WO2001081338A1

WO2001081338A1 - Substituted sulfonylaminopyrimidines

Info

Publication number: WO2001081338A1
Application number: PCT/EP2001/004133
Authority: WO
Inventors: Christoph Boss; Martin Bolli; Martine Clozel; Walter Fischli; Thomas Weller
Original assignee: Actelion Pharmaceuticals Ltd
Current assignee: Actelion Pharmaceuticals Ltd
Priority date: 2000-04-25
Filing date: 2001-04-11
Publication date: 2001-11-01
Anticipated expiration: 2002-10-25
Also published as: AU2001265871A1

Abstract

The present invention relates to novel substituted pyrimidines of the general formula I and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of the general formula (I) and especially their use as endothelin receptor antagonists.

Description

SUBSTITUTED SU FONYLAMINOPYRIMIDINES

The present invention relates to novel substituted pyrimidines of the general formula I and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of the general formula I and especially their use as endothelin receptor antagonists.

Endothelins (ET-1 , ET-2, and ET-3) are 21 -amino acid peptides produced and active in almost all tissues (Yanagisawa M et al.: Nature (1988) 332:411. Endothelins are potent vasoconstrictors and important mediators of cardiac, renal, endocrine and immune functions (McMillen MA et al.: J Am Coll Surg (1995) 180:621). They participate in bronchoconstriction and regulate neurotransmitter release, activation of inflammatory cells, fibrosis, cell proliferation and cell differentiation (Rubanyi GM et al.: Pharmacol Rev (1994) 46:328).

Two endothelin receptors have been cloned and characterized in mammals (ET_A, ET_B) (Arai H et al.: Nature (1990) 348:730; Sakurai T et al.: Nature (1990) 348:732). The ET_A receptor is characterized by higher affinity for ET-1 and ET-2 than for ET-3. It is predominant in vascular smooth muscle cells and mediates vasoconstricting and proliferative responses (Ohlstein EH et al.: Drug Dev Res (1993) 29:108). In contrast, the ET_B receptor has equivalent affinity for the 3 endothelin isopeptides and binds the linear form of endothelin, tetra-ala-endothelin, and sarafotoxin S6C (Ogawa Y et al.: BBRC (1991) 178:248). This receptor is located in the vascular endothelium and smooth muscles, and is also particularly abundant in lung and brain. The ET_B receptor from endothelial cells mediates transient vasodilator responses to ET-1 and ET-3 through the release of nitric oxide and/or prostacyclin whereas the ETB receptor from smooth muscle cells exerts vasoconstricting actions (Sumner MJ et al.: Brit J Pharmacol (1992) 107:858). ET_A and ET_B receptors are highly similar in structure and belong to the superfamily of G-protein coupled receptors.

A pathophysiological role has been suggested for ET-1 in view of its increased plasma and tissue levels in several disease states such as hypertension, sepsis, atherosclerosis, acute myocardial infarction, congestive heart failure, renal failure, migraine and asthma. As a consequence, endothelin receptor antagonists have been studied extensively as potential therapeutic agents. Endothelin receptor antagonists have demonstrated preclinical and/or clinical efficacy in various diseases such as cerebral vasospasm following subarachnoid hemorrhage, heart failure, pulmonary and systemic hypertension, neurogenic inflammation, renal failure and myocardial infarction.

Today, no endothelin receptor antagonist is marketed yet, several are in clinical trials. However, these molecules possess a number of weaknesses such as complex synthesis, low solubility, high molecular weight, poor pharmacokinetics or safety problems (e.g. liver enzyme increases). Furthermore, the contribution of differential ET_A / ETB receptor blockade to the clinical outcome is not known. Thus, tailoring of the physicochemical, pharmacokinetic properties and the selectivity profile of each antagonist for a given clinical indication is mandatory. We have discovered a new class of substituted pyrimidines of the structure below and found that they allow the specific tailoring described above.

The inhibitory activity of the compounds of formula 1 on endothelin receptors can be demonstrated using the test procedures described hereinafter: For the evaluation of the potency and efficacy of the compounds of the general formula I the following tests were used:

1) Inhibition of endothelin binding to membranes from CHO cells carrying human ET receptors:

For competition binding studies, membranes of CHO cells expressing human recombinant ET_A or ET_B receptors were used. Microsomal membranes from recombinant CHO cells were prepared and the binding assay made as previously described (Breu et al, FEBS Lett 1993; 334:210).

The assay was performed in 200 uL 50 mM Tris/HCI buffer, pH 7.4, including 25 mM MnCI₂, 1 mM EDTA and 0.5% (w/v) BSA in polypropylene microtiter plates. Membranes containing 0.5 ug protein were incubated for 2 h at 20°C with 8 pM [¹²⁵I]ET-1 (4000 cpm) and increasing concentrations of unlabelled antagonists. Maximum and minimum binding were estimated in samples without and with 100 nM ET-1 , respectively. After 2 h, the membranes were filtered on filterplates containing GF/C filters (Glass Filters Type C, Unifilterplates from Canberra Packard S.A. Zurich, Switzerland). To each well, 50 uL of scintillation cocktail was added (MicroScint 20, Canberra Packard S.A. Zurich, Switzerland) and the filter plates counted in a microplate counter (TopCount, Canberra Packard S.A. Zurich, Switzerland).

All the test compounds were dissolved, diluted and added in DMSO. The assay was run in the presence of 2.5% DMSO which was found not to interfere significantly with the binding. IC₅₀ was calculated as the concentration of antagonist inhibiting 50 % of the specific binding of ET-1. For reference compounds, the following IC₅₀ values were found: ET_A cells: 0.075 nM (n=8) for ET-1 and 118 nM (n=8) for ET-3; ET_B cells: 0.067 nM (n=8) for ET-1 and 0.092 nM (n=3) for ET-3.

The IC₅₀ values obtained with compounds of formula I are given in Table 1. Table 1:

IC₅₀[nM]

Compound of

ET_A ET_B

Example 1 11 37

Example 24 7 33

Example 28 22 58

Example 30 391 100

Example 34 1224 56

Example 37 52 170

Example 42 17 81

Example 51 91 366

Example 53 62 66

Example 64 61 164

Example 65 21 17

Example 66 35 72

Example 67 26 44

Example 68 23 54

Example 73 16 43

Example 77 26 292

Example 81 21 305

Example 82 16 1280

Example 83 6 288

2) Inhibition of endothelin-induced contractions on isolated rat aortic rings (ET_A receptors) and rat tracheal rings (ET_B receptors):

The functional inhibitory potency of the endothelin antagonists was assessed by their inhibition of the contraction induced by endothelin-1 on rat aortic rings (ET_A receptors) and of the contraction induced by sarafotoxin S6C on rat tracheal (ET_B receptors). Adult Wistar rats were anesthetized and exsanguinated. The thoracic aorta or trachea were excised, dissected and cut in 3-5 mm rings. The endothelium/epithelium was removed by gentle rubbing of the intimal surface. Each ring was suspended in a 10 ml isolated organ bath filled with Krebs-Henseleit solution (in mM; NaCI 115, KCl 4.7, MgSO₄ 1.2, KH₂P0₄ 1.5, NaHCO₃ 25, CaCl₂ 2.5, glucose 10) kept at 37°C and gassed with 95% O₂ and 5% CO₂. The rings were connected to force transducers and isometric tension was recorded (EMKA Technologies SA, Paris, France). The rings were stretched to a resting tension of 3 g (aorta) or 2 g (trachea). Cumulative doses of ET-1 (aorta) or sarafotoxin S6C (trachea) were added after a 10 min incubation with the test compound or its vehicle. The functional inhibitory potency of the test compound was assessed by calculating the concentration ratio, i.e. the shift to the right of the EC₅₀ induced by different concentrations of test compound. EC₅₀ is the concentration of endothelin needed to get a half-maximal contraction, pA₂ is the negative value of the logarithm of the antagonist concentration which induces a two-fold shift in the EC₅₀ value.

The pA₂ values obtained with compounds of formula I are given in Table 2.

Table 2:

pA₂

Compound of aortic rings trachea

Example 1 7.20 6.72

Example 24 7.58

Example 66 7.14

Example 82 7.50

Example 83 7.51 Because of their ability to inhibit the endothelin binding, the described compounds can be used for treatment of diseases which are associated with an increase in vasoconstriction, proliferation or inflammation due to endothelin. Examples of such diseases are hypertension, coronary diseases, cardiac insufficiency, renal and myocardial ischemia, renal failure, cerebral ischemia, dementia, migraine, subarachnoidal hemorrhage, Raynaud's syndrome, portal hypertension and pulmonary hypertension. They can also be used for atherosclerosis, prevention of restenosis after balloon or stent angioplasty, inflammation, inflammatory bowel disease, stomach and duodenal ulcer, cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, gram negative septicemia, shock, pain, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, therapy and prophylaxis of diabetic complications, complications of vascular or cardiac surgery or after organ transplantation, complications of cyclosporin treatment, as well as other diseases presently known to be related to endothelin.

The compounds can be administered orally, rectally, parenterally, e.g. intravenously, intramuscularly, subcutaneously, intrathecally or transdermally; or sublingually or as ophthalmic preparation or administered as aerosol. Examples of applications are capsules, tablets, oral administered suspensions or solutions, suppositories, injections, eye-drops, ointments or aerosols/nebulizers.

Preferred applications are intravenous, intra-muscular, eye drops or oral administrations. The dosage used depends upon the type of the specific active ingredient, the age and the requirements of the patient and the kind of application. Generally, dosages of 0.1 - 50 mg / kg body weight per day are considered. The preparations with compounds can contain inert or as well pharmacodynamically active excipients. Tablets or granules, for example, could contain a number of binding agents, filling excipients, carrier substances or diluents. The present invention relates to novel substituted pyrimidines of the general formula I,

general formula 1 wherein

R¹ represents aryl; aryl-lower alkyl; aryl-lower alkenyl; heteroaryl; heteroaryl- lower alkyl;

R² represents hydrogen; halogen; trifluoromethyl; lower alkyl; lower alkyl- amino; lower alkyloxy; lower alkyl-sulfono; lower alkyl-sulfinyl; lower alkylthio; lower alkylthio-lower alkyl; hydroxy-lower alkyl; hydroxy-lower alkyloxy; lower alkyloxy-lower alkyl; lower alkyloxy-lower alkyloxy; hydroxy-lower alkyloxy- lower alkyl; hydroxy-lower alkyloxy-lower alkyloxy; lower alkyloxy-lower alkyloxy-lower alkyloxy; hydroxy-lower alkyl-amino; lower alkyl-amino-lower alkyl; amino; di-lower alkyl-amino; [N-(hydroxy-lower alkyl)-N-(lower alkyl-amino; aryl; aryl-amino; aryl-lower alkyl-amino; aryl-thio; aryl-lower alkyl-thio; aryloxy; aryl-lower alkyl-oxy; aryl-lower alkyl; arylsulfinyl; heteroaryl; heteroaryloxy; heteroaryl-lower alkyl-oxy; heteroarylamino; heteroaryl-lower alkylamino; heteroaryl-lower alkylthio; heteroaryl-lower alkyl; heteroaryl- sulfinyl; heterocyclyl; heterocyclyl-lower alkyloxy; heterocyclyloxy; heterocyclylamino; heterocyclyl-lower alkylamino; heterocyciylthio; heterocyclyl-lower alkylthio; heterocyclyl-lower alkyl; heterocyclylsulfinyl; cycloalkyl; cycloalkyloxy; cycloalkyl-lower alkyloxy; cycloalkylamino; cycloalkyl-lower alkylamino; cycloalkylthio; cycloalkyl-lower alkylthio; cycloalkyl-lower alkyl; cycloalkylsulfinyl; cyano; aminocarbonyl; alkoxycarbonyl; carboxyl;

R³ represents phenyl; mono-, di- or tri-substituted phenyl substituted with lower alkyl, lower alkenyl, lower alkyloxy, amino, lower alkylamino, amino- lower alkyl, trifluoromethyl, trifluoromethoxy, halogen, lower alkylthio, hydroxy, hydroxy-lower alkyl, cyano, carboxyl, lower alkanoyl, formyl; benzofuranyl; aryl; heteroaryl;

X represents oxygen; sulfur; NH; CH₂ or a bond;

R⁴ represents one of the following residues:

wherein

R and R »10 each independently represent hydrogen, or lower alkyl;

R⁶ represents hydrogen, OR⁷, or NR⁸R⁹;

W represents O, or NR⁵;

Y represents O, NR⁹;

Z represents O, NR⁹, S, SO, or SO₂; R⁷ represents hydrogen; lower alkyl; 2-, 4- or 6-pyrimidinyl optionally mono- or disubstituted with lower alkyl, lower alkoxy, halogen; or a group -CO-NR^aR^b, or -CO-R^b;

R⁸ represents hydrogen, lower alkyl;

R⁹ represents hydrogen, lower alkyl, aryl, aralkyl, or a group -CO-NR^aR^b, or -

CO-R^b;

R^a represents hydrogen, lower alkyl; cycloalkyl, or aryl;

R^b represents lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, aryl or heteroaryl;

m represents the numbers 0 or 1 ; n and q each independently represent the numbers 0, 1 , or 2; and wherein the sum m + n + q is not zero; p represents the numbers 1 , 2, 3, or 4; r and t each independently represent the numbers 1 or 2; s represents the numbers 1, 2, or 3;

and pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the meso-forms and pharmaceutically acceptable salts thereof.

In the definitions of the general formula I - if not otherwise stated - the expression lower alkyl means straight and branched chain groups with one to seven carbon atoms, preferably 1 to 4 carbon atoms. Examples of lower alkyl and lower alkoxy groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert.-butyl, pentyl, hexyl, heptyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec.-butoxy and tert.-butoxy. Lower alkylendioxy-groups are preferably methylen-dioxy, ethylen-dioxy, propylene- dioxy and butylene-dioxy- groups. Examples of lower alkanoyl-groups are acetyl, propanoyl and butanoyl. Lower alkenylen means e.g.vinylen, propenylen and butenylen. Lower alkenyl and lower aikynyl means groups like ethylen, propylen, butylen, 2-methyl-propenyl, and ethinylen, propinylen, butinylen, pentinylen, 2-methyl-pentinylen etc. Lower alkenyloxy means allyloxy, vinyloxy, propenyloxy and the like. Lower alkylenoxy means e.g. ethylenoxy, propylenoxy. The expression cycloalkyl means a saturated cyclic hydrocarbon ring with 3 to 7 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, which may be adequately substituted with lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, lower alkoxy-lower alkyl and lower alkenylen groups. The expression heterocyclyl referes to saturated or unsaturated (but not aromatic) four, five-, six- or seven- membered rings containing one or two nitrogen, oxygen or sulfur atoms which may be the same or different and which rings may be substituted with lower alkyl, amino, lower alkylamino, nitro, hydroxy, lower alkoxy, cyano, aminocarbonyl, alkoxycarbonyl, or carboxyl. Examples of heterocyclyl substituents are piperidinyl, morpholinyl. thiomorpholinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, 1 ,4-dioxanyl, pyrrolidinyl, tetrahydrofuranyl, 2,5-dihydro-(1 H)-pyrrolyl, 2,5-dihydro-(1H)-imidazolyl, pyrazolidinyl, 5-oxo- 1 ,2,4-oxadiazolyl, 5-oxo-1 ,2,4-thiadiazolyl, 5-thioxo-1 ,2,4-oxadiazolyl, 2-oxo- 1 ,2,3,5-oxathiadiazolyl, etc. and substituted derivatives of such rings with substituents as outlined above. The expression heteroaryl means six- membered aromatic rings containing one to three nitrogen atoms, benzo- fused six-membered aromatic rings containing one to three nitrogen atoms, purinyl, five-membered aromatic rings containing one oxygen or one nitrogen or one sulfur atom, benzo-fused five-membered aromatic rings containing one oxygen or one nitrogen or one sulfur atom, five membered aromatic rings containig an oxygen and nitrogen atom and benzo-fused derivatives thereof, five membred aromatic rings containing a sulfur and a nitrogen atom and benzo fused derivatives thereof, five membered aromatic rings containing two nitrogen atoms and benzo-fused derivatives thereof, five membered aromatic rings containing three nitrogen atoms and benzo fused derivatives thereof, or the tetrazolyl ring. Such heteroaryl rings may be substituted with lower alkyl, lower alkenyl, amino, amino-lower alkyl, halogen, hydroxy, lower alkoxy, lower alkylamino, trifluoromethoxy, trifluoromethyl, cyano, aminocarbonyl, alkoxycarbonyl, carboxyl, heterocyclyl (preferably 5-oxo-1 ,2,4-oxadiazolyl, 5- oxo-1 ,2,4-thiadiazolyl, 5-thioxo-1 ,2,4-oxadiazolyl, 2-oxo-1 ,2,3,5- oxathiadiazolyl), or heteroaryl (preferably tetrazolyl). Examples of heteroaryl rings are furanyl, thienyl, pyrrolyl, pyridinyl, indolyl, quinolinyl, isoquinolinyl, imidazolyl, triazinyl, thiazinyl, thiazolyl, isothiazolyl, pyridazinyl, oxazolyl, isoxazolyl. The expression aryl represents unsubstituted as well as mono-, di- or tri-substituted aromatic rings with 6 to 10 carbon atoms like phenyl or naphtyl rings which may be substituted with aryl, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkenyloxy, lower alkynyl-lower alkyloxy, lower alkenylen, lower alkylenoxy, lower alkylenoxy or lower alkylendioxy forming with the phenyl ring a five- or six-membered ring, hydroxy-lower alkyl, hydroxy-lower alkenyl, hydroxy-lower alkyl-lower alkynyl, lower alkyloxy-lower alkyl, lower alkyloxy-lower alkyloxy, trifluoromethyl, trifluoromethoxy, cycloalkyl, hydroxy-cycloalkyl, heterocyclyl, heteroaryl.

It is understood that the substituents outlined relative to the expressions cycloalkyl, heterocyclyl, heteroraryl and aryl have been omitted in the definitions of the general Formulae I, II, III and IV in claims 1 to 5 for clarity reasons but the definitions in Formulae I, II, III and IV in claims 1 to 5 should be read as if they are included therein.

The expression pharmaceutically acceptable salts encompasses either salts with inorganic acids or organic acids like hydrohalogenic acids, e.g. hydrochloric or hydrobromic acid; sulfuric acid, phosphoric acid, nitric acid, citric acid, formic acid, acetic acid, maleic acid, tartaric acid, methylsulfonic acid, p- toluenesulfonic acid and the like or in case the compound of formula I is acidic in nature with an inorganic base like an alkali or earth alkali base, e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide etc.

The compounds of the general formula I might have one or more asymmetric carbon atoms and may be prepared in form of optically pure enantiomers or diastereomers, mixtures of enantiomers or diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates. The present invention encompasses all these forms. Mixtures may be separated in a manner known per se, i.e. by column chromatography, thin layer chromatography, HPLC, crystallization etc. Because of their ability to inhibit the endothelin binding, the described compounds of the general formula I and their pharmaceutically acceptable salts may be used for treatment of diseases which are associated with an increase in vasoconstriction, proliferation or inflammation due to endothelin. Examples of such diseases are hypertension, coronary diseases, cardiac insufficiency, renal and myocardial ischemia, renal failure, cerebral ischemia, dementia, migraine, subarachnoidal hemorrhage, Raynaud's syndrome, portal hypertension and pulmonary hypertension. They can also be used for atherosclerosis, prevention of restenosis after balloon or stent angioplasty, inflammation, stomach and duodenal ulcer, cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, gram negative septicemia, pain, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, therapy and prophylaxis of diabetic complications, complications of vascular or cardiac surgery or after organ transplantation, complications of cyclosporin treatment, as well as other diseases presently known to be related to endothelin.

These compositions may be administered in enteral or oral form e.g. as tablets, dragees, gelatine capsules, emulsions, solutions or suspensions, in nasal form like sprays or rectically in form of suppositories. These compounds may also be administered in intramuscular, parenteral or intraveneous form, e.g. in form of injectable solutions.

These pharmaceutical compositions may contain the compounds of formula I as well as their pharmaceutically acceptable salts in combination with inorganic and/or organic excipients which are usual in the pharmaceutical industry like lactose, maize or derivatives thereof, talcum, stearinic acid or salts of these materials.

For gelatine capsules vegetable oils, waxes, fats, liquid or half-liquid polyols etc. may be used. For the preparation of solutions and sirups e.g. water, polyols, saccharose, glucose etc. are used. Injectables are prepared by using e.g. water, polyols, alcohols, glycerin, vegetable oils, lecithin, liposomes etc. Suppositories are prepared by using natural or hydrogenated oils, waxes, fatty acids (fats ), liquid or half-liquid polyols etc.

The compositions may contain in addition preservatives, stabilisation improving substances, viscosity improving or regulating substances, solubility improving substances, sweeteners, dyes, taste improving compounds, salts to change the osmotic pressure, buffer, antioxidants etc.

The compounds of formula I may also be used in combination with one or more other therapeutically useful substances e.g. α- and β-blockers like phentolamine, phenoxybenzamine, atenolol, propranolol, timolol, metoprolol, carteolol etc.; vasodilators like hydralazine, minoxidil, diazoxide, flosequinan etc.; calcium-antagonists like diltiazem, nicardipine, nimodipine, verapamil, nifedipine etc.; ACE-inhibitors like cilazapril, captopril, enalapril, lisinopril etc.; potassium activators like pinacidil etc.

Angiotensin II antagonists; diuretics like hydrochlorothiazide, chlorothiazide, acetolamide, bumetanide, furosemide, metolazone, chlortalidone etc.; sympatholitics like methyldopa, clonidine, guanabenz, reserpine etc.; and other therapeutics which serve to treat high blood pressure or any cardiac disorders.

The dosage may vary within wide limits but should be adapted to the specific situation. In general the dosage given in oral form should daily be between about 3 mg and about 3 g, preferably between about 5 mg and about 1 g, especially preferred between 5 mg and 300 mg, per adult with a body weight of about 70 kg. The dosage should be administered preferably in 1 to 3 doses per day which are of equal weight. As usual children should receive lower doses which are adapted to body weight and age.

A preferred group of compounds are compounds of formula I wherein R¹, R², and R⁴ are as defined above, and wherein R³ represents phenyl, or mono substituted phenyl substituted with lower alkyl, lower alkyloxy, trifluoromethyl, trifluoromethoxy, or halogen;

X represents oxygen or a single bond,

and pharmaceutically acceptable salts thereof.

Another group of preferred compounds are compounds of formula II

formula II

wherein R², R³, R⁴, and X are defined as in formula I above, and R¹ represents lower alkyl, and hydroxy-lower alkyl,

and pharmaceutically acceptable salts thereof.

Another group of preferred compounds are compounds of formula

wherein R .1 , R _D3 , O R4 , and X are defined as in formula I above,

and pharmaceutically acceptable salts thereof.

Yet another group of preferred compounds are compounds of formula IV

wherein R >1 , D R2 , C R»3 , and X are defined as in formula I above, and pharmaceutically acceptab\e salts thereof.

Another group of preferred compounds are the compounds described as final products in the Examples 1 to 92 as given below, and pharmaceutically acceptable salts thereof.

The compounds of the general formula 1 are prepared by reacting compounds of the formula V with an excess of the alcohol or the amine VI in the presence or absence of a base (e.g. triethylamine, Hϋnig's base, etc.) or with an excess of the alkoxide of VI, in a polar solvent such as DMF, DMSO, THF, dimethoxyethane, etc. at temperatures between 0 and 120°C. For some of the compounds I where Y or Z represents the functionality NR⁹, or R⁶ represents OR⁷ or NR⁸R⁹, the corresponding free amino- or alkohol- functionalities may be protected with a suitable protecting group (e.g. tert.- butyloxy carbonyl (BOC) in the case of NH or NHR⁹, tetrahydropyranyl (THP) in the case of OH (T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd Edition, Wiley & Sons, New York 1991 ; P. J. Kocienski, Protecting Groups, Thieme Verlag, Stuttgart, New York 1994), prior to the reaction of VI with compounds of formula V. In those cases where Y or Z represents NR⁹, or R⁶ represents NR⁸R⁹, the corresponding free amine resulting after the cleavage of the protecting group may then be reacted further with a carbamoylating agent such as a carbamoyl chloride or an isocyanate, or with an acylating agent such as an acyl chloride, a carboxylic acid anhydride or a carboxylic acid in the presence of a dehydrating agent (e.g. a carbodiimide, BOP, or PyBOP), or with a compound R⁸-L or R⁹-L where L represents a reactive leaving group such as chlorine, bromine, an alkylsulfone, a sulfonate, etc. In the case where R⁶ represents OR⁷, the free alcohol resulting after the cleavage of the protecting group may be reacted further with a carbamoylating agent such as a carbamoyl chloride or an isocyanate, or with an acylating agent such as an acyl chloride, a carboxylic acid anhydride or a carboxylic acid in the presence of a dehydrating agent (e.g. a carbodiimide, BOP, or PyBOP), or with a compound R⁷-L where L represents a reactive leaving group such as chlorine, bromine, a sulfone, a sulfonate, etc.

formula I

Compounds V are prepared from the corresponding dichloro compounds VII (Bioorg. Med. Chem. Letters 7 (1997), 2223-2228, Chimia 50 (1996), 519- 524, and references cited therein).

Treatment of VII with an excess of the appropriate sulfonamide potassium salt in the presence or absence of a base (e.g. triethylamine, Hϋnig's base) in a solvent (e.g DMF, DMSO) at room temperature to 50°C furnished the desired compounds V. The sulfonamide potassiums salts may be prepared according to e.g. Bioorg. Med. Chem. Letters 7 (1997), 2223-2228.

Compounds VII could be prepared by treating the corresponding compounds VIII (or tautomeric forms thereof) at elevated temperatures with a chlorinating agent such as POCI₃, PCI₅, or mixtures thereof, etc. each in the presence or absence of a base such as N,N-dialkylaniline or benzyltriethyl ammoniumchloride (e.g. Bioorg. Med. Chem. Lett., 7 (1997), 2223 - 2228; J. Med. Chem., 41 (1998), 3793 - 3803; J. Chem. Soc. 1959, 2214; Bull. Soc. Chim. Fr. 1959, 741-742).

In a standard method as described by Pinner (for a review see e.g. The Pyrimidines, by D.J. Brown, Wiley Interscience, New York 1970), the compounds VIII (or the corresponding tautomers) resulted from condensation of the corresponding amidines IX (isolated as hydrochloride salts) with the appropriate malonic ester derivatives X in the presence of a sodium alkoxide in a solvent such as methanol, ethanol, etc. at room temperature (e.g. Bull. Soc. Chim. Fr. 1960, 1648).

The amidines IX were prepared form the corresponding nitriles XI by treating the nitriles XI either with sodium methylate in methanol followed by the addition of ammoniumchloride, or with lithium hexamethyldisilazan followed by the addition of hydrochloric acid in isopropanol (Advanced Organic Chemistry, by J. March, 3^rd edtion, Wiley 1985, p. 803 and references cited therein).

XI

The malonic ester derivatives X were either commercially available or were prepared following the procedures found in the literature starting from commercially available chloro- or bromomalonates (e.g. J. Am. Chem. Soc. 62 (1940), 1154, 1155; ibid. 74 (1952), 4466; J. Chem. Soc. Perkin 1 , 1979, 2382-2386; Collect. Czech. Chem. Comm. 55 (1990), 1278-1289; J. Med. Chem. Chim. Ther. 26 (1991), 599-604; Bull. Soc. Chim. Fr. 1973, 2065- 2071).

Depending on the nature of R², the following steps may offer a simpler synthetic acces to compounds of formula I. Compounds of formula I may be obtained by treating compounds XII with R²H or its salt (e.g. sodium salt) in the presence or absence of a base such as triethylamine, Hϋnig's base, etc.

XII formula I

Depending on the nature of R²H, functionalities of R²H other than the nucleophilic reaction centre evoking the desired substitution of the 2- methylsulfonyl pyrimidine may require protection during the introduction of R² to the scaffold XII. For instance, amines may be protected as carbamates (e.g t.-BOC), alcohols can be protected by ketal or acetal formation (e.g THP) (T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd Edition, Wiley & Sons, New York 1991 ; P. J. Kocienski, Protecting Groups, Thieme Verlag, Stuttgart, New York 1994). These protecting groups are cleaved in a final step e.g. by treatment with an acid such as TFA, HCI, etc. The sulfones XII are easily obtained by oxidising the corresponding sulfides XIII with an oxidising agent such as 3-chloroperbenzoic acid, peracetic acid, hydrogenperoxide, bleach, chlorine, etc. (e.g. Heterocycles 23 (1985), 611- 616; J. Heterocycl. Chem. 18 (1981 ), 799-800; Synth. Comm. 23 (1993), 715- 723; J. Chem. Soc. 1949, 2490-2495; J. Chem. Soc. 1957, 1830-1832; J. Med. Chem. 27 (1984), 1621-1629; Chem. Pharm. Bull. 39 (1991), 775-783; Bioorg. Med. Chem. Lett. 9 (1999), 1403-1408) in a solvent such as dichloromethane, methanol, acetonitrile, THF, DMF, acetic acid, water, etc., and mixtures thereof at temperatures between 0 and 80°C.

Compounds XIII are prepared by reacting the monochlorides XIV with an excess of VI in the presence or absence of a base (e.g. triethylamine, Hϋnig's base, etc. ) or with an excess of the alkoxide of VI, in a polar solvent such as

DMF, DMSO, THF, dimethoxyethane, etc., at temperatures between 0 and

80°C. Additional functionalites of VI may be protected during the introduction of VI to the monochloride XIV. Amines, for instance, may be protected as carbamates, amides, imides, azides etc., while alcohols may be protected as e.g. acetals or ketals, ethers, etc.. Such protecting groups may be cleaved by treatment with acid (e.g TFA, HCI, etc.) or by treatment with a reducing agent

(e.g. hydrogen in the presence of a catalyst such as Pd/C, PtO₂, etc). Free amines resulting after the cleavage of the protecting group may be reacted further with a carbamoylating agent such as a carbamoyl chloride or an isocyanate, with an acylating agent such as an acyl chloride, a carboxylic acid anhydride or a carboxylic acid in the presence of a dehydrating agent (e.g. a carbodiimide, BOP, or PyBOP), or with a compound R⁸-L, or R⁹-L where L represents a reactive leaving group such as chlorine, bromine, a sulfone, a sulfonate, etc. Free alcohols resulting after the cleavage of the protecting group may be reacted further with a carbamoylating agent such as a carbamoyl chloride or an isocyanate, with an acylating agent such as an acyl chloride, a carboxylic acid anhydride or a carboxylic acid in the presence of a dehydrating agent (e.g. a carbodiimide, BOP, or PyBOP), or with a compound R⁷-L where L represents a reactive leaving group such as chlorine, bromine, a sulfone, a sulfonate, etc. Cleavage of the protecting group (T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd Edition, Wiley & Sons, New York 1991 ; P. J. Kocienski, Protecting Groups, Thieme Verlag, Stuttgart, New York 1994) and further derivatisation of the deprotected functionalities of VI may occur immediately after the introduction of the alcohol VI to the monochloride XIV, but may also be performed with benefit after the introduction of R² to XII.

XIV XIII

Treatment of the dichlorocompounds XV with an excess of the appropriate sulfonamide potassium salt in the presence or absence of a base (e.g. triethylamine, Hϋnig's base) in a polar solvent (e.g DMF, DMSO, etc.) at room temperature furnished the desired compounds XIV. The sulfonamide potassium salts may be prepared according to e.g. Bioorg. Med. Chem. Letters 7 (1997), 2223-2228.

XV XIV

Compounds XV could be prepared by treating the corresponding compounds XVI (or tautomeric forms thereof) at elevated temperatures with a chlorinating agent such as POCI₃, PCI₅, or mixtures thereof, etc. each in the presence or absence of a base such as N.N-dialkylaniline or benzyltriethyl ammoniumchloride (e.g. Aust. J. Chem. 43 (1990), 47-53; J. Med. Chem. 27 (1984), 1621-1629).

XVI XV

Compounds XV were obtained by treating compounds XVII (or tautomeric forms thereof) with methyliodide in the presence of a base (e.g. sodium hydroxide, sodium methoxide, etc.) in a solvent such as water, methanol, ethanol, etc. (e.g. Aust. J. Chem. 44 (1991 ), 129-134; ibid. 43 (1990), 55-62; J. Med. Chem. 27 (1984), 1621-1629; J. Am. Chem. Soc. 81 (1959), 193-195; ibid. 74 (1952), 1644-1646; J. Chem. Soc. 1959, 525-528, ibid. 1956, 1019- 1028, ibid. 1954, 2060-2069). Compounds XVII were prepared by treating the malonic ester derivatives X and with thiourea in the presence of a base (e.g sodium alkoxides) in a polar solvent (e.g. methanol, ethanol, DMF, or mixtures thereof) at room temperature to 50°C (e.g. Eur. J. Med. Chem. Chim. Ther. 30 (1995), 769-778; Collect. Czech. Chem. Commun. 59 (1994), 957-977; ibid. 47 (1982), 2525-2529; Aust. J. Chem. 44 (1991 ), 129-134; ibid. 43 (1990), 55-62; Bull. Chim. Soc. Fr. 1988, 1005-1008; Pharmazie 38 (1983), 65-66; J. Am. Chem. Soc. 77 (1955), 745-748; J. Chem. Soc. 1954, 3263-3268).

X XVII

As the case may be, compounds with one or more optically active carbon atoms are resolved into pure enantiomers or diastereomers, mixtures of enantiomers or diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates in a manner known per se, and, if desired, synthesised compounds of formula I were converted into a pharmaceutically acceptable salt in a manner known per se. Examples

The following examples illustrate the invention but do not at all limit the scope thereof. All temperatures are stated in °C.

The compounds given below were prepared according to the procedure described above. All compounds were characterized by ¹H-NMR (300MHz) and occasionally by ¹³C-NMR (75MHz) (Varian Oxford, 300MHz; chemical shifts are given in ppm relative to the solvent used; multiplicities: s = singlet, d = doublet, t = triplet; m = multiplet), by LC-MS (Waters Micromass; ZMD- platform with ESI-probe with Alliance 2790 HT; Column: 2x30mm, Gromsil ODS4, 3μm, 120A; Gradient: 0 - 100% acetonitrile in water, 6 min, with 0.05% formic acid, flow: 0.45ml/min; the retention time t._R is given in min, molecular mass of the fraction at t._R), by thin-layer chromatography (tic), (tlc- plates from Merck, silica gel 60 F₂₅ ) and occasionally by melting point. Abbreviations: CHO = Chinese Hamster Ovary, EDTA = ethylenediamine tetraacetate, BOP = benzotriazole-1-yl-oxy-tris(dimethylamino)-phosphonium hexafluorophosphate, PyBOP = benzotriazole-1-yl-oxy-tris-pyrrolidino- phosphonium hexafluorophosphate, DCM = dichloromethane, MeOH = methanol, DME = 1 ,2-dimethoxyethane, DMF = N,N-dimethylformamide, THF = tetrahydrofuran, DMSO = dimethyl sulfoxide, DMPU = 1 ,3-dimethyl-3,4,5,6- tetrahydro-2(1 H)-pyrimidinone, TFA = trifluoroacetic acid, min = minute, h = hour, r.t. = room temperature.

Example 1

a) To a solution of 0.23 g sodium in 40 ml methanol was added 10.62 g 4- cyanopyridine at r.t.. Stirring was continued for 6 h followed by the addition of 5.9 g ammoniumchloride and stirring was continued for another 10 h. Then 120 ml diethylether was added and the precipitate was filtered off after 30 min and washed once with 20 ml of diethylether. The product was dried under high vacuum. 14.95 g 4-amidino-pyridine hydrochloride was obtained as a white powder, which contains a small amount of NaCI.

b) 48 ml 2-methoxy-phenol (guaiacol) was slowly added to a stirred suspension of 70.8 g potassium carbonate in 480 ml acetone followed by heating to 45°C. Then 63.2 ml dimethylchloromalonate in 50 ml acetone was added within 20 min. The reaction mixture was heated to reflux for 16 h. The solvent was evaporated under reduced pressure, the residue taken into water and extracted with DCM. The combined organic layers were dried over sodium sulfate and evaporated. The oily product was crystallized from methyl- tert.-butyl-ether. 86 g dimethyl-(2-methoxyphenoxy)malonate was obtained.

c) To a stirred solution of 9.7 g sodium methylate in 100 ml methanol a solution of 21.7 g dimethyl-(2-methoxyphenoxy)malonate in 50 ml methanol was added within 15 min and stirring was continued for 30 min followed by the addition of 15.0 g 4-amidino-pyridine hydrochloride followed by stirring at r.t. for 20 h. The reaction mixture was concentrated in vacuo. The solid residue was stirred with ether. The obtained powder was filtered off and dissolved in 300 ml water. Acetic acid was added to pH = 4. The precipitated product was filtered off, washed with water and dried in vacuo at 50°C. 20.1 g 5-(2-methoxyphenoxy)-4,6-dihydroxy-2-(4-pyridyl)-pyrimidine (is possibly also present as the tautomeric 5-(2-methoxyphenoxy)-2-(4-pyridyl)- tetrahydropyrimidine-4,6-dion) was obtained as a white powder.

d) 10 g of 5-(2-methoxyphenoxy)-4,6-dihydroxy-2-(4-pyridyl)-pyrimidine, 11.2 g of N-ethyldiisopropylamine, 11 g of tetraethylammoniumchloride and 13.8 g of phosphorous pentachloride were dissolved in 25 ml phosphorous oxychloride and heated to reflux for 3 h. The mixture was evaporated in vacuo, toluene was added and the mixture was again evaporated. The residue was taken into DCM and poured onto ice/water. The layers were separated, the organic layer was washed with water, dried over sodium sulfate and evaporated. After recrystallization from acetone, 6.52 g of 4,6- dichloro-5-(2-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine was obtained.

e) 5-lsopropyl pyridine-2-sulfonamide potassium salt was prepared according to procedures disclosed in EP 0713875 A1 and Bioorganic & Medicinal

Chemistry Letters, 7 (1997), 2223-2228.

f ) 1 g of 4,6-dichloro-5-(2-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine and 1.43 g of 5-isopropyl pyridine-2-sulfonamide potassium salt were suspended in 20 ml of dry DMF. The mixture was stirred under argon at r.t. and became clear within a few h. After 16 h at r.t., most of the solvent was removed by evaporation under reduced pressure. The residue was taken up in 20 ml water and the pH was adjusted to 4-5 by adding about 1 ml of acetic acid. A precipitate formed. The precipitate was filtered off, washed with water and dried. The yellow powder was further purified by column chromatography on silica gel eluting first with hexane: ethyl acetate 1 :1 then with DCM : MeOH 10 : 1. 1.43 g of 5-isopropyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(4-pyridyl)-4- pyrimidinyl]-2-pyridine sulfonamide was obtained as a slightly yellow powder. LC-MS: t_R = 5.00 min, [M+1]⁺ = 512.19, [M-1V = 510.26.

g) To a suspension of 47 mg of NaH in 4 ml of dry DMF was added 800 mg of rac-(tetrahydro-furan-2-yl)-methanol. The mixture was stirred at r.t. until gas evolution had stopped. 100 mg of 5-isopropyl-N-[6-chloro-5-(2- methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide was added and the resulting mixture was stirred at 95°C for 3 h. The solution was poured onto 75 ml of ethyl acetate and washed with 50 ml of 10% aqueous citric acid followed by 50 ml of water. The organic layer was separated and evaporated. The crude product was purified by column chromatography on silica gel eluting with DCM containing 2% of methanol. The solid obtained was washed with a small amount of diethyl etherhexane 1 :2. This gave 79 mg of rac-5-isopropyl-N-[5-(2-methoxyphenoxy)-2-(4-pyridyl)-6-

(tetrahydrofuran-2-yl-methoxy)-4-pyrimidinyl]-2-pyridine sulfonamide as an almost colourless solid. LC-MS: t_R = 4.79 min, [M+1]⁺ = 578.30, [M-1]^" = 576.43. Example 2

To a suspension of 47 mg of NaH in 4 ml of dry DMF was added 797 mg of tetrahydro-2H-pyran-4-ol . The mixture was stirred at r.t. until gas evolution had stopped. 100 mg of 5-isopropyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(4- pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 1f) was added and the resulting mixture was stirred at 95°C for 16 h. The solution was poured into 50 ml of ethyl acetate and washed with 50 ml of 10% aqueous citric acid and twice with 50 ml of water. The organic layer was separated, dried over MgSO , and evaporated. The crude product was purified on prep, tic plates (silica gel, layer thickness 0.5 mm, ethyl acetate). This furnished 68 mg of 5- isopropyl-N-[5-(2-methoxyphenoxy)-2-(4-pyridyl)-6-(tetrahydro-pyran-4-yloxy)- 4-pyrimidinyl]-2-pyridine sulfonamide as a colourless foam. LC-MS: t_R = 4.68 min, [M+1]⁺ = 578.36, [M-1]^" = 576.32.

Example 3

To a suspension of 47 mg of NaH in 4 ml of THF and 1 ml of DMF was added 0.2 ml of hydroxymethyl cyclopropane at r.t.. After the evolution of hydrogen had stopped, 100 mg of 5-isopropyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(4- pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 1f) was added and the mixture was stirred for 16 h at r.t.. Eventually, the solvent was removed in vacuo and the resulting residue was dissolved in water. Upon the addition of acetic acid a precipitate formed. The precipitate was collected, washed with water and was recrystallised from methanol. This gave 59 mg of 5-isopropyl- N-[5-(2-methoxyphenoxy)-2-(4-pyridyl)-6-(cyclopropylmethoxy)-4-pyrimidinyl]- 2-pyridine sulfonamide as a powder. LC-MS: t_R = 5.25 min, [M+1]⁺ = 548.27, [M-1]- = 546.38.

Example 4

To a suspension of 47 mg of NaH in 4 ml of THF and 1 ml of DMF was added 0.3 ml of hydroxymethyl cyclohexane at r.t.. After the evolution of hydrogen had stopped, 100 mg of 5-isopropyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(4- pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 1f) was added and the mixture was stirred for 48 h at r.t.. Eventually, the solvent was removed in vacuo and the resulting residue was dissolved in water. Upon the addition of acetic acid a precipitate formed. The precipitate was collected, washed with methanol/diethyl ether and dried. This yielded 64 mg of 5-isopropyl-N-[5-(2- methoxyphenoxy)-2-(4-pyridyl)-6-(cyclohexylmethoxy)-4-pyrimidinyl]-2- pyridine sulfonamide as a beige powder. LC-MS: t_R = 6.13 min, [M+1]⁺ = 590.20, [M-1]^" = 588.22.

Example 5

To a suspension of 47 mg of NaH in 4 ml of THF and 1 ml of DMF was added 0.2 ml of cyclopentanol at r.t.. After the evolution of hydrogen had stopped, 100 mg of 5-isopropyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(4-pyridyl)-4- pyrimidinyl]-2-pyridine sulfonamide (Example 1f) was added and the mixture was stirred for 26 h at r.t.. Eventually, the solvent was removed in vacuo and the resulting residue was dissolved in water and the pH of the resulting solution was adjusted to 4-5 by adding acetic acid. The aqueous layer was extracted with ethyl acetate. The organic layer was separated, dried over MgSO₄ and evaporated. The residue was dissolved in methanol/diethyl ether. Impurities precipitated and were filtered off. The filtrate was evaporated and dried. This gave 50 mg of 5-isopropyl-N-[5-(2-methoxyphenoxy)-2-(4-pyridyl)- 6-(cyclopentyloxy)-4-pyrimidinyl]-2-pyridine sulfonamide as a beige solid. LC- MS: t_R = 5.54 min, [M+1]⁺ = 562.30, [M-1]^' = 560.43.

Example 6

To a solution of 0.24 ml of 1-(2-hydroxyethyl)-pyrrolidine in 15 ml of DMF was added 115 mg of NaH at r.t.. After hydrogen evolution had stopped, 205 mg of 5-isopropyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]- 2-pyridine sulfonamide (Example 1f) was added. The mixture was stirred at r.t. for 50 h. Eventually, the solvent was removed in vacuo, and the residue was dissolved in ethyl acetate. The organic layer was extracted with 10% aqueous citric acid and water. The combined aqueous layers were adjusted to pH 7 by adding sat. aqueous K₂CO₃ and extracted three times with DCM. The organic layer was collected, dried over MgSO₄ and evaporated. The crude product was purified by chromatography on prep, tic plates (silica gel, layer thickness 0.5 mm, ethyl acetate:methanol:sat. aq. ammonia 8:2:1) and recrystallisation from 2-propanol. This furnished 35 mg of 5-isopropyl-N-[5-(2- methoxyphenoxy)-2-(4-pyridyl)-6-(2-pyrrolidin-1-yl-ethoxy)-4-pyrimidinyl]-2- pyridine sulfonamide as pale yellow crystals. LC-MS: t_R = 3.34 min, [M+1]⁺ = 591.39, [M-1]- = 589.47.

Example 7

To a solution of 0.23 ml of 1-(2-hydroxyethyl)-2-pyrrolidone in 15 ml of DMF was added 115 mg of NaH at r.t.. After hydrogen evolution had stopped, 205 mg of 5-isopropyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(4-pyridyl)-4- pyrimidinyl]-2-pyridine sulfonamide (Example 1f) was added. The mixture was stirred at r.t. for 16 h. Eventually, the solvent was removed in vacuo, and the residue was dissolved in ethyl acetate. The organic layer was washed with 10% aqueous citric acid. The aqueous phase was extracted two more times with ethyl acetate and once with DCM. The combined organic layers were washed with water and brine, dried over MgSO₄ and evaporated. The crude product was purified by chromatography on prep, tic plates (silica gel, layer thickness 0.5 mm, ethyl acetate:methanol:sat. aq. ammonia 8:2:1). This gave 93 mg of 5-isopropyl-N-[5-(2-methoxyphenoxy)-2-(4-pyridyl)-6-[2-(2-oxo- pyrrolidin-1-yl)-ethoxy]-4-pyrimidinyl]-2-pyridine sulfonamide as a yellow foam. LC-MS: t_R = 4.19 min, [M+1]⁺ = 605.35, [M-1]- = 603.48. Example 8

To a solution of 268 mg of 1-(2-hydroxyethyl)-2-imidazolidinone in 15 ml of DMF was added 115 mg of NaH at r.t.. After hydrogen evolution had stopped, 205 mg of 5-isopropyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(4-pyridyl)-4- pyrimidinyl]-2-pyridine sulfonamide (Example 1f) was added. The mixture was stirred at r.t. for 80 h and at 40°C for another 8 h. Eventually, the solvent was removed in vacuo, and the residue was dissolved in ethyl acetate. The organic layer was washed with 10% aqueous citric acid. The aqueous phase was extracted two more times with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO₄ and evaporated. The crude product was treated several times with hexane. The hexane was decanted. The remaining solid was recrystalised from 2-propanol. The crystals were collected, washed with 2-propanol and diethyl ether, and dried. This furnished 56 mg of 5-isopropyl-N-[5-(2-methoxyphenoxy)-2-(4-pyridyl)-6- {2-(2-oxo-imidazolidin-1 -yl)-ethoxy}-4-pyrimidinyl]-2-pyridine sulfonamide as pale yellow crystals. LC-MS: t_R = 4.00 min, [M+1]⁺ = 606.31 , [M-1]^' = 604.44.

Example 9

A solution of 100 mg of 5-isopropyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(4- pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 1f) in 1.5 ml of morpholine was stirred at 95°C for 16 h. The mixture was diluted with 75 ml of ethyl acetate and washed twice with 50 ml of 10% aqueous citric acid and once with 50 ml of water. The organic layer was dried over MgSO₄ and evaporated. The crude product was purified by column chromatography on silica gel eluting with hexane containing 60 to 85% ethyl acetate. This yielded 68 mg of 5-isopropyl-N-[5-(2-methoxyphenoxy)-2-(4-pyridyl)- 6-morpholin-4- yl-4-pyrimidinyl]-2-pyridine sulfonamide as a colourless foam. LC-MS: t_R = 4.48 min, [M+1]⁺ = 563.32, [M-1]^' = 561.46.

Example 10

To a suspension of 47 mg of NaH in 4 ml of THF and 1 ml of DMF was added 0.2 ml of rac-3-hydroxy-1-methyl-piperidine at r.t.. After the evolution of hydrogen had stopped, 100 mg of 5-isopropyl-N-[6-chloro-5-(2- methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide

(Example 1f) was added and the mixture was stirred for 24 h at r.t.

Eventually, the solvent was removed in vacuo and the resulting residue was dissolved in water and the pH of the resulting solution was adjusted to 7 by adding acetic acid. The precipitate that formed was collected, washed with water and dried. This gave 60 mg of rac-5-isopropyl-N-[5-(2- methoxyphenoxy)-2-(4-pyridyl)-6-(1-methyl-piperidin-3-yloxy)-4-pyrimidinyl]-2- pyridine sulfonamide as a beige solid. LC-MS: t_R = 3.63 min, [M+1]⁺ = 591.20, [M-1]^' = 589.42. Example 11

To a suspension of 47 mg of NaH in 4 ml of THF and 1 ml of DMF was added 0.2 ml of 4-hydroxy-1-methyl-piperidine at r.t.. After the evolution of hydrogen had ceased, 100 mg of 5-isopropyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(4- pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 1f) was added and the mixture was stirred at r.t. for 48 h. Eventually, the solvent was removed in vacuo and the resulting residue was dissolved in water and the pH of the resulting solution was adjusted to 7 by adding acetic acid. The precipitate that formed was collected, washed with water and dried. This gave 62 mg of 5- isopropyl-N-[5-(2-methoxyphenoxy)-2-(4-pyridyl)-6-(1~methyl-piperidin-4- yloxy)-4-pyrimidinylJ-2-pyridine sulfonamide as a beige solid. LC-MS: t_R = 3.35 min, [M+1]⁺ = 591.15, [M-1]^' = 589.18.

Example 12

To a solution of 0.26 ml of 4-(2-hydroxyethyl)-morpholine in 15 ml of DMF was added 115 mg of NaH at r.t.. After hydrogen evolution had stopped, 205 mg of 5-isopropyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(4-pyridyl)-4- pyrimidinyl]-2-pyridine sulfonamide (Example 1f) was added. The mixture was stirred at r.t. for 16 h and at 40°C for another 5 h. Eventually, the solvent was removed in vacuo, and the residue was dissolved in ethyl acetate. The organic layer was washed with 10% aqueous citric acid. The aqueous phase was extracted two more times with ethyl acetate, was then adjusted to pH 7 by adding sat. aqueous K₂CO₃ and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO₄ and evaporated. The crude product was purified by chromatography on prep, tic plates (silica gel, layer thickness 0.5 mm, ethyl acetate:methanol:sat. aq. ammonia 8:2:1 ) and recrystallised from 2-propanol. This furnished 40 mg of 5-isopropyl-N-[5-(2- methoxyphenoxy)-2-(4-pyridyl)-6-(2-morpholin-4-yl-ethoxy)-4-pyrimidinyl]-2- pyridine sulfonamide as colourless crystals. LC-MS: t_R = 3.26 min, [M+1]⁺ = 607.38, [M-1]^" = 605.49.

Example 13

To a suspension of 156 mg of NaH (60% in mineral oil) in 2 ml of DME 1 ml of rac.-trans-(2-hydroxymethyl-cyclopropyl)-methanol (prepared starting from racemic diethyl trans-cyclopropanedicarboxylate following the procedure given by J. Ramnauth, E. Lee-Ruff in Can. J. Chem. 75 (1997), 518-522) was added. The resulting yellow solution was stirred for 10 min before 200 mg of 5-isopropyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2- pyridine sulfonamide (Example 1f) was added. The mixture was stirred at 80°C for 17 h before it was diluted with 100 ml of 10% aq. citric acid. The mixture was extracted four times with 50 ml of ethyl acetate, the combined organic layer was washed with twice with 50 ml of 10% citric acid and four times with 50 ml of water, dried over MgSO₄ and evaporated. The crude product was purified by column chromatography on silica gel eluting with ethyl acetate to give 57 mg of rac.-5-isopropyl-pyridine-2-sulfonic acid [6-(trans-2- hydroxymethyl-cyclopropylmethoxy)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl- pyrimidin-4-yl]-amide as a yellow solid. LC-MS: t_R = 4.45 min, [M+1]⁺ = 578.43, [M-1]^' = 576.39.

Example 14

To a suspension of 156 mg of NaH (60% in mineral oil) in 4 ml of DME 1 ml of (l-hydroxymethyl-cyclopropyl)-methanol (prepared starting from diethyl cyclopropane-dicarboxylate following the procedure given by J. Ramnauth, E. Lee-Ruff in Can. J. Chem. 75 (1997), 518-522) was added. The resulting suspension was stirred for 10 min at r.t. before 200 mg of 5-isopropyl-N-[6- chloro-5-(2-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 1f) was added. The mixture was stirred at 80°C for 18 h before it was diluted with 50 ml of 10% aq. citric acid. The mixture was extracted four times with 50 ml of ethyl acetate, the combined organic layer was washed with twice with 50 ml of water, dried over MgSO₄ and evaporated. The residue was suspended in 15 ml of diethyl ether, stirred for 1 h at r.t.. The solid material was collected and dried to furnish 174 mg of 5- isopropyl-pyridine-2-sulfonic acid [6-(1 -hydroxymethyl-cyclopropylmethoxy)-5- (2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide as a beige solid. LC-MS: t_R = 4.34 min, [M+1]⁺ = 578.40, [M-1]^' = 576.34. Example 15

To a suspension of 128 mg of NaH (60% in mineral oil) in 12 ml of DMF 660 mg of (2-hydroxymethyl-tetrahydro-furan-2-yl)-methanol was added. The mixture was stirred for 5 min at r.t. before 150 mg of 5-isopropyl-N-[6-chloro- 5-(2-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 1f) was added. The mixture was stirred at 70°C for 1 week before it was diluted with 75 ml of ethyl acetate and washed with 50 ml of 10% aq. citric acid and 2x25 ml of water. The organic layer was evaporated and the crude product was purified by chromatography on prep, tic-plates with ethyl acetate:methanol: sat. aq. NH₃ 4:1 :0.5 to yield 45 mg of rac.-5-isopropyl- pyridine-2-sulfonic acid [6-(2-hydroxymethyl-tetrahydro-furan-2-ylmethoxy)-5- (2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide as a slightly yellow crystalline solid. LC-MS: t_R = 4.16 min, [M+1]⁺ = 608.46, [M-1]^' = 606.39.

Example 16

To a suspension of 85 mg of NaH (60% in mineral oil) in 6 ml of DMF 454 mg of (R)-γ-hydroxymethyl-γ-butyrolactone was added. The mixture was stirred for 5 min at r.t. before 100 mg of 5-isopropyl-N-[6-chloro-5-(2- methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide

(Example 1f) was added. The suspension was stirred at 60°C for 28 h. The mixture was diluted with 75 ml of ethyl acetate and washed with 50 ml of 10% aq. citric acid and 2x25 ml of water. The organic layer was evaporated and the crude product was purified by chromatography on prep, tic-plates with DCM containing 8% of methanol to yield 70 mg of (R)-5-isopropyl-pyridine-2- sulfonic acid [5-(2-methoxy-phenoxy)-6-(5-oxo-tetrahydro-furan-2-ylmethoxy)- 2-pyridin-4-yl-pyrimidin-4-yi]-amide as a yellow foam. LC-MS: t_R = 4.30 min, [M+1]⁺ = 592.46, [M-1]^' = 590.43.

Example 17

To a suspension of 128 mg of NaH (60% in mineral oil) in 6 ml of DMF 454 mg of (S)-5-hydroxymethyl-dihydro-furan-2-one was added. The mixture was stirred for 5 min at r.t. before 180 mg of 5-isopropyl-N-[6-chloro-5-(2- methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide

(Example 1f) was added. The suspension was stirred at 60°C for 48 h. The mixture was diluted with 75 ml of ethyl acetate and washed with 50 ml of 10% aq. citric acid and 2x50 ml of water. The organic layer was evaporated and the crude product was purified by chromatography on prep, tic-plates with DCM containing 10% of methanol to yield 131 mg of (S)-5-isopropyl-pyridine- 2-sulfonic acid [5-(2-methoxy-phenoxy)-6-(5-oxo-tetrahydro-furan-2- ylmethoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide as a pale yellow solid. LC-MS: t_R = 4.26 min, [M+1]⁺ = 592.44, [M-1]^' = 590.38. Example 18

To a suspension of 128 mg of NaH (60% in mineral oil) in 6 ml of DMF 674 mg of (R)-5-hydroxymethyl-pyrrolidin-2-one was added. The mixture was stirred for 5 min at r.t. before 150 mg of 5-isopropyl-N-[6-chloro-5-(2- methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide

(Example 1f) was added. The mixture was stirred at 65°C for 144 h. After 120 h further 200 mg of (R)-5-hydroxymethyl-pyrrolidinone has been added. EventuaUy, the mixture was diluted with 75 ml of ethyl acetate and washed with 50 ml of 10% aq. citric acid and 2x25 ml of water. The organic layer was evaporated and the crude product was purified by chromatography on prep, tic-plates with DCM containing 10% of methanol to yield 30 mg of (R)-5- isopropyl-pyridine-2-sulfonic acid [5-(2-methoxy-phenoxy)-6-(5-oxo-pyrrolidin- 2-ylmethoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide as a pale yellow solid. LC- MS: t_R = 3.98 min, [M+1]⁺ = 591.44, [M-1]^" = 589.37.

Example 19

To a suspension of 85 mg of NaH (60% in mineral oil) in 4 ml of DMF 406 mg of anhydroerythritol was added. The mixture was stirred for 5 min at r.t. before 100 mg of 5-isopropyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(4-pyridyl)-4- pyrimidinyl]-2-pyridine sulfonamide (Example 1f) was added. The mixture was stirred for 24 h at r.t. and 72 h at 60°C. The mixture was diluted with 75 ml of ethyl acetate and washed with 50 ml of 10% aq. citric acid and 2x50 ml of water. The organic layer was evaporated and the crude product was purified by chromatography on prep, tic-plates with DCM containing 7% of methanol to yield 88 mg of rac.-(3'R, 4'S)-5-isopropyl-pyridine-2-sulfonic acid [6-(4'- hydroxy-tetrahydrofuran-3'-yloxy)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl- pyrimidin-4-yl]-amide as a white solid. LC-MS: t_R = 4.07 min, [M+1]⁺ = 580.42, [M-1]^" = 578.39.

Example 20

To a suspension of 64 mg of NaH (60% in mineral oil) in 5 ml of DMF 350 mg of 1 ,4-anhydro-2-deoxy-D-erythro-pentitol (prepared starting from 2-deoxy-D- ribose following the procedure described by H.K. Chenault, R. F. Mandes in Tetrahedron 53 (1997), 11033-11038) was added. The mixture was stirred for 5 min at r.t. before 150 mg of 5-isopropyl-N-[6-chloro-5-(2-methoxyphenoxy)- 2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 1f) was added. The mixture was stirred for 72 h at r.t. and 24 h at 50°C. Further 175 mg of 1 ,4-anhydro-2-deoxy-D-erythro-pentitol and 32 mg of NaH was added and stirring was continued for 96 h at 50°C. The mixture was diluted with 75 ml of ethyl acetate and washed with 2x50 ml of 10% aq. citric acid and 50 ml of water. The organic layer was evaporated and the crude product was purified by chromatography on prep, tic-plates with ethyl acetate: methanol :sat. aq. NH₃ 4:1 :0.5 to yield 128 mg of [2'R, 3'S]-5-isopropyl-pyridine-2-sulfonic acid [6-(3'-hydroxy-tetrahydrofuran-2'-ylmethoxy)-5-(2-methoxy-phenoxy)-2- pyridin-4-yl-pyrimidin-4-yl]-amide as a pale ye))ow foam. LC-MS: t_R = 3.98 min, [M+1]⁺ = 594.47, [M-1]^' = 592.40. Example 21

a) To a solution of 6.43 g of 1 ,4-anhydro-2-deoxy-5-O-(tert.- butyldimethylsilyl)-D-erythro-pentitol (prepared starting from 2-deoxy-D-ribose following the the procedure given by H.K. Chenault and R. F. Mandes in Tetrahedron 53 (1997), 11033-11038), 4.22 g of benzoic acid and 9.07 g of triphenylphosphine in 50 ml of dry THF, 6.02 g of diethyl azodicarboxylate was added in portions. The resulting solution was stirred at r.t. for 2 h before it was diluted with 250 ml of ethyl acetate, washed twice with 200 ml of sat. aq. NaHCO₃-solution and 250 ml of water. The organic phase was evaporated and the crude product was purified by column chromatography on silica gel eluting with heptane : ethyl acetate 9:1. This gave 5.59 g of 1 ,4-anhydro-3-O- benzoyl-2-deoxy-5-O-(tert.-butyldimethylsilyl)-D-threo-pentitol as a pale yellow oil. ¹H-NMR(300MHz, CDCI₃): 0.00(s, 3H), 0.05(s, 3H), 0.86(s, 9H), 2.17(dddd, J=2.0, 4.6, 9.5, 13.8, 1 H), 2.41(ddt, J_d=5.7, 13.9, J_t=8.4, 1 H), 3.90- 3.94(m, 2H), 3.98(dt, J_d=4.7, J_t=8.6, 1 H), 4.07(dt, J_d=4.0, J_t=6.0, 1 H), 4.13(dd, J=8.3, 15.7, 1 H), 5.66-5.71 (m, 1 H), 7.45-7.52(m, 2H), 7.58-7.64(m, 1 H), 8.04- 8.10(m, 2H).

b) A solution of 5.59 g of 1 ,4-anhydro-3-O-benzoyl-2-deoxy-5-O-(tert.- butyldimethylsilyl)-D-threo-pentitol in 300 ml of THF:methanol:H₂O 5:4:1 and 50 ml of 1 M NaOH was stirred at 0°C for 3 h before it was extracted with 300 ml of ethyl acetate. The organic phase was washed three times with 200 ml of water and evaporated. The crude product was purified by column chromatography on silica gel eluting with hexane:ethyl acetate 4:1 to give 2.5 g of 1,4-anhydro-2-deoxy-5-O-(tert.-butyldimethylsilyl)-D-threo-pentitol as a colourless oil. ¹H-NMR(300MHz, CDCI₃): 0.00(s, 3H), 0.01 (s, 3H), 0.81 (s, 9H), 1.81-1.91(m, 1H), 1.95-2.08(m, 1H), 3.30(d, J=4.6, 1 H), 3.68-3.76(m, 2H), 3.82-3.86(m, 2H), 3.88-4.03(m, 1H), 4.37-4.44(m, 1H).

c) A solution of 2.5 g of 1 ,4-anhydro-2-deoxy-5-O-(tert.-butyldimethylsilyl)-D- threo-pentitol and 6.79 g of tetrabutylammonium fluoride trihydrate in 100 ml of THF was stirred at r.t. for 20 h before 7 g of Amberlyst-15 (Na⁺-form) was addde. Stirring was continued for 1.5 h. The mixture was filtered and the filtrate was evaporated. The resulting oil was purified by column chromatography on silica gel eluting with ethyl acetate containing 0-5% of methanol to furnish 1.02 g of 1,4-anhydro-2-deoxy-D-threo-pentitol as a pale brown oil. ¹H-NMR(300MHz, D₆-DMSO): 1.68-1.78(m, 1 H), 1.92-2.05(m, 1 H), 3.40-3.45(m, 1 H), 3.50-3.64(m, 3H), 3.81 (q, J=7.8, 1 H), 4.15-4.21 (m, 1 H), 4.34-4.41 (m, 1 H), 4.62(d, J=4.6, 1 H).

d) To a solution of 415 mg of 1 ,4-anhydro-2-deoxy-D-threo-pentitol in 4 ml of DMF was added 77 mg of NaH (60% in mineral oil). After evolution of gas had ceased, 150 mg of 5-isopropyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(4- pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 1f) was added and the resulting mixture was stirred at 60°C for 96 h before it was diluted with 75 ml of ethyl acetate and washed with 75 ml of 10% aq. citric acid followed by 75 ml of water. The organic phase was evaporated and the crude product was purified on prep, tic-plates with ethyl acetate:methanol:sat. aq. NH₃ 5:1 :0.5 to give 55 mg of [2'R, 3'R]-5-isopropyl-pyridine-2-sulfonic acid [6-(3'- hydroxy-tetrahydrofuran-2'-ylmethoxy)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl- pyrimidin-4-yl]-amide as a colourless foam. LC-MS: t_R = 4.15 min, [M+1]⁺ = 594.58, [M-1]^' = 592.42.

Example 22

Fro Example 21 , 21 mg of [2'R, 3'R]-5-isopropyl-pyridine-2-sulfonic acid [6- (2'-hydroxymethyl-tetrahydrofuran-3'-yloxy)-5-(2-methoxy-phenoxy)-2-pyridin- 4-yl-pyrimidin-4-yl]-amide was isolated as a by-product as a colourless foam. LC-MS: t_R = 3.96 min, [M+1]⁺ = 594.57, [M-1]^' = 592.41.

Example 23

To a suspension of 77 mg of NaH (60% in mineral oil) in 5 ml of DMF 415 mg of 1 ,4-anhydro-2-deoxy-L-erythro-pentitol (prepared starting from 2-deoxy-L- ribose following the procedure described by H.K. Chenault, R. F. Mandes in Tetrahedron 53 (1997), 11033-11038) was added. The mixture was stirred for 5 min at r.t. before 150 mg of 5-isopropyl-N-[6-chloro-5-(2-methoxyphenoxy)- 2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 1f) was added. The mixture was stirred at 60°C. After 48 h and 96 h, a further portion of 330 mg of 1 ,4-anhydro-2-deoxy-L-erythro-pentitol and 60 mg of NaH was added. Eventually, the mixture was diluted with 75 ml of ethyl acetate and washed with 50 ml of 10% aq. citric acid and 50 ml of water. The organic layer was evaporated and the crude product was purified by chromatography on prep, tic-plates with ethyl acetate:methanol:sat. aq. NH₃ 5:1 :0.5 to yield 58 mg of [2'S, 3'R]-5-isopropyl-pyridine-2-sulfonic acid [6-(3'-hydroxy-tetrahydrofuran- 2'-ylmethoxy)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide as a pale yellow foam. LC-MS: t_R = 3.98 min, [M+1]⁺ = 594.51 , [M-1]^' = 592.23. Example 24

a) 5-isopropyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-{2-(1 H-tetrazol-5-yl)- pyridin-4-yl}-pyrimidin-4-yl]-2-pyridine sulfonamide was prepared according to procedures given in EP-00979822 and WO-09619459.

b) To a suspension of 50 mg of NaH in 6 ml of DMF was added 0.7 ml of rac- (tetrahydro-furan-2-yl)-methanol at r.t.. After the evolution of hydrogen had ceased, 100 mg of 5-lsopropyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-{2-(1 H- tetrazol-5-yl)-pyridin-4-yl}-pyrimidin-4-yl]-2-pyridine sulfonamide was added and the mixture was stirred at r.t. for 72 h and at 40°C for 24 h. Eventually, the mixture was diluted with 75 ml of ethyl acetate and washed with 50 ml of 10% aqueous citric acid followed by 50 ml of water. The organic layer was separated and evaporated. The remaining residue was purified on prep, tic plates (silica gel, thickness 0.5 mm, DCM:methanol:water:acetic acid 100:20:2:1 ). This furnished 70 mg of rac-5-isopropyl-N-[5-(2-methoxy- phenoxy)-6-(tetrahydrofuran-2-yl-methoxy)-2-{2-(1 H-tetrazol-5-yl)-pyridin-4- yl}-pyrimidin-4-yl]-2-pyridine sulfonamide as an almost colourless powder. LC- MS: t_R = 4.93 min, [M+1]⁺ = 646.42, [M-1]^' = 644.37.

Example 25

To a suspension of 61 mg of NaH in 4 ml of THF and 2 ml of DMF was added 0.3 ml of hydroxymethyl cyclopropane at r.t. After the evolution of hydrogen had ceased, 120 mg of 5-isopropyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-{2- (1 H-tetrazol-5-yl)-pyridin-4-yl}-pyrimidin-4-yl]-2-pyridine sulfonamide

(Example 24a) was added and the mixture was stirred at r.t. for 18 h. Eventually, the solvent was removed in vacuo and the resulting residue was dissolved in water and the pH of the resulting solution was adjusted to 4-5 by adding acetic acid. The precipitate that formed was collected and dried. The material was recrystallised from methanol/diethyl ether. This gave 70 mg of 5- isopropyl-N-[6-(cyclopropylmethoxy)-5-(2-methoxyphenoxy)-2-{2-(1 H-tetrazol- 5-yl)-pyridin-4-yl}-pyrimidin-4-yl]-2-pyridine sulfonamide as a beige solid. LC- MS: t_R = 5.39 min, [M+1]⁺ = 616.41 , [M-1]^' = 614.60.

Example 26

To a suspension of 61 mg of NaH in 4 ml of THF and 2 ml of DMF was added 0.3 ml of rac-1-cyclopropylethanol at r.t.. After the evolution of hydrogen had ceased, 120 mg of 5-isopropyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-{2-(1H- tetrazol-5-yl)-pyridin-4-yl}-pyrimidin-4-yl]-2-pyridine sulfonamide (Example 24a) was added and the mixture was stirred at r.t. for 18 h. Eventually, the solvent was removed in vacuo and the resulting residue was dissolved in water and the pH of the resulting solution was adjusted to 4-5 by adding acetic acid. The precipitate that formed was collected and dried. The material was recrystallised from methanol/diethyl ether. This gave 75 mg of rac-5- isopropyl-N-[6-(1-cyclopropyl-ethoxy)-5-(2-methoxyphenoxy)-2-{2-(1H- tetrazol-5-yl)-pyridin-4-yl}-pyrimidin-4-yl]-2-pyridine sulfonamide as a pale beige solid. LC-MS: t_R = 5.49 min, [M+1]⁺ = 630.42, [M-1]^' = 628.60.

Example 27

To a suspension of 61 mg of NaH in 4 ml of THF and 2 ml of DMF was added 0.3 ml of cyclobutanol at r.t.. After the evolution of hydrogen had ceased, 120 mg of 5-isopropyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-{2-(1H-tetrazol-5-yI)- pyridin-4-yl}-pyrimidin-4-yl]-2-pyridine sulfonamide (Example 24a) was added and the mixture was stirred at r.t. for 18 h. Eventually, the solvent was removed in vacuo and the resulting residue was dissolved in water and the pH of the resulting solution was adjusted to 4-5 by adding acetic acid. The precipitate that formed was collected and dried. The material was recrystallised from methanol/diethyl ether. This gave 80 mg of 5-isopropyl-N- [6-cyclobutyloxy-5-(2-methoxyphenoxy)-2-{2-(1H-tetrazol-5-yl)-pyridin-4-yl}- pyrimidin-4-yl]-2-pyridine sulfonamide as an almost colourless solid. LC-MS: t_R = 5.45 min, [M+1f = 616.38, [M-1]^' = 614.56.

Example 28

a) A solution of 32.75 g of dimethyl-(2-methoxyphenoxy)malonate (Example 1b) in 250 ml of methanol was cooled to 0°C. 20.0 g sodium methylate was added portionwise and upon completion of the addition the mixture was stirred at r.t. for 6 h. Then 25.0 g of morpholinoformamidine hydrobromide was added and stirring was continued for 72 h. The solvent of the beige suspension was evaporated and the residue was washed twice with 150 ml of diethyl ether. The remaining powder was dissolved in 200 ml of water. Upon adjusting the pH to 4 with 50 ml of acetic acid a precipitate formed. The precipitate was collected, washed with water and dried under high vacuum to yield 17.01 g of 5-(2-methoxyphenoxy)-4,6-dihydroxy-2-(N-morpholino)- pyrimidine (or a tautomer) as a slightly beige powder.

b) At 0°C, 50 ml of POCI₃ was carefully added to 27.5 ml of Hϋnig's base. To this mixture 17 g of 5-(2-methoxyphenoxy)-4,6-dihydroxy-2-(N-morpholino)- pyrimidine was added portionwise. The resulting mixture was stirred overnight at 130°C. The excess of reagents was evaporated and traces of POCI₃ were removed by coevaporation with toluene. The black residue was treated with 50 ml of DCM and 50 ml of a water:ice mixture. After stirring for 15 min, the mixture was diluted with 400 ml of water and 400 ml of DCM. The organic layer was separated and washed with 300 ml of water. The aqueous layer was extracted with 400 ml of DCM. The combined DCM layers were dried over Na₂SO₄ and the solvent was removed to a volume of about 100 ml. The remaining solution was filtered over 50 g of silica gel eluting with DCM. The filtrate was evaporated. The resulting residue was suspended in 50 ml of diethyl ether. The solid was filtered off and dried to give 13.85 g of 4,6- dichloro-5-(2-methoxyphenoxy)-2-(N-morpholino)-pyrimidine as a white crystalline powder.

c) To a suspension of 4 g of 4,6-dichloro-5-(2-methoxyphenoxy)-2-(N- morpholino)-pyrimidine in 60 ml of DMSO was added 5.32 g of 5-isopropyl-2- pyridine sulfonamide potassium salt (Example 1e) and 0.98 ml of Hϋnig's base. The mixture was stirred at 65°C for 72 h. The dark solution was poured onto 500 ml of water and quickly filtered through celite. The filtrate was extracted with 500 ml and 250 ml of diethyl ether. The organic layers were extracted with 100 ml of water. The aqueous layers were combined, acidified with 3.5 ml of acetic acid and cooled to 0°C. The precipitate that formed was collected, washed with cold water and dried under high vacuum to furnish 4.94 g of 5-isopropyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(N-morpholino)-4- pyrimidinyl]-2-pyridine sulfonamide as a brownish powder. LC-MS: t_R = 5.46 min, [M+1 = 520.22, [M-1]^" = 518.36.

d). To a suspension of 47 mg of NaH in 5 ml of dry DMF was added 800 mg of rac-(tetrahydro-furan-2-yl)-methanol. The mixture was stirred at r.t. until gas evolution had stopped. Then, 100 mg of of 5-isopropyl-N-[6-chloro-5-(2- methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide was added and the resulting mixture was stirred at 95°C for 18 h. The solution was poured onto 50 ml of ethyl acetate and washed with 50 ml of 10% aqueous citric acid followed by 50 ml of water. The organic layer was separated, dried over MgSO₄ and evaporated. The crude product was purified by column chromatography on silica gel eluting hexane:ethyl acetate 1 :1. Product containing fractions were again washed twice with water and evaporated. This gave 91 mg of rac-5-isopropyl-N-[5-(2-methoxy-phenoxy)-2-morpholin-4- yl-6-(tetrahydrofuran-2-yl-methoxy)-pyrimidin-4-yl]-2-pyridine sulfonamide as a colourless foam. LC-MS: t_R = 5.28 min, [M+1]⁺ = 586.36, [M-1]^" = 584.50.

Example 29

To a suspension of 46 mg of NaH in 5 ml of dry DMF was added 780 mg of (3-methyl-oxetan-3-yl)-methanol. The mixture was stirred at r.t. until gas evolution had ceased. Then, 100 mg of of 5-isopropyl-N-[6-chloro-5-(2- methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 28c) was added and the resulting mixture was stirred at 95°C for 24 h. The solution was diluted with 50 ml of ethyl acetate and washed once with 50 ml of 10% aqueous citric acid and three times with 50 ml of water. The organic layer was separated, dried over MgSO₄ and evaporated. The crude product was recrystallised from 2 ml of ethyl acetate at 4°C. The colourless crystals were collected and dried to furnish 61 mg of 5-isopropyl-N-[5-(2- methoxy-phenoxy)-6-(3-methyl-oxetan-3-yl-methoxy)-2-morpholin-4-yl- pyrimidin-4-yl]-2-pyridine sulfonamide. LC-MS: t_R = 5.13 min, [M+1]⁺ = 586.38, [M-1]^" = 584.34.

Example 30

To a solution of 268 mg of 1-(2-hydroxyethyl)-2-imidazolidinon in 15 ml of DMF was added 115 mg of NaH at r.t.. After hydrogen evolution had stopped,

208 mg of 5-isopropyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(N-morpholino)-4- pyrimidinyl]-2-pyridine sulfonamide (Example 28c) was added. The mixture was stirred at 90°C for 30 h. Eventually, the solvent was removed in vacuo, and the residue was dissolved in ethyl acetate. The organic layer was washed with 10% aqueous citric acid. The aqueous phase was extracted two more times with ethyl acetate. The combined organic layers were washed with 50 ml of water followed by 50 ml of brine, dried over MgSO₄ and evaporated. The crude product was purified by chromatography on prep, tic plates (silica gel, thickness 0.5 mm, ethyl acetate:methanol:sat. aqueous ammonia 8:2:1). This furnished 102 mg of 5-isopropyl-N-[5-(2-methoxyphenoxy)-2-morpholin-4-yl-6-

{2-(2-oxo-imidazolidin-1 -yl)-ethoxy}-4-pyrimidinyl]-2-pyridine sulfonamide as colourless crystals. LC-MS: t_R = 4.51 min, [M+1]⁺ = 614.35, [M-1]^' = 612.48. Example 31

To a solution of 1342 mg of 1 ,2:3,4-di-O-isopropylidene-α-D-galactopyranose in 20 ml of dry DMF 523 mg of NaH (55% in mineral oil) was added. The mixture was stirred at r.t. for 1 h before 520 mg of 5-isopropyl-N-[6-chloro-5- (2-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 28c) was added. The mixture was stirred at 50°C for 16 h. The solution was cooled and diluted with 50 ml of 10% aq. citric acid. The precipitate that formed was collected, washed with water, hexane and diethyl ether/hexane and dried to give 608 mg of 5-isopropyl-pyridine-2-sulfonic acid [5-(2-methoxy-phenoxy)-2-morpholin-4-yl-6-(1 ,2:3,4-di-O-isopropylidene-α-D- galactopyranos-6-yl)-pyrimidin-4-yl]-amide as a beige powder. LC-MS: t = 5.77 min, [M+1]⁺ = 744.55, [M-1]^' = 742.68.

Example 32

A solution of 595 mg of 5-isopropyl-pyridine-2-sulfonic acid [5-(2-methoxy- phenoxy)-2-morpholin-4-yl-6-(1 ,2:3,4-di-O-isopropylidene- -D- galactopyranos-6-yl)-pyrimidin-4-yl]-amide (Example 31) in 10 ml of THF, 5 ml of water and 0.5 ml of TFA was stirred at r.t. for 60 h and at 60°C for 140 h. The solvent was removed in vacuo to give the crude product as a brownish foam. A part of the crude product was purified on prep, tic-plates with DCM:methanol 7:1 to give 48 mg of an anomeric mixture of 5-isopropyl- pyridine-2-sulfonic acid [5-(2-methoxy-phenoxy)-2-morpholin-4-yl-6-(D- galacto-pyranos-6-yl)-pyrimidin-4-yl]-amide as a colourless foam. LC-MS: t_R = 4.02 min, [M+1]⁺ = 664.46, [M-1]^" = 662.60.

Example 33

a) Racemic 1 ,4-anhydro-2,3-isopropylidene-ribitol (rac-(3aR, 4R, 6aS)- (2,2- dimethyl-tetrahydro-furo[3,4-d][1 ,3]dioxol-4-yl)-methanol) was prepared starting from ribitol (adonitol) in analogy to the procedures given by S. Shuto, Y. Ueno, A. Matsuda in J. Org. Chem. 63 (1998), 8815-8824 and by T.W. Greene and P. G. M. Wuts in Protective Groups in Organic Synthesis, 2nd Edition, Wiley 1991. ¹H-NMR(300MHz, CD₃OD): 1.32(s, 3H), 1.45(s, 3H), 3.49(d, J=4.6, 1 H), 3.53(dd, J=2.4, 5.7, 1 H), 3.86(d, 10.4, 1 H), 3.91-4.02(m, 1 H), 4.07-4.14(m, 1 H), 4.65-4.72(m, 1 H).

b) To a solution of 436 mg of rac.-1 ,4-anhydro-2,3-isopropylidene-ribitol in 15 ml of dry DMF 262 mg of NaH (55% in mineral oil) was added. The mixture was stirred at r.t. for 45 min before 260 mg of 5-isopropyl-N-[6-chloro-5-(2- methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 28c) was added. After stirring for 16 h at 50°C, the solvent was removed. The remaining residue was partitioned between 75 ml of 10% aq. citric acid and 75 ml of ethyl acetate. The organic phase was washed with brine and water, and evaporated. The residue was dissolved in DCM, methanol was added and the DCM was carefully removed in vacuo. The crystals that formed were collected, washed with cold 2-propanol and dried to give 245 mg of rac.-(3a'R, 4'R, 6a'S)-5-isopropyl-pyridine-2-sulfonic acid [6- (2^,,2'-dimethyl-tetrahydro-furo[3,4-d][1 ,3]dioxol-4^,-ylmethoxy)-5-(3-methoxy- phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-amide as pale yellow crystal. LC- MS: t_R = 5.10 min, [M+1]⁺ = 658.50, [M-1]^" = 656.62.

Example 34

A solution of 210 mg of rac.-(3a'R, 4'R, 6a'S)-5-isopropyl-pyridine-2-sulfonic acid [6-(2^,,2'-dimethyl-tetrahydro-furo[3,4-d][1 ₎3]dioxol-4'-ylmethoxy)-5-(3- methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-amide (Example 33) in 8 ml of THF, 4 ml of water and 0.5 ml of TFA was stirred at r.t. for 100 h and at 50°C for 72 h. The solvent was removed and the crude product was purified by crystallisation from 2-propanol. The crystals were collected, washed with 2-propanol and diethyl ether and dried to give 125 mg of rac.-(2'R, 3'S, 4'S)-5- isopropyl-pyridine-2-sulfonic acid [6-(3',4'-dihydroxy-tetrahydrofuran-2'- ylmethoxy)-5-(3-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-amide as pale yellow crystals. LC-MS: t_R = 4.20 min, [M+1]⁺ = 618.49.

Example 35

a) (3aS, 4R, 6aR)-(2,2-dimethyl-tetrahydro-furo[3,4-d][1 ,3]dioxol-4-yl)- methanol was prepared starting from D-arabitol in analogy to the procedures given by S. Shuto, Y. Ueno, A. Matsuda in J. Org. Chem. 63 (1998), 8815- 8824 and by T.W. Greene and P. G. M. Wuts in Protective Groups in Organic Synthesis, 2nd Edition, Wiley 1991.

b) To a solution of 155 mg of (3aS, 4R, 6aR)-(2,2-dimethyl~tetrahydro~ furo[3,4-d][1.3]dioxol-4-yl)-methanol in 15 ml of dry DMF 155 mg of NaH (55% in mineral oil) was added. The mixture was stirred at r.t. for 1 h before 260 mg of 5-isopropyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(N-morpholino)-4- pyrimidinyl]-2-pyridine sulfonamide (Example 28c) was added. After stirring for 72 h at 50°C the mixture was diluted with 50 ml of 10% aq. citric acid and extracted with 75 ml of ethyl acetate. The organic phase was washed with brine and water, and evaporated. The crude product was purified on prep, tic- plates with toluene:ethyl acetate 1 :1 to give 82 mg of (3a'S, 4'R, 6a'R)-5- isopropyl-pyridine-2-sulfonic acid [6-(2^,,2'-dimethyl-tetrahydro-furo[3,4- d][1 ,3]dioxol-4'-ylmethoxy)-5-(3-methoxy-phenoxy)-2-morpholin-4-yl- pyrimidin-4-yl]-amide as a colourless foam. MS: t_R = 0.98 min (Column: 4.6x50mm, Develosil RPAqueous, 5 μm, 120 A; Gradient: 5 - 95% acetonitrile in water, 1 min, with 0.04% formic acid, flow: 4.5 ml/min), [M+1]⁺ = 658.13.

c) A solution of 80 mg of (3a'S, 4'R, 6a'R)-5-isopropyl-pyridine-2-sulfonic acid [6-(2',2'-dimethyl-tetrahydro-furo[3,4-d][1 ,3]dioxol-4'-ylmethoxy)-5-(3-methoxy- phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-amide in 8 ml of THF, 4 ml of water and 0.5 ml of TFA was stirred at at 50°C for 90 h. The solvent was removed and the crude product was purified on prep, tic-plates with ethyl acetate to furnish 20 mg of (2'R, 3'R, 4'R)-5-isopropyl-pyridine-2-sulfonic acid [6-(3',4'- dihydroxy-tetrahydrofuran-2'-ylmethoxy)-5-(3-methoxy-phenoxy)-2-morpholin- 4-yl-pyrimidin-4-yl]-amide as colourless foam. LC-MS: t_R = 0.87 min (Column: 4.6x50mm, Develosil RPAqueous, 5 μm, 120 A; Gradient: 5 - 95% acetonitrile in water, 1 min, with 0.04% formic acid, flow: 4.5 ml/min), [M+1]⁺ = 618.20. Example 36

In analogy to Example 35, 22 mg of (2'S, 3'S, 4'S)-5-isopropyl-pyridine-2- sulfonic acid [6-(3',4'-dihydroxy-tetrahydrofuran-2'-ylmethoxy)-5-(3-methoxy- phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-amide were obtained as colourless foam starting from L-arabitol. LC-MS: t_R = 0.88 min (Column: 4.6x50mm, Develosil RPAqueous, 5 μm, 120 A; Gradient: 5 - 95% acetonitrile in water, 1 min, with 0.04% formic acid, flow: 4.5 ml/min), [M+1]⁺ = 618.15.

Example 37

a) To a solution of 5.17 g of sodium in 200 ml of methanol 21.1 g of dimethyl- (2-methoxyphenoxy)malonate (Example 1b) was added and the mixture was stirred at r.t. for 30 min. To the slurry 12.0 g of cyclopropylamidine hydrochloride was added. The mixture was stirred at r.t. for 22 h. Eventually, the solvent was removed in vacuo. The remaining residue was suspended in 250 ml of diethyl ether. The ether was decanted and the remaining solid was dissolved in 250 ml of water. The solution was acidified with 25% aqueous hydrochloric acid. The precipitate that formed was collected, washed with water and dried at 60°C under high vacuum to give 19.26 g of 5-(2- methoxyphenoxy)-4,6-dihydroxy-2-cyclopropyl-pyrimidine as a colourless powder. LC-MS: t_R = 2.74 min, [M+1]⁺ = 275.24, [M-1]^" = 273.29. b) To a suspension of 8.22 g of 5-(2-methoxyphenoxy)-4,6-dihydroxy-2- cyclopropyl-pyrimidine in 87 ml of POCI₃, 12 ml of N,N-dimethylaniline was added. The mixture became clear and was stirred at 130°C for 3.5 h. Excess POCI₃ was removed in vacuo, remaining traces of POCI3 were coevaporated with toluene. The remaining sirup was poured on an ice-water mixture and the resulting solution was extracted three times with diethyl ether. The organic layers were combined, washed once with 1 N aqueous hydrochloric acid and twice with water, treated with activated charcoal, dried over MgSO₄ and evaporated. The residue was crystallised from a diethyl ether/hexane to give 6.64 g of 4,6-dichloro-2-cyclopropyl-5-(2-methoxyphenoxy)-pyrimidine as a beige powder. LC-MS: t_R = 5.36 min, [M+1]⁺ = 311.19.

c) A solution of 3.3 g of 4,6-dichloro-2-cyclopropyl-5-(2-methoxyphenoxy)- pyrimidine and 5.2 g of 5-isopropyl pyridine-2-sulfonamide potassium salt

(Example 1e) in 30 ml of DMSO was stirred at r.t. for 24 h. The mixture was diluted with 150 ml of water and extracted twice with diethyl ether. Upon acidifying the aqueous phase with acetic acid a precipitate formed. The precipitate was collected, suspended in methanol, filtered off again and dried. This yielded 4.04 g of 5-isopropyl-N-[6-chloro-2-cyclopropyl-5-(2- methoxyphenoxy)-4-pyrimidinyl]-2-pyridine sulfonamide as a white powder. LC-MS: t_R = 5.64 min, [M+1]⁺ = 475.19, [M-1]^" = 473.29.

d) To a suspension of 51 mg of NaH in 7 ml of dry DMF was added 860 mg of rac-(tetrahydro-furan-2-yl)-methanol. The mixture was stirred at r.t. until gas evolution had ceased. Then, 100 mg of 5-isopropyl-N-[6-chloro-2-cyclopropyl- 5-(2-methoxyphenoxy)-4-pyrimidinyl]-2-pyridine sulfonamide was added and the resulting mixture was stirred at 85°C for 18 h. The solution was poured onto 75 ml of ethyl acetate and washed twice with 50 ml of 10% aqueous citric acid and two more times with 50 ml of water. The organic layer was separated and evaporated. The crude product was purified by column chromatography on silica gel eluting with hexane:ethyl acetate 1:1. This furnished 82 mg of rac-5-isopropyl-N-[2-cyclopropyl-5-(2-methoxyphenoxy)-6- (tetrahydrofuran-2-yl-methoxy)-4-pyrimidinyl]-2-pyridine sulfonamide as a colourless foam. LC-MS: t_R = 5.51 min, [M+1]⁺ = 541.57, [M-1]^" = 539.09.

Example 38

To a suspension of 50 mg of NaH in 4 ml of THF and 1 ml of DMF was added 0.3 ml of hydroxymethyl cyclopropane. The mixture was stirred at r.t. until gas evolution had ceased. Then, 100 mg of 5-isopropyl-N-[6-chloro-2-cyclopropyl- 5-(2-methoxyphenoxy)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 37c) was added and the resulting mixture was stirred at r.t. for 48 h. Eventually, the solvent was removed in vacuo and the remaining residue was dissolved in water. The precipitate that formed upon acidifying the solution with acetic acid was collected. The solid was recrystallised from acetone/methanol/diethyl ether. This gave 65 mg of 5-isopropyl-N-[2-cyclopropyl-6-cyclopropylmethoxy- 5-(2-methoxyphenoxy)-4-pyrimidinyl]-2-pyridine sulfonamide as a brown powder. LC-MS: t_R = 5.86 min, [M+1]⁺ = 511.36, [M-1]^" = 509.49.

Example 39

To a suspension of 50 mg of NaH in 4 ml of THF and 1 ml of DMF was added 0.3 ml of rac-1-cyclopropylethanol. The mixture was stirred at r.t. until gas evolution had ceased. Then, 100 mg of 5-isopropyl-N-[6-chloro-2-cyclopropyl-

5-(2-methoxyphenoxy)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 37c) was added and the resulting mixture was stirred at r.t. for 48 h. Eventually, the solvent was removed in vacuo and the remaining residue was dissolved in water. The precipitate that formed upon acidifying the solution with acetic acid was collected. The precipitate was recrystallised from acetone/methanol/diethyl ether. The crystals were dissolved again in diethyl ether, insoluble impurities were filtered off and the filtrate was evaproated and dried to give 50 mg of rac-5-isopropyl-N-[2-cyclopropyl-6-(1-cyclopropyl- ethoxy)-5-(2-methoxyphenoxy)-4-pyrimidinyl]-2-pyridine sulfonamide as a beige powder. LC-MS: t_R = 6.03 min, [M+1]⁺ = 525.37, [M-1]^" = 523.51.

Example 40

a) To a solution of 635 mg of Na-methylate in 150 ml of methanol 5.0 g of 5- isopropyl-pyridine-2-sulfonic acid [6-chloro-2-(2-cyano-pyridin-4-yl)-5-(2- methoxy-phenoxy)-pyrimidin-4-yl]-amide (prepared according to procedures given in EP-00979822 and WO-09619459) was added. The resulting suspension was stirred at 45°C for 24 h before and 785 mg of hydroxylamine hydrochloride was added. The suspension was stirred at 45°C for 15 min and evaporated. The residue was suspended in diethyl ether, filtered off, washed with diethyl ether and dried to give 4.1 g of 4-[4-chloro-6-(5-isopropyl-pyridine- 2-sulfonylamino)-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-N-hydroxy-pyridine- 2-carboxamidine as a beige powder. LC-MS: t_R = 5.18 min, [M+1]⁺ = 570.25, [M-1]^" = 568.36.

b) To a suspension of 1.0 g of 4-[4-chloro-6-(5-isopropyl-pyridine-2- sulfonylamino)-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-N-hydroxy-pyridine-2- carboxamidine in 25 ml of dry acetonitrile 322 mg of 1 ,1'-carbonyldiimidazole followed by 855 μl of 1 ,5-diazabicyclo[4.3.0]non-5-ene was added. The suspension was stirred at r.t. for 20 h before it was evaporated. The residue was dissolved in 50 ml of water. The precipitate that formed upon the addition of 1 ml of acetic acid was collected, washed with water and diethyl ether and dried to furnish 870 mg of 5-isopropyl-pyridine-2-sulfonic acid {6-chloro-5-(2- methoxy-phenoxy)-2-[2-(5-oxo-4,5-dihydro-[1 ,2,4]oxadiazol-3-yl)-pyridin-4-yl]- pyrimidin-4-yl}-amide as a beige powder. LC-MS: t_R = 5.32 min, [M+1]⁺ = 596.28, [M-1]^' = 594.42.

c) To a suspension of 73 mg of NaH (60% in mineral oil) in 5 ml of DMF 342 mg of rac-(tetrahydro-furan-2-yl)-methanol was added. The mixture was stirred for 5 min before 100 mg of 5-isopropyl-pyridine-2-sulfonic acid {6- chloro-5-(2-methoxy-phenoxy)-2-[2-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)- pyridin-4-yl]-pyrimidin-4-yl}-amide was added. The solution was stirred at 60°C for 18 h. The reaction mixture was diluted with 75 ml of ethyl acetate and washed with 50 ml of 10% aq. citric acid, 2x25 ml of water. The organic phase was evaporated and the crude product was purified on prep, tic-plates with DCM containing 8% of methanol to yield 90 mg of rac.-5-isopropyl- pyridine-2-sulfonic acid [5-(2-methoxy-phenoxy)-2-[2-(5-oxo-4,5-dihydro- [1 ,2,4]oxadiazol-3-yl)-pyridin-4-yl]-6-(tetrahydrofuran-2-ylmethoxy)-pyrimidin- 4-yl]-amide as a white solid. LC-MS: t_R = 5.21 min, [M+1]⁺ = 662.51 , [M-1]^" = 660.46.

Example 41

a) A suspension of 950 mg of 4-[4-chloro-6-(5-isopropyl-pyridine-2- sulfonylamino)-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-N-hydroxy-pyridine-2- carboxamidine (Example 40a), 345 mg of 1 ,1'-thiocarbonyldiimidazole and 812 μl of 1 ,5-diazabicyclo[4.3.0]non-5-ene in 25 ml of acetonitrile was stirred at r.t. for 3 days. The solvent was removed and the residue was treated with 50 ml of water. The pH of the mixture was adjusted to 4-5 by adding 1 ml of acetic acid. The solid material was collected, washed with water and diethyl ether, and ethyl acetate:diethyl ether 1 :3 and dried to give 920 mg of 5- isopropyl-pyridine-2-sulfonic acid {6-chloro-5-(2-methoxy-phenoxy)-2-[2-(5- thioxo-4,5-dihydro-[1 ,2,4]oxadiazol-3-yl)-pyridin-4-yl]-pyrimidin-4-yl}-amide as a beige powder. LC-MS: t_R = 5.04 min, [M+1]⁺ = 610.14, [M-1]^" = 612.37.

b) To a suspension of 107 mg of NaH (60% in mineral oil) in 8 ml of DMF 501 mg of rac-(tetrahydro-furan-2-yl)-methanol was added. The mixture was stirred for 5 min before 150 mg of 5-isopropyl-pyridine-2-sulfonic acid {6- chloro-5-(2-methoxy-phenoxy)-2-[2-(5-thioxo-4,5-dihydro-[1 ,2,4]oxadiazol-3- yl)-pyridin-4-yl]-pyrimidin-4-yl}-amide was added. The solution was stirred at 65°C for 24 h. The reaction mixture was diluted with 75 ml of ethyl acetate and washed with 50 ml of 10% aq. citric acid, 2x25 ml of water. The organic phase was evaporated and the crude product was purified on prep, tic-plates with DCM containing 5% of methanol to yield 90 mg of rac.-5-isopropyl- pyridine-2-sulfonic acid {5-(2-methoxy-phenoxy)-6-(tetrahydrofuran-2- ylmethoxy)-2-[2-(5-thioxo-4,5-dihydro-[1 ,2,4]oxadiazol-3-yl)-pyridin-4-yl]- pyrimidin-4-yl}-amide as a white solid. LC-MS: t_R = 5.35 min, [M+1]⁺ = 678.44, [M-1]^" = 676.35.

Example 42

a) 4,6-Dichloro-5-(2-methoxy-phenoxy)-2-(2-methyl-1-oxy-pyridin-4-yl)- pyrimidine was prepared starting from 2-methyi-isonicotinonitrile (prepared according to A. Ashimori et al. Chem. Pharm. Bull. 38 (1990), 2446-2458) in analogy to the procedures given in WO-0052007 and WO-0042035. LC-MS: t_R = 4.81 min, [M+1]⁺ = 378.27, ¹H-NMR(300MHz, D₆-DMSO): 2.44(s, 3H), 3.84(s, 3H), 6.81-6.87(m, 1H), 6.90-6.94(m, 1H), 7.07-7.19(m, 2H), 8.04(dd, J=2.7, 7.0, 1 H), 8.26(d, J=2.7, 1 H), 8.37(d, J=7.0, 1 H).

b) A mixture of 1.5 g of 4,6-dichloro-5-(2-methoxy-phenoxy)-2-(2-methyl-1- oxy-pyridin-4-yl)-pyrimidine and 2.08 g of 5-isopropyl pyridine-2-sulfonamide potassium salt (Example 1e) in 35 ml of DMF was stirred at r.t. for 20 h. The resulting clear solution was diluted with 50 ml of water and 50 ml of diethyl ether. The mixture was cooled with an ice-bath and the pH was adjusted to 4 by adding acetic acid. The precipitate that formed was collected, washed with water and diethyl ether and dried to give 1.85 g of 5-isopropyl-pyridine-2- sulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2-(2-methyl-1 -oxy-pyridin-4-yl)- pyrimidin-4-yl]-amide as a beige powder. LC-MS: t_R = 4.85 min, [M+1]⁺ = 542.34, [M-1]^" = 540.30.

c) To a suspension of 161 mg of NaH (60% in mineral oil) in 6 ml of DMF and 6 ml of THF 753 mg of rac-(tetrahydro-furan-2-y!)-methanol was added. The mixture was stirred for 10 min before 200 mg of 5-isopropyl-pyridine-2- sulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2-(2-methyl-1 -oxy-pyridin-4-yl)- pyrimidin-4-yl]-amide was added. The mixture was stirred at 70°C for 18 h before it was diluted with 75 ml of ethyl acetate and washed with 50 ml of 10% aq. citric acid, 2x25 ml of water. The organic phase was evaporated and the crude product was purified on prep, tic-plates with DCM containing 10% of methanol to yield 170 mg of rac.-5-isopropyl-pyridine-2-sulfonic acid [5-(2- methoxy-phenoxy)-2-(2-methyl-1-oxy-pyridin-4-yl)-6-(tetrahydrofuran-2- ylmethoxy)-pyrimidin-4-yl]-amide as a beige foam. LC-MS: t_R = 4.86 min, [M+1]⁺ = 608.34, [M-1]^' = 606.44.

d) A solution of 165 mg of rac.-5-isopropyl-pyridine-2-sulfonic acid [5-(2- methoxy-phenoxy)-2-(2-methyl-1-oxy-pyridin-4-yl)-6-(tetrahydrofuran-2- ylmethoxy)-pyrimidin-4-yl]-amide in 5 ml of acetic anhydride was refluxed for 90 min. The solution was cooled to 70°C and 20 ml of methanol was added. The mixture was refluxed for 1 h before it was evaporated. The residue was dissolved in 20 ml of THF:methanol:water and 3 ml of 1 M NaOH was added. The solution was stirred at 0°C for 1 h before it was diluted with 75 ml of ethyl acetate and washed with 50 ml 10% aq. citric acid and 2x50 ml of water. The organic phase was evaporated and the crude product was purified on prep, tic-plates with DCM containing 10% of methanol to give 97 mg of rac-5- isopropyl-pyridine-2-sulfonic acid [2-(2-hydroxymethyl-pyridin-4-yl)-5-(2- methoxy-phenoxy)-6-(tetrahydrofuran-2-ylmethoxy)-pyrimidin-4-yl]-amide as a beige solid. LC-MS: t_R = 4.44 min, [M+1]⁺ = 608.58, [M-1]^' = 606.51.

Example 43

a) 4,6-dihydroxy-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidine [or its tautomer 5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-tetrahydropyrimidine-4,6- dion] was prepared as disclosed in EP 0 526 708 A1 from 2-amidino- pyrimidine and dimethyl-(o-methoxyphenoxy)-malonate.

b) 4,6-dichloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidine was prepared as disclosed in EP 0 526 708 A1 from 4,6-dihydroxy-5-(o- methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidine (which may also be present in the tautomeric form 5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-tetrahydro- pyrimidine-4,6-dione).

c) A solution of 3.5 g of 4,6-dichloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)- pyrimidine and 4.98 g of 5-isopropyl-2-pyridine sulfonamide potassium salt (Example 1 , section e) in 40 ml of DMSO was stirred at r.t. for 4 h. The mixture was poured onto water and extracted twice with diethyl ether. The aqueous layer was acidified with acetic acid. The precipitate that formed was collected, washed with water and diethyl ether and dried to furnish 5.1 g of 5- isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]- 2-pyridine sulfonamide as a white solid. LC-MS: t_R = 4.87 min, [M+1]⁺ = 513.32, [M-1]^' = 511.26.

d) To a suspension of 85 mg of NaH (60% in mineral oil) in 6 ml of DMF 800 mg of rac-(tetrahydro-furan-2-yl)-methanol was added. The mixture was stirred for 10 min before 100 mg of 5-isopropyl-N-[6-chloro-5-(o- methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide was added. The mixture was stirred at r.t. for 22 h before it was diluted with 75 ml of ethyl acetate and washed with 50 ml of 10% aq. citric acid, 3x50 ml of water. The organic phase was evaporated and the crude product was purified by column chromatography on silica gel eluting with DCM containing 0-5% of methanol to yield 103 mg of rac.-5-isopropyl-pyridine-2-sulfonic acid [5-(2- methoxy-phenoxy)-6-(tetrahydrofuran-2-ylmethoxy)-[2,2']bipyrimidinyl-4-yl]- amide as a pale yellow foam. LC-MS: t_R = 4.77 min, [M+1]⁺ = 579.40, [M-1]^" = 577.36.

Example 44

a) A solution of 5.0 g of benzo[1 ,3]dioxol-5-carbonitrile and 7.97 g of lithium bis(trimethylsilyl)amide in 30 ml of diethyl ether was stirred at r.t. for 72 h. The brown mixture was cooled with an ice bath and treated with 14 ml of 5 N HCI in 2-propanol and 100 ml of diethyl ether. The mixture was stirred for 1 h and the precipitate that formed was collected and dried to give 7.3 g of benzo[1 ,3]dioxole-5-carboxamidine hydrochoride as a beige powder. ¹H- NMR(300MHz, D₆-DMSO): 6.17(s, 2H), 7.14(d, J=8.1 , 1 H), 7.45-7.51 (m, 2H), 8.88(s br, 4H). b) At 0°C 32.15 g of sodium methylate was added to a solution of 47.75 g of dimethyl-(2-methoxyphenoxy)malonate (Example 1b) in 500 ml of methanol. After stirring was continued for 0.5 h 47.15 g of benzo[1 ,3]dioxole-5- carboxamidine hydrochoride was added and the resulting mixture was stirred at r.t. for 20 h. Eventually, the solvent was removed in vacuo and 500 ml of diethyl ether was added. The precipitate that formed was collected and washed with additional diethyl ether. The material was dissolved in 300 ml of water and the pH of the solution was adjusted to 4 using acetic acid. The thick suspension was stirred for 30 min. Finally, the precipitate was collected, washed with 200 ml of water followed by 200 ml of diethyl ether, and dried to give 46.02 g of 2-(benzo[1 ,3]dioxol-5-yl)-5-(2-methoxyphenoxy)-4,6- dihydroxy-pyrimidine (or a tautomer) as a beige powder. LC: t_R = 3.73 min; ¹H-NMR(300MHz, D₆-DMSO): 3.81 (s, 3H); 6.12(s, 2H); 6.62(d, J=7.7, 1 H); 6.75(t, J=7.4, 1 H); 6.89(t, J=7.4, 1H); 6.96-7.08(m, 2H); 7.62(s, 1H); 7.70(d, J=7.8, 1H).

c) To a mixture of 2-(benzo[1 ,3]dioxol-5-yl)-5-(2-methoxyphenoxy)-4,6- dihydroxy-pyrimidine in 100 ml of POCI₃ was added 40 ml of N,N- dimethylaniline. The mixture was stirred at 130°C for 5 h. The excess of POCI₃ was distilled off under reduced pressure. At 0°C, 200 ml of methanol followed by 200 ml of water was slowly added to the remaining sirup. The precipitate that formed was collected, washed with water and diethyl ether, and dried to give 18.43 g of 2-(benzo[1 ,3]dioxol-5-yl)-4,6-dichloro-5-(2- methoxyphenoxy)-pyrimidine as a slightly brown powder. LC-MS: t_R = 5.91 min, [M+1]⁺ = 391.13.

d) A mixture of 4.5 g of 2-(benzo[1 ,3]dioxol-5-yl)-4,6-dichloro-5-(2- methoxyphenoxy)-pyrimidine and 5.48 g of 5-isopropyl pyridine-2-sulfonamide potassium salt (Example 1e) in 50 ml of DMSO was stirred at r.t. for 18 h. The dark brown solution was poured into a mixture of 500 ml of water and 300 ml of diethyl ether. The resulting suspension was stirred for 30 min. The aqueous phase containing the precipitate was acidified using acetic acid and stirred. Eventually, the precipitate was collected, washed with 30 ml of water and 30 ml of diethyl ether, and dried to give 5-isopropyl-N-[2-(benzo[1 ,3]dioxol-5-yl)- 6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]-2-pyridine sulfonamide as a beige powder. LC-MS: t_R = 5.83 min, [M+1]⁺ = 555.20, [M-1]^' = 553.29.

e) To a suspension of 43 mg of NaH in 5 ml of dry DMF was added 735 mg of rac-(tetrahydro-furan-2-yl)-methanol. The mixture was stirred at r.t. until gas evolution had stopped. Then, 100 mg of 5-isopropyl-N-[2-(benzo[1 ,3]dioxol-5- yl)-6-chloro-5-(2-methoxyphenoxy)-4-pyrimidinyl]-2-pyridine sulfonamide was added and the resulting mixture was stirred at 85°C for 16 h. The solution was poured into 50 ml of ethyl acetate and washed with 50 ml of 10% aqueous citric acid and twice with 50 ml of water. The organic layer was separated, dried over MgSO , and evaporated. The crude product was purified by crystallisation from ethyl acetate. The crystals were collected, washed with ethyl acetate and diethyl ether, and dried. This furnished 94 mg of rac-5- isopropyl-N-[2-(benzo[1 ,3]dioxol-5-yl)-5-(2-methoxyphenoxy)-6-(tetrahydro- furan-2-yl-methoxy)-4-pyrimidinyl]-2-pyridine sulfonamide as a beige solid. LC-MS: t_R = 6.02 min, [M+1]⁺ = 621.44, [M-1]^' = 619.41.

Example 45

a) To a solution of 24.5 g of sodium methylate in 400 ml of methanol was added 42.2 g of dimethyl-(2-methoxyphenoxy)malonate (Example 1 b). The mixture was stirred for 30 min. At 10°C 15.2 g of thiourea was added and stirring was continued at r.t. for 24 h. Eventually, the solvent was removed under reduced pressure. The residue was taken up in 800 ml of water and to the resulting solution 14 ml of methyliodide was added. The mixture was stirred at r.t. for 3 h. Then, 60 ml of 25% aqueous hydrochloric acid was slowly added. The precipitate that formed was collected, washed with water, and dried. This furnished 37.7 g of 5-(2-methoxy-phenoxy)-2-methylsulfanyl- pyrimidine-4,6-diol (or a tautomer) as a beige powder. LC-MS: t_R = 3.22 min, [M+1]⁺ = 281.20, [M-1]^' = 279.25.

b) To a suspension of 38 g of 5-(2-methoxy-phenoxy)-2-methylsulfanyl- pyrimidine-4,6-diol (or a tautomer) in 190 ml of POCI₃ was added 64 ml of N,N-dimethylaniline. The mixture was stirred at 130°C for 3 h. Excess of POCI₃ was removed under reduced pressure, traces of POCI₃ were removed by co-evaporation with toluene. The remaining residue was purified by a short column chromatography (silica gel, eluting with chloroform) to give 33.75 g of 4,6-dichloro-5-(2-methoxy-phenoxy)-2-methylsulfanyl-pyrimidine as a white solid. LC: t_R = 5.73 min; ¹H-NMR(300 MHz, CDCI₃): 2.59(s, 3H); 3.92(s, 3H); 6.58(d, J=8, 1 H); 6.85(dt, J_d=1 , J_t=8, 1 H); 7.00(d, J=8, 1 H); 7.08(t, J=8, 1H).

c) A mixture of 6 g of 4,6-dichloro-5-(2-methoxy-phenoxy)-2-methylsulfanyl- pyrimidine and 9.5 g of 5-isopropyl pyridine-2-sulfonamide potassium salt (Example 1e) in 60 ml of DMSO was stirred at r.t. for 24 h. To the solution 1 g of 5-isopropyl pyridine-2-sulfonamide potassium salt was added and stirring was continued for another 24 h. The mixture was poured into 350 ml of water and the pH of the resulting solution was adjusted to 4 by adding acetic acid. A fine precipitate formed. The mixture was stirred at 0°C for 1 h. Finally, the precipitate was collected, washed with water, and dried. The resulting powder was suspended in 250 ml of tert.-butylmethylether, stirred for 1 h and filtered off again. The solid collected was once more treated with 150 ml of tert.- butylmethylether, filtered off, and dried. This gave 7.58 g of 5-isopropyl-N-[6- chloro-5-(2-methoxy-phenoxy)-2-methyIsulfanyl-pyrimidin-4-yl]-2-pyridine sulfonamide as a white powder. LC-MS: t_R = 5.50 min, [M+1]⁺ = 481.20, [M-1]^" = 479.33.

d) To a suspension of 0.98 g of NaH in 30 ml of DMF was added 8.35 g of rac-(tetrahydro-furan-2-yl)-methanol at r.t.. After the evolution of hydrogen had ceased, 2.0 g of 5-isopropyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2- methylsulfanyl-pyrimidin-4-yl]-2-pyridine sulfonamide was added. The thick slurry was diluted with 30 ml of DMF and 10 ml of DMPU and stirred at r.t. for 48 h. Eventually, the mixture was poured into 200 ml of 10% aqueous citric acid and extracted twice with 250 ml of ethyl acetate. The organic layers were combined, washed once with 100 ml of 10% aqueous citric acid and twice with 100 ml of water, and evaporated. The remaining residue was purified by column chromatography on silica gel eluting with ethyl acetate. This gave 1.73 g of 5-isopropyl-N-[5-(2-methoxy-phenoxy)-2-methylsulfanyi-6- (tetrahydrofuran-2-ylmethoxy)-pyrimidin-4-yl]-2-pyridine sulfonamide as an almost colourless oil. LC-MS: t_R = 5.43 min, [M+1]⁺ = 547.36, [M-1]^" = 545.34.

Example 46

From Example 45d 661 mg of rac-5-isopropyl-N-[5-(2-methoxy-phenoxy)-2,6- bis-(tetrahydrofuran-2-ylmethoxy)-pyrimidin-4-yl]-2-pyridine sulfonamide was isolated as a by-product as a mixture of diastereoisomers in form of a colourless foam. LC-MS: t_R = 5.15 min, [M+1]⁺ = 601.45, [M-1]^" = 599.41.

Example 47

A solution of 1.64 g of 3-chloroperbenzoic acid in 45 ml of DCM was added dropwise to a solution of 1.66 g of rac-5-isopropyl-N-[5-(2-methoxy-phenoxy)- 2-methylsulfanyl-6-(tetrahydrofuran-2-ylmethoxy)-pyrimidin-4-yl]-2-pyridine sulfonamide (Example 45) in 15 ml of DCM at 0°C. Upon completion of the addition the mixture was stirred at r.t. for 2.5 h. The mixture was diluted with 250 ml of DCM, washed with 5% aqueous Na₂S₂O₃, and 2x200 ml of water. The separated organic layer was dried over MgSO and evaporated. The remaining residue was purified by column chromatography on silica gel eluting with ethyl acetate containing 10% of hexane. This gave 2.1 g of rac-5- isopropyl-N-[2-methanesulfonyl-5-(2-methoxy-phenoxy)-6-(tetrahydrofuran-2- y!methoxy)-pyrimidin-4-yl]-2-pyridine sulfonamide as a pale yellow solid. LC- MS: t_R = 5.08 min, [M+1]⁺ = 579.42, [M-1]^" = 577.41.

Example 48

To a solution of 150 mg of rac-5-isopropyl-N-[2-methanesulfonyl-5-(2- methoxy-phenoxy)-6-(tetrahydrofuran-2-ylmethoxy)-pyrimidin-4-yl]-2-pyridine sulfonamide (Example 47) in 4 ml of DMSO was added 36 mg of K₂CO₃ followed by 34 mg of KCN. The mixture was stirred at r.t. for 5 h, then at 70°C for 16 h. Eventually, the mixture was diluted with 75 ml of ethyl acetate and washed once with 50 ml of 10% aqueous citric acid, and twice with 50 ml of water. The organic layer was separated and evaporated. The resulting residue was purified on prep, tic plates (silica gel, thickness 0.5 mm, DCM wtih 5% of methanol). This furnished 88 mg of rac-5-isopropyl-N-[2-cyano-5- (2-methoxy-phenoxy)-6-(tetrahydrofuran-2-ylmethoxy)-pyrimidin-4-yl]-2- pyridine sulfonamide as a colourless foam. LC-MS: t_R = 5.49 min, [M+1]⁺ = 526.16, [M-1]^" = 524.03. Example 49

A suspension of 60 mg of rac-5-isopropyl-N-[2-cyano-5-(2-methoxy-phenoxy)- 6-(tetrahydrofuran-2-ylmethoxy)-pyrimidin-4-yl]-2-pyridine sulfonamide

(Example 48), 74 mg of NaN₃, and 61 mg of NH CI in 5 ml of DMF was stirred at 80°C for 16 h. The mixture was diluted with 75 ml of ethyl acetate and washed twice with 50 ml 10% aqueous citric acid followed by 50 ml of water. The organic layer was separated and evaporated. The crude product was purified on prep, tic plates (silica gel, thickness 0.5 mm, DCM: methanol .water.acetic acid 100:20:2:1). This gave 50 mg of rac-5- isopropyl-N-[5-(2-methoxy-phenoxy)-6-(tetrahydrofuran-2-ylmethoxy)-2-(1 H- tetrazol-5-yl)-pyrimidin-4-yl]-2-pyridine sulfonamide as a white powder. LC- MS: t_R = 4.84 min, [M+1]⁺ = 569.38, [M-1]^" = 567.29.

Example 50

To a suspension of 62 mg of NaH in 2 ml of dimethoxyethane was added 2 ml of ethylene glycol. After the evolution of hydrogen had ceased, 150 mg of rac- 5-isopropyl-N-[2-methanesulfonyl-5-(2-methoxy-phenoxy)-6-(tetrahydrofuran- 2-ylmethoxy)-pyrimidin-4-yl]-2-pyridine sulfonamide (Example 47) was added. The resulting solution was stirred at 85°C for 16 h. Eventually, the mixture was poured into 75 ml of ethyl acetate and washed once with 50 ml of 10% aqueous citric acid and twice with 25 ml of water. The organic layer was separated and evaporated. The remaining residue was purified by column chromatography on silica gel eluting with ethyl acetate. This yielded 76 mg of rac-5-isopropyl-N-[2-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-6- (tetrahydrofuran-2-ylmethoxy)-pyrimidin-4-yl]-2-pyridine sulfonamide as a colourless foam. LC-MS: t_R = 4.78 min, [M+1]⁺ = 561.51 , [M-1]^" = 559.35.

Example 51

To a suspension of 41 mg of NaH in 2 ml of dimethoxyethane was added 2 ml of 2-methoxyethanol. After the evolution of hydrogen had stopped, 100 mg of rac-5-isopropyl-N-[2-methanesulfonyl-5-(2-methoxy-phenoxy)-6-(tetrahydro- furan-2-ylmethoxy)-pyrimidin-4-yl]-2-pyridine sulfonamide (Example 47) was added. The resulting solution was stirred at 85°C for 16 h. Eventually, the mixture was poured into 75 ml of ethyl acetate and washed twice with 50 ml of 10% aqueous citric acid and twice with 25 ml of water. The organic layer was separated and evaporated. The remaining residue was purified on prep. tlc-plates (silica gel, thickness 2 mm, DCM with 7% of methanol). This yielded 63 mg of rac-5-isopropyl-N-[2-(2-methoxyethoxy)-5-(2-methoxy-phenoxy)-6- (tetrahydrofuran-2-ylmethoxy)-pyrimidin-4-yl]-2-pyridine sulfonamide as an almost colourless foam. LC-MS: t_R = 5.26 min, [M+1]⁺ = 575.27, [M-1]^" = 573.12. Example 52

To a suspension of 41 mg of NaH in 2 ml of diethyleneglycol monoethyl ether was added 2 ml of 1 ,2-dimethoxyethane. After the evolution of hydrogen had stopped, 100 mg of rac-5-isopropyl-N-[2-methanesulfonyl-5-(2-methoxy- phenoxy)-6-(tetrahydrofuran-2-ylmethoxy)-pyrimidin-4-yl]-2-pyridine sulfonamide (Example 47) was added. The resulting solution was stirred at 85°C for 16 h. Eventually, the mixture was poured into 75 ml of ethyl acetate and washed twice with 50 ml of 10% aqueous citric acid and twice with 25 ml of water. The organic layer was separated and evaporated. The remaining residue was purified on prep, tlc-plates (silica gel, thickness 2 mm, DCM with 7% of methanol). This yielded 59 mg of rac-5-isopropyl-N-[2-{2-(2- methoxyethoxy)-ethoxy}-5-(2-methoxy-phenoxy)-6-(tetrahydrofuran-2- ylmethoxy)-pyrimidin-4-yl]-2-pyridine sulfonamide as an almost colourless gum. LC-MS: t_R = 5.45 min, [M+1]⁺ = 633.26, [M-1]^" = 631.11.

Example 53

A solution of 150 mg of rac-5-isopropyl-N-[2-methanesulfonyl-5-(2-methoxy- phenoxy)-6-(tetrahydrofuran-2-ylmethoxy)-pyrimidin-4-yl]-2-pyridine sulfonamide (Example 47) in 3 ml of 2-(methylamino)-ethanol was stirred at 85°C for 16 h. The mixture was poured into 75 ml of ethyl acetate and washed twice with 50 ml of 10% aqueous citric acid and once with 25 ml of water. The organic layer was separated and evaporated. The crude product was purified by column chromatography on silica gel eluting with ethyl acetate to give 97 mg of rac-5-isopropyl-N-[2-{(2-methoxy)-ethylamino}-5-(2-methoxy- phenoxy)-6-(tetrahydrofuran-2-ylmethoxy)-pyrimidin-4-yl]-2-pyridine sulfonamide as a colourless foam. LC-MS: t_R = 5.01 min, [M+1]⁺ = 574.53, [M- 1]^' = 572.42.

Example 54

A solution of 41 mg of NaH in 4 ml of 4-(2-hydroxyethyl)-morpholine was diluted with 2 ml of DMF. To this mixture 100 mg of rac-5-isopropyl-N-[2- methanesulfonyl-5-(2-methoxy-phenoxy)-6-(tetrahydrofuran-2-ylmethoxy)- pyrimidin-4-yl]-2-pyridine sulfonamide (Example 47) was added and the resulting solution was stirred at 80°C for 20 h. The mixture was poured into 75 ml of ethyl acetate and washed once with 50 ml of 5% aqueous citric acid and twice with 25 ml of water. The organic layer was separated and evaporated. The remaining residue was purified on prep, tlc-plates (silica gel, thickness 0.5 mm, DCM with 6% of methanol). This gave 27 mg of rac-5-isopropyl-N-[5- (2-methoxy-phenoxy)-2-(2-morpholin-4-yl-ethoxy)-6-(tetrahydrofuran-2- ylmethoxy)-pyrimidin-4-yl]-2-pyridine sulfonamide as a sticky, white powder. LC-MS: t_R = 3.70 min, [M+1]⁺ = 630.46, [M-1]^' = 628.36. Example 55

A solution of 100 mg of rac-5-isopropyl-N-[2-methanesulfonyl-5-(2-methoxy- phenoxy)-6-(tetrahydrofuran-2-ylmethoxy)-pyrimidin-4-yl]-2-pyridine sulfonamide (Example 47) in 2 ml of furfurylamine was stirred at 75°C for 44 h. The dark mixture was poured into 75 ml of ethyl acetate and washed twice with 50 ml of 10% aqueous citric acid and once with 50 ml of brine. The organic layer was separated and evaporated. The crude product was purified on prep, tlc-plates (silica gel, thickness 0.5 mm, DCM with 5% of methanol) to give 53 mg of rac-5-isopropyl-N-[2-{(furan-2-ylmethyl)-amino}-5-(2-methoxy- phenoxy)-6-(tetrahydrofuran-2-ylmethoxy)-pyrimidin-4-yl]-2-pyridine sulfonamide as a beige foam. LC-MS: t_R = 5.48 min, [M+1]⁺ = 596.40, [M-1]^" = 594.31.

Example 56

A solution of 75 mg of rac.-5-isopropyl-N-[2-methanesulfonyl-5-(2-methoxy- phenoxy)-6-(tetrahydrofuran-2-ylmethoxy)-pyrimidin-4-yl]-2-pyridine sulfonamide (Example 47) in 2 ml of N-(2-aminoethyl)-morphoiine was stirred at 85°C for 16 h before it was diluted with 75 ml of ethyl acetate and washed with 50 ml of 10% aq. citric acid and 50 ml of water. The organic phase was evaporated and the crude product was purified on prep, tlc-plates with DCM containing 5% of methanol to furnish 45 mg of rac.-5-isopropyl-pyridine-2- sulfonic acid [5-(2-methoxy-phenoxy)-2-(2-morpholin-4-yl-ethylamino)-6- (tetrahydro-furan-2-ylmethoxy)-pyrimidin-4-yl]-amide as a white powder. LC- MS: t_R = 3.70 min, [M+1]⁺ = 629.44, [M-1]^" = 627.36.

Example 57

To a suspension of 57 mg of NaH in 4 ml of DMF 152 mg of indole was added. The mixture was stirred for 10 min and 75 mg of rac.-5-isopropyl-N-[2- methanesulfonyl-5-(2-methoxy-phenoxy)-6-(tetrahydrofuran-2-ylmethoxy)- pyrimidin-4-yl]-2-pyridine sulfonamide (Example 47) was added. The mixture was stirred at 75°C for 16 h before it was diluted with 75 ml of ethyl acetate and washed with 50 ml of 10% aq. citric acid and 50 ml of water. The organic phase was evaporated and the crude product was purified on prep, tlc-plates with hexane:ethyl acetate 1 :1 to furnish 36 mg of rac.-5-isopropyl-pyridine-2- sulfonic acid [2-indol-1 -yl-5-(2-methoxy-phenoxy)-6-(tetrahydrofuran-2- ylmethoxy)-pyrimidin-4-yl]-amide as a white powder. LC-MS: t_R = 6.39 min, [M+1]⁺ = 616.36, [M-1]^" = 614.28.

Example 58

To a suspension of 52 mg of NaH in 2 ml of DMF 2 ml of 1-(2-hydroxyethyl)- 2-pyrrolidone was added. The mixture was stirred for 10 min and 75 mg of rac.-5-isopropyl-N-[2-methanesulfonyl-5-(2-methoxy-phenoxy)-6- (tetrahydrofuran-2-ylmethoxy)-pyrimidin-4-yl]-2-pyridine sulfonamide

(Example 47) was added. The clear solution was stirred at 80°C for 16 h before it was diluted with 75 ml of ethyl acetate and washed with 50 ml of 10% aq. citric acid and 50 ml of water. The organic phase was evaporated and the crude product was purified on prep, tlc-plates with hexane:ethyl acetate 1 :1 to furnish 43 mg of rac.-5-isopropyl-pyridine-2-sulfonic acid [5-(2- methoxy-phenoxy)-2-[2-(2-oxo-pyrrolidin-1-yl)-ethyloxy]-6-(tetrahydro-furan-2- ylmethoxy)-pyrimidin-4-yl]-amide as an almost colourless foam. LC-MS: t_R = 4.86 min, [M+1]⁺ = 628.41 , [M-1]^" = 626.33.

Example 59

To a suspension of 57 mg of NaH in 3 ml of DMF 337 mg of 1-(2- hydroxyethyl)-2-imidazolidinone was added. The mixture was stirred for 10 min and 75 mg of rac.-5-isopropyl-N-[2-methanesulfonyl-5-(2-methoxy- phenoxy)-6-(tetrahydrofuran-2-ylmethoxy)-pyrimidin-4-yl]-2-pyridine sulfonamide (Example 47) was added. The clear pink solution was stirred at 85°C for 16 h before it was diluted with 75 ml of ethyl acetate and washed with 50 ml of 10% aq. citric acid and 50 ml of water. The organic phase was evaporated and the crude product was purified on prep, tlc-plates with DCM containing 10% of methanol to furnish 14 mg of rac.-5-isopropyl-pyridine-2- sulfonic acid [5-(2-methoxy-phenoxy)-2-[2-(2-oxo-imidazolidin-1 -yl)-ethoxy]-6- (tetrahydro-furan-2-ylmethoxy)-pyrimidin-4-yl]-amide as a colourless foam. LC-MS: t_R = 4.72 min, [M+1]⁺ = 629.41, [M-1]^" = 627.34.

Example 60

To a suspension of 52 mg of NaH in 3 ml of DMF 371 mg of N-(2- hydroxyethyl)-succinimid was added. The mixture was stirred for 10 min and 75 mg of rac.-5-isopropyl-N-[2-methanesulfonyl-5-(2-methoxy-phenoxy)-6- (tetrahydrofuran-2-ylmethoxy)-pyrimidin-4-yl]-2-pyridine sulfonamide

(Example 47) was added. The brown solution was stirred at 85°C for 16 h before it was diluted with 75 ml of ethyl acetate and washed with 50 ml of 10% aq. citric acid and 50 ml of water. The organic phase was evaporated and the crude product was purified on prep, tlc-plates with DCM containing 8% of methanol to furnish 36 mg of rac.-5-isopropyl-pyridine-2-sulfonic acid [2-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-5-(2-methoxy-phenoxy)-6-(tetrahydro- furan-2-ylmethoxy)-pyrimidin-4-yl]-amide as a colourless foam. LC-MS: t_R = 4.91 min, [M+1]⁺ = 642.43, [M-1]^" = 640.38.

Example 61

To a solution of 565 mg of tropine in 20 ml of DMF 420 mg of NaH (55% in mineral oil) was added. The mixture was stirred at r.t. for 1 h. 475 mg of rac- 5-isopropyl-N-[2-methanesulfonyl-5-(2-methoxy-phenoxy)-6-(tetrahydrofuran- 2-ylmethoxy)-pyrimidin-4-yl]-2-pyridine sulfonamide (Example 47) was added and the resulting mixture was stirred at r.t. for 16 h. The solvent was removed in vacuo and the residue was partitioned between 10% aq. citric acid and DCM. The aq. phase was extracted two more times with DCM and the organic phase was washed twice with water before it was dried over MgSO and evaporated. The crude product was purified on prep, tlc-plates with DCM:methanol 8:1 to furnish 152 mg of (1'R, 3'S, 5'S,2"R/S) 5-isopropyl- pyridine-2-sulfonic acid [5-(2-methoxy-phenoxy)-2-(8'-methyl-8'-aza- bicyclo[3.2.1]oct-3'-yloxy)-6-(tetrahydrofuran-2"-ylmethoxy)-pyrimidin-4-yl]- amide as a colourless foam. LC-MS: t_R = 4.13 min, [M+1]⁺ = 653.59, [M-1]^" = 651.72.

Example 62

A solution of 75 mg of rac.-5-isopropyl-N-[2-methanesulfonyl-5-(2-methoxy- phenoxy)-6-(tetrahydrofuran-2-ylmethoxy)-pyrimidin-4-yl]-2-pyridine sulfonamide (Example 47) in 2 ml of 2-methoxy-ethylamine was stirred at 85°C for 16 h. The mixture was diluted with 75 ml of ethyl acetate and washed with 50 ml of 10% aq. citric acid and 50 ml of water. The organic phase was evaporated and the crude product was purified on prep, tlc-plates with DCM containing 5% of methanol to furnish 50 mg of rac.-5-isopropyl- pyridine-2-sulfonic acid [2-(2-methoxy-ethylamino)-5-(2-methoxy-phenoxy)-6- (tetrahydrofuran-2-ylmethoxy)-pyrimidin-4-yl]-amide as a colourless foam. LC- MS: t_R = 5.13 min, [M+1]⁺ = 574.37, [M-1]^" = 572.30. Example 63

A suspension of 120 mg of rac.-5-isopropyl-N-[2-methanesulfonyl-5-(2- methoxy-phenoxy)-6-(tetrahydrofuran-2-ylmethoxy)-pyrimidin-4-yl]-2-pyridine sulfonamide (Example 47) in 2 ml of thiomorpholine was heated to 85°C. The clear solution was stirred for 144 h at 85°C before it was diluted with 75 ml of ethyl acetate and washed with 50 ml of 10% aq. citric acid and 50 ml of water. The organic phase was evaporated and the crude product was purified by column chromatography on silica gel eluting with heptane:ethyl acetate 4:3 to furnish 80 mg of rac.-5-isopropyl-pyridine-2-sulfonic acid [5-(2-methoxy- phenoxy)-6-(tetrahydrofuran-2-ylmethoxy)-2-thiomorphoiin-4-yl-pyrimidin-4- yl]-amide as a beige foam. LC-MS: t_R = 5.65 min, [M+1]⁺ = 602.42, [M-1]^" = 600.37.

Example 64

A solution of 50 mg of rac.-5-isopropyl-pyridine-2-sulfonic acid [5-(2-methoxy- phenoxy)-6-(tetrahydrofuran-2-ylmethoxy)-2-thiomorpholin-4-yl-pyrimidin-4- yl]~amide (Example 63) in 4 ml of acetonitrile was treated with 50 μl of peracetic (39% in acid in acetic acid). The mixture was stirred at r.t. for 3 h before it was diluted with 75 ml of ethyl acetate and washed with 50 ml of 10% aq. citric acid and 50 ml of water. The organic phase was evaporated to fumish 49 mg of rac.-5-isopropyl-pyridine-2-sulfonic acid [2-(1 ,1-dioxo-1λ⁶- thiomorpholin-4-yl)-5-(2-methoxy-phenoxy)-6-(tetrahydrofuran-2-ylmethoxy)- pyrimidin-4-yl]-amide as a colourless foam. LC-MS: t_R = 5.05 min, [M+1]⁺ = 634.39, [M-1]^' = 632.34.

Example 65

a) To a solution of 1.2 g NaOH and 5.2 g KMnO in 80 ml of water 6.0 g of 5- isopropyl pyridine-2-sulfonamide (Example 1e) was added. The dark suspension was stirred at r.t. for 24 h. The resulting brown solution was neutralised with 1 N HCI and 1.2 g of oxalic acid was added. The mixture was stirred for 30 min until evolution of gas had ceased and filtered over a pad of silica gel. The clear, colourless filtrate was evaporated and dried to give 5.76 g of 5-(1-hydroxy-1-methyl-ethyl)-pyridine-2-sulfonic acid amide as a white solid. The material was dissolved in 200 ml of methanol and 2.99 g of potassium tert.-butylate was added. The solution was stirred for 5 min, evaporated and the residue was dried to give 6.9 g of 5-(1 -hydroxy- 1-methyl- ethyl)-pyridine-2-sulfonic acid amide potassium salt as a pale beige solid. ¹H- NMR(300MHz, D₆-DMSO): 1.44(s, 3H), 5.39(s, 1 H), 7.18(s, 2H), 7.84(dd, J=0.9, 8.1, 1 H), 8.06(dd, J=2.2, 8.1 , 1H), 8.78(dd, 0.7, 2.2, 1H).

b) A suspension of 2.0 g 4,6-dichloro-5-(2-methoxyphenoxy)-2-(4-pyridyl)- pyrimidine and 2.19 g of 5-(1-hydroxy-1-methyl-ethyl)-pyridine-2-sulfonic acid amide potassium salt in 25 ml of DMSO and 1 ml of triethylamine was stirred at r.t. for 17 h. The mixture was poured into 200 ml of water and 200 ml of diethyl ether and stirring was continued for 30 min. The mixture was filtered, the filtrate was extracted with diethyl ether before it was acidified with acetic acid. The precipitate that formed was collected, washed with diethyl ether and dried to give 1.07 g of 5-(1-hydroxy-1-methyl-ethyl)-pyridine-2-sulfonic acid [6- chloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide as a brownish powder. LC-MS: t_R = 4.06 min, [M+1]⁺ = 528.23, [M-1]^" = 526.33.

c) To a suspension of 124 mg of NaH in 8 ml of DMF was added 580 mg of rac-(tetrahydro-furan-2-yl)-methanol at r.t.. After the evolution of gas had ceased, 150 mg of 5-(1-hydroxy-1-methyl-ethyl)-pyridine-2-sulfonic acid [6- chloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide was added. The mixture was stirred at 70°C for 24 h. The mixture was diluted with 75 ml of ethyl acetate and washed with 50 ml of 10% aq. citric acid and 2x25 ml of water. The organic phase was evaporated and the crude product was purified on prep, tlc-plates with DCM containing 10% of methanol to furnish 113 mg of rac.-5-(1-hydroxy-1-methyl-ethyl)-pyridine-2-sulfonic acid [5-(2- methoxy-phenoxy)-2-pyridin-4-yl-6-(tetrahydrofuran-2-ylmethoxy)-pyrimidin-4- yl]-amide as an off-white solid. LC-MS: t_R = 4.03 min, [M+1]⁺ = 594.43, [M-1]^" = 592.35.

Example 66

a) A solution of 15.2 g of 4-tert.-butylbenzene sulfonyl chloride in 150 ml of THF was cooled with an ice bath. 15.2 ml of 25% aqueous ammonium hydroxide solution was added dropwise. After the addition was completed, the solution was stirred at r.t. for 15 min. The solvent was removed in vacuo. The residue was again dissolved in ethyl acetate and washed twice with water. The organic phase was dried over Na₂SO , evaporated and dried. The resulting 14.8 g of a white powder was dissolved in 75 ml of methanol and 7.5 g of potassium tert. butylate was added. The solution was briefly stirred at r.t. and evaporated. The resulting residue was carefully dried to give 16.3 g of 4- tert.-butylbenzene sulfonamide potassium salt as a white solid.

b) To a solution of 6.1 g of 4,6-dichloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)- pyrimidine (Example 1d) in 100 ml of dry DMF 8.8 g of 4-tert. -butyl benzene sulfonamide potassium salt was added at r.t.. The solution was stirred over night at r.t.. The solution was added to a mixture of 150 ml of water and 100 ml of diethyl ether. The pH was adjusted to 5 by adding acetic acid. The precipitate that formed was collected, washed with water and diethyl ether. The resulting powder was suspended in boiling ethyl acetate. The mixture was allowed to cool in an icebath. Eventually, the solid material was collected and dried to yield 6.6 g of 4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2- (4-pyridyl)-4-pyrimidinyl]-benzene sulfonamide as beige crystals. LC-MS: t_R = 5.80 min, [M+1]⁺ = 525.31 , [M-1]^" = 523.48

c) To a suspension of 76 mg of NaH in 5 ml of DMF was added 389 mg of rac-(tetrahydro-furan-2-yl)-methanol at r.t.. After the evolution of gas had ceased, 150 mg of 4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(4- pyridyl)-4-pyrimidinyl]-benzene sulfonamide was added at 50°C. The mixture was stirred at 80°C for 16 h before it was diluted with 75 ml of ethyl acetate and washed with 50 ml of 10% aq. citric acid and 2x25 ml of water. The organic phase was dried over MgSO , evaporated and the crude product was purified by column chromatography on silica gel eluting with ethyl acetate to furnish 74 mg of rac.-4-tert-butyl-N-[5-(2-methoxy-phenoxy)-2-pyridin-4-yl-6- (tetrahydrofuran-2-ylmethoxy)-pyrimidin-4-yl]-benzenesulfonamide as an off- white solid. LC-MS: t_R = 5.62 min, [M+1]⁺ = 591.38, [M-1]^" = 589.34.

Example 67

a) A solution of 20 g of 4-[4,6-dichloro-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]- pyridine-2-carbonitrile (prepared following the procedures given in EP- 00979822 and WO-09619459) and 20.2 g of 4-tert.-butylbenzene sulfonamide potassium salt (Example 66a) in 100 ml of DMSO and 9.2 ml of ethyl- diisopropylamine was stirred at r.t. for 18 h. The mixture was diluted with 1.2 l of water and 300 ml of diethyl ether and acidified with acetic acid. The precipitate that formed was collected, washed with water and diethyl ether and dried to give 20.88 g of 4-tert.-butyl-N-[6-chloro-2-(2-cyano-pyridin-4-yl)- 5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulfonamide as a beige powder. LC-MS: t_R = 6.23 min, [M+1]⁺ = 550.39, [M-1]^" = 548.31.

b) A solution of 6.1 g of 4-tert.-butyl-N-[6-chloro-2-(2-cyano-pyridin-4-yl)-5-(2- methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulfonamide in 35 ml of DMF was treated with 2.5 ml of hydrazine monohydrate at 10-15°C. The mixture was stirred at r.t. for 24 h before it was cooled with an ice-bath and carefully diluted with 45 ml of water. The pH was adjusted to 5-6 by the addition of acetic acid and the resulting suspension was diluted with 25 ml of water and stirred for 30 min. The solid material was collected, washed with water and dried to give 6.72 g of 4-[4-(4-tert.-butyl-benzenesulfonylamino)-6-chloro-5-(2- methoxy-phenoxy)-pyrimidin-2-yl]-pyridine-2-carboximidoyl hydrazide as beige powder. LC-MS: t_R = 4.29 min, [M+1]⁺ = 582.30, [M-1]^" = 580.43.

c) A suspension of 3.0 g of 4-[4-(4-tert.-butyl-benzenesulfonylamino)-6-chloro- 5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine-2-carboximidoyl hydrazide in 15 ml of DMF was cooled with an ice-bath before 6.2 ml of water and 1.6 ml of 37% aq. HCI followed by 652 mg of NaNO₂ in 1.6 ml of water was added. The mixture was stirred at r.t. for 24 h. The mixture was further diluted with 7.5 ml of water and stirred for 2h at 0°C. The solid material was collected, washed with water and diethyl ether.hexane 1 :1 to give 2.4 g of 4-tert-butyl-N- {6-chloro-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazol-5-yl)-pyridin-4-yl]- pyrimidin-4-yl}-benzenesulfonamide as a brownish powder. LC-MS: t_R = 5.66 min, [M+1]⁺ = 593.30, [M-1]^" = 591.46.

d) To a suspension of 110 mg of NaH (60% in mineral oil) in 8 ml of DMF was added 516 mg of rac-(tetrahydro-furan-2-yl)-methanol at r.t.. After the evolution of gas had ceased, 150 mg of 4-tert-butyl-N-{6-chloro-5-(2-methoxy- phenoxy)-2-[2-(1 H-tetrazol-5-yl)-pyridin-4-yl]-pyrimidin-4-yl}- benzenesulfonamide was added. The mixture was stirred at 60°C for 24 h. The mixture was diluted with 75 ml of ethyl acetate and washed with 50 ml of 10% aq. citric acid and 2x25 ml of water. The organic phase was evaporated and the crude product was purified on prep, tlc-plates with DCM:methanol:water:acetic acid 100:20:2:1 to furnish 113 mg of rac.-4-tert- butyl-N-{5-(2-methoxy-phenoxy)-6-(tetrahydro-furan-2-ylmethoxy)-2-[2-(1H- tetrazol-5-yl)-pyridin-4-yl]-pyrimidin-4-yl}-benzenesulfonamide as a beige foam. LC-MS: t_R = 5.55 min, [M+1]⁺ = 659.48, [M-1]^" = 657.41.

Example 68

a) A solution of 2.0 g of 4,6-dichloro-5-(2-methoxyphenoxy)-2-(N-morpholino)- pyrimidine (Example 28b) and 2.96 g of 4-tert.-butylbenzene sulfonamide potassium salt (Example 66a) in 30 ml of DMSO was stirred at r.t. for 24 h. After 1 g of 4-tert.-butylbenzene sulfonamide potassium salt had been added, stirring was continued for another 24 h at r.t. followed by 16 h at 55°C. Eventually, the mixture was poured into 350 ml of water and 350 ml of ether. The mixture was acidified by adding acetic acid. A white, sticky precipitate formed. The mixture was stirred at 0°C for 1 h. The precipitate was filtered off, washed with water and ether and dissolved again in ethyl acetate. The solvent was removed in vacuo and the remaining solid was suspended in 100 ml of diethyl ether. The solid was filtered off, washed with additional diethyl ether and dried to give 2.57 g of 4-tert.-butyl-N-[6-chloro-5-(2-methoxy- phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-benzene sulfonamide as a white powder. LC-MS: t_R = 5.98 min, [M+1]⁺ = 533.29, [M-1]^" = 531.41.

b) To a suspension of 45 mg of NaH in 5 ml of dry DMF was added 766 mg of rac-(tetrahydro-furan-2-yl)-methanol. The mixture was stirred at r.t. until gas evolution had stopped. Then, 100 mg of 4-tert.-butyl-N-[6-chloro-5-(2- methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-benzene sulfonamide was added and the resulting mixture was stirred at 95°C for 18 h. The solution was poured onto 50 ml of ethyl acetate and washed with 50 ml of 10% aqueous citric acid followed by 50 ml of water. The organic layer was separated, dried over MgSO and evaporated. The crude product was purified by column chromatography on silica gel eluting hexane:ethyl acetate 1:1. Product containing fractions were again washed twice with water and evaporated. This gave 93 mg of rac-4-tert.-butyl-N-[5-(2-methoxy-phenoxy)-2-morpholin-4- yl-6-(tetrahydro-furan-2-ylmethoxy)-pyrimidin-4-yl]-benzene sulfonamide as a colourless foam. LC-MS: t_R = 5.87 min, [M+1f = 599.39, [M-1]^' = 597.52.

Example 69

To a suspension of 90 mg of NaH in 10 ml of dry DMF was added 1.53 g of rac.-(3-methyl-oxetan-3-yl)-methanol. The mixture was stirred at r.t. until gas evolution had stopped. Then, 200 mg of of 4-tert.-butyl-N-[6-chloro-5-(2- methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-benzene sulfonamide (Example 68a) was added and the resulting mixture was stirred at 95°C for 16 h. The solution was poured into 100 ml of ethyl acetate and washed once with 100 ml of 10% aqueous citric acid and twice with 100 ml of water. The organic layer was separated, dried over MgSO₄ and evaporated. The crude product was purified by column chromatography on silica gel eluting hexane:ethyl acetate 1 :1. The product was further purified by crystallisation from ethyl acetate/diethyl ether/heptane at 4°C. This gave 124 mg of rac.-4-tert.-butyl-N- [5-(2-methoxy-phenoxy)-6-(3-methyl-oxetan-3-yl-methoxy)-2-morpholin-4-yl- pyrimidin-4-yl]-benzene sulfonamide as a white solid. LC-MS: t_R = 5.64 min, [M+1]⁺ = 599.35, [M-1]^" = 597.38.

Example 70

a) A solution of 3.3 g of 4,6-dichloro-2-cyclopropyl-5-(2-methoxyphenoxy)- pyrimidine (Example 37b) and 5.5 g of 4-tert.-butylbenzene sulfonamide potassium salt (Example 66a) in 30 ml of DMSO was stirred at r.t. for 24 h. The mixture was diluted with 150 ml of water. Upon acidifying the aqueous phase with acetic acid a precipitate formed. The precipitate was collected, and washed with water. The material was recrystallised from methanol. This yielded 4.22 g of 4-tert.-butyl-N-[6-chloro-2-cyclopropyl-5-(2- methoxyphenoxy)-4-pyrimidinyl]-benzene sulfonamide as a white solid. LC- MS: t_R = 6.24 min, [M+1]⁺ = 488.23, [M-1]^" = 486.32.

b) To a suspension of 49 mg of NaH in 5 ml of DMF was added 840 mg of rac-(tetrahydro-furan-2-yl)-methanol. After the evolution of hydrogen had stopped, 100 mg of 4-tert.-butyl-N-[6-chloro-2-cyclopropyl-5-(2- methoxyphenoxy)-4-pyrimidinyl]-benzene sulfonamide was added. The resulting solution was stirred at 85°C for 16 h. Eventually, the mixture was poured into 50 ml of ethyl acetate and washed once with 50 ml of 10% aqueous citric acid and twice with 50 ml of water. The organic layer was separated and evaporated. The remaining residue was purified by column chromatography on silica gel eluting with hexane:ethyl acetate 2:1 to 1 :1. This furnished 115 mg of rac-4-tert.-butyl-N-[2-cyclopropyl-5-(2-methoxyphenoxy)- 6-(tetrahydrofuran-2-yl-methoxy)-4-pyrimidinyl]-benzene sulfonamide as a colourless foam. LC-MS: t_R = 6.15 min, [M+1]⁺ = 554.21 , [M-1]^" = 552.13.

Example 71

To a suspension of 50 mg of NaH in 4 ml of THF and 1 ml of DMF was added 0.3 ml of cyclopropylmethanol. After the evolution of hydrogen had stopped, 100 mg of 4-tert.-butyl-N-[6-chloro-2-cyclopropyl-5-(2-methoxyphenoxy)-4- pyrimidinyl]-benzene sulfonamide (Example 70a) was added. The resulting solution was stirred at r.t. for 48 h. Finally, the solvent was removed under reduced pressure and the remaining residue was dissolved in water. The solution was acidified with acetic acid. The precipitate that formed was filtered off. The filtrate was evaporated and purified by column chromatography on silica gel eluting with hexane:ethyl acetate 2:1. This furnished 45 mg of 4- tert.-butyl-N-[2-cyclopropyl-6-cyclopropylmethoxy-5-(2-methoxyphenoxy)-4- pyrimidinylj-benzene sulfonamide as a beige foam. LC-MS: t_R = 6.50 min, [M+1]⁺ = 524.38, [M-1]^" = 522.51.

Example 72

To a suspension of 50 mg of NaH in 4 ml of THF and 1 ml of DMF was added 0.3 ml of rac.-1-cyclopropylethanol. After the evolution of hydrogen had stopped, 100 mg of 4-tert.-butyl-N-[6-chloro-2-cyclopropyl-5-(2- methoxyphenoxy)-4-pyrimidinyl]-benzene sulfonamide (Example 70a) was added. The resulting solution was stirred at r.t. for 48 h. Finally, the solvent was removed under reduced pressure and the remaining residue was dissolved in water. The solution was acidified with acetic acid. The precipitate that formed was filtered off. The material was further purified by column chromatography on silica gel eluting with hexane:ethyl acetate 2:1. This furnished 52 mg of rac.-4-tert.-butyl-N-[2-cyelopropyl-6-(1-cyclopropylethoxy)- 5-(2-methoxyphenoxy)-4-pyrimidinyl]-benzene sulfonamide as a beige foam. LC-MS: t_R = 6.63 min, [M+1]⁺ = 538.29, [M-1]^" = 536.34.

Example 73

a) A mixture of 820 mg of 4,6-dichloro-5-(2-methoxy-phenoxy)-2-(2-methyl-1- oxy-pyridin-4-yl)-pyrimidine (Example 42a) and 1.2 g of 4-tert.-butylbenzene sulfonamide potassium salt (Example 66a) in 20 ml of DMSO was stirred at r.t. for 24 h. The resulting clear solution was diluted with 50 ml of water and 50 ml of diethyl ether. The mixture was cooled with an ice-bath and the pH was adjusted to 4 by adding acetic acid. The precipitate that formed was collected, washed with water and diethyl ether and dried to give 728 mg of 4- tert.-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-(2-methyl-1-oxy-pyridin-4-yl)- pyrimidin-4-yI]-benzenesulfonamide as a beige powder. LC-MS: t_R = 5.39 min, [M+1]⁺ = 555.54, [M-1]^" = 553.50.

b) To a suspension of 197 mg of NaH in 8 ml of DMF was added 920 mg of rac-(tetrahydro-furan-2-yl)-methanol. After the evolution of hydrogen had ceased, 250 mg of 4-tert.-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-(2- methyl-1 -oxy-pyridin-4-yl)-pyrimidin-4-yl]-benzenesulfonamide was added. The resulting solution was stirred at 65°C for 24 h. The mixture was poured into 75 ml of ethyl acetate and washed once with 75 ml of 10% aqueous citric acid and twice with 25 ml of water. The organic layer was separated and evaporated to give crude rac.-4-tert-butyl-N-[5-(2-methoxy-phenoxy)-2-(2- methyl-1-oxy-pyridin-4-yl)-6-(tetrahydro-furan-2-ylmethoxy)-pyrimidin-4-yl]- benzene-sulfonamide as a yellow oil. LC-MS: t = 5.35 min, [M+1]⁺ = 621.48, [M-1]^" = 619.40.

c) A solution of the crude rac.-4-tert-butyl-N-[5-(2-methoxy-phenoxy)-2-(2- methyl-1-oxy-pyridin-4-yl)-6-(tetrahydro-furan-2-ylmethoxy)-pyrimidin-4-yl]- benzene-sulfonamide in 5 ml of acetic anhydride was heated to 130°C for 100 min. The solution was cooled to 70°C, 20 ml of methanol was added and the mixture was refluxed for 30 min. The solution was evaporated and the remaining residue was dissolved in 20 ml of THF:methanol:water 5:4:1 and treated with 4 ml of 1 M NaOH at 0°C. The reaction mixture was stirred at 0°C for 1 h before it was diluted with 75 ml of ethyl acetate and washed with 75 ml of 10% aq. citric acid, followed by 50 ml of water. The organic phase was evaporated and the crude product was purified on prep, tlc-plates with DCM containing 5% of methanol to furnish 111 mg of rac.-4-tert.-butyl-N-[2-(2- hydroxymethyl-pyridin-4-yl)-5-(2-methoxy-phenoxy)-6-(tetrahydrofuran-2-yl- methoxy)-pyrimidin-4-yl]-benzenesulfonamide as a beige foam. LC-MS: t_R = 4.93 min, [M+1]⁺ = 621.62, [M-1]^" = 619.57.

Example 74

a) 4-tert.-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimi- dinyl]-benzene sulfonamide was prepared as disclosed in EP 0 526 708 A1 from 4,6-dichloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidine and 4- tert.-butyl benzene sulfonamide potassium salt (Example 66a). LC-MS: t = 5.50 min, [M+1]⁺ = 526.29, [M-1]^" = 524.43.

b) To a suspension of 48 mg of NaH in 5 ml of DMF was added 830 mg of rac-(tetrahydro-furan-2-yl)-methanol. After the evolution of hydrogen had stopped, 100 mg of 4-tert.-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(2- pyrimidinyl)-4-pyrimidinyl]-benzene sulfonamide was added. The resulting solution was stirred at 95°C for 16 h. Eventually, the mixture was poured into 50 ml of ethyl acetate and washed with 50 ml of 10% aqueous citric acid and with 50 ml of water. The organic layer was separated, dried over MgSO and evaporated. The remaining residue was purified on prep, tlc-plates (silica gel, thickness 2 mm, DCM containing 10% of methanol). This furnished 57 mg of rac.-4-tert.-butyl-N-[5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-6- (tetrahydrofuran-2-yl-methoxy)-4-pyrimidinyl]-benzene sulfonamide as a slightly yellow foam. LC-MS: t_R = 5.32min, [M+1]⁺ = 592.36, [M-1]^" = 590.30.

Example 75

a) A solution of 10 g of dimethyl-(2-methoxyphenoxy)malonate (Example 1b) in 80 ml dry methanol was cooled to 0°C. 6.71 g of sodium methylate was added portionwise. To the suspension was added 2.84 g of acetamidine hydrochloride and the mixture was stirred overnight at r.t.. The solvent was removed under reduced pressure and the residue was suspended in 100 ml of diethyl ether. The solid was filtered off, washed with another portion of 100 ml of diethyl ether and dissolved in 50 ml of water. The pH was adjusted to 4 by adding 25 ml of glacial acetic acid. The white precipitate that formed was filtered off, washed with water and dried to yield 5.17 g of 5-(2- methoxyphenoxy)-4,6-dihydroxy-2-methyl-pyrimidine (or a tautomer) as a white powder. ¹H-NMR(300 MHz, D₆-DMSO): 2.25(s, 3H); 3.78(s, 3H); 6.56(dd, J=1.4, 8.1 , 1 H); 6.74(dt, J_d=1.5, J_t=8.1 , 1 H); 6.86(dt, J_d=1.4, J_t=7.5, 1 H); 6.97(dd, J=1.3, 7.8, 1 H).

b) A solution of 10.9 g of 5-(2-methoxyphenoxy)-4,6-dihydroxy-2-methyl- pyrimidine (or a tautomer) in 150 ml of POCI₃ was stirred at 50°C for 72 h. The excess of POCI₃ was evaporated, toluene was added to coevaporate traces of POCI₃. Eventually, an ice/water mixture was carefully added to the residue and the pH was adjusted to 8 using 3 N sodium hydroxide solution. The mixture was further diluted with 300 ml of water and extracted with 500 ml of DCM. The organic layer was separated, washed with 300 ml of water, dried over Na₂SO and evaporated. The residue was dissolved again in DCM and filtered through a pad of silica gel eluting with DCM. The solvent was removed in vacuo. The resulting residue was dried to furnish 8.7 g of 4,6- dichloro-5-(2-methoxyphenoxy)-2-methyl-pyrimidine as a beige powder. ¹H- NMR(300 MHz, CDCI₃): 2.72(s, 3H); 3.90(s, 3H); 6.58(dd, J=1 , 8, 1H); 6.85(dt, J_d=1 , J_t=8, 1H); 7.00(dd, J=1 , 8, 1 H); 7.09(dt, J_d=1 , J_t=8, 1 H);

c) To a solution of 1.0 g of 4,6-dichloro-5-(2-methoxyphenoxy)-2-methyl- pyrimidine in 20 ml of DMSO was added 1.76 g of 4-tert.-butyl-benzene sulfonamide potassium salt (Example 66a). The mixture was stirred for 72 h at r.t.. The solution was diluted with 250 ml of water and extracted twice with 200 ml of diehtyl ether. The organic layers were extracted twice with water. The combined aqueous layers were acidified to pH 4 with 5 ml of acetic acid and cooled to 0°C. The precipitated product was filtered off and dried in vacuo to give 1.05 g of 4-tert.-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2- methyl-4-pyrimidinyl]-benzene sulfonamide as a pale beige powder. LC-MS: t_R = 5.64 min, [M+1]⁺ = 462.51 , [M-1]^" = 460.63.

d) To a suspension of 52 mg of NaH in 5 ml of DMF was added 900 mg of rac-(tetrahydro-furan-2-yl)-methanol. After the evolution of hydrogen had stopped, 100 mg of 4-tert.-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-methyl- 4-pyrimidinyl]-benzene sulfonamide was added. The resulting solution was stirred at 95°C for 16 h. Eventually, the mixture was poured into 50 ml of ethyl acetate and washed once with 50 ml of 10% aqueous citric acid and twice with 50 ml of water. The organic layer was separated, dried over MgSO , and evaporated. The remaining residue was purified by column chromatography on silica gel eluting with hexane:ethyl acetate 10:7. This furnished 107 mg of rac-4-tert.-butyl-N-[5-(2-methoxyphenoxy)-2-methyl-6-(tetrahydro-furan-2-yl- methoxy)-4-pyrimidinyl]-benzene sulfonamide as a slightly beige foam. LC- MS: t_R = 5.84 min, [M+1]⁺ = 528.36, [M-1]^" = 526.32. Example 76

a) A mixture of 4.50 g of 2-(benzo[1 ,3]dioxol-5-yl)-4,6-dichloro-5-(2- methoxyphenoxy)-pyrimidine (Example 44c) and 5.78 g of 4-tert.- butylbenzene sulfonamide potassium salt (Example 66a) in 50 ml of DMSO was stirred at r.t. for 20 h. The solution was poured into a mixture of 500 ml of water and 500 ml of diethyl ether. A white precipitate separated immediately. The mixture was stirred for 30 min. The precipitate was filtered off, washed with 30 ml of water followed by 30 ml of diethyl ether, and dried to furnish 6.85 g of 4-tert.-butyl-N-[2-(benzo[1 ,3]dioxol-5-yl)-6-chloro-5-(2- methoxyphenoxy)-pyrimidin-4-yl]-benzene sulfonamide as a white powder. LC-MS: t_R = 6.34 min, [M+1]⁺ = 568.23, [M-1]^" = 566.33.

b) To a suspension of 42 mg of NaH in 5 ml of DMF was added 720 mg of rac-(tetrahydro-furan-2-yl)-methanol. After the evolution of hydrogen had stopped, 100 mg of 4-tert.-butyl-N-[2-(benzo[1 ,3]dioxol-5-yl)-6-chloro-5-(2- methoxyphenoxy)-pyrimidin-4-yl]-benzene sulfonamide was added. The resulting solution was stirred at 85°C for 16 h. Eventually, the mixture was poured into 50 ml of ethyl acetate and washed once with 50 ml of 10% aqueous citric acid and twice with 50 ml of water. The organic layer was separated, dried over MgSO₄, and evaporated. The remaining residue was purified by column chromatography on silica gel eluting with hexane:ethyl acetate 4:3. This furnished 106 mg of rac-4-tert.-butyl-N-[2-(benzo[1 ,3]dioxol- 5-yl)-5-(2-methoxyphenoxy)-6-(tetrahydrofuran-2-yl-methoxy)-pyrimidin-4-yl]- benzene sulfonamide as a colourless foam. LC-MS: t_R = 6.62 min, [M+1]⁺ = 634.48, [M-1]^" = 632.43. Example 77

a) To a suspension of 70 g of 2-bromo-5-methyl pyridine in 500 ml of water 200 ml 25% aqueous hydrochloric acid was added at r.t.. To the clear solution 68 g of thiourea was added and the mixture was heated to reflux. After 4 h another 34 g and after 18 h further 17 g of thiourea was added. After 24 h the solution was cooled with an ice bath and 360 ml of 4 N sodium hydroxide solution was added. A precipitate formed which dissolved upon adding 600 ml of DCM. The organic layer was separated and washed with 500 ml of water. The aqueous phase was acidified to pH 3 using hydrochloric acid and repeatedly extracted with DCM. The combined organic layers were dried over MgSO₄, evaporated and dried under reduced pressure. This gave 46.9 g of a yellow solid which was recrystallised from boiling ethanol to furnish 37.6 g of 5-methyl-2-thio-pyridine in form of pale yellow platelets which sinter at 168°C and gradually melt between 179 and 190°C. ¹H-NMR(CDCI₃, 300 MHz): 2.17 (s, 3H); 7.24(dd, J=2.0, 8.8, 1H); 7.41 (t, J=1.0, 1 H); 7.47 (d, J=8.8, 1 H); 14.03(s br, 1 H).

b) To a mixture of 100 ml of 25 % aqueous hydrochloric acid and 250 ml of DCM was added 18 g of 5-methyl-2-thio-pyridine. While the mixture was vigorously stirred and kept at -10°C, 250 ml of an aqueous solution containing 13% of sodium hypochlorite was carefully added. Upon completion of the addition, stirring was continued for 10 min. The organic layer was separated. To the aqueous layer 250 ml of DCM was added and the mixture was again treated as before with a further 250 ml of an aqueous solution containing 13% of sodium hypochlorite. Upon completion of the addition, the organic layer was separated. The aqueous layer was extracted five times with 200 ml DCM. The organic layers were combined, dried over MgSO₄, and evaporated. The resulting oil was dissolved in 125 ml of THF and cooled to - 20°C. 25 ml of saturated aqueous ammonium hydroxide solution was slowly added. The mixture was stirred overnight at r.t.. Excess of ammonia was neutralised by adding hydrochloric acid and the THF was removed in vacuo. The remaining aqueous solution was extracted three times with 150 ml of ethyl acetate. The combined organic layers were dried over MgSO₄ and the solvent was evaporated. The remaining solid was recrystallised from boiling ethyl acetate to yield 13.35 g of 5-methyl-2-pyridine sulfonamide in form of beige crystals. ¹H-NMR(D₆-DMSO, 300 MHz): 2.37(s, 3H); 7.36(s, 2H); 7.78- 7.85(m, 2H); 8.53(s, 1 H); LC-MS: t_R = 2.32 min, [M+1]⁺ = 173.04, [M-1]^" = 171.10.

c) To a solution of 18.54 g of 5-methyl-2-pyridine sulfonamide in 400 ml of methanol was added 12.08 g of potassium tert.-butylate. The solution was stirred at r.t. for 5 min. The solvent was removed under reduced pressure and the residue was dried under high vacuum to give 22.64 g of 5-methyl-2- pyridine sulfonamide potassium salt as a beige solid.

d) Under argon, 4 g of 4,6-dichloro-5-(2-methoxyphenoxy)-2-(4-pyridyl)- pyrimidine (Example 1d) was dissolved in 40 ml of dry DMF and 3.62 g of 5- methylpyridine-2-sulfonamide potassium salt followed by 2.95 ml of Hϋnig's base was added. The dark solution was stirred at r.t. for 22 h. A further portion of 0.75 g of 5-methylpyridine-2-sulfonamide potassium salt was added and stirring was continued for 18 h. The reaction mixture was poured onto 150 ml of 10% citric acid in water and extracted four times with 150 ml of ethyl acetate. The combined organic phase was washed with water, dried over MgSO , and evaporated. The resulting residue was suspended in 20 ml of methanol and 20 ml of acetone. The precipitate was collected, washed with methanol:diethyl ether 1:1 and dried. This furnished 4.56 g of 5-methyl-N-[6- chloro-5-(2-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide as a beige powder. LC-MS: t_R = 4.38 min, [M+1]⁺ = 484.58, EMIT = 482.51. e) To a suspension of 360 mg of NaH in 20 ml of DMF was added 1.69 g of rac-(tetrahydro-furan-2-yl)-methanol. The mixture was stirred at r.t. for 15 min and 400 mg of 5-methyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(4-pyridyl)-4- pyrimidinyl]-2-pyridine sulfonamide was added. The resulting mixture was stirred at r.t. for 48 h and at 50°C for 4 h. The mixture was diluted with 200 ml of ethyl acetate and washed twice with 100 ml of 10% aqueous citric acid and twice with 100 ml of water. The organic layer was separated and evaporated. The remaining residue was purified by column chromatography on silica gel eluting with DCM containing 3% of methanol. This furnished 314 mg of rac-5- methyl-pyridine-2-sulfonic acid [5-(2-methoxy-phenoxy)-2-pyridin-4-yl-6- (tetrahydrofuran-2-ylmethoxy)-pyrimidin-4-yl]-amide as a pale yellow solid. LC-MS: t_R = 4.39 min, [M+1]⁺ = 550.38, [M-1]^" = 548.27.

Example 78

To a suspension of 50 mg of NaH in 4 ml of THF and 1 ml of DMF was added 0.3 ml of hydroxymethyl cyclopropane. The mixture was stirred at r.t. until gas evolution had ceased. Then, 100 mg of 5-methyl-N-[6-chloro-5-(2- methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide

(Example 77d) was added and the resulting mixture was stirred at r.t. for 48 h. Eventually, the solvent was removed in vacuo and the remaining residue was dissolved in water. The precipitate that formed upon acidifying the solution with acetic acid was collected and dried. This gave 61 mg of 5-methyl-N-[6- cyclopropylmethoxy-5-(2-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2- pyridine sulfonamide as a beige powder. LC-MS: t_R = 4.79 min, [M+1]⁺ = 520.30, [M-1]^" = 518.41. Example 79

To a suspension of 50 mg of NaH in 4 ml of THF and 1 ml of DMF was added 0.3 ml of cyclohexylmethanol. After evolution of hydrogen had ceased, 100 mg of 5-methyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]- 2-pyridine sulfonamide (Example 77d) was added and the resulting mixture was stirred at r.t. for 48 h. Eventually, the solvent was removed in vacuo and the remaining residue was dissolved in water. The precipitate that formed upon acidifying the solution with acetic acid was collected. The material was further purified by crystallisation from methanol/diethyl ether. This gave 52 mg of 5-methyl-N-[6-cyclohexylmethoxy-5-(2-methoxyphenoxy)-2-(4-pyridyl)-4- pyrimidinyl]-2-pyridine sulfonamide as a beige powder. LC-MS: t_R = 5.70 min, [M+1]⁺ = 562.35, [M-1]^" = 560.49.

Example 80

To a suspension of 50 mg of NaH in 4 ml of THF and 1 ml of DMF was added 0.3 ml of cyclohexanol. After evolution of hydrogen had ceased, 100 mg of 5- methyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2- pyridine sulfonamide (Example 77d) was added and the resulting mixture was stirred at r.t. for 48 h. Eventually, the solvent was removed in vacuo and the remaining residue was dissolved in water. The precipitate that formed upon acidifying the solution with acetic acid was collected. The material was further purified by crystallisation from methanol/diethyl ether. This gave 54 mg of 5- methyl-N-[6-cyclohexyloxy-5-(2-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]- 2-pyridine sulfonamide as a beige powder. LC-MS: t_R = 5.34 min, [M+1]⁺ = 548.33, [M-1]^" = 546.46.

Example 81

a) To a suspension of 4 g of 4,6-dichloro-5-(2-methoxyphenoxy)-2-(N- morpholino)-pyrimidine (Example 28b) in 20 ml of DMSO was added 4.72 g of 5-methyl-2-pyridine sulfonamide potassium salt (Example 77c). The mixture was stirred at 55°C for 17 h. The dark solution was poured into 500 ml of water and quickly filtered through celite. The filtrate was extracted with 500 ml and 250 ml of diethyl ether. The organic layers were extracted with 100 ml of water. The aqueous layers were combined, acidified with 3.5 ml of acetic acid and cooled to 0°C. The precipitate that formed was collected, washed with cold water and dried under high vacuum to furnish 4.42 g of 5-methyl-N-[6- chloro-5-(2-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide as a brownish powder. LC-MS: t_R = 4.80 min, [M+1]⁺ = 492.31, [M-1]^" = 490.37.

b) To a suspension of 48 mg of NaH in 5 ml of DMF was added 830 mg of rac-(tetrahydro-furan-2-yl)-methanol. After the evolution of hydrogen had ceased, 100 mg of 5-methyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(N- morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide was added. The resulting solution was stirred at 95°C for 26 h. Eventually, the mixture was poured into 50 ml of ethyl acetate and washed with 50 ml of 10% aqueous citric acid and with 50 ml of water. The organic layer was separated, dried over MgSO₄, and evaporated. The remaining residue was purified by column chromatography on silica gel eluting with hexane:ethyl acetate 2:3. This furnished 89 mg of rac-5-methyl-N-[5-(2-methoxyphenoxy)-2-(N-morpholino)-6-(tetrahydrofuran- 2-yl-methoxy)-4-pyrimidinyl]-2-pyridine sulfonamide as a colourless foam. LC- MS: t_R = 4.90 min, [M+1]⁺ = 558.34, [M-1]^' = 556.48.

Example 82

a) A solution of 5 g of 4-[4,6-dichloro-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]- pyridine-2-carbonitrile (prepared following the procedures given in EP- 00979822 and WO-09619459) and 4.23 g of 5-methyl-2-pyridine sulfonamide potassium salt (Example 77c) in 50 ml of DMSO and 2.34 ml of ethyl- diisopropylamine was stirred at r.t. for 18 h. Further 1.41 g of 5-methyl-2- pyridine sulfonamide potassium salt was added and stirring was continued for 4 h. The mixture was diluted with 500 ml of water and 300 ml of diethyl ether. The suspension was filtered and the collected solid material was washed with water and diethyl ether and dried to give 6.99 g of 5-methyl-pyridine-2- sulfonic acid [6-chloro-2-(2-cyano-pyridin-4-yl)-5-(2-methoxy-phenoxy)- pyrimidin-4-yl]-amide as a beige powder. LC-MS: t_R = 5.33 min, [M+1]⁺ = 509.29, [M-1]^' = 507.31.

b) To a suspension of 4.66 g of 5-methyl-pyridine-2-sulfonic acid [6-chloro-2- (2-cyano-pyridin-4-yl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide in 150 ml of methanol 625 mg of sodium methylate was added. The suspension was stirred at 45°C for 20 h before 772 mg of hydroxylamine hydrochloride was added. Stirring was continued at 45°C for 15 min. The solvent was removed in vacuo and the remaining residue was suspended in 100 ml of diethyl ether. The solid material was collected, washed and dried to give 5.36 g of 4-[4- chloro-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)- pyrimidin-2-yl]-N-hydroxy-pyridine-2-carboxamidine as a beige powder. LC- MS: t_R = 4.79 min, [M+1]⁺ = 542.31 , [M-1]^' = 540.45.

c) To a suspension of 2.68 g of 4-[4-Chloro-5-(2-methoxy-phenoxy)-6-(5- methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-N-hydroxy-pyridine-2- carboxamidine in 50 ml of acetonitrile 908 mg of 1 ,1'-carbonyldiimidazole followed by 2.41 ml of 1 ,5-diazabicyclo[4.3.0]non-5-ene was added. The mixture was stirred at r.t. for 18 h. Further 454 mg of 1 ,1'-carbonyldiimidazole and 1.2 ml of 1 ,5-diazabicyclo[4.3.0]non-5-ene was added and stirring was continued for 20 h. The mixture was evaporated and the remaining residue was suspended in 100 ml of water, acidified with 3.5 ml of acetic acid, treated with 150 ml of ethyl acetate and stirred for 30 min. The solid material was collected, washed and dried to give 1.94 g of 5-methyl-pyridine-2-sulfonic acid {6-chloro-5-(2-methoxy-phenoxy)-2-[2-(5-oxo-4,5-dihydro-[1 ,2,4]oxadiazol-3- yl)-pyridin-4-yl]-pyrimidin-4-yl}-amide as a grey powder. LC-MS: t_R = 4.92 min, [M+1]⁺ = 568.31.

d) To a suspension of 115 mg of NaH (60% in mineral oil) in 8 ml of DMF was added 539 mg of rac-(tetrahydro-furan-2-yl)-methanol at r.t.. After the evolution of gas had ceased, 150 mg of 5-methyl-pyridine-2-sulfonic acid {6- chloro-5-(2-methoxy-phenoxy)-2-[2-(5-oxo-4,5-dihydro-[1 ,2,4]oxadiazol-3-yl)- pyridin-4-yl]-pyrimidin-4-yl}-amide was added. The mixture was stirred at 75°C for 4 h. The mixture was diluted with 75 ml of ethyl acetate and washed with 50 ml of 10% aq. citric acid and 2x50 ml of water. The organic phase was evaporated and the crude product was purified on prep, tlc-plates with DCM:methanol:water:acetic acid 100:20:2:1 to furnish 111 mg of rac-5- methyl-pyridine-2-sulfonic acid [5-(2-methoxy-phenoxy)-2-[2-(5-oxo-4,5- dihydro-[1 ,2,4]oxadiazol-3-yl)-pyridin-4-yl]-6-(tetrahydrofuran-2-ylmethoxy)- pyrimidin-4-yl]-amide as white crystals. LC-MS: t_R = 4.89 min, [M+1]⁺ = 634.44, [M-1]^' = 632.39. Example 83

a) To a suspension of 2.68 g of 4-[4-Chloro-5-(2-methoxy-phenoxy)-6-(5- methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-N-hydroxy-pyridine-2- carboxamidine (Example 82 b) in 50 ml of acetonitrile 1.02 g of 1 ,1'- thiocarbonyldiimidazole followed by 2.41 ml of 1 ,5-diazabicyclo[4.3.0]non-5- ene was added. The mixture was stirred at r.t. for 18 h. Further 500 mg of 1 ,1'-thiocarbonyldiimidazole and 1.2 ml of 1 ,5-diazabicyclo[4.3.0]non-5-ene was added and stirring was continued for 20 h. The mixture was evaporated and the remaining residue was dissolved in 100 ml of water, acidified with 3.5 ml of acetic acid, treated with 150 ml of ethyl acetate and stirred for 30 min. The solid material was collected, washed and dried to give 1.56 g of 5-methyl- pyridine-2-sulfonic acid {6-chloro-5-(2-methoxy-phenoxy)-2-[2-(5-thioxo-4,5- dihydro-[1 ,2,4]oxadiazol-3-yl)-pyridin-4-yl]-pyrimidin-4-yl}-amide as a beige powder. LC-MS: t_R = 5.16 min, [M+1]⁺ = 584.28, [M-1]^' = 582.40.

b) To a suspension of 112 mg of NaH (60% in mineral oil) in 8 ml of DMF was added 524 mg of rac-(tetrahydro-furan-2-yl)-methanol at r.t.. After the evolution of gas had ceased, 150 mg of 5-methyl-pyridine-2-sulfonic acid {6- chloro-5-(2-methoxy-phenoxy)-2-[2-(5-thioxo-4,5-dihydro-[1 ,2,4]oxadiazol-3- yl)-pyridin-4-yl]-pyrimidin-4-yl}-amide was added. The mixture was stirred at 75°C for 4 h. The mixture was diluted with 75 ml of ethyl acetate and washed with 50 ml of 10% aq. citric acid and 2x50 ml of water. The organic phase was evaporated and the crude product was purified on prep, tlc-plates with DCM:methanol:water:acetic acid 100:20:2:1 to furnish 88 mg of rac.-5-methyl- pyridine-2-sulfonic acid {5-(2-methoxy-phenoxy)-6-(tetrahydro-furan-2- ylmethoxy)-2-[2-(5-thioxo-4,5-dihydro-[1 ,2,4]oxadiazol-3-yl)-pyridin-4-yl]- pyrimidin-4-yl}-amide as a pale yellow foam. LC-MS: t = 5.17 min, [M+1]⁺ = 650.45, [M-1]^" = 648.37.

Example 84

a) A mixture of 750 mg of 4,6-dichloro-5~(2-methoxy-phenoxy)-2-(2-methyl-1- oxy-pyridin-4-yl)-pyrimidine (Example 42a) and 917 mg of 5-methyl-2-pyridine sulfonamide potassium salt (Example 77c) in 15 ml of DMF was stirred at r.t. for 24 h. The resulting clear solution was diluted with 50 ml of water and 50 ml of diethyl ether. The mixture was cooled with an ice-bath and the pH was adjusted to 4 by adding acetic acid. The mixture was extracted twice with 150 ml of ethyl acetate. The organic phase was evaporated and the crude product was purified by column chromatography on silica gel eluting with ethyl acetate:heptane 10:1 followed by DCM containing 7% of methanol to give 958 mg of 5-methyl-pyridine-2-sulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2-(2- methyl-1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-amide as a pale beige solid. LC-MS: t_R = 4.51 min, [M+1]⁺ = 514.37, [M-1]^" = 512.35.

b) To a suspension of 212 mg of NaH in 20 ml of DMF was added 993 mg of rac-(tetrahydro-furan-2-yl)-methanol. After the evolution of hydrogen had ceased, 250 mg of 5-methyl-pyridine-2-sulfonic acid [6-chloro-5-(2-methoxy- phenoxy)-2-(2-methyl-1 -oxy-pyridin-4-yl)-pyrimidin-4-yl]-amide was added. The resulting solution was stirred at 60°C for 72 h. The mixture was poured into 75 ml of ethyl acetate and washed once with 50 ml of 10% aqueous citric acid and twice with 25 ml of water. The organic layer was separated and evaporated and the crude product was purified on prep, tlc-plates with DCM containing 10% of methanol to furnish 211 mg of rac.-5-methyl-pyridine-2- sulfonic acid [5-(2-methoxy-phenoxy)-2-(2-methyl-1-oxy-pyridin-4-yl)-6- (tetrahydro-furan-2-ylmethoxy)-pyrimidin-4-yl]-amide as an almost colourless foam. LC-MS: t_R = 4.50 min, [M+1]⁺ = 580.44, [M-1]^" = 578.39.

c) A solution of 190 mg of rac.-5-methyl-pyridine-2-sulfonic acid [5-(2- methoxy-phenoxy)-2-(2-methyl-1-oxy-pyridin-4-yl)-6-(tetrahydro-furan-2- ylmethoxy)-pyrimidin-4-yl]-amide in 5 ml of acetic anhydride was heated to 135°C for 90 min. The solution was cooled to 70°C, 20 ml of methanol was added and the mixture was refluxed for 30 min. The solution was evaporated and the remaining residue was dissolved in 20 ml of THF:methanol:water 5:4:1 and treated with 3 ml of 1 M NaOH at 0°C. The reaction mixture was stirred at 0°C for 1 h before it was diluted with 75 ml of ethyl acetate and washed with 50 ml of 10% aq. citric acid, followed by 2x25 ml of water. The organic phase was evaporated and the crude product was purified on prep, tlc-plates with DCM containing 5% of methanol to furnish 96 mg of rac-5- methyl-pyridine-2-sulfonic acid [2-(2-hydroxymethyl-pyridin-4-yl)-5-(2- methoxy-phenoxy)-6-(tetrahydrofuran-2-ylmethoxy)-pyrimidin-4-yl]-amide as a beige solid. LC-MS: t_R = 4.09 min, [M+1]⁺ = 580.44.

Example 85

a) To a suspension of 2.0 g of 4,6-dichloro-5-(o-methoxyphenoxy)-2-(2- pyrimidinyl)-pyrimidine (Example 43b) and 2.65 g of 5-methyl-2-pyridine sulfonamide potassium salt (Example 77c) in 40 ml of DMF was added 10 ml of DMSO. The mixture became clear and stirring was continued for 16 h at r.t.. Upon pouring the mixture onto 50 ml of 10% citric acid in water a white precipitate formed. The precipitate was collected, washed with water and ethyl acetate, and dried. This furnished 2.67 g of 5-methyl-N-[6-chloro-5-(o~ methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide as a white powder. LC-MS: t_R = 4.23 min, [M+1]⁺ = 485.56, [M-1]^" = 483.48.

b) To a suspension of 108 mg of NaH in 8 ml of DMF was added 505 mg of rac-(tetrahydro-furan-2-yl)-methanol. After the evolution of hydrogen had ceased, 130 mg of 5-methyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(2- pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide was added. The resulting solution was stirred at 60°C for 24 h. The mixture was poured into 75 ml of ethyl acetate and washed once with 50 ml of 10% aqueous citric acid and twice with 50 ml of water. The organic layer was separated, evaporated and the crude product was purified on prep, tlc-plates with DCM containing 10% of methanol to furnish 132 mg of rac.-5-methyl-pyridine-2-sulfonic acid [5-(2- methoxy-phenoxy)-6-(tetrahydrofuran-2-ylmethoxy)-[2,2']bipyrimidinyl-4-yl]- amide as a pale yellow foam. LC-MS: t_R = 4.30 min, [M+1]⁺ = 551.37, [M-1]^" = 549.31.

Example 86

To a suspension of 1.29 g of NaH in 75 ml of DMF was added 12.04 g of rac- (tetrahydro-furan-2-yl)-methanol in portions. After the evolution of hydrogen had ceased, 1.5 g of 5-methyl-pyridine-2-sulfonic acid [6-chloro-2-(2-cyano- pyridin-4-yl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide (Example 82a) was added. The resulting solution was stirred at r.t. for 24 h. The mixture was diluted with 150 ml of ethyl acetate and washed once with 200 ml of 10% aqueous citric acid, 150 ml of brine and twice with 150 ml of water. The organic layer was evaporated and the crude product was purified by column chromatography on silica gel eluting with DCM containing 2% of methanol. Product containing fractions were evaporated and the remaining solid was suspended in 20 ml of ethyl acetate, stirred at 45°C for 30 min, collected and dried to give 983 mg of rac.-5-methyl-pyridine-2-sulfonic acid [2-(2-cyano- pyridin-4-yl)-5-(2-methoxy-phenoxy)-6~(tetrahydrofuran-2-ylmethoxy)- pyrimidin-4-yl]-amide as a white solid. LC-MS: t_R = 5.15 min, [M+1]⁺ = 575.54, [M-1]^" = 573.47.

Example 87

To a suspension of 50 mg of rac.-5-methyl-pyridine-2-sulfonic acid [2-(2- cyano-pyridin-4-yl)-5-(2-methoxy-phenoxy)-6-(tetrahydrofuran-2-ylmethoxy)- pyrimidin-4-yl]-amide (Example 86) in 10 ml of methanol 24 mg of sodium methylate was added. The suspension became clear for a short period of time before a new precipitate formed. The suspension was stirred at 65°C for 26 h. At r.t., 46 mg of aminoacetaldehyde dimethyl acetal was added to the clear solution and stirring was continued for 2 h. 10 μl of 4 M HCI in dioxane was added and the resulting blue solution was stirred at r.t. for 72 h. The solvent was evaporated, the residue was suspended in 5 ml of dioxan and 200 μl of BF₃-OEt₂ was added. The mixture was stirred at 55°C for 20 h before it was diltuted with 75 ml of ethyl acetate and washed with 50 ml of 10% aq. citric acid and 50 ml of water. The organic phase was evaporated and the crude product was purified on prep, tlc-plates with DCM containing 10% of methanol to give 32 mg of rac.-5-methyl-pyridine-2-sulfonic acid [2-[2-(1 H-imidazol-2- yl)-pyridin-4-yl]-5-(2-methoxy-phenoxy)-6-(tetrahydro-furan-2-ylmethoxy)- pyrimidin-4-yl]-amide as a pale green solid. LC-MS: t_R = 3.84 min, [M+1]⁺ = 616.48, [M-1]^" = 614.42. Example 88

A suspension of 350 mg of rac.-5-methyl-pyridine-2-sulfonic acid [2-(2-cyano- pyridin-4-yl)-5-(2-methoxy-phenoxy)-6-(tetrahydrofuran-2-ylmethoxy)- pyrimidin-4-yl]-amide (Example 86) and 99 mg of sodium methylate in 20 ml of methanol was stirred at 65°C for 72 h. At r.t. 130 mg of ammonium chloride was added and the mixture was stirred at r.t. for 24 h. The solvent was removed and the residue was suspended in 20 ml of acetonitrile. The solid material was collected, washed with water and dried to give 221 mg of rac-4- [5-(2-methoxy-phenoxy)-4-(5-methyl-pyridine-2-sulfonylamino)-6-(tetrahydro- furan-2-ylmethoxy)-pyrimidin-2-yl]-pyridine-2-carboxamidine hydrochloride as a white powder. LC-MS: t_R = 3.66 min, [M+1]⁺ = 592.46, [M-1]^" = 590.40.

Example 89

a) A solution of 6.8 g of sodium methylate in 200 ml of methanol was cooled to 0°C. A solution of 10.3 g of diethyl 2-(p-tolyl)-malonate in 50 ml of methanol was slowly added. Upon completion of the addition the solution was allowed to come to r.t. and 7.57 g of 4-amidino-pyridine hydrochloride (Example 1a) was added. The mixture was stirred at r.t. for 16 h. Eventually, the solvent was removed under reduced pressure and the remaining residue was dissolved in 2 M hydrochloric acid. The solution was extracted with diethyl ether, then adjusted to pH 5 with 10 M sodium hydroxide solution. A precipitate formed. The precipitate was collected, washed with cold water and dried at 60°C under high vacuum. This gave 8.77 g of 2-pyridin-4-yl-5-p-tolyl- pyrimidine-4,6-diol (or a tautomer) as orange crystals.

b) To a mixture of 8.0 g of 2-pyridin-4-yl-5-p-tolyl-pyrimidine-4,6-diol and 100 ml of POCI3 25 ml of diethylamine was added at r.t.. The mixture was stirred for 16 h at 60°C. The excess of POCI₃ was distilled off under reduced pressure. The remaining oil was dissolved in 300 ml of DCM and treated with 300 ml of water. The aqueous layer was separated and extracted three times with DCM. The combined organic layers were washed with water and brine, dried over MgSO₄, and evaporated. The resulting residue was suspended in isopropanol. The solid material was collected, washed with isopropanol, and diethyl ether and dried to give 7.2 g of 4,6-dichloro-2-(4-pyridyl)-5-(p-tolyl)- pyrimidine as a white crystalline powder.

c) A mixture of 654 mg of 4,6-dichloro-2-(4-pyridyl)-5-(p-tolyl)-pyrimidine and 1051 mg of 5-isopropyl-2-pyridine sulfonamide potassium salt (Example 1e) in 20 ml of DMF was stirred for 16 h at r.t.. Eventually, the solvent was distilled off under reduced pressure and the resulting residue was treated with 100 ml of 10% aqueous acetic acid and 100 ml of DCM. The layers were separated. The aqueous layer was extracted two more times with DCM. The combined organic layers were washed once with water, dried over MgSO₄, and evaporated. The remaining residue was crystallised from isopropanol:diethyl ether. The yellow crystals were collected, washed with cold isopropanol and diethyl ether, and dried under high vacuum to furnish 870 mg of 5-isopropyl-N-[6-chloro-5-(p-tolyl)-2-(4-pyridyl)-4-pyrimidinyi]-2- pyridine sulfonamide. LC-MS: t_R = 5.06 min, [M+1]⁺ = 480.40, [M-1]^" = 478.48.

d) To a suspension of 50 mg of NaH in 5 ml of DMF was added 850 mg of rac-(tetrahydro-furan-2-yl)-methanol. After the evolution of hydrogen had stopped, 100 mg of 5-isopropyl-N-[6-chloro-5-(p-tolyl)-2-(4-pyridyl)-4- pyrimidinyl]-2-pyridine sulfonamide was added. The resulting solution was stirred at 85°C for 20 h. Eventually, the mixture was poured into 75 ml of ethyl acetate and washed twice with 50 ml of 10% aqueous citric acid and twice with 50 ml of water. The organic layer was separated and evaporated. The remaining residue was purified by column chromatography on silica gel eluting with a gradient from hexane:ethyl acetate 1 :1 to pure ethyl acetate. This furnished 100 mg of rac-5-isopropyl-N-[5-(p-tolyl)-2-(4-pyridyl)-6- (tetrahydrofuran-2-yl-methoxy)-4-pyrimidinyl]-2-pyridine sulfonamide as a colourless powder. LC-MS: t_R = 5.13 min, [M+1f = 546.30, [M-1]^" = 544.16.

Example 90

a) To a solution of 115 g of 3-methoxyphenol in 1000 ml of acetone was added 151 g of K2CO3. The suspension was stirred at 40°C for 15 min. A solution of 133 ml of dimethylchloromalonate was added over period of 45 min. The resulting brown suspension was stirred overnight at 70°C. Finally, the solvent was removed under reduced pressure and the residue was taken up in 1000 ml of water and extracted twice with 500 ml of DCM. The combined organic layers were washed with 500 ml of water, dried over Na₂SO₄, and evaporated to give 230 g of crude dimethyl-(3- methoxyphenoxy)malonate as an orange oil. The product was not purified any further.

b) To a solution of 15.42 g of sodium methylate in 450 ml of methanol was added 15.0 g of 4-amidino-pyridine hydrochloride (Example 1a) at 0°C. The suspension was stirred for 10 min. The addition of 31.46 g of dimethyl-(3- methoxyphenoxy)-malonate followed and the suspension was stirred at r.t. for 17 h. The solvent was removed in vacuo and the residue was suspended in diethyl ether. The solid material was filtered off and dissolved in 300 ml of water. Upon acidifying the orange solution with 30 ml of acetic acid a greenish precipitate formed. The precipitate was collected, washed with 500 ml of water and dried to give 23.78 g of 5-(3-methoxyphenoxy)-4,6-dihydroxy-2-(4- pyridyl)-pyrimidine (or a tautomer) as a greenish solid. LC-MS: t_R = 3.04 min, [M+1]⁺ = 312.17, [M-1]^" = 310.20.

c) A suspension of 23.78 g of 5-(3-methoxyphenoxy)-4,6-dihydroxy-2-(4- pyridyl)-pyrimidine (or a tautomer) in 180 ml of POCI₃ was heated to 120°C. The mixture became clear at about 80°C and was stirred for 16 h. The dark mixture was diluted with 200 ml of toluene and excess of POCI₃ was removed under reduced pressure. Traces of POCI₃ were removed by co-evaporation with toluene. The resulting residue was dissolved in 300 ml of DCM, washed with 150 ml of water and 150 ml of sat. aqueous NaHCO₃. The aqueous layers were extracted with 2x100 ml of DCM. The combined organic layers were dried over MgSO₄ and evaporated. The crude product was further purified by column chromatography on silica gel eluting with a gradient of heptane:ethyl acetate from 1:1 to 1:2 to give 15.87 g of 4,6-dichloro-5-(3- methoxyphenoxy)-2-(4-pyridyl)-pyrimidine as a beige solid. LC-MS: t_R = 5.41 min, [M+1]⁺ = 348.04; ¹H-NMR(300 MHz, CDCI₃): 3.81 (s, 3H); 6.40(ddd, J=0.9, 2.4, 8.1 , 1H); 6.49(t, J=2.4, 1H); 6.69(ddd, J=0.9, 2.4, 8.4, 1H); 7.21- 7.26(m, 1H); 8.32(dd, J=1.5, 4.8, 2H); 8.82(d, J=6, 2H).

d) A suspension of 6 g of 4,6-dichloro-5-(3-methoxyphenoxy)-2-(4-pyridyl)- pyrimidine and 9.04 g of 5-isopropyl pyridine-2-sulfonamide potassium salt (Example 1e) in 150 ml of DMF was stirred at r.t. for 20 h. The resulting solution was poured into 500 ml of 10% aqueous citric acid and extracted with 5 portions of 150 ml of ethyl acetate. The precipitate that formed in the aqueous layer was filtered off and dried. The filtrate was extracted with 2x100 ml of DCM. The organic layers were combined and evaporated. The remaining residue was dissolved in 500 ml of ethyl acetate and washed with 3x 200 ml of water. The precipitate that formed in the aqueous phase was collected, washed with water and dried. The two precipitates together furnished 6.68 g of 5-isopropyl-N-[6-chloro-5-(3-methoxyphenoxy)-2-(4- pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide as a yellow powder. LC-MS: t_R = 4.72 min, [M+1]⁺ = 512.32, [M-1]^' = 510.29.

e) To a suspension of 47 mg of NaH in 4 ml of DMF was added 800 mg of rac-(tetrahydro-furan-2-yl)-methanol. After the evolution of hydrogen had stopped, 100 mg of 5-isopropyl-N-[6-chloro-5-(3-methoxyphenoxy)-2-(4- pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide was added. The resulting solution was stirred at 90°C for 18 h. Eventually, the mixture was poured into

50 ml of 10% aqueous citric acid and was extracted three times with 25 ml of ethyl acetate. The combined organic layers were washed with 50 ml of 10% aqueous citric acid and 50 ml of water, dried over MgS0₄₎ and evaporated.

The remaining residue was suspended in 20 ml of tert.-butylmethylether. The solid material was filtered off and dried to furnish 86 mg of rac-5-isopropyl-N-

[5-(3-methoxyphenoxy)-2-(4-pyridyl)-6-(tetrahydrofuran-2-yl-methoxy)-4- pyrimidinyl]-2-pyridine sulfonamide as a colourless powder. LC-MS: t_R = 4.79 min, [M+1]⁺ = 578.46, [M-1]^' = 576.46.

Example 91

a) To a suspension of 100 mg of NaH in 5 ml of THF 500 mg of rac-3- hydroxy-piperidine-1 -carboxylic acid tert-butyl ester was added and the mixture was stirred for 40 min. 2.5 ml of DMF followed by 100 mg of 5- isopropyl-N-[6-chloro-5-(3-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2- pyridine sulfonamide (Example 90d) was added and the mixture was stirred at r.t. for 24 h. Further 100 mg of NaH and 500 mg of rac.-3-hydroxy-piperidine- 1 -carboxylic acid tert-butyl ester was added and stirring was continued at 50°C for 7 h. The solvent was removed and the resulting residue was treated with water, acidified with acetic acid and extracted with DCM. The organic phase was evaporated and the crude product was purified by column chromatography on silica gel eluting with ethyl acetate to give 300 mg of rac- 3-[6-(5-isopropyl-pyridine-2-sulfonylamino)-5-(3-methoxy-phenoxy)-2-pyridin- 4-yl-pyrimidin-4-yloxy]-piperidine-1 -carboxylic acid tert-butyl ester still contaminated with rac.-3-hydroxy-piperidine-1 -carboxylic acid tert-butyl ester. LC-MS: t_R = 5.54 min, [M+1]⁺ = 677.53, [M-1]^' = 675.74.

b) A solution of 164 mg of rac.-3-[6-(5-isopropyl-pyridine-2-sulfonylamino)-5- (3-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid tert-butyl ester in 1 ml of dioxane was treated with 2 ml of 4 M HCI in dioxane. The solution was stirred at r.t. for 8 days. The solvent was removed and the residue was partitioned between DCM and brine. The organic phase was dried over Na₂SO₄, evaporated and dried to give 95 mg of rac-5- isopropyl-pyridine-2-sulfonic acid [5-(3-methoxy-phenoxy)-6-(piperidin-3- yloxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide as a pale yellow foam. LC-MS: t_R = 3.44 min, [M+1]⁺ = 577.39, [M-1]^" = 575.49.

Example 92

a) A suspension of 6 g of 4,6-dichloro-5-(3-methoxyphenoxy)-2-(4-pyridyl)- pyrimidine (Example 90c) and 9.53 g of 4-tert.-butylbenzene sulfonamide potassium salt (Example 66a) in 150 ml of DMF was stirred at r.t. for 20 h. The resulting red solution was poured into 250 ml of 10% aqueous citric acid and extracted with 3 portions of 150 ml of ethyl acetate. The organic phase was evaporated and the residue was suspended in 80 ml of tert.-butylmethyl ether and stirred for 15 min. The solid material was collected and dried to give 7.58 g of 4-tert.-butyl-N-[6-chloro-5-(3-methoxy-phenoxy)-2-pyridin-4-yl- pyrimidin-4-yl]-benzenesulfonamide as a beige solid. LC-MS: t_R = 5.83 min, [M+1]⁺ = 525.38, [M-1]^' = 523.38.

b) To a suspension of 76 mg of NaH in 4 ml of DMF was added 778 mg of rac-(tetrahydro-furan-2-yl)-methanol. After the evolution of hydrogen had ceased, 100 mg of 4-tert.-butyl-N-[6-chloro-5-(3-methoxy-phenoxy)-2-pyridin- 4-yl-pyrimidin-4-yl]-benzenesulfonamide was added. The resulting solution was stirred at 90°C for 18 h. Eventually, the mixture was poured into 50 ml of 10% aqueous citric acid and was extracted three times with 25 ml of ethyl acetate. The combined organic layers were washed with 50 ml of 10% aqueous citric acid and 50 ml of water, dried over MgSO₄, and evaporated. The remaining residue was purified by column chromatography on silica gel eluting with DCM containing 1 % of methanol. Product containing fractions were evaporated, dissolved in 20 ml of ethyl acetate and washed three times with water. The organic phase was evaporated and the residue was suspended in 2 ml of diethyl ether. The solid material was collected and dried to give 112 mg of rac.-4-tert.-butyl-N-[5-(3-methoxy-phenoxy)-2-pyridin-4-yl-6- (tetrahydro-furan-2-ylmethoxy)-pyrimidin-4-yl]-benzenesulfonamide as a white solid. LC-MS: t_R = 5.71 min, [M+1]⁺ = 591.45, [M-1]^" = 589.43.

Claims

1. The present invention relates to novel substituted pyrimidines of the general formula I,

general formula 1 wherein

R² represents hydrogen; halogen; trifluoromethyl; lower alkyl; lower alkylamino; lower alkyloxy; lower alkyl-sulfono; lower alkyl-sulfinyl; lower alkylthio; lower alkylthio-lower alkyl; hydroxy-lower alkyl; hydroxy-lower alkyloxy; lower alkyloxy-lower alkyl; lower alkyloxy-lower alkyloxy; hydroxy-lower alkyloxy- lower alkyl; hydroxy-lower alkyloxy-lower alkyloxy; lower alkyloxy-lower alkyloxy-lower alkyloxy; hydroxy-lower alkyl-amino; lower alkyl-amino-lower alkyl; amino; di-lower alkyl-amino; [N-(hydroxy-lower alkyl)-N-(lower alkyl)]- amino; aryl; aryl-amino; aryl-lower alkyl-amino; aryl-thio; aryl-lower alkyl-thio; aryloxy; aryl-lower alkyl-oxy; aryl-lower alkyl; arylsulfinyl; heteroaryl; heteroaryloxy; heteroaryl-lower alkyl-oxy; heteroarylamino; heteroaryl-lower alkylamino; heteroaryl-lower alkylthio; heteroaryl-lower alkyl; heteroaryl- sulfinyl; heterocyclyl; heterocyclyl-lower alkyloxy; heterocyclyloxy; heterocyclylamino; heterocyclyl-lower alkylamino; heterocyclylthio; heterocyclyl-lower alkylthio; heterocyclyl-lower alkyl; heterocyclylsulfinyl; cycloalkyl; cycloalkyloxy; cycloalkyl-lower alkyloxy; cycloalkylamino; cycloalkyl-lower alkylamino; cycloalkylthio; cycloalkyl-lower alkylthio; cycloalkyl-lower alkyl; cycloalkylsulfinyl; cyano; aminocarbonyl; alkyloxycarbonyl; carboxyl;

R³ represents phenyl; mono-, di- or tri-substituted phenyl substituted with lower alkyl, lower alkenyl, lower alkyloxy, amino, lower alkylamino, amino- lower alkyl, trifluoromethyl, trifluoromethoxy, halogen, lower alkylthio, hydroxy, hydroxy-lower alkyl, cyano, carboxyl, alkoxy carbonyl, lower alkanoyl, formyl; benzofuranyl; aryl; heteroaryl;

X represents oxygen; sulfur; NH; CH₂ or a bond;

R represents one of the following residues:

-N Z

_2)r

wherein

R⁵ and R¹⁰ each independently represent hydrogen or lower alkyl;

R⁶ represents hydrogen, OR⁷, or NR⁸R⁹;

W represents O, or NR⁵;

Y represents O, NR⁹; Z represents O, NR⁵, S, SO, or SO₂;

R⁷ represents hydrogen; lower alkyl; 2-, 4- or 6-pyrimidinyl optionally mono- or disubstituted with lower alkyl, lower alkoxy, halogen; or a group -CO-NR^aR^b, or -CO-R^b;

R⁸ represents hydrogen, lower alkyl;

R⁹ represents hydrogen, lower alkyl, aryl, aralkyl, or a group -CO-NR^aR^b, or-

CO-R^b;

R^a represents hydrogen, lower alkyl; cycloalkyl, or aryll;

m represents the numbers 0 or 1 ; n and q each independently represent the numbers 0, 1 , or 2; and wherein the sum m+n+q is not zero; p represents the numbers 1 , 2, 3, or 4; r and t each independently represent the numbers 1 , or 2; s represents the numbers 1 , 2, or 3;

2. Compounds of formula I wherein R¹, R², and R⁴ are as defined in claim 1 , and wherein

R³ represents phenyl, or mono substituted phenyl substituted with lower alkyl, lower alkyloxy, trifluoromethyl, trifluoromethoxy, or halogen;

X represents oxygen or a single bond, and pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the meso-forms and pharmaceutically acceptable salts thereof.

3. Compounds of formula II

formula II

wherein R², R³, R⁴, and X are defined as in claim 1 above, and R¹¹ represents lower alkyl, hydroxy-lower alkyl,

4. Compounds of formula III

wherein R¹, R³, R⁴, and X are defined as in claim I above,

5. Compounds of formula IV

wherein R¹, R², R³, and X are defined as in claim I above,

6. The compounds as described as final products in any of the Examples 1 to 92.

7. Pharmaceutical compositions for the treatment of disorders which are associated with a role of endothelin, such as migraine, asthma or inflammatory disorders, containing a compound of any one of claims 1 to 6, and one or more compounds influencing blood pressure or any cardiac disorder or stemming from the class of diuretics or sympatholitics, and usual carrier materials and adjuvants.

8. Pharmaceutical compositions for the treatment of disorders which are associated with a role of endothelin, especially circulatory disorders such as hypertension, ischaemia, vasospasm and angina pectoris and proliferative disorders such as cancer, containing a compound of any one of claims 1 to 6 and usual carrier materials and adjuvants.

9. The compounds of any one of the claims 1 to 6 for use as medicaments for the treatment of disorders which are associated with a role of endothelin, especially circulatory disorders such as hypertension, ischaemia, vasospasm and angina pectoris, proliferative disorders such as cancer, migraine and inflammatory disorders.

10. The compounds of any one of the claims 1 to 6 for use as medicaments for the treatment of disorders which are associated with a role of endothelin, and require mixed ET_A and ET_B blocking activity for treatment.

11. The compounds of any one of the claims 1 to 6 for use as medicaments for the treatment of disorders which are associated with a role of endothelin, and require selective ETA blocking activity for treatment.

12. The compounds of any one of the claims 1 to 6 for use as medicaments for the treatment of disorders which are associated with a role of endothelin, and require selective ETB blocking activity for treatment.

13. The use of one or more compounds of any one of claims 1 to 6 as active ingredients for the production of pharmaceutical compositions for the treatment of disorders associated with a role of endothelin, especially circulatory disorders such as hypertension, ischaemia, vasospasm and angina pectoris and proliferative disorders such as cancer.

14. The use of one or more compounds of any one of claims 1 to 6 as active ingredients for the production of pharmaceutical compositions for the treatment of disorders associated with endothelin activities, such as migraine, asthma or inflammatory disorders.

15. A process for the manufacture of pharmaceutical compositions for the treatment of disorders associated with a role of endothelin containing one or more compounds as claimed in any one of claims 1 to 6 as active ingredients which process comprises mixing one or more active ingredient with pharmaceutically acceptable excipients in a manner known per se.

16. The invention as hereinbefore described.