WO2007135427A1

WO2007135427A1 - 1,4-disubstituted piperazine and 1,4-disubstituted azepane as 11 -beta-hydroxysteroid dehydrogenase 1 inhibitors

Info

Publication number: WO2007135427A1
Application number: PCT/GB2007/001902
Authority: WO
Inventors: Peter William Rodney Caulkett; William Mccoull; Martin Packer; Paul Robert Owen Whittamore
Original assignee: AstraZeneca UK Ltd; AstraZeneca AB
Current assignee: AstraZeneca UK Ltd; AstraZeneca AB
Priority date: 2006-05-23
Filing date: 2007-05-23
Publication date: 2007-11-29
Anticipated expiration: 2008-11-23

Abstract

Compounds of formula (I): wherein variable groups are defined within; their use in the inhibition of 11βHSD1, processes for making them and pharmaceutical compositions comprising them are described.

Description

1,4--DISUBSTITUTED PIPERAZINE AND 1,4-DISUBSTITUTED AZEPANE AS 11-BETA-HYDROXYSTEROID DEHYDROGENASE 1 INHIBITORS.

This invention relates to chemical compounds, or pharmaceutically acceptable salts thereof. These compounds possess human 11-β-hydroxysteroid dehydrogenase type 1 enzyme s (11 βHSDl) inhibitory activity and accordingly have value in the treatment of disease states including metabolic syndrome and are useful in methods of treatment of a warm-blooded animal, such as man. The invention also relates to processes for the manufacture of said compounds, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments to inhibit 11 βHSDl in a warm-blooded animal, such as man. Q Glucocorticoids (Cortisol in man, corticosterone in rodents) are counter regulatory hormones i.e. they oppose the actions of insulin (Dallman MF, Strack AM, Akana SF et al. 1993; Front Neuroendocrinol 14, 303-347). They regulate the expression of hepatic enzymes involved in gluconeogenesis and increase substrate supply by releasing glycerol from adipose tissue (increased lipolysis) and amino acids from muscle (decreased protein synthesis and 5 increased protein degradation). Glucocorticoids are also important in the differentiation of pre-adipocytes into mature adipocytes which are able to store triglycerides (Bujalska IJ et al. 1999; Endocrinology 140, 3188-3196). This may be critical in disease states where glucocorticoids induced by "stress" are associated with central obesity which itself is a strong risk factor for type 2 diabetes, hypertension and cardiovascular disease (Bjorntorp P & Q Rosmond R 2000; Int. J. Obesity 24, S80-S85)

It is now well established that glucocorticoid activity is controlled not simply by secretion of Cortisol but also at the tissue level by intracellular interconversion of active Cortisol and inactive cortisone by the 11-beta hydroxysteroid dehydrogenases, 11 βHSDl (which activates cortisone) and llβHSD2 (which inactivates Cortisol) (Sandeep TC & Walker 5 BR 2001 Trends in Endocrinol & Metab. 12, 446-453). That this mechanism may be important in man was initially shown using carbenoxolone (an anti-ulcer drug which inhibits both 11 βHSDl and 2) treatment which (Walker BR et al. 1995; J. Clin. Endocrinol. Metab. 80, 3155-3159) leads to increased insulin sensitivity indicating that 1 lβHSDl may well be regulating the effects of insulin by decreasing tissue levels of active glucocorticoids (Walker 0 BR et al. 1995; J. Clin. Endocrinol. Metab. 80, 3155-3159). Clinically, Gushing 's syndrome is associated with Cortisol excess which in turn is associated with glucose intolerance, central obesity (caused by stimulation of pre-adipocyte differentiation in this depot), dyslipidaemia and hypertension. Gushing' s syndrome shows a number of clear parallels with metabolic syndrome. Even though the metabolic syndrome is not generally associated with excess circulating Cortisol levels (Jessop DS et al. 2001 ; J. Clin. Endocrinol. Metab. 86, 4109-4114) abnormally high llβHSDl activity within tissues would be expected to have the same effect. In obese men it was shown that despite having similar or lower plasma Cortisol levels than lean controls, llβHSDl activity in subcutaneous fat was greatly enhanced (Rask E et al. 2001; J. Clin. Endocrinol. Metab. 1418-1421). Furthermore, the central fat, associated with the metabolic syndrome expresses much higher levels of 1 lβHSDl activity than subcutaneous fat (Bujalska IJ et al. 1997; Lancet 349, 1210-1213). Thus there appears to be a link between glucocorticoids, 1 lβHSDl and the metabolic syndrome. llβHSDl knock-out mice show attenuated glucocorticoid-induced activation of gluconeogenic enzymes in response to fasting and lower plasma glucose levels in response to stress or obesity (Kotelevtsev Y et al. 1997; Proc. Natl. Acad. Sci USA 94, 14924-14929) indicating the utility of inhibition of 1 lβHSDl in lowering of plasma glucose and hepatic glucose output in type 2 diabetes. Furthermore, these mice express an anti-atherogenic lipoprotein profile, having low triglycerides, increased HDL cholesterol and increased apo-lipoprotein AI levels. (Morton NM et al. 2001 ; J. Biol. Chem. 276, 41293-41300). This phenotype is due to an increased hepatic expression of enzymes of fat catabolism and PP ARa. Again this indicates the utility of 1 lβHSDl inhibition in treatment of the dyslipidaemia of the metabolic syndrome.

The most convincing demonstration of a link between the metabolic syndrome and 11 βHSD 1 comes from recent studies of transgenic mice over-expressing 11 βHSD 1

(Masuzaki H et al. 2001; Science 294, 2166-2170). When expressed under the control of an adipose specific promoter, llβHSDl transgenic mice have high adipose levels of corticosterone, central obesity, insulin resistant diabetes, hyperlipidaemia and hyperphagia. Most importantly, the increased levels of llβHSDl activity in the fat of these mice are similar to those seen in obese subjects. Hepatic 11 βHSDl activity and plasma corticosterone levels were normal, however, hepatic portal vein levels of corticosterone were increased 3 fold and it is thought that this is the cause of the metabolic effects in liver.

Overall it is now clear that the complete metabolic syndrome can be mimicked in mice simply by overexpressing llβHSDl in fat alone at levels similar to those in obese man. 11 βHSD 1 tissue distribution is widespread and overlapping with that of the glucocorticoid receptor. Thus, llβHSDl inhibition could potentially oppose the effects of glucocorticoids in a number of physiological/pathological roles. 1 lβHSDl is present in human skeletal muscle and glucocorticoid opposition to the anabolic effects of insulin on protein turnover and glucose metabolism are well documented (Whorwood CB et al. 2001; J. Clin. Endocrinol. Metab. 86, 2296-2308). Skeletal muscle must therefore be an important target for 1 lβHSDl based therapy.

Glucocorticoids also decrease insulin secretion and this could exacerbate the effects of glucocorticoid induced insulin resistance. Pancreatic islets express llβHSDl and carbenoxolone can inhibit the effects of 11-dehydocorticosterone on insulin release (Davani B et al. 2000; J. Biol. Chem. 275, 34841 -34844). Thus in treatment of diabetes 11 βHSD 1 inhibitors may not only act at the tissue level on insulin resistance but also increase insulin secretion itself.

Skeletal development and bone function is also regulated by glucocorticoid action.

I lβHSDl is present in human bone osteoclasts and osteoblasts and treatment of healthy volunteers with carbenoxolone showed a decrease in bone resorption markers with no change in bone formation markers (Cooper MS et al 2000; Bone 27, 375-381). Inhibition of

I 1 βHSDl activity in bone could be used as a protective mechanism in treatment of osteoporosis.

Glucocorticoids may also be involved in diseases of the eye such as glaucoma. 11 βHSDl has been shown to affect intraocular pressure in man and inhibition of 11 βHSD 1 may be expected to alleviate the increased intraocular pressure associated with glaucoma (Rauz S et al. 2001; Investigative Opthalmology & Visual Science 42, 2037-2042).

There appears to be a convincing link between 1 lβHSDl and the metabolic syndrome both in rodents and in humans. Evidence suggests that a drug which specifically inhibits 11 βHSD 1 in type 2 obese diabetic patients will lower blood glucose by reducing hepatic gluconeogenesis, reduce central obesity, improve the atherogenic lipoprotein phenotype, lower blood pressure and reduce insulin resistance. Insulin effects in muscle will be enhanced and insulin secretion from the beta cells of the islet may also be increased.

Currently there are two main recognised definitions of metabolic syndrome.

1) The Adult Treatment Panel (ATP III 2001 JMA) definition of metabolic syndrome indicates that it is present if the patient has three or more of the following symptoms:

> Waist measuring at least 40 inches (102 cm) for men, 35 inches (88 cm) for women;

> Serum triglyceride levels of at least 150 mg/dl (1.69 mmol/1);

> HDL cholesterol levels of less than 40 mg/dl (1.04 mmol/1) in men, less than 50 mg/dl (1.29 mmol/1) in women; > Blood pressure of at least 135/80 mm Hg; and / or

> Blood sugar (serum glucose) of at least 110 mg/dl (6.1 mmol/1).

2) The WHO consultation has recommended the following definition which does not imply causal relationships and is suggested as a working definition to be improved upon in due course: >^■ The patient has at least one of the following conditions: glucose intolerance, impaired glucose tolerance (IGT) or diabetes mellitus and/or insulin resistance; together with two or more of the following:

> Raised Arterial Pressure;

> Raised plasma triglycerides > Central Obesity

> Microalbuminuria

We have found that the compounds defined in the present invention, or a pharmaceutically acceptable salt thereof, are effective llβHSDlinhibitors, and accordingly have value in the treatment of disease states associated with metabolic syndrome. Accordingly there is provided a compound of formula (1) or a salt thereof:

(1) wherein:

Ring A is phenyl, optionally substituted by 1, 2 or 3 substituents independently selected from

R¹; R¹ is selected from hydroxy, nitro, halo, trifluoromethyl, Ci_-4alkyl, hydroxyC_1-4alkyl,

CF₃CH(OH)-, CF₃C(Me)(OH)-, C_Malkoxy, cyano, C_1-4alkylsulfonyl, C_1-4alkylcarbonyl and

C_1-4alkylcarbonylamino;

Ring B is pyridyl, optionally substituted in the 2-, 2'-, 3- or 3'- positions (relative to the point of attachment) (where available) by 1 or 2 substituents independently selected from R², and/or substituted on the 4-position (relative to the point of attachment) (where available) with a substituent selected from R³;

R² is selected from halo, cyano, trifluoromethyl, d^alkyl and Ci_-4alkoxy;

R³ is selected from halo, cyano, Ci_-3alkylsulfonyl and -CONR⁴R⁵;

R⁴ and R⁵ are independently selected from hydrogen and C_1-4alkyl; or R⁴ and R⁵ together with the nitrogen to which they are attached form an azetidinyl or pyrrolidinyl ring; n is O, 1 or 2;

R⁶ is selected from methyl and hydroxymethyl;

L¹ is selected from -CH₂-, -CH₂CH₂-, -CH(Me)- and -CMe₂-; provided that: when Ring A is unsubstituted phenyl, L¹ is CH₂ and n = 0 then Ring B is not unsubstituted 2- pyridyl.

It will be understood that the formula (1) encompasses the following formulae (IA)

(containing a piperazine ring) and (IB) (containing a homopiperazine ring):

(IA)

(IB)

It will be understood that each R⁶ group may be attached to any carbon atom in the piperazine or homopiperazine ring, including gem di-sύbstitution.

In this specification the term "alkyl" includes both straight and branched chain alkyl groups but references to individual alkyl groups such as "propyl" are specific for the straight chain version only. For example, "Ci-ealkyl" and "C_1-4alkyl" includes propyl, isopropyl and t-butyl. However, references to individual alkyl groups such as 'propyl' are specific for the straight chained version only and references to individual branched chain alkyl groups such as 'isopropyl' are specific for the branched chain version only. A similar convention applies to other radicals therefore "Ci^alkylcarbonyl" would include prop-1-ylcarbonyl, but-3- ylcarbonyl.

The term "halo" refers to fluoro, chloro, bromo and iodo. Where optional substituents are chosen from "one or more" groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.

Examples of "C_1-4alkoxy" include methoxy, ethoxy andpropoxy. Examples of "C₁-4alkylcarbonylamino" include formamido, acetamido and propionylamino. Examples of "C_1-3alkylsulphonyl" include mesyl and ethylsulphonyl. Examples of "C_Malkanoyl" include propionyl and acetyl. Examples of "Cμaalkyl" include methyl, ethyl, propyl andisopropyl. Examples of "C^aUcyl" include the examples of "C^aUcyl" as well as butyl and tert-butyl. Examples of "hydroxy C₁ _₄alkyl" include hydroxymethyl, hydroxyethyl, l-hydroxyprop-2-yl and l-hydroxyprop-3-yl. Examples of "Ci_-4alkylcarbonyl" include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl and tert-butylcarbonyl.

The present invention relates to the compounds of formula (1) as hereinbefore defined as well as to the salts thereof. Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula (1) and their pharmaceutically acceptable salts.

A suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid. In addition a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with o methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

Some compounds of the formula (1) may have chiral centres and/or geometric isomeric centres (E- and Z- isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers that possess llβHSDl s inhibitory activity.

The invention relates to any and all tautomeric forms of the compounds of the formula

(1) that possess llβHSDl inhibitory activity.

It is also to be understood that certain compounds of the formula (1) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be o understood that the invention encompasses all such solvated forms which possess 11 βHSD 1 inhibitory activity.

In one embodiment of the invention are provided compounds of formula (1); in an alternative embodiment are provided pharmaceutically-acceptable salts of compounds of formula (1). ₅ Particular values of variable groups are as follows. Such values may be used where appropriate with any of the definitions, claims or embodiments defined hereinbefore or hereinafter, for compounds of formula (1), (IA) and/or (IB).

1) Ring A is phenyl, substituted by 1 or 2 substituents independently selected from R¹

2) R¹ is selected from hydroxy, nitro, fluoro, chloro, trifluoromethyl, C_1-4alkyl, 0 hydroxyC_1-4alkyl, CF₃C(OH)(Me)-, cyano, methylcarbonyl, methylsulfonyl

3) R¹ is selected from fluoro, chloro, trifluoromethyl, methyl, hydroxyethyl, cyano, methylcarbonyl, methylsulfonyl and CF₃C(OH)(Me)- 4) R¹ is selected from fluoro, chloro, trifluoromethyl, methyl, hydroxyethyl, cyano, methylcarbonyl and methylsulfonyl

5) R¹ is selected from fluoro, chloro, trifluoromethyl, C].₄alkyl and CF₃C(OH)(Me)-

6) R¹ is selected from fluoro, chloro, trifluoromethyl and Cμ₄alkyl 7) R¹ is CF₃C(OH)(Me)-

8) Ring B is 2-pyridyl or 4-pyridyl

9) Ring B is substituted in the 2- and/or 2'- positions (relative to the point of attachment) by one or two, as appropriate, substituents independently selected from R², particularly wherein R² is selected from chloro, fluoro and trifluoromethyl 10) Ring B is substituted on the 4- position (relative to the point of attachment) (where available) with a substituent selected from R³

11) R² is selected from fluoro, chloro, cyano, trifluoromethyl, C_1-4alkyl and C_1-4alkoxy

12) R² is selected from fluoro, chloro, cyano, trifluoromethyl, C_1-4alkyl and methoxy

13) R² is selected from chloro, fluoro and trifluoromethyl 14) R² is 3-trifluoromethylpyrid-2-yl or 3,5-dichloroρyrid-4-yl

15) R³ is selected from fluoro, chloro, cyano, d-salkylsulfonyl, -CONHMe and -CONMe₂

16) R³ is -CONR⁴R⁵ wherein R⁴ and R⁵ together with the nitrogen to which they are attached form an azetidinyl or pyrrolidinyl ring

17) n is 0 or 1 18) n is O

19) R⁶ is methyl

20) R⁶ is hydroxymethyl

21) L¹ is -CH₂- or -CH₂CH₂, particularly -CH₂-

22) L¹ is -CH(Me)- 23) L¹ is -CMe₂-

In another aspect of the invention, suitable compounds of the invention are any one or more of the Examples or a salt thereof.

In another aspect of the invention, suitable compounds of the invention are any one or more of the following or a salt thereof:

1 -benzylsulfonyl-4-(3 ,5-dichloropyridin-4-yl)- 1 ,4-diazepane; l-benzylsulfonyl-4-(3,5-dichloropyridin-4-yl)-2-methyl-piperazine; l-(3,5-dichloropyridin-4-yl)-4-[[3-(trifluoromethyl)phenyl]metliylsulfonyl]piperazine; l-[(3,4-dichlorophenyl)methylsulfonyl]-4-(3,5-dichloropyridin-4-yl)piperazine; l-(3,5-dichloropyridin-4-yl)-4-[(3-methylphenyl)methylsulfonyl]piperazine; l-(3,5-dichloropyridin-4-yl)-4-[(2-fluorophenyl)methylsulfonyl]piperazine; l-(3,5-dichloropyridin-4-yl)-4-[(3-fluorophenyl)methylsulfonyl]piperazine; l-[(2-chlorophenyl)methylsulfonyl]-4-(3,5-dichloropyridin-4-yl)piρerazine; l-[(3-chlorophenyl)methylsulfonyl]-4-(3,5-dichloropyridin-4-yl)piρerazine; l-[(2,4-dichlorophenyl)methylsulfonyl]-4-(3,5-dichloropyridin-4-yl)piperazine; l-(3,5-dichloropyridin-4-yl)-4-[(3-nitrophenyl)methylsulfonyl]piperazine; l-[(2-fluorophenyl)methylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine; l-[(2-fluorophenyl)methylsulfonyl]-2-methyl-4-[3-(trifluoromethyl)pyridin-2-yl]ρiperazine; l-[(2-fluorophenyl)methylsulfonyl]-4-[3-(trifluorometliyl)pyridin-2-yl]-l,4-diazepane;

2-[4-[(2-fluorophenyl)methylsulfonyl]-3-methyl-piperazin-l-yl]pyridine-3-carbonitrile;

1 - [(2-fluorophenyl)methylsulfonyl] -2,2-dimethyl-4- [3 -(trifluoromethyl)pyridin-2- yl]piperazine;

[l-[(2-fluorophenyl)methylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-2- yl]methanol; l-[[4-(trifluoromethyl)phenyl]methylsulfonyl]-4-[3-(trifluoromethyl)pyridm-2-yl]piperazine; l-[[3-(trifluoromethyl)phenyl]methylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piρerazine; l-[(4-fluorophenyl)methylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine; l-[(3-fluorophenyl)methylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine;

1 - [(2-chlorophenyl)methylsulfonyl] -4- [3 -(trifluoromethyl)pyridin-2-yl]piperazine; l-[(3-chlorophenyl)methylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine; l-[[2-(trifluoromethyl)phenyl]methylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piρerazine; l~[(2,6-difluorophenyl)methylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piρerazine; l-[l-(2-fluoroρhenyl)ethylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine; l-[2-(2-fluorophenyl)propan-2-ylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine; l-[3-[[4-[3-(trifluoromethyl)pyridin-2-yl]piρerazin-l-yl]sulfonylmethyl] ρhenyl]ethanone; l-[4-[[4-[3-(trifluoromethyl)pyridin-2-yl]piρerazin-l-yl]sulfonylmethyl]phenyl]ethanone; 1,1,1 -trifluoro-2-[3-[[4-[3-(trifluoromethyl)pyridin-2-yl]piperazm-l - yl]sulfonylmethyl]phenyl]propan-2-ol; 1,1,1 -trifluoro-2- [4- [[4-[3 -(trifluoromethyl)pyridin-2-yl]piperazin- 1 - yl] sulfonylmethyl]phenyl]propan-2-ol; and

1 -[3 - [[4- [3 -(trifluoromethyl)pyridin-2-yl]piperazin- 1 -yl] sulfonylmethyl]phenyl] ethanol.

Another aspect of the present invention provides a process for preparing a compound of formula (1) or a pharmaceutically acceptable salt thereof which process (wherein variable groups are, unless otherwise specified, as defined in formula (I)) comprises of: a) reaction of a compound of Formula (2) with a compound of Formula (3):

(2) (3)

wherein X¹ is a leaving group; or b) reaction of a compound of Formula (4) with a compound of Formula (5):

(4) (5) wherein X² is a leaving group; or c) reaction of a compound of Formula (6) with an organometallic reagent to give a compound of Formula (7):

(6) (7)

and thereafter if necessary or desirable: i) converting a compound of the formula (1) into another compound of the formula (1); ii) removing any protecting groups; iii) resolving enantiomers; iv) forming a salt thereof.

Examples of conversions of a compound of Formula (1) into another compound of Formula (1), well known to those skilled in the art, include functional group interconversions such as hydrolysis, hydrogenation, hydrogenolysis, oxidation or reduction, and/or further functionalisation by standard reactions such as amide or metal-catalysed coupling, or nucleophilic displacement reactions.

Suitable conditions for the above processes a) to c) are as follows. a) Process a) may be carried out in a suitable solvent such as DCM, DMF, pyridine or water, typically with the addition of a base such as triethylamine, DIPEA, pyridine, or aqueous sodium hydroxide.

Compounds of formula (3) may be made by reaction of a compound of Formula (8) with a compound of Formula (9):

(8) (9) wherein X³ is a leaving group and R is hydrogen or a suitable protecting group, followed by removal of said protecting group if appropriate; b) Process b) may be carried out without solvent, or in a suitable solvent such as DMA, DMF or xylene; typically the reaction is carried out without solvent at elevated temperature, using Microwave or conventional heating.

Compounds of formula (4) may be made by reaction of a compound of Formula (10) with a compound of Formula (11):

(10) (11)

wherein X⁴ is a leaving group and R is hydrogen or a suitable protecting group, followed by removal of said protecting group if appropriate. c) Process c) is typically carried out in an anhydrous aprotic solvent such as THF or diethyl ether; examples of suitable organometallic reagents for process c) are alkyl or aryl magnesium halides (Grignard reagent), alkyl or aryl lithium, or trimethyl (trifluoromethyl) silane (Ruppert's reagent). Suitable examples of leaving groups for processes a) to c) are: fluoro, chloro, bromo, iodo, mesylate, tosylate or triflate.

Suitable examples of protecting groups for processes a) to c) are: tert-butyl oxycarbonyl (Boc), benzyloxycarbonyl (Z), acetyl or trifluoracetyl.

The reactions described above may be performed under standard conditions known to the person skilled in the art. The intermediates described above are commercially available, are known in the art or may be prepared by known procedures and/or by the procedures shown above.

It will be appreciated that certain of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group. Particular examples of modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.

It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for illustration see T. W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein. A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or ^-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a /-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example hydroxylamine, or with hydrazine. A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon. A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a ^-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifiuoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.

As stated hereinbefore the compounds defined in the present invention possess 11 βHSDl inhibitory activity. These properties may be assessed using the following assay. Assay

The conversion of cortisone to the active steroid Cortisol by 11 βHSDl oxo-reductase activity, can be measured using a competitive homogeneous time resolved fluorescence assay (HTRF) (CisBio International, R&D, Administration and Europe Office, In Vitro Technologies — HTRF® / Bioassays BP 84175, 30204 Bagnols/Ceze Cedex, France. Cortisol bulk HTRF kit: Cat No. 62CORPEC).

The evaluation of compounds described herein was carried out using a baculovirus expressed N terminal 6-His tagged full length human 1 lβHSDl enzyme(*l). The enzyme was purified from a detergent solublised cell lysate, using a copper chelate column. Inhibitors of 11 βHSDl reduce the conversion of cortisone to Cortisol, which is identified by an increase in signal, in the above assay.

Compounds to be tested were dissolved in dimethyl sulphoxide (DMSO) to 1OmM and diluted further in assay buffer containing 10% DMSO to 10 fold the final assay concentration. Diluted compounds were then plated into black 384 well plates (Matrix, Hudson NH, USA). The assay was carried out in a total volume of 20μl consisting of cortisone (Sigma, Poole, Dorset, UK, 16OnM), glucose-6-phosphate (Roche Diagnostics, ImM), NADPH (Roche Diagnostics, lOOμM), glucose-6-phosρhate dehydrogenase (Roche Diagnostics, 12.5μg/ml), EDTA (Sigma, Poole, Dorset, UK, ImM), assay buffer (K₂HPO₄ZKH₂PO₄, 10OmM) pH 7.5, recombinant 1 iβHSDl (1.5μg/ml) plus test compound. The assay plates were incubated for 25 minutes at 37°C after which time the reaction was stopped by the addition of lOμl of 0.5mM glycerrhetinic acid plus cortisol-XL665. lOμl of anti-cortisol Cryptate was then added and the plates sealed and incubated for 6 hours at room temperature. Fluorescence at 665nm and 620nm was measured and the 665nm:620nm ratio calculated using an Envision plate reader.

This data was then used to calculate IC₅₀ values for each compound (Origin 7.5, Microcal software, Northampton MA, USA).

•1 The Journal of Biological Chemistry, Vol. 26, No 25, ppl6653 - 16658

Compounds of the present invention typically show an IC₅0 of less than 30μM, and preferably less than 5 uM. For example, the following results were obtained:

According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the Examples, or a pharmaceutically acceptable salt thereof, as defined hereinbefore in association with a pharmaceutically-acceptable diluent or carrier. The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing). In general, compositions in a form suitable for oral use are preferred.

The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.

Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p_-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.

Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p_-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxy ethylene sorbitan monooleate. The emulsions may also contain sweetening, flavouring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.

The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.

Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metere'd quantity of active ingredient. For further information on formulation the reader is referred to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

We have found that the compounds defined in the present invention, or a pharmaceutically acceptable salt thereof, are effective 11 βHSD 1 inhibitors, and accordingly have value in the treatment of disease states associated with metabolic syndrome.

It is to be understood that where the term "metabolic syndrome" is used herein, this relates to metabolic syndrome as defined in 1) and/or 2) or any other recognised definition of this syndrome. Synonyms for "metabolic syndrome" used in the art include Reaven's Syndrome, Insulin Resistance Syndrome and Syndrome X. It is to be understood that where the term "metabolic syndrome" is used herein it also refers to Reaven's Syndrome, Insulin Resistance Syndrome and Syndrome X.

According to a further aspect of the present invention there is provided a compound of formula (1), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in a method of prophylactic or therapeutic treatment of a warm-blooded animal, such as man.

Thus according to this aspect of the invention there is provided a compound of formula (1), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use as a medicament.

According to another feature of the invention there is provided the use of a compound of formula (1), or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the production of an 11 βHSDl inhibitory effect in a warm-blooded animal, such as man. Where production of or producing an 1 lβHSDl inhibitory effect is referred to suitably this refers to the treatment of metabolic syndrome. Alternatively, where production of an 1 lβHSDl inhibitory effect is referred to this refers to the treatment of diabetes, obesity, hyperlipidaemia, hyperglycaemia, hyperinsulinemia or hypertension, particularly diabetes and 5 obesity. Alternatively, where production of an 11 βHSDl inhibitory effect is referred to this refers to the treatment of glaucoma, osteoporosis, tuberculosis, dementia, cognitive disorders or depression.

Alternatively, where production of an 1 lβHSDl inhibitory effect is referred to this refers to the treatment of cognitive disorders, such as improving the cognitive ability of an io individual, for example by improvement of verbal fluency, verbal memory or logical memory, or for treatment of mild cognitive disorders. See for example WO03/086410 and references contained therein, and Proceedings of National Academy of Sciences (PNAS), 2001, 98(8), 4717-4721.

Alternatively, where production of an 1 lβHSDl inhibitory effect is referred to this I₅ refers to the treatment of, delaying the onset of and/or reducing the risk of atherosclerosis - see for example J. Experimental Medicine, 2005, 202(4), 517-527.

Alternatively, where production of an 1 lβHSDl inhibitory effect is referred to this refers to the treatment of Alzheimers and/or neurodegenerative disorders.

According to a further feature of this aspect of the invention there is provided a ₂o method for producing an 1 lβHSDl inhibitory effect 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 (1), or a pharmaceutically acceptable salt thereof.

In addition to their use in therapeutic medicine, the compounds of formula formula (1), or a pharmaceutically acceptable salt thereof, are also useful as pharmacological tools in ₂₅ the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of 1 lβHSDl in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.

The inhibition of 1 lβHSDl described herein may be applied as a sole therapy or may involve, in addition to the subject of the present invention, one or more other substances 30 and/or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment. Simultaneous treatment may be in a single tablet or in separate tablets. For example agents than might be co-administered with 11 βHSD 1 inhibitors, particularly those of the present invention, may include the following main categories of treatment:

1) Insulin and insulin analogues; 2) Insulin secretagogues including sulphonylureas (for example glibenclamide, glipizide), prandial glucose regulators (for example repaglinide, nateglinide), glucagon-like peptide 1 agonist (GLPl agonist) (for example exenatide, liraglutide) and dipeptidyl peptidase IV inhibitors (DPP-IV inhibitors);

3) Insulin sensitising agents including PPARγ agonists (for example pioglitazone and rosiglitazone);

4) Agents that suppress hepatic glucose output (for example metformin);

5) Agents designed to reduce the absorption of glucose from the intestine (for example acarbose);

6) Agents designed to treat the complications of prolonged hyperglycaemia; e.g. aldose reductase inhibitors

7) Other anti-diabetic agents including phosotyrosine phosphatase inhibitors, glucose 6 - phosphatase inhibitors, glucagon receptor antagonists, glucokinase activators, glycogen phosphorylase inhibitors, fructose 1,6 bisphosphastase inhibitors, glutamine:fructose -6-phosphate amidotransferase inhibitors 8) Anti-obesity agents (for example sibutramine and orlistat);

9) Anti- dyslipidaemia agents such as, HMG-CoA reductase inhibitors (statins, eg pravastatin); PP ARa agonists (fibrates, eg gemfibrozil); bile acid sequestrants (cholestyramine); cholesterol absorption inhibitors (plant stanols, synthetic inhibitors); ileal bile acid absorption inhibitors (IBATi), cholesterol ester transfer protein inhibitors and nicotinic acid and analogues (niacin and slow release formulations);

10) Antihypertensive agents such as, β blockers (eg atenolol, inderal); ACE inhibitors (eg lisinopril); calcium antagonists (eg. nifedipine); angiotensin receptor antagonists (eg candesartan), α antagonists and diuretic agents (eg. furosemide, benzthiazide); l l)Haemostasis modulators such as, antithrombotics, activators of fibrinolysis and antiplatelet agents; thrombin antagonists; factor Xa inhibitors; factor Vila inhibitors; antiplatelet agents (eg. aspirin, clopidogrel); anticoagulants (heparin and Low molecular weight analogues, hirudin) and warfarin; and

12) Anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs (eg. aspirin) and steroidal anti-inflammatory agents (eg. cortisone). In the above other pharmaceutical composition, process, method, use and medicament manufacture features, the alternative and preferred embodiments of the compounds of the invention described herein also apply. Examples

The invention will now be illustrated in the following Examples, in which standard techniques known to the skilled chemist and techniques analogous to those described in these Examples may be used where appropriate, and in which, unless otherwise stated: (i) evaporations were carried out by rotary evaporation in vacuo and where applicable were carried out after removal of residual solids such as drying agents by filtration; (ii) all reactions were carried out under an inert atmosphere at ambient temperature, typically in the range 18-25°C, with solvents of HPLC grade under anhydrous conditions, unless otherwise stated;

(iii) yields are given for illustration only and are not necessarily the maximum attainable; (iv) the structures of the end products of the formula (1) were generally confirmed by proton nuclear magnetic resonance (NMR) and mass spectral techniques; magnetic resonance chemical shift values were measured in deuterated DMSO (unless otherwise stated) on the delta scale (ppm downfield from tetramethylsilane); proton data is quoted unless otherwise stated; spectra were recorded on a Bruker Avance 400MHz spectrometer; and peak multiplicities are shown as follows: s, singlet; d, doublet; dd, double doublet; t, triplet; tt, triple triplet; q, quartet; tq, triple quartet; m, multiplet; br, broad; LCMS were recorded on a system comprising Waters 2790 LC equipped with a Waters 996 Photodiode array detector and Micromass ZMD MS (using a Phenomenex® Synergi 4μ MAX-RP 8OA 50x2 mm column), or a Waters 2795 LC equipped with a Waters 2996 Photodiode array detector and Micromass ZQ MS (using a Phenomenex® Gemini 5μ Cl 8 1 lOAngstrom 50x2 mm column), and eluting with a flow rate of 1.1 ml/min with 5% (Water/Acetonitrile (1 : 1) + 1% formic acid) and a gradient increasing from 0-95% of acetonitrile over the first 4 minutes, the balance (95-0%) being water; mass spectra (MS) (loop) were recorded on a Micromass LCT equipped with HP 1100 detector, or a Thermo LCQ; unless otherwise stated the mass ion quoted is (MH-H⁺);

(v) intermediates were fully characterised unless otherwise stated and purity was assessed by LCMS and NMR analysis; (vi) where solutions were dried magnesium sulphate was the drying agent;

(vii) where an Isolute SCX-2 column is referred to, this means an "ion exchange" extraction cartridge for adsorption of basic compounds, i.e. a polypropylene tube containing a benzenesulphonic acid based strong cation exchange sorbent, used according to the manufacturers instructions obtained from International Sorbent Technologies Limited, Dyffryn Business Park, Hengeod, Mid Glamorgan, UK, CF82 7RJ; viii) where an Isolute-NH2 column is referred to, this means an "ion exchange" extraction cartridge for adsorption of acidic compounds, i.e. a polypropylene tube containing a amino silane covalently bonded to a silica particle used according to the manufacturers instructions obtained from International Sorbent Technologies Limited, Dyffryn Business Park, Hengeod, Mid Glamorgan, UK, CF82 7RJ; ix) where as Isco CombiFlash Optix-10 parallel flash chromatography system is referred to this means an automated chromatography workstation capable of carrying out up to 10 purifications in parallel via flash chromatography using pre packed silica cartridges; x) where a "Biotage 9Og silica column" is referred to this means an automated chromatography workstation capable of carrying out up to 4 purifications in parallel via flash chromatography using pre packed silica cartridges, eg Si 12+M available from Biotage Inc. A Dyax Corp. Company; and xi) where a "Genevac HT4" is referred to, this means a centrifugal evaporator capable of the simultaneous evaporation of multiple samples supplied by Genevac Ltd, The Sovereign Centre, Farthing Road, Ipswich, Suffolk IPl 5AP, UK.

(xiii) the following abbreviations may be used hereinbefore or hereinafter: -

DCM Dichloromethane

DIPEA Di-isopropyl ethylamine

EtOAc Ethyl acetate [1] The m/z value for the (M+H)⁺ molecular ion is based on the ³⁵Cl isotope. When there are multiple chlorine atoms in the molecule, the m/z is based on the first peak of the isotope pattern.

Unless otherwise stated, all compounds containing one or more chiral centres exist in the (RS) (racemic) form.

Example 1 : 1-Benzylsulf onyl-4-(3,5-dichloropyridin-4-yl)-l,4-diazepane

A solution of l-(3,5-dichloropyridin-4-yl)-l,4-diazepane (Intermediate A, 100 mg, 0.41 mmol) in DCM (1 ml) was added to α-toluene sulfonyl chloride (79 mg, 0.41 mmol) under a nitrogen atomosphere. DIPEA (0.22 ml, 1.22 mmol) was then added and the mixture stirred overnight at ambient temperature. The reaction mixture was washed with water and the products isolated by flash column chromatography (Combi-Flash Optix 10 ^® on a 12g silica s cartridge, eluting with a 1 : 1 mixture of EtOAc and isohexane) to give the title compound as a colourless solid, ¹HNMR (400 MHz, CDCl₃) δ 1.90 - 1.96 (2H, m), 3.22 - 3.27 (4H, m), 3.33 (2H, t), 3.40 (2H, t), 4.27 (2H, s), 7.37 - 7.41 (5H, m), 8.39 (2H, s), m/z 400 (M+H)⁺ [I].

It will be appreciated that the above reaction may be performed with slight modifications, Q known to those skilled in the art, eg. order of addition of reagents, choice of base (DIPEA, triethylamine or pyridine may all be used); additionally, different methods of purification may be used, eg. normal phase or reverse phase silica may be used, together with the appropriate eluent(s). The following compounds were prepared by an essentially similar method: S

0

Example 2: l-benzylsulfonyl-4-(3,5-dichloropyridin-4-yl)-2-methyl-piperazine Example 3 : l-(3,5-dichloropyridin-4-yl)-4-[[3-(trifluoromethyl)phenyl] methylsulfonyl]piperazine Example 4: l-[(3,4-dichlorophenyl)methylsulfonyl]-4-(3,5-dichloropyridin-4-yl)piperazme Example 5 : 1 -(3 , 5-dichloropyridin-4-y l)-4- [(3 -methylρhenyl)methylsulfonyl]piperazine Example 6: 1 -(3,5-dichloropyridin-4-yl)-4-[(2-fluorophenyl)methylsulfonyl]piperazine Example 7: l-(3,5-dichloropyridin-4-yl)-4-[(3-fluorophenyl)methylsulfonyl]piperazήie Example 8 : 1 -[(2-chlorophenyl)methylsulfonyl]-4-(3 ,5-dichloropyridin-4-yl)piperazine Q Example 9: l-[(3-chlorophenyl)methylsulfonyl]-4-(3,5-dichloropyridin-4-yl)piperazine

Example 10: l-[(2,4-dichlorophenyl)metliylsulfonyl]-4-(3,5-dichloropyridin-4-yl)piperazine Example 11 : l-(3,5-dichloropyridin-4-yl)-4-[(3-nitrophenyl)methylsulfonyl]piperazine Example 12: 1 -[(2-fluorophenyl)methy lsulfonyl] -4- [3 -(trifluoromethyl)pyridin-2- yljpiperazine s Example 13: l-[(2-fluorophenyl)methylsulfonyl]-2-methyl-4-[3-(trifluorometliyl)pyridin-2- yljpiperazine

Example 14: 1- [(2-fluorophenyl)methylsulfonyl]-4- [3-(trifluoromethyl)pyridin-2-yl] - 1 ,4- diazepane Example 15: 2-[4-[(2-fluorophenyl)methylsulfonyl]-3-methyl-piρerazin-l-yl]pyridine-3- Q carbonitrile Example 16: 1 -[(2-fluorophenyl)methylsulfonyl]-2,2-dimethyl-4-[3-(trifluoromethyl)pyridin-

2-yl]piperazine

Example 17: [l-[(2-fluorophenyl)methylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2- yl]piperazin-2-yl]methanol Example 18: l-[[4-(trifluoromethyl)phenyl]methylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2- yljpiperazine

Example 19: l-[[3-(trifluoromethyl)phenyl]metliylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2- yl]piperazine

Example 20: 1 -[(4-fluorophenyl)methylsulfonyl]-4-[3-(trifluoromethyl)ρyridin-2- yl]piperazine

Example 21 : l-[(3-fluorophenyl)methylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2- yl]piperazine

Example 22 : 1 -[(2-chlorophenyl)methylsulfonyl] -4- [3 -(trifluoromethy l)pyridin-2- yl]piperazine Example 23: l-[(3-chlorophenyl)methylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2- yl]piperazine

Example 24: l-[[2-(trifluoromethyl)phenyl]methylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2- yl]piperazine

Example 25: l-[(2,6-difluoroρhenyl)methylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2- yljpiperazine

[2] Examples 16 and 17 were prepared by reacting the appropriate piperazine with n-butyl litium in THF at -65 ⁰C to -55 ⁰C under an atmosphere of argon, and adding the sulfonyl chloride to the anion thus generated.

Intermediates for Examples 1 - 25:

[3] The requisite l-(3,5-dichloropyridin-4-yl)piperazine starting material is available from commercial sources.

Intermediate A: l-(3,5-dichloroρyridin-4-yl)-l,4-diazepane

1,4-diazepane (5.49g, 54.8 mmol) and 3,4,5-trichloropyridine (2g, 3.0 mmol) were combined without solvent and the mixture heated with stirring at 90 ⁰C for 2.5 hours. The reaction mixture was cooled to room temperature and the product purified by flash column chromatography (CombiFlash ^® Companion ™ , 4Og silica column, eluting with a 10:1 mixture of DCM and methanol) to give the title compound as a yellow oil (2.06 g, 76% ); ¹H NMR (400 MHz, CDCl₃) δl.88 - 1.94 (2H, m), 3.02 - 3.04 (2H, m), 3.09 (2H, t), 3.34 - 3.37 (4H, m), 8.39 (2H, s), m/z 246 (M+H)⁺ [I].

Intermediate B: The requisite (RS)-I -(3,5-dichloropyridin-4-yl)-3-methyl-piperazine was prepared as follows:

(RS) l-benzyl-3-methyl-piperazine

5 (RS) 2-methylpiperazine (5.0g, 49.9 mmol) was dissolved in ethanol (28.7 ml) and the solution was treated sequentially with benzyl chloride (6.32g, 49.9 mmol) and sodium hydrogen carbonate (12.59g, 149.8 mmol). The resulting mixture was heated at reflux for 40 hours and then cooled to ambient temperature; the mixture was acidified to pH3 by the addition of aqueous hydrochloric acid HCl (approx. 1 M) and then extracted with DCM (3 x o 50 mL). The aqueous extract was basified by the addition of sodium hydroxide (approx IM), and then extracted with DCM (3 x 100 mL). The organic extracts were dried (MgSO₄) and concentrated in vacuo to give a yellow oil which was purified by flash column chromatography (4Og silica column, eluting with DCM containing 10% of methanol) to give the title compound as a pale yellow oil (which was contaminated with bis-benzylated 5 product) 2.36 g, 25% ,¹H NMR (400 MHz, CDCl₃) δ 1.01 (d, 3H), 1.66 (t, IH), 1.69 (s, IH), 2.77 (m, 2H), 2.93 (m, 3H), 3.49 (s, 2H), 7.28 (m, 5H). (RS) tert-butyl 4-benzyl-2-methyl-piperazine-l-carboxylate

A solution of di-tert-butyl-dicarbonate (3.03g, 13.89 mmol) in DCM (9 ml) was added to a solution of (RS) l-benzyl-3-methyl-piperazine (2.36g, 12.4 mmol) in DCM (32 ml) and the resulting solution was stirred overnight at ambient temperature under a nitrogen atmosphere. The reaction mixture was then partitioned between DCM (30 ml) and saturated NaHCO₃ soln. (30 ml); the layers were separated and the aqueous layer washed further with DCM (3 x 20 ml). The organic extracts were combined, dried (MgSO₄), and concentrated in vacuo to give an oil which was purified by flash column chromatography on silica, eluting with a mixture of isohexane and EtOAc (3:1 v/v) to give the title compound as a colourless oil, 3.41g, 95%,^!H NMR (400 MHz, CDCl₃) δ 1.24 (d, 3H), 1.45 (s, 9H), 2.00 (m, IH), 2.12 (dd, IH), 2.59 (d, IH), 2.75 (d, IH), 3.11 (m, IH), 3.47 (q, 2H), 3.80 (d, IH), 4.17 (s, IH), 7.32 (m, 5H).

(RS) tert-butyl 2-methylpiperazine-l-carboxylate

A mixture of (RS) tert-butyl 4-benzyl-2-methyl-piperazine-l-carboxylate (3.41 g, 11.7 mmol), ethanol (125 ml) and Pearlman's catalyst (0.854 g, 6.08 mmol) was hydrogenated at 36 psi at ambient temperature overnight. The mixture was filtered and the solids were washed successively with ethanol, DCM and MeOH. The combined filtrate and washings were concentrated in vacuo, redissolved in DCM, then filtered and concentrated in vacuo to give the title compound as a beige oil wt. 2.0 g, 86%; the NMR spectrum was consistent with that quoted in J. Org. Chem βO 4183 (1995). (RS) tert-butyl 4-(3,5-dichloropyridin-4-yl)-2-methyl-piperazine-l-carboxylate

(RS) tert-butyl 2-methylpiperazine-l-carboxylate (2.2Og, 10.98 mmol) and 3,4,5 trichloropyridine were combined and heated at 100 ⁰C for 64 hours. The reaction mixture was cooled to ambient temperature and purified by flash column chromatography (4Og silica column, eluting with DCM containing 0 - 10% of methanol) to give the title compound as a brown oil, 5.87 g, 100 %, ¹H NMR (400 MHz, DMSOd₆) δ 1.22 (3H, d), 1.42 (9H, s), 2.74- 3.09 (5H, m), 3.76 - 3.77 (2H, m), 7.96 (2H, s), m/z 346 (M+H)⁺ [I].

(RS)-l-(3,5-dichloropyridin-4-yl)-3-methyl-piperazine

(RS) tert-butyl 4-(3,5-dichloropyridin-4-yl)-2-methyl-piperazine-l-carboxylate (5.87g, 16.95 mmol) was treated with a solution of hydrogen chloride in dioxane (16 ml of 4M solution). The resulting mixture was stirred at ambient temperature overnight and then concentrated in vacuo to give a residue which was triturated with diethyl ether to give the title compound as a beige solid, 3.36 g, 70% yield, ¹H NMR (400 MHz, DMSO-d₆) δ 1.29 - 1.33 (3H, m), 3.21- 3.37 (3H, m), 3.37-3.52 (3H, m), 3.60-3.71 (IH, m), 7.95 (2H, s), 8.48 (IH, br), m/z 246 (M+H)⁺ [I].

Intermediate C: l-[3-(trifluoromethyl)pyridin-2-yl]piperazine

Piperazine (10.11 g, 117.58) and 2-chloro-3-(trifluoromethyl)pyridine (3.0 g, 23.51 mmol) were weighed into a round-bottomed flask and DMF (3 ml) was added. The mixture was heated to 90 ⁰C until the solid piperazine had melted and then stirred at 90 ⁰C for ¹A hour and then 70⁰C for a further hour. The reaction mixture was cooled to ambient temperature and EtOAc (150 ml) was added; the resulting solution was washed with water (150 ml) and then brine (100 ml). The organic phase was then dried (MgSO₄), filtered and concentrated in vacuo to give the title compound as a pale yellow oil, 4.14 g, 76% , ¹H NMR (400 MHz, CDCl₃) δ 3.01 (4H₅ 1), 3.26 (4H, t), 6.96 - 6.99 (IH, m), 7.85 - 7.87 (IH, m), 8.42 - 8.44 (IH, m), m/z 232 (M+H)⁺.

Intermediate D: 3-methyl-l-[3-(trifluoromethyl)pyridin-2-yl]piperazine

The title compound was synthesised in a manner essentially similar to that described for Intermediate A, starting from 2-chloro-3-(trifluoromethyl)pyridine and (RS) 2-methyl piperazine, ¹H NMR (400 MHz, DMSO-d₆) δ 0.96 - 0.98 (3H, d), 2.17 (IH, s), 2.73 - 2.91 (4H, m), 3.3-3.4 (3H,m), 7.12 - 7.15 (IH, m), 8.02 - 8.04 (IH, m), 8.49 - 8.50 (IH, m), m/z 246 (M+H)⁺.

Intermediate E: l-[3-(trifluoromethyl)pyridin-4-yl]-l ,4-diazepane

The title compound was synthesised in a manner essentially similar to that described for Intermediate A, starting from 2-chloro-3-(trifluoromethyl)pyridme and homopiperazine^H NMR (400 MHz, DMSO-d₆) δ 1.79 - 1.85 (2H, m), 2.77 (2H, t), 2.92 - 2.95 (2H, m), 3.42 (IH, s), 3.50 (2H, t), 3.58 (2H, t), 6.90 - 6.93 (IH, m), 7.93 - 7.96 (IH, m), 8.35 - 8.37 (IH, m), m/z 246 (M+H)⁺.

Intermediate F: (RS) 2-(3-methylpiperazin-l-yl)pyridine-3-carbonitrile

The title compound was synthesised in a manner essentially similar to that described for Intermediate A, starting from 2-chloro-3-cyano pyridine and (RS) 2-methyl piperazine^H NMR (400 MHz, DMSO-d₆) δ 2.55 - 2.60 (2H₅ m), 2.70 - 2.79 (2H, m), 2.90 - 2.97 (2H, m), 4.06 - 4.11 (2H, m), 6.86 - 6.89 (IH, m), 8.02 - 8.05 (IH, m), 8.38 - 8.40 (IH, m), m/z 203 (M+H)⁺.

Intermediate G: 3,3-dimethyl-l-[3-(trifluoromethyl)pyridin-2-yl]piperazine

A mixture of 2,2-dimethylpiperazine (200 mg, 1.75 mmol) and 2-chloro-3-(trifluoromethyl) pyridine (318 mg, 1.75 mmol) in butyronitrile (5 ml) was heated in the Biotage Intitiator Sixty™ for 2 hrs at 200°C. The reaction mixture was concentrated to a brown oil which was purified by chromatography (12g silica column eluting with a gradient of 0-20% methanol in DCM) to give the title compound, 366mg, 81%, ¹H NMR (400 MHz, DMSOd₆) δ 1.32 (6H, s), 3.09 (2H, s), 3.17 - 3.22 (4H, m), 7.32 - 7.35 (IH, m), 8.14 - 8.16 (IH, m), 8.60 - 8.62 (IH, s m), m/z 260 (M+H)⁺.

Intermediate H: (RS) [4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-2-yl]methanol

The title compound was synthesised in a manner essentially similar to that described for o Intermediate G, starting from 2-chloro-3-(trifluoromethyl) pyridine and (RS) 2- hydroxymethyl piperazine, ¹H NMR (400 MHz, DMSOd₆) δ 2.63 - 2.68 (IH, m), 2.83 - 2.94 (4H, m), 2.99 - 3.02 (IH, m), 3.17 (IH, d), 3.40 - 3.49 (2H₃ m), 4.77 (IH, t), 7.17 - 7.20 (IH, m), 8.05 - 8.07 (IH, m), 8.51 - 8.53 (IH, m), m/z 262 (M+H)⁺.

5 The requisite (RS) 2-hydroxymethyl piperazine may be prepared as described in J. Med. Chem. 36 (15) pp2075 - 2083 (1993). Example 26: l-fl-(2-FIuorophenyl)ethvIsulfonvIl-4-[3-(trifluoromethyl)pyridin-2- ylipiperazine

A solution of l-[(2-fluorophenyl)methylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2- yl]piperazine (186 mg, 0.46 mmol) in DMF (1.8 ml) was stirred at room temperature and sodium hydride (18.2 mg of a 60% dispersion in mineral oil, 0.46 mmol) was added in portions. The mixture was stirred until all effervescence had ceased and a colour change from clear colourless solution to a brown solution had been observed. Iodomethane (29 μl) was then added dropwise and the resulting yellow mixture was stirred for 1 h. A further portion of sodium hydride (18.2 mg of a 60% dispersion in mineral oil, 0.46 mmol) was added and the mixture was stirred over night at ambient temperature. EtOAc (20 ml) was added to the reaction, and the resulting mixture was washed with deionised water ( 5 x 20 ml). The organic portion was dried (MgSO₄) and concentrated in vacuo. The product was isolated by preparative HPLC to give the title compound as a colourless gum (25 mg), ¹H NMR (400 MHz, DMSO-d₆) δ 1.67 (3H, d), 3.00-3.15 (6H, m), 3.19 - 3.23 (2H, m), 4.82 (IH, q), 7.24 - 7.30 (3H, m), 7.42 - 7.47 (IH, m), 7.59 - 7.63 (IH, m), 8.08 - 8.11 (IH, m), 8.54 - 8.56 (IH, m), m/z 418 (M+H)⁺.

Example 27; l-f2-(2-fluorophenyl)propan-2-vIsulfonyll-4-f3-(trifluoromethyl)pyridin-2- yll piper azine

A solution of l-[(2-fluorophenyl)methylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2- yl]piperazine (100 mg, 0.25 mmol) in THF (0.98 ml) was stirred at room temperature and sodium hydride (20 mg of a 60% dispersion in mineral oil, 0.50 mmol,) was added. The mixture was stirred until all effervescence had ceased and iodomethane (31 μl, 0.50 mmol) was then added dropwise. The resulting yellow mixture was then stirred at ambient temperature for 2 days. Following this the crude mixture was concentrated in vacuo, the residue dissolved in EtOAc, and the solution washed with distilled water (10 ml) and brine (2 x 10 ml). The organics were dried (MgSO₄) and concentrated in vacuo to give a yellow solid which was then purified by flash column chromatography to give the title compound as a colourless crystalline solid (130 mg), ¹H NMR (400 MHz₅ DMSO-d₆) δ 1.83 (3H, s), 1.84 (3H, s), 3.01-3.09 (4H, m), 3.10-3.19 (4H, m), 7.19 - 7.28 (3H, m), 7.43 - 7.48 (IH, m), 7.65 - 7.69 (IH, m), 8.07 - 8.09 (IH, m), 8.54 - 8.56 (IH, m), m/z 432 (M+H)⁺.

The requisite l-[(2-fluorophenyl)methylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2- yl]piperazine starting material for Examples 26 and 27 was prepared as described in Example 12.

Example 28: l-f3-ff4-f3-(trifluoromethyl)pyridin-2-yllpiperazin-l-vnsulfonylmethyl1 phenyl] ethanone

A solution of l-[(3-bromophenyl)methylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2- yl]piperazine (1.0 g, 2.15 mmol) in 1,4-dioxan (6.5 ml) was treated with tris(dibenzylideneacetone)dipalladium (40 mg, 0.04 mmol) and triphenylarsine (53 mg, 0.17 mmol). The reaction mixture was degassed three times and then tributyl(l-ethoxyvinyl)tin (1.455 ml, 4.31 mmol) was added and the mixture stirred at 80 ⁰C under a nitrogen atmosphere for 16 hrs. The resulting ethoxyvinylether was worked up by filtration through an SCX-2 cartridge to give the required methylketone, which was then purified by flash column chromatography. The product was triturated with isohexane/diethylether to give the title compound as a grey solid, (537 mg, 58% yield) ¹H NMR (400 MHz, DMSO-d₆) 52.60 (3H, s), 3.18 (4H, m), 3.37 (4H,m), 4.62 (2H, s), 7.25 - 7.28 (IH, m), 7.57 (IH, t), 7.71 (IH, d), 7.97 - 7.99 (IH, m), 8.05 (IH, s), 8.09 - 8.11 (IH, m), 8.55 - 8.57 (IH, m), m/z 428 (M+H)⁺.

The requisite 1 -[(3-bromophenyl)methylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2- yl]piperazine starting material was prepared from (3-bromophenyl)methanesulfonyl chloride and l-[3-(trifluoromethyl)pyridin-2-yl]piperazine in a manner essentially similar to that described for Example I₃ ¹H NMR (400 MHz, DMSOd₆) δ 3.28 (4H, m), 3.29 (4H, m), 4.55 (2H, s), 7.23 - 7.28 (IH, m), 7.37 (IH, t), 7.44 - 7.46 (IH, m), 7.57 - 7.60 (IH, m), 7.66 (IH, t), 8.06 - 8.12 (IH, m), 8.56 - 8.57 (IH, m), m/z 466 (M+H)+ based on ⁸¹Br isotope.

Example 29: l-[4-[[443-(trifluoromethylWridin-2-yl1piperazin-l- yli sulf onylmethyll phenyl] ethanone

The title compound was prepared in a manner essentially similar to that described in Example 28, starting from l-[(4-bromophenyl)methylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2- yl]piperazine, ¹H NMR (400 MHz, DMSO-d₆) δ 2.60 (3H, s), 3.18-3.23 (4H, m), 3.29-3.33 (4H, m), 4.61 (2H, s), 7.25 - 7.28 (IH, m), 7.59 (2H, d), 7.98 (2H, d), 8.09 - 8.12 (IH, m), 8.56 - 8.57 (IH, m), m/z 428 (M+H)⁺.

The requisite l-[(4-bromophenyl)methylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2- yljpiperazine starting material was prepared from (4-bromophenyl)methanesulfonyl chloride and l-[3-(trifluoromethyl)pyridin-2-yl]piperazine piperazine in a manner essentially similar to that described for Example 1, ¹HNMR (400 MHz, DMSO-d₆) 63.19 (4H, m), 3.22-3.40 (4H, m), 4.52 (2H, s), 7.25 - 7.28 (IH, m), 7.38 - 7.41 (2H, m), 7.60 - 7.63 (2H, m), 8.09 - 8.12 (IH, m), 8.56 - 8.57 (IH, m), m/z 466 (M+H)+ based on ⁸¹Br isotope.

Example 30: lJ,l-Trifluoro-2-f3-fr4-r3-(trifluoromethvI)pyridin-2-yllpiperazm-l- yllsuIfonylmethyIlphenyllpropan-2-ol

A solution of l-[3-[[4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-l-yl] sulfonylmethyl] phenyl] ethanone (100 mg, 0.23 mmol) in THF (2ml) and was treated sequentially with (trifluoromethyl) trimethylsilane (0.15 niL, 0.24 mmol) and cesium fluoride (4 mg, 0.02 mmol). The reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere and was then quenched with a solution of HCl in dioxane (8 ml of 4M solution), and the resulting mixture stirred for 5 hours. The reaction mixture was then concentrated in vacuo to give a yellow oil which was purified by flash column chromatography (12g silica cartridge, eluting sequentially with neat isohexane, isohexane containing 40% v/v of ethyl acetate, then isohexane containing 80% v/v of ethyl acetate). The resulting product was further purified by preparative HPLC (C 18 Reversed Phase silica eluting with a gradient consisting of 5-95% acetonitrile in water, with the addition of TFA [0.2% ] to the eluant) to give the title compound as a colourless dry film, 38.5 mg, 34%, ¹H NMR (400 MHz, CDCl₃) δ 1.80 (3H, s), 2.98 - 3.06 (4H, m), 3.21 - 3.32 (4H, m), 3.81 (IH, br), 4.30 (2H, d), 7.12 - 7.15 (IH, m), 7.40 - 7.44 (IH, m), 7.50-7.55 (2H, m), 7.75 (IH₅ s), 7.86 - 7.93 (IH, m), 8.47 - 8.49 (IH, m), m/z 498 (M+H)⁺.

The requisite l-[3-[[4-[3-(trifluoromethyl)pyridin-2-yl]ρiperazin-l-yl] sulfonylmethyl] phenyl] ethanone starting material was prepared as described in Example 28.

Example 31: l,l,l-trifluoro-2-f4-[f4-f3-(trifluoromethyl)pyridin-2-yl1piperazin-l- yll sulfonylmethyll phenyll propan-2-ol

The title compound was prepared in an essentially similar manner to that described for Example 30, starting from l-[4-[[4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-l- yl]sulfonylmethyl]phenyl]ethanone, ¹H NMR (400 MHz, DMSO-d₆) δl.70 (3H, s), 3.16-3.23 (4H, m), 3.24-3.33, (4H₅ m), 4.50 (2H, s), 6.58 (IH, s), 7.25 - 7.28 (IH, m), 7.46 (2H, d), 7.61 (2H, d), 8.09 - 8.11 (IH, m), 8.56 - 8.57 (IH₅ m), m/z 498 (M+H)⁺. The requisite l-[4-[[4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-l- yl]sulfonylmethyl]phenyl]ethanone starting material was prepared as described in Example 29.

Example 32: l-[3-[[4-f3-(trifluoromethvDpyridin-2-yllpiperazin-l- yll sulf onylmethyll phenyl] ethanol

A solution of l-[3-[[4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-l-yl] sulfonylmethyl] phenyl] ethanone (100 mg, 0.23 mmol) in THF (3 ml) and was treated with sodium borohydride (9 mg, 0.23 mmol) and the reaction mixture was stirred at ambient temperature for 48 hrs. under a nitrogen atmosphere. The reaction mixture was then quenched by the addition of water, and the resulting mixture extracted with ethyl acetate. The organic extracts were combined, dried (MgSO₄) and concentrated in vacuo to give a yellow oil which was purified by flash column chromatography (12g silica cartridge, eluting with a gradient of neat isohexane to isohexane containing 80% v/v of ethyl acetate) to give the title compound as a clear colourless film, 51 mg, 52%, ¹H NMR (400 MHz, CDCl₃) δ 1.51 (3H, d), 2.62 (IH, br), 3.04-3.15 (4H, m), 3.22 - 3.33 (4H, m), 4.28 (2H, d), 4.93 (IH, q), 7.07 - 7.10 (IH, m), 7.35 - 7.40 (3H, m), 7.46 (IH, s), 7.88 - 7.90 (IH, m), 8.45 - 8.47 (IH, m), m/z 430 (M+H)+.

The requisite l-[3-[[4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-l-yl] sulfonylmethyl] phenyl] ethanone starting material was prepared as described in Example 28.

Claims

1. A compound of formula ( 1 ) or a salt thereof:

s (1) wherein:

R¹; o R¹ is selected from hydroxy, nitro, halo, trifluoromethyl, C_1-4alkyl, hydroxyC^alkyl,

CF₃CH(OH)-, CF₃C(Me)(OH)-, C_1-4alkoxy, cyano, Ci_-4alkylsulfonyl, Ci_-4alkylcarbonyl and

Ci_-4alkylcarbonylamino;

Ring B is pyridyl, optionally substituted in the 2-, T-, 3- or 3'- positions (relative to the point of attachment) (where available) by 1 or 2 substituents independently selected from R², and/or s substituted on the 4-position (relative to the point of attachment) (where available) with a substituent selected from R³;

R² is selected from halo, cyano, trifluoromethyl, C_1-4alkyl and C_1-4alkoxy;

R³ is selected from halo, cyano, C_1-3alkylsulfonyl and -CONR⁴R⁵;

R⁴ and R⁵ are independently selected from hydrogen and Ci_-4alkyl; or 0 R⁴ and R⁵ together with the nitrogen to which they are attached form an azetidinyl or pyrrolidinyl ring; n is 0, 1 or 2;

R⁶ is selected from methyl and hydroxymethyl;

L¹ is selected from -CH₂-, -CH₂CH2-, -CH(Me)- and -CMe₂-; 5 provided that: when Ring A is unsubstituted phenyl, L¹ is CH₂ and n = 0 then Ring B is not unsubstituted 2- pyridyl.

2. A compound according to claim 1 wherein Ring B is 2-pyridyl or 4-pyridyl.

3. A compound according to claim 1 wherein Ring B is substituted in the 2- and/or T- positions (relative to the point of attachment) by one or two, as appropriate, substituents independently selected from R², particularly wherein R² is selected from chloro, fluoro and trifluoromethyl.

4. A compound according to any one of claims 1 and 3, wherein Ring B is substituted on the 4- position (relative to the point of attachment) (where available) with a substituent selected from R³.

5. A compound according to any one of claims 1 to 4, wherein R¹ is independently selected from fluoro, chloro, trifluoromethyl, C_1-4alkyl and CF₃C(OH)(Me)-.

6. A compound according to any one of claims 1 to 5, wherein R² is independently selected from fluoro, chloro, cyano, trifluoromethyl, C_1-4alkyl and methoxy.

7. A compound according to any one of claims 1 to 6, wherein R³ is selected from fluoro, chloro, cyano, Cioalkylsulfonyl, -CONHMe and -CONMe₂.

8. A compound according to any one of claims 1 to 7, wherein R³ is -CONR⁴R⁵ wherein R⁴ and R⁵ together with the nitrogen to which they are attached form an azetidinyl or pyrrolidinyl ring.

9. A compound according to any one of claims 1 to 8, wherein L¹ is -CH₂- or -CH₂CH₂-.

10. A compound according to claim 1, which is selected from the following or a salt thereof:

1 -benzylsulfonyl-4-(3 ,5-dichloropyridin-4-yl)- 1 ,4-diazepane; 1 -benzylsulfonyl-4-(3 ,5-dichloropyridin-4-yl)-2-methyl-ρiρerazine; l-(3,5-dichloropyridin-4-yl)-4-[[3-(trifluoromethyl)phenyl]methylsulfonyl]piρerazine; l-[(3,4-dichlorophenyl)methylsulfonyl]-4-(3,5-dichloropyridin-4-yl)ρiperazine; l-(3,5-dichloropyridin-4-yl)-4-[(3-methylphenyl)methylsulfonyl]piperazine; l-(3,5-dichloropyridin-4-yl)-4-[(2-fluorophenyl)methylsulfonyl]piperazine; l-(3,5-dichloropyridin-4-yl)-4-[(3-fluorophenyl)metliylsulfonyl]piperazine;

1 - [(2-chlorophenyl)methylsulfonyl] -4-(3 , 5 -dichloropyridin-4-yl)piperazine; l-[(3-chlorophenyl)methylsulfonyl]-4-(3,5-dichloropyridin-4-yl)piperazine; l-[(2,4-dichlorophenyl)methylsulfonyl]-4-(3₅5-dichloropyridin-4-yl)piperazine; l-(3,5-dichloropyridin-4-yl)-4-[(3-nitrophenyl)methylsulfonyl]piperazine; l-[(2-fluorophenyl)methylsulfonyl]-4-[3-(trifluoromethyl)pyridm-2-yl]piperazine; l-[(2-fluorophenyl)methylsulfonyl]-2-methyl-4-[3-(trifluorometliyl)pyridin-2-yl]piperazme; l-[(2-fluorophenyl)methylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]-l,4-diazepane;

[ 1 - [(2-fluorophenyl)methylsulfonyl] -4- [3 -(trifluoromethyl)pyridin-2-yl]piperazin-2- yl]methanol; l-[[4-(trifluoromethyl)phenyl]methylsulfonyl]-4-[3-(trifluorometliyl)pyridin-2-yl]piperazine;

1 - [ [3 -(trifluoromethyl)phenyl]methylsulfonyl] -4- [3 -(trifluoromethyl)pyridin-2-yl]piperazine; l-[(4-fluorophenyl)methylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine; l-[(3-fluorophenyl)methylsulfonyl]-4-[3-(trifluorometliyl)pyridin-2-yl]piperazine; l-[(2-chlorophenyl)methylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine; l-[(3-chlorophenyl)methylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine; l-[[2-(trifluoromethyl)phenyl]metliylsulfonyl]-4-[3-(trifluoroniethyl)pyridin-2-yl]piperazine; l-[(2,6-difluorophenyl)methylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine; l-[l-(2-fluorophenyl)ethylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine; 1 - [2-(2-fluorophenyl)propan-2-ylsulfonyl] -4- [3 -(trifluoromethyl)pyridin-2-yl]piperazine; l-[3-[[4-[3 -(trifluoromethyl)pyridin-2-yl]piperazin- 1 -yl] sulfonylmethyl] phenyl] ethanone;

1 - [4- [ [4- [3 -(trifluoromethyl)pyridin-2-yl]piperazin- 1 -yl] sulfonylmethyl]phenyl] ethanone;

1,1,1 -trifluoro-2-[3-[[4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-l - yl]sulfonylmethyl]phenyl]propan-2-ol; 1,1,1 -trifluoro-2-[4- [ [4- [3 -(trifluoromethyl)pyridin-2-yl]piperazin- 1 - yl] sulfonylmethyl]phenyl]propan-2-ol; and l-[3-[[4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-l-yl]sulfonylmethyl]phenyl]ethanol.

11. A pharmaceutical composition, which comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 in association with a pharmaceutically-acceptable diluent or carrier.

12. A compound of formula (1), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, for use in a method of prophylactic or therapeutic treatment of a warm-blooded animal, such as man.

13. A compound of formula (1), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 for use as a medicament.

14. The use of a compound of formula (1), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 in the manufacture of a medicament for use in the production of an s 11 βHSDl inhibitory effect in a warm-blooded animal, such as man.

15. A process for preparing a compound according to claim 1, which process (wherein variable groups are, unless otherwise specified, as defined in formula (1) in claim 1) comprises of: o a) reaction of a compound of Formula (2) with a compound of Formula (3):

(2) (3)

wherein X¹ is a leaving group; or 5 b) reaction of a compound of Formula (4) with a compound of Formula (5):

(6) (7)