KR100847203B1 - Pyrimidine derivatives - Google Patents

Abstract

The compounds of formula (I) and pharmaceutically acceptable salts and esters thereof can be used in the form of pharmaceutical compositions.

Formula I

Where

R ¹ to R ⁵ are as defined in claim 1.

Description

Pyrimidine derivatives {PYRIMIDINE DERIVATIVES}

The present invention relates to novel pyrimidine derivatives useful as 11b-HSD1 inhibitors (T2D).

The present invention relates in particular to compounds of formula (I) and pharmaceutically acceptable salts and esters thereof.

Where

R ¹ is alkyl, cycloalkyl, cycloalkylalkoxy, alkoxyalkyl, cycloalkylalkoxyalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, aryloxyalkyl, amino or aminoalkyl,

R ² is hydrogen, alkyl or aryl,

R ³ is hydrogen, alkyl or aryl,

R ⁴ is independently from alkyl, cycloalkyl, halogen, alkoxy, cyano, trifluoromethyl, aryl, arylalkyl, aryloxy, oxazolyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl and thiazolyl Phenyl, naphthyl, thiophenyl, quinolyl, piperidyl, morpholyl or thiomorpholyl, optionally substituted with one or more substituents selected,

R ⁵ is hydrogen, alkyl, aralkyl, cycloalkylalkyl or aminocarbonylalkyl,

Provided N- (2,6-dimethyl-4-pyrimidinyl) -benzenesulfonamide, 2-chloro-N- (2-methyl-4-pyrimidinyl) -p-toluenesulfonamide, N- (2- (Dimethylamino) -6-methyl-5-propyl-4-pyrimidinyl) -benzenesulfonamide and 2,4,5-trichloro-N- (2,6-dimethyl-4-pyrimidinyl) -benzene Sulfonamides are excluded.

Glucocorticoids (cortisol in humans, corticosterone in mice and rats) are an important class of adrenocorticosteroids that regulate a number of metabolic and homeostatic processes and form key components that respond to stress. Glucocorticoids work through intracellular glucocorticoid receptors and in some tissues through mineral corticosteroid receptors, both of which are nuclear transcription factors. Glucocorticoid action on target tissues depends not only on circulating steroid concentrations and cellular expression of receptors, but also on intracellular enzymes that determine the extent to which glucocorticoids access receptors in their active form. 11β-hydroxysteroid dehydrogenase (11β-HSD) catalyzes the interconversion of the main active 11-hydroxy-glucocorticoid (cortisol in humans) and its inactive 11-keto metabolite (cortisone in humans). do.

The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) interconverts inactive glucocorticoids into active glucocorticoids, and plays an important role in the activation of corticosteroid receptors in target tissues by local control of cellular agent concentrations. F. F. Hoffmann-La Roche, in a recent study, analyzed gene expression differences in skinny and obese humans using gene array technology to identify specific differences in gene expression that may be associated with insulin resistance or metabolic modification. Was assayed. The study revealed that mRNA for 11β-HSD1 is approximately doubled up in adipose tissue of obese humans. Moreover, 11β-HSD1 overexpressing adipocytes in mice results in visceral obesity and X syndrome phenotype (Masuzaki H. et al., Science. 2001 Dec 7; 294 (5549): 2166-70). Taken together, these data strongly support that 11β-HSD1 plays an important role in inducing obesity and impairing glucose homeostasis and lipid parameters. Thus, selective inhibition of this enzyme can lower blood sugar levels in normal type 2 diabetic patients, normalize increased lipid parameters, and / or reduce the weight of obese subjects.

The first pharmacological indicator that human 11β-HSD1 inhibition plays a beneficial role is obtained using carbenoxolone, an anti-ulcer drug that inhibits both 11β-HSD1 and the related enzyme 11β-HSD2. Treatment with carbenoxolone increases insulin sensitivity, indicating that inhibition of 11β-HSD1 can reduce cellular cortisol levels and minimize some of its deleterious effects (Walker et al. 1995; J. Clin. Endocrinol). Metab. 80, 31155-3159).

11β-HSD1 is expressed in a number of tissues including liver, adipose tissue, vascular smooth muscle, pancreas and brain. Its activity depends on NADP (H) and its affinity for the substrate is relatively low (relative to 11β-HSD2). In tissues, 11β-HSD1 is bi-directional, homogenizing and, when purified, exhibits both 11β-dehydrogenase and 11β-reductase responses, with greater stability of dehydrogenase activity (see PM Stewart and ZS Krozowski, Vitam. Horm). 57 (1999), pp. 249-324). However, when enzyme activity is tested in intact cells, 11β-reductase activity, which regenerates active glucocorticoids from inactive 11-keto forms, is predominant. This glucocorticoid regeneration amplifies glucocorticoid activity by increasing effective intracellular glucocorticoid levels. It is this increased cellular cortisol concentration that can increase hepatic glucose production, adipocyte differentiation and insulin resistance.

Inhibition of 11β-HSD1 not only reduces the usual X syndrome / diabetes related symptoms, but the X syndrome / diabetes related symptoms are alleviated without major side effects. Studies with nonspecific inhibitor carbenoxolone highlight the importance of developing specific 11β-HSD1 inhibitors. Inhibition of the 11β-HSD2 enzyme causes increased resistance and increases blood pressure. In contrast, inhibition of 11β-HSD1 was found in 11β-HSD1 knockout mice to be healthy and resistant to hyperglycemia caused by obesity or stress (see Kotelevtsev Y. et al., Proc Natl Acad). Sci USA. 1997 Dec 23; 94 (26): 14924-9), will have sufficient resistance. Similarly, when fasted, these mice attenuated the activation of major liver enzymes involved in glucose synthesis. In addition, these mice have improved lipid and lipoprotein profiles, suggesting that inhibition of HSD1 can be very potent and safe. In a recent report, 11β-HSD1 inhibitors reduced hypertension (see Masuzaki H. et al., J Clin Invest. 2003 July; 112 (1): 83-90; Rauz S. et al., QJM. 2003 July; 96 (7): 481-90) to improve cognition (Sandeep TC. Et al., Proc Natl Acad Sci USA. 2004 Apr. 27; 101 (17): 6734-9) or to improve Alzheimer's defects. It points out that it can be advantageous. Taken together, 11β-HSD1 inhibition may be a safe and effective way to treat symptoms of diabetes, obesity and other diseases.

Compounds of formula (I) and pharmaceutically acceptable salts and esters thereof have novel and useful pharmacological properties. In particular, they are 11b-HSD1 inhibitors (T2D) and exhibit selectivity for the relevant 11β-HSD2 enzyme. Thus, compounds that are specific 11β-HSD1 inhibitors (T2D) lower blood sugar levels and modulate lipid parameters in patients with type 2 diabetes, for example, by regulating local concentrations of active glucocorticoid cortisol in target tissues (liver, adipose tissue). It is shown how to normalize.

The compounds of the present invention can be used to prevent and / or treat metabolic disorders, obesity, dyslipidemiae, hypertension and / or diabetes, in particular type II diabetes.

The compounds of the present invention may also be used to prevent and / or treat ocular pressure, cognition, Alzheimer's and / or neurodegeneration.

It is an object of the present invention to provide compounds of formula (I) and their salts and esters, as well as their use as therapeutically active substances, methods of preparing the compounds, intermediates, pharmaceutical compositions, the compounds and pharmaceutically acceptable salts and esters thereof. Use of the compound and its esters and salts thereof, and metabolic disorders for the prevention and / or treatment of diseases, containing, especially for eating disorders, obesity, dyslipidemia, hypertension and / or diabetes, in particular type II diabetes, , Obesity, dyslipidemia, hypertension and / or diabetes, especially type II diabetes, for the preparation of a medicament for the treatment or prophylaxis of the compound and its salts and esters.

The compounds of the present invention may further be combined with PPAR (α, β, δ) agonists, DHEA (dehydroepiandrosterone), DPPIV inhibitors, insulin and / or lipolytic inhibitors, in particular orlistat.

In the description of the invention, the term "alkyl", alone or in combination, is a straight or branched chain alkyl group having 1 to 8 carbon atoms, preferably a straight or branched chain alkyl group having 1 to 6 carbon atoms, particularly preferably 1 to 4 carbon atoms It means a straight or branched chain alkyl group of. Examples of straight and branched C ₁ -C ₈ alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, isomeric pentyl, isomeric hexyl, isomeric heptyl and isomeric octyl, preferably Are methyl and ethyl, most preferably methyl.

The term "cycloalkyl", alone or in combination, means cycloalkyl having 3 to 8 carbon atoms, preferably cycloalkyl having 3 to 6 carbon atoms. Examples of C ₃ -C ₈ cycloalkyl are cyclopropyl, methyl-cyclopropyl, dimethylcyclopropyl, cyclobutyl, methyl-cyclobutyl, cyclopentyl, methyl-cyclopentyl, cyclohexyl, methyl-cyclohexyl, dimethyl-cyclohexyl , Cycloheptyl and cyclooctyl, preferably cyclopropyl.

The term "alkoxy", alone or in combination, means a group of the formula alkyl-O-, wherein the term "alkyl" is as defined above, for example, methoxy, ethoxy, n-propoxy, iso Propoxy, n-butoxy, isobutoxy, secondary-butoxy and tert-butoxy, preferably methoxy and ethoxy, most preferably methoxy.

The term “aryl” alone or in combination, halogen, trifluoromethyl, trifluoromethoxy, amino, alkyl, alkoxy, alkylcarbonyl, cyano, carbamoyl, alkoxycarbamoyl, methylenedioxy, carboxy, alkoxy One or more substituents each independently selected from carbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxy, nitro, alkyl-SO _2- , amino-SO _2- , cycloalkyl, and the like By phenyl or naphthyl group optionally containing 1 to 3 is meant. Preference is given to phenyl or naphthyl, in particular phenyl, optionally substituted with one to three, preferably one or two substituents independently selected from alkyl, halogen, alkoxy, trifluoromethoxy, nitro and trifluoromethyl. Phenyl is particularly preferred.

The term "aryloxy", alone or in combination, refers to an aryl-O- group wherein the term "aryl" is as defined above.

The term "aralkyl", alone or in combination, means an arylalkyl group, wherein the terms "aryl" and "alkyl" are as defined above.

The term “heterocyclyl”, alone or in combination, means a saturated, partially unsaturated or aromatic 5- to 10-membered heterocycle containing one or more hetero atoms selected from nitrogen, oxygen and sulfur. If desired, it may be substituted by one or more carbon atoms, for example halogen, alkyl, alkoxy, oxo or the like and / or secondary nitrogen atoms (ie -NH-) by alkyl, cycloalkyl, aralkoxycarbonyl, alka It may be substituted with noyl, phenyl or phenylalkyl, or tertiary nitrogen atoms (ie = N-) may be substituted with an oxido, preferably halogen, alkyl, cycloalkyl and alkoxy. Examples of such heterocyclyl groups are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrazoyl, imidazoyl (e.g. imidazol-4-yl and 1-benzyloxycarbo) Yl-imidazol-4-yl), pyrazoyl, pyridyl, pyrazinyl, pyrimidinyl, hexahydro-pyrimidinyl, furyl, thienyl thiazolyl, oxazolyl, indolyl (e.g. 2-indolyl) , Quinolyl such as 2-quinolyl, 3-quinolyl and 1-oxido-2-quinolyl, isoquinolyl such as 1-isoquinolyl and 3-isoquinolyl, tetrahydroquinolyl (E.g. 1,2,3,4-tetrahydro-2-quinolyl), 1,2,3,4-tetrahydroisoquinolyl (e.g. 1,2,3,4-tetrahydro-1-oxo Isoquinolyl) and quinoxalinyl. Preferred examples are thiophenyl, quinolyl, piperidyl, morpholyl, thiomorpholyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl and thiazolyl.

The term "amino", alone or in combination, refers to a primary, secondary or tertiary amino group bonded via a nitrogen atom, the secondary amine group containing an alkyl or cycloalkyl substituent, and the tertiary amine group It contains two similar or different alkyl or cycloalkyl substituents or contains two nitrogen substituents which together form a ring, for example -NH ₂ , methylamino, ethylamino, dimethylamino, diethylamino, methyl-ethyl Amino, pyrrolidin-1-yl or piperidino and the like, preferably primary amino, dimethylamino and diethylamino, in particular dimethylamino.

The term "halogen" alone or in combination means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

The term "carbonyl", alone or in combination, refers to a -C (O)-group.

The term "oxy", alone or in combination, refers to an -O- group.

The term "nitro", alone or in combination, refers to a -NO ₂ group.

The term "cyano" alone or in combination refers to the group -CN.

The term “pharmaceutically acceptable salts” refers to salts that retain the biological effects and properties of the free base or free acid that are biologically or otherwise desired. The salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, preferably hydrochloric acid, and acetic acid, propionic acid, glycolic acid, pyruvic acid, oxylic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, It is formed using organic acids such as citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine and the like. In addition, these salts can be prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium salts, and the like. Salts derived from organic bases include primary, secondary and tertiary amines, substituted amines including substituted natural amines, cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, di Ethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polymine resin and the like, but are not limited thereto. The compounds of formula (I) may also exist in zwitterion form. Particularly preferred pharmaceutically acceptable salts of compounds of formula I are hydrochlorides.

The compounds of formula (I) can also be solvated, eg hydrated. Solvation can be carried out during the preparation process or can occur, for example, as a result of hygroscopicity of the initial anhydrous compound of formula (I). The term "pharmaceutically acceptable salts" also includes physiologically acceptable solvates.

"Pharmaceutically acceptable ester" means that the functional group can be derivatized to provide a derivative in which the compound of formula (I) can be reversed in vivo to the parent compound. Examples of such compounds are physiologically acceptable and metabolically labile ester derivatives such as methoxymethyl esters, methylthiomethyl esters and pivaloyloxymethyl esters. All physiologically acceptable equivalents of the compounds of formula (I), similar to metabolically labile esters, which can produce the parent compounds of formula (I) in vivo, are also within the scope of the present invention.

Compounds of formula (I) may contain several asymmetric centers and are optically pure enantiomers, mixtures of enantiomers such as racemates, optically pure diastereomers, mixtures of diastereomers, diastereomeric la It may be present in the form of a semi- or diastereomeric racemate.

Preference is given to compounds of the formula (I) and pharmaceutically acceptable salts thereof, in particular compounds of the formula (I).

R ¹ is alkyl, cycloalkyl, alkoxyalkyl, cycloalkylalkoxyalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, aryloxyalkyl, amino or aminoalkyl and R ² is hydrogen or alkyl and R ³ is hydrogen Or alkyl and R ⁴ is alkyl, cycloalkyl, halogen, alkoxy, cyano, trifluoromethyl, aryl, arylalkyl, aryloxy, oxazolyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl and thiazolyl Compounds of formula I and pharmaceutically acceptable, wherein phenyl, naphthyl, thiophenyl, quinolyl, piperidyl, morpholyl or thiomorpholinyl, optionally substituted with one or more substituents independently selected from R ⁵ is hydrogen or alkyl Salts and esters thereof are preferred, provided that N- (2,6-dimethyl-4-pyrimidinyl) -benzenesulfonamide, 2-chloro-N- (2-methyl-4-pyrimidinyl) -p-toluene Sulfonamide, N- (2- (dimethylamino)- 6-Methyl-5-propyl-4-pyrimidinyl) -benzenesulfonamide and 2,4,5-trichloro-N- (2,6-dimethyl-4-pyrimidinyl) -benzenesulfonamide are excluded .

Preference is also given to compounds of the formula (I) in which R ¹ is alkyl, cycloalkyl, alkoxyalkyl, cycloalkylalkoxyalkyl, heterocyclyl, heterocyclylalkyl or aryl.

A compound of Formula I, wherein R ¹ is methyl, ethyl, cyclopropyl, cyclobutyl, isopropyl, tert-butyl, methoxymethyl, cyclopropylmethoxymethyl, 2-methyl-thiazolyl, morpholinylmethyl or phenyl This is particularly preferred.

Preference is also given to compounds of the formula (I) in which R ² is hydrogen.

Another preferred object of the invention is a compound of formula (I) wherein R ² is methyl.

Preference is given to compounds of the formula (I) in which R ³ is hydrogen.

Another preferred embodiment of the invention is a compound of formula I, wherein R ⁵ is hydrogen.

Preference is also given to compounds of the formula (I) in which R ⁵ is methyl.

R ⁴ is phenyl, naphthyl, thiophenyl, qui, optionally substituted with one or more, preferably one or three substituents independently selected from alkyl, halogen, alkoxy, trifluoromethyl, aryl, oxazolyl and pyridinyl Preference is also given to compounds of the formula (I) which are noryl or piperidyl.

Preference is furthermore given to compounds of the formula (I) in which R ⁴ is phenyl substituted with one or more, preferably 1 to 3 substituents independently selected from alkyl, cycloalkyl, halogen, alkoxy, trifluoromethyl, phenyl and oxazolyl. .

Preferred are compounds of formula I, wherein R ⁴ is phenyl, naphthyl, quinolyl or piperidyl.

R ⁴ is independently from alkyl, cycloalkyl, halogen, alkoxy, cyano, trifluoromethyl, aryl, arylalkyl, aryloxy, oxazolyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl and thiazolyl Preference is also given to compounds of the formula (I) which are thiophenyl, morpholyl or thiomorpholyl optionally substituted with one or more, preferably one to three substituents selected.

Examples of preferred compounds of formula (I)

1. 3-chloro-2-methyl-N- (2-methyl-pyrimidin-4-yl) -benzenesulfonamide,

2. 3-chloro-N- (2-cyclopropyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide,

3. N- (2-cyclopropyl-pyrimidin-4-yl) -2,5-difluoro-benzenesulfonamide,

4. Naphthalene-2-sulfonic acid (2-cyclopropyl-pyrimidin-4-yl) -amide,

5. Biphenyl-4-sulfonic acid (2-cyclopropyl-pyrimidin-4-yl) -amide,

6. Quinolin-8-sulfonic acid (2-cyclopropyl-pyrimidin-4-yl) -amide,

7. N- (2-cyclopropyl-pyrimidin-4-yl) -benzenesunponamide,

8. N- (2-cyclopropyl-pyrimidin-4-yl) -5-fluoro-2-methyl-benzenesulfonamide,

9. N- (2-cyclopropyl-pyrimidin-4-yl) -3-methoxy-benzenesulfonamide,

10.N- (2-cyclopropyl-pyrimidin-4-yl) -2-methoxy-5-methyl-benzenesulfonamide,

11. 3-chloro-N- (2-cyclopropyl-pyrimidin-4-yl) -4-methoxy-benzenesulfonamide,

12. 5-chloro-N- (2-cyclopropyl-pyrimidin-4-yl) -2-methoxy-benzenesulfonamide,

13. 5-Fluoro-N- (2-isopropyl-pyrimidin-4-yl) -2-methyl-benzenesunponamide,

14. 3,4-dichloro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide,

15.N- (2-isopropyl-pyrimidin-4-yl) -4- (1.3-oxazol-5-yl) -benzenesulfonamide,

16. 2,4-dichloro-N- (2-isopropyl-pyrimidin-4-yl) -6-methyl-benzenesulfonamide,

17. 2,3-dichloro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide,

18. 4,5-dichloro-thiophene-2-sulfonic acid (2-isopropyl-pyrimidin-4-yl) -amide,

19. 5-pyridin-2-yl-thiophene-2-sulfonic acid (2-isopropyl-pyrimidin-4-yl) -amide,

20. 3-chloro-N- (2-isopropyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide,

21.N- (2-isopropyl-pyrimidin-4-yl) -3-trifluoromethyl-benzenesulfonamide,

22. N- (2-isopropyl-pyrimidin-4-yl) -2-trifluoromethyl-benzenesulfonamide,

23. 5-Chloro-thiophene-2-sulfonic acid (2-isopropyl-pyrimidin-4-yl) -amide,

24. N- (2-isopropyl-pyrimidin-4-yl) -4-trifluoromethyl-benzenesulfonamide,

25. Piperidine-1-sulfonic acid (2-isopropyl-pyrimidin-4-yl) -amide,

26. Naphthalene-2-sulfonic acid (2-isopropyl-pyrimidin-4-yl) -amide,

27. Biphenyl-4-sulfonic acid (2-isopropyl-pyrimidin-4-yl) -amide,

28. 2,5-difluoro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide,

29. N- (2-isopropyl-pyrimidin-4-yl) -3,4-dimethoxy-benzenesulfonamide,

30.N- (2-tert-butyl-pyrimidin-4-yl) -3,4-dichloro-benzenesulfonamide,

31.N- (2-tert-butyl-pyrimidin-4-yl) -5-fluoro-2-methyl-benzenesulfonamide,

32. Naphthalene-2-sulfonic acid (tert-butyl-pyrimidin-4-yl) -amide,

33.N- (2-tert-butyl-pyrimidin-4-yl) -2,5-difluoro-benzenesulfonamide,

34.N- (2-tert-butyl-pyrimidin-4-yl) -4- (1.3-oxazol-5-yl) -benzenesulfonamide,

35. 3-chloro-N- (2-ethyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide,

36. 2,4-dichloro-N- (2-ethyl-pyrimidin-4-yl) -6-methyl-benzenesulfonamide,

37. 4-chloro-N- (2-ethyl-pyrimidin-4-yl) -2,5-dimethyl-benzenesulfonamide,

38. 3-Chloro-N- (2-cyclobutyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide,

39. naphthalene-2-sulfonic acid (2-cyclobutyl-pyrimidin-4-yl) -amide,

40. 5-Pyridin-2-yl-thiophene-2-sulfonic acid (2-cyclobutyl-pyrimidin-4-yl) -amide,

41. 2,4-Dichloro-N- (2-cyclobutyl-pyrimidin-4-yl) -6-methyl-benzenesulfonamide,

42. 3,4-dichloro-N- (2-methoxymethyl-pyrimidin-4-yl) -benzenesulfonamide,

43. 3-chloro-N- (2-cyclopropylmethoxymethyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide,

44. 3-Chloro-2-methyl-N- (2-morpholin-4-ylmethyl-pyrimidin-4-yl) -benzenesulfonamide,

45. naphthalene-2-sulfonic acid (2,6-dimethyl-pyrimidin-4-yl) -amide,

46. 3-chloro-N- (2-cyclopropyl-pyrimidin-4-yl) -2-N-dimethyl-benzenesulfonamide,

47. 3,4-Dichloro-N- (2-isopropyl-pyrimidin-4-yl) -N-methyl-benzenesulfonamide,

48. 3-Chloro-2-methyl-N- (2-phenyl-pyrimidin-4-yl) -benzenesulfonamide and

49. 3-chloro-2-methyl-N- [2- (2-methyl-thiazol-4-yl) -pyrimidin-4-yl] -benzenesulfonamide.

Another example of a preferred compound is

50. 3-Chloro-N- (2-methoxymethyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide,

51. naphthalene-2-sulfonic acid (2,5,6-trimethyl-pyrimidin-4-yl) -amide,

52. 4,5-dichloro-2-fluoro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide,

53. 2,4-difluoro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide,

54. 2-chloro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide,

55. 4-chloro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide,

56. 3-chloro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide,

57. 2,4-dichloro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide,

58. 2,4-Dichloro-N- (2-isopropyl-pyrimidin-4-yl) -5-methyl-benzenesulfonamide,

59. 2,5-dichloro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide,

60. 3-Bromo-5-chloro-thiophene-2-sulfonic acid (2-isopropyl-pyrimidin-4-yl) -amide,

61. 2,4-Dichloro-N- (2-cyclopropyl-pyrimidin-4-yl) -6-methyl-benzenesulfonamide,

62. 4-chloro-N- (2-cyclopropyl-pyrimidin-4-yl) -2,5-dimethyl-benzenesulfonamide,

63. N- (2-cyclopropyl-pyrimidin-4-yl) -2,4-dimethoxy-benzenesulfonamide,

64. 3-Chloro-N- (2-cyclopentyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide,

65. 5-phenyl-thiophene-2-sulfonic acid (2-cyclopropyl-pyrimidin-4-yl) -amide,

66. 3-chloro-N- (2-cyclopropylmethoxy-pyrimidin-4-yl) -2-methyl-benzenesulfonamide,

67. 2-[(3,4-Dichloro-benzenesulfonyl)-(2-isopropyl-pyrimidin-4-yl) -amino] -N, N-dimethyl-acetamide,

68. N-benzyl-3-chloro-N- (2-cyclopropyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide,

69. 3-Chloro-N-cyclopropylmethyl-N- (2-cyclopropyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide and

70. 3-Chloro-2-methyl-N- (6-phenyl-pyrimidin-4-yl) -benzenesulfonamide.

Examples of particularly preferred compounds of formula I are

3-chloro-2-methyl-N- (2-methyl-pyrimidin-4-yl) -benzenesulfonamide,

3-chloro-N- (2-cyclopropyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide,

N- (2-cyclopropyl-pyrimidin-4-yl) -2,5-difluoro-benzenesulfonamide,

Naphthalene-2-sulfonic acid (2-cyclopropyl-pyrimidin-4-yl) -amide,

Biphenyl-4-sulfonic acid (2-cyclopropyl-pyrimidin-4-yl) -amide,

5-fluoro-N- (2-isopropyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide,

3,4-dichloro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide,

N- (2-isopropyl-pyrimidin-4-yl) -4- (1.3-oxazol-5-yl) -benzenesulfonamide,

2,4-dichloro-N- (2-isopropyl-pyrimidin-4-yl) -6-methyl-benzenesulfonamide,

2,3-dichloro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide,

5-Pyridin-2-yl-thiophene-2-sulfonic acid (2-isopropyl-pyrimidin-4-yl) -amide,

3-chloro-N- (2-isopropyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide,

N- (2-isopropyl-pyrimidin-4-yl) -3-trifluoromethyl-benzenesulfonamide,

N- (2-isopropyl-pyrimidin-4-yl) -2-trifluoromethyl-benzenesulfonamide,

5-Chloro-thiophene-2-sulfonic acid (2-isopropyl-pyrimidin-4-yl) -amide,

N- (2-isopropyl-pyrimidin-4-yl) -4-trifluoromethyl-benzenesulfonamide,

Naphthalene-2-sulfonic acid (2-isopropyl-pyrimidin-4-yl) -amide,

Biphenyl-4-sulfonic acid (2-isopropyl-pyrimidin-4-yl) -amide,

2,5-difluoro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide,

N- (2-isopropyl-pyrimidin-4-yl) -3,4-dimethoxy-benzenesulfonamide,

N- (2-tert-butyl-pyrimidin-4-yl) -4-oxazol-5-yl-benzenesulfonamide,

3-chloro-N- (2-ethyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide,

2,4-dichloro-N- (2-ethyl-pyrimidin-4-yl) -6-methyl-benzenesulfonamide,

3-chloro-N- (2-cyclobutyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide,

Naphthalene-2-sulfonic acid (2-cyclobutyl-pyrimidin-4-yl) -amide,

5-Pyridin-2-yl-thiophene-2-sulfonic acid (2-cyclobutyl-pyrimidin-4-yl) -amide,

2,4-dichloro-N- (2-cyclobutyl-pyrimidin-4-yl) -6-methyl-benzenesulfonamide,

3-chloro-N- (2-cyclopropyl-pyrimidin-4-yl) -2-N-dimethyl-benzenesulfonamide and

3,4-dichloro-N- (2-isopropyl-pyrimidin-4-yl) -N-methyl-benzenesulfonamide.

The process for the preparation of formula (I) is an object of the present invention.

Compounds of formula (I) of the present invention may be prepared in sequential or convergent routes. The synthesis of the present invention is shown in the following scheme. The skills required to carry out the reaction and to purify the obtained product are known to those skilled in the art. Substituents and indices used in the description of the following methods have the meanings described above unless indicated to the contrary.

In general, the compounds of formula (I) are readily obtainable by sulfonylation of 4-amino-pyrimidine suitably substituted with sulfonyl chloride under various conditions known to those skilled in the art. Examples of such conditions are THF under reflux conditions, for example, in the presence of pyridine or a base such as potassium carbonate, sodium carbonate, sodium hydride, triethylamine and the like at elevated temperatures.

Compounds of formula (I) in which R ⁵ is H are treated with a base (e.g. sodium hydride, cesium carbonate, potassium carbonate, etc.) in a solvent such as DMF or THF, and then the resulting anions are alkylhalide (e.g. The nitrogen of the sulfonamide may optionally be further substituted by alkylation with methyl iodide, ethyl bromide, benzyl bromide, etc.) to introduce the desired R ⁵ substituent.

Suitably substituted 4-amino-pyrimidine (A) is commercially available, known in the literature, or can be prepared analogously to the procedure of the literature from known starting materials. A convenient method of synthesis uses amidine or amidine salt (B) as starting material, which material is prepared under the conditions described more readily in J. Heterocyclic Chem. 14, 1977, 1413-1414. Treatment with acrylonitrile, such as chloro-acrylonitrile or 3-ethoxy-acrylonitrile (when amidine salts are used as starting materials, treatment with bases such as triethyl amine, sodium ethoxide, potassium carbonate, etc. After releasing amidine). Another method for the preparation of suitably substituted 4-amino-pyrimidines is available from the literature.

Additional, but optional modifications are possible when there is a side chain suitably substituted at position 2 of the 4-amino-pyrimidine intermediate (A), for example when there are leaving groups such as halides in the side chain. For example, leaving groups can be exchanged by treating a suitable starting material with alcohol and base (a) to provide an aryl ether or alkyl ether, as shown in Scheme A below, or by treating with amine (b) Derivatives may be provided. If the leaving group is attached directly to position 2 of the pyrimidine nucleus, the reaction with the alcohol is similarly possible to give O-substituted 2-hydroxy-4-aminopyrimidine (Scheme B).

The conversion of a compound of formula (I) to a pharmaceutically acceptable salt thereof may be carried out using an inorganic acid (e.g. hydrochloric or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) or an organic acid (e.g. acetic acid, citric acid, maleic acid, fumaric acid , Tartaric acid, methanesulfonic acid or p-toluenesulfonic acid). Corresponding carboxylate salts can also be prepared by treating with a physiologically suitable base from the compound of formula (I).

The conversion of a compound of formula (I) to a pharmaceutically acceptable ester or amide thereof, for example, may be carried out by the addition of a suitable amino or hydroxyl group present in the molecule to a carboxylic acid (e.g. acetic acid), a reagent for condensation (e.g. benzotriazole 1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP) or N, N-dicyclohexylcarbodiimide (DCCI)) to achieve carboxylic esters or carboxylic acid amides.

Preferred methods for preparing compounds of formula (I) as defined above include reacting compounds of formula (A) in the presence of compounds of formula (B):

Where

R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above.

For example, it is particularly preferred to carry out the above reaction in pyridine or THF, in particular in the presence of a base such as potassium carbonate, sodium carbonate, sodium hydride or triethyl amine. It is highly desirable to carry out the above reaction at 50 to 70 ° C. in the presence of pyridine. It is also highly desirable to carry out the above method under reflux conditions in the presence of THF.

Preferred intermediates

2-cyclopropyl-pyrimidin-4-ylamine,

2-isopropyl-pyrimidin-4-ylamine,

2-3-butyl-pyrimidin-4-ylamine,

2-ethyl-pyrimidin-4-ylamine,

2-cyclobutyl-pyrimidin-4-ylamine,

2-methoxymethyl-pyrimidin-4-ylamine,

2-cyclopropylmethoxymethyl-pyrimidin-4-ylamine,

2-morpholin-4-ylmethyl-pyrimidin-4-ylamine,

2-phenyl-pyrimidin-4-ylamine and

2- (2-methyl-thiazol-4-yl) -pyrimidin-4-ylamine.

Another object of the invention is a compound of formula (I) for use as a therapeutically active substance.

The object of the present invention is also the above compounds for the preparation of a medicament for the prevention and treatment of diseases caused by disorders associated with the enzyme 11β-hydroxysteroid dehydrogenase 1 (11bHSD1).

Also an object of the present invention is a pharmaceutical composition comprising a compound of formula (I) and a therapeutically inert carrier.

Another preferred embodiment of the invention is the use of a compound of formula (I) for the manufacture of a medicament for the treatment and prevention of diabetes, obesity, eating disorders, dyslipidemia and hypertension.

Particular preference is given to the use of the compounds of formula I for the manufacture of a medicament for the treatment and prevention of type II diabetes.

Another object of the invention comprises a compound of formula (I) prepared according to any one of the above methods.

The object of the present invention is also a method of treating and preventing diabetes, obesity, eating disorders, dyslipidemia and hypertension, comprising administering an effective amount of a compound of formula (I).

Particularly preferred are methods for treating and preventing type II diabetes, including administering an effective amount of a compound of formula (I).

Assay Procedure

Transient expression and partial purification

The cDNA encoding the human 11β-HSD1 protein is cloned into the expression vector pcDNA3 (Stratagene). The construct (Alex Odermatter et al .; J Biol Chem., 1999, Vol. 274, Issue 40,28762-28770) is used for transient expression of proteins in HEK293 cells using lipofectamine [ATCC No .: CRL-1573, see Graham, FL, Smiley, J., Russell, WC, Nairn, R. (1977) .After 48 hours of transfection, cells were treated with ice cold PBS (phosphate buffered saline) 2. Wash two times Add two doses of ice-cold lysis buffer (50 mM Tris; pH 7.5; 1 mM EDTA; 100 mM NaCl) to one dose of cell suspension in PBS Cells are lysed by porter-homogenization (20 strokes). Was crushed with a tip ultrasonic crusher (output 10%; 2 x 30 seconds) and washed with low speed centrifugation (10 minutes x 9000 g; 4 ° C.) The microsomal fractions were collected by high speed centrifugation (60 minutes x 110,000 g). The resulting pellet is suspended in storage buffer (20 mM Tris pH 7.5; 1 mM EDTA; 10% glycerol) and centrifugation is repeated. The pellet obtained is taken back into storage buffer and kept frozen in liquid nitrogen until an aliquot is used.

Generation of stable cell lines expressing 11β-HSD1

The same construct used for transient expression of human 11β-HSD1 is used to establish cell lines that stably express proteins. Briefly, (HEK293) cells are transfected with 11β-HSD1 construct using lipofectamine reagent (Gibco BRL) according to manufacturer's instructions. After 2 days of transfection, geneticin selection (0.8 mg / ml) is initiated and several stable clones are isolated. One clone is further used for pharmacological characterization.

Microbody Analysis

Microbodies isolated from HEK293 cells transiently expressing human 11β-HSD1 (see above for details) were analyzed in assay buffer (100 mM NaCl; 1 mM EDTA; 1 mM EGTA; 1 mM MgCl; 250 mM sucrose; 20 mM Tris pH 7.4; Cortisone 50 to Incubate with different concentrations of test substance in 200 nM and 1 mM of NADPH. After incubation at 37 ° C. for 60 minutes, the assay is stopped by heating to 80 ° C. (5 minutes) and adding the inhibitor carbenoxolone (1 uM). The amount of cortisol produced in this assay is measured using a commercially available ELISA-based cortisol detection kit (commercially available from Assay Design, Inc.). Inhibitors are characterized at IC ₅₀ values, such as concentrations at which cortisol production is reduced by 50%.

In this test, the preferred compounds described above have an IC ₅₀ value of less than 1000 nM, and more preferred compounds have an IC ₅₀ value of less than 100 nM. Most preferred compounds have an IC ₅₀ value of less than 10 nM.

Cell analysis

To determine the effect of inhibitors on intact cells, HEK293 cells (see above) stably expressing human 11β-HSD1 are cultured in 96 well plates in DMEM. Inhibitors are first added to the cells and then cortisone after 60 minutes. After incubation for 60 minutes in a 5% CO ₂ atmosphere at 37 ° C., a portion of the medium is removed and the conversion from cortisone to cortisol is measured using a commercially available ELISA kit (Assay Design, Inc.).

The results obtained upon microsomal analysis using representative compounds of the present invention as test compounds are shown in the following table:

The compounds have an IC ₅₀ of less than 100 uM and more preferred compounds have an IC ₅₀ of less than ₂₀ uM, in particular less than ₅ uM. Most preferred compounds have an IC ₅₀ of less than 0.5 uM. These results are obtained using the above test.

The compounds of formula (I) and pharmaceutically acceptable salts and esters thereof can be used as medicaments (eg in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered into the body, for example orally (e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), intranasally (e.g. in the form of nasal sprays) or It may be administered rectally (eg in the form of suppositories). However, it may also be administered parenterally, for example intramuscularly or intravenously (eg in the form of injectable solutions).

The compounds of formula (I) and pharmaceutically acceptable salts and esters thereof can be processed using pharmaceutically inert inorganic or organic adjuvant for preparing tablets, coated tablets, dragees and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as adjuvant for tablets, dragees and hard gelatin capsules.

Suitable reinforcing agents for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid materials and liquid polyols and the like.

Suitable reinforcing agents for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like.

Suitable adjuvant for injection solvents are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

Suitable adjuvant for suppositories are, for example, natural or hardened oils, waxes, fats, semisolid or liquid polyols and the like.

In addition, the pharmaceutical preparations may contain preservatives, solubilizers, viscosity increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for changing the osmotic pressure, buffers, blockers or antioxidants. They may also contain other therapeutically useful substances.

In the present invention, the compounds of formula (I) and pharmaceutically acceptable salts thereof can be used for the prevention and treatment of arthritis, cardiovascular disease, diabetes, renal failure, and especially eating disorders and obesity. The dosage can vary within wide limits and can, of course, be adapted to the individual requirements of each particular case. In general, for oral administration, a daily dosage of about 0.1 to 20 mg per kg body weight, preferably about 0.5 to 4 mg (eg about 300 mg per person), for example from 1 to 1, which may consist of the same amount Three individual doses are suitable. However, it is obvious that the upper limit can be exceeded if it is indicated to be exceeded.

The invention is now illustrated by the non-limiting examples.

Example 1 3-Chloro-2-methyl-N- (2-methyl-pyrimidin-4-yl) -benzenesulfonamide

2-methyl-pyrimidin-4-ylamine (91 mg, Gabriel, Chem. Ber. Ber. 37, 1904, 3641) and 3-chloro-2-methyl-benzenesulfonyl chloride (179 mg) pyridine (5 mL) Dissolved in, and the resulting mixture is stirred at 50-60 ° C. for 48 h. The mixture is then evaporated in vacuo and the residue is dissolved in ethyl acetate. The solution is washed twice with 1M CuSO ₄ solution, dried over Na ₂ SO ₄ , filtered and then evaporated. The residue is purified by flash chromatography (CH ₂ Cl ₂ / MeOH / NH ₃ 90: 10: 0.5) to give the desired product 3-chloro-2-methyl-N- (2-methyl-pyrimidin-4-yl). -Benzenesulfonamide is obtained as a yellow powder (22 mg). MS (ESI ⁻ ): 297.1 ([MH] ⁻ ).

Example 2: 3-Chloro-N- (2-cyclopropyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide

Step A: 2-cyclopropyl-pyrimidin-4-ylamine

Cyclopropylcarbamidine hydrochloride (3.0 g) is added to sodium methoxide solution (5.4 M, 4.61 mL) and the mixture is stirred for 1 hour. The suspension is filtered to remove precipitated NaCl and the filtrate is evaporated in vacuo to give a light brown residue (2.86 g). 3-ethoxyacrylonitrile (2.55 mL) is added and the mixture is heated at 135 ° C. for 3 hours and then stirred at room temperature for another 12 hours. The reaction mixture is immediately flash chromatographed (silica gel, ethyl acetate) to separate the desired 2-cyclopropyl-pyrimidin-4-ylamine as a light brown foam (1.53 g). ¹ H NMR (δ, CDCl ₃ ): 8.09 (d, 1H), 6.18 (d, 1H), 4.68 (br s, 2H), 2.04-1.98 (m, 1H), 1.08-1.04 (m, 2H), 0.97-0.92 (m, 2 H). MS (ESI): 136.2 (MH < ⁺ & gt ^; ).

Alternatives to Step A:

Cyclopropylcarbamidine hydrochloride (7.61 g) is dissolved in ethanol (125 mL) and triethylamine (19.35 mL) and 2-chloro-acrylonitrile (5.52 mL) are added. The resulting orange yellow solution is refluxed for 30 minutes. The mixture is cooled down and left in the refrigerator overnight. The solid is filtered off and the filtrate is concentrated in vacuo. The residue is purified by flash chromatography (ethyl acetate / methanol 9: 1) to give 2-cyclopropyl-pyridin-4-ylamine (4.2 g) as a light brown solid, which is still contaminated with unidentified components but additionally Use without purification. ¹ H NMR (δ, DMSO-d ₆ ) product signal only): 7.88 (d, 1H), 6.64 (br s, 2H), 6.16 (d, 1H), 1.89-1.82 (m, 1H), 0.87-0.81 (m, 4 H).

Step A is described in Singh and Lesher, J. Heterocyclic Chem. 1977, 14 (8), 1413-1414.

Step B: 3-Chloro-N- (2-cyclopropyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide

The material was light yellow solid (0.067 g) from 2-cyclopropyl-pyrimidin-4-ylamine (0.126 g) and 3-chloro-2-methyl-benzenesulfonyl chloride (0.2 g) similar to Example 1. Obtained as MS (ESI ⁻ ): 322.2 ([MH] ⁻ ).

Example 3: N- (2-cyclopropyl-pyrimidin-4-yl) -2,5-difluoro-benzenesulfonamide

This material was lightened from 2-cyclopropyl-pyrimidin-4-ylamine (0.150 g) and 2,5-difluoro-benzenesulfonyl chloride (0.236 g) similarly to steps A and B of Example 2. Obtained as a yellow foam (0.1 g). MS (ESI): 312.1 (MH < ⁺ & gt ^; ).

Example 4: Naphthalene-2-sulfonic acid (2-cyclopropyl-pyrimidin-4-yl) -amide

This material was light yellow foam (0.1 g) from 2-cyclopropyl-pyrimidin-4-ylamine (0.1 g) and naphthalene-2-sulfonyl chloride (0.044 g) similar to step A and step B of Example 2. Obtained as MS (ESI ⁻ ): 324.1 ([MH] ⁻ ).

Example 5: Biphenyl-4-sulfonic acid (2-cyclopropyl-pyrimidin-4-yl) -amide

This material is light yellow foam (from 2 cyclopropyl-pyrimidin-4-ylamine (0.1 g) and biphenyl-4-sulfonyl chloride (0.18 g) similar to step A and step B of Example 2). 0.032 g). ^{MS (ESI -): 350.2 (} [MH] -).

Example 6: Quinoline-8-sulfonic acid (2-cyclopropyl-pyrimidin-4-yl) -amide

This material was light yellow foam (8 mg) from 2-cyclopropyl-pyrimidin-4-ylamine (0.1 g) and quinoline-8-sulfonyl chloride (0.16 g) similar to steps A and B of Example 2. Obtained as ^{MS (ESI -): 325.1 (} [MH] -).

Example 7: N- (2-cyclopropyl-pyrimidin-4-yl) -benzenesulfonamide

This material is obtained as a pale yellow foam (36 mg) from 2-cyclopropyl-pyrimidin-4-ylamine (0.1 g) and benzenesulfonyl chloride (0.125 g) similarly to steps A and B of Example 2. . ^{MS (ESI -): 274.0 (} [MH] -).

Example 8: N- (2-cyclopropyl-pyrimidin-4-yl) -5-fluoro-2-methyl-benzenesulfonamide

This material is obtained as a pale yellow foam (76 mg) from 2-cyclopropyl-pyrimidin-4-ylamine (0.1 g) and benzenesulfonyl chloride (0.178 g) similarly to steps A and B of Example 2. . MS (ESI ⁻ ): 306.2 ([MH] ⁻ ).

Example 9: N- (2-cyclopropyl-pyrimidin-4-yl) -3-methoxy-benzenesulfonamide

This material was prepared in yellow foam (108 mg) from 2-cyclopropyl-pyrimidin-4-ylamine (0.13 g) and 3-methoxy-benzenesulfonyl chloride (0.2 g) similarly to steps A and B of Example 2. Obtained as MS (ESI ⁻ ): 304.1 ([MH] ⁻ ).

Example 10 N- (2-cyclopropyl-pyrimidin-4-yl) -2-methoxy-5-methyl-benzenesulfonamide

This material is 2-cyclopropyl-pyrimidin-4-ylamine (0.15 g) and 2-methoxy-5-methyl-benzenesulfonyl chloride (0.3 g) light, similar to steps A and B of Example 2. Obtained as a brown solid (63 mg). MS (ESI ⁻ ): 318.0 ([MH] ⁻ ).

Example 11: 3-Chloro-N- (2-cyclopropyl-pyrimidin-4-yl) -4-methoxy-benzenesulfonamide

This material was prepared from 2-cyclopropyl-pyrimidin-4-ylamine (0.15 g) and 3-chloro-4-methoxy-benzenesulfonyl chloride (0.32 g) similarly to steps A and B of Example 2. Obtained as a yellowish brown solid (40 mg). MS (ESI): 340.1 (MH < ⁺ & gt ^; ).

Example 12: 5-Chloro-N- (2-cyclopropyl-pyrimidin-4-yl) -2-methoxy-benzenesulfonamide

This material was prepared from 2-cyclopropyl-pyrimidin-4-ylamine (0.15 g) and 5-chloro-2-methoxy-benzenesulfonyl chloride (0.32 g) similarly to steps A and B of Example 2. Obtained as a light brown solid (15 mg). MS (ESI ⁻ ): 338.1 ([MH] ⁻ ).

Example 13: 5-Fluoro-N- (2-isopropyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide

Step A: 2-isopropyl-pyrimidin-4-ylamine

This compound is obtained as a pale yellow foam (1.36 g) from cyclopropylcarbamidine hydrochloride (3 g) and 3-ethoxyacrylonitrile (2.5 mL) similar to step A of Example 2. MS (ESI): 138.1 (MH < ⁺ & gt ^; ).

Step B: 5-Fluoro-N- (2-isopropyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide

This material is similar to Example 1 as light yellow foam (72 mg) from 2-isopropyl-pyrimidin-4-ylamine (0.13 g) and 5-fluoro-2-methylbenzenesulfonyl chloride (0.32 g). To obtain. MS (ESI ⁻ ): 308.1 ([MH] ⁻ ).

Example 14 3,4-Dichloro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide

This material is obtained as a pale yellow solid (295 mg) from 2-isopropyl-pyrimidin-4-ylamine (0.23 g) and 3,4-dichloro-benzenesulfonyl chloride (0.41 g) similarly to Example 13. . ^{MS (ESI -): 343.9 (} [MH] -).

Example 15 N- (2-isopropyl-pyrimidin-4-yl) -4- (1.3-oxazol-S-yl) -benzenesulfonamide

This material was light yellow from 2-isopropyl-pyrimidin-4-ylamine (0.174 g) and 4- (1.3-oxazol-5-yl) -benzenesulfonyl chloride (0.31 g) similar to Example 13. Obtained as a foam (295 mg). ^{MS (ESI -): 343.0 (} [MH] -).

Example 16: 2,4-dichloro-N- (2-isopropyl-pyrimidin-4-yl) -6-methylbenzenesulfonamide

This material was light yellow powder (87 mg) from 2-isopropyl-pyrimidin-4-ylamine (0.15 g) and 2,4-dichloro-6-methyl-benzenesulfonyl chloride (0.284 g) similar to Example 13. Obtained as MS (ESI ⁻ ): 358.0 ([MH] ⁻ ).

Example 17 2,3-dichloro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide

This material is obtained as light yellow powder (110 mg) from 2-isopropyl-pyrimidin-4-ylamine (0.15 g) and 2,3-dichloro-benzenesulfonyl chloride (0.268 g) similarly to Example 13. . MS (ESI ⁻ ): 343.9 ([MH] ⁻ ).

Example 18 4,5-dichloro-thiophene-2-sulfonic acid (2-isopropyl-pyrimidin-4-yl) -amide

This material was light yellow foam (28 mg) from 2-isopropyl-pyrimidin-4-ylamine (0.15 g) and 4,5-dichloro-thiophene-2-sulfonyl chloride (0.275 g) similar to Example 13. Obtained as ^{MS (ESI -): 350.0 (} [MH] -).

Example 19 5-Pyridin-2-yl-thiophene-2-sulfonic acid (2-isopropyl-pyrimidin-4-yl) -amide

This material was light yellow foam from 2-isopropyl-pyrimidin-4-ylamine (0.2 g) and 5-pyridin-2-yl-thiophene-2-sulfonyl chloride (0.379 g) similar to Example 13. Obtained as (24 mg). ^{MS (ESI -): 359.0 (} [MH] -).

Example 20: 3-Chloro-N- (2-isopropyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide

This material is similar to Example 13 as a pale yellow foam (72 mg) from 2-isopropyl-pyrimidin-4-ylamine (0.13 g) and 3-chloro-2-methyl-benzenesulfonyl chloride (0.2 g). To obtain. ^{MS (ESI -): 324.1 (} [MH] -).

Example 21 N- (2-isopropyl-pyrimidin-4-yl) -3-trifluoromethyl-benzenesulfonamide

This material was obtained as pale yellow foam (62 mg) from 2-isopropyl-pyrimidin-4-ylamine (0.2 g) and 3-trifluoromethyl-benzenesulfonyl chloride (0.357 g) similarly to Example 13. do. ^{MS (ESI -): 344.0 (} [MH] -).

Example 22 N- (2-isopropyl-pyrimidin-4-yl) -2-trifluoromethyl-benzenesulfonamide

This material was obtained as light yellow powder (60 mg) from 2-isopropyl-pyrimidin-4-ylamine (0.2 g) and 2-trifluoromethyl-benzenesulfonyl chloride (0.357 g) similarly to Example 13. do. MS (ESI ⁻ ): 344.1 ([MH] ⁻ ).

Example 23 5-Chloro-thiophene-2-sulfonic acid (2-isopropyl-pyrimidin-4-yl) -amide

This material was obtained as a pale yellow powder (49 mg) from 2-isopropyl-pyrimidin-4-ylamine (0.2 g) and 5-chloro-thiophene-2-sulfonyl chloride (0.316 g) similarly to Example 13. To obtain. MS (ESI ⁻ ): 316.0 ([MH] ⁻ ).

Example 24 N- (2-isopropyl-pyrimidin-4-yl) -4-trifluoromethyl-benzenesulfonamide

This material was obtained as light brown foam (211 mg) from 2-isopropyl-pyrimidin-4-ylamine (0.2 g) and 4-trifluoromethyl-benzenesulfonyl chloride (0.357 g) similarly to Example 13. do. MS (ESI ⁻ ): 344.1 ([MH] ⁻ ).

Example 25 Piperidine-1-sulfonic acid (2-isopropyl-pyrimidin-4-yl) -amide

This material is obtained from 2-isopropyl-pyrimidin-4-ylamine (0.2 g) and piperidine-1-sulfonyl chloride (0.295 g) similarly to Example 13 except that the coupling reaction is 105 ° C. Proceeds at an elevated temperature. The desired product is obtained as a pale yellow foam (139 mg). MS (ESI ⁻ ): 283.1 ([MH] ⁻ ).

Example 26 Naphthalene-2-Sulfonic Acid (2-Isopropyl-pyrimidin-4-yl) -amide

This material was obtained from 2-isopropyl-pyrimidin-4-ylamine (0.13 g) and naphthalene-2-sulfonyl chloride (0.344 g) similar to Example 13 except that pyridine was converted to THF (5 mL). Replace and react for 24 hours under reflux conditions using potassium carbonate (0.144 g) as base. After cooling, the mixture is filtered and evaporated in vacuo before the product is separated by flash chromatography. The desired product is obtained as a yellow foam (53 mg). ^{MS (ESI -): 326.2 (} [MH] -).

Example 27 Biphenyl-4-sulfonic acid (2-isopropyl-pyrimidin-4-yl) -amide

This material was obtained from 2-isopropyl-pyrimidin-4-ylamine (0.13 g) and biphenyl-4-sulfonyl chloride (0.383 g) similar to Example 13 except that pyridine was dioxane (5 mL). ) And reacted at 90 ° C. for 12 hours using potassium carbonate (0.144 g) as the base. After cooling, the mixture is filtered and evaporated in vacuo before the product is separated by flash chromatography. The desired product is obtained as a yellow foam (31 mg). MS (ESI ⁻ ): 352.2 ([MH] ⁻ ).

Example 28: 2,5-difluoro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide

This material is obtained from 2-isopropyl-pyrimidin-4-ylamine (0.13 g) and 2,5-difluoro-benzenesulfonyl chloride (0.322 g) similarly to Example 13 except that pyridine is THF (5 ml) and potassium carbonate (0.144 g) was used as the base and reacted under reflux conditions for 12 hours. After cooling, the mixture is filtered and evaporated in vacuo before the product is separated by flash chromatography. The desired product is obtained as a yellow foam (78 mg). ^{MS (ESI -): 312.0 (} [MH] -).

Example 29 N- (2-isopropyl-pyrimidin-4-yl) -3,4-dimethoxy-benzenesulfonamide

This material is obtained from 2-isopropyl-pyrimidin-4-ylamine (0.13 g) and 3,3-dimethoxy-benzenesulfonyl chloride (0.359 g) similarly to Example 13 except that pyridine is obtained from THF ( 5 ml) and potassium carbonate (0.144 g) is used as the base and reacted under reflux conditions for 12 hours. After cooling, the mixture is filtered and evaporated in vacuo before the product is separated by flash chromatography. The desired product is obtained as a yellow foam (21 mg). MS (ESI ⁻ ): 336.1 ([MH] ⁻ ).

Example 30 N- (tert-butyl-pyrimidin-4-yl) -3,4-dichloro-benzenesulfonamide

Step A: 2-3-butyl-pyrimidin-4-ylamine

This material is obtained as yellow foam (2.28 g) from tert-butylcarbamidine hydrochloride (3.0 g) and 3-ethoxyacrylonitrile (2.2 mL) similar to step A of Example 13. MS (EI): 151.0 (M ⁺ ), 136.0 ([M-CH ₃ ] ⁺ ).

Step B: N- (2-tert-butyl-pyrimidin-4-yl) -3,4-dichloro-benzenesulfonamide

The material was prepared from a white foam (0.134) from 2-3-butyl-pyrimidin-4-ylamine (0.15 g) and 3,3-dichloro-benzenesulfonyl chloride (0.244 g) similar to step B of Example 13. obtained as g). MS (ESI ⁻ ): 357.9 ([MH] ⁻ ).

Example 31 N- (tert-butyl-pyrimidin-4-yl) -5-fluoro-2-methyl-benzenesulfonamide

Similar to Example 30, this material was prepared in light brown foam with 2-3-butyl-pyrimidin-4-ylamine (0.15 g) and 5-fluoro-2-methyl-benzenesulfonyl chloride (0.21 g). 118 mg). MS (ESI ⁻ ): 322.2 ([MH] ⁻ ).

Example 32: Naphthalene-2-sulfonic acid (tert-butyl-pyrimidin-4-yl) -amide

This material is obtained as light yellow foam (141 mg) from 2-3-butyl-pyrimidin-4-ylamine (0.15 g) and naphthalene-2-sulfonyl chloride (0.23 g) similarly to Example 30. ^{MS (ESI -): 340.1 (} [MH] -).

Example 33 N- (2-tert-butyl-pyrimidin-4-yl) -2,5-difluoro-benzenesulfonamide

This material was light brown foam (156 mg) from 2-3-butyl-pyrimidin-4-ylamine (0.15 g) and 2,5-difluoro-benzenesulfonyl chloride (0.21 g) similar to Example 30. Obtained as ^{MS (ESI -): 326.2 (} [MH] -).

Example 34 N- (tert-butyl-pyrimidin-4-yl) -4- (1.3-oxazol-5-yl) -benzenesulfonamide

This material is similar to Example 30 from 2-3-butyl-pyrimidin-4-ylamine (0.2 g) and 4- (1.3-oxazol-5-yl) -benzenesulfonyl chloride (0.322 g). Obtained as a white foam (104 mg). MS (ESI ⁻ ): 357.2 ([MH] ⁻ ).

Example 35 3-chloro-N- (2-ethyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide

Step A: 2-ethyl-pyrimidin-4-ylamine

This intermediate is prepared according to an alternative to step A of Example 2, propionamidine hydrochloride [1.45 g, see Synth. Commun. 12 (13), 1982, 989-993 and Tetrahedron Lett. 31 (14), Obtained from propionitrile similarly as described in 1990,1969-1972) and from 2-chloro-acrylonitrile (1.17 mL). 2-ethyl-pyrimidin-4-ylamine is obtained as a light brown solid (0.89 g): ¹ H NMR (δ, DMSO-d ₆ ): 7.96 (d, 1H), 6.68 (br s, 2H), 6.21 (s, 1 H), 2.55 (q, 2 H), 1.18 (t, 3 H).

Step B: 3-Chloro-N- (2-ethyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide

The compound was obtained as colorless solid (86 mg) from 2-ethyl-pyrimidin-4-ylamine (0.25 g) and 3-chloro-2-methyl-benzenesulfonyl chloride (0.55 g) according to step B of Example 2. To obtain. ^{MS (ESI -): 310.0 (} [MH] -).

Example 36: 2,4-dichloro-N (2-ethyl-pyrimidin-4-yl) -6-methyl-benzenesulfonamide

This material was light brown solid (78 mg) from 2-ethyl-pyrimidin-4-ylamine (0.19 g) and 2,4-dichloro-6-methyl-benzenesulfonyl chloride (0.48 g) similar to Example 35. Obtained as MS (ESI): 346.0 (MH < ⁺ & gt ^; ).

Example 37: 4-Chloro-N- (2-ethyl-pyrimidin-4-yl) -2,5-dimethyl-benzenesulfonamide

This material was light brown solid (59 mg) from 2-ethyl-pyrimidin-4-ylamine (0.19 g) and 4-chloro-2,5-dimethyl-benzenesulfonyl chloride (0.423 g) similar to Example 35. Obtained as MS (ESI): 326.1 (MH < ⁺ & gt ^; ).

Example 38: 3-Chloro-N- (2-cyclobutyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide

Step A: 2-cyclobutyl-pyrimidin-4-ylamine

This intermediate was prepared from cyclobutanecarboxamidine hydrochloride [0.3 g, according to Step A of Example 2, from Synth. Commun. 12 (13), 1982, 989-993 and Tetrahedron Lett. 31 (cyclobutanecarbonyl). 14), 1990, 1969-1972) and from 3-ethoxy-acrylonitrile (0.3 g). 2-Cyclobutyl-pyrimidin-4-ylamine is obtained as a light brown solid (0.26 g): ¹ H NMR (δ, DMSO-d ₆ ): 7.98 (d, 1H), 6.66 (br s, 2H ), 6.21 (s, 1H), 3.35-3-37 (m, 1H), 2.33-2.23 (m, 2H), 2.19-2.12 (m, 2H), 1.99-1.88 (m, 1H), 1.82-1.74 (m, 1 H).

Step B: 3-Chloro-N (2-cyclobutyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide

The compound was light brown solid (47) from 2-cyclobutyl-pyrimidin-4-ylamine (0.15 g) and 3-chloro-2-methyl-benzenesulfonyl chloride (0.27 g) according to step B of Example 2. mg). MS (ESI): 338.1 (MH < ⁺ & gt ^; ).

Example 39: Naphthalene-2-sulfonic acid (2-cyclobutyl-pyrimidin-4-yl) -amide

This material is obtained as orange solid (53 mg) from 2-cyclobutyl-pyrimidin-4-ylamine (0.19 g) and naphthalene-2-sulfonyl chloride (0.27 g) similarly to Example 38. MS (ESI ⁻ ): 338.3 ([M ⁻ H] ⁻ ).

Example 40 5-Pyridin-2-yl-thiophene-2-sulfonic acid (2-cyclobutyl-pyrimidin-4-yl) -amide

This material was light brown solid from 2-cyclobutyl-pyrimidin-4-ylamine (0.25 g) and 5-pyridin-2-yl-thiophene-2-sulfonyl chloride (0.47 g) similar to Example 38. Obtained as (36 mg). MS (ESI): 373.1 (MH < ⁺ & gt ^; ).

Example 41: 2,4-dichloro-N- (2-cyclobutyl-pyrimidin-4-yl) -6-methyl-benzenesulfonamide

This material was light brown solid (36 mg) from 2-cyclobutyl-pyrimidin-4-ylamine (0.144 g) and 2,4-dichloro-6-methyl-benzenesulfonyl chloride (0.3 g) similar to Example 38. Obtained as MS (ESI): 372.1 (MH < ⁺ & gt ^; ).

Example 42: 3,4-dichloro-N- (2-methoxymethyl-pyrimidin-4-yl) -benzenesulfonamide

Step A: 2-methoxymethyl-pyrimidin-4-ylamine

2-methoxymethyl-pyrimidin-4-ylamine, which is described in patent document BE641253 (1964) of Ciba Ltd., is known according to an alternative to step A of Example 2 -Methoxy-acetamidine hydrochloride [0.3 g, similar to that described in Synth. Commun. 12 (13), 1982, 989-993 and Tetrahedron Lett. 31 (14), 1990, 1969-1972). Obtained from 2-methoxyacetonitrile] and 2-chloro-acetonitrile (0.2 mL). 2-methoxymethyl-pyrimidin-4-ylamine is obtained as off-white solid (0.11 g): ¹ H NMR (δ, CDC1 ₃ ): 8.22 (d, 1H), 6.32 (d, 1H), 4.98 ( br s, 2H), 4.49 (s, 2H), 3.50 (s, 3H). MS (ESI): 140.3 (MH < ⁺ & gt ^; ).

Step B: 3,4-Dichloro-N- (2-methoxymethyl-pyrimidin-4-yl) -benzenesulfonamide

This compound was obtained as a pale yellow solid (10 mg) from 2-methoxymethyl-pyrimidin-4-ylamine (50 mg) and 3,4-dichlorobenzenesulfonyl chloride (111 mg) similar to step B of Example 2. do. MS (ESI): 348.3 (MH < ⁺ & gt ^; ).

Example 43: 3-Chloro-N- (2-cyclopropylmethoxymethyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide

Step A: 2-cyclopropylmethoxymethyl-pyrimidin-4-ylamine

Hydroxymethylcyclopropane (0.17 g) is dissolved in THF (2 mL) and sodium hydride dispersion (55% in oil, 0.1 g) is added at 0 ° C. After the mixture was stirred for 30 minutes, 2-chloromethyl-pyrimidin-4-ylamine (0.2 g, EP 61318 A2 (1982); EP 60094 A2 in THF (7 mL); (1982) is added dropwise. The resulting mixture is heated to reflux for 2 hours, cooled and water is added. The mixture is extracted with ethyl acetate and the organic layers combined, then dried over Na ₂ S0 ₄ , filtered and evaporated. The residue is purified by flash chromatography (ethyl acetate / methanol 9: 1) to give 2-cyclopropylmethoxymethyl-pyrimidin-4-ylamine as a colorless solid (54 mg). ¹ H NMR (δ, CDCl ₃ ): 8.22 (d, 1H), 6.32 (d, 1H), 4.98 (br s, 2H), 4.58 (s, 2H), 3.46 (d, 2H), 1.21-1.12 ( m, 1H), 0.59-0.53 (m, 2H), 0.27-0.24 (m, 2H). MS (ESI): 180.3 (MH < ⁺ & gt ^; ).

Step B: 3-Chloro-N- (2-cyclopropylmethoxymethyl-pyrimidin-4-yl) -2-methyl- benzenesulfonamide

The compound was light yellow solid from 2-cyclopropylmethoxymethyl-pyrimidin-4-ylamine (54 mg) and 2-chloro-3-methyl-benzenesulfonyl chloride (81 mg) similar to step B of Example 2. Obtained as (13 mg). MS (ESI): 368.0 (MH < ⁺ & gt ^; ).

Example 44 3-Chloro-2-methyl-N- (2-morpholin-4-ylmethyl-pyrimidin-4-yl) -benzenesulfonamide

Step A: 2-Morpholin-4-ylmethyl-pyrimidin-4-ylamine

According to a procedure known from J. Chem. Soc. Perkin. Trans. I, 1996, 2925, 2-chloromethyl-pyrimidin-4-ylamine (0.35 g, EP 61318 A2 No. 1982; EP 60094 A2 (1982) is dissolved in ethanol (10 mL) and triethylamine (0.51 mL) and morpholine (0.21 mL) are added. The mixture is heated to reflux for 48 hours, then cooled and evaporated in vacuo. The residue is dissolved in ethyl acetate and washed with 3N NaOH saturated with NaCl. The aqueous layer is reextracted 5 times with ethyl acetate and the combined organic layers are dried over Na ₂ S0 ₄ , filtered and evaporated. Flash chromatography (ethyl acetate / methanol 8: 2) affords the desired product 2-morpholin-4-ylmethyl-pyrimidin-4-ylamine as a light brown solid (0.23 g). ¹ H NMR (δ, DMSO-d ₆ ): 7.99 (d, 1H), 6.79 (br s, 2H), 6.28 (d, 1H), 3.56-3.53 (m, 4H, 3.36 (s, 2H), 2.46 -2.43 (m, 4H) .MS (ESI): 194.9 (MH ⁺ ).

Step B: 3-Chloro-2-methyl-N- (2-morpholin-4-ylmethyl-pyrimidin-4-yl) -benzenesulfonamide

The compound was purified from 2-morpholin-4-ylmethyl-pyrimidin-4-ylamine (230 mg) and 2-chloro-3-methyl-benzenesulfonyl chloride (319 mg) similarly to step B of Example 2. Obtained as a yellow solid (65 mg). MS (ESI): 383.1 (MH < ⁺ & gt ^; ).

Example 45: Naphthalene-2-sulfonic acid (2,6-dimethyl-pyrimidin-4-yl) -amide

This material was obtained as white foam (119 mg) from 2,6-dimethyl-pyrimidin-4-ylamine (0.1 g, commercially available) and naphthalene-2-sulfonyl chloride (0.185 g) similarly to Example 1. do. MS (ESI ⁻ ): 312.0 ([MH] ⁻ ).

Example 46: 3-Chloro-N- (2-cyclopropyl-pyrimidin-4-yl) -2-N-dimethyl-benzenesulfonamide

3-Chloro-N- (2-cyclopropyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide (80 mg, Example 2) was dissolved in DMF (2 mL) at room temperature under argon and cesium carbonate (121 mg) is added. After 20 minutes, methyl iodide (46 mg, 0.02 mL) is added dropwise and the resulting mixture is stirred for 2 hours. The reaction mixture is poured into iced water saturated with NaCl and the product is extracted with ethyl acetate. The organic layer is washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by flash chromatography (gradient of ethyl acetate in heptanes), dried in vacuo and then 3-chloro-N- (2-cyclopropyl-pyrimidin-4-yl) -2-N-dimethyl- Benzenesulfonamide is obtained as the main product (50 mg, colorless oil). MS (ESI): 338.1 (MH < ⁺ & gt ^; ).

As a byproduct of the reaction, 3-chloro-N- [2-cyclopropyl-3-methyl-3H-pyrimidine- (4E) -ylidene] -2-methyl-benzenesulfonamide was also added as a white foam (11 mg). Separate. MS (ESI): 338.0 (MH < ⁺ & gt ^; ).

Example 47 3,4-dichloro-N- (2-isopropyl-pyrimidin-4-yl) -N-methyl- benzenesulfonamide

This material was similar to Example 46 cesium carbonate in DMF (2 mL) from 3,4-dichloro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide (76 mg, Example 14). (107 mg) and methyl iodide (40 mg). 3,4-Dichloro-N- (2-isopropyl-pyrimidin-4-yl) -N-methyl-benzenesulfonamide is obtained as a colorless oil (55 mg). MS (ESI): 360.1 (MH < ⁺ & gt ^; ).

Example 48: 3-chloro-2-methyl-N- (2-phenyl-pyrimidin-4-yl) -benzenesulfonamide

This material is similar to Example 1 according to 2-phenyl-pyrimidin-4-ylamine [134 mg, according to Singh and Lesher, J. of Heterocyclic Chem. 1977, 14 (8), 1413-1414. Prepared as described in Step A of Example 2] and 2-chloro-3-methyl-benzenesulfonyl chloride (194 mg) are obtained as a colorless solid (60 mg). MS (ESI): 360.3 (MH < ⁺ & gt ^; ).

Example 49: 3-Chloro-2-methyl-N- [2- (2-methyl-thiazol-4-yl) -pyrimidin-4-yl] -benzenesulfonamide

Step A: 2- (2-Methyl-thiazol-4-yl) -pyrimidin-4-ylamine

This material was prepared from 2-ethyl-thiazole-4-carboxamidine hydrochloride (3 g) as described in step A of Example 2 with sodium ethoxide (3.13 mL of 5.4 M solution) and 3-ethoxyacrylonitrile. Treatment with (1.73 mL) yields 2- (2-ethyl-thiazol-4-yl) -pyrimidin-4-yl amine (2.56 g) as a brown solid. MS (ESI): 193.3 (MH < ⁺ & gt ^; ).

Step B: 3-Chloro-2-methyl-N- [2- (2-methyl-thiazol-4-yl) -pyrimidin-4-yl] -benzenesulfonamide

This material is similar to Example 1 2- (2-methyl-thiazol-4-yl) -pyrimidin-4-ylamine (179 mg) and 2-chloro-3-methyl-benzenesulfonyl chloride (200 mg) Obtained as a pale yellow foam (54 mg). MS (ESI ⁻ ): 379.0 ([MH] ⁻ ).

Example 50: 3-Chloro-N- (2-methoxymethyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide

This material is similar to Step B of Example 42, 2-methoxymethyl-pyrimidin-4-ylamine (obtained in Step A of Example 42, 50 mg) and 3-chloro-2-methyl-benzenesulfonyl Obtained as a pale yellow solid (11 mg) from chloride (97 mg). MS (ESI): 328.1 (MH < ⁺ & gt ^; ).

Example 51: Naphthalene-2-sulfonic acid (2,5,6-trimethyl-pyrimidin-4-yl) -amide

Step A: 2,5,6-trimethyl-pyrimidin-4-ylamine

4-chloro-2,5,6-trimethyl-pyrimidine [143 g, CAS 34916-70-6, see Curd, R., J. Chem. Soc. (1946), 362, 365)] Treat with 100% NH ₃ (900 g) for 6 hours at < RTI ID = 0.0 > The reaction mixture is cooled down and evaporated. The residue is dissolved in water (200 mL) and extracted with CHCl ₃ . The organic layer is separated and the aqueous phase is saturated with Na ₂ CO ₃ . The aqueous solution is extracted four times with more CHCl ₃ and the combined organic extracts are evaporated to give 30 g of residue. The residue is dissolved in ethyl acetate and precipitated with petroleum ether. The solid is filtered and dried to afford 17 g of 2,5,6-trimethyl-pyrimidin-4-ylamine. Melting point: 187 ° C.

Step B: Naphthalene-2-sulfonic acid (2,5,6-trimethyl-pyrimidin-4-yl) -amide

This material was obtained in low yield as light brown foam (8 mg) from 2,5,6-trimethyl-pyrimidin-4-ylamine (100 mg) and naphthalene-2-sulfonyl chloride (165 mg) similarly to Example 1. do. MS (ESI ⁻ ): 326.3 ((MH) ⁻ ).

Example 52: 4,5-Dichloro-2-fluoro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide

This material is similar to Example 13 as orange powder (107 mg) from 2-isopropyl-pyrimidin-4-ylamine (200 mg) and 4,5-dichloro-2-fluoro-benzenesulfonyl chloride (384 mg). To obtain. MS (ESI ⁻ ): 362.0 ((MH) ⁻ ).

Example 53: 2,4-difluoro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide

This material is obtained as yellow powder (68 mg) from 2-isopropyl-pyrimidin-4-ylamine (200 mg) and 2,4-difluoro-benzenesulfonyl chloride (300 mg) similarly to Example 13. MS (ESI ⁻ ): 312.0 ((MH) ⁻ ).

Example 54: 2-Chloro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide

This material is obtained as light yellow foam (127 mg) from 2-isopropyl-pyrimidin-4-ylamine (200 mg) and 2-chloro-benzenesulfonyl chloride (308 mg) similarly to Example 13. MS (ESI ⁻ ): 310.0 ((MH) ⁻ ).

Example 55 4-chloro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide

This material is obtained as light yellow foam (127 mg) from 2-isopropyl-pyrimidin-4-ylamine (200 mg) and 4-chloro-benzenesulfonyl chloride (308 mg) similarly to Example 13. MS (ESI ⁻ ): 310.0 ((MH) ⁻ ).

Example 56: 3-Chloro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide

This material is obtained as light yellow foam (175 mg) from 2-isopropyl-pyrimidin-4-ylamine (200 mg) and 3-chloro-benzenesulfonyl chloride (308 mg) similarly to Example 13. MS (ESI ⁻ ): 310.0 ((M ⁻ H) ⁻ ).

Example 57: 2,4-dichloro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide

This material is obtained as orange powder (163 mg) from 2-isopropyl-pyrimidin-4-ylamine (200 mg) and 2,4-dichloro-benzenesulfonyl chloride (358 mg) similarly to Example 13. MS (ESI ⁻ ): 344.0 ((M ⁻ H) ⁻ ).

Example 58: 2,4-dichloro-N- (2-isopropyl-pyrimidin-4-yl) -5-methyl-benzenesulfonamide

This material was obtained as orange powder (194 mg) from 2-isopropyl-pyrimidin-4-ylamine (200 mg) and 2,4-dichloro-5-methyl-benzenesulfonyl chloride (378 mg) similarly to Example 13. do. MS (ESI ⁻ ): 358.0 ((MH) ⁻ ).

Example 59: 2,5-dichloro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide

This material is obtained as orange powder (160 mg) from 2-isopropyl-pyrimidin-4-ylamine (200 mg) and 2,5-dichloro-benzenesulfonyl chloride (358 mg) similarly to Example 13. MS (ESI ⁻ ): 344.0 ((MH) ⁻ ).

Example 60 3-Bromo-5-chloro-thiophene-2-sulfonic acid (2-isopropyl-pyrimidin-4-yl) -amide

This material is similar to Example 13 in orange powder (12 mg) from 2-isopropyl-pyrimidin-4-ylamine (200 mg) and 3-bromo-5-chloro-thiophene-2-sulfonyl chloride (431 mg). As a low yield. MS (ESI ⁻ ): 393.8 ((MH) ⁻ ).

Example 61 2,4-Dichloro-N- (2-cyclopropyl-pyrimidin-4-yl) -6-methyl-benzenesulfonamide

This material is similar to Example 2 as a light brown solid (75 mg) from 2-cyclopropyl-pyrimidin-4-ylamine (190 mg) and 2,4-dichloro-6-methyl-benzenesulfonyl chloride (438 mg). To obtain. MS (ESI): 358.1 (MH < ⁺ & gt ^; ).

Example 62: 4-Chloro-N- (2-cyclopropyl-pyrimidin-4-yl) -2,5-dimethyl-benzenesulfonamide

This material was obtained as light brown solid (73 mg) from 2-cyclopropyl-pyrimidin-4-ylamine (190 mg) and 4-chloro-2,5-dimethylbenzenesulfonyl chloride (403 mg) similarly to Example 2. do. MS (ESI): 338.0 (MH < ⁺ & gt ^; ).

Example 63 N- (2-cyclopropyl-pyrimidin-4-yl) -2,4-dimethoxy-benzenesulfonamide

This material is obtained in low yield as a colorless solid (13 mg) from 2-cyclopropylpyrimidin-4-ylamine (150 mg) and 2,4-dimethoxy-benzenesulfonyl chloride (315 mg) similarly to Example 2. . MS (ESI ⁻ ): 334.1 ((MH) ⁻ ).

Example 64 3-chloro-N- (2-cyclopentyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide

Step A: 2-cyclopentyl-pyrimidin-4-ylamine

The material was obtained as amorphous glass (142 mg) from cyclopentanecarboxamidine hydrochloride (CAS 68284-02-6) (500 mg) and 2-chloroacrylonitrile (324 mg) according to an alternative to step A of Example 2. To obtain. MS (ESI): 164.6 (MH ⁺ ). The substance is contaminated with several byproducts that cannot be identified.

Step B: 3-Chloro-N- (2-cyclopentyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide

This material was light brown solid (75 mg) from 2-cyclopentyl-pyrimidin-4-ylamine (158 mg) and 3-chloro-2-methyl-benzenesulfonyl chloride (261 mg) similar to step B of Example 2. Obtained as MS (ESI): 352.4 (MH < ⁺ & gt ^; ).

Example 65 5-phenyl-thiophene-2-sulfonic acid (2-cyclopropyl-pyrimidin-4-yl) -amide

This material is similar to Example 2 with 2-cyclopropyl-pyrimidin-4-ylamine (100 mg) and 5-phenyl-thiophene-2-sulfonyl chloride [203 mg, CAS 97272-02-1, see references. : Prepared according to Sone et al., Bull. Chem. Soc. J. (1985), 58 (3), 1063) as a colorless solid (33 mg). MS (ESI ⁻ ): 356.3 ((MH) ⁻ ).

Example 66: 3-Chloro-N- (2-cyclopropylmethoxy-pyrimidin-4-yl) -2-methyl-benzenesulfonamide

Step A: 2-cyclopropylmethoxy-pyrimidin-4-ylamine

Cyclopropylmethanol (724 mg) is dissolved in DMF (4 mL) and treated with sodium hydride (401 mg, 60% in mineral oil) at 0 ° C. for 30 minutes. Then according to 4-amino-2-chloro-pyrimidine [260 mg, CAS 7461-50-9 or in J. Am. Chem. Soc. 1930, 52, 1152-1157) in DMF (4 mL). Manufacture]. The mixture is stirred at room temperature for 1 hour and then at 50 ° C. overnight. The mixture is poured into water and saturated with NaCl. The aqueous solution is extracted with ethyl acetate and the organic layer is washed with brine, then dried over Na ₂ SO ₄ and evaporated to dryness. The residue is purified by flash chromatography using a gradient of ethyl acetate in heptane as eluent. The desired product is obtained as a pale yellow oil (169 mg). MS (El): 166.2 (M + H ⁺ ).

Step B: 3-Chloro-N- (2-cyclopropylmethoxy-pyrimidin-4-yl) -2-methyl-benzenesulfonamide

This material is similar to Example 1 as light yellow foam (14 mg) from 2-cyclopropylmethoxy-pyrimidin-4-ylamine (220 mg) and 3-chloro-2-methyl-benzenesulfonyl chloride (161 mg). Obtained in low yields. MS (ESI ⁻ ): 352.1 ((MH) ⁻ ).

Example 67: 2-[(3,4-Dichloro-benzenesulfonyl)-(2-isopropyl-pyrimidin-4-yl) -amino] -N, N-dimethyl-acetamide

3,4-Dichloro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide (80 mg, Example 14) is dissolved in DMF (1 mL) and treated with cesium carbonate (113 mg). . 2-Chloro-N, N-dimethylacetamide (37 mg) is added to the mixture, and the resulting suspension is stirred at room temperature for 49 hours and then at 80 ° C. for 24 hours. The mixture is diluted with ethyl acetate, washed with brine, dried over Na ₂ SO ₄ and evaporated to dryness. The residue is purified by flash chromatography on silica gel using DCM / MeOH / NH ₄ 0H (9: 1: 0.1) as eluent. The desired product is obtained as a colorless glass (28 mg). MS (ESI): 431.3 (MH < ⁺ & gt ^; ).

Example 68 N-benzyl-3-chloro-N- (2-cyclopropyl-pyrimidin-4-yl) -2-methyl- benzenesulfonamide

This material is similar to Example 67, using benzyl chloride (61 mg) as alkylating agent, 3-chloro-N- (2-cyclopropyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide (120 mg, Obtained from Example 2). The desired material is obtained as a colorless oil (74 mg). MS (EI): 414.1 (M + H ⁺ ).

Example 69 3-chloro-N-cyclopropylmethyl-N- (2-cyclopropyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide

This material was prepared in the same manner as in Example 67 using 3-chloro-N- (2-cyclopropyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide using bromomethyl-cyclopropane (65 mg) as the alkylating agent. Obtained from (120 mg, Example 2). The desired material is obtained as a colorless oil (89 mg). MS (EI): 377 (M ⁺ ), 378.3 (M + H ⁺ ).

Example 70: 3-Chloro-2-methyl-N- (6-phenyl-pyrimidin-4-yl) -benzenesulfonamide

This material was light yellow foam from 6-phenyl-pyrimidin-4-ylamine (97 mg, CAS 3435-29-8) and 3-chloro-2-methyl-benzenesulfonyl chloride (128 mg) similar to Example 1. Obtained as (67 mg). MS (ESI ⁻ ): 358.0 ((MH) ⁻ ).

Example A

The compounds of formula (I) can be used in a manner known per se as the active ingredient for preparing tablets of the following composition:

Example  B

The compounds of formula (I) can be used in a manner known per se as the active ingredient for preparing capsules of the following composition:

Claims (26)

A compound of formula (I) or a pharmaceutically acceptable salt thereof: Formula I

Where R ¹ is C _1-6 alkyl, C _3-8 cycloalkyl, C _3-6 cycloalkyl-C _1-3 alkoxy, C _1-3 alkoxy-C _1-3 alkyl, C _3-6 cycloalkyl-C _{1 -3} alkoxy-C _1-3 alkyl, thiazolyl, morpholinyl-C _1-3 alkyl or phenyl; R ² is hydrogen, C _1-3 alkyl or phenyl; R ³ is hydrogen or C _1-3 alkyl; R ⁴ is phenyl, naphthyl, thiophenyl, quinolyl optionally substituted with one or more substituents independently selected from C _1-3 alkyl, halogen, C _1-3 alkoxy, trifluoromethyl, phenyl, oxazolyl and pyridinyl Or piperidyl; R ⁵ is hydrogen, C _1-3 alkyl, benzyl, C _3-6 cycloalkyl-C _1-3 alkyl or aminocarbonyl-C _1-3 alkyl; Provided that N- (2,6-dimethyl-4-pyrimidinyl) -benzenesulfonamide, 2-chloro-N- (2-methyl-4-pyrimidinyl) -p-toluenesulfonamide and 2,4, 5-trichloro-N- (2,6-dimethyl-4-pyrimidinyl) -benzenesulfonamide is excluded. The method of claim 1, R ¹ is C _1-6 alkyl, C _3-8 cycloalkyl, C _1-3 alkoxy-C _1-3 alkyl, C _3-6 cycloalkyl-C _1-3 alkoxy-C _1-3 alkyl, thiazolyl, Morpholinyl-C _1-3 alkyl or phenyl; R ² is hydrogen or C _1-3 alkyl; R ³ is hydrogen or C _1-3 alkyl; R ⁵ is hydrogen or C _1-3 alkyl. The method of claim 1, R ¹ is C _1-6 alkyl, C _3-8 cycloalkyl, C _1-3 alkoxy-C _1-3 alkyl, C _3-6 cycloalkyl-C _1-3 alkoxy-C _1-3 alkyl, thiazolyl, Morpholinyl-C _1-3 alkyl or phenyl. The method according to claim 1 or 2, R ¹ is methyl, ethyl, cyclopropyl, cyclobutyl, isopropyl, tert-butyl, methoxymethyl, cyclopropylmethoxymethyl, 2-methyl-thiazolyl, morpholinylmethyl or phenyl. The method according to claim 1 or 2, R ² is hydrogen. The method according to claim 1 or 2, R ² is methyl. The method according to claim 1 or 2, R ³ is hydrogen. The method according to claim 1 or 2, R ⁵ is hydrogen. The method according to claim 1 or 2, R ⁵ is methyl. delete The method according to claim 1 or 2, R ⁴ is phenyl substituted with one or more substituents independently selected from C _1-3 alkyl, halogen, C _1-3 alkoxy, trifluoromethyl, phenyl and oxazolyl. The method according to claim 1 or 2, R ⁴ is phenyl, naphthyl, quinolyl or piperidyl. The method according to claim 1 or 2, R ⁴ is thiophenyl optionally substituted with one or more substituents independently selected from C _1-3 alkyl, halogen, C _1-3 alkoxy, trifluoromethyl, phenyl, oxazolyl and pyridinyl. The method according to claim 1 or 2, 3-chloro-2-methyl-N- (2-methyl-pyrimidin-4-yl) -benzenesulfonamide, 3-chloro-N- (2-cyclopropyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide, N- (2-cyclopropyl-pyrimidin-4-yl) -2,5-difluoro-benzenesulfonamide, Naphthalene-2-sulfonic acid (2-cyclopropyl-pyrimidin-4-yl) -amide, Biphenyl-4-sulfonic acid (2-cyclopropyl-pyrimidin-4-yl) -amide, Quinoline-8-sulfonic acid (2-cyclopropyl-pyrimidin-4-yl) -amide, N- (2-cyclopropyl-pyrimidin-4-yl) -benzenesunponamide, N- (2-cyclopropyl-pyrimidin-4-yl) -5-fluoro-2-methyl-benzenesulfonamide, N- (2-cyclopropyl-pyrimidin-4-yl) -3-methoxy-benzenesulfonamide, N- (2-cyclopropyl-pyrimidin-4-yl) -2-methoxy-5-methyl-benzenesulfonamide, 3-chloro-N- (2-cyclopropyl-pyrimidin-4-yl) -4-methoxy-benzenesulfonamide, 5-chloro-N- (2-cyclopropyl-pyrimidin-4-yl) -2-methoxy-benzenesulfonamide, 5-fluoro-N- (2-isopropyl-pyrimidin-4-yl) -2-methyl-benzenesunponamide, 3,4-dichloro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide, N- (2-isopropyl-pyrimidin-4-yl) -4- (1.3-oxazol-5-yl) -benzenesulfonamide, 2,4-dichloro-N- (2-isopropyl-pyrimidin-4-yl) -6-methyl-benzenesulfonamide, 2,3-dichloro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide, 4,5-dichloro-thiophene-2-sulfonic acid (2-isopropyl-pyrimidin-4-yl) -amide, 5-Pyridin-2-yl-thiophene-2-sulfonic acid (2-isopropyl-pyrimidin-4-yl) -amide, 3-chloro-N- (2-isopropyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide, N- (2-isopropyl-pyrimidin-4-yl) -3-trifluoromethyl-benzenesulfonamide, N- (2-isopropyl-pyrimidin-4-yl) -2-trifluoromethyl-benzenesulfonamide, 5-Chloro-thiophene-2-sulfonic acid (2-isopropyl-pyrimidin-4-yl) -amide, N- (2-isopropyl-pyrimidin-4-yl) -4-trifluoromethyl-benzenesulfonamide, Piperidine-1-sulfonic acid (2-isopropyl-pyrimidin-4-yl) -amide, Naphthalene-2-sulfonic acid (2-isopropyl-pyrimidin-4-yl) -amide, Biphenyl-4-sulfonic acid (2-isopropyl-pyrimidin-4-yl) -amide, 2,5-difluoro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide, N- (2-isopropyl-pyrimidin-4-yl) -3,4-dimethoxy-benzenesulfonamide, N- (2-tert-butyl-pyrimidin-4-yl) -3,4-dichloro-benzenesulfonamide, N- (2-tert-butyl-pyrimidin-4-yl) -5-fluoro-2-methyl-benzenesulfonamide, Naphthalene-2-sulfonic acid (2-tert-butyl-pyrimidin-4-yl) -amide, N- (2-tert-butyl-pyrimidin-4-yl) -2,5-difluoro-benzenesulfonamide, N- (2-tert-butyl-pyrimidin-4-yl) -4- (1.3-oxazol-5-yl) -benzenesulfonamide, 3-chloro-N- (2-ethyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide, 2,4-dichloro-N- (2-ethyl-pyrimidin-4-yl) -6-methyl-benzenesulfonamide, 4-chloro-N- (2-ethyl-pyrimidin-4-yl) -2,5-dimethyl-benzenesulfonamide, 3-chloro-N- (2-cyclobutyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide, Naphthalene-2-sulfonic acid (2-cyclobutyl-pyrimidin-4-yl) -amide, 5-Pyridin-2-yl-thiophene-2-sulfonic acid (2-cyclobutyl-pyrimidin-4-yl) -amide, 2,4-dichloro-N- (2-cyclobutyl-pyrimidin-4-yl) -6-methyl-benzenesulfonamide, 3,4-dichloro-N- (2-methoxymethyl-pyrimidin-4-yl) -benzenesulfonamide, 3-chloro-N- (2-cyclopropylmethoxymethyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide, 3-chloro-2-methyl-N- (2-morpholin-4-ylmethyl-pyrimidin-4-yl) -benzenesulfonamide, Naphthalene-2-sulfonic acid (2,6-dimethyl-pyrimidin-4-yl) -amide, 3-chloro-N- (2-cyclopropyl-pyrimidin-4-yl) -2-N-dimethyl-benzenesulfonamide, 3,4-dichloro-N- (2-isopropyl-pyrimidin-4-yl) -N-methyl-benzenesulfonamide, 3-chloro-2-methyl-N- (2-phenyl-pyrimidin-4-yl) -benzenesulfonamide and 3-chloro-2-methyl-N- [2- (2-methyl-thiazol-4-yl) -pyrimidin-4-yl] -benzenesulfonamide Compound selected from the group consisting of. The method according to claim 1 or 2, 3-chloro-N- (2-methoxymethyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide, Naphthalene-2-sulfonic acid (2,5,6-trimethyl-pyrimidin-4-yl) -amide, 4,5-dichloro-2-fluoro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide, 2,4-difluoro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide, 2-chloro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide, 4-chloro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide, 3-chloro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide, 2,4-dichloro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide, 2,4-dichloro-N- (2-isopropyl-pyrimidin-4-yl) -5-methyl-benzenesulfonamide, 2,5-dichloro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide, 3-bromo-5-chloro-thiophen-2-sulfonic acid (2-isopropyl-pyrimidin-4-yl) -amide, 2,4-dichloro-N- (2-cyclopropyl-pyrimidin-4-yl) -6-methyl-benzenesulfonamide, 4-chloro-N- (2-cyclopropyl-pyrimidin-4-yl) -2,5-dimethyl-benzenesulfonamide, N- (2-cyclopropyl-pyrimidin-4-yl) -2,4-dimethoxy-benzenesulfonamide, 3-chloro-N- (2-cyclopentyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide, 5-phenyl-thiophene-2-sulfonic acid (2-cyclopropyl-pyrimidin-4-yl) -amide, 3-chloro-N- (2-cyclopropylmethoxy-pyrimidin-4-yl) -2-methyl-benzenesulfonamide, 2-[(3,4-dichloro-benzenesulfonyl)-(2-isopropyl-pyrimidin-4-yl) -amino] -N, N-dimethyl-acetamide, N-benzyl-3-chloro-N- (2-cyclopropyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide, 3-Chloro-N-cyclopropylmethyl-N- (2-cyclopropyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide and 3-Chloro-2-methyl-N- (6-phenyl-pyrimidin-4-yl) -benzenesulfonamide Compound selected from the group consisting of. The method according to claim 1 or 2, 3-chloro-2-methyl-N- (2-methyl-pyrimidin-4-yl) -benzenesulfonamide, 3-chloro-N- (2-cyclopropyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide, N- (2-cyclopropyl-pyrimidin-4-yl) -2,5-difluoro-benzenesulfonamide, Naphthalene-2-sulfonic acid (2-cyclopropyl-pyrimidin-4-yl) -amide, Biphenyl-4-sulfonic acid (2-cyclopropyl-pyrimidin-4-yl) -amide, 5-fluoro-N- (2-isopropyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide, 3,4-dichloro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide, N- (2-isopropyl-pyrimidin-4-yl) -4- (1.3-oxazol-5-yl) -benzenesulfonamide, 2,4-dichloro-N- (2-isopropyl-pyrimidin-4-yl) -6-methyl-benzenesulfonamide, 2,3-dichloro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide, 5-Pyridin-2-yl-thiophene-2-sulfonic acid (2-isopropyl-pyrimidin-4-yl) -amide, 3-chloro-N- (2-isopropyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide, N- (2-isopropyl-pyrimidin-4-yl) -3-trifluoromethyl-benzenesulfonamide, N- (2-isopropyl-pyrimidin-4-yl) -2-trifluoromethyl-benzenesulfonamide, 5-Chloro-thiophene-2-sulfonic acid (2-isopropyl-pyrimidin-4-yl) -amide, N- (2-isopropyl-pyrimidin-4-yl) -4-trifluoromethyl-benzenesulfonamide, Naphthalene-2-sulfonic acid (2-isopropyl-pyrimidin-4-yl) -amide, Biphenyl-4-sulfonic acid (2-isopropyl-pyrimidin-4-yl) -amide, 2,5-difluoro-N- (2-isopropyl-pyrimidin-4-yl) -benzenesulfonamide, N- (2-isopropyl-pyrimidin-4-yl) -3,4-dimethoxy-benzenesulfonamide, N- (2-tert-butyl-pyrimidin-4-yl) -4-oxazol-5-yl-benzenesulfonamide, 3-chloro-N- (2-ethyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide, 2,4-dichloro-N- (2-ethyl-pyrimidin-4-yl) -6-methyl-benzenesulfonamide, 3-chloro-N- (2-cyclobutyl-pyrimidin-4-yl) -2-methyl-benzenesulfonamide, Naphthalene-2-sulfonic acid (2-cyclobutyl-pyrimidin-4-yl) -amide, 5-Pyridin-2-yl-thiophene-2-sulfonic acid (2-cyclobutyl-pyrimidin-4-yl) -amide, 2,4-dichloro-N- (2-cyclobutyl-pyrimidin-4-yl) -6-methyl-benzenesulfonamide, 3-chloro-N- (2-cyclopropyl-pyrimidin-4-yl) -2-N-dimethyl-benzenesulfonamide and 3,4-Dichloro-N- (2-isopropyl-pyrimidin-4-yl) -N-methyl-benzenesulfonamide Compound selected from the group consisting of. A process for preparing a compound according to claim 1, comprising reacting a compound of formula A in the presence of a compound of formula B: Formula A

Formula B

Where R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined in claim 1. The method according to claim 1 or 2, Compounds for use as therapeutically active substances. The method according to claim 1 or 2, A compound for the manufacture of a medicament for the prevention and treatment of diseases caused by disorders associated with the enzyme 11β-hydroxysteroid dehydrogenase 1 (11bHSD1). delete A pharmaceutical composition for the treatment and prevention of diabetes, obesity, eating disorders and dyslipidemiae, comprising the compound according to claim 1 or 2 and a therapeutically inert carrier. A pharmaceutical composition for treating and preventing type II diabetes, comprising a compound according to claim 1 or 2 and a therapeutically inert carrier. delete delete delete delete