiently acidic with a base.

Throughout the specification and the appended claims, a given chemical formula or name shall encompass all stereo and optical isomers and racemates thereof as well as mixtures in different proportions of the separate enantiomers, where such isomers and enantiomers exist, as well as pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates Isomers may be separated using conventional techniques, e g chromatography or fractional crystallisation The enantiomers may be isolated by separation of racemate for example by fractional crystallisation, resolution or HPLC The diastereomers may be isolated by separation of isomer mixtures for instance by fractional crystallisation, HPLC or flash chromatography Alternatively the stereoisomers may be made by chiral synthesis from chiral starting mateπals under conditions which will not cause racemisation or epimeπsation, or by deπvatisation, with a chiral reagent All stereoisomers are included within the scope of the invention All tautomers, where possible, are included within the scope of the invention The present invention also encompasses compounds containing one or more isotopes for example ¹⁴C, ^{1 1}C or ¹⁹F and their use as isotopically labelled compounds for pharmacological and metabolic studies The present invention also encompasses prodrugs of a compound of formula I that is compounds which are converted into a compound of formula I in vivo The following definitions shall apply throughout the specification and the appended claims

Unless otherwise stated or indicated, the term "alkyl" denotes either a straight or branched alkyl group Examples of said alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl or t-butyl Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl and tertiary butyl Methods of preparation

Compounds of formula I in which R¹ , R² and R³ are as previously defined may be prepared as shown in Synthetic Routes 1, 2 and 3 in which R represents a protecting group for hydroxy, Me = methyl and Et =ethyl Synthetic Route 1

Synthetic Route 2

Synthetic Route 3

Compounds of formula I in which R¹ and R³ are as initially defined and R² represents a group CH₂OH may be prepared by reacting a compound of formula II

in which R¹ and R³ are as initially defined with a reducing agent in the presence of an inert organic solvent at a temperature in the range of 0 to 100⁰C. Suitable reducing agents include borohydrides for example sodium borohydride, or sodium triacetoxyborohydride. Suitable solvents include dichloroethane, THF or methanol.

Compounds of formula II are believed to be novel and form another part of the present invention.

Particular compounds of formula II are

in which R³ is chloro or fluoro. In another aspect the present invention provides a process for the preparation of a compound of formula III

in which R" and R are as previously defined comprising reacting a compound of formula IV

IV in which R² and R³ are as previously defined and R represents a protecting group for a phenolic hydroxy with a cyclisation agent and a deprotecting agent for example an acid, e.g. trifluoroacteic acid or sulphuric acid, or a base, optionally in the presence of an inert solvent, for example toluene at a temperature in the range of 0 to 100⁰C .

Suitable protecting groups for a phenolic hydroxy are those described in "Protective Groups in Organic Synthesis" by T. W. Greene and P. G. M. Wuts, 3rd Edition John Wiley and Sons , Inc Chapter 3 pages 246 to 292. Particular protecting groups include Ci_-4 alkoxyC]_₄alkyl groups, for example ethoxyethyl, arlyalkyl groups, for example benzyl, esters, for example pivaloyl, or

groups for example trimethylsilyl or t- butyldimethylsilyl.

Arylalkyl groups may be removed by hydrogenation in the presence of a catalyst by methods known to those skilled in the art.

groups may be removed fluoride ion, a dilute acid or a dilute base. For a full list of methods see the reference in the paragraph above.

The conversion of IV into III may be carried out as a one-step or a two-step process. For example if the protecting group is removable by acid, for example ethoxyethyl, then the cyclisation and protecting group removal may be accomplished in the same step.

If the protecting group is one that is removable by base, for example pivaloyl, then the cyclisation may be accomplished in the presence of an acid and then the deprotection accomplished in the presence of a base for example sodium or potassium hydroxide. In this case the reaction may still be carried out as a one-pot process. Suitable acids include trifluoroacetic acid, methanesulphonic acid, 4- toluenesulphonic acid, hydrochloric acid or sulphuric acid. Suitable solvents include hydrocarbons, for example toluene, or ethers for example, tetrahydrofuran or methyl tert- butyl ether. In another aspect the present invention provides a compound of formula IV

IV in which R² and R³ are as previously defined and R represents a protecting group for hydroxy, for example ethoxyethyl or pivaloyl.

Particular compounds of formula IV are IVa and IVb.

Compounds of formula IV may be prepared by reacting a compound of formula V

V in which R³ is chloro or fluoro with a compound of formula VI

Vl in which R represents a protecting group for a phenolic hydroxy, X is a leaving group, for example halo e.g. chloro or bromo and R² is a previously defined, particularly methyl, in an inert solvent, for example NN-dimethylformamide or tetrahydrofuran, in the presence of a base, for example sodium hydride, lithium bis(trimethylsilyl)amide, potassium carbonate or cesium carbonate, at a temperature in the range of -8O⁰C to 100⁰C, particularly -20⁰C to 5O⁰C optionally in the presence of a catalyst, for example an iodide salt e.g. tetrabutylammonium iodide.

In another aspect the present invention provides a compound of formula V

V in which R³ is chloro or fluoro.

Compounds of formulae II, III, IV and V may be prepared as shown in Synthetic routes 1 ,2 or 3 or as described in the examples or by analogous methods. Pharmaceutical preparations

The compounds of the invention will normally be administered via the oral, parenteral, intravenous, intramuscular, subcutaneous or in other injectable ways, buccal, rectal, vaginal, transdermal and/or nasal route and/or via inhalation, in the form of pharmaceutical preparations comprising the active ingredient or a pharmaceutically acceptable addition salt, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated and the route of administration, the compositions may be administered at varying doses.

Suitable daily doses of the compounds of the invention in the therapeutic treatment of humans are about 0.001 -10 mg/kg body weight, preferably 0.01-1 mg/kg body weight. Oral formulations are preferred particularly tablets or capsules which may be formulated by methods known to those skilled in the art to provide doses of the active compound in the range of 0.5mg to 500mg for example 1 mg, 3 mg, 5 mg, 10 mg, 25mg, 50mg, lOOmg and 250mg.

According to a further aspect of the invention there is also provided a pharmaceutical formulation including any of the compounds of the invention, or pharmaceutically acceptable derivatives thereof, in admixture with pharmaceutically acceptable adjuvants, diluents and/or carriers. Pharmacological properties

The compounds of formula (I) are useful for the treatment of obesity or being overweight, (e.g., promotion of weight loss and maintenance of weight loss), prevention of weight gain (e.g., medication-induced or subsequent to cessation of smoking), for modulation of appetite and/or satiety, eating disorders (e.g. binge eating, anorexia, bulimia and compulsive), cravings (for drugs, tobacco, alcohol, any appetizing macronutrients or non-essential food items), for the treatment of psychiatric disorders such as psychotic and/or mood disorders, schizophrenia and schizo-affective disorder, bipolar disorders, anxiety, anxio-depressive disorders, depression, mania, obsessive-compulsive disorders, impulse control disorders (e.g., Gilles de Ia Tourette's syndrome), attention disorders like ADD/ADHD, stress, and neurological disorders such as dementia and cognitive and/or memory dysfunction (e.g., amnesia, Alzheimer's disease, Pick's dementia, dementia of ageing, vascular dementia, mild cognitive impairment, age-related cognitive decline, and mild dementia of ageing), neurological and/or neurodegenerative disorders (e.g. Multiple Sclerosis, Raynaud's syndrome, Parkinson's disease, Huntington's chorea and Alzheimer's disease), demyelinisation-related disorders, neuroinflammatory disorders (e.g., Guillain- Barre syndrome). The compounds are also potentially useful for the prevention or treatment of dependence and addictive disorders and behaviours (e.g., alcohol and/or drug abuse, pathological gambling, kleptomania), drug withdrawal disorders (e.g., alcohol withdrawal with or without perceptual disturbances; alcohol withdrawal delirium; amphetamine withdrawal; cocaine withdrawal; nicotine withdrawal; opioid withdrawal; sedative, hypnotic or anxiolytic withdrawal with or without perceptual disturbances; sedative, hypnotic or anxiolytic withdrawal delirium; and withdrawal symptoms due to other substances), alcohol and/or drug-induced mood, anxiety and/or sleep disorder with onset during withdrawal, and alcohol and/or drug relapse.

The compounds are also potentially useful for the prevention or treatment of neurological dysfunctions such as dystonias, dyskinesias, akathisia, tremor and spasticity, treatment of spinal cord injury, neuropathy, migraine, vigilance disorders, sleep disorders (e.g., disturbed sleep architecture, sleep apnea, obstructive sleep apnea, sleep apnea syndrome), pain disorders, cranial trauma.

The compounds are also potentially useful for the treatment of immune, cardiovascular disorders (e.g. atherosclerosis, arteriosclerosis, angina pectoris, abnormal heart rhythms, and arrhythmias, congestive heart failure, coronary artery disease, heart disease, hypertension, prevention and treatment of left ventricular hypertrophy, myocardial infarction, transient ischaemic attack, peripheral vascular disease, systemic inflammation of the vasculature, septic shock, stroke, cerebral apoplexy, cerebral infarction, cerebral ischaemia, cerebral thrombosis, cerebral embolism, cerebral hemorrhagia, metabolic disorders (e.g. conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, diabetes mellitus, dyslipidemia, fatty liver, gout, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hyperuricacidemia, impaired glucose tolerance, impaired fasting glucose, insulin resistance, insulin resistance syndrome, metabolic syndrome, syndrome X, obesity- hypoventilation syndrome (Pickwickian syndrome), type I diabetes, type II diabetes, low HDL- and/or high LDL-cholesterol levels, low adiponectin levels), reproductive and endocrine disorders (e.g. treatment of hypogonadism in males, treatment of infertility or as contraceptive, menstrual abnormalities/emmeniopathy, polycystic ovarian disease, sexual and reproductive dysfunction in women and men (erectile dysfunction), GH-deficient subjects, hirsutism in females, normal variant short stature) and diseases related to the respiratory (e.g. asthma and chronic obstructive pulmonary disease) and gastrointestinal systems (e.g. dysfunction of gastrointestinal motility or intestinal propulsion, diarrhea, emesis, nausea, gallbladder disease, cholelithiasis, obesity-related gastro-esophageal reflux, ulcers).

The compounds are also potentially useful as agents in treatment of dermatological disorders, cancers (e.g. colon, rectum, prostate, breast, ovary, endometrium, cervix, gallbladder, bile duct), craniopharyngioma, Prader-Willi syndrome, Turner syndrome, Frohlich's syndrome, glaucoma, infectious diseases, urinary tract disorders and inflammatory disorders (e.g. arthritis deformans, inflammation, inflammatory sequelae of viral encephalitis, osteoarthritis) and orthopedic disorders. The compounds are also potentially useful as agents in treatment of (esophageal) achalasia. In another aspect the present invention provides a compound of formula I as previously defined for use as a medicament.

In a further aspect the present invention provides the use of a compound of formula I in the preparation of a medicament for the treatment or prophylaxis of obesity or being overweight, (e.g., promotion of weight loss and maintenance of weight loss), prevention of weight gain (e.g., medication-induced or subsequent to cessation of smoking), for modulation of appetite and/or satiety, eating disorders (e.g. binge eating, anorexia, bulimia and compulsive), cravings (for drugs, tobacco, alcohol, any appetizing macronutrients or non-essential food items), for the treatment of psychiatric disorders such as psychotic and/or mood disorders, schizophrenia and schizo-affective disorder, bipolar disorders, anxiety, anxio-depressive disorders, depression, mania, obsessive-compulsive disorders, impulse control disorders (e.g., Gilles de Ia Tourette's syndrome), attention disorders like ADD/ADHD, stress, and neurological disorders such as dementia and cognitive and/or memory dysfunction (e.g., amnesia, Alzheimer's disease, Pick's dementia, dementia of ageing, vascular dementia, mild cognitive impairment, age-related cognitive decline, and mild dementia of ageing), neurological and/or neurodegenerative disorders (e.g. Multiple Sclerosis, Raynaud's syndrome, Parkinson's disease, Huntington's chorea and Alzheimer's disease), demyelinisation-related disorders, neuroinflammatory disorders (e.g., Guillain- Barre syndrome).

In a further aspect the present invention provides the use of a compound of formula I in the preparation of a medicament for the treatment or prophylaxis of dependence and addictive disorders and behaviours (e.g., alcohol and/or drug abuse, pathological gambling, kleptomania), drug withdrawal disorders (e.g., alcohol withdrawal with or without perceptυal disturbances; alcohol withdrawal delirium; amphetamine withdrawal; cocaine withdrawal; nicotine withdrawal; opioid withdrawal; sedative, hypnotic or anxiolytic withdrawal with or without perceptual disturbances; sedative, hypnotic or anxiolytic withdrawal delirium; and withdrawal symptoms due to other substances), alcohol and/or drug-induced mood, anxiety and/or sleep disorder with onset during withdrawal, and alcohol and/or drug relapse.

In a further aspect the present invention provides the use of a compound of formula I in the preparation of a medicament for the treatment or prophylaxis of neurological dysfunctions such as dystonias, dyskinesias, akathisia, tremor and spasticity, treatment of spinal cord injury, neuropathy, migraine, vigilance disorders, sleep disorders (e.g., disturbed sleep architecture, sleep apnea, obstructive sleep apnea, sleep apnea syndrome), pain disorders, cranial trauma.

In a further aspect the present invention provides the use of a compound of formula I in the preparation of a medicament for the treatment or prophylaxis of immune, cardiovascular disorders (e.g. atherosclerosis, arteriosclerosis, angina pectoris, abnormal heart rhythms, and arrhythmias, congestive heart failure, coronary artery disease, heart disease, hypertension, prevention and treatment of left ventricular hypertrophy, myocardial infarction, transient ischaemic attack, peripheral vascular disease, systemic inflammation of the vasculature, septic shock, stroke, cerebral apoplexy, cerebral infarction, cerebral ischaemia, cerebral thrombosis, cerebral embolism, cerebral hemorrhagia, metabolic disorders (e.g. conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, diabetes mellitus, dyslipidemia, fatty liver, gout, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hyperuricacidemia, impaired glucose tolerance, impaired fasting glucose, insulin resistance, insulin resistance syndrome, metabolic syndrome, syndrome X, obesity- hypoventilation syndrome (Pickwickian syndrome), type I diabetes, type II diabetes, low HDL- and/or high LDL-cholesterol levels, low adiponectin levels), reproductive and endocrine disorders (e.g. treatment of hypogonadism in males, treatment of infertility or as contraceptive, menstrual abnormalities/emmeniopathy, polycystic ovarian disease, sexual and reproductive dysfunction in women and men (erectile dysfunction), GH-deficient subjects, hirsutism in females, normal variant short stature) and diseases related to the respiratory (e.g. asthma and chronic obstructive pulmonary disease) and gastrointestinal systems (e.g. dysfunction of gastrointestinal motility or intestinal propulsion, diarrhea, emesis, nausea, gallbladder disease, cholelithiasis, obesity-related gastro-esophageal reflux, ulcers).

In a further aspect the present invention provides the use of a compound of formula I in the preparation of a medicament for the treatment or prophylaxis of dermatological disorders, cancers (e.g. colon, rectum, prostate, breast, ovary, endometrium, cervix, gallbladder, bile duct), craniopharyngioma, Prader-Willi syndrome, Turner syndrome, Frohlich's syndrome, glaucoma, infectious diseases, urinary tract disorders and inflammatory disoerders (e.g. arthritis deformans, inflammation, inflammatory sequelae of viral encephalitis, osteoarthritis) and orthopedic disorders.

In a still further aspect the present invention provides a method comprising administering a pharmacologically effective amount of a compound of formula I to a patient in need thereof for the prophylaxis or treatment of obesity or being overweight, (e.g., promotion of weight loss and maintenance of weight loss), prevention of weight gain (e.g., medication-induced or subsequent to cessation of smoking), for modulation of appetite and/or satiety, eating disorders (e.g. binge eating, anorexia, bulimia and compulsive), cravings (for drugs, tobacco, alcohol, any appetizing macronutrients or nonessential food items), for the treatment of psychiatric disorders such as psychotic and/or mood disorders, schizophrenia and schizo-affective disorder, bipolar disorders, anxiety, anxio-depressive disorders, depression, mania, obsessive-compulsive disorders, impulse control disorders (e.g., Gilles de Ia Tourette's syndrome), attention disorders like ADD/ADHD, stress, and neurological disorders such as dementia and cognitive and/or memory dysfunction (e.g., amnesia, Alzheimer's disease, Pick's dementia, dementia of ageing, vascular dementia, mild cognitive impairment, age-related cognitive decline, and mild dementia of ageing), neurological and/or neurodegenerative disorders (e.g. Multiple Sclerosis, Raynaud's syndrome, Parkinson's disease, Huntington's chorea and Alzheimer's disease), demyelinisation-related disorders, neuroinflammatory disorders (e.g., Guillain- Barre syndrome).

In a still further aspect the present invention provides a method comprising administering a pharmacologically effective amount of a compound of formula I to a patient in need thereof for the prophylaxis or treatment of dependence and addictive disorders and behaviours (e.g., alcohol and/or drug abuse, pathological gambling, kleptomania), drug withdrawal disorders (e.g., alcohol withdrawal with or without perceptual disturbances; alcohol withdrawal delirium; amphetamine withdrawal; cocaine withdrawal; nicotine withdrawal; opioid withdrawal; sedative, hypnotic or anxiolytic withdrawal with or without perceptual disturbances; sedative, hypnotic or anxiolytic withdrawal delirium; and withdrawal symptoms due to other substances), alcohol and/or drug-induced mood, anxiety and/or sleep disorder with onset during withdrawal, and alcohol and/or drug relapse.

In a still further aspect the present invention provides a method comprising administering a pharmacologically effective amount of a compound of formula I to a patient in need thereof for the prophylaxis or treatment of neurological dysfunctions such as dystonias, dyskinesias, akathisia, tremor and spasticity, treatment of spinal cord injury, neuropathy, migraine, vigilance disorders, sleep disorders (e.g., disturbed sleep architecture, sleep apnea, obstructive sleep apnea, sleep apnea syndrome), pain disorders, cranial trauma. In a still further aspect the present invention provides a method comprising administering a pharmacologically effective amount of a compound of formula I to a patient in need thereof for the prophylaxis or treatment of immune, cardiovascular disorders (e.g. atherosclerosis, arteriosclerosis, angina pectoris, abnormal heart rhythms, and arrhythmias, congestive heart failure, coronary artery disease, heart disease, hypertension, prevention and treatment of left ventricular hypertrophy, myocardial infarction, transient ischaemic attack, peripheral vascular disease, systemic inflammation of the vasculature, septic shock, stroke, cerebral apoplexy, cerebral infarction, cerebral ischaemia, cerebral thrombosis, cerebral embolism, cerebral hemorrhagia, metabolic disorders (e.g. conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, diabetes mellitus, dyslipidemia, fatty liver, gout, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hyperuricacidemia, impaired glucose tolerance, impaired fasting glucose, insulin resistance, insulin resistance syndrome, metabolic syndrome, syndrome X, obesity- hypoventilation syndrome (Pickwickian syndrome), type I diabetes, type II diabetes, low HDL- and/or high LDL-cholesterol levels, low adiponectin levels), reproductive and endocrine disorders (e.g. treatment of hypogonadism in males, treatment of infertility or as contraceptive, menstrual abnormalities/emmeniopathy, polycystic ovarian disease, sexual and reproductive dysfunction in women and men (erectile dysfunction), GH-deficient subjects, hirsutism in females, normal variant short stature) and diseases related to the respiratory (e.g. asthma and chronic obstructive pulmonary disease) and gastrointestinal systems (e.g. dysfunction of gastrointestinal motility or intestinal propulsion, diarrhea, emesis, nausea, gallbladder disease, cholelithiasis, obesity-related gastro-esophageal reflux, ulcers).

In a still further aspect the present invention provides a method comprising administering a pharmacologically effective amount of a compound of formula I to a patient in need thereof for the prophylaxis or treatment of dermatological disorders, cancers (e.g. colon, rectum, prostate, breast, ovary, endometrium, cervix, gallbladder, bile duct), craniopharyngioma, Prader-Willi syndrome, Turner syndrome, Frohlich's syndrome, glaucoma, infectious diseases, urinary tract disorders and inflammatory disorders (e.g. arthritis deformans, inflammation, inflammatory sequelae of viral encephalitis, osteoarthritis) and orthopedic disorders. The compounds of the present invention are particularly suitable for the treatment of obesity or being overweight, (e.g., promotion of weight loss and maintenance of weight loss), prevention or reversal of weight gain (e.g., rebound, medication-induced or subsequent to cessation of smoking), for modulation of appetite and/or satiety, eating disorders (e.g. binge eating, anorexia, bulimia and compulsive), cravings (for drugs, tobacco, alcohol, any appetizing macronutrients or non-essential food items).

The compounds of formula (I) are useful for the treatment of obesity, psychiatric disorders such as psychotic disorders, schizophrenia, bipolar disorders, anxiety, anxio- depressive disorders, depression, cognitive disorders, memory disorders, obsessive- compulsive disorders, anorexia, bulimia, attention disorders like ADHD, epilepsy, and related conditions, and neurological disorders such as dementia, neurological disorders(e.g. Multiple Sclerosis), Raynaud's syndrome, Parkinson's disease, Huntington's chorea and Alzheimer's disease. The compounds are also potentially useful for the treatment of immune, cardiovascular, reproductive and endocrine disorders, septic shock and diseases related to the respiratory and gastrointestinal systems (e.g. diarrhea). The compounds are also potentially useful as agents in treatment of extended abuse, addiction and/or relapse indications, e.g. treating drug (nicotine, ethanol, cocaine, opiates, etc) dependence and/or treating drug (nicotine, ethanol, cocaine, opiates, etc) withdrawal symptoms. The compounds may also eliminate the increase in weight that normally accompanies the cessation of smoking.

In another aspect the present invention provides a compound of formula I as previously defined for use as a medicament. In a further aspect the present invention provides the use of a compound of formula

I in the preparation of a medicament for the treatment or prophylaxis of obesity, psychiatric disorders such as psychotic disorders, schizophrenia, bipolar disorders, anxiety, anxio-depressive disorders, depression, cognitive disorders, memory disorders, obsessive- compulsive disorders, anorexia, bulimia, attention disorders like ADHD, epilepsy, and related conditions, neurological disorders such as dementia, neurological disorders (e.g. Multiple Sclerosis), Parkinson's Disease, Huntington's Chorea and Alzheimer's Disease, immune, cardiovascular, reproductive and endocrine disorders, septic shock, diseases related to the respiratory and gastrointestinal systems (e.g. diarrhea), and extended abuse, addiction and/or relapse indications, e.g. treating drug (nicotine, ethanol, cocaine, opiates, etc) dependence and/or treating drug (nicotine, ethanol, cocaine, opiates, etc) withdrawal symptoms.

In a still further aspect the present invention provides a method of treating obesity, psychiatric disorders such as psychotic disorders such as schizophrenia and bipolar disorders, anxiety, anxio-depressive disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorders, anorexia, bulimia, attention disorders like ADHD, epilepsy, and related conditions, neurological disorders such as dementia, neurological disorders (e.g. Multiple Sclerosis), Parkinson's Disease, Huntington's Chorea and Alzheimer's Disease, immune, cardiovascular, reproductive and endocrine disorders, septic shock, diseases related to the respiratory and gastrointestinal systems (e.g. diarrhea), and extended abuse, addiction and/or relapse indications, e.g. treating drug (nicotine, ethanol, cocaine, opiates, etc) dependence and/or treating drug (nicotine, ethanol, cocaine, opiates, etc) withdrawal symptoms comprising administering a pharmacologically effective amount of a compound of formula I to a patient in need thereof.

The compounds of the present invention are particulary suitable for the treatment of obesity, e.g. by reduction of appetite and body weight, maintenance of weight reduction and prevention of rebound. The compounds of the present invention may also be used to prevent or reverse medication-induced weight gain, e.g. weight gain caused by antipsychotic (neuroleptic) treatment(s). The compounds of the present invention may also be used to prevent or reverse weight gain associated with smoking cessation.

5 The compounds of the present invention are suitable for use in treating the above indications in juvenile or adolescent patient populations.

The compounds of the present invention may also be suitable for use in the regulation of bone mass and bone loss and therefore useful in the treatment of osteoporosis and other bone diseases. io The compounds of the present invention may also be used in the treatment of hepatic diseases, for example hepatic fibrosis, alcoholic liver cirrhosis, chronic viral hepatitis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis or liver cancer. Combination Therapy

The compounds of the invention may be combined with another therapeutic agent i s that is useful in the treatment of obesity such as other anti-obesity drugs, that affect energy expenditure, glycolysis, gluconeogenesis, glucogenolysis, lipolysis, lipogenesis, fat absorption, fat storage, fat excretion, hunger and/or satiety and/or craving mechanisms, appetite/motivation, food intake, or G-I motility.

The compounds of the invention may further be combined with another therapeutic

20 agent that is useful in the treatment of disorders associated with obesity such as hypertension, hyperlipidaemias, dyslipidaemias, diabetes, sleep apnea, asthma, heart disorders, atherosclerosis, macro and micro vascular diseases, liver steatosis, cancer, joint disorders, and gallbladder disorders. For example, a compound of the present invention may be used in combination with a another therapeutic agent that lowers blood pressure or

25 that decreases the ratio of LDL: HDL or an agent that causes a decrease in circulating levels of LDL-cholesterol. In patients with diabetes mellitus the compounds of the invention may also be combined with therapeutic agents used to treat complications related to microangiopathies.

The compounds of the invention may be used alongside other therapies for the

30 treatment of obesity and its associated complications the metabolic syndrome and type 2 diabetes, these include biguanide drugs, insulin (synthetic insulin analogues) and oral antihyperglycemics (these are divided into prandial glucose regulators and alpha- glucosidase inhibitors).

In another aspect of the invention, the compound of formula I, or a pharmaceutically acceptable salt thereof may be administered in association with a PPAR modulating agent. PPAR modulating agents include but are not limited to a PPAR alpha and/or gamma agonist, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof. Suitable PPAR alpha and/or gamma agonists, pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof are well known in the art.

In addition the combination of the invention may be used in conjunction with a sulfonylurea. The present invention also includes a compound of the present invention in combination with a cholesterol-lowering agent. The cholesterol-lowering agents referred to in this application include but are not limited to inhibitors of HMG-CoA reductase (3- hydroxy-3-methylglutaryl coenzyme A reductase). Suitably the HMG-CoA reductase inhibitor is a statin. In the present application, the term "cholesterol-lowering agent" also includes chemical modifications of the HMG-CoA reductase inhibitors, such as esters, prodrugs and metabolites, whether active or inactive.

The present invention also includes a compound of the present invention in combination with an inhibitor of the ileal bile acid transport system (IBAT inhibitor). The present invention also includes a compound of the present invention in combination with a bile acid binding resin.

The present invention also includes a compound of the present invention in combination with a bile acid sequestering agent, for example colestipol or cholestyramine or cholestagel. According to an additional further aspect of the present invention there is provided a combination treatment comprising the administration of an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration one or more of the following agents selected from: a CETP (cholesteryl ester transfer protein) inhibitor; a cholesterol absorption antagonist; a MTP (microsomal transfer protein) inhibitor ; a nicotinic acid derivative, including slow release and combination products; a phytosterol compound ; probucol; an anti-coagulant; an omega-3 fatty acid ; another anti-obesity compound for example sibutramine, phentermine, orlistat, bupropion, ephedrine, thyroxine; an antihypertensive compound for example an angiotensin converting enzyme (ACE) inhibitor, an angiotensin II receptor antagonist, an adrenergic blocker, an alpha adrenergic blocker, a beta adrenergic blocker, a mixed alpha/beta adrenergic blocker, an adrenergic stimulant, calcium channel blocker, an AT-I blocker, a saluretic, a diuretic or a vasodilator; a melanin concentrating hormone (MCH) modulator; an NPY receptor modulator; an orexin receptor modulator; a phosphoinositide-dependent protein kinase (PDK) modulator; or modulators of nuclear receptors for example LXR, FXR, RXR, GR, ERRα, β, PP ARa, β, γ and RORalpha; a monoamine transmission-modulating agent, for example a selective serotonin reuptake inhibitor (SSRI), a noradrenaline reuptake inhibitor (NARI), a noradrenaline-serotonin reuptake inhibitor (SNRI), a monoamine oxidase inhibitor (MAOI), a tricyclic antidepressive agent (TCA), a noradrenergic and specific serotonergic antidepressant

(NaSSA); an antipsychotic agent for example olanzapine and clozapine; a serotonin receptor modulator; a leptin/leptin receptor modulator; a ghrelin/ghrelin receptor modulator; a DPP-IV inhibitor; or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier to a warmblooded animal, such as man in need of such therapeutic treatment. According to an additional further aspect of the present invention there is provided a combination treatment comprising the administration of an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration of very low calorie diets (VLCD) or low-calorie diets (LCD).

Therefore in an additional feature of the invention, there is provided a method for the treatment of obesity and its associated complications in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof in simultaneous, sequential or separate administration with an effective amount of a compound from one of the other classes of compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof. Therefore in an additional feature of the invention, there is provided a method of treating hyperlipidemic conditions in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof in simultaneous, sequential or separate administration with an effective amount of a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.

According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, and a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in association with a pharmaceutically acceptable diluent or carrier. According to a further aspect of the present invention there is provided a kit comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.

According to a further aspect of the present invention there is provided a kit comprising: a) a compound of formula I, or a pharmaceutically acceptable salt thereof, in a first unit dosage form; b) a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof; in a second unit dosage form; and c) container means for containing said first and second dosage forms.

According to a further aspect of the present invention there is provided a kit comprising: a) a compound of formula I, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier, in a first unit dosage form; b) a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in a second unit dosage form; and c) container means for containing said first and second dosage forms. According to another feature of the invention there is provided the use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment of obesity and its associated complications in a warm-blooded animal, such as man.

According to another feature of the invention there is provided the use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment of hyperlipidaemic conditions in a warm-blooded animal, such as man.

According to a further aspect of the present invention there is provided a combination treatment comprising the administration of an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration of an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier to a warm-blooded animal, such as man in need of such therapeutic treatment.

Furthermore, a compound of the invention may also be combined with therapeutic agents that are useful in the treatment of disorders or conditions associated with obesity

(such as type II diabetes, metabolic syndrome, dyslipidemia, impaired glucose tolerance, hypertension, coronary heart disease, non-alcoholic steatohepatitis, osteoarthritis and some cancers) and psychiatric and neurological conditions.

It will be understood that there are medically accepted definitions of obesity and being overweight. A patient may be identified by, for example, measuring body mass index

(BMI), which is calculated by dividing weight in kilograms by height in metres squared, and comparing the result with the definitions.

As the compounds of formula I are useful in causing smoking cessation, preventing weight gain resulting from smoking cessation, treating nicotine withdrawal and preventing nicotine dependence they may also be combined with other compounds known to have one or more of these effects for example nicotine, a nicotine agonist or a partial agonist, a monoamine oxidase inhibitor or antidepressants such as bupropion, doxepine, nortriptyline or an anxiolytic such as buspirone or clonidine.

Pharmacological Activity Compounds of the present invention are active against the receptor product of the

CB l gene. The affinity of the compounds of the invention for central cannabinoid receptors is demonstrable in methods described in Devane et al , Molecular

Pharmacology, 1988, 34,605 or those described in WO01/70700 or EP 656354.

Alternatively the assay may be performed as follows. lOμg of membranes prepared from cells stably transfected with the CBl gene were suspended in 200μl of 10OmM NaCl, 5mM MgCl₂, ImM EDTA, 5OmM HEPES (pH 7.4),

ImM DTT, 0.1% BSA and lOOμM GDP. To this was added an EC80 concentration of agonist (CP55940), the required concentration of test compound and 0.1 μCi [³⁵S]-GTPyS.

The reaction was allowed to proceed at 30⁰C for 45 min. Samples were then transferred on to GF/B filters using a cell harvester and washed with wash buffer (5OmM Tris (pH 7.4),

5mM MgCb, 5OmM NaCl). Filters were then covered with scintillant and counted for the amount of [³⁵S]-GTPyS retained by the filter. Activity is measured in the absence of all ligands (minimum activity) or in the presence of an EC80 concentration of CP55940 (maximum activity). These activities are set as 0% and 100% activity respectively. At various concentrations of novel ligand, activity is calculated as a percentage of the maximum activity and plotted. The data are fitted using the equation y=A+((B-A)/l+((C/x) LJD)) and the IC50 value determined as the concentration required to give half maximal inhibition of GTPγS binding under the conditions used.

The compounds of the present invention are active at the CB l receptor (IC50 <1 micromolar). Most preferred compounds have IC50 <200 nanomolar. For example, Example 1 has an IC50 of 1.6nM. Example 2 has an IC50 of 2.9nM. Example 3 has an IC50 of 1. InM. Example 4 has an IC50 of 1.8nM.

The compounds of the invention are believed to be selective CBl antagonists or inverse agonists. Certain compounds of the invention represent a selection from compounds covered generically by other patent applications. The potency, selectivity profile and side effect propensity may limit the clinical usefulness of hitherto known compounds with alleged CB l antagonistic/inverse agonistic properties. In this regard, preclinical evaluation of compounds of the present invention in models of gastrointestinal and/or cardiovascular function indicates that they offer significant advantages compared to representative reference CB 1 antagonist/inverse agonist agents. The compounds of the present invention may provide additional benefits in terms of potency, selectivity profile, bioavailability, half-life in plasma, blood brain permeability, plasma protein binding (for example higher free fraction of drug) or solubility compared to representative reference CBl antagonists/inverse agonist agents.

The compounds of the present invention have improved solubility in organic solvents compared to compounds in the prior art. For example, Example 19 of

WO03/0271 14 (2-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-3-methyl-5-( 1 -piperidinyl)- 1 , 5, 6, 7-tetrahydro-4//-pyrrolo-[3,2-c]pyridin-4-one) was found to be insoluble in dimethyl sulfoxide whereas the compounds of the present invention were all soluble in dimethyl sulfoxide. It would be expected that this increase in solubility in organic solvents would lead to improvements in bioavailability and ease of manufacture and formulation.

The utility of the compounds of the present invention in the treatment of obesity and related conditions is demonstrated by a decrease in body weight in cafeteria diet- induced obese mice. Female C57B1/6J mice were given ad libitum access to calorie-dense 'cafeteria' diet (soft chocolate/cocoa-type pastry, chocolate, fatty cheese and nougat) and standard lab chow for 8-10 weeks. Compounds to be tested were then administered systemically (iv, ip, sc or po) once daily for a minimum of 5 days, and the body weights of the mice monitored on a daily basis. Simultaneous assessment of adiposity was carried by means of DEXA imaging at baseline and termination of the study. Blood sampling was also carried out to assay changes in obesity-related plasma markers. Compounds of the present invention show superior weight reduction compared to prior art compounds.

Examples

Abbreviations

DCM dichloromethane

DDQ 2,3-dichloro-5,6-dicyano-l ,4-benzoquinone

DME dimethoxyethane

DMF dimethylformamide

DMSO dimethyl sulfoxide

EtOAc ethyl acetate

LiHMDS lithium bis(trimethylsilyl)amide

MeTHF 2-methyltetrahydrofuran

MeOH methanol p-TSA 4-toluenesulphonic acid rt room temperature

TBAF tetrabutylammonium fluoride

TEA triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran t triplet

S singlet d doublet q quartet qvint quintet m multiplet br broad bs broad singlet dm doublet of multiplet bt broad triplet dd doublet of doublets

General Experimental Procedures

Mass spectra were recorded on either a Micromass ZQ single quadrupole or a Micromass LCZ single quadrupole mass spectrometer both equipped with a pneumatically assisted electrospray interface (LC-MS). H NMR measurements were performed on either a Varian Mercury 300 or a Varian Inova 500, operating at H frequencies of 300 and 500 MHz respectively. Chemical shifts are given in ppm with CDCl₃ as internal standard. CDCI₃ is used as the solvent for NMR unless otherwise stated. Purification was performed on a semipreparative HPLC (or hplc - High Performance Liquid Chromatography ) with a mass triggered fraction collector, Shimadzu QP 8000 single quadrupole mass spectrometer equipped with 19 x 100 mm C8 column. The mobile phase used was, if nothing else is stated, acetonitrile and buffer (0.1 M ammonium acetate: acetonitrile 95:5). Example 1

4-[l-(2,4-dichlorophenv0-3-methyl-4-oxo-5-piperidin-l-yl-4,,5,6,7-tetrahvdro-lH- pyrrolo[3,2-c]pyridin-2-yl| phenyl propane-1-sulfonate Step 1 3-(Piperidin-l-ylamino)-propionic acid methyl ester

To a solution of 1 -aminopiperidine (100 g, 1.00 mol) in dry methanol at 0⁰C, methyl acrylate (99.0 ml, 1.10 mol) was added dropwise. The resulting mixture was stirred at room temperature overnight. After evaporation of the solvent, heptane was added to the residue, and the white solid (impurity) removed by filtration. The filtrate was concentrated to dryness to afford 80.0 g (43%) of the title compound as a yellow oil. Alternatively this reaction was performed at 5O⁰C using toluene as the solvent with a 0.7 molar excess of 1- aminopiperidine. Excess 1-aminopiperidine was removed from the residue by co- distillation with xylene, then toluene and then hexane. Step 2 N-(2-Methoxycarbonylethyl)-N-piperidin-l-yl-maloamic acid ethyl ester To a solution of 3-(piperidin-l-ylamino)propionic acid methyl ester (80.0 g, 0.43 mol) in dichloromethane was added triethylamine (71.0 ml, 0.50 mol) followed by slow addition of ethyl malonyl chloride (60.0 ml, 0.47 mol) at 0⁰C. The resulting slurry was stirred at room temperature for 4 hours. Water was added and the phases separated. The organic phase was dried filtered and concentrated. Flash chromatography (toluene : EtOAc 9: 1 - 1 : 1) gave 81.O g (63%) of the product as an oil used without further purification. Alternatively the reaction was performed using 2-methyltetrahydrofuran as the solvent and N-methylmorpholine as the base. The reaction was also performed with methyl malonyl chloride which gave N-(2-methoxycarbonylethyl)-N-piperidin-l-yl-maloamic acid methyl ester m.p. 54-57⁰C which was used as an alternative in the next step. Step 3 2,4-Dioxo-[ l,r^'|bipiperidinyl-3-carboxylic acid ethyl ester To a solution of N-(2-methoxycarbonylethyl)-N-piperidin-l-yl-maloamic acid ethyl ester (60.0 g, 0.20 mol) in a mixture of THF (1 100 ml) and DMF (490 ml) was added cesium carbonate (195 g, 0.60 mol). The resulting mixture was boiled under reflux (80 ⁰C) for 48 hours. The cooled reaction mixture was filtered and the filtrate evaporated. The combined filtered solid and the filtrate residue were purified by flash chromatography (CH₂CI₂ : MeOH 70 : 30) to give 15.0 g (28%) of the title compound as a pale yellow oil. Alternatively the reaction was performed using toluene as the solvent and N-(2- methoxycarbonylethyl)-N-piperidin-l-yl-maloamic acid methyl ester and adding the base sodium methoxide in methanol (1.4 equivs) at below 10⁰C then boiling under reflux for 1 hour. Concentration, addition of water and acidification to pH6 with cone. HCl produced 2,4-dioxo-[l ,l ^']bipiperidinyl-3-carboxylic acid methyl ester m.p. 157-159⁰C after filtration and washing with water. This methyl ester was used as an alternative in the next step. Step 4 rκriBipiperidinyl-2,4-dione

The ethyl ester product from step 3 was dissolved in 10% acetic acid (250 ml) and the solution boiled under reflux for one hour. The cooled reaction mixture was evaporated, and the residue purified by flash chromatography (CH₂CI₂ : acetone 9: 1 - 1 : 1) to give 4.00 g (36%) of the title compound as a semi-solid.

Alternatively the methyl ester was heated at reflux for 2 hours in a mixture of water (2 equivalents) and acetonitrile (10 volumes) at pH 3 (adjusted by addition of dilute HCl approx 5 M) and the product hydrochloride m.p. 89-90⁰C purified by crystallisation from ethyl acetate /hexane. Step 5 2-bromo- 1 -(^"4-hydroxyphenvπpropan- 1 -one

Acetic acid (25 ml) was added to l-(4-hydroxyphenyl)propan-l-one (10.000 g, 66.587 mmol) and pyridine hydroperbromide (24.767 g, 69.916 mmol) at rt. The reaction mixture was stirred at rt for 3 h and 5 min. Water (1 10 ml) was added dropwise during 20 min and after 30 min of stirring more water (40 ml) was added during 5 min. The mixture was cooled to 0 ⁰C and left at rt overnight. Solid material had formed in the reaction mixture which was collected by filtration, washed with water and dried under vacuum to yield the product as a solid (13.76 g, 90%). 1H-NMR (400 MHz, CDCl₃) δ 7.96 (d, 2H), 6.91 (d, 2H), 5.25 (q, IH), 1.87 (d, 3H). MS m/z 229 (M+H)⁺.

Alternatively the reaction was performed by adding a mixture of l-(4-hydroxyphenyl)- propan-1-one (1 equivalent) in ethyl acetate (5 volumes) to a mixture of ground CuBr₂ (2 equivs) in ethyl acetate (7.5 volumes) which was being boiled under reflux with vigorous stirring. After boiling for 4 hours the mixture was filtered at 60⁰C through a filtration aid. The residue was washed with ethyl acetate and the filtrate and washings were treated with activated charcoal, filtered and evaporated to give the product. Step 6 2-bromo- 1 -\4-( 1 -ethoxyethoxy)phenyl1propan- 1 -one

Ethoxyethene (3.148 g, 43.655 mmol) and TFA (0.249 g, 2.183 mmol) was added to a suspension of 2-bromo- l-(4-hydroxyphenyl)propan-l -one (5.000 g, 21.827 mmol) in toluene (50 ml) at rt. The reaction mixture was stirred at 30⁰C for 2 h and 30 min. The solvent was evaporated to yield the product as an oil (6.83 g, 100%). 1H-NMR (400 MHz, DMSO) δ 7.98 (d, 2H), 7.09 (d, 2H), 5.72 (q, I H), 5.62 (q, IH), 3.68- 3.57 (m, I H), 3.51-3.41 (m, IH), 1.73 (d, 3H), 1.40 (d, 3H), 1.06 (t, 3H). MS m/z 301 (M+H)⁺. Step 7 4-[(2,4-dichlorophenyl)amino1- 1 -piperidin- 1 -yl-5.6-dihydropyridin-2( lHVone

l ,l'-bipiperidine-2, 4-dione (1.000 g, 4.739 mmol) and 2,4-dichloroaniline (0.921 g, 5.687 mmol) were dissolved in 2-methyltetrahydrofuran (10 ml) and the reaction mixture was boiled under reflux for 22 h whilst the water formed was removed using a Dean and Stark apparatus. Upon cooling to rt the product precipitated and was collected by filtration to yield a white solid (1.490 g, 92%). MS m/z 340 (M+Η)⁺.

Step 8 4-[(2,4-dichlorophenvPaminol-3- {2-[4-( 1 -ethoxyethoxy)phenyll- 1 -methyl-2- oxoethvU - 1 -piperidin- 1 -yl-5,6-dihvdropyridin-2( l//)-one

4-[(2,4-dichlorophenyl)amino]-l -piperidin- 1 -yl-5,6-dihydropyridin-2( lH)-one (450 mg, 1.323 mmol) suspended in TΗF (7 ml) was added during 15 min to NaH (67 mg, 2.645 mmol) suspended in THF (5 ml) at 5 ⁰C under nitrogen. After the resulting mixture had been stirred at 0 ⁰C for 1 h tetrabutylammonium iodide (49 mg, 0.132 mmol) was added followed by dropwise addition of 2-bromo- 1 -[4-( 1 -ethoxyethoxy)phenyl]propan- 1 -one (597 mg, 1.984 mmol) dissolved in THF (5 ml) during 15 min. After the addition the cooling bath was removed and the reaction was continued at rt overnight. Water was added and the solvent was removed by evaporation. The residue was partitioned between DCM and water. The organic phase was dried (MgSO₄), filtered and evaporated to yield an orange oil (1.030 g, 90%). MS m/z 560 (M+H)⁺. Step 9 1 -(2,4-dichlorophenyl)-2-(4-hvdroxyphenyl)-3-methyl-5-piperidin- 1 -yl- 1 ,5,6,7- tetrahydro-4H-pyrrolo[^'3,2-c1pyridin-4-one

TFA (22 mg, 0.194 mmol) was added to 4-[(2,4-dichlorophenyl)amino]-3-{2-[4-(l- ethoxyethoxy)phenyl]- 1 -methyl-2-oxoethyl} - 1 -piperidin- 1 -yl-5,6-dihydropyridin-2( IH)- one (1.090 g, 1.945 mmol) dissolved in toluene (15 ml) under nitrogen. The reaction mixture was stirred at 60 ⁰C for 2 h, adding more TFA (89 mg, 0.778 mmol) after 50 min.

When the mixture had reached rt the product was collected by filtration and recrystallised from methanol to yield a beige solid (0.560 g, 55%). 1H-NMR (400 MHz, DMSO) δ 9.59-9.28 (br, IH), 7.72 (d, IH), 7.43 (dd, IH), 7.37 (d,

IH), 6.82 (d, 2H), 6.59 (d, 2H), 3.62-3.54 (m, 2H), 3.27-2.90 (br, 4H), 2.61-2.43 (m, 2H),

2.12 (s, 3H), 1.61 - 1.45 (br, 4H), 1.39- 1.24 (br, 2H). MS m/z 470 (M+H)⁺.

Step 10 4-[l-(2,4-dichlorophenyl)-3-methyl-4-oxo-5-piperidin-l-yl-4,5,6,7-tetrahydro-lH-

Pyrrolor3,2-clpyridin-2-yllphenyl propane- 1 -sulfonate

1 -(2,4-dichlorophenyl)-2-(4-hydroxyphenyl)-3-methyl-5-piperidin- 1 -yl- 1 ,5,6,7-tetrahydro- 4H-pyrrolo[3,2-c]pyridin-4-one, prepared as described at Step 6 (300 mg, 0.638 mmol) was suspended in DCM (12 ml) at rt and TEA (98 ul, 0.702 mmol) was added. The reaction mixture was cooled with an ice bath and propane- 1-sulfonyl chloride (100 mg, 0.702 mmol) was added dropwise. The ice bath was removed after the addition. The reaction mixture was stirred at rt for 6 h, adding more propane- 1-sulfonyl chloride (25 mg, 0.178 mmol) after 4 h and 45 min. Water was added and the phases separated on a phase separator. The organic phase was evaporated. Purified by hplc to yield the title compound as a white solid after freeze drying (197 mg, 54%). ¹H-NMR (400 MHz, CDCl₃) δ 7.44 (d, IH), 7.19-7.03 (m, 5H), 6.97 (d, I H), 3.74-3.61 (m, 2H), 3.59-2.74 (br, 4H), 3.20-3.13 (m, 2H), 2.70-2.61 (m, I H), 2.59-2.49 (m, I H), 2.34 (s, 3H), 2.02-1.91 (m, 2H), 1.76-1.48 (br, 4H), 1.44-1.33 (m, 2H), 1.08 (t, 3H). HRMS Calcd for [C₂₈ H₃ι Cl₂ N₃ O₄ S+H]⁺: 576.148. Found: 576.149. Example 2

2-(4-butoxyphenyl)-l-(2,4-dichlorophenyl)-3-methyl-5-piperidin-l-yl-l,5,6,7- tetrahvdro-4H-pyrrolof3,2-clpyridin-4-one

1 -(2,4-dichlorophenyl)-2-(4-hydroxyphenyl)-3-methyl-5-piperidin- 1 -yl- 1 ,5,6,7-tetrahydro- 4H-pyrrolo[3,2-c]pyridin-4-one, prepared as described in Ex. 1, Step 9 (91 mg, 0.194 mmol) was suspended in acetonitrile ( 10 ml) and 1-bromobutane (87 mg, 0.638 mmol) was added followed by anhydrous potassium carbonate (93 mg, 0.670 mmol). The reaction mixture was refluxed for 6 h, adding more 1-bromobutane (87 mg, 0.638 mmol) after 4 h. The solvent was evaporated and the residue redissolved in DCM. Water was added and the phases separated on a phase separator. The organic phase was evaporated. Purified by hplc to yield the title compound as a white solid after freeze-drying (61 mg, 59%). ¹H-NMR (400 MHz, CDCl₃) δ 7.42 (d, I H), 7.16-7.1 1 (m, IH), 6.99-6.90 (m, 3H), 6.71 (d, 2H), 3.87 (t, 2H), 3.73-3.60 (m, 2H), 3.60-2.72 (br, 4H), 2.72-2.48 (m, 2H), 2.31 (s, 3H), 1.76- 1.50 (m, 6H), 1.50-1.34 (m, 4H), 0.94 (t, 3H). HRMS Calcd for [C₂₉ H₃₃ Cl₂ N₃ O₂+H]⁺: 526.203. Found: 526.202. Example 3

4-[l-(2,4-dichlorophenvπ-3-rmethoxymethyl)-4-oxo-5-piperidin-l-yl-4,5,6,7- tetrahvdro-lH-pyrrolo[3,2-c|pyridin-2-yllphenvI 3,3,3-trifluoropropane-l-sulfonate Step 1 4-[(2,4-dichlorophenyl)amino1-3-[2-(4-methoxyphenyl)-2-oxoethyl1- 1 -piperidin- 1 - yl-5,6-dihvdropyridin-2(lH)-one

4-[(2,4-dichlorophenyl)amino]- 1 -piperidin- 1 -yl-5,6-dihydropyridin-2( lH)-one, prepared as described in Ex. 1, Step 4 (5.000 g, 14.695 mmol) was added to NaH (0.431 g, 17.958 mmol) suspended in dry THF (80 ml) at 0 ⁰C under nitrogen. After the resulting mixture had been stirred at 0 ⁰C for 1 h tetrabutylammonium iodide (0.543 g, 1.470 mmol) was added followed by dropwise addition of 2-bromo-l-(4-methoxyphenyl)ethanone (5.049 g, 22.043 mmol) dissolved in dry THF (20 ml). The reaction mixture was stirred at 0 ⁰C for 1 h and 20 min and continued at rt overnight, adding more 2-bromo-l-(4-methoxyphenyl)- ethanone (1.683 g, 7.348 mmol) after 2 h and 45 min. Water was added and the solvent was removed by evaporation. The residue was partitioned between toluene and water. The organic phase was filtered and the solvent was removed from the filtrate by evaporation and the resdue obtained was purified by flash chromatography (5-30 % EtOAc in toluene) to yield a yellow solid after evaporation (2.536 g, 35%). ¹H-NMR (400 MHz, CDCl₃) δ 8.40 (s, I H), 8.28 (d, 2H), 7.39 (d, I H), 7.16-7.1 1 (m, IH), 6.91 (d, 2H), 6.83 (d, IH), 4.03 (s, 2H), 3.84 (s, 3H), 3.37 (t, 2H), 3.34-2.54 (br, 4H), 2.51 (t, 2H), 1.69-1.51 (br, 4H), 1.41- 1.32 (m, 2H). MS m/z 488 (M+H)⁺.

Step 2 1 -(2,4-dichlorophenyl)-2-(4-methoxyphenyl)-5-piperidin- 1 -yl- 1 ,5,6,7-tetrahvdro- 4H-pyrrolor3,2-c1pyridin-4-one

4-[(2,4-dichlorophenyl)amino]-3-[2-(4-methoxyphenyl)-2-oxoethyl]- 1 -piperidin- 1 -yl-5,6- dihydropyridin-2(lH)-one (2.536 g, 5.192 mmol) was dissolved in dry toluene (50 ml) and 4-toluenesulfonic acid monohydrate (99 mg, 0.519 mmol) was added. The reaction mixture was stirred at reflux for 1 h. Water and toluene were added and the phases separated. The organic phase was evaporated and purified by flash chromatography (10-30% EtOAc in toluene) to yield the product as an orange solid (2 001 g, 82%) H-NMR (400 MHz,

CDCl₃) δ 7 49 (d, IH), 7 25-7 20 (m, IH), 7 06 (d, IH), 6 97 (d, 2H), 6 73-6 67 (m, 3H),

3 75-3 63 (m, 5H), 3 61-2 75 (br, 4H), 2 73-2 52 (m, 2H), 1 71-1 54 (br, 4H), 1 45-1 36 (m,

2H) MS m/z 470 (M+H)⁺

Step 3 1 -(2,4-dichlorophenyl)-3-iodo-2-(4-methoxyphenvπ-5-piperidin- 1 -yl- 1 ,5,6,7- tetrahvdro-4H-pyrrolo[3,2-clpyπdin-4-one

N-iodosuccinimide (1 328 g, 5 902 mmol) was added to l-(2,4-dichlorophenyl)-2-(4- methoxyphenyl)-5-pipeπdin-l-yl-l ,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyπdin-4-one

I O (2 524 g, 5 366 mmol) dissolved in DMF (50 ml) The reaction mixture was stirred at rt overnight Next morning more N-iodosuccinimide (362 mg, 1 609 mmol) was added and after 3 h even more (362 mg, 1 609 mmol) The reaction mixture was stirred at rt overnight EtOAc and water were added, the phases separated and the organic phase washed with brine and evaporated Purified by flash chromatography (5-20% EtOAc in

15 toluene) to yield the product (1 740 g, 54%) MS m/z 596 (M+Η)⁺ Step 4 Ethyl-3-f 1 -(2,4-dichlorophenyl)-2-(4-methoxyphenyl)-4-oxo-5-piperidin- 1 -yl- 4.5.6.7-tetrahvdro- lH-pyrrolof3,2-clpyridin-3-yllacrylate

A mixture of l-(2,4-dichlorophenyl)-3-iodo-2-(4-methoxyphenyl)-5-pipeπdin-l-yl-l,5,6,7-

20 tetrahydro-4H-pyrrolo[3,2-c]pyπdin-4-one (1 588 g, 2 663 mmol), acrylic acid ethyl ester (533 mg, 5 326 mmol), tetrabutylammonium chloride (814 mg, 2 929 mmol), palladium(II) acetate (30 mg, 0 133 mmol) and anhydrous sodium carbonate (310 mg, 2 929 mmol) in DMF (30 ml) was stirred at 80 ⁰C overnight More anhydrous sodium carbonate (141 mg, 1 331 mmol), tetrabutylammonium chloride (370 mg, 1 331 mmol) and palladium(II) acetate (30 mg, 0.133 mmol) were added and the reaction continued at 80 ⁰C for 6 h and

30 min. Water and EtOAc were added and the phases separated. The organic phase was washed with brine and evaporated. Purified by flash chromatography (2-20% EtOAc in toluene) to yield the product (1.077 g, 71%). MS m/z 568 (M+H)⁺.

Step 5 1 -(2,4-dichlorophenyl)-2-(4-methoxyphenylV4-oxo-5-piperidin- 1 -yl-4, 5,6,7- tetrahvdro-lH-pyrrolo[3,2-clpyridine-3-carbaldehyde

A mixture of ethyl-3-[ 1 -(2,4-dichlorophenyl)-2-(4-methoxyphenyl)-4-oxo-5-piperidin- 1 - yl-4, 5,6, 7-tetrahydro-lH-pyrrolo[3,2-c]pyridin-3-yl]acrylate (594 mg, 1.045 mmol), osmium tetroxide (2.5% solution in tert-butanol, 0.655 ml, 0.052 mmol) and sodium metaperiodate (670 mg, 3.135 mmol) in TΗF (10 ml) and water (3 ml) was stirred at rt overnight. Next morning more sodium metaperiodate (1 12mg, 0.524 mmol) was added. After 2 h and 20 min EtOAc was added and the mixture washed with water and brine and evaporated. Purified by flash chromatography (25-50% EtOAc in toluene) to yield the product (302 mg, 58%). MS m/z 498 (M+Η)⁺.

Step 6 1 -(2,4-dichlorophenyl)-3-(hvdroxymethyl)-2-(4-methoxyphenyl)-5-piperidin- 1 -yl- 1.5,6,7-tetrahvdro-4H-pyrrolo[3,2-clpyridin-4-one

A mixture of l -(2,4-dichlorophenyl)-2-(4-methoxyphenyl)-4-oxo-5-piperidin-l-yl-4, 5,6,7- tetrahydro-lH-pyrrolo[3,2-c]pyridine-3-carbaldehyde (302 mg, 0.606 mmol) and NaBH₄

(69 mg, 1.818 mmol) in THF (4 ml) and MeOH (2 ml) was stirred at rt overnight. EtOAc was added and the mixture washed with water and brine. The solvent was evaporated to yield the product (275 mg, 91%).

Step 7 4-r i-(2,4-dichlorophenyl)-3-(methoxymethyP)-4-oxo-5-piperidin-l-yl-4, 5,6,7- tetrahvdro- lH-pyrrolo[3,2-clpyridin-2-yllphenyl 3,33-trifluoropropane-l -sulfonate

Boron tribromide (1 ml, IM in DCM) was added to a solution of l-(2,4-dichlorophenyl)-3- (hydroxymethyl)-2-(4-methoxyphenyl)-5-piperidin-l-yl- 1 ,5,6, 7-tetrahydro-4H- pyrrolo[3,2-c]pyridin-4-one (125 mg, 0.250 mmol) in DCM (3 ml) at 0 ⁰C. The reaction mixture was stirred at 0 ⁰C for 2 h and 45 min. MeOH (1 ml) was added and after 10 min pyridine (0.5 ml) was added. The solvent was removed by evaporation. Purified by flash chromatography (2.5-5% MeOH in DCM followed by 0-5% MeOH in DCM). A mixture of the crude, 3,3,3-trifluoro-propane-l-sulfonyl chloride (87 mg, 0.442 mmol) and TEA (45 mg, 0.442 mmol) in DCM (2 ml) was stirred at 0 ⁰C for 45 min. Water was added and the phases separated on a phase separator. The solvent was evaporated and the product purified by flash chromatography (50% EtOAc in heptane) to yield the title compound (37 mg, 23%). ¹H-NMR (500 MHz, CD₂Cl₂) δ 7.56 (d, I H), 7.34-7.27 (m, 3H), 7.19 (d, 2H), 7.13 (d, IH), 4.65 (d, I H), 4.42 (d, IH), 3.78-3.68 (m, 2H), 3.61-2.88 (br, 4H), 3.55-3.48 (m, 2H), 3.42 (s, 3H), 2.88-2.76 (m, 2H), 2.76-2.57 (m, 2H), 1.86-1.52 (br, 4H), 1.52-1.38 (br, 2H).

HRMS Calcd for [C₂₉ H₃₀ Cl₂ F₃ N₃ O₅ S+H]⁺: 660.131. Found: 660.131. Example 4

4-[l-(2-chloro-4-fluorophenv0-3-(hvdroxymethv0-4-oxo-5-piperidin-l-yl-4.5,6,7- tetrahydro-lH-pyrrolo[3,2-c|pyridin-2-vHphenyl 3,3,3-trifluoropropane-l-sulfonate Step 1 1 -(2-chloro-4-fluorophenyl)-2-(4-methoxyphenyl)-5-piperidin- 1 -yl- 1 ,5,6 J- tetrahvdro-4H-pyrrolor3,2-clpyridin-4-one

4-[(2-chloro-4-fluorophenyl)amino]- 1 -piperidin- 1 -yl-5,6-dihydropyridin-2( lH)-one, (prepared by methods analogous to those described in Ex. 1 , Steps 1 -7 but using 2-chloro- 4-fluoroaniline instead of 2,4-dichloroaniline) (9.928 g, 30.661 mmol) was added to NaH (0.809 g, 33.727 mmol) suspended in dry THF (100 ml) at O ⁰C under nitrogen. After the resulting mixture had been stirred at O ⁰C for 15 min a mixture of 2-bromo-l-(4- methoxyphenyl)ethanone (10.250 g, 44.746 mmol) and tetrabutylammonium iodide (1.133 g, 3.066 mmol) dissolved in dry THF (100 ml) was added dropwise during 20 min. The reaction mixture was stirred at 0 ⁰C for 1 h and 25 min. Water (35 ml) was added and the solvent was removed by evaporation. The residue was partitioned between toluene and water. The organic phase was filtered and the solvent was removed by evaporation. The product was purified by flash chromatography (10-50 % EtOAc in toluene) to yield crude 4-[(2-chloro-4-fluorophenyl)amino]-3-[2-(4-methoxyphenyl)-2-oxoethyl]- 1 -piperidin- 1 -yl- 5,6-dihydropyridin-2(lH)-one (1.584 g) and l-(2-chloro-4-fluorophenyl)-2-(4- methoxyphenyl)-5-piperidin-l-yl-l,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (2.881 g). The crude 4-[(2-chloro-4-fluorophenyl)amino]-3-[2-(4-methoxyphenyl)-2- oxoethyl]-l -piperidin- l-yl-5,6-dihydropyridin-2(lH)-one (1.584 g) was dissolved in toluene (15 ml) and trifluoroacetic acid (50 ul, 0.676 mmol) was added. The reaction mixture was stirred at 60 C for 1 h and 25 min, adding more trifluoroacetic acid (50 ul, 0.676 mmol) after 45 min. The solvent was evaporated and the product purified by flash chromatography (10-40 % EtOAc in toluene) to yield the product as a yellow solid (3.344 g, 24 % totally over two steps). ¹H-NMR (400 MHz, CDCl₃) δ 7.26-7.09 (m, 2H), 7.00- 6.93 (m, 3H), 6.73-6.67 (m, 3H), 3.75-3.64 (m, 5H), 3.64-2.73 (br, 4H), 2.73-2.50 (m, 2H), 1.72- 1.53 (m, 4H), 1.47-1.34 (m, 2H). MS m/z 454 (M+H)⁺.

Step 2 1 -(2-chloro-4-fluorophenyl)-3-iodo-2-(4-methoxyphenyl)-5-piperidin- 1 -yl- 1 ,5,6,7- tetrahvdro-4H-pyrrolor3,2-clpyridin-4-one

N-iodosuccinimide (259 mg, 1.151 mmol) was added to l-(2-chloro-4-fluorophenyl)-2-(4- methoxyphenyl)-5-piperidin-l-yl-l,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (475 mg, 1.046 mmol) dissolved in DMF (10 ml). The reaction mixture was stirred at rt overnight with foil covering the flask. Next morning more N-iodosuccinimide (71 mg, 0.314 mmol) was added and 1 h later EtOAc and water were added. The phases were separated and the organic phase was washed with brine and evaporated. The product was purified by flash chromatography (5-10% EtOAc in toluene) to yield an orange solid (368 mg, 61%). ¹H-NMR (400 MHz, CDCl₃) δ 7.17-6.87 (m, 5H), 6.76-6.71 (m, 2H), 3.77-3.64

(m, 5H), 3.64-2.70 (br, 4H), 2.70-2.52 (m, 2H), 1.75-1.47 (br, 4H), 1.47-1.32 (br, 2H).

MS m/z 580 (M+H)⁺.

Step 3 Ethyl-3-[ 1 -(2-chloro-4-fluorophenyl)-2-(4-methoxyphenyl)-4-oxo-5-piperidin- 1 -yl-

4,5,6J-tetrahvdro-lH-pyrrolor3.2-clpyridin-3-vHacrylate

To 1 -(2-chloro-4-fluorophenyl)-3-iodo-2-(4-methoxyphenyl)-5-piperidin- 1 -yl- 1 ,5,6,7- tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (380 mg, 0.655 mmol), tetrabutylammonium chloride (200 mg, 0.721 mmol), palladium(II) acetate (7 mg, 0.033 mmol) and anhydrous sodium carbonate (76 mg, 0.721 mmol) under nitrogen was added dry DMF (8 ml) and acrylic acid ethyl ester (131 mg, 1.31 1 mmol). The reaction mixture was stirred at 80 ⁰C for 4 h and 25 min. Water and EtOAc were added and the phases separated. The organic phase was washed with brine and evaporated. The product was purified by flash chromatography (2-20% EtOAc in toluene) to yield a slightly yellow solid (243 mg, 67 %). ¹H-NMR (400 MHz, CDCl₃) δ 7.72 (d, IH), 7.16-6.86 (m, 6H), 6.72 (d, 2H), 4.10 (q, 2H), 3.74-3.63 (m, 5H), 3.63-2.64 (br, 4H), 2.64-2.46 (m, 2H), 1.83-1.47 (br, 4H), 1.47-1.32 (m, 2H), 1.21 (t, 3H). MS m/z 552 (M+H)⁺. Step 4 Ethyl-3-f 1 -(2-chloro-4-fluorophenyl)-2-(4-hydroxyphenyl)-4-oxo-5-piperidin- 1 -yl- 4,5,6J-tetrahvdro-lH-pyrrolor3,2-clpyridin-3-yl1acrylate

Ethyl-3-[ 1 -(2-chloro-4-fluorophenyl)-2-(4-methoxyphenyl)-4-oxo-5-piperidin- 1 -yl-4, 5,6,7- tetrahydro-lH-pyrrolo[3,2-c]pyridin-3-yl]acrylate (1.330 g, 2.409 mmol) was dissolved in DCM (60 ml) and the mixture was cooled with an ice bath. Boron tribromide (15 ml, IM in DCM) was added and the reaction mixture was stirred at 0 ⁰C for 1 h and 10 min. Water was added and the phases separated. The organic phase was washed with brine and evaporated to yield the crude product as an orange solid (1.296 g). MS m/z 538 (M+H)⁺. Step 5 Ethyl-3-f 1 -(2-chloro-4-fluorophenyl)-4-oxo-5-piperidin- 1 -yl-2-(4- { [(3.3,3- trifluoropropyl)sulfonyl]oxy}phenvπ-4,5,6,7-tetrahvdro-lH-pyrrolo[3,2-clpyridin-3- yllacrylate

To ethyl-3-[ 1 -(2-chloro-4-fluorophenyl)-2-(4-hydroxyphenyl)-4-oxo-5-piperidin- 1 -yl- 4,5,6,7-tetrahydro-lH-pyrrolo[3,2-c]pyridin-3-yl]acrylate (1.296 g) in DCM (25 ml) was added TEA (3.357 ml, 24.088 mmol) and 3,3,3-trifluoro-propane-l-sulfonyl chloride (2.368 g, 12.044 mmol) at 0 ⁰C. The reaction mixture was stirred at 0 ⁰C for 50 min, washed with water and 0.1 M HCl (aq) and evaporated to yield the crude product (1.682 g). MS m/z 698 (M+Η)⁺.

Step 6 4-[ l-(2-chloro-4-fluorophenyl)-3-formyl-4-oxo-5-piperidin- l-yl-4,5,6J-tetrahydro- lH-pyrrolo[3,2-c1pyridin-2-yllphenyl 3,3,3-trifluoropropane-l -sulfonate

Ethyl-3-[ l -(2-chloro-4-fluorophenyl)-4-oxo-5-piperidin-l-yl-2-(4-{[(3,3,3- trifluoropropyl)sulfonyl]oxy}phenyl)-4,5,6,7-tetrahydro-lH-pyrrolo[3,2-c]pyridin-3- yljacrylate (1.682 g) was dissolved in TΗF (40 ml) and water (20 ml) and sodium metaperiodate ( 1.546 g, 7.227 mmol) and osmium tetroxide (2.5% solution in tert-butanol, 1.00 ml, 0.080 mmol) were added. The reaction mixture was strirred at it. After 5 h and 15 min more osmium tetroxide (0.50 ml, 0.040 mmol) was added. The reaction was left overnight. Water and EtOAc were added, the phases separated and the organic phase washed with brine and evaporated. Purified by flash chromatography (15-30% ethyl acetate in toluene) to yield the product as a yellow solid (752 mg, 50% over three steps). ¹H-NMR (400 MHz, CDCl₃) δ 10.61 (s, I H), 7.23-6.87 (m, 7H), 3.79-3.65 (m, 2H), 3.65- 2.77 (br, 4H), 3.40-3.33 (m, 2H), 2.75-2.48 (m, 4H), 1.75-1.45 (br, 4H), 1.43-1.32 (m, 2H). MS m/z 628 (M+H)⁺.

Step 7 4-[ l-(2-chloro-4-fluorophenyl)-3-(hvdroxymethyl)-4-oxo-5-piperidin-l-yl-4, 5,6,7- tetrahvdro-lH-pyrrolo[3,2-clpyridin-2-yllphenyl 3,3,3-trifluoropropane-l -sulfonate

4-[ l-(2-chloro-4-fluorophenyl)-3-formyl-4-oxo-5-piperidin-l-yl-4,5,6J-tetrahydro-lH- pyrrolo[3,2-c]pyridin-2-yl]phenyl 3,3,3-trifluoropropane-l -sulfonate (153 mg, 0.244 mmol) was dissolved in dry MeOH (5 ml) and NaBH₄ (18 mg, 0.487 mmol) was added. The reaction mixture was stirred at rt for 1 h and 30 min, adding more dry MeOH (2 ml) after 10 min. Water and DCM were added and the phases separated. The organic phase was washed with water and evaporated. Purified by flash chromatography (35% EtOAc in toluene). The product was precipitated from DCM/heptane and isolated by filtration to yield the title compound as a white solid (121 mg, 79%)

¹H-NMR (400 MHz, CDCl₃) δ 7.21-7.16 (m, IH), 7.13-6.99 (m, 5H), 6.96-6.88 (m, IH), 5.63 (t, IH), 4.65-4.47 (m, 2H), 3.78-3.64 (m, 2H), 3.57-2.53 (br, 4H), 3.44-3.37 (m, 2H), 2.79-2.53 (m, 4H), 1.79-1.49 (br, 4H), 1.46-1.35 (br, 2H). HRMS Calcd for [C₂₈ H₂₈ Cl F₄ N₃ O₅ S+H]⁺: 630.145. Found: 630.147.

Claims

Claims

1. A compound of formula I

in which R¹ represents a C₃.₇ alkyl group or a C₃.₇ alkylsulfonyl group, and additionally when R² represents a

group substituted by hydroxy or a C^alkoxy group then R¹ represents a C₃.7 alkyl group substituted by one or more fluoro, or a C₃.₇ alkylsulfonyl group substituted by one or more fluoro; R² represents a

group optionally substituted by hydroxy or a C^alkoxy group; is an optional additional bond between positions 6 and 7 but only when R² represents a C_Malkyl group substituted by hydroxy or by a Ci^alkoxy group; and

R³ represents fluoro or chloro; or a pharmaceutically acceptable salt thereof.

2. A compound of formula I as represented by formula IA

IA in which R¹ represents a C₃.₇ alkyl group or a C₃.₇ alkylsulfonyl group, and additionally when R² represents a C

i^alkyl group substituted by hydroxy or a group then R¹ represents a C₃.₇ alkyl group substituted by one or more fluoro, or a C₃.7 alkylsulfonyl group substituted by one or more fluoro; R² represents a C^aHcyl group optionally substituted by hydroxy or a Q^alkoxy group; is an optional additional bond between positions 6 and 7; and

R³ represents fluoro or chloro; or a pharmaceutically acceptable salt thereof.

3. A compound of formula I as represented by formula IB

IB in which in which R represents a C₃.₇ alkyl group, a C₃.₇ alkyl group substituted by one or more fluoro, a C₃.7 alkylsulfonyl group or a C₃.7 alkylsulfonyl group substituted by one or more fluoro;

R^2a represents a C^alkyl group; is an optional additional bond between positions 6 and 7; and

R³ represents fluoro or chloro; or a pharmaceutically acceptable salt thereof.

4. A compound of formula I as represented by formula IC

IC

in which R represents a C₃.₇ alkylsulfonyl group;

R² represents a

group optionally substituted by hydroxy or a C|.₃alkoxy group; is an optional additional bond between positions 6 and 7; and

R³ represents fluoro or chloro; or a pharmaceutically acceptable salt thereof.

5. A compound selected from one or more of the following: 4-[ l -(2,4-dichlorophenyl)-3-methyl-4-oxo-5-piperidin-l-yl-4,5,6,7-tetrahydro- lH- pyrrolo[3,2-c]pyridin-2-yl]phenyl propane- 1 -sulfonate;

2-(4-butoxyphenyl)- 1 -(2,4-dichlorophenyl)-3-methyl-5-piperidin- 1 -yl- 1 ,5,6,7-tetrahydro- 4H-pyrrolo[3,2-c]pyridin-4-one; 4-[ l-(2,4-dichlorophenyl)-3-(methoxymethyl)-4-oxo-5-piperidin-l-yl-4,5,6,7-tetrahydro- lH-pyrrolo[3,2-c]pyridin-2-yl]phenyl 3,3,3-trifluoropropane-l -sulfonate; or 4-[ l-(2-chloro-4-fluorophenyl)-3-(hydroxymethyl)-4-oxo-5-piperidin-l-yl-4,5,6,7- tetrahydro-lH-pyrrolo[3,2-c]pyridin-2-yl]phenyl 3,3,3-trifluoropropane-l -sulfonate; or a pharmaceutically acceptable salt thereof.

6. A compound of formula I as claimed in any one of claims 1 to 5 for use as a medicament.

7. A pharmaceutical formulation comprising a compound of formula I as claimed in any one of claims 1 to 5 and a pharmaceutically acceptable adjuvant, diluent or carrier.

8. Use of a compound of formula I as claimed in any one of claims 1 to 5 in the preparation of a medicament for the treatment or prophylaxis of obesity, psychiatric disorders such as psychotic disorders, schizophrenia and bipolar disorders, anxiety, anxio- depressive disorders, depression, cognitive disorders, memory disorders, obsessive- compulsive disorders, anorexia, bulimia, attention disorders, epilepsy, and related conditions, dementia, neurological disorders, Parkinson's Disease, Ηuntington's Chorea and Alzheimer's Disease, immune, cardiovascular, reproductive and endocrine disorders, septic shock, diseases related to the respiratory and gastrointestinal systems, and extended abuse, addiction and/or relapse indications.

9. A method of treating obesity, psychiatric disorders, psychotic disorders, schizophrenia and bipolar disorders, anxiety, anxio-depressive disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorders, anorexia, bulimia, attention disorders, epilepsy, and related conditions, neurological disorders, Parkinson's Disease, Ηuntington's Chorea and Alzheimer's Disease, immune, cardiovascular, reproductive and endocrine disorders, septic shock, diseases related to the respiratory and gastrointestinal system, and extended abuse, addiction and/or relapse indications, comprising administering a pharmacologically effective amount of a compound of formula I as claimed in as claimed in any one of claims 1 to 5 to a patient in need thereof.

10. A compound as defined in as claimed in any one of claims 1 to 5 for use in the treatment of obesity.

1 1. A compound of formula II

in which R represents a C₃.7 alkyl group, a C₃.7 alkyl group substituted by one or more fluoro, a C₃-₇ alkylsulfonyl group or a C₃.7 alkylsulfonyl group substituted by one or more fluoro;

R³ represents fluoro or chloro; and is an optional additional bond between positions 6 and 7.

12. A process for the preparation of a compound of formula III

in which R² and R³ are as defined in claim 1 comprising reacting a compound of formula IV

IV in which R² and R³ are as defined in claim 1 and R represents a protecting group for a phenolic hydroxy, with an acid, optionally in the presence of an inert solvent, at a temperature in the range of 0 to 100⁰C .

13. A compound of formula IV

IV in which R² and R³ are as defined in claim 1 and R represents a protecting group for hydroxy.

14. The compound IVa or IVb

15. A process for the preparation of a compound of formula IV comprising reacting a compound of formula V

V in which R , 3 is chloro or fluoro with a compound of formula VI

Vl in which R represents a protecting group for hydroxy, X is a leaving group and R² is as defined in claim 1 an inert solvent in the presence of a base at a temperature in the range of -80⁰C to 100⁰C optionally in the presence of a catalyst.

16. A compound of formula V

V in which R is chloro or fluoro.