AU2007205749A1 - Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1 - Google Patents

Description

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION Standard Patent Applicant(s): BIOVITRUM AB Invention Title: INHIBITORS OF 11-BETA-HYDROXY STEROID DEHYDROGENASE TYPE 1 The following statement is a full description of this invention, including the best method for performing it known to me/us: NHIBITORS OF 11-BETA-HYDROXY STEROID

DEHYDROGENASE

TYPE 1 TECHNICAL

FIELD

The present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, as well as to the use of the compounds in medicine and for the preparation of a medicament which acts on the human 11-phydroxysteroid dehydrogenase type 1 enzyme (11 HSD1).

BACKGROUND

1. Glucorticoids, diabetes and hepatic lucose production It has been known for more than half a century that glucocorticoids have a central role in diabetes, e.g. the removal of the pituitary or the adrenal gland from a diabetic animal alleviates the most severe symptoms of diabetes and lowers the concentration of glucose in the blood (Long, C.D. and F.D.W. Leukins (1936) J. Exp. Med. 63: 465-490; Houssay, B.A. (1942) Endocrinology 30: 884-892). It is also well established that glucocorticoids enable the effect of glucagon on the liver.

The role of 1 IpHSD as an important regulator of local glucocorticoid effect and thus of hepatic glucose production is well substantiated (see e.g. Jamieson et al. (2000) J.

Endocrinol. 165: p, 685-692). The hepatic insulin sensitivity was improved in healthy Shuman volunteers treated with the non-specific 1 IpHSDI inhibitor carbenoxolone (Walker, B.R. et al. (1995) J. Clin. Endocrinol. Metab. 80: 3155-3159). Furthermore, the expected mechanism has been established by different experiments with mice and rats.

These studies showed that the mRNA levels and activities of two key enzymes in hepatic glucose production were reduced, namely: the rate-limiting enzyme in gluconeogenesis, phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6Pase) catalyzing the last common step of gluconeogenesis and glycogenolysis. Finally, the blood glucose level and hepatic glucose production is reduced in mice having the 1 IPHSD1 gene knocked-out. Data from this model also confirm that inhibition of 1 1pHSDl will not cause hypoglycemia, as predicted since the basal levels of PEPCK and G6Pase are regulated independently of glucocorticoids (Kotelevtsev, Y. et al., (1997) Proc. Natl. Acad. Sci. USA 94: 14924-14929).

FR 2,384,498 discloses compounds having a high hypoglycemic effect. Therefore, treatment of hyperglycemia with these compounds may lead to hypoglycemia.

2. Possible reduction of obesity and obesity related cardiovascular risk factors Obesity is an important factor in syndrome X as well as in the majority 80%) of type 2 diabetic, and omental fat appears to be of central importance. Abdominal obesity is closely associated with glucose intolerance, hyperinsulinemia, hypertriglyceridemia, and other factors of the so-called syndrome X raised blood pressure, decreased levels of HDL and increased levels ofVLDL) (Montague O'Rahilly, Diabetes 49: 883-888, 2000). Inhibition of the enzyme in pre-adipocytes (stromal cells) has been shown to decrease the rate of differentiation into adipocytes. This is predicted to result in diminished expansion (possibly reduction) of the omental fat depot, i.e. reduced central obesity (Bujalska, S. Kumar, and P.M. Stewart (1997) Lancet 349: 1210-1213).

Inhibition of 11 3HSD in mature adipocytes is expected to attenuate secretion of the plasminogen activator inhibitor 1 (PAI-I) an independent cardiovascular risk factor (Halleux, C.M. et al. (1999) J. Clin. Endocrinol. Metab. 84: 4097-4105). Furthermore, there is a clear correlation between glucocorticoid "activity" and cardiovascular risk factore suggesting that a reduction of the glucocorticoid effects would be beneficial (Walker, B.R. et al. (1998) Hypertension 31: 891-895; Fraser, R. et al. (1999) Hypertension 33: 1364-1368).

Adrenalectomy attenuates the effect of fasting to increase both food intake and hypothalamic neuropeptide Y expression. This supports the role of glucocorticoids in promoting food intake and suggests that inhibition of 11 PHSD1 in the brain might increase satiety and therefore reduce food intake (Woods, S.C. et al. (1998) Science, 280: 1378-1383).

3. Possible beneficial effect on the pancreas Inhibition of 11HSD1 in isolated murine pancreatic p-cells improves the glucose-stimulated insulin secretion (Davani, B. et al. (2000) J. Biol. Chem. 2000 Nov 275(45): 34841-4). Glucocorticoids were previously known to reduce pancreatic insulin release in vivo (Billaudel, B. and B.C.J. Sutter (1979) Horm. Metab. Res. 11: 555- 560). Thus, inhibition of 11 PHSDl is predicted to yield other beneficial effects for diabetes treatment, besides effects on liver and fat.

4. Possible beneficial effects on cognition and dementia Stress and glucocorticoids influence cognitive function (de Quervain,

B.

Roozendaal, and J.L. McGaugh (1998) Nature 394: 787-790). The enzyme 11 PHSDl controls the level of glucocorticoid action in the brain and thus contributes to neurotoxicity (Rajan, C.R.W. Edwards, and J.R. Seckl, J. (1996) Neuroscience 16: Seckl, Front. (2000) Neuroendocrinol. 18: 49-99). Unpublished results indicate significant memory improvement in rats treated with a non-specific 11P HSD1 inhibitor Seckl, personal communication). Based the above and on the known effects of glucocorticoids in the brain, it may also be suggested that inhibiting 1 I3HSDl in the brain may result in reduced anxiety (Tronche, F. et al. (1999) Nature Genetics 23: 99- 103). Thus, taken together, the hypothesis is that inhibition of 1 13HSDI in the human brain would prevent reactivation of cortisone into cortisol and protect against deleterious glucocorticoid-mediated effects on neuronal survival and other aspects of neuronal function, including cognitive impairment, depression, and increased appetite (previous section).

WO 99/02502 discloses 5HT 6 receptor antagonists for the treatment of CNS disorders. Such antagonists ofthiazole structure differ from the compounds according to the present invention in that the former have an aryl group in 4-position. Furthermore, nothing is said about the activity on 11 HSD1.

Possible use of immuno-modulation using 11 HSD1 inhibitors The general perception is that glucocorticoids suppress the immune system. But in fact there is a dynamic interaction between the immune system and the HPA (hypothalamo-pituitary-adrenal) axis (Rook, G.A.W. (1999) Baillibr's Clin. Endocrinol.

Metab. 13: 576-581). The balance between the cell-mediated response and humoral responses is modulated by glucocorticoids. A high glucocorticoid activity, such as at a state of stress, is associated with a humoral response. Thus, inhibition of the enzyme 11pHSDI has been suggested as a means of shifting the response towards a cell-based reaction.

In certain disease states, including tuberculosis, lepra and psoriasis the immune reaction is normaly biased towards a humoral response when in fact the appropriate response would be cell based. Temporal inhibition of 11 HSD1, local or systemic, might be used to push the immune system into the appropriate response (Mason, D. (1991) Immunology Today 12: 57-60; Rook et al., supra).

An analogous use of 11 HSD1 inhibition, in this case temporal, would be to booster the immune response in association with immunization to ensure that a cell based response would be obtained, when desired.

6. Reduction of intraocular pressure Recent data suggest that the levels of the glucocorticoid target receptors and the 1 13HSD enzymes determines the susceptibility to glaucoma (Stokes, J. et al. (2000) Invest. Ophthalmol. 41: 1629-1638). Further, inhibition of 1 1pHSD1 was recently presented as; a novel approach to lower the intraocular pressure (Walker E. A. et al, poster P3-698 at the Endocrine society meeting June 12-15, 1999, San Diego). Ingestion of carbenoxolone, a non-specific inhibitor of 11 pHSDI, was shown to reduce the intraocular pressure by 20% in normal subjects. In the eye, expression of 1 1 PHSD1 is confined to basal cells of the corneal epithelium and the non-pigmented epithelialium of the cornea (the site of aqueous production), to ciliary muscle and to the sphincter and dilator muscles of the iris. In contrast, the distant isoenzyme 11 3HSD2 is highly expressed in the nonpigmented ciliary epithelium and corneal endothelium. None of the enzymes is found at the trabecular meshwork, the site of drainage. Thus, 11 PHSD1 is suggested to have a role in aqueous production, rather than drainage, but it is presently unknown if this is by interfering with activation of the glucocorticoid or the mineralocorticoid receptor, or both.

7. Reduced osteoporosis Glucocorticoids have an essential role in skeletal development and function but are detrimental in excess. Glucocorticoid-induced bone loss is derived, at least in part, via inhibition of bone formation, which includes suppression ofosteoblast proliferation and collagen synthesis (Kim, S.L. Cheng, and G.S. Kim (1999) J. Endocrinol. 162: 371- 379). The negative effect on bone nodule formation could be blocked by the non-specific inhibitor carbenoxolone suggesting an important role of 1 IPHSD1 in the glucocorticoid effect (Bellows, A. Ciaccia, and J.N.M. Heersche, (1998) Bone 23: 119-125). Other data suggest a role of 1 1PHSD1 in providing sufficiently high levels of active glucocorticoid in osteoclasts, and thus in augmenting bone resorption (Cooper, M.S. et al.

(2000) Bone 27: 375-381). Taken together, these different data suggest that inhibition of 11 PHSDI may have beneficial effects against osteoporosis by more than one mechanism working in parallel.

8. Reduction of hypertension Bile acids inhibit I l -hydroxysteroid dehydrogenase type 2. This results in a shift in the overall body balance in favour of cortisol over cortisone, as shown by studying the ratio of the urinary metabolites (Quattropani C, Vogt B, Odermatt A, Dick B, Frey BM, Frey FJ. 2001. J Clin Invest. Nov;108(9):1299-305. "Reduced activity of 1 betahydroxysteroid dehydrogenase in patients with cholestasis".). Reducing the activity of 11 pHSDI in the liver by a selective inhibitor is predicted to reverse this imbalance, and acutely counter the symptoms such as hypertension, while awaiting surgical treatment removing the biliary obstruction.

WO 99/65884 discloses carbon substituted aminothiazole inhibitors ofcyclin dependent kinases. These compounds may e.g. be used against cancer, inflammation and arthritis. US 5,856,347 discloses an antibacterial preparation or bactericide comprising 2aminothiazole derivative and/or salt thereof. Further, US 5,403,857 discloses benzenesulfonamide derivatives having 5-lipoxygenase inhibitory activity. Additionally, 0 tetrahydrothiazolo[5,4-c]pyridines are disclosed in: Analgesic tetrahydrothiazolo[5,4- CN c]pyridines. Fr. Addn. (1969), 18 pp, Addn. to Fr. 1498465. CODEN: FAXXA3; FR 94123 19690704 CAN 72:100685 AN 1970:100685 CAPLUS and 4,5,6,7- Tetrahydrothiazolo[5,4-c]pyridines. Neth. Appl. (1967), 39 pp. CODEN: NAXXAN NL S6610324 19670124 CAN 68:49593, AN 1968: 49593 CAPLUS. However, none of the above disclosures discloses the compounds according to the present invention, or their 0^ use for the treatment of diabetes, obesity, glaucoma, osteoporosis, cognitive disorders, Simmune disorders, depression, and hypertension.

S 10 US 5,594,021 and US 6,030,991 disclose compounds inhibiting the binding of an endothelin peptide to an endothelin receptor. Such compounds of thiazole structure differ O from the compounds according to the present invention in that the former are unsubstituted in both 4- and 5-position. Furthermore, nothing is said about the activity on 11PHSD1.

WO 01/54691 discloses thiazole compounds as antimicrobial agents. Only the antibacterial effect of such compounds has been shown in the pharmacological examples.

These compounds differ from the compounds according to the present invention in that the former either are unsubstituted in 5-position or have a free amino group in 2-position.

US 5,783,597 discloses thiophene derivatives as inhibitors of PGE 2 and LTB 4 Nothing is said about the activity on 11 HSD 1.

Consequently, there is a need of new compounds that are useful in the treatment of diabetes, obesity, glaucoma, osteoporosis, cognitive disorders, immune disorders, depression, and hypertension.

SUMMARY OF THE INVENTION The compounds according to the present invention solves the above problems and embraces a novel class of compounds which has been developed and which inhibit the human 1 l-3-hydroxysteroid dehydrogenase type 1 enzyme (11-p-HSDI), and may therefore be of use in the treating disorders such as diabetes, obesity, glaucoma, osteoporosis, cognitive disorders, immune disorders, and hypertension.

There is disclosed a compound of formula TN

B

wherein C) 5 Tis an aryl ring or heteroaryl ring, optionally independently substituted by [Pin, wherein n is an integer 0-5, and R is hydrogen, aryl, heteroaryl, a heterocyclic ring, optionally halogenated CI-6-alky1, optionally halogenated C,-6-alkoxy, CI.6-alkylsulfontyl, carboxy, cyano, nitro, halogen, aryloxy, arylsulfonyl, arylamino, wherein aryl, heteroaryl and aryloxy residues and heterocyclic rings can further be optionally substituted in one or more positions independently of each other by CI-6-acyl, CI-6-alkylthio, cyano, nitro, hydrogen, halogen, optionally halogenated C 1 -6-alkyl, optionally halogenated CI-6-alkoxy, anmide which is optionally mono- or di-substituted, (benzoylamino)methyl, carboxy, 2thienylmethylamino or ({[4-(2-ethoxy-2-oxoethyl)-l ,3-thiazol-2-yl]aznino) carbonyl); or T is selected from 5-(dimethylamino)-l-naphthyl and phenyl substituted with one or more of benzeneanino, benzylazuino, 3-pyridylmethylaniino and 2-thienylinethylamino;

R

1 is hydrogen Or C!..6-allcyl; X is Cl- 2 or GO; Y is CH 2 CO or a single bond; B is hydrogen, CI-6-alkyI or dimethylaminomethyl; R 2 is selected from C1-6-alcyl, azido, arylthio, heteroarylthio, halogen, hydroxymneth~yl, 2 -hydroxyethylaminomethyl, methylsulfonyloxymethyl, 3-oxo-4moipholinolmylmethylene, C l-6-alkoxycarbonyl, 5-methyl- 1,3 ,4-oxadiazol-2-yl; NR 3 1, 4 wherein R 3 and R 4 are each independently selected from hydrogen, ethyl, isopropyl, n-propyl, optionally halogenated C1-6-alkylsulfonyl,

C

1 6 -alkoxy, 2methoxyethyl, 2-hydroxyethyl, I -methylimi dazolylsulfonyl,

CI-

6 -acyl, cyclohexylmethyl, cyclopropanecarbonyl, aryl, optionally halogenated arylsulfonyl, flirylcarbonyl, tetrabydro-2..furanylmethyl, N-carbethoxypiperidyl, or CI-6-alkyl substituted with one or more aryl, heterocyclic or heteroaryl, or

NR

3 R represent together heterocyclic systems which can be imidazole, piperidine, pyrrolidine, piperazine, morpholine, oxazepine, oxazole, thiomorpholine, 1,1 dioxidothiomorpholine, 2-(3,4-dlhydro-2(l H)isoquinolinyl), (I S,4S)-2-oxa-5azabicyclo[2.2.l1 hept-5-yl, which heterocyclic systems can be optionally substituted by

C,.

6 -all, CI-6-acyl, hydroxy, oxo, t-butoxycarbonyl; OCONRR, wherein W( and R4' are each independently selected from hydrogen, Ci.6-allcyl or form together with the N-atom. to which they are attached morpholinyl;

R

5 0, wherein R 5 is hydrogen 1 optionally halogenated C,-6-alkyl, aryl, heteroaryl, CI.6-acyl, CI..

6 -alklsulfonyl, arylcarbonyl, heteroarylcarbonyl, 2-carbomethoxyphenyl; or a salt, hydrate or solvate thereof; with the proviso that when: Xis CH 2 Y is CH 2 then R 2 is not methyl, ethyl, diethylarnino, 1-pyrrolidinyl, and 1 -piperidinyl; X is CH 2 Y is CH 2 R 2 is morpholinyl, then T is not 4-methyiphenyl; X is CR 2 Y is CO, then R 2 is not hydroxy; X is Gil 2 Y is a single bond, then R 2 is not ethyl, n-propyl; X is CH 2 Y is a single bond, R 2 is methyl, B is methyl, then T is not 3-chloro-2methfyiphenyl; is GO, Y is a single bond, then R 2 is not methyl; X is GO, Y is a single bond, R 2 isethoxy, B is methyl, then T is not 3-cbloro-2methyiphenyl, 1,1 '-biphenyl-4-yl, 4-n-propylphcnyl, 2,4-dichloro-6-methylphenyl, and 2,4,6-Irichiorophenyl.

The present invention provides a compound of formula (1) T N B X R2 wherei n T is an aryl ring or heteroaryl ring, optionally independently substituted by [RIn, wherein n is an integer 0-5, and R is hydrogen, aryl, heteroaryl, a heterocyclic ring, optionally halogenated C 1 6 -alkyl, optionally halogenated C,- 6 -alkoxy, C,- 6 alkylsulf'onyl, carboxy, cyano, nitro, halogen, aryloxy, arylsulfonyl, arylamino, whereini aryl, heteroaryl and aryloxy residues and heterocyclic rings are further optionally substituted in one or more positions independently of each other by CI- 6 -acyl, C 1 6 alkylthio, cyano, nitro, hydrogen, halogen, optionally halogenated Ci.

6 -alkyl, optionally halogenated CI.

6 -alkoxy, amide which is optionally mono- or di-substituted, (benzoyl amino)methyl, carboxy, 2-thienylmethylamino or ({([4-(2-ethoxy-2-oxoethyl)- N -thiazuol-2-yI] amino) carbonyl); or T is selected from 5 -(dimethyl amino)-1I-naphthyl ;Z and phenyl substituted with one or more of benzeneamino, benzylamino, 3pyridylmethylamino and 2 -thienyl methyl amino; R' is hydrogen or CI- 6 -alkyl; X is CH 2 or CO; Y is CO; B is hydrogen, CI- 6 -alkyl or dimethylaminomethyl;

R

2 is selected from C 1 6 -alkyl, azido, arylthio, heteroarylthio, halogen, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl, 3-oxo-4morpho linolinylmethylene, C 1 6-alkoxycarbonyl, 5-methyl- 1,3 ,4-oxadiazol-2-yI; c-iNR R wherein R 3 and R( are each independently selected from hydrogen, ethyl, isopropyl, n-propyl, optionally halogenated C 1 4 -alkyl sulfonyl, C 1 alkoxy, 2-methoxyethyl, 2-hydroxyethyl, I -methylimidazolylsulfonyl, C 1 6-acyl, is cyclohexylmethyl, cyclopropanecarbonyl, aryl, optionally halogenated arylsul fonyl, furylcarbonyl, tetrahydro-2-furanylmethyl, N-carbethoxYPiperidyl, or C I alkyl substituted with one or more aryl, heterocyclic or heteroaryl, or NR 3 R 4 represent together heterocyclic systems which are imidazole, pipendine, pyrrolidine, piperazine, morpholine, oxazepine, oxazole, thiomorpholine, 1 ,ldioxidothiomorpholine, 2-(3 ,4-dihydro-2( 1 H)isoquinolinyl), or (I S,4S)-2-oxa-5azabicyclo[2.2.]]hept-5-yl, which heterocyclic systems are optionally substituted by C 1 6 -alkyl, C 1 6 -acyl, hydroxyl, oxo, t-butoxycarbonyl; OCONR R wherein R 3 and R 4 are each independently selected from hydrogen, C I 6 -alkyl or formn together with the N-atom to which they are attached morphcilinyl;

R

5 0, wherein R 5 is hydrogen, optionally halogenated C 1 6 -alkyl, aryl, heteroaryl, C 1 6 -acyl, C 1 .galkylsulfonyl, arylcarbonyl, heteroarylcarbonyl, 2carbomnethoxyphenyl; or a salt, hydrate or solvate thereof; 3 0 with the proviso that when: X is CH 2 Y is CO, then R2 is not hydroxy; provided that the compound is not one of the following: ethyl [(2,4-dichloro-5 -methylphenyl)sul fonyl ]amino)} 1 ,3 -thiazol-5 -yI)acetate ethyl (2 -chilorophenyl)sul fonyl ]amino) 3-thiazol1-5 -yl)acetate 3 5 ethyl (2 {[(2,4-difluorophenyl)sul fonyl]amino 1,3 ethyl -dichlorothien-3 -yl)sul fonyl] amino) 1 ,3 -thiazol-5 -yl)acetate ethyl {[(2-chlorophenyl)sulfonyl]amino }-1I,3-thiazol-5-yl)acetate ethyl -naphthylsulfonyl)amino]- 1 ,3-thiazol-5-yl acetate ethyl (2 -chloro-2 -methylphenyl)sul fonyl] amino)} 1, 3 -thiazol1- ;Z -chloro-2-methylphenyl)sulfonyl] amino) 1,3 -thiazol-5 -yl)-N-methylacetamide [(';-chloro-2-methylphenyl)sulfonylI amino I 1,3 ethyl 1,1 '-biphenyl-4-ylsulfonyl)amino]- 1 ,3-thiazol-5-yl acetate ethyl [(4-nitrophenyl)sul fonyl ]amino) 1-1,3 -thi azol -5 -yI)acetate ethyl [(4-methoxyphenyl)sul fonyl] amino 1,3 -thiazol-5 -yI)acetate ethyl -dichlorophenyl)sulfonyl] amino) 1-1,3 -thiazol-5 -yI)acetate 3-chloro-N-[5-(2-hydroxyethyl)- 1,3-thiazol-2-yl]-2-methylbenzenesulfonamide 3-chlorc'-N-[5-(2-ethoxyethyl)-1I,3-thiazol-2-yl]-2-methylbenzenesulfonamide ethyl -chlorophenyl)sulfonyl] amino 11,3 riethyl [(4-fluorophenyl)sul fonyl] amino 1,3 -thiazol-5 -yl)acetate ethyl (2 [(4-isopropylphenyl)sul fonyl] amino} 1,3 -thiazol -5 -yl)acetate ethyl [2 -(f{[4-({[4-(2-ethoxy-2-oxoethyl)- 1,3 -thiazol-2yljamino I carbonyl)phenyl] sulfonyl amino)- 1,3 -thiazol-5 -yl] acetate -chl oro -2-methylphenyl)sul fonyl] amino ,3-thiazol -5 -yl)-N,N diethylacetamide ethyl [2 [2-(tri fluoromethyl)phenyl] sul fonyl })am ino)- 1, 3 -thi azol -5 -yl]acetate ethyl [3 -(tri fluoromethyl)phenyl] sulIfonyl) amino)- 1 ,3 -thiazol-5 -y1] acetate ethyl [2 [4-(tri fl uoromethyl)phenyl ]sulIfonyl )}amino)- 1, ,3-thiazol-5 -yl ]acetate methyl -chloro-2 -methylphenyl)sulIfonyl] amino) 3-thiazol1- 3 -chloro-N-[5-(2-isopropoxyethyl)- 1,3-thiazol-2-yl]-2-methylbenzenesulfonamide 3 -chloro-N-[5-(2-methoxyethyl)- 1,3 -thiazol-2-yl]-2-methylbenzenesulfonamide -chloro-2-methylphenyl)sulfonyl]amino }-1I,3-thiazol-5-yl)ethyl methanesulfonate -chloro-2-methylphenyl)sulfonyl] amino)} 1 ,3 -thiazol 3 -chiloro-N (5 fluoroethoxy)ethyl] 1 ,3-thiazol -2-yl 1-2 methyl benzenesulfonamide 3 -chloro-2-methyl-N- 5- [2-(2,2,2-trifluoroethoxy)ethyl]- 1,3-thiazol-2yl benzene sulIfonam ide 2 -chloro-2-methylphenyl)sul fonyl] amino 1,3 -thiazol -5-yl)ethyl acetate 3 -chl oro-2-methylI-N 5-(2-morphol in-4-yl ethyl)- 1 ,3 -thiazol-2-yl]benzenesul fonamide N- [5-(2-bromoethyl)- 1,3 -thiazol-2-yl]-3 -chloro-2-methylbenzenesulfonamide 1(3 -chloro-2-methylphenyl)sulfonyl]amino 1,3 -thiazol-5-yl)ethyl morpholine-4carboxylate -chloro-2-rnethylphenyl)sul fonyl ]amino) -1,3-thiazol-5-yl)ethyl diethylcarbamnate [(2,-chloro-2-methylphenyl)sulfonyll amino) -1,3 -thiazol-5 -yl)ethyl propionate 2 -chloro-2-methylphenyl)sul fonyl] amino ,3-thiazol1-5 -yl)ethyl 2methyipropanoate -chloro-2-methylphenyl)sulfonyl] amino -1 ,3 -thiazol-5 -yl)ethyl 2-furoate -chloro-2-methylphenyl)sulfonyl] amino) -1,3 -thiazol-5 -yI)ethyl benzoate {[(3-chloro-2-methylphenyl)sulfonyl]amino methylacetamide -chloro-2-methylphenyl)sulfonyl] amino} -1,3-thiazol-5-yl)ethyl ethylcarbamate {[(3-chloro-2-methylphenyl)sulfonyl]amino ethylacetamide 3 -chloro-2-methyl-N-[5-(2-oxopentyl)- 1,3 -thiazol-2-yl]benzenesulfonamide N- 1,1 -dioxidothiomorpholin-4-yl)-2-oxoethyl]- 1,3-thiazol-2-yl propylbenzenesul fonamide 2,4-dichloro-6-methyl-N- {5-[2-(4-methylpiperazin-1I-yl)-2-oxoethyl]-1I,3-thiazol-2yl benzenesulfonamide 3 -chlorci-2-methyl-N- {5-[2-(3-oxomorpholin-4-yl)ethyl]- 1 ,3-thiazol-2yl benzenesulfonamide 2,4-dichloro-6-methyl-N-[5-(2-morpholin-4-yi-2-oxoethyl)- 1 ,3-thiazol-2yl]benzenesulfonamide N-[5-(2-morpholin-4-yl-2-oxoethyl)- 1 ,3-thiazol-2-yl]- 1,1 '-biphenyl-4-sulfonamide N-[5-(2-morpholin-4-yI-2-oxoethyl)- I ,3-thiazol-2-yl]-4-propylbenzenesulfonamide -oxo-2-thiomorpholin-4-ylethyl)- I ,3-thiazol-2-yl]-1,1 I'-biphenyl-4-sulfonamide N-[5-(2-oxo-2-thiomorpholin-4-ylethyl)- 1 ,3 -thiazol1-2 -y I]-4-propyl benzenes ul fonam ide 2,4-dichiloro-6-methyl-N-[5-(2-oxo-2-thiomorpholin-4-ylethyl)- 1 ,3-thiazol-2yljbenzenesulfonamide N-[5-(2-oxo-2-piperidin- 1 -ylethyl)- 1 ,3-thiazol-2-yl]- 1,1 '-biphenyl-4-sulfonamide N-[5-(2-oxo-2-piperidin- I -ylethyl)- 1 ,3-thiazol-2-yl]-4-propylbenzenesulfonamide 2,4-dichiloro-6-methyl-N-[5-(2-oxo-2-piperidin- 1 -ylethyl)- 1,3 -thiazol-2yl]benzenesulfonamide ethyl oxo(2- [(4-propylphenyl)sul fonyl ]amino} -1,3 -thiazol-5 -yI)acetate ethyl (2 -chloro-2 -methyl phenyl)sul fonyl] amino)} 1 ,3 -thiazol-5 -yl)(oxo)acetate ethyl o.xo(2- {[(2,4,6-trichlorophenyl)sul fonyl]amino ethyl 1,1'-biphenyl-4-ylsulfonyl)amino]- 1,3 -thiazol-5-yl }(oxo)acetate 3-chloro-2-methyl-N-[4-methyl-5-(2-morpholin-4-yl-2-oxoethyl)- 1,3 -thiazol-2yl]benzenesulfonamide 2,4,6-trichloro-N-[4-methyl-5-(2-morpholin-4-yI-2-oxoethyl)- 1,3 -thiazol-2yl]benzenesulfonamide 2-f{ 1,1'-biphenyl-4-ylsulfonyl)amino]- 1,3-thiazol-5-yl }-N-ethyl-N-methylacetamide N-ethyl-N-methyl-2-(2- [(4-propylphenyl)sulfonyl]amino) -1,3-thiazol-5-yI)acetamide [(2,4-dichloro-6-methylphenyl)sulfonyl] amino) 1,3-thiazol-5-yl)-N-ethyl-Nmethylacetamide N-[4-methyl-5-(2-morpholin-4-yl-2-oxoethyl)- 1,3 -thiazol-2-yI]- 1,1 '-biphenyl-4sulfonamide 2-2-(11 1'-biphenyl-4-ylsulfonyl)amino]- 1,3-thiazol-5-yl)}-N-isopropyl-Nmethylacetamide 2- 1,1 '-biphenyl-4-ylsulfonyl)amino]- 1,3 -thiazol-5-yl -N,N-diethylacetaniide N,N-diethyl-2-(2- [(4-propylphenyl)sulfonyl]amino) -1,3-thiazol-5-yl)acetamide [(2-,4-dichloro-6-methylphenyl)sulfonyl]amino 1 diethylacetamide ethyl [(4-bromo-5-chlorothien-2-yI)sul fonyl] amino 1 ,3 -thiazo 1-5 -yl)acetate ethyl -bromo-5-chlorothien-2-yl)sulfonyl] amino) 1,3 -thiazol-5 -yl)acetate ethyl 1-methyl-5-(trifluoromethyl)- 1H-pyrazol-3-yl]thien-2yl sul fonyl)amino]- I ,3-thiazol-5-yl I acetate ethyl {5-[2-(methylthio)pyrimidin-4-yIjthien-2-yl }sulfonyl)amino]-1I,3-thiazol-5yl }acetate 2- 1,1'-biphenyl-4-ylsulfonyl)amino]-1I,3-thiazol-5-yl }-N,N-diisopropylacetamide N,N-diisopropyl-2-(2- {[(4-propylphenyl)sulfonyl]amino [(2,4-dichloro-6-methylphenyl)sul fonyl] amino) -1,3 -thi diisopropylacetamide methyl (4-methyl-2- [(2,4,6-trichlorophenyl)sulfonyl] amino)} 1 ,3 -thiazol-5 -yI)acetate [(3-chloro-2-methylphenyl)sulfonyl] amino I 1,3 dipropylacetamide 3-chloro-2-methyl-N-[5-(2-oxo-2-piperazin-1I-ylethyl)-1I,3 -thiazol-2yI]benzenesulfonamide 4-bromo:-2-methyl-N-[5-(2-morpholin-4-yl-2-oxoethyl)- 1 ,3-thiazol-2yl]benzenesulfonamide N-[5-(2-morpholin-4-yI-2-oxoethyl)- 1 ,3-thiazol-2-yl]-2,4bis(tri fluoromethyl)benzenesulfonamide 2-methy l-N-[5-(2-morpholin-4-yI-2-oxoethyl)- 1,3 -thiazol-2-yl]-4- (tri fluor-omethoxy)benzenesul fonamide -morpholin-4-yl-2-oxoethyl)- I ,3-thiazol-2-yl]-4-phenoxybenzenesulfonamide ethyl ,4-trichlorophenyl)sulfonyl]amino} -1,3 ethyl (2-f [(4-bromo-2,5-difluorophenyl)sulfonyl] amino) -1,3 ethyl [4-(tri fl uoromethoxy)phenyl ]sulfonyl amino)- 1, ,3-thiazol1-5 -yl] acetate ethyl [4-(phenylsulfonyl)thien-2-yl] sulfonyl amino)- 1,3 -thiazol-5-yl] acetate ethyl [5 -(phenyl sul fonyl)thien-2 -yl] sul fonyl amino)- 1, 3 -thiazol1-5 -yl] acetate ethyl [(2,6-dichlorophenyl)sulfonyl] amino}I 1,3 -thiazol-5 -yl)acetate ethyl [(2,4-dichlorophenyl)sul fonyl] amino) 3-thiazol-5 -yl)acetate tert-butyl f [(3-chloro-2-methylphenyl)sulfonyl]amino} 1,3-thiazol-5yl)acetyl ]piperazine- I -carboxylate [(-')-chloro-2-methylphenyl)sul fonyl] amino) -1,3 dimethylacetamide 3-chloro-2-methyl-N- f 5- [2-(pyridin-3 -yloxy)ethyl]- I ,3-thiazol-2yI benzenesulfonamide -chlIoro-2-methy lphenyl)sul fonyll amino) -1,3 -thiazol-5-y1)-N-isopropyl-Nmethylacetamide -chloro-2-methylphenyl)sul fonyll amino)} I1,3 -thiazol-5 -yl)-N-ethyl-Nmethylacetamide 3 -chloro-2-methyl-N-[5-(2-oxo-2-thiomorpholin-4-ylethyl)- 1,3-thiazol-2yl]benzenesulfonamide ethyl {[(4-bromo-2-fluorophenyl)sulfonyl]amino ,3-thiazol-5-y1)acetate 3 -chloro-2-methyl-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1I,3-thiazol-2yIlbenzenesulfonamide methyl {[(4-chlorophenyl)sulfonyl]amino }-4-methyl- 1,3 methyl -chloro-2-methylphenyl)sulfonyl] amino I -4-methyl- 1,3 -thiazol -5 yl)acetate -chloro-2-methylphenyl)sul fonyl] amino) -1,3 -thiazol diisopropylacetamide 3 -chloro-2-methyl-N- [5 -(2-oxo-2-pyrrol idin- 1 -yl ethyl)- 1,3 -thiazol-2yl]benzenesul fonamide ethyl (2 -methoxyphenyl)sul fonyl] amino)} I1,3 -thiazol-5 -yl)acetate ethyl (2 -fl uoro-2 -methylphenyl)sul fonyl ]amino I 1, 3 -thi azol1-5 -yl)acetate 3 0 ethyl {[(4-propylphenyl)sulfonyl]amino 3-chloro-2-methyl-N-[5-(2-oxo-2-piperidir- 1-ylethyl)- 1,3-thiazol-2yljbenzenesulfonamide ethyl ,5 -dichlorophenyl)sul fonyl] amino) ethyl (2 f [(3,4-dichlorophenyl)sul fonyl] amino) ethyl (2 [(2,4-di ch loro-6-methyl phenyl)sul fonyl ]amino) 1, 3 -thi azoI- 5 -yl)acetate 3 -chloro-2-methyl-N-[5-(morpholin-4-ylmethyl)- 1,3 -thiazol-2-yl]benzenesulfonamide 3 -chloro-N-({5-[2-( 1H-imidazol- 1-yl)ethyl]- 1,3 -thiazol-2-yi)}-2methylbenzenesulfonamide N -chloro-2-methylphenyl)sulfonyl] amino 1 ;Zethyl {[2-methyl-4-(trifluoromethoxy)phenyl]sulfonyl amino)- 1,3 yIjacetate ethyl ,4-trifluorophenyl)sulfonyl]amino} 1,3-thiazol-5-yl)acetate ethyl f [(2,4,6-tri fluorophenyl)sul fonyl] amino) 1,3-thiazol-5-yl)acetate 3 -chiloro--2-methyl-N-(5 [(methylsulfonyl)amino] ethyl) -1,3-thiazol-2yl)benzenesulfonamide ethyl -chlorothien-2-yl)sulfonyl] amino) 1,3 ethyl {[(2-chloro-4-fluorophenyl)sulfonyl]amino ethyl {[(5-isoxazol-3-ylthien-2-yl)sulfonyljamino (1 ~ethyl {[(4-phenoxyphenyl)sulfonyl]amino 1,3 ethyl [2,4-bis(trifluoromethyl)phenyl] sulfonyl amino)- 1 ,3 -thiazol-5 -yl] acetate 3 -chloro-2-methyl-N- [2-(3-oxo- 1,4-oxazepan-4-yl)ethyl]- 1,3-thiazol-2yl Ibenzenesulfonamide 3-chloro -2-methyl-N- 5-[2-(2-oxopyrrolidin- 1 -yl)ethyl]- I ,3-thiazol-2yl I benzenesulfonamide 3-chloro-2-methyl-N-(5- 2- [methyl (methylsulfonyl)amino] ethyl) -1,3-thiazol-2yl)benzenesulfonamide -chloro-2-methylphenyl)sulfonyllamino} 1 ,3 methylcyclopropanecarboxamide 3 -chloro-2-methyl-N- 5-[2-(4-methyl-2-oxopiperazin- I -yl)ethyl]- 1,3 -thiazol-2ylI }benzenesulfonamide 3 -chloro-2-methyl-N-[5-(2- [(trifluoromethyl)sulfonyl]amino ethyl)- I ,3-thiazol-2yl]benzenesulfonamide 2,4-dichloro-N- 5-[2-(3-oxomorpholin-4-yl)ethyl]- 1 ,3 -thiazol-2yl benzenesulfonamide 2,4-dichloro-6-methyl-N- 5 -oxomorpholin-4-yl)ethyl]- I ,3-thiazol-2yI benzenesulfonamide 4-(2-furyl)-N-[5-(2-morpholin-4-yl-2-oxoethyl)- 1 ,3-thiazol-2-yl]benzenesulfonamide 5'-fluorc'-2'-methoxy-N-[5-(2-morpholin-4-yl-2-oxoethyl)- 1,3 -thiazol-2-y]- -1,1Fbiphenyl-4-sulfonamide 4-(5-methylthien-2-yl)-N-[5-(2-morpholin-4-yl-2-oxoethyl)- I ,3-thiazol-2ylbenzenesulfonamnide 3'-acetyl-N-[5-(2-morpholin-4-yl-2-oxoethyl)- I ,3-thiazol-2-yi]- 1,1 F-biphenyl-4sulfonamnide N- [5-(2-morpholin-4-yl-2-oxoethyl)- 1,3 -thiazol-2-yl]-4'-(trifluoromethoxy)- 1,1Vbiphenyl-4-sul fonamide 3',4'-dichloro-N-[5-(2-morpholin-4-yl-2-oxoethyl)- 1,3 -thiazol-2-yl] -1,1 '-biphenyl-4sulfonamide 1,3 -benzodioxol-5 [5-(2-morpholin-4-yl-2-oxoethyl)- 1 ,3 -thiazol-2yl]benzenesulfonamide N- [5 -(2-morphol in-4-y1-2-oxoethyI)- 1 ,3 -thiazol-2-yl]-4-pyridin-4ylbenzenesulfonamnide {[5-(2-morpholin-4-y1-2-oxoethyl)- I ,3-thiazol-2-yl]amino sulfonyl)- 1,1Fbiphenyl-3-yl]acetamide N-[5-(2..morpholin-4-yl-2-oxoethyl)- 1 ,3-thiazol-2-yi]-4-thien-3 -ylbenzenesulfonamide N-[5-(2.-morpholin-4-yl-2-oxoethyl)- 1 ,3-thiazol-2-yl]-4-thien-2-ylbenzenesulfonaniide {[5-('2-morpholin-4-yl-2-oxoethyl)- 1 ,3-thiazol-2-yl]amino sulfonyl)- 1,1 -biphenyl- 4-carboXylic acid 4'-(metfhylhio)-N-[5-(2-morpholin-4-yl-2-oxoethyl)-1I,3 -thiazol-2-yI]- 1,1'-biphenyl-4sulfonamnide N-[5-(2-morpholin-4-yl-2-oxoethyl)- I ,3-thiazol-2-yl]-3',5'-bis(trifluoromethyl)- 1,1Vbiphenyl-4-sul fonamide 4'-chloro-N-[5-(2-morphol in-4-yl-2-oxoethyl)- 1,3 -thiazol-2-yi]- 1,1 F-biphenyl-4sulfonamide N- [5-(2-morpholin-4-yl-2-oxoethyl)- I ,3-thiazol-2-yl]-3 '-nitro- 1,1 F-biphenyl-4sulfonamide isopropyl -chloro-2-methylphenyl)sul fonyl ]amino)} 1,3 It is preferred that: T is selected from 5-chloro- 1,3-dimethyl-I H-pyrazol-4-yl; 4-chiloro-2,3,1 benzoxadiazolyl; 5-(dimethylamino)- I -naplithyl; 1 -methylimidazol-4-yl; 1 -naplithyl; 2naphthyl; 8-quinolinyl; thienyl substituted with one or more of (benzoylainino)methyl, bromo, chioro, 3isoxazolyl, 2-(mcthylsulfanyl)-4-pyrimidinyl, I -mcthyl-5-(trifluoromethyl)pyrazol-3-yI, phenylsulfonyl, pyridyl; phenyl substituted withi one or more of 3-acetylaruinophenyl, 3-acetyiphenlyl, benzeneamino, I ,3-benzodioxol-5 -yl, 2-benzofuryl, benzylam-ino, bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, chioro, 4-carboxyphenyl, 3-chioro- 2-cyanophenoxy, 4-chiorophenyl, 5 -chloro-2-thienyl, cyano, 3 ,4-dicblorophenyl, etho xy-2-oxoethyl)- 1,3 -thi azol-2 -yl ]amino)} carbonyl), fluoro, S -fluoro-2-methoxyphenyl, 2-filryl, hydrogen, iodo, isoPropyl, methanesulfonyl, methoxy, methyl, 4-methyl-i- Piperazinyl, 4.-methyl-i -piperidinyl, 4-methylsulfanylphenyl, 5-methyl-2-thienyl, 4morpholinyl, nitro, 3-nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 3pyridylmethylamino, 1 -pyrroliclinyl, 2-thienyl, 3-thienyl, 2 -thienylmethylamino, trifluoromethoxy, 4 -trifluoromethoxyphenyl, trifluoromethyl; or R' is hydrogen or methyl; is CH 2 or CO; Y is CO; B is hydrogen, methyl or dimethylaminomethyl; R2is selected from n-propyl, azido, bromo, chioro, 2-pyridinylsulfanyl, 3 -oxo-4-morpholinolinylmethylene, ethoxycarbonyl, 5-methyl-i 3 ,4-oxadiazol-:2-yl, hydroxymethyl, 2hydroxyethylaminomethyl, methiylsulfonyloxymethyl;

NR

3

R

4 wherein R 3 and R 4 are each independently selected from ac~etyl, benzhydryl, 1,3 -benzodioxol-5-yhmethyl, benzyl, 3 -chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexyhuethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2flirylinethyl, hydtrogen, 2-hydroxyethyl, 1H-indol-3 -yl)ethyl, isopropyl, methoxy, 2methoxyethyl, 1 -methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1 S)-phenylethyl, n-propyl, tetrahydro-2-fiiranylxnethyl, trifluoromethylsulfonyl, N-earbethoxypiperidyl; or NR 3R4 represent together 4 -acetylpiperazinyl, 4 -t-butoxycarbonylpiperazinyl, 2- (3 ,4-dihydro-2( IH)isoquinolinyl), 2

R,

6 S)-2,6-dimethyhmorpholinyl, (2R)-2,4-dimethyl- 1 -piperazinyl, 2 -hydroxy-3-oxomorpholinyl, imidazolyl, 2 -methyl-3-oxornorpholinyl, 4methyl- 2 -oxopiperaziiyl, 4-methylpiperazinyl, morpholinyl, (1 S,4S)-2-oxa-5-azabicyclo[2 .2.1I ]hept-5 -yl, 2 -oxoimidazolinyl, 3 -oxomorpholinyl, 3-oxo- 1 ,4-oxazepinyl, 2oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1,1 dioxido-tihomorpholinyl;

OCONR

3 R 4 wherein R 3 and R 4 are each independently selected from ethyl, hydrogen or form together with the N-atomn to which they are attached morpholinyl; R 5 0, wherein R 5 is acetyl, benzoyl, bcnzyl, ethyl, 2-fluoroethyl, 2 -furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2 -carbomethoxyphenyl, methylsulfonyl, phenyl, n-propionyl, 3 -pyridinyl, 2,2,2-tri fluoro ethyl; with the proviso that when: X is CH 2 Y is CO, then 1(2 is not hydroxy; When X is CH 2 and Y is CH 2 then it is preferred that: R(2 is selected from n-propyl, azido, bromo, chioro, 2-pyridinylsulfanyl, 3-oxo-4mozrpholinolinylmethylene, ethoxycarbonyl, 5-methyl- 1,3 ,4-oxadiazol-2-yl, hydroxymethyl, 2 -hydroxyethylaminometliyl, methylsulfonyloxymethyl; NR 3 W, wherein:

R

3 and W( are either each independently selected from acetyl, benzhydryl, 1,3benzyl, 3 -chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, 2-flirylcarbonyl, 2-furylniethyl, hydrogen, 2-hydroxyethyl, 2-(lH-indol-3-yl)ethyl, isopropyl, methoxy, 2methoxyethyl, methyl, 4-(1 -methylimidazolyl)suilfonyl, methylsulfonyl, phenyl, (1 S)-phenylethyl, n-propyl, tetrahydro-2-fiiranylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; or (ii) R 3 is ethyl and R(4 is selected from acetyl, benzhydryl, ylmethyl, benzyl, 3 -chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyL. 2-furylcarbonyl, 2-fiuyhnethyl, hydrogen, 2-hydroxyethyl, 2-(IH-indol-3-yl)ethyl, isopropyl, methoxy, 2methoxyethyl, methyl, 4 -(l-methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1 S)-phenylethyl, n-propyl, tetrahydro-2-fiiranylmethyl, trifluoromethylsulfonyl, N-carbethoxypiperidyl; NR 3 R 4 represent together 4 -acetylpiperazinyl, 4 -t-butoxycarbonylpiperazinyl, 2- (3 ,4-dihydro-2(l iH)isoquinolinyl), (2R ,6S)-2,6-dimethylmorpholin7l, (2R)-2,4-dimethyl- 1 -piperazinyl, 2-hydroxy-3 -oxomorpholinyl, imidazolyl, 2-methyl-3 -oxoniorpholinyl, 4methyl- 2 -oxopiperazinyl, 4 -methylpiperazinyl, (1 S, 4 S)-2.-oxa-5-aza-bicyclo[2.2 I yl, 2-oxoirni dazolinyl, 3 -oxomnorpholinyl, 3-oxo-1I, 4 -oxazepinyl, 2 -oxooxazolinyl, piperazinyl; pyrrolidonyl, thiomnorpholinyl; 1, 1l-dioxido-thiomiorpholinyi;

OCC)NR

3 R wherein R 3 and R 4 are each independently selected from ethyl, hydrogen or formi together morpholinyl;

R

5 0, wherein R 5 is acetyl, benzoyi, beuzyl, ethyl, 2-fluoroethyl, 2-fuirylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methyl suifonyl, phenyl, il-propionyl1, 3-pyridinyl, 2,2,2-trifluoroethyl.

When X is C11 2 ,Y is CH 2 and NR 3

R

4 represent together morpholiny., then it is preferred that T is selected from 5-chioro-1,3-dimethyl-1H-pyrazol-4-yl; 4-chloro-2,3,1benzoxadiazolyl; 5-(dimethyiamino)-l1-naphthyl; 1 -methylimidazol-4-yl; 1 -naphthyl; 2naphthyl; 8-quinolinyl; thienyl substituted with one or more of (benzoylaniino)mnethyl, bromo, chloro, 3isoxazolyl, 2-(methylsulfanyl)-4-pyrimidinyl, 1 -methyl-5-(trifluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl; phenyl. substituted with either: one or more of 3-acetylarninophenyl, 3-acetyiphenyl, benzeneamino, 1,3- 2-benzofuryl, benzylaniino, bromo, butoxy, carboxy, chioro, 4-carboxyphenyl, 3-cbloro-2.-cyanophenoxy, 4chlorophenyl, 5-chloro-2-thienyl, cyano, 3,4-dichiorophenyl, ({[4-(2-ethoxy-2oxoethyl)-1I,3-thiazoi-2-yi]amino}carbony), fluoro, 5-fluoro-2-niethoxyphenyl, 2fiaryl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, 4-methyl-I piperazinyl, 4-methyl-i -piperidinyl, 4-methylsulfanyiphenyl, 5-methyl-2-thienyl, 4-morpholinyl, nitro, 3-nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 3pyridylmethylamino, 1 -pyrrolidinyl, 2-thienyl, 3-thienyl, 2-thienylnethylamino, trifluoromethoxy, 4-trifluoromethoxyphenyl, trifluoromethyl; or one or more of methyl in any of positions 2, 3, 5 or 6.

When X is Gil 2 and Y is CO, then it is preferred that R 2 is selected from n-propyi, azido, bromo, chioro, 2-pyridinyisulfanyl, 3-oxo-4-morpholinolinylm ethylene, ethoxycarbonyl, 5-methyl-i ,3,4-oxadiazol-2-yl, hydroxym ethyl, 2hydroxyethylaminomethyl, methyisulfonyloxymethyl;

NR

3

R

4 wherein R 3 and RW are each independently selected from acetyl, benzhydryl, 1 ,3-benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2furylmethyl, hydrogen, 2-hydroxyethyl, 2-(l H-indol-3-yl)ethyl, isopropyl, methoxy, 2methoxyethyl, methyl, 4-(l1 -methylimidazoiyl)sulfonyl, methylsulfonyl, phenyl, (1 S)phenylethyl, n-propyi, tetrahydro-2-furanyhmethyl, trifluoromethylsulfonyl, Ncarbethoxypiperidyl; or INR 3 R 4 represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2- (3,4-dihydro-2(l H)isoquinolinyl), (2R,,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl- 1 -piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (1 S,4S)-2-oxa-5-azabicyclo[2.2. 1 ]hept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo- 1,4-oxazepinyl, 2oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1,1dioxido-thiomorpholinyl;

OCONR

3

R

4 wherein R 3 and R 4 are each independently selected from ethyl, hydrogen or form together with the N-atomn to which they are attached morpholinyl;

R

5 0, wherein R 5 is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-ftirylcaxibonyl, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, npropionyl, 3 -pyridinyl, 2,2,2-trifluoro ethyl.

.When X is CH 2 and Y is a single bond, then it is preferred that R 2 is selected from azido, bromo, chioro, 2-pyridinylsulfanyl, 3-oxo-4--morpholinolinylmethylene, ethoxycarbonyl, 5-methyl-i ,3,4-odxadiazol-2-yl, hydroxymethyl, 2hydroxyethiylaminomethyl, methylsulfonyloxymethyl; NR 3 W, wherein R3~ and R 4 are each independently selected from acetyl, benzhydryl, 1 ,3-benzodioxol-5-ylmnethyl, benzyl, 3-cbloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-fuirylcarbonyl, 2furylmethyl, hydrogen, 2-hydroxyethyl, 2-(lH-indol-3-yl)ethyl, isopropyl, methoxy, 2methoxyethyl, methyl, 4-(l -methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (I S)phenylethyl, n-propyl, tetrahydro-2-furanyhmethyl, trifluoromethylsulfonyl, Ncarbethoxypiperidyl; or NR 3 R 4 represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2- (3,4-dihydro-2( 1H)isoquinolinyl), (2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl- I -piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4mcthyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (1 S,4S)-2-oxa-5-azabicyclo[2.2 .1 ]hept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo- I ,4-oxazepinyl, 2oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; ],I1dioxido-thiomorpholinyl;

OCONR

3 R wherein R 3 and R 4 are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl;

R

5 0, wherein R 5 is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-f'urylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl, 2,2,2-trifluoroethyl.

When X is CH 2 Y is a single bond, R 2 is methyl and B is methyl, then it is preferred that T is selected from 5-chloro- 1 ,3-dimethyl- 1 H-pyrazol-4-yl; 4-chloro-2,3, 1benzoxadiazolyl; 5-(dimethylamino)-l1-naphthyl; 1 -methylimidazol-4-yl; 1-naphthyl; 2naphthyl; 8-quinolinyl; thienyl substituted with one or more of (benzoylamnino)methyl, bromo, ebloro, 3 isoxazolyl, 2 -(methylsulfanyl).4-pyrimidinyl, 1 -methyl-5-(trifluoromethyl)pyrazol-3yl, phenylsulfontyl, pyridyl; phenyl. substituted with either: one or more of 3 -acetylamtinophenyl, 3-acetyiphenyl, benzeneamnino, 1,3- 2-benzofinyl, benzylamino, 3 ,S-bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, 4-carboxyphenyl, 3-chloro-2-cyanophenoxy, 4chiorophenyl, 5-chloro-2-thienyl, cyano, 3 ,4-dichorophenyl, [4-(2-ethoxy-2oxoethyl)- 1, 3 -tbiazol-2-yl]axninolcarbonyl), fluoro, 5-fluoro-2-methoxyphenyl, 2furyl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, methyl, 4-methyl- Ipiperazinyl, 4 -methyl-l1-pip eridinyl, 4-methylsulfanylphenyl, 5-methyl-2-thienyl, 4-morpholinyl, nitro, 3-nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 3pyridylnethylamino, I -pyrrolidinyl, 2-thienyl, 3-thienyl, 2 -thienylmethylamino, trifiuoromethoxy, 4-trifluoromethoxyphenyl, trifluoromethyl; or (ii) one or more of 3 -acetylaminophenyl, 3-acetyiphenyl, benzeneamino, 1,3- 2-benzofuryl, berizylamino, 3 ,S-bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, chioro, 4-earboxyphenyl, 3 -chloro-2-cyanophenoxy, 4chlorophenyl, 5-cbloro-2-thienyl, cyano, 3,4-dichlorophenyl, [4-(2-ethoxy-2oxoethyl)- 1,3 -thi azol-2-yl] amino)I carbonyl), fluoro, 5-fluoro-2-methoxyphenyl, 2furyl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, 4-methyl-ipiperazinyl, 4-methyl- I -piperidinyl, 4-methylsulfanyiphenyl, 5-methyl-2-thienyl, 4-morpholinyl, nitro, 3-nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 3pyridylmethylamino, 1 -pyrrolidinyl, 2-thienyl, 3-thienyl, 2 -thienylmethylamino, trifluoromethoxy, 4 -trifluoromethoxyphenyl, trifluoromethyl; or ii) one or more chioro and, in positions 3, 4, 5, one or more methyl.

When X is CO and Y is a single bond, then it is preferred that R2 is selected from n-propyl, azido, bromo, chioro, 2-pyridinylsulfanyl, 3 -oxo- 4 -morpholinolinyhnethylene, ethoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl, hydroxymethyl, 2hydroxyethylaminomethyl, methylsulfonyloxymethyl; NRR, wherein R 3 and R 4 are each independently selected from acetyl, benzhydryl, 1 ,3-benzodioxol-5-ylmethyl, benzyl, 3-cbloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexyhuethyl, cyclopropanecabonyl, ethyl, 2-furylcarbonyl, 2furylmethyl, hydrogen, 2-hydroxyethyl, 2-(IH-indol-3-yl)ethyl, isopropyl, methoxy, 2methoxyethyl, methyl, 4-(l -methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (I S)phenylethyl, n-propyl, tetahydro-2-fuiranylmethyl, tifluoromethylsulfonyl,

N-

carbethoxypiperidyl; or NR 3

R

4 represent together 4-acetylpiperazinyl, 4 -t-butoxycarbonylpiperazinyl, 2- (3 ,4-dihydro-2( 1H)isoquinolinyl), (2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl- 1 -piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (1 S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo-1 ,4-oxazepinyl, 2oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1,1 dioxido-thiomorpholinyl;

OCONR

3

R

4 wherein W 3 and R 4 are each independently selected from ethyl, hydrogen or form together with the N-atom. to which they are attached morpholinyl;

R

5 0, wherein R 5 is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl, 2o hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl, 2,2,2-trifluoroethyl; When X is CO and Y is a single bond and R 2 is ethoxy, then it is preferred that T is selected from 5-chloro- I ,3-dimethyl- I H-pyrazol-4-yl; 4-cbloro-2,3, I -benzoxadiazolyl; 5-(dimethylamino)-l1-naphthyl; 1 -methylimidazol-4-yl; 1 -naphthyl; 2-naphthyl; 8quinolinyl; thienyl substituted with one or more of (benzoylamnino)methyl, bromno, chloro, 3isoxazolyl, 2-(methylsulfanyl)-4-pyrimidinyl, 1 -methy1-5-(trifluoromethyl)pyrazol-3-y1, phenylsulfonyl, pyridyl; phenyl substituted with either: one or more of 3-acetylaminophenyl, 3-acetylphenyl, benzeneamino, 1,3- 2-benzofiyl, benzylamino, 3 bromno, butoxy, carboxy, 4-carboxyphenyl, 3-chloro-2-cyanophenoxy, 4chiorophenyl, 5-chloro-2-thienyl, cyano, 3 ,4-dicblorophenyl, [4-(2-ethoxy-2oxoethyl)- 1,3 -tliiazol-2-yl]amnino }carbonyl), fluoro, 5-fluoro-2-methoxyphenyl, 2fury], hydrogen, iodo, isopropyl, methanesalfonyl, methoxy, 4-methyl-I piperazinyl, 4-methyl-i -piperidinyl, 4-methlsulfanylphenyl, 5-methyl-2-thienyl, 4-morpholinyl, nitro, 3-nitrophenyl, phenoxy, 4-pyridyl, 3-pyridylinethylamino, 1pyrrolidinyl, 2-thienyl, 3-thienyl, 2-thienylmethylamino, trifluoromethoxy, 4trifluoromethoxyphenyl, trifluoromethyl; one or more of methyl; one or more of chioro, phenyl and n-propyl in either position, and methyl in any of positions 3, 4 or (iv) one or more of n-propyl and phenyl in any of positions 2, 3, 5 or 6.

The following compounds are disclosed: o ethyl 2 4 -dichloro-5-methylphenyl)sulfonyl]aniino ethyl (2 ({[(4-chlorophenyl)sulfonyl] amino) 1,3 -thiazol-5 -yl)acetate ethyl {[(2,4-difluorophenyl)sulfonyl] amino) -1 ethyl 2 ,S-dicblootbi en-3-yl)sulfonyl] amino)} -1 9 ethyl 2 -cblorophenyl)sulfonyl]amino) I *ethyl 1-naphthylsulfonyl)amnino]- 1,3-thiazol-5-yl} acetate *ethyl f 3 -chl oro-2-methylphenyl)sulfonyl] amino) -1,3-thiazol-5-yl)acetate

{I(

3 -chloro-2-methylphenyl)sulfonyl]amino} -1 methylacetamide f 3 -ehloro-2-mediylphenyl)sulfonyl] arino} 1,3-thiazol-5 -yl)-Nethylacetaniide *ethyl 1,1'-biphenyl-4-ylsulfonyl)aniino]- 1,3 -thiazol-5-yl) acetate *ethyl {[(4-nitrophenyl)sulfonyl]amino 1,3 *ethyl (2 [(4-methoxyphenyl)sulfbnyl] amino I 1,3 *ethyl {[(2,5-dichlorophenyl)sulfonyl]amnino)}-1 3 -chloro-N-[5-(2-hydroxyethyl)-l ,3-tbi azol-2-yl]-2-methylbenzenesulfonarnide 3 -chloro-N-[5-(2-ethoxyethyl)- 1, 3 -thiazol- 2 -yl]-2-methylbenzenesulfonamide *ethyl 3 -chlorophenyl)sulfonyl] amino) 1,3 *ethyl [(4-fluorophcnyl)sulfonyl]amino) 1,3-thiazol-5-yl)acetate ethyl {[(4-isopropylphenyl)sulfonyl] amino *ethyl {[4-(2-ethoxy-2-oxoethyl)- 1,3 -thiazol-2yllamnino carbonyl)phenyl]sulfonyl) am-ino)- 1,3 -thiazol-5-yl] acetate 3 -clhloro- 2 -methylpheny1)su~fony1]amiio}-1 ,3-tbiazol-5-y1)-NNdiethylacetamide e ethyl 2 -(trifluoromethyl)phenyl] sulfonyl) amino)- I ,3-thiazol- 5-yl] acetate ethyl 3 -(trifluoromethyl)phenyl]sulfonyl} amino)- 1, 3 ethyl 4 -(trifluoromnethyl)phenyl] sulfonyl} amino)- 1 3 -tbiazol-5-yl] acetate Methyl 3 -chloro-2-methylphenyl)sulfonyl] amino) 1, 3 (Example 2) *3-chloro-N-[1 5 2 -isopropoxyethyl)- l, 3 -thiazol-2-yl]-2-methylbenzenesulfonamide 3 -chloro-N-[5-(2-methoxyethyl). 3 -tbiazol- 2 -yl]-2-methylbenzenesulAfonan-jde -chloro-2-methylphemyl)sulfonyl] amnino} -1,3-thiazol-5-yl)ethyl methanesulfonate 3 -cloro- 2 -methylphenyl)sulfony1] amino) -1,3 *3-cbloro-N- 5 2 2 -fluoroethoxy)ethyl]-l ,3-thiazol-2-yl methylbenzenesulfonamide 3 -cbloro-2-methyl-N- f{ 5 2 2 ,2,2-trifluoroethoxy)ethylp- I,3-thiazol-2yl}benzenesulfonarnide 3 -chloro-2-methylphenyl)sufonyl]mino ,3-thazol-5-yl)ethyl acetate 3 -chloro- 2 -methyl-N-[5-(2-morpholin-4ylethyl).1 ,3-thiazol-2yl]benzenesulfonamnide (Example 1) *N-[5-(2-bromoethyl1) 3tizl2yl--hoo2-ehlezneufnmd 3 -chloro-2-methylphenyl)sulfonyl]amnino morpholine-4-carboxylate -I 3 -chloro-2-m ethylpheny)sulfonyl] amino)} -l ,3-thi diethylcarbamate 9 3 -chloro- 2 -methylphenyl)sufony]mino 3 propionate 3 -chloro- 2 -methylphenyl)sulfonyl]aino)}-1 ,3-thiazol-5-yl)ethyl 2methylpropanoate -chloro- 2 -methylphenyl)sulfonyl] amino l, 3 -"hazol-5-yl)ethyl 2-furoate 3 -chloro- 2 -methylphenyl)sulfonyl]amino l, 3 -thiazol-5-yI)ethyl benzoate 3 -chloro-2-methylphenyl)su fonyl]an'ino} 1, 3 N-methylacetamide -chloro-2-methylphenyl)sulfonyl] amino} -1 ethylcaibamate {[(3-chloro-2-methylphenyl)sulfonyl] amino) 1,3-thiazol-5-yl)ethylj-N- ;Z ethylacetarnide 3-chlor-o-2-methyl-N-[5-(2-oxopentyl)-1 ,3-thiazol-2-yljbenzenesullbnamide 9N- I -doxidothiomorpholin-4-yl)-2-oxoethyl]- I,3-thiazol-2-yl} -4propylbenzenesulfonamnide 2,4-dicliloro-6-methyl-N- f 5-[2-(4-methylpiperazin- 1-yl)-2-oxoethyl]-1I,3-thiazol- 2-yl~benzenesulfonarnide N 10 0 3-chloro-2-methyl-N- {5-[2-(3-oxomorpholin-4-yl)ethyl]- 1,3 -thiazol-2yl)benzenesulfonaxnide 0 2,4-dichloro-6-methyl-N-[5-(2-morpholin-4-yl-2-oxoethyl). 1,3 -thazol-2ylbenzenesulfonamide N-[5-(2-morpholin-4-yl-2-oxoethyl)- 1,3-thiazol-2-yl]-1, 1 -biphenyl-4sulfonamide N-[5-(2-morpholin-4-yl-2-oxoethyl)-l ,3-tbiazol-2-yl]-4propylbenzenesulfonamide e N-[5-(2-oxo-2-thiomorpholin-4ylethyl)-1 ,3-thiazol-2-yl]-1,1 I'-biphenyl-4sulfonamide 0 N- [5-(2-oxo-2-tbiomorpholin-4-ylethyl)- 1,3-thiazol-2-yl]-4propylbenzenesulfonamide 2 ,-dichloro6-methyl-N-[5-(2-oxo-2-homorpholin-4-ylethyl). 1 ,3-thiazol-2yl]benzenesulfonainide *N-[5-(2-oxo-2-piperidin- I1-ylethyl)-1 ,3-thiazol-2-yl]- 1,1 '-biphenyl-4-sulfonamide *N-[5-(2-oxo-2-piperidin- 1 -ylethyl)-1I,3-tbiazol-2-yl]-4-propylbenzenesulfonamide 2 ,4-dichloro-6-methyl-N-[5-(2-oxo-2-piperidin-1 -ylethyl)- I ,3-thiazol-2yl]benzenesmlfonamide *ethyl oxo(2- [(4-propylphenyl)sulfonyl] amino) ,3 -thiazol- *ethyl (2 [(3-chloro-2 -methylphenyl)sulfonyl] amino) -1,3 -thiazol-5 yI)(oxo)acetate *ethyl oxo(2- f [(2,4,6-trichlorophenyl)sulfonyl]amino) -1,3-tbiazol-5-yl)acetate *ethyl I'-biphenyl-4-ylsulfonyl)aniino]- 1,3-thiazol-5-yl }(oxo)acetate 3-hoo2mty--4mty--(-opoi- l2ooty ,3-thiazol-2yl]benzenesulfonamide 2 4 6 -trichloro-N-[4-methyl-5-(2-morphoin-4y-2-oxoethy).1 ,3-tbiazol-2yl]benzenesulfonamide 2- 1 '-biphenyl-4-ylsulfbnyl)amino]- 1 ,3-thiazol-5-yl} -N-ethyl-Nmethylacetamide N-ethyl-N-methyl-2-(2- 4 -propylphenyl)sulfonylanijno yl)acetaniide 9 {[(2,4-dichloro-6-methylphenyl)sulfonylaiino N-methylacetaniide e N-[1 4 -methyl-5-(2-morpholin-4-yl-2-oxoethyl). I ,3-tliiazol-2-yl]-1 ,1'-bipbenyl-4sulfonamide, I '-biphenyl-4-ylsulfonyl)axnino]- 1,3-thiazol-5.-yl -N-isopropyl-Nmethylacetamide 2- 1 '-biphenyl-4-ylsulfonyl)amino]-1I,3-thiazol-5-yl -NN-diethylacetaniide *N,N-diethyl-2-(2- {[(4-propylphenyl)sulfonyl] amino)- 1,3 2 ,4-dichloro-6-methylphenyl)sulfonyl] amino}I -1 diethylacetaniide *ethyl 4 -bromo-5-chlorothien-2-yI)sulfonyl]amino} -1 *ethyl 3 -bromo-5-chlorothien-2-yl)sulfonyl] amino}I 1,3 *ethyl I-methyl-5-(trifluoromethyl)- 1H-pyrazol-3 -yl]thien-2yl) sulfonyl)arnino]- l,3-thiazol-5-yl} acetate *ethyl {5-[2-(methylthio)pyrimiddin-4-yl]thien.2yl} sulfonyl)amino] -1,3acetate ,1 ?-biphenyl-4-ylsulfonyl)amino]- l,3-thazol-5-yl} -N,Ndiisopropylacetamide *N,N-diisopropyl-2-(2- (4-propylphenyl)sulfonyl]amino} -1 yl)acetarnide {[(2,4-dichloro-6 -methylphenyl)sulfonyl] amino -1,3 -thi diisopropylacetamide *methyl (4-methyl-2- {[(2,4,6-trichlorophenyl)sulfonyl]amino} -1 yl)acetate [(3-chloro-2-methylphenyl)sulfonyl] amino) 1,3-thiazol-5-yl).NNdipropylacetamnide c-I 3 -chloro-2-methyl-N-[5-(2-oxo-2-piprain.1 -ylethyl)-1 ,3-tbiazol-2- ;Z ylbenzenesulfonaxnide 0 4 bromo- 2 -methyl-N-[5-(2-tnorpholin-4yl.2oxoefiyl).1 ,3 -thiazol-2- 2 yljbelnzenesulfonamide a N-[5-(2-morpholin-4-yl-2-oxoethyl).1 ,3-thiazol-2-yl]-2,4bis(trifluoromethyl)benzenesulfonainide 2 -methyl-N-[5-(2-morpholin-4yl-2-oxoethyl) 1 ,3-thiazol-2-yl]-4-.

(trifluoromethoxy)benzenesulfonwnide *N-[5-(2-mol-pholin-4-yl-2-oxoethyl).1,3-thiazol-2-yl]-4phenoxybenzenesulfonamide *ethyl 2 3 ,4-trichlorophenyl)sulfonyl] amino -1 *ethyl 4 -bromo-2,5 -difluorophenyl)sulfonyl] amino) 1,3 -thiazol-5 -yl)acetate *ethyl 4 -(trifluoromethoxy)phenyl]sulfonyl} amino)- 1 3 -thiazol-5-yl] acetate *ethyl 4 -(phenylsulfonyl)tbien-2-yl]sulfonyl }amino)-1I,3-tbi azol-5-yl] acetate *ethyl -(phenylsulfony)thien-2-y]sulfony} amino)- 1 ,3 -thiazol-5-yl] acetate *ethyl {[(2,6-dichloropbenyl)sulfonyl]amino} 1,3-thiazol-5-yI)acetate *ethyl 2 4 -dichlorophenyl)sulfonyl]amino atert-butyl 3 -chloro-2-methylphenyl)sulfonyl]amino yl)acetyl]piperazine- I -carboxylatc 3 -chloro-2-methylphenyl)sulfonyl) amino) 1-1,3 dimethylacetamide *3-cbloro-2-methyl-N- 5 -[2-(pyridin-3-yloxy)ethyl]- 1 ,3-thiazol-2yl~benzenesulfonamide {[(3-chloro-2-methylphenyl)suifonyl]amino 1- 1, 3 N-methylacetamide 13-choro-2-methylphenyl)sulfonyl] amino) 1,3 methylacetamide *3-chloro-2-methyl-N- [5 2 -oxo-2-thiomorpholin-4-ylethyl)- 1,3 -thiazol-2yl]benzenesulfonainide *ethyl 4 -bromo-2-fluorophenyl)sulfonyl]amino 1-1 *3-chloro-2-methyl-N-[5-(2-morpholin-4-yl-2-oxoethyl) 1 ,3-tbiazol-2yIjbenzenesulfbnamide (Example 4) *methyl f 4 -chlorophenyl)sulfonyl]amino}-4-methyl- 1 *methyl. f 3 -chloro-2-methylphenyl)sulfonyl]amino} -4-methyl-I yl)acetate f [(3-chloro-2-methylphenyl)sulfonyl]amino}- 1 diisopropylacetamide (Example *3-chloro-2-methyl-N-[5-(2-oxo-2-py-olidin-.1 -ylethyl)-1 ,3-thiazol-2yl]benzenesulfonamide *ethyl f 3 -methoxyphenyl)sulfonyl]amino} -1 *ethyl f [(5-fluoro-2-methylphenyl)sulfonyllamino} -l *ethyl {[(4-propylphenyl)sulfonyl] amino} I 3 -chloro-2-methyl-N-[5-(2-oxo-2-piperidin-I -yl ethyl)- 1,3-thiazol-2yl]benzenesulfonamide *ethyl {[(3,5-dchlorophenyl)sulfonyl] amino) *ethyl ,4-dichlorophenyl)sulfonyl] amino)} -1 3 *ethyl 2 4 -dchloro-6-methylphenyl)sulfonyl]amino} -1I,3-tbiazol-5-yl)acetate *3 -chloro-2-methyl-N-[5-(morpholin-4-ylmethyl). I,3-tbiazol-2yljbenzenesulfonamide *3-ohloro-N- 1-imnidazol- 1-yl)ethyl]- 1,3 -thiazol-2-yI)}-2methylbenzenesulfonamide [(3-chloro-2-methylphenyl)sulfonyl] amino) 1,3-thiazol-5yl)ethyl]acetamide *ethyl {[2-methyl-4-(trifluoromethoxy)phcnyl]sulfonyl} amino)- 1,3-thiazol-5ylacetate *ethyl ,4-trifluorophenyl)sulfonyl]amino} -1I,3-tbiazol-5-yl)acetatc *ethyl [(2,4,6-trifluorophenyl)sulfonyl] amino)} 1 ,3 -tbiazol- *3 -chloro-2-methyl-N-(5- 2 -[(methylsulfonyl)aminojethyl} -1,3 -thiazol-2yl)benzenesulfonantide *ethyl f [(5-chlorothien-2-yl)sulfony] amino) 1,3-thiazol-5-yl)acetate *ethyl {[(2-chloro-4-fluorophenyl)sulfonyl]amino *ethyl {[(5-isoxazol-3-ylthi en-2-yl)sulfonyl] amino) 1,3 -thi *ethyl {[(4-phenoxyphenyl)sulfonyl]amino} -1I,3-tbiazol-5-yl)acetate ethyl 2 -({[2,4-bis(trifluoromethyl)phenyl]sulfonyl amino)- 1,3 yl] acetate CI 3-chloro-2-methyl-N- {5-[2-(3-oxo-1 ,4-oxazepan-4-yl)ethyl]- 1,3-thiazol-2yl~benzenesulfonamide 3-chloro-2-methyl-N- {5-[2-(2-oxopyrrolidin- 1-yl)ethyl]-l ,3-tbiazol-2yllbenzenesulfonamide e 3-chloro-2-methyl-N-{5- {2-[methyl(methylsulfonyl)amino]ethyl> 1 ,3-thiazol-2yl)benzenesulfonamide -chloro-2-methylphenyl)sulfonyl] amino} -1 methylcyclopropanecarboxainide s 3-cbloro-2-methyl-N- {S-12-(4-methyl-2-oxopiperazin- 1-yl)ethyl]-1 ,3-tkiazol-2yl~benzenesulfonainide 3 -chloro-2-methyl-N- [5 [(trifluorornethyl)sulfbnyl] amino) ethyl)- 1,3 -thiazol- 2-yl]benzenesulfonaniide a 2,4-dichloro-N- {5-[2-(3-oxomorpholin-4-yl)ethyl]-1I,3-thiazol-2yllbenzenesulfonamide e 2,4-dichloro-6-methyl-N- {5-[2-(3-oxomorpholin-4-yl)ethyl]-1I,3-thiazol-2yl }benzenesulfonamide 4-(2-furyl)-N-[5-(2-morpholinA-yl-2-oxoethyl) 1 ,3-thiazol-2yl]benzenesulfonaniide 5'fur-'mtox--5(-opoln4y -xehl,3-thiazol-2-yl]-l, 1' biphenyl-4-sulfonamidc 4 5 -methylthien-2-yl)-N-[5-(2-morpholinA.yl2oxocthyl).1,3 -thiazol-2yl]benzenesulfonam-ide 3?.accty-[5-$(2 -morpholin4y2xo etl)- 1,3 -thiazol-2-yl]- 1, 1 '-biphenyl-4sulfonamide N-[5-(2-morphoin-4-y1-2-oxoethyl)4 ,3 -thiazol-2-yl]-4'-(trifluoromethoxy)- 1,1' biphenyl-4-sulfonamnide 3 4 -dichloro-N-[5-(2-morpholin-4-yl-2-oxoethyly 1,3 -thiazol-2-yl]- 1,1'-biphenyl- 4-sulfonamide 1,3 -benzodioxo1-5-y)-N[5-(2morpholin-4-y[-2oxoy).I ,3-thiazol-2yl]benzenesulfonamide e N-[5-(2-morpholin-4-yl-2-oxoethyl)- 1,3-thiazol-2-yl]-4-pyridin-4ylbenzenesulfonamide {[5-(2-morpholin-4-y-2-oxoethy)-1 ,3-thi azol-2-yl]amino }sulfonyl)- 1,1 biphenyl-3-yl]acetanide N-[5-(2-morpholin-4-yl-2-oxoethyl) 1 ,3-thiazol-2-yl]-4-thien-3 ylbenzenesulfonamide.

N-[5-(2-morphoin-4-y-2-.oxoethyl)-1,3-thiazol-2-yl]-4-thien-2ylbenzenesulfonamide G {[5-(2-morpholin-4.yl-2-oxoethyl)- 1 ,3-thiazol-2-yl] amino) sulfonyl)- 1, 1biphenyl-4-carboxylic acid 4t (methythio)-N-[5-(2-morpholin-4y-2-oxoethyl).1 ,3-thiazol-2-yl]- biphenyl-4-sulfonamide 0 N-[5-(2-morpholin-4-yl-2-oxoethyl).1 ,3-thiazol-2-yl]-3 1,1 '-biphenyl-4-sulfonamide 9 4 '-chloro-N-[5-(2-morpholin-4-yl2oxoethyl).1 ,3-tbiazol-2-yl]-1 1'-biphenyl-4sulfonamriide N-{[5-(2-morpholin-4-yl-2-oxoethyl). 1 ,3-thiazol-2-yl]-3'-nitro-1 1 '-biphenyl-4sulfonamide isopropyl {[(3-chloro-2-methylphenyl)sulfonyl]amino} -1 Another object of the present invention is a compound as described above for medical use.

Another object of the present invention is a method for the treatment or prevention of diabetes, syndrome X, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, hypertension, osteoporosis, dementia, depression, virus diseases or inflammatory disorders without causing hypoglycemia and to achieve immunomodulation, preferably tuberculosis, lepra, and psoriasis, said method comprising administering to a mammal, including a human, in need of such treatment identified as in need thereot) an effective amount of a compound of formula as defined above or a composition having a compound of form-ula in it.

In another aspect, this invention features a method for inhibiting a human 1 1-Phydroxysteroid dehydrogenase type 1 enzyme. The method includes administering to a subject mammal, human, or animal) in need thereof identified as in need thereof) an effective amount of a compound of formula as defined above or a composition having formula in it.

The present invention also features a method for treating 11 -P-hydroxysteroid dehydrogenase type 1 enzyme-mediated disorders. The method includes administering to a subject mammal, human, or animal) in need thereof identified as in need thereof) an effective amount of a compound of formula defined above or a composition having formula in it. The 11-P-hydroxysteroid dehydrogenase type 1 enzyme-mediated disorder is any disorder or symptom wherein the 11-P-hydroxysteroid dehydrogenase type 1 enzyme is involved in the process or presentation of the disorder or the symptom. The 11-0-hydroxysteroid dehydrogenase type 1 enzyme-mediated disorders include, but are not limited to, diabetes, syndrome X, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, hypertension, osteoporosis, dementia, depression, virus diseases, inflammatory disorders, and immuno-modulation.

Preferred examples of immuno-modulation are tuberculosis, lepra, and psoriasis. When the disorder is hyperglycemia, the treatment thereof does not cause hypoglycaemia.

The methods delineated herein can also include the step of identifying that the subject is in need of treatment of diseases or disorders described above. The identification can be in the judgment of a subject or a health professional and can be subjective opinion) or objective measurable by a test or a diagnostic method).

These compounds may also be used in the manufacture of a medicament for the prevention, management or treatment of diabetes, syndrome X, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, hypertension, osteoporosis, dementia, depression, virus diseases or inflammatory disorders without causing hypoglycemia and 31 N:\Melbourne\Casea\Patent\52000-52999\P52913.AU.1\Specis\amendments dcc 8/08/07 to achieve immuno-modulation. Preferred examples of irnmuno-modulation are tuberculosis, lepra, and psoriasis.

It is preferred that: T is selected from 5-chloro-1,3-dimethyl-1H-pyrazo1A..yl; 4-chloro-2,3,lbenzoxadiazolyl; 5-(dimethylamino)-l1-naphthyl; 1 -methylimidazol..4-yl; 1 -naphthyl; 2naphthyl; 8-quinolinyl; thienyl substituted with one or more of (benzoylamino)mnethyl, bromo, chloro, 3isoxazolyl, 2 -(methylsulfanyl)-4-pyrimidinyl, 1 -methyl-5-(rfluoromethyl)pyzol.3-yl, phenylsulfonyl, pyridyl; phenyl substituted with one or more of acetylamino, 3 -acetylaniinophenyl, 3acetyiphenyl, benzeneamino, l,3-benzodioxol-5-yl, 2-benzofuryl, benzylamino, bis(trifluoromethyl)phenyl, bromno, butoxy, carboxy, chioro, 4-carboxyphenyl, 3-chioro- 2-cyanophenoxy, 4-chlorophenyl, 5 -chloro-2-thienyl, cyano, 3 ,4-dichlorophenyl, ethoxy-2-oxoethyl)- I,3-thi azol-2-yl] amino}I carbonyl), fluoro, 5-fluoro-2-methoxyphenyl, 2-ftuyl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, methyl, 4-methyl-ipiperazinyl, 4-methyl-i -piperidinyl, 4-methylsulfanyiphenyl, 5-methyl-2-thienyl, 4morpholinyl, nitro, 3-nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 3pyridylmethylamidno, 1 -pyrrolidinyl, 2-thienyl, 3-thienyl, 2-thienylmethylamino, trifluoromethoxy, 4-trifluoromethioxyphenyl, trifluoromethyl; or R' is hydrogen or methyl; X is CH 2 or CO; Y is CO; B is hydrogen, methyl or dimethylaminomethy]; R 2 is selected from n-propyl, azido, bromo, chioro, 2-pyridinylsulfanyl, 3-oxo-4-morpholinolinylmethylene, ethoxycarbonyl, 5-methyl-i ,3,4-oxadiazol-2-yl, hydroxymethyl, 2hydroxycthylaminomethyl, m ethylsul fonyloxym ethyl; NR 3 1R 4 wherein R 3 and R 4 are each independently selected from acetyl, WC benzhydryl, 1 ,3-benzodioxol-5-ylmethyl, benzyl, 3 -chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-flirylcarbonyl, 2furylmethyl, hydrogen, 2-hydroxyethyl, 1H-indol-3-yl)cthyl, isopropyl, methoxy, 2methoxyethyl, methyl, 4 -(1l-methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (I S)phenylethyl, n-propyl, tetrahydro-2-furanyhnethyl, trifluoromethylsulfonyl,

N-

carbethoxypiperidyl; or

NR

3

R

4 represent together 4-acetylpiperazinyl, 4 -t-butoxYeadbOnYlPipctaziy, 2- 3 4 -dihydro-2(1H)isoquinolinyl), 2

R,

6 S)-2, 6 -dimethylmorpholinyl, (2R)-2,4-dimethyl- 1 -piperazinyl, 2 -hydroxy-3-oxomorpholjnyl, imidazolyl, 2-methyl-3 -oxomorpholinyl, 4methyl-2-oxopiperazinyl, 4 -methylpiperazinyl, morpholinyl, (1 S, 4 bi cyclo[2.2. 1]hept-5-yl, 2 -oxoimidazolinyl, 3 -oxomorpholinyl, 3-oxo-1I, 4 -oxazepinyl, 2oxooxazolinyl, pip erazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, tbiomnorpholinyl; 1,1 dioxido-thiomorpholinyl; OCONR 3

R

4 wherein R' and RW are each independently selected from ethyl, hydrogen or form together with the N-atomn to which they are attached morpholinyl; R 5 0, wherein R 5 is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2 -carbomethoxyphenyl, methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl, 2 ,2,2-trifluoroethyl; with the proviso that when: X is CH 2 Y is CO, then R 2 is not hydroxy.

When X is CR 2 and Y is CH 2 then it is preferred that:

R

2 is selected from n-propyl, azido, bromo, chioro, 2-pyridinylguManyl, 3-oxo-4no rpholinolinylmethylene, ethoxycarbonyl, 5-methyl-i ,3 ,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymnethyl;

NR'R

4 wherein R 3 and R 4 are either each independently selected from acetyl, benzhydryl, 1,3-b enzodioxol-5-ylmethyl, benzyl, 3 -cbloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2flirylmethyl, hydrogen, 2-hydroxyethyl, 2-(l H-indol-3-yl)ethyl, isopropyl, methoxy, 2methoxyethyl, methyl, 4-(l -methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (I S)phenylethyl, n-propyl, tetrahiydro-2-furanylmethyl, trifluoromethylsulfonyl, Ncarbethoxypiperidyl; or

NR

3

R

4 represent together 4-acetylpiperazinyl, 4 -t-butoxycarbonylpiperazinyl, 2- (3 ,4-dihydro-2( 1H)isoquinolinyl), (2R,6 S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl 1-pip erazinyl, 2 -hydroxy-3-oxomorpholinyl, imidazolyl, 2 -methyl-3-oxomorpholinyl, 4methyl-2-oxopiperazinyl, 4 -methylpiperazinyl, morpholinyl, (IS ,4S)-2-oxa-5-azabicyclo[2.2.1I]hept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo- 1,4-oxazepinyl, 2oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1,1 dioxido-thiomorpholinyl;

;ZNRR

4 wherein R' and Re are each independently selected from ethyl, hydrogen or form together morpholinyl;

R

5 0, wherein R 5 is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-fixiylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl, 2,2,2-trifluoroethyl.

When X is CH 2 and Y is a single bond, then it is preferred that R 2 is selected from azido, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4-morpholinolinyhnethylene, ethoxycarbonyl, 5-methyl-i ,3,4-oxadiazol-2-yL, hydroxymethyl, 2hydroxyethylamidnomethyl, methylsulfonyloxymethyl;

NR

3

R

4 wherein R' and R 4 are each independently selected from acetyl, benzhydryl, I ,3-benzodioxol-5-ylmethyl, benzyl, 3-cbloro-2-methylphenylsulfony, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2furylinethyl, hydrogen, 2-hydroxyethyl, 2-(lH-indol-3-yl)ethyl, isopropyl, methoxy, 2methoxyethyl, methyl, 4-(l -methylmidazolyl)sulfonyl, methylsulfonyl, phenyl, (IlS)phenylethyl, n-propyl, tetrahydro-2-furanylmethyl, trifluoromethylsulfonyl, Ncarbethoxypiperidyl; or *NRWR represent together 4-acetylpiperazinyl, 4-t-butoxycarbonylpiperazinyl, 2- (3 ,4-dihydro-2(1 H)isoquinolinyl), (2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl- 1 -piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (I S,4S)-2-oxa-5-azabicyclo[2.2.1I]hept-5 -yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo-l ,4-oxazepinyl, 2oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomnorpholinyl; 1,1dioxido-thiomorpholinyl;

OCONR

3

R

4 wherein and R 4 are each independently selected from ethyl, hydrogen or form together with the N-atomn to which they are attached morpholinyl; WO,. wherein R 5 is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-fuirylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl, 2,2,2-trifluoroethyl.

When X is CU 2 Y is a single bond, R2 is methyl and B is methyl, then it is preferred that T is selected from 5-chloro- 1,3-dimethyl-1I H-pyrazol-4-yl; 4-chloro-2,3,1 benzoxadiazolyl; 5-(dimethylamino)- 1-naphthyl; 1 -methylimidazol-4-yl; 1-naphthyl; 2naphthyl; 8-quinolinyl; thienyl substituted with one or more of (benzoylamino)methyl, bromo, chioro, 3isoxazolyl, 2-(methylsulfanyl)-4-pyrimidinyl, 1 -methyl-5-(trifluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl; phenyl substituted with either: one or more of 3-acetylaminophenyl, 3-acetyiphenyl, benzeneamino, 1,3- 2-benzoftuyl, benzylamino, bromo, butoxy, carboxy, 4-carboxyphenyl, 3-chloro-2-cyanophenoxy, 4chiorophenyl, 5-chloro-2-thienyl, cyano, 3,4-dichiorophenyl, ({[4-(2-ethoxy-2oxoethyl)- 1 ,3-thiazol-2-yl] amino)} carbonyl), fluoro, 5-fluoro-2-methoxyphenyl, 2furyl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, methyl, 4-methyl-i piper-azinyl, 4-methyl-i -piperidinyl, 4-methylsulfanyiphenyl, 5-methyl-2-thienyl, 4-morpholinyl, nitro, 3-nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 3pyridylmethylamino, 1-pyrrolidinyl, 2-thienyl, 3-thienyl, 2-thienylmethylamino, frifluoromethoxy, 4-trifluoromethoxyphenyl, trifluoromethyl; or one or more of 3-acetylaminophenyl, 3-acetyiphenyl, benzeneamino, 1,3- 2-beazofuryl, beuzylainino, bromo, butoxy, carboxy, chioro, 4-carboxyphenyl, 3-chloro-2-cyanophenoxy, 4chlorophenyl, 5-chloro-2-tbienyl, cyano, 3,4-diclilorophenyl, [4-(2-ethoxy-2oxo ethyl)- 1,3-tbi azol-2-yl] am ino} carbonyl), fluoro, 5-fluoro-2-methoxyphenyl, 2furyl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, 4-methyl-Ipiperazinyl, 4-methyl- I -piperidinyl, 4-methylsulfanyiphenyl, 5-methyl-2-thienyl, 4-morpholinyl, nitro, 3-nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 3pyridylmethylamino, 1-pyrrolidinyl, 2-thienyl, 3-thienyl, 2-thienylmethylamino, trifluoromethoxy, 4-trifluoromethoxyphenyl, trifluoromethyl; or one or more chioro and, in positions 3, 4, 5, one or more methyl.

When X is CO and Y is a single bond, then it is preferred that R 2 is selected from n-propyl, azido, bromo, chioro, 2 -pyridinylsulfanyl, 3-oxo-4-morpholinolinylmethylene, ethoxycarbonyl, 5-methyl-I ,3,4-oxadiazol-2-yl, hydroxymethyl, 2hydroxyethylaminomethyl, methylsulfonyloxymethyl; NR 3 W, wherein R 3 and R 4 are each independently selected from acetyl, benzhydryl, 1 ,3-benzodioxol-5-yhnethyl, benzyl, 3 -chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2tuaryhmethyl, hydrogen, 2-hydroxyethyl, 2-(IH-indol-3-yl)ethyl, isopropyl, methoxy, 2methoxyethyl, methyl, 4-(1 -uethylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (I s)- CI phenylethyl., n-propyl, tetrahydro-2-fiuranylmethyl, trifluoromethylsulfonyl, N- ;Z carbethoxypiperidyl; or NR 3 RW represent together 4-acetylpiperazinyl, 4 -t-butoxycarbonylpiperazinyl, 2- (3,4-dihydro-2( IH)isoquinolinyl), (2R,6S)-2,6-dimethylmorpholinyl, (2R)-2,4-dimethyl- 1-piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3 -oxomorpholinyl, 4methyl-2-oxopiperazinyl, 4-methylpiperazinyl, morpholinyl, (1 S,4S)-2-oxa-5-azabicyclo[2 .2.1 ]hept-5-yl, 2-oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo- 1,4-.oxazepinyl, 2oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1,1 dioxido-thomorpholinyl;

OCONR

3

R

4 wherein R' and R 4 are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl; R 5 0, wherein R 5 is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2-furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl, 2,2,2-trifluoroethyl; When X is CO and Y is a single bond and R 2 is ethoxy, then it is preferred that T is selected from 5-chloro-1 ,3-dimethyl-1H-pyrazol-4-yl; 4-chloro-2,3, 1-benzoxadiazolyl; 5-(diniethylaniino)-l1-naphthyl; I -methyliinidazol-4-yl; 1 -naphthyl; 2-naphthyl; 8quinolinyl; thienyl substituted with one or more of (benzoylamino)methyl, bromo, chloro, 3isoxazolyl, 2-(methylsulfanyl)-4-pyrimidinyl, 1 -methyl-5-(trifluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl; phenyl. substituted with either: one or more of acetylamino, 3-acetylaminophenyl, 3-acetyiphenyl, beazeneamino, 1,3 -benzodioxol-5-yl, 2-benzofiuyl, benzylamino, 3 bromo, butoxy, carboxy, 4-carboxyphenyl, 3 -chloro-2-cyanophenoxy, 4chiorophenyl, 5-chloro-2-tbienyl, cyano, 3 ,4-dichlorophenyl, [4-{2-ethoxy-2oxoethyl)- 1,3-thiazol-2-yljamino} carbonyl), fluoro, 5-fluoro-2-methoxyphenyl, 2fiuyl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, 4-methyl-I piperazinyl, 4-methyl-I -piperidinyl, 4-methylsulfanyiphenyl, 5-methyl-2-thienyl, 4 -morpholinyl, nitro, 3-nitrophenyl, phenoxy, 4-pyridyl, 3-pyridylmethylamnino, 1 pyrrolidinyl, 2-thienyl, 3-thienyl, 2-thienylmethylamino, trifluoromethoxy, 4trifluoromethoxyphenyl, trifluoromethyl; (ii) one or more of methyl; (iii) one or more of chloro, phenyl and n-propyl in either position, and methyl in any of positions 3, 4 or (iv) one or more ofn-propyl and phenyl in any of positions 2, 3, 5 or 6.

Specific examples of compounds according to the present invention are given above and also the following compound: [(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)acetic acid (Example 3).

Another object of the present invention is a pharmaceutical composition comprising at least one compound of formula as defined above, and a pharmaceutically acceptable carrier.

Also within the scope of this invention is a method for making a compound of formula The method includes taking any intermediate compound delineated herein, reacting it with any one or more reagents to form a compound of formula including any processes specifically delineated herein.

Other features and advantages of the invention will be apparent from the detailed description and the claims.

DETAILED DESCRIPTION OF THE INVENTION The compounds according to the present invention may be used in several indications which involve 11-P3-hydroxysteroid dehydrogenase type 1 enzyme. Thus, the compounds according to the present invention may be used against dementia (see WO97/07789), osteoporosis (see Canalis E 1996, Mechanisms of glucocorticoid action in bone: implications to glucocorticoid-induced osteoporosis, Journal of Clinical Endocrinology and Metabolism, 81, 3441-3447) and may also be used disorders in the immune system (see Franchimont et al, "Inhibition ofThl immune response by glucocorticoids: dexamethasone selectively inhibits IL-12-induced Stat 4 phosphorylation in T lymphocytes", The journal of Immunology 2000, Feb 15, vol 164 pages 1768- 74) and also in the above listed indications.

The various terms used, separately and in combinations, in the above definition of the compounds having the formula will be explained.

The term "aryl" in the present description is intended to include aromatic rings (monocyclic or bicyclic) having from 6 to 10 ring carbon atoms, such as phenyl (Ph) and naphthyl, which optionally may be substituted by CI--alkyl. Examples of substituted aryl groups are benzyl, and 2-methylphenyl.

The term "heteroaryl" means in the present description a monocyclic, bi- or tricyclic aromatic ring system (only one ring need to be aromatic) having from 5 to 14, preferably 5 to 10 ring atoms such as 5, 6, 7, 8, 9 or 10 ring atoms (mono- or bicyclic), in which one or more of the ring atoms are other than carbon, such as nitrogen, sulfur, oxygen and selenium as part of the ring system. Examples of such heteroaryl rings are pyrrole, imidazole, thiophene, furan, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, tetrazole, chroman, isochroman, quinoline, quinoxaline, isoquinoline, phthalazine, cinnoline, quinazoline, indole, isoindole, indoline, isoindoline, benzothiophene, benzofuran, isobenzofuran, benzoxazole, 2,1,3-benzoxadiazole, benzothiazole, 2,1,3-benzothiazole, 2,1,3-benzoselenadiazole, benzimidazole, indazole, benzodioxane, indane, 1,2,3,4tetrahydroquinoline, 3,4-dihydro-2H-1 ,4-benzoxazine, 1,5-naphthyridine, 1,8naphthyridine, acridine, fenazine and xanthene.

The term "heterocyclic" in the present description is intended to include unsaturated as well as partially and fully saturated mono-, bi- and tricyclic rings having from 4 to 14, preferably 4 to 10 ring atoms having one or more heteroatoms oxygen, sulfur, or nitrogen) as part of the ring system and the remainder being carbon, such as, for example, the heteroaryl groups mentioned above as well as the corresponding partially saturated or fully saturated heterocyclic rings. Exemplary saturated heterocyclic rings are azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine and 1,4oxazepane.

CI-

6 -alkyl in the compound of formula according to the present application, which may be straight, branched or cyclic, is preferably Cl-4-alkyl. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, and cyclohexyl. For parts of the range "C--alkyl" all subgroups thereof are contemplated such as CI.s-alkyl, C 1 -4-alkyl, CI.

3 -alkyl, C 1 2 -alkyl,

C

2 alkl, C2.s-alkyl, C 2 -alyl, C2- 3 -alkl, C 3 6 -alkyl, C4s-a1kCyl, etc.

CI--alkoxy, in the compound of formula according to the present application may be straight or branched, is preferably C14-alkoxy. Exemplary alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, and isohexyloxy. For parts of the range "Ci.-alkoxy" all subgroups thereof are contemplated such as Ci.--alkoxy, C.4-alkoxy, Ci.

3 -alkoxy, CI- 2 alkoxy, C 2 alkoxy, C2.s-alkoxy, C2 4 -alkoxy, C2.3-alkoxy, C3.-alkoxy, C 4 s-alkoxy, etc.

Ci-6-acyl, in the compound of formula according to the present application may be saturated or unsaturated and is preferably Cl-4-acyl. Exemplary acyl groups include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, butenoyl 3butenoyl), hexenoyl 5-hexenoyl). For parts of the range "Ci.

6 -acyl" all subgroups thereof are contemplated.such as Ci-5-acyl, Cl.

4 -acyl, C 1 3 -acyl, Ci.

2 -acyl, C2.,-aeyl, C2- 5 acyl, C2.4-acyl, C2.3-acyl, C3--acyl, C4--acyl, etc.

C

2 -alkenyl in the compound of formula according to the present application, which may be straight, branched or cyclic, is preferably C2-4-alkenyl. Exemplary alkenyl groups include vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 1pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl, and 1-cyclohexenyl. For parts of the range

"C

2 -6-alkenyl" all subgroups thereof are contemplated such as C2-5-alkenyl, C 2 4-alkenyl, C2-3-alkenyl, C3 6 -alkenyl, C4-5-alkenyl, etc.

The term "halogen" in the present description is intended to include fluorine, chlorine, bromine and iodine.

The term "sulfanyl" in the present description means a thio group.

With the expression mono- or di-substituted is meant in the present description that the functionalities in question may be substituted with independently H, Ci.

6 -acyl, C 2 6-alkenyl, Ci.

6 -(cyclo)alkyl, aryl, pyridylmethyl, or heterocyclic rings e.g. azetidine, pyrrolidine, piperidine, piperazine, morpholine and thiomorpholine, which heterocyclic rings optionally may be substituted with Ci-6-alkyl.

Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term "stable", as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein therapeutic administration to a subject for the treatment of disease, 11I HSD1 inhibition, 11 HSD1-mediated disease).

The term "prodrug forms" in the present description means a pharmacologically acceptable derivative, such as an ester or an amide, which derivative is biotransformed in the body to form the active drug (see Goodman and Gilman's, The Pharmacological basis of Therapeutics, 8 th ed., McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs, p. 13- "Pharmaceutically acceptable" means in the present description being useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use.

"Pharmaceutically acceptable salts" mean in the present description salts which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with organic and inorganic acids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid and the like. Base addition salts may be formed with organic and inorganic bases, such as sodium, ammonia, potassium, calcium, ethanolamine, diethanolamine, N-methylglucamine, choline and the like. Included in the invention are pharmaceutically acceptable salts or compounds of any of the formulae herein.

Pharmaceutical compositions according to the present invention contain a pharmaceutically acceptable carrier together with at least one of the compounds comprising the formula as described herein above, dissolved or dispersed therein as an active, antimicrobial, ingredient. In a preferred embodiment, the therapeutic composition is not immunogenic when administered to a human patient for therapeutic purposes, unless that purpose is to induce an immune response.

The preparation of a pharmacological composition that contains active ingredients dissolved or dispersed therein is well understood in the art. Typically such compositions are prepared as sterile injectables either as liquid solutions or suspensions, aqueous or non-aqueous, however, solid forms suitable for solution, or suspensions, in liquid prior to use can also be prepared. The preparation can also be emulsified.

The active ingredient may be mixed with excipients, which are pharmaceutically acceptable and compatible with the active ingredient and in amounts suitable for use in the therapeutic methods described herein. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like and combinations thereof. In addition, if desired, the composition may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like which enhance the effectiveness of the active ingredient. Adjuvants may also be present in the composition.

Pharmaceutically acceptable carriers are well known in the art. Exemplary of liquid carriers are sterile aqueous solutions that contain no materials in addition to the active ingredients and water, or contain a buffer such as sodium phosphate at physiological pH value, physiological saline or both, such as phosphate-buffered saline.

Still further, aqueous carriers can contain more than one buffer salt, as well as salts such as sodium and potassium chlorides, dextrose, propylene glycol, polyethylene glycol and other solutes.

Liquid compositions can also contain liquid phases in addition to and to the exclusion of water. Exemplary of such additional liquid phases are glycerine, vegetable oils such as cottonseed oil, organic esters such as ethyl oleate, and water-oil emulsions.

The pharmaceutical composition according to one of the preferred embodiments of the present invention comprising compounds comprising the formula may include pharmaceutically acceptable salts of that component therein as set out above.

Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the polypeptide) that are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic acid, tartaric acid, mandelic acid and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine and the like.

The preparations according to the preferred embodiments may be administered orally, topically, intraperitoneally, intraarticularly, intracranially, intradermally, intramuscularly, intraocularly, intrathecally, intravenously, subcutaneously. Other routes are known to those of ordinary skill in the art.

The orally administrable compositions according to the present invention may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be in unit dose presentation form and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, traganath or polyvinyl-pyrrolidone; fillers e.g. lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant e.g. magnesium stearate, talc, polyethylene glycol or silica; disintegrants e.g. potato starch, or acceptable wetting agents such as sodium lauryl sulfate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of e.g. aqueous or oily suspensions, solutions, emulsions, syrups or elixirs or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, e.g. sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents e.g. lecithin, sorbitan monooleate or acacia, non-aqueous vehicles (which may include edible oils), e.g. almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives e.g. methyl or propyl phydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.

"An effective amount" refers to an amount of a compound which confers a therapeutic effect on the treated subject. The therapeutic effect may be objective measurable by some test or marker) or subjective subject gives an indication of or feels an effect). A pharmaceutical composition according to the present invention, may comprise typically an amount of at least 0.1 weight percent of compound comprising the formula per weight of total therapeutic composition. A weight percent is a ratio by weight of total composition. Thus, for example, 0.1 weight percent is 0.1 grams of compound comprising the formula per 100 grams of total composition. A suitable daily oral dose for a mammal, preferably a human being, may vary widely depending on the condition of the patient. However a dose of compound comprising the formula of about 0.1 to 300 mg/kg body weight may be appropriate.

The compositions according to the present invention may also be used veterinarily and thus they may comprise a veterinarily acceptable excipient or carrier. The compounds and compositions may be thus administered to animals, cats, dogs, or horses, in treatment methods.

The compounds of the present invention in labelled form, e.g. isotopically labelled, may be used as a diagnostic agent.

This invention relates to methods of making compounds of any of the formulae herein comprising reacting any one or more of the compounds of the formulae delineated herein, including any processes delineated herein. The compounds of formula above may be prepared by, or in analogy with, conventional methods, and especially according to or in analogy with the following methods. Further, the pharmacology in-vitro was studied using the following reagents and methods.

The chemicals used in the synthetic routes delineated herein may include, for example, solvents, reagents, catalysts, and protecting group and deprotecting group reagents. The methods described above may also additionally include steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow synthesis of the compounds. In addition, various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing applicable compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.GM. Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley and Sons (1999); L. Fieser and M.

Fieser, Fieser and Fieser Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia ofReagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.

All publications mentioned herein are hereby incorporated by reference. By the expression "comprising" means "including but not limited to." Thus, other nonmentioned substances, additives or carriers may be present.

The invention will now be described in reference to the following Examples.

These Examples are not to be regarded as limiting the scope of the present invention, but shall only serve in an illustrative manner.

EXAMPLES

EXPERIMENTAL METHODS Scintillation Proximity Assay 2(n) 3 H]-cortisone was purchased from Amersham Pharmacia Biotech. Anticortisol monoclonal mouse antibody, clone 6D6.7 was obtained from Immunotech and Scintillation proximity assay (SPA) beads coated with monoclonal antimouse antibodies were from Amersham Pharmacia Biotech. NADPH, tetrasodium salt was from Calbiochem and glucose-6-phosphate was supplied by Sigma. The human 11-Phydroxysteroid dehydrogenase type-1 enzyme (11-P-HSDI) was expressed in Pichia pastoris. 18-P-glycyrrhetinic acid (GA) was obtained from Sigma. The serial dilutions of the compounds were performed on a Tecan Genesis RSP 150. Compounds to be tested were dissolved in DMSO (1 mM) and diluted in 50 mM Tris-HCI, pH 7.2 containing 1 mM EDTA.

The multiplication of plates was done on a WallacQuadra. The amount of the product 3 H]-cortisol, bound to the beads was determined in a Packard, Top Count microplate liquid scintillation counter.

The 11 -0-HSDI enzyme assay was carried out in 96 well microtiter plates (Packard, Optiplate) in a total well volume of 220 pL and contained 30 mM Tris-HCl, pH 7.2 with 1 mM EDTA, a substrate mixture tritiated Cortisone/NADPH (175 nM 181 PM), G-6-P (1 mM) and inhibitors in serial dilutions (9 to 0.15 gM). Reactions were initiated by the addition of human 1 1-p-HSDI, either as Pichiapastoris cell homogenate or microsomes prepared from Pichia pastoris (the final amount of enzyme used was varied between 0.057 to 0.11 mg/mL). Following mixing, the plates were shaken for 30 to minutes at room temperature. The reactions were terminated with 10 giL 1 mM GA stop solution. Monoclonal mouse antibody was then added (10 IL of 4 pM) followed by 100 jpL of SPA beads (suspended according to the manufacturers instructions).

Appropriate controls were set up by omitting the 11-P-HSDI to obtain the non-specific binding (NSB) value.

The plates were covered with plastic film and incubated on a shaker for minutes, at room temperature, before counting. The amount of 3 H]-cortisol, bound to the beads was determined in a microplate liquid scintillation counter.

The calculation of the Ki values for the inhibitors was performed by use of Activity Base. The Ki value is calculated from ICso and the Km value is calculated using the Cheng Prushoff equation (with reversible inhibition that follows the Michaelis- Menten equation): Ki ICso(l+[S]/Km) [Cheng, Prushoff W.H. Biochem.

Pharmacol. 1973, 22, 3099-3108]. The IC 50 is measured experimentally in an assay wherein the decrease of the turnover of cortisone to cortisol is dependent on the inhibition potential of each substance. The Ki values of the compounds of the present invention for the 11-p-HSD1 enzyme lie typically between about 10 nM and about 10 pM.

COMPOUND PREPARATION General: For preparative straight phase HPLC purification a Phenomenex column (250 x 21.1 mm, 10 pm) was used on a Gilson system eluting with ethanol in chloroform (gradient from 0 10% in 10 min) with a flow of 20 mL/min. Column chromatography was performed on silica using Silica gel 60 (230-400 mesh), Merck. Melting points were determined on a Gallenkamp apparatus. Elemental analyses were recorded using a Vario EL instrument. HPLC analyses were performed using a Hypersil Elite column (150 x 4.6 mm, 3p) with a flow of 3 mL min on a Waters 600E system with monitoring at 254 nm.

Reverse phase preparative HPLC was carried out on a 100 x 21.2 mm, 5pt Hypersil Elite column eluting with a gradient of 5% ACN in 95% water to 95% ACN in 5% water (0.2% TFA buffer) over 10 mins at a flow rate of20 mL min with the UV detector set at 254 nm. Thin layer chromatography was carried out using pre-coated silica gel F-254 plates (thickness 0.25 mm). Electrospray MS spectra were obtained on a Micromass platform LCMS spectrometer. Crude, worked up compounds were purified by flash column chromatography using pre packed silica SPE columns (10 g silica) on an Isco Foxy 200 Combiflash system, and a gradient of 16.67% ethyl acetate in hexane increasing incrementally to 100% ethyl acetate.

List ofAbbreviations ACN acetonitrile DCM dichloromethane DIEA N,N-diisopropylethylamine DMAP 4-dimethylaminopyridine DME ethyleneglycol dimethyl ether DMF dimethylformamide DMSO dimethyl sulfoxide EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EDTA ethylenediaminetetraacetic acid HCOOH formic acid HOAT 1-hydroxy-7-azabenzotriazole HOBT 1-hydroxybenzotriazole hydrate HPLC high performance liquid chromatography MTBE tert-butyl methyl ether RP LC-MS reversed-phase liquid chromatography-mass spectrometry TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran SULFONAMIDE

COUPLINGS:

METHOD A: 1 Eq of the 2 -aminothiazole was dissolved in pyridine (0.5 M solution). The sulfonyl chloride (1.2 eq) was added and the reaction mixture was stirred at ambient temperature under nitrogen atmosphere for 15 h. The reaction mixture was poured into aqueous HC1 (1 If the product precipitated it was collected on a filter and washed with aqueous HCI (1 M) and recrystallised from ethanol. In case an oil was obtained, the crude was extracted with DCM and worked up and purified using standard procedures.

METHOD B: A solution of the 2-aminothiazole derivative (1 eq), triethylamine (2 eq) and DMAP (1 eq) in DMF (1 M) and DCM (0.225 M) was dispensed into a reaction vial. The sulfonyl chloride (1.2 eq) was dissolved in DCM (0.33 M) and added. The reaction mixtures were kept at room temperature over night. The mixture was then added to petroleum ether (10 times reaction volume). After some hours in refrigerator the supernatants were decanted and (a portion of) the residual materials were dissolved in DMSO-methanol-acetic acid (300 pL 500 pL 50 pL) and purified by preparative LCMS (acetonitrile-water gradients). The purest fractions were collected and lyophilized.

Alternatively, the crude was isolated using extractive work-up and purified using standard procedures.

SAPONIFICATIONS:

METHOD C: 1 Eq of the ester was suspended in 95% ethanol (0.1 M) and treated with KOH (aqueous, 6 eq). Water was added until a clear solution was achieved. The reaction mixture was stirred for 2-3 h at ambient temperature. The solvent was removed under reduced pressure and the crude was redissolved in water. Addition of cone. HC1 until pH 2 gave a precipitate which was collected on a filter and washed with cold water and dried.

AMIDE COUPLINGS: METHOD D: The carboxylic acid ester was dissolved (0.05 M) in a large excess of the amine in or 70% water-solution. The reaction mixture was stirred at ambient temperature over night. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography on silica gel eluting with methanol in

DCM.

METHOD E: The carboxylic acid was suspended in DCM (0.05M) followed by the addition of EDCI (1.1 eq), triethylamine (3 eq), DMAP (0.5 eq) and the amine of choice (1.2 eq).

DMF was added when the starting materials did not dissolve properly. The reaction mixture was stirred at ambient temperature over night. The organic phase was washed with aqueous HC1 (1 dried over sodium sulfate, filtered and evaporated in vacuo. The crude product amide was purified by flash column chromatography on silica gel, eluting with methanol in DCM or ethyl acetate.

METHOD F: The carboxylic acid was suspended in DCM (0.1 M) and cooled to 0°C under nitrogen atmosphere. EDCI (1 eq), HOAT (1 eq) or HOBT (1 eq) was added, followed by TEA (2.2 eq). After 10 min, the amine of choice (1.2 eq) was added and the reaction mixture was allowed to warm to ambient temperature. After 5 h, the DCM phase was washed with aqueous HCI (1 M) and worked up and purified as described in METHOD

E.

METHOD G: Under N 2 -atmosphere, aluminium chloride (1 eq) was suspended in DCM (0.1 M) and treated with the amine of choice (4 eq) at ambient temperature. After 10 min, the alkyl ester (1 eq) was added and the reaction mixture was stirred until starting material had been consumed (TLC). Quenching with saturated aqueous sodium hydrogen carbonate or aqueous HC1 (1 M) and extractive workup with ethyl acetate gave the crude products which were then purified by flash chromatography on silica gel eluting with DCM methanol mixtures.

FORMATION OF THIAZOLE RING: METHOD H: To a solution or suspension of an optionally substituted thiourea in ethanol 1 equivalent of a-haloketone was added at room temperature. The reaction mixture was stirred in a sealed tube at 95 0 C for 4 h, cooled, concentrated, redissolved in ethyl 1o acetate, washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate and chromatographed on silica gel using petroleum-ether and ethyl acetate as eluents.

METHOD I: To a 0.5 M solution of ketone (1 eq) and thiourea (2 eq) in ethanol at 60 0 C, 1 eq of iodine was added in one portion. The reaction tube was sealed and the reaction mixture was stirred at 100°C for 16 hours. After evaporation of the solvent the residue was taken up in DCM, washed with saturated aqueous sodium hydrogen carbonate, dried with magnesium sulfate. Products were purified by chromatography on silica gel using a gradient of petroleum-ether ethyl acetate from 8:1 to 2:1 for elution.

A CYLA TIONS: METHOD J: To a solution of the alcohol in dry pyridine (0.3 1.1 eq of acid chloride was added at 0 OC. The reaction mixture was stirred at room temperature for 6 h, concentrated, co-evaporated with acetonitrile, re-dissolved in DCM. washed with aqueous HCI (0.5 M), dried with sodium sulfate and chromatographed on silica gel using petroleum-ether and ethyl acetate as eluents.

CARBAMATES:

METHOD K: To a solution of the alcohol in dry pyridine (0.3 1.5 eq of 4-nitrophenyl chloroformate (0.5 M in dry pyridine) was added at 0°C. After the reaction mixture was stirred at room temperature for 12 1h, 5 eq of primary or secondary amine were added at OTC. The solution was stirred at room temperature for 3 h, concentrated, co-evaporated with acetonitrile, re-dissolved in DCM, washed with aqueous HCl (0.5 M) and saturated aqueous sodium bicarbonate, dried with sodium sulfate and chromatographed on silica gel using DCM and methanol as eluents.

SULFOATL CHLORIDES Arylsulfonyl chlorides that were not commercially available were prepared from the aniline derivatives according to literature procedures (see for instance: Hoffman, R.

V. (198 1) Org. Synth. 60: 12 1).

2 -amino-5-thiazoleacetic acid, ethyl ester is available from Ambinter, 46 quai Louis Bleriot, Paris, F-750 16, France. The preparation thereof has been described in: Aryl diazo compounds and diazonium salts as potential irreversible probes of the GABA receptor. Bouchet, Marie Jeanne; Rendon, Alvaro; Werrnuth, Camille G.; Goeldner, Maurice; Hirth, Christian. Fac. Pharm., Univ. Louis Pasteur, Strasbourg, Fr.

J. Med. Chem. (1987), 30(12), 2222-7. CODEN: JMCMAR ISSN: 0022-2623.

Journal written in English. CAN 107:198180 AN 1987:598180 CAPLUS; and Growth regulating activity of some thiazole-, thiazoline-, and thlazolidineacetic acids. Garraway, J. L. Dep. Phys. Sci., Wye Coil., Ashford/Kent, Engl. Pestic. Sci. (1974), 185-8. CODEN: PSSCI3G Journal written in English.

CAN 8:73315 AN 1974:473315

CAPLUS

PREPARATION OF COMPOUNDS IN EXAMPLES EXAMPLE I 3-chloro-2-methvl-N- r5-2-mon~holin4-ylethly. 1.3 -thiazol-2yllbenzenesulfonamide Step a preparation of 2 -(2-arnino-1I 3 2 ,3-dichlorotetrahydrofurane (5 g; 0,035 mol) and thiourea (2,7 g; 0,035 mol) were refiuxed for 12 hi in water (20 nil). Then 40 ml of 40% NaOH (aq) were added, the reaction mixture was cooled to room temperature and stirred for one hour. The formed precipitate was filtered off, dried at reduced pressure and recrystallized from EtOH/Et 2

O.

HCl, 2M in Et 2 O, was added to form the HC1-salt which was isolated by filtration and dried. Yielded 3,8 g, 61% 'H NMR (400 MHz, DMSO-d 6 8 ppm 2.71 J=4.88 Hz, 2 H) 3.53 J=5.62 Hz, 2 H) 4.17 1 H) 7.06 1 H) 9.37 2 MS m/z: M+H 145 Step b preparation of 3-hoo2mty--5:2mr~oi--l~y) 1 .3-thiazol-2yllbenzenesulfonamide 2 2 -amino-1,3-thiazol-5-yl)ethanol 16 g; 0,89 nimol), 3-chloro-2methylbenzenesulfonyl chloride (0,62 g; 2,8 nimol) and NaQH (0,093 g; 2,3 nimol) were dissolved in 9 mlA THF:H 2 0 and stirred over night The reaction mixture was extracted twice with dichioromethane and the organic layers was combined, dried over MgSO0 4 and concentrated. The crude material was then stirred in morpholine (10 ml) over night. The reaction mixture was concentrated and purified on preparative RP LC-MS, then further purified on a preparative TLC-column (Trikonex, FlashTube

T

m 2008) eluted with CHC1 3 /MeOH 40/3 triethylamine The substance was visualized by UV-Iight, the relevant band cut out and the silica-gel extracted with the eluent. Fitration and concentration yielded a product which was still found to contain a number of impurities.

This was further purified on preparative RP LC-MS. Yield 0,8 mg.

1H NMR (400 MHz, methanol-d 4 6 ppm 2.65 (mn, 3 H) 3.10 (in, 4 H) 3.28 (in, 2 H) 3.45 (in, 2 H) 3.70 (mn, 2 H) 4.02 (mn, 2 H) 7.00 (mn, 11H) 7.24 J=7.81 Hz, 1 H) 7.54 J=8.06 Hz, 1 H) 7.91 J=7.57 Hz, I MIS m/z: M+H 402. HRMS (El) calcd for

C

16

H

20 C1N 3 0 3

S

2 401.0635, found 401.0627.

EXAMPLE 2 methyl f 3 -chloro-2-methvlp~henvl)sulfonvllan-inol -1I,3-thiazol-5yl)acetate Step a preparation of methyl 3 -bromo4-oxobutanoate Firstly, methyl 4-oxobutanoate was synthesized from the commercially available methyl 4,4-diinethoxybutyrate according to a literature procedure; Will, S. Magriotis, Marinelli, E. Dolan, Johnson, F. J Org. Chem., 1985, 50, 543 3-5434.

Secondly, methyl 3 -bromo-4-oxobutano ate was obtained from methyl 4oxobutanoate following a literature procedure; Aeberli, Erlenmeyer. H. He!. Chim.

Acta., 1950, 70, 503-505.

Step b preparation of methyl f r(3-chloro-2-methyvhenvl)sulfonyllamino 1,3- N-aioabntiy)3clro2mtybneeufnmd (0.4 g, 1.5 mmol) and methyl 3-bromo-4-oxobutanoate (0.3 g, 1.5 mxnol), dissolved in pyridine (5 mL), were irradiated in a microwave oven for 2.5 nmin at 130 The solvent was removed under reduced pressure and the product separated from the starting materials using preparative HPLC (yield 0.2g, 1H NMR (400 MHz, CD 3 OD) 6 ppm 2.70 3 H) 3.69 J=1.22 Hz, 2 H) 3.70 l0 3 H) 6.98 .r-1.10 Hz, I H) 7.29 J=8.30 Hz, I H) 7.57 (dd, J=8.06, 1.46 Hz, I H) 7.96 (in, I MS mlz: M+H 361.

EXAMPLE 3 ff(3-chloro-2-methylphenyl)sulfonyllaminol -1 acid To methyl f{[(3-chloro-2-methylphenyl)sulfonyl amino) 1,3 yl)acetate (Example 2) (0.2 g, 0.55 inmol) dissolved in EtOH (5.5 mL) was added aqueous KOH (0.6 mL, 5.5 Mo. The reaction mixture was stirred at room temperature for 1 h. The solvent was then removed under reduced pressure and the crude product 2o dissolved in water. The aqueous phase was acidified using conc. HCI so that the product precipitated. Filtration and washing with water (5 mL) afforded 0.2 g, 97% product. The product was used without any further purification.

EXAMPLE 4 3-chloro-2-methvl-N-[5-(2-morpholin4v[l2oxoethly. 1 3-thiazol-2yllbenzenesulfonaniide To a solution of -chloro- 2 -methylphenyl)sulfonyl]ainino yl)acetic acid (Example 3) (0.09 g, 0.25 minol) in CH 2 Cl 2 (5.0 mL) and DMF (0.5 mL) were added EDGI (0.05 g, 0.27 minol), DMAP (0.02 g, 0. 12 mmol), triethylamine 1 mL, 0.75 mmol) and morpholine (0.03 inL, 0.30 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then washed with I M HCI (2x1 5 mL) and the organic layer was collected. The organic phase was dried (MgSO 4 and concentrated under reduced pressure. Purification using preparative HPLC afforded the desired product (0.01g) in 10% yield.

S

1 H NMR (400 MHz, acetone-d 6 8 ppm 2.67 3 H) 3.47-3.63 8 H) 3.82 (d, I J=1.22 Hz, 2 H) 7.05 JF1.22 Hz, 1 H) 7.33 J-8.30 Hz, 1 H) 7.57 1 H) 7.98 (dd, J=8.06, 1.22 Hz, 1 MS m/z: M+H 416.

EXAMPLE 5 r(3-chlor-2-methylhenvl)sulfonylamno diisopropylacetamide n 10 To a solution of 3 -chloro-2-methylphenyl)sulfonyl]amino)-l,3-thiazol-5yl)acetic acid (Example 3) (0.09 g, 0.25 mmol) in CH 2 C1 2 (5.0 mL) and DMF (0.5 mL) g were added EDCI (0.05 g, 0.27 mmol), DMAP (0.02 g, 0.12 mmol), triethylamine (0.1 N mL, 0.75 mmol) and diisopropylamine (0.04 mL, 0.30 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then washed with I M HC1 (2x15 mL) and the organic layer was collected. The organic phase was dried (MgSO 4 and concentrated under reduced pressure. Purification using preperative HPLC afforded the desired product (0.01g) in 9% yield.

'H NMR (400 MHz, CDC1 3 6 ppm 1.21 J=6.10 Hz, 6 H) 1.34 J=6.59 Hz, 6 H) 2.64 3 H) 3.61 J=19.53 Hz, 1 H) 3.63 2 H) 3.89 1 H) 6.94 1 H) 7.23 1 H) 7.52 J=7.81 Hz, 1 H) 8.04 J=7.81 Hz, 1 MS m/z: M+H 430.

Various embodiments of the present invention have been described above but a person skilled in the art realizes further minor alterations which would fall into the scope of the present invention. The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.

It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art, in Australia or any other country.

Claims (20)

1. A compound of formula (1) N N B S R2 wherein T is an aryl ring or heteroaryl ring, optionally independently substituted by [R]n, wherein n is an integer 0-5, and R is hydrogen, aryl, heteroaryl, a heterocyclic ring, optionally halogenated Cj-6galkyl, optionally halogenated Cj-6galkoxy, C 1 6 alkylsulfonyl, carboxy, cyano, nitro, halogen, aryloxy, arylsulfonyl, arylamino, wherein aryl, heteroaryl and arytoxy residues and heterocyclic rings are further optionally substituted in one or more positions independently of each other by CI. 6 -acyl, C 1 6 alkylthio, cyano, nitro, hydrogen, halogen, optionally halogenated Ci. 6 -alkyl, optionally halogenated C 1 6 -alkoxy, amide which is optionally mono- or di-substituted, (benzoylamino)methyl, carboxy, 2-thienylmethylamino or [4-(2-ethoxy-2-oxoethyl)- 1,3 -thiazol -2-yI] amino) carbonyl); or T is selected from and phenyl substituted with one or more of benzenearnino, benzylamino, 3- pyridylmethylamino and 2-thienylmethylamino;, R' is hydrogen or C 1 6 -alkyl; X is CH 2 or CO; Y is CO; B is hydrogen, C 1 6 -alkyl or dimethylaminomethyl; R 2 is selected from C 16 -alkyl, azido, arylthio, heteroarylthio, halogen, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl, 3 -oxo-4- morpholinolinylmethylene, C 1 6 -alkoxycarbonyl, 5-methyl- 1,3 ,4-oxadiazol-2-yl; NR R wherein R 3 and R 4 are each independently selected from hydrogen, ethyl, isopropyl, n-propyl, optionally halogenated C 1 6 -alkylsulfonyl, C 1 6 alkoxy, 2-methoxyethyl, 2-hydroxyethyl, I -methylimidazolylsulfonyl, C 1 6 -acyl, cyclohexylmethyl, cyclopropanecarbonyl, aryl, optionally halogenated arylsulfonyl, furylcarbonyl, tetrahydro-2-furanylmethyl, N-carbethoxypiperidyl, or C 1 6 -alkyl substituted with one or more aryl, heterocyclic or heteroaryl, or NR 3 R 4 represent together heterocyclic systems which are imidazole, pipendine, pyrrolidine, piperazine, morpholine, oxazepine, oxazole, thiomorpholine, 54 N:\Melbou~rre\Caes\Patent\5200-52999\P52913.AU. 1\Specis\c1aims.doc 09/08/07 I ,ldioxidothiomorpholine, 2-(3 ,4-dihydro-2( I H)isoquinolinyl), or (1 S,4S)-2-oxa-5- azabicyclo[2.2.1]hept-5-yl, which heterocyclic systems are optionally substituted by C 1 j. 6 -alkyl, C 1 6 -acyl, hydroxyl, oxo, t-butoxycarbonyl; OCONR R wherein R 3 and R 4 are each independently selected from hydrogen, C I 6 -alkyl or form together with the N-atom to which they are attached morpholinyl; R 5 0, wherein R 5 is hydrogen, optionally halogenated CI- 6 -alkyl, aryl, heteroaryl, C 1 6 -acyl, C 1 6 -alkylsulfonyl, arylcarbonyl, heteroarylcarbonyl, 2- carbomethoxyphenyl; or a salt, hydrate or solvate thereof, with the proviso that when: X is CH 2 Y is CO, then R 2is not hydroxy; provided that the compound is not one of the following: ethyl [(2,4-dichloro-5-methylphenyl)sulfonyl] amino) -1,3 ethyl (2 [(4-chlorophenyl)sul fonyl] amino) -1,3 -thiazol- ethyl f [(2,4-di fluorophenyl)sul fonyl] amino)} 1,3 ethyl ichlorothien-3 -yI)sul fonyl] amino) -1,3 -thiazol-5 -yl)acetate ethyl (2 (2-chl orophenyl)sul fonyl Iamino) 3-thi azol- ethyl -naphthylsulfonyl)amino]- I ,3-thiazol-5-yl} acetate ethyl f -chloro-2-methylphenyl)sulfonylI amino) I 2 -chloro-2 -methylphenyl)sul fortylIIamino) 3 -thi azol1-

2-(2 -chiloro-2-methylphenyl)sul fonyl ]amino I ,3-thiazol1- ethyl '-biphenyl-4-ylsulfonyl)amino]- 1 ,3-thiazol-5-yl acetate ethyl [(4-nitrophenyl)sul fonyl] amino I 1 ,3 -thiazol-5 -yl)acetate ethyl {[(4-methoxyphenyl)sulfonyl]amino 1,3 ethyl [(2,5-dichlorophenyl)sul fonyl] amino) -1,3 -thiazol -5 -yl)acetate 3 -chloro-N-[5-(2-hydroxyethyl)-1I,3-thiazol-2-yl]-2-methylbenzenesulfonamide 3 -chloro-N-[5-(2-ethoxyethyl)-1I,3-thiazol-2-yl]-2-methylbenzenesulfonamide ethyl -chlorophenyl)sul fonyl ]amino)} 1,3 -thiazol-5 -yl)acetate ethyl [(4-fl uorophenyl)sul fonyl] amino)} 1,3 -thiazol -5 -yl)acetate ethyl {[(4-isopropylphenyl)sulfonyl]amino 1,3 ethyl {[4-(2-ethoxy-2-oxoethyl)-1I,3 -thiazol-2- yl ]amino I carbonyl)phenyl] sulfonyl amino)- 1, 3 -thiazol-5 -yljacetate -chloro-2-methylphenyl)sul fonyl] amino) -1,3 diethylacetamide ethyl [2-(trifluoromethyl)phenyl] sul fonyl amino)- 1 ,3 -thiazol-5 -yl] acetate ethyl 3-(tri fluoromethyl)phenyl] sul fonyl amino)- 1 ,3 -thiazoI- 5 -yl ]acetate N:\Melbourne\Caaee\Patent\52OOO-52999\P52913 .AU.I\Specis\Claims.doc 09/08/07 ethyl [4-(trifluoromethyl)phenyl]sulfonyl amino)- 1,3 -thiazol-5 -yl] acetate methyl -chiloro-2-methylphenyl)sul fonyl] amino) -1,3 -thiazol-5 -yl)acetate 3 -chloro-N -[5-(2-isopropoxyethyl)- 1,3 -thiazol-2-yl]-2-methylbenzenesulfonamide 3 -chloro-N-[5-(2-methoxyethyl)- 1,3-thiazol-2-yl]-2-methylbenzenesulfonamide -chloro-2-methylphenyl)sul fonyl] amino) 3-thiazol1-5 -yl)ethyl methanesulfonate -chloro-2-methylphenyl)sulfonyl] amino -1 ,3

3-chloro-N- {5-[2-(2-fluoroethoxy)ethyl]- 1,3-thiazol-2-yl methylbenzenesulfonamide 3 -chi oro-2 -methyl (5 5-[2-(2,2,2-tri fluoroethoxy)ethyl] 1, ,3-thiazo 1-2 yl benzenesulfonamide 2 -chloro-2 -methylphenyl)sul fonyl] amino 11,3 -thiazol1- 5-yl)ethyl acetate 3 -ch loro-2 -methyl -N -(2-morphol in-4-yl ethyl)- 1, ,3-thiazol-2 -yl] benzenesul fonam ide N-[5-(2-bromoethyl)- 1,3 -thiazol-2-yl]-3-chloro-2-methylbenzenesulfonamide 2 -chl oro-2-methy lphenylI)sul fonyll amino) ,3-thiazo I-5-yl)ethyl morpholine-4- carboxylate -chloro-2-methylphenyl)sulfonyl] amino) -1,3 diethylcarbamate 2 -chloro-2 -methylphenyl)sulfonyl] amino) -1,3 -thiazol-5 -yl)ethyl propionate 2 -chloro-2 -methy lphenylI)sulfonyl] amino 11,3 -thiazol1-5 -yl)ethyl 2- methyipropanoate -chloro-2-methylphenyl)sulfonyl]amino ,3-thiazol-5-yl)ethyl 2-furoate -chloro-2-methylphenyl)sulfonyljamino} -1 ,3-thiazol-5-yl)ethyI benzoate -chloro-2-methylphenyl)sul fonyl] amino) 1,3 methylacetamide -chloro-2-methylphenyl)sul fonyl] amino)} 1 ,3 ethylcarbamate {[(3-chloro-2-methylphenyl)sulfonyl]amino} -1 ethylacetamide 3 -chloro-2-methyl-N-[5-(2-oxopentyl)-1I,3-thiazol-2-yllbenzenesulfonamide I-dioxidothiomorpholin-4-yI)-2-oxoethyl]- 1,3-thiazol-2-yl} -4- propylbenzenesulfonamide 2,4-dichloro-6-methyl-N- {5-[2-(4-methylpiperazin-1I-yI)-2-oxoethyl]-1I,3 -thiazol-2- yll}benzenesulfonamide 3 -chloro-2-methyl-N- {5-[2-(3-oxomorpholin-4-yl)ethyl]- 1,3 -thiazol-2- yl benzenesulfonamide 2,4-dichloro-6-methyl-N-[5-(2-morpholin-4-yl-2-oxoethyl)- I ,3-thiazol-2- 56 N:\Melbourne\Cases\Patent\S2000-52999\P52913.ATJ1\Specis\Clainadoc 09/08/07 yl] benzenesulfonamide N-[5-(2-morpholin-4-yl-2-oxoethyl)- I ,3-thiazol-2-yl]- 1,1 '-biphenyl-4-sulfonamide N- [5-(2-morpholin-4-yl-2-oxoethyl)- 1,3 -thiazol-2-yl] -4-propylbenzenesulfonamide N-[5-(2-oxo-2-thiomorpholin-4-ylethyl)- 1 ,3-thiazol-2-yl]- 1,1 '-biphenyl-4-sulfonamide N-[5-(2-oxo-2-thiomorpholin-4-ylethyl)- 1 ,3-thiazol-2-yl]-4-propylbenzenesulfonamide 2,4-dichloro-6-methyl-N-[5-(2-oxo-2-thiomorpholin-4-ylethyl)- 1,3-thiazol-2- yl] benzenesulfonamide N-[5-(2-oxo-2-piperidin- I -ylethyl)- 1 ,3-thiazol-2-yl]- 1,1 '-biphenyl-4-sulfonamide -(2-oxo-2-piperidin- 1 -ylethyl)- 1,3 -thiazol-2-yl] -4-propylbenzenesulfonamide 2,4-dichloro-6-methyl-N-[5-(2-oxo-2-piperidin- 1 -ylethyl)- I ,3-thiazol-2- yl]benzenesulfonamide ethyl oxo(2- {[(4-propylphenyl)sulfonyl]amino} -1 ethyl -chloro-2-methylphenyl)sulfonyl] amino) -1,3 -thiazol-5 -yl)(oxo)acetate ethyl oxo(2- [(2,4,6-trichlorophenyl)sulfonyl] amino) 1-1,3 ethyl 1,1'-biphenyl-4-ylsulfonyl)amino]-1I,3-thiazol-5-yl }(oxo)acetate 3-chloro-2-methyl-N-[4-methyl-5-(2-morpholin-4-yl-2-oxoethyl)-1I,3-thiazol-2- yI]benzenesul fonamide 2,4,6-trichloro-N-[4-methyl-5-(2-morpholin-4-yl-2-oxoethyl)- 1 ,3-thiazol-2- yl]benzenesulfonamide I 1'-biphenyl-4-ylsulfonyl)amino]- 1 ,3-thiazol-5-yI -N -ethyl -N -methylacetamide N-ethyl-N-methyl-2-(2- [(4-propylphenyl)sulfonyllamino) -1,3-thiazol-5-yl)acetamide [(2,4-dichloro-6-methylphenyl)sul fonyl] amino) -1,3 -thiazol-5 -yl)-N-ethyl-N- methylacetamide N-[4-methyl-5-(2-morpholin-4-yl-2-oxoethyl)- 1,3 -thiazol-2-yl]- 1,1 '-biphcnyl-4- sulfonamide 2- 1,1 -biphenyl-4-ylsulfonyl)amino]- 1,3-thiazol-5-yl }-N-isopropyl-N- methylacetamide 2- 1,1'-biphenyl-4-ylsulfonyl)amino]-1I,3-thiazol-5-yl }-N,N-diethylacetamide N,N-diethyl-2-(2- [(4-propylphenyl)sulfonyl] amino) 1 ,3 {[(2,4-dichloro-6-methylphenyl)sulfonyl]amino 1,3 diethylacetamide ethyl (2 t [(4-bromo-5 -chl orothien-2 -yl)sul fonyl Iamino) 3 -thiazol 5-y I)acetate ethyl -bromo- 5-chl orothien-2 -yl)sul fonyl ]amino) 3 -thiazol1-5 -yI)acetate ethyl I-methyl-5-(trifluoromethyl)- IH-pyrazol-3-yI]thien-2- yl I sulfonyl)amino]- 1 ,3-thiazol-5-yl acetate ethyl {5-[2-(methylthio)pyrimidin-4-yl]thien-2-yl }sulfonyl)amino]- 1,3-thiazol-5- yl acetate 57 N:\Melbourne\Cases\Patent\52OOO-52999\P52913 .At.1\Specis\Claims.doc 09/08/07 2-f{ 1,1 '-biphenyl-4-ylsulfonyl)amino]-1I,3-thiazol-5-yl }-N,N-diisopropylacetamide N,N-diisopropyl-2-(2- [(4-propylphenyl)sulfonyl]amino) -1,3 [(2,4-dichloro-6-methylphenyl)sulfonyl]amino)}-1 diisopropylacetamide methyl (4-methyl-2- [(2,4,6-trichlorophenyl)sulfonyl] amino) 1,3 -thiazol-5 -yl)acetate -chloro-2 -methylphenyl)sul fonyl] amino} 1, ,3-thiazol-5 -yl)-N,N- dipropylacetamide 3 -chloro-2-methyl [5 -oxo-2-piperazin- 1 -yl ethyl)- 1 ,3 -thiazol1-2- yl] benzenesulfonamide

4-bromo-2-methyl-N-[5-(2-morpholin-4-yl-2-oxoethyl)- 1 ,3-thiazol-2- yI]benzenesulfonamide N-[5-(2-morpholin-4-yl-2-oxoethyl)- 1 ,3-thiazol-2-yl]-2,4- bis(trifluoromethyl)benzenesulfonamide 2-methyl-N-[5-(2-morpholin-4-yl-2-oxoethyl)- 1 ,3-thiazol-2-yl]-4- (trifluoromethoxy)benzenesulfonamide N- [5 -(2-morphol in-4-yl-2-oxoethyl)- 1,3 -thiazol-2-yl] -4-phenoxybenzenesulfonamide ethyl ,4-trichlorophenyl)sulfonyl]amino ethyl (2 [(4-bromo-2,5 -di fluorophenyl)sul fonyll amino) -1,3 -thiazol-5 -yl)acetate ethyl [4-(trifl uoromethoxy)phenyl] sul fonyl amino)- 1 ,3 -thiazol-5-yl] acetate ethyl [2 [4-(phenylIsulfonyl)thien-2 -yl] sul fonyl am ino)- 1, ,3-thiazol1- 5-ylj acetate ethyl -(phenylsulfonyl)thien-2-yl] sulfonyl amino)- 1 ,3 -thiazol-5 -ylj acetate ethyl f [(2,6-dichlorophenyl)sul fonyl] amino) 1,3 -thiazol-5 -yl)acetate ethyl [(2,4-dichlorophenyl)sul fonyl] amino) -1,3 -thiazol-5 -yl)acetate tert-butyl {[(3-chloro-2-methylphenyl)sulfonyl]amino yl)acetyl]piperazine-lI-carboxylate -chloro-2-methylphenyl)sulfonyl]amino dimethylacetamide 3-chloro-2-methyl-N- {5-[2-(~pyridin-3-yloxy)ethyl]- I,3-thiazol-2- yI }benzenesulfonamide 3 0 -chloro-2-methylphenyl)sulfonyl]amino 1,3 methylacetamide -chloro-2-methylphenyl)sulfonylI amino) 1,3 -thiazol-5-yl)-N-ethyl -N- methylacetamide 3 -chloro-2-methyl-N-[5-(2-oxo-2-thiomorpholin-4-ylethyl)- 1,3 -thiazol-2- yllbenzenesulfonamide ethyl (2 [(4-bromo-2-fluorophenyl)sulfonyl] amino 1 ,3 -thi azol-5 -yl)acetate 3 -chloro-2-methyl-N-[5-(2-morpholin-4-yl-2-oxoethyl)- 1,3 -thiazol-2- 58 N:\Melbourne\Cases\Paelt\52000-52999\P52913.AU. I\Specis\Claimsdoc 09/08/07 yl] benzenesulfonamide methyl (2 [(4-chlorophenyl)sul fonyl] amino) -4-methyl 1,3 -thiazol1-5 -yl)acetate methyl -chloro-2-methylphenyl)sulfonyl]amino} -4-methyl-i yl)acetate -chloro-2-methylphenyl)sulfonyl] amino) -1,3 -thiazol-5 -yl)-N,N- diisopropylacetamide 3 -chloro-2-methyl [5 -oxo-2-pyrrolid in- I -yl ethyl)- 1,3 -thiazol1-2 yl]benzenesulfonamide ethyl -methoxyphenyl)sulfonyl] amino) -1,3 ethyl -fluoro-2-methylphenyl)sulfonyl] amino} I ethyl [(4-propylphenyl)sul fonyl] amino) -1,3 -thiazol-5 -yl)acetate 3 -chloro-2-methyl-N-[5-(2-oxo-2-piperidin- 1-ylethyl)- 1,3 -thiazol-2- yl]benzenesulfonamide ethyl ,5-dichlorophenyl)sulfonyl]amino ethyl (2 ,4-d ichlorophenyl)sul fonyl] amino) 3-thiazol -5 -yl)acetate ethyl (2 ichloro-6-methylphenyl)sul fonyl] amino) -1,3 -thiazol 3-chloro-2-methyl-N-[5-(morpholin-4-ylmethyl)- 1 ,3-thiazol-2-yl]benzenesulfonamide 3 -chloro-N- 5-[2-(lI H-imidazol- 1 -yl)ethyl]- 1 ,3-thiazol-2-yI -2- methylbenzenesulfonamide -chloro-2-methylphenyl)sul fonyl] amino) 1,3-thiazol-5-yl)ethyl]acetamide ethyl {[2-rnethyl-4-(trifluoromethoxy)phenyl] sulfonyl amino)- 1,3 ylacetate ethyl ,4-trifluorophenyl)sulfonyl] amino) 1,3 -thiazol-5 -yl)acetate ethyl (2 [(2,4,6-tri fluorophenyl)sul fonyl] amino) -1,3 3 -ch loro-2-methyl 2- [(methyl sul fonyl)ami no] ethyl) 3-thi azol1-2- yl)benzenesulfonamide ethyl -chlorothien-2-yl)sulfonyl] amino) 1,3 -thiazol-5 -yl)acetate ethyl [(2-chloro-4-fl uorophenyl)sulfonyl ]amino I 1,3 -thiazol-5 -yl)acetate ethyl -i soxazol-3 -ylthien-2-yl)sul fonyll amino)} 1,3 -thiazol-5 -yl)acetate ethyl [(4-phenoxyphenyl)sulfonyl] amino) -1,3 ethyl [2 [2,4-b is(tri fluoromethyl)phenyl sul fonyl I} ami no)- 1 ,3 -thiazol1-5 -ylI]acetate 3 -chloro-2-methyl-N- 1,4-oxazepan-4-yl)ethyl]- 1,3 -thiazol-2- yl benzenesulfonamide 3 -chloro-2(--methyl-N- 5- [2-(2-oxopyrrolidin- 1 -yl)ethyl]- 1 ,3-thiazol-2- yl) benzenesulfonamide 3 -chloro-2-methyl-N-(5- f 2- [methyl (methyl sul fonyl)ami no] ethyl) -1,3 -thiazol-2- yl)benzenesulfonamide 59 N:\Melbourne\Cases\Patent\52OO-52999\P52913AU.1\Specis\Caim19doc 09/08/07 -chiloro-2-methylphenyl)sul fonyll amino) ,3-thiazol1-5 -y1)ethyl] -N- methylcyclopropanecarboxamide 3-chloro-2-methyl-N- [2-(4-methyl-2-oxopiperazin- 1-yl)ethyl]- 1,3-thiazol-2- yl benzenesulfonamide 3-chloro-2-methyl-N-[5-(2- [(trifluoromethyl)sul fonyl ]amino) ethyl)- 1 ,3-thiazol-2- yl]benzenesulfonamide 2,4-dichloro-N- -oxomorpholin-4-yl)ethyl]- 1,3 -thiazol-2- yI benzenesulfonamide 2,4-dichloro-6-methyl-N- (5 -oxomorpholin-4-yl)ethyl] ,3 -thiazol-2- yl) benzenesulfonamide 4-(2-furyl)-N-[5-(2-morpholin-4-yI-2-oxoethyl)- 1,3 -thiazol-2-yl]benzenesulfonamide 5'-fluoro-2'-methoxy-N-[5-(2-morpholin-4-yl-2-oxoethyl)- 1 ,3-thiazol-2-yl]- 1,1V- biphenyl-4-sulfonamide 4-(5-methylthien-2-yI)-N-[5-(2-morpholin-4-yI-2-oxoethyl)- 1 ,3-thiazol-2- yl]benzenesulfonamide 3'-acetyl-N-[5-(2-morpholin-4-yl-2-oxoethyl)- 1 ,3-thiazol-2-yl]- 1,1 '-biphenyl-4- sulfonamide N-[5-(2-morpholin-4-yI-2-oxoethyl)- 1 ,3-thiazol-2-yI]-4'-(trifluoromethoxy)- 1,1F- biphenyl-4-sulfonamide 3',4'-dichloro-N-[5-(2-morpholin-4-yl-2-oxoethyl)- I ,3-thiazol-2-yi]- 1,1 F-biphenyl-4- sulfonamide 1,3 -benzodioxol-S-yl)-N-[5-(2-morpholin-4-yl-2-oxoethyl)- 1,3 -thiazol-2- yl]benzenesulfonamide N-[5-(2-morpholin-4-yl-2-oxoethyl)- I ,3-thiazol-2-yi]-4-pyridin-4- ylbenzenesulfonamide {[5-(2-morpholin-4-yi-2-oxoethyl)- 1 ,3 -thiazol-2-yl] amino)} sul fonyl)- 1,1V biphenyl-3 -yl]acetamide N-[5-(2-morpholin-4-yI-2-oxoethyl)- 1 ,3-thiazol-2-yl]-4-thien-3 -ylbenzenesulfonamide N-[5-(2-morpholin-4-yI-2-oxoethyl)- 1,3 -thiazol-2-yI]-4-thien-2-ylbenzenesulfonamide -(2-morpholin-4-yl-2-oxoethyl)- 1,3 -thiazol-2-ylamnino sulfonyl)- 1, 1 -biphenyl- 4-carboxylic acid 4'-(methylthio)-N-[5-(2-morpholin-4-yl-2-oxoethyl)- 1,3 -thiazol-2-yl]- 1,1 '-biphenyl-4- sulfonamide N-[5-(2-morpholin-4-yl-2-oxoethyl)-1I,3-thiazol-2-yI]-3',5'-bis(trifluoromethyl)- 1,1'- biphenyl-4-sulfonamide 4'-chloro-N-[5-(2-morpholin-4-yl-2-oxoethyl)- 1,3 -thiazol-2-yl]- 1,1 '-biphenyl-4- sulfonamide N:\Melbourne\Cases\Patent\52000-52999\P52913.AU. 1\Specis\Claims .doc 09/08/07 N-[5-(2-morpholin-4-yl-2-oxoethyl)- 1,3 -thiazol-2-yl]-3'-nitro- 1,1 F-biphenyl-4- sulfonamide ;Z isopropyl -chloro-2-methylphenyl)sul fonyl ]amino} 1,3 -thiazol 2. The compound according to claim 1, wherein T is selected from 5-chloro-1,3-dimethyl-lH-pyrazol-4-yl; 4-chloro- 2,3,1 -benzoxadiazolyl; 5 imethyl amino)- 1 -naphthyl; 1 -methylimidazol-4-yl; I- naphthyl; 2-naphthyl; 8-quinolinyl; thienyl substituted with one or more of (benzoylamino)methyl, bromo, chloro, 3-isoxazolyl, 2-(methylsulfanyl)-4-pyrimidinyl, (tri fluoromethyl)pyrazol-3 -yl, phenyl sulfonyl, pyridyl; (Ni phenyl substituted with one or more of 3-acetylaminophenyl, 3- acetylphenyl, benzeneamino, 1 ,3-benzodioxol-5-yl, 2-benzofuryl, benzylamino, bis(trifluoromethyl)phenyl, bromno, butoxy, carboxy, chloro, 4-carboxyphenyl, 3 -chloro- 2-cyanophenoxy, 4-chiorophenyl, 5-chloro-2-thienyl, cyano, 3,4-dichlorophenyl, Q{[4- (2-ethoxy-2-oxoethyl)- 1, ,3-thi azol -2-yl ]amino I carbonyl), fluoro, 5-fluoro-2- methoxyphenyl, 2-furyl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, methyl, 4-methyl-i -piperazinyl, 4-methyl- I -piperidinyl, 4-methylsulfanylphenyl, 5-methyl-2- thienyl, 4-morpholinyl, nitro, 3-nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyidyl, 3- pyridylmethylamino, I1-pyrrolidinyl, 2-thienyl, 3-thienyl, 2-thienylmethylamino, trifluoromethoxy, 4-trifluoromethoxyphenyl, trifluoromethyl; or R' is hydrogen or methyl; X is CR 2 or CO; Y is CO; B is hydrogen, methyl or dimethylaminomethyl; R 2 is selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4- morpholinolinyl-methylene, ethoxycarbonyl, 5-methyl- 1,3 ,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl; NR R wherein R and R are each independently selected from acetyl, benzhydryl, I ,3-benzodioxol-5-ylmethyl, bcnzyl, 3-chloro-2-methylphcnylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2- furylmethyl, hydrogen, 2-hydroxyethyl, 2-(1 i-indol-3-yI)ethyl, isopropyl, methoxy, 2- methoxvethyl, 4-(lI -methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1 S)- phenylethyl, n-propyl, tetrahydro-2-furanylmethyl, trifluoromethylsulfonyl, N- carbethoxypiperidyl; or NR 3 R 4 represent together 4-acetylpiperazinyl, 4-t- 61 N:\Melbourne\Casee\Patent\52000-52999\P52913.AU. 1\Specis\Claimsdoc 09/08/07 butoxycarbonylpiperazinyl, 2-(3,4-dihydro-2(1 H)isoquinolinyl), (2R,6S)-2,6- dimethylmorpholinyl, (2R)-2,4-dimethyl-1 -piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4-methyl-2-oxopiperazinyl, 4- methylpiperazinyl, morpholinyl, (I S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl, 2- oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo-1 ,4-oxazepinyl, 2-oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1,1 dioxido- thiomorpholinyl; OCONR 3 R 4 wherein R and R 4 are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl; R 5 0, wherein R 5 is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2- furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl, 2,2,2-trifluoroethyl; with the proviso that when: X is CH 2 Y is CO, then R2 is not hydroxy. 3. A pharmaceutical composition comprising a compound according to claim 1 or 2, and a pharmaceutically acceptable carrier. 4. A method for the treatment or prevention of diabetes, syndrome X, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, hypertension, osteoporosis, dementia, depression, virus diseases or inflammatory disorders without causing hypoglycemia and to achieve immuno-modulation, said method comprising administering to a mammal in need of such treatment an effective amount of a compound according to claim 1 or 2. The method according to claim 4, wherein the immuno-modulation is selected from tuberculosis, lepra, and psoriasis.

6. The method according to claim 4, wherein T is selected from 5-chloro-1,3-dimethyl-l I-I-pyrazol-4-yl; 4-chloro- 2,3,1 -benzoxadiazolyl; 5-(dimethylamino)- I -naphthyl; 1-methylimidazol-4-yl; 1- naphthyl; 2-naphthyl; 8-quinolinyl; thienyl substituted with one or more of (benzoylamino)methyl, bromo, chloro, 3-isoxazolyl, 2-(methylsul fanyl)-4-pyrimidinyl, (trifluoromethyl)pyrazol-3-yl, phenylsulfonyl, pyridyl; phenyl substituted with one or more of acetylamino, 3- 62 N:\Melbourne\Cases\Patent\S2000-52999\PS2913.AU.1\Specis\Claims.doc 09/08/07 acetylaminophenyl, 3-acetyiphenyl, benzeneamino, 1,3-benzodioxol-5-yl, 2-benzofuryl, N benzylamino, 3 ,5-bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, chioro, 4- ;Z carboxyphenyl, 3-chloro-2-cyanophenoxy, 4-chiorophenyl, 5 -chloro-2-thienyl, cyano, 3 ,4-dichlorophenyl, [4-(2-ethoxy-2-oxoethyl)- 1 ,3 -thiazol-2-yl] amino)} carbonyl), fluoro, 5-fluoro-2-methoxyphenyl, 2-furyl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, methyl, 4-methyl-1I-piperazinyl, 4-methyl-1I-piperidinyl, 4- methylsulfanyiphenyl, 5-methyl-2-thienyl, 4-morpholinyl, nitro, 3 -nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 3 -pyridylmethyl amino, I1-pyrrolidinyl, 2-thienyl, 3 -thienyl, 2-thienylmethylamino, trifluoromethoxy, 4-trifluoromethoxyphenyl, trifluoromethyl; or R' is hydrogen or methyl; CX Xis CH 2 or CO; Y is CO; B is hydrogen, methyl or dimethylaminomethyl; R 2 i selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4- morpholinolinylmethylene, ethoxycarbonyl, 5-methyl-l,3,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl; NR R wherein R 3 and R 4 are each independently selected from acetyl, benzhydryl, 1,3 -benzodioxol-5-ylmethyl, benzyl, 3 -chloro-2-methylphenyl sulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2- furylmethyl, hydrogen, 2-hydroxyethyl, 2-(1IH-indol-3 -yl)ethyl, isopropyl, methoxy, 2- methoxyethyl, methyl, 1 -methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (1 S)- phenylethyl, n-propyl, tetrahydro-2-furanylmethyl, trifluoromethylsulfonyl, N- carbethoxypiperidyl; or NR 3 R 4 represent together 4-acetylpiperazinyl, 4-t- butoxycarbonylpiperazinyl, 2-(3 ,4-dihydro-2( IH)isoquinolinyl), (2R,6S)-2,6- dimethylmorpholinyl, (2R)-2,4-dimethyl- I-piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4-methyl-2-oxopiperazinyl, 4- methylpiperazinyl, morpholinyl, (1 S,4S)-2-oxa-5-aza-bicyclo[2.2. 1]hept-5-yI, 2- oxoimidazolinyl, 3-oxomorpholinyl, 3 -oxo- 1,4-oxazepinyl, 2-oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1, 1 -dioxido- thiomorpholinyl; OCONR R wherein R 3 and R 4 are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl; R 5 0, wherein R 5 is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2- 63 N:\Melbourne\Cases\Patent\52000-52999\P52913.AU. 1\Specis\Claims.doc 09/08/07 furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n-propionyl, 3 -pyridinyl, 2,2,2-trifluoroethyl;

7. The method according to claim 4, wherein the compound is selected from the compounds as defined in claim 1 or 2, and (2-{[(3-chloro-2- methylpheny I )sul fonyl ]amino) 3 -thi azol -5 -yl)acetic acid.

8. A method for inhibiting a human 1 l-p-hydroxysteroid dehydrogenase type I enzyme, comprising administering to a subject in need thereof an effective amount of a compound according to claim 1 or 2.

9. The method according to claim 8, wherein T is selected from 5-chloro-I,3-dimethyl-1IH-pyrazol-4-yl; 4-chloro- 2,3,1 -benzoxadiazolyl; 5 -(dimethylamino)-l1-naphthyl; I -methylimidazol-4-yl; I naphthyl; 2-naphthyl; 8-quinolinyl; thienyl substituted with one or more of (benzoylamino)methyl, bromo, chloro, 3-isoxazolyl, 2-(methylsulfanyl)-4-pyrimidinyl, 1 (trifluoromethyl)pyrazol-3 -y1, phenylsulfonyl, pyridyl; phenyl substituted with one or more of acetylamino, 3- acetylaminophenyl, 3 -acetylphenyl, benzeneamino, I ,3-benzodioxol-5 -yl, 2-benzofuryl, benzylamino, 3-5 -bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, chloro, 4- carboxyphenyl, 3-chloro-2-cyanophenoxy, 4-chiorophenyl, 5-chloro-2-thienyl, cyano, 3 ,4-dichlorophenyl, [4-(2-ethoxy-2-oxoethyl)- 1,3-thiazol-2-yl]amino }carbonyl), fluoro, 5-fluoro-2-methoxyphenyl, 2-furyl. hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, methyl, 4-methyl-1I-piperazinyl, 4-methyl- I -piperidinyl, 4- methylsulfanylphenyl, 5-methyl-2-thienyl, 4-morpholinyl, nitro, 3-nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 3 -pyridylmethylamino, I1-pyrrolidinyl, 2-thienyl, 3 -thienyl, 2-thienylmethylamino, tri fluoromethoxy, 4-tn fluoromethoxyphenyl, trifluoromethyl; or R' is hydrogen or methyl; X is CH 2or CO; Y is CO; B is hydrogen, methyl or dimethylaminomethyl; R 2is selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4- morpholinolinyl-methylene, ethoxycarbonyl, 5-methyl- 1,3 ,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl; 64 N:\Melbourne\Cases\Patent\52OOO-52999\PS2913.AU.1\Specis\Claimns.doc 09/08/07 NR 3 R 4 wherein R 3 and R 4 are each independently selected from acetyl, benzhydryl, 1,3-benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2- furylmethyl, hydrogen, 2-hydroxyethyl, 2-(1H-indol-3-yl)ethyl, isopropyl, methoxy, 2- methoxyethyl, methyl, 4-(1l-methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (I S)- phenylethyl, n-propyl, tetrahydro-2-furanylmethyl, trifluorormethylsulfonyl, N- carbethoxypiperidyl; or NR 3 R 4 represent together 4-acetylpiperazinyl, 4-t- butoxycarbonylpiperazinyl, 2-(3,4-dihydro-2(1 H)isoquinolinyl), (2R,6S)-2,6- dimethylmorpholinyl, (2R)-2,4-dimethyl-1 -piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4-methyl-2-oxopiperazinyl, 4- methylpiperazinyl, morpholinyl, (1 S,4S)-2-oxa-5-aza-bicyclo[2.2. I1]hept-5-yl, 2- oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo-1,4-oxazepinyl, 2-oxooxazolinyl, piperazinyl; piperdinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1,1 -dioxido- thiomorpholinyl; OCONRR 4 wherein R and R 4 are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl; R 5 0O, wherein RS 5 is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2- furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl, 2,2,2-trifluoroethyl. The method according to claim 8, wherein the compound is selected from the compounds as defined in claim 1 or 2, and (2-{[(3-chloro-2- methylphenyl)sulfonyl]amino}-1,3-thiazol-5-y I )acetic acid.

11. The method according to claim 8, wherein the subject is a human.

12. A method for treating a 1 I-p-hydroxysteroid dehydrogenase type 1 enzyme-mediated disorder, comprising administering to a subject in need thereof an effective amount of a compound according to claim I or 2.

13. The method according to claim 12, wherein the disorder is selected from diabetes, syndrome X, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, hypertension, osteoporosis, dementia, depression, virus diseases, inflammatory disorders, and immuno-modulation, wherein the treatment of hyperglycemia does not cause hypoglycemia. N:\Melbourne\Cases\Patent\52000-52999\P52913AU.1\Specis\Claims.doc 09/08/07

14. The method according to claim 13, wherein the immuno-modulation is selected from tuberculosis, lepra, and psoriasis.

15. The method according to claim 12, wherein T is selected from 5-chloro-i,3-dimethyl-lH-pyrazol-4-yl; 4-chioro- 2,3,1 -benzoxadiazolyl; 5-(dimethylamino)-lI-naphthyl; I -methylimidazol-4-y 1; 1- naphthyl; 2-naphthyl; 8-quinolinyl; thienyl substituted with one or more of (benzoylamino)methyl, bromo, chioro, 3-isoxazolyl, 2-(methylsulfanyl)-4-pyrimidinyl, 1 (trifluoromethyl)pyrazol-3 -yl, phenylsul fonyl, pyridyl; phenyl substituted with one or more of acetylamino, 3-acetylaminophenyl, 3- acetyiphenyl, benzeneamino, I ,3-benzodioxol-5-yl, 2-benzofuiryl, benzylamino, bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, chioro, 4-carboxyphenyl, 3-chioro- 2-cyanophenoxy, 4-chiorophenyl, 5-chloro-2-thienyl, cyano, 3,4-dichlorophenyl, (2-ethoxy-2-oxoethyl)- 1, ,3-thiazol -2-yl] amino) }carbonyl), fluoro, 5-fluoro-2- methoxyphenyl, 2-furyl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, methyl, 4-methyl- I -piperazinyl, 4-methyl- I -piperidinyl, 4-methylsulfanylphenyl, 5-methyl-2- thienyl, 4-morpholinyl, nitro, 3-nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 3- pyridylmethylamino, I1-pyrrolidinyl, 2-thienyl, 3-thienyl, 2-thienylmethylamino, trifluoromethoxy, 4-tn fluoromethoxyphenyl, trifluoromethyl; or R' is hydrogen or methyl; X is CH 2 or GO; Y is CO; B is hydrogen, methyl or dimethylaminomethyl; R 2 is selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4- morpholinolinyl-methylene, ethoxycarbonyl, 5-methyl-l,3 ,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl; NR R wherein R 3 and R 4 are each independently selected from acetyl, benzhydryl, 1 ,3-benzodioxol-5-ylmethyl, benzyl, 3-chloro-2-niethylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2-hydroxyethyl, 2-(lH-indol-3-yl)ethyl, isopropyl, methoxy, 2- methoxyethyl, methyl, 4-(lI -methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (I S)- phenylethyl, n-propyl, tetrahydro-2-furanylmethyl, trifluoromethylsulfonyl, N- carbethoxypiperidyl; NR 3 R 4 represent together 4-acetylpiperazinyl, 4-t- 66 N:\Melbourne\Cases\Paieni\52000-52999\P52913.AU.1\Specia\Claimns.doc 09/08/07 butoxycarbonylpiperazinyl, 2-(3,4-dihydro-2(1 H)isoquinolinyl), (2R,6S)-2,6- dimethylmorpholinyl, (2R)-2,4-dimethyl-1 -piperazinyl, 2-hydroxy-3-oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4-methyl-2-oxopiperazinyl, 4- methylpiperazinyl, morpholinyl, (1 S,4S)-2-oxa-5-aza-bicyclo[2.2. I ]hept-5-yl, 2- oxoimidazolinyl, 3-oxomorpholinyl, 3-oxo-1,4-oxazepinyl, 2-oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomorpholinyl; 1,l-dioxido- thiomorpholinyl; OCONR 3 R 4 wherein R 3 and R 4 are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached morpholinyl; R 5 0, wherein R 5 is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2- furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl, 2,2,2-trifluoroethyl.

16. The method according to claim 12, wherein the compound is selected from the compounds as defined in claim 1 or 2, and (2-{[(3-chloro-2- methylphenyl)sulfonyl]amino }-1,3-thiazol-5-yl)acetic acid.

17. The method according to claim 12, wherein the subject is a human.

18. Use of a compound according to claim 1 or 2 in the manufacture of a medicament for the prevention, management or treatment of diabetes, syndrome X, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, hypertension, osteoporosis, dementia, depression, virus diseases or inflammatory disorders without causing hypoglycemia and to achieve immuno-modulation; for inhibiting a human I-P- hydroxysteroid dehydrogenase type 1 enzyme; or for treating a I 1-p-hydroxysteriod dehydrogenase type 1 enzyme-mediated disorder.

19. The use according to claim 18, wherein the immuno-modulation is selected from tuberculosis, lepra, and psoriasis. The use according to claim 18 or 19, wherein T is selected from 5-chloro-1,3-dimethyl-l H-pyrazol-4-yl; 4-chloro- 2,3,1-benzoxadiazolyl; 5-(dimethylamino)- I -naphthyl; I -methylimidazol-4-yl; 1- naphthyl; 2-naphthyl; 8-quinolinyl; thienyl substituted with one or more of (benzoylamino)methyl, bromo, chloro, 3-isoxazolyl, 2-(methylsu 1 fanyl)-4-pyrimidinyl, 67 N:\Melbourne\Cases\Patent\52000-52999\P52913.Au.1\Specis\Claimsdoc 09/08/07 (trifluoromethyl)pyrazol-3 -yl, phenylsulfonyl, pyridyl; phenyl substituted with one or more of acetylamino, 3- acetylamninophenyl, 3-acetyiphenyl, benzeneamino, 1 ,3-benzodioxol-5-yi, 2-benzofuryl, benzylamnino, 3,5-bis(trifluoromethyl)phenyl, bromo, butoxy, carboxy, chloro, 4- carboxyphenyl, 3 -chloro-2-cyanophenoxy, 4-chiorophenyl, 5 -chloro-2-thienyl, cyano, 3 ,4-dichlorophenyl, (1 -ethoxy-2-oxoethyl)- 1, ,3-thiazol -2-yl] amino)} carbonyl), fluoro, 5-fluoro-2-methoxyphenyl, 2-furyl, hydrogen, iodo, isopropyl, methanesulfonyl, methoxy, methyl, 4-methyl- I -piperazinyl, 4-methyl- I -piperidinyl, 4- methylsul fanyiphenyl, 5-methyl-2-thienyl, 4-morpholinyl, nitro, 3 -nitrophenyl, phenoxy, phenyl, n-propyl, 4-pyridyl, 3-pyridylmethylamnino, I1-pyrrolidinyl, 2-thienyl, 3-thienyl, 2-thienylmethylamino, trifluoromethoxy, 4-trifluoromethoxyphenyl, trifluoromethyl; or R' is hydrogen or methyl; X is CH 2 or CO; Y is CO; B is hydrogen, methyl or dimethylaminomethyl; R 2 is selected from n-propyl, azido, bromo, chloro, 2-pyridinylsulfanyl, 3-oxo-4- morpholinolinylmethylene, ethoxycarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl, hydroxymethyl, 2-hydroxyethylaminomethyl, methylsulfonyloxymethyl; NR R wherein R 3 and R 4 are each independently selected from acetyl, benzhydryl, 1 ,3-benzodioxol-5-ylmethyl, benzyl, 3 -chloro-2-methylphenylsulfonyl, cyclohexyl, cyclohexylmethyl, cyclopropanecarbonyl, ethyl, 2-furylcarbonyl, 2-furylmethyl, hydrogen, 2-hydroxyethyl, 2-(1lH-indol-3-yl)ethyl, isopropyl, methoxy, 2- methoxyethyl, methyl, 1 -methylimidazolyl)sulfonyl, methylsulfonyl, phenyl, (I S)- phenylethyl, n-propyl, tetrahydro-2-furanylmethyl, trifluoromethylsulfonyl, N- carbethoxypiperidyl; or NR 3 R 4 represent together 4-acetylpiperazinyl, 4-t- butoxycarbonylpiperazinyl, 2-(3 ,4-dihydro-2( 1 H)isoquinolinyl), (2R,6S)-2,6- dimethylmorpholinyl, (2R)-2,4-dimethyl- 1 -piperazinyl, 2-hydroxy-3 -oxomorpholinyl, imidazolyl, 2-methyl-3-oxomorpholinyl, 4-methyl-2-oxopiperazinyl, 4- methylpiperazinyl, morpholinyl, (1 S,4S)-2-oxa-5-aza-bicyclo[2.2. 1]hept-5-yI, 2- oxoimidazolinyl, 3 -oxomorpholinyl, 3-oxo-1I,4-oxazepinyl, 2-oxooxazolinyl, piperazinyl; piperidinyl; pyrrolidinyl; pyrrolidonyl, thiomnorpholinyl; 1, 1 -dioxido- thiomnorpholinyl; OCONR R wherein R 3 and R 4 are each independently selected from ethyl, hydrogen or form together with the N-atom to which they are attached 68 N:\Melbourne\Cases\Patent\52000-52999\P52913.AU.1\Specie\Claims.doc 09/08/07 ;Z3 morpholinyl; R 5 0, wherein R 5 is acetyl, benzoyl, benzyl, ethyl, 2-fluoroethyl, 2- furylcarbonyl, hydrogen, isobutyryl, isopropyl, methyl, 2-carbomethoxyphenyl, methylsulfonyl, phenyl, n-propionyl, 3-pyridinyl, 2,2,2-trifluoroethyl;

21. The use according to any one of claims 18 to 20, wherein the compound is selected from the compounds as defined in claim 1 or 2, and (2-{[(3-chloro-2- methylpheny I)sulfonyl]amino }-1,3-thiazol-5-yl)acetic acid.

22. Compounds according to claim 1 or 2, processes for their preparation or pharmaceutical compositions containing them, substantially as herein described with reference to any one of the examples.

23. Methods or uses for the treatment or prevention of diabetes, syndrome X, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, hypertension, osteoporosis, dementia, depression, virus diseases or inflammatory disorders without causing hypoglycemia and to achieve immuno-modulation; for inhibiting a human 11- p-hydroxysteriod dehydrogenase type 1 enzyme; or for treating a 11 -P-hydroxysteriod dehydrogenase type 1 enzyme- medicated disorder, substantially as herein described with reference to the examples. 69 N: \Melbourne\Cases\Patent\52000-52999\P52913 .AU. \Specis\Claims .doc 09/08/07